Potential Utility of PPARγ Agonists in the Eradication of Chronic Myeloid Leukemia Stem Cells

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Saleh, Hanan Gawish, Mohamed Mabed This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7140724/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML), yet persistent leukemia stem cells (LSCs) remain a barrier to cure. PPARγ agonists like pioglitazone have been proposed to enhance eradication of LSCs when used alongside TKIs. This study investigated the impact of adding pioglitazone to imatinib therapy in 26 newly diagnosed chronic-phase CML patients. Patients received imatinib (400 mg) plus pioglitazone (15 mg) daily for six months, with follow-up extending to 60 months. Treatment responses and adverse events were recorded, and expression levels of CITED2 and HIF2α genes were measured before and after therapy, compared to a control group of 52 matched patients treated with imatinib alone. The combination therapy showed improved early cytogenetic and molecular responses, though long-term outcomes were not significantly different. Significant reductions in median CITED2 (from 276.3 to 2.6; p = 0.005) and HIF2α (from 2.7 to 1; p = 0.026) expression were observed post-treatment. These results suggest that pioglitazone may enhance early molecular response and suppress LSC-associated genes, but further research is needed to confirm its long-term benefit and clarify the role of PPARγ modulation in CML management. Clinical Trial Number : NCT04883125. Chronic myeloid leukemia Leukemic stem cells PPARγ agonists pioglitazone CITED2 gene HIF2α gene Figures Figure 1 Figure 2 Introduction Chronic myeloid leukemia (CML) is a myeloproliferative disorder that is characterized by the cytogenic hallmark "Philadelphia chromosome (Ph+)". The use of tyrosine kinase inhibitors (TKIs) has revolutionized the treatmentof CML and improved the patients’ survival dramatically [ 1 ]. Moreover, the obtained deep molecular responses have encouraged starting the treatments free remission (TFR) trials. However 50% of the patients relapse [ 2 ]. Researches owed this relapse mainly to the presence of quiescent/therapy resistant leukemic stem cells (LSCs) [ 3 ]. They also proved that LSCs are “Not oncogene-addicted” i.e. their survival is not strictly dependent on BCR-ABL1 kinase activity alone but on many other signaling pathways [ 4 ]. Studies have reported how strong the extra-activated STAT5 can regulate the quiescence/proliferation of LSCs through many target genes for example: Hypoxia inducible factor genes and CITED2 genes [ 5 , 6 ]. Peroxisome proliferator-activated receptor gamma (PPARγ) is one of nuclear-hormone receptors that regulate cellular differentiation, proliferation and apoptosis. Combining pioglitazone (PPARγ agonist) with imatinib has increased the anti-leukemic effect in vitro [ 7 – 9 ] and in vivo studies [ 5 , 10 ]. This was explained by its ability to down regulate the STAT5 target genes and subsequently impact the LSC cell cycle and increase their sensitivity to therapy [ 7 , 8 ]. Aim of the study The objective of this study was to assess the therapeutic impact of combining glitazones with tyrosine kinase inhibitors (TKIs) in the treatment of newly diagnosed patients with chronic phase chronic myeloid leukemia (CML-CP). The primary endpoint was to evaluate the safety profile of the combination regimen. Secondary endpoints included assessment of short-term (at 3, 6, and 12 months) and long-term treatment responses and efficacy, based on molecular response milestones. The tertiary endpoint involved evaluating changes in the expression levels of the CITED2 and HIF2α genes before treatment and after 6 months of therapy. Study Design and Methodology Study Design This was a prospective, non-randomized interventional study conducted at the Oncology Center, Mansoura University (OCMU), Egypt, from January 2017 to January 2022. Ethical approval was obtained from the Faculty of Medicine Ethical Committee (MD/17.12.30), and the study was registered as a clinical trial (NCT04883125). Study Population The study included 26 newly diagnosed patients with chronic phase Philadelphia chromosome–positive chronic myeloid leukemia (CML), with the sample size calculated to detect a 25% absolute increase in major molecular response (MMR) at 12 months (from 25–50%), assuming a significance level (α) of 0.05 and a statistical power of 80% [ 11 ]. Eligible participants were adults aged 18 to 60 years of both sexes, diagnosed with de novo chronic phase CML, and who provided written informed consent in accordance with the Declaration of Helsinki. Exclusion criteria included advanced disease stages (accelerated or blast phase), atypical CML, and any significant organ dysfunction. Diagnosis and Treatment CML diagnosis was confirmed via real-time quantitative PCR (RT-qPCR) for the BCR/ABL gene. Bone marrow examination and flow cytometry were performed to evaluate cellularity and rule out advanced stages. Patients received a combination of pioglitazone 15 mg and imatinib 400 mg, both once daily, for 6 months, with close clinical monitoring. All clinical data, adverse effects, and treatment responses were recorded in OCMU’s electronic medical records. BCR/ABL transcript levels were monitored by real-time quantitative PCR (RT-qPCR) at 3, 6, 12, 24, 36, 48, and 60 months to evaluate treatment response. Molecular responses were categorized according to log reductions on the International Scale (IS) as follows: Early Molecular Response (EMR) was defined as BCR/ABL IS ≤ 10% at 3 months; Complete Cytogenetic Response (CCyR) corresponded to the absence of Philadelphia chromosome–positive metaphases in ≥ 20 bone marrow cells, approximated by BCR/ABL IS < 1%; Major Molecular Response (MMR) was defined as BCR/ABL IS ≤ 0.1%; Deep Molecular Response (DMR) as BCR/ABL IS ≤ 0.01%; and Complete Molecular Response (CMR) as undetectable BCR/ABL transcripts on the IS. Outcomes and Evaluation I. Safety Treatment safety was defined by the absence of grade 3–4 hematologic or non-hematologic toxicities at any time [ 12 ]. II. Efficacy Efficacy was assessed via achievement of molecular response milestones. Any progression to accelerated or blast phase during follow-up was documented. A historical control group of 52 age- and gender-matched chronic phase CML (Ph+) patients treated with imatinib 400 mg alone was used for comparison of clinical and molecular outcomes. III. Gene Expression Analysis Expression levels of CITED2 and HIF2α were evaluated by RT-qPCR before treatment and at 6 months. These were compared with levels in a third group of 12 age- and gender-matched healthy blood donors. Statistical Analysis Statistical analysis was performed using SPSS Version 25.0. Normality was tested using the Kolmogorov-Smirnov test (p > 0.05 considered normal). Normally distributed variables were compared using the Student’s t-test , while non-parametric variables were analyzed using the Mann–Whitney U test . Chi-square or Fisher’s exact test was used for categorical variables, as appropriate. Results Demographic data of both groups The study group comprised 15 males (57.7%) and 11 females (42.3%), with a mean age of 43.2 ± 12.7 years. The historical control group included 27 males (51.9%) and 25 females (48.1%), with a mean age of 44.5 ± 13.3 years. No statistically significant differences were observed between the two groups in terms of demographic characteristics, clinical parameters, laboratory findings, or the various risk scoring systems [Table 1] . Safety of imatinib and pioglitazone combination Over the follow up time, edema was the most frequently reported complaint among patients in the study group (p < 0.001), whereas muscle aches were more commonly reported in the historical group (p = 0.026). Lower limb edema was observed in 85% (n = 22) of patients in the study group, compared to 23% (n = 11) in the historical group. Additionally, patients in the study group exhibited a significant increase in body weight over time. The mean (± SD) body weight was 78.3 ± 10.6 kg at baseline, 80 ± 11.05 kg at 3 months, and 83.6 ± 11.17 kg at 6 months, with a median weight gain of 5 kg (range: 0–10 kg). During follow-up, none of the patients in the study group exhibited abnormal elevations or reductions in random blood glucose (RBG) or fasting blood glucose (FBG) levels. Cytopenic episodes—including neutropenia, anemia, and thrombocytopenia—were observed in both groups; however, there were no significant differences in the severity grades of these hematologic abnormalities between the two groups [Table 2] . Response and efficacy evaluation of imatinib and pioglitazone combination Q- PCR of BCR/ABL gene evaluation [table 3] : At baseline, the median BCR/ABL gene expression level was 81% (range = 32–380) in the study group compared to 88% (range = 26–365) in the historical cohort (P = 0.215) . The median BCR/ABL gene expression was downregulated in pioglitazone group compared to the historical group significantly at the 3rd ( 3.65% vs 7%; P = 0.046) and the 6th month (0.75% vs 0.2%; P = 0.049) , though it was marginallyinsignificant at 12th month (0.25% vs0.1%: P = 0.056). However, starting from 18th month the difference between both groups was statistically insignificant (0.02% vs 0.06%; P = 0.317). This insignificant difference remained through the 24th, 36th, 48th and 60th months among both groups [Table 3]. The achieved milestones/depth of molecular response [Table 4] : EMR was significantly obtained in 92.3% of the study group patients (P = 0.003) at 3 months while at 6 months the difference between both groups was not significant (P = 0.163). CCYR was achieved in 65.4% (N = 17), 100% (N = 22) of the study group patients and 46% (N = 23), 74.2% (N = 26) of the historical group patients at 6, 12 months respectively with a highsignificant difference only at 12 months (P = 0.009) . MMR was achieved in 23% (N = 6), 77.3% (N = 17) of the patients of the study group and 18% (N = 9), 54.3% (N = 19) of the other group at 6, 12 months respectively (P = 0.598, 0.08 ). However, MMR was attained significantly among patients of the study group at 18 months (P = 0.016 ) and 36 months (P = 0.03) . The other time points (24 months, 48 months and 60 months) did not show any further statistical significance (P = 0.407, 0.124, 0.383) respectively. Complete molecular response (CMR) was not significantly achieved at any time point in either group, with median times to CMR of 48 months (range: 18–60) in the study group and 36 months (range: 18–48) in the control group (P = 0.929). Deep molecular response (DMR) was significantly different between the groups only at the 36-month time point (P = 0.023) , while no significant differences were observed at other time points. The median time to DMR was 18 months (range: 6–36) in the study group and 21 months (range: 6–48) in the control group (P = 0.152). Treatment failure and transformation to advanced stages : During the study period, first-line treatment failure occurred in 7 patients (26.9%) in the study group compared to 27 patients (51.9%) in the control group, with a statistically significant difference (P = 0.036). The median time to treatment failure was 6 months (range: 6–24) in the study group and 12 months (range: 6–72) in the historical group (P = 0.243). Regarding disease progression, only one patient (3.8%) in the study group progressed to the accelerated phase (AP) after 18 months of therapy, compared to three patients (5.8%) in the control group, with no statistically significant difference (P = 0.717). Detection of the CITED2and HIF2 α genes expression levels (pre-treatment, post-treatment in the study group and in the healthy control group) [tables 5,6] : CITED2 gene expression was measured in study group patients prior to treatment, revealing a median expression level of 276.3 (range: 1–241,221.7). This baseline level was significantly elevated—approximately 288-fold—compared to age- and gender-matched healthy controls ( P₁ < 0.001) . Following the combined treatment regimen, CITED2 expression decreased significantly to a median of 2.6 (range: 0.006–86,475.3) ( P₂ = 0.005) , with no statistically significant difference compared to the control group ( P₃ = 0.119)[Figure 1]. HIF2α gene expression was assessed in patients before treatment revealing a median of 2.7 (range = 0.041-1255647). This pretreatment expression level is significantly higher (7 folds) when compared to the healthy control group ( P1 = 0.004) . The gene expression level also decreased significantly after receiving the combined treatment to a median of 1 (range = 0.006–47.2) ( P2 = 0.026) that was not significantly different from the normal subject’s level ( P3 = 0.082)[Figure 2] .No significant associations were found between the median pretreatment genes expression level with demographic, and laboratory data among study groups. No significant difference between the pre-treatment and the post-treatment levels among responders and non-responders. Discussion Although the quantum leap in the response spectrum after using TKIs in treating CML, TKIs alone (even the new generations) are still unable to completely eliminate the LSCs and cure CML [ 13 , 14 ]. LSCs act as the game player in TKIs resistance and disease relapse [ 3 , 4 ]. Combining pioglitazone (FDA approved PPARγagonist in treating T2DM) with imatinib was reported to push LSCs out of their quiescence that can deplete theCML stem cell pool [ 5 ].To our knowledge, there are no population-based studies of this combination therapy in newly diagnosed CML patients. We aimed -in the study- to evaluate the safety and efficacy of this combination as upfront treatment line whether it could help to obtain deeper and may be faster molecular responses or not. In the present study, 26 newly diagnosed chronic phase Philadelphia chromosome-positive (Ph + CP) chronic myeloid leukemia (CML) patients—without advanced disease or organ dysfunction—were treated with a combination of imatinib (400 mg) and pioglitazone (15 mg) daily. The pioglitazone dose was chosen to minimize potential adverse effects. Consistent with most other studies, the treatment duration was set at six months [ 10 , 15 ]. Regarding the safety profile of the combination therapy, pioglitazone was generally well tolerated among the majority of patients. No episodes of hypoglycemia or grade 3–4 adverse events were observed. The most commonly reported adverse effects were edema and increased body weight. Edema of varying severity was observed in 84.6% of patients, predominantly presenting as grade 2 pedal edema. This was effectively managed with furosemide (40 mg), and no patient discontinued treatment due to adverse effects. In comparison, a clinical trial conducted at Emory University ( NCT02730195 ) reported pedal edema in 55% and facial edema in 11.1% of participants. In the ACTIM trial, one patient withdrew due to grade 2 edema [ 10 ], while another study reported discontinuation of pioglitazone in two patients due to pedal edema [ 16 ]. The EDI-PIO trial noted a need to reduce the pioglitazone dose to 30 mg on alternate days in response to worsening periorbital and limb edema [ 17 ]. With respect to weight gain, a median increase of 5 kg (range: 1–10 kg) was observed in 88.4% of patients. Due to the absence of body weight data in the control group's retrospective records, direct comparison was not feasible. In the EDIPIO trial, a statistically significant increase in mean body weight was reported following pioglitazone treatment (83.7 ± 22 kg; P = 0.003), likely attributable to the higher doses used (30–45 mg daily) [ 17 ]. In contrast, the French study reported a non-significant weight increase in 50% of patients (N = 12) [ 10 ], while Goyal et al. observed no weight gain in their cohort [ 16 ]. These discrepancies may be influenced by ethnic and dietary differences across study populations. Anemia and neutropenia were observed in 57.6% and 53.8% of patients, respectively, while thrombocytopenia was reported in 38.4%. These hematologic toxicities were managed effectively by temporarily withholding treatment for up to 1–2 weeks [ 13 ]. In comparison, Rousselot et al. reported a statistically significant incidence of anemia ( P = 0.03) after 12 months of therapy [ 10 ], whereas the Emory University trial ( NCT02730195 ) documented only a single case of anemia over a 6-month period. Goyal et al. did not observe any reduction in hemoglobin levels in their study population [ 16 ]. In terms of efficacy, a significant reduction in BCR-ABL1 transcript levels was observed in both groups at 3 and 6 months. Despite comparable clinicopathological characteristics and risk profiles between the groups, the study cohort demonstrated a 12-month complete cytogenetic response (CCyR) rate of 100% (N = 22), which was significantly higher than that of the imatinib-only group ( P = 0.009). Additionally, a greater proportion of patients in the study group achieved a 12-month major molecular response (MMR) (65.3%) compared to 50% in the historical control group, although this difference did not reach statistical significance [table 4]. At 6 months, 23% of patients in the combination therapy group achieved MMR, a rate that was not statistically significant compared to the control group ( P = 0.598). This finding is consistent with Goyal et al., who reported a 22.5% MMR rate when pioglitazone was used as an adjunctive therapy [ 16 ]. Notably, previous in vivo studies assessing the efficacy of the imatinib–pioglitazone combination were conducted in CML patients who had already received treatment but had not yet achieved MMR or complete molecular response (CMR), aiming to deepen their molecular response [ 5 , 10 , 16 , 18 ]. In contrast, our study employed pioglitazone as part of the initial, upfront treatment strategy. To evaluate the potential benefit of using the combination as upfront therapy, we compared our findings with outcomes from various imatinib trials. Studies using standard-dose imatinib (400 mg/day) have reported 12-month CCyR and MMR rates ranging from 55–66% and 22–38%, respectively, while high-dose imatinib (600–800 mg/day) achieved rates of approximately 65% for CCyR and 45–55% for MMR. Additionally, the three largest trials employing second-generation TKIs as first-line treatment—ENESTnd, DASISION, and BEFORE—reported 12-month CCyR rates of 80%, 77%, and 77%, and corresponding MMR rates of 44%, 46%, and 47%, respectively [ 19 , 20 ]. Notably, the 12-month MMR rate observed in our study is also comparable to that reported in the EPIC trial [ 21 ]. A detailed analysis of molecular responses demonstrated that a significantly greater proportion of patients treated with the combination therapy achieved early molecular response (EMR) at 3 months compared to the imatinib-only group (92.3% vs. 59.6%, P = 0.003). These results are comparable to EMR rates reported in major frontline TKI trials—ENESTnd (91%), DASISION (84%), and BEFORE (75%) [ 22 ]. Moreover, although not statistically significant, 9% of patients in the combination group achieved MR^4.5 at 12 months. This rate aligns with previously reported 12-month MR^4.5 rates of 9% for high-dose imatinib, 11% for nilotinib, 5% for dasatinib, and 8% for bosutinib [ 19 ]. While these trials involved larger patient cohorts, achieving similar molecular outcomes with fewer adverse effects and lower treatment costs highlights the potential of this combination as a viable therapeutic option, particularly in resource-limited settings [ 23 ]. These promising early results encouraged us to monitor long-term outcomes with the aim of identifying a potentially accelerated path to treatment-free remission (TFR). However, the findings did not meet these expectations. Beyond the first year, the decline in BCR-ABL1 transcript levels was not statistically significant in either cohort [Table 3]. Similarly, the proportions of patients achieving complete molecular response (CMR) and deep molecular response (DMR) over time were largely comparable between the groups, with the exception of a statistically significant difference in the 3-year DMR rate ( P = 0.023) [table 4]. The 5-yearfollow up results were not different among the two groups as well. The M4.5 rate was 37.5% that is less than 42% and 54% reported results from DASISION andENESTnd [ 19 ].These responses may not persist due to the short duration of pioglitazone treatment or the small sample size (after excluding non-responders). The potential efficacy may be enhanced with higher doses, extended duration or by implying pulsed (on/off) therapeutic cycles. Consideringan alternative perspective 'TreatmentFailure,' the study group demonstrated significantly fewer failing (p = 0.03) and non-significant less progressed patients. This may suggest a potential hidden benefit of the combination therapy thatpossibly improving long-term disease control and eligibility for treatment-free remission planning. The early results were supportingthe suggested proposal about the synergism between the PPARγagonists and TKIs in affecting the CML LSCs through inhibition of STAT5 and its target genes [ 8 , 10 , 24 ]. Therefore, w e tested the pretreatment and post treatment gene expression levels of CITED2 and HIF2α . Both genes were found to be significantly overexpressed in the pretreatment samples. The over expression has been already detected in many pretreated CML and AML patients for CITED2 gene [ 25 – 27 ] and for the HIF2α in myeloid leukemia cell lines U937, HL60 and THP1 [ 28 ]. These studies emphasizetheir role in regulating the oncogene-induced quiescent LSCs poolimplying a worse prognosis [ 29 – 32 ]. Notably, the expression levels of both genes significantly decreased in post-treatment samples ( P = 0.005 and P = 0.026, respectively), and were not significantly different from those observed in the healthy control group ( P = 0.11 and P = 0.08, respectively). These findings suggest a potential effect of the combination therapy on leukemic stem cells (LSCs). This observation aligns with the results reported by Stephan Prost et al. [ 5 ]. In contrast, Lopes et al. found no significant changes in HIF2α and CITED2 expression before and after pioglitazone treatment at 3 and 6 months following imatinib discontinuation [ 33 ]. Further analysis revealed no significant associations between pretreatment median levels of CITED2 and HIF2α gene expression and the demographic, clinical, or laboratory parameters within the study group. These findings are consistent with previous reports showing a lack of correlation between the expression of these genes and clinical or laboratory characteristics in both myeloid leukemia and various solid tumors [ 30 , 34 , 35 ]. Additionally, no significant differences were observed in post-treatment gene expression levels between responders and non-responders. This may suggest a limited prognostic value of these genes and highlights the need for further investigation in larger patient cohorts [ 36 ]. Conclusion In our study, adding pioglitazone to imatinib in newly diagnosed CML showed short-term benefit but lacked long-term durability.These responses may not persist due to the short duration of pioglitazone treatment or the small sample size. The potential efficacy may be enhanced with higher doses, extended duration or by implying pulsed (on/off) therapeutic cycles. Although CITED2 and HIF2α expression decreased with treatment, these changes did not align with BCR-ABL1 transcript levels, suggesting limited utility as molecular markers. Their potential prognostic value, however, warrants further investigation in larger studies. Limitations This study has several limitations that should be acknowledged. First, the small sample size (n = 26) limits the statistical power and generalizability of the findings. Additionally, the use of a historical control group rather than a randomized, contemporaneous control introduces potential selection and information biases, and the lack of randomization and blinding increases the risk of bias in outcome assessment.Moreover, although short-term responses appeared promising, the long-term outcomes did not align, indicating a lack of durability in response. The wide variability observed in CITED2 and HIF2a gene expression levels may reflect inter-patient differences or inconsistencies in measurement techniques, and the clinical relevance of the gene expression changes remains unclear, as the study did not directly assess leukemic stem cell burden. Finally, the study's focus on newly diagnosed chronic phase patients limits the applicability of results to broader CML populations. Declarations Data Availability Declaration: The clinical and genetic data supporting the findings of this study are not publicly available due to institutional restrictions. However, the data do not contain identifiable human subject information, and there are no legal or ethical limitations preventing their use. Data may be made available to qualified researchers upon reasonable request and subject to approval by the corresponding institutional review board and data access committee. Requests for access to the data can be submitted through the Annals of Hematology journal in accordance with its data access policies. Funding Declaration: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors Author Contribution Mohamed Mabed: Conceptualized and designed the study, supervised patient recruitment, and contributed to data interpretation and manuscript writing.Basma Atef: Collected clinical data, coordinated sample collection and processing, and performed follow-up evaluations and response assessments.Shaimaa El-Ashwah: Performed follow-up evaluations and response assessments and contributed to data interpretation and manuscript writing.Layla M. Saleh Carried out molecular analyses, including gene expression assays for CITED2 and HIF2α, performed statistical analysis, and contributed to drafting the results section.Hanan Gawish: Contributed to the literature review, data interpretation, reporting side effects of the drug, manuscript editing, and critically revised the work for important intellectual content. References Sampaio MM, Santos MLC, Marques HS (2021) Chronic myeloid leukemia—from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol –02(2):69–94. 10.5306/wjco.v12.i2.69 Sharf G, Marin C, Bradley JA et al (2020) Treatment-free remission in chronic myeloid leukemia: the patient perspective and areas of unmet needs. Leukemia 34(8):2102–2112 Zhai X, Jiang X (2022) Properties of leukemic stem cells in regulating drug resistance in acute and chronic myeloid leukemias. 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Blood 123(21):3316–3326 Korthuis PM, Berger G, Bakker B et al (2015) CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia. Leukemia 29(3):625–635 Sontakke P, Koczula KM, Jaques J et al (2016) Hypoxia-like signatures induced by BCR-ABL potentially alter the glutamine uptake for maintaining oxidative phosphorylation. PLoS ONE 11(4):e0153226 Lawson H, van de Lagemaat LN, Barile M et al (2021) CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation. Stem Cell Rep 16(11):2784–2797 Lopès A, Miranda E, Póvoa V et al (2019) Pioglitazone did not affect PPARG, STAT5, HIF2α and CITED2 gene expression in chronic myeloid leukemia patients with deep molecular response. Blood 134(Suppl 1):1637 Minemura H, Takagi K, Sato A et al (2016) CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance. Cancer Sci 107(12):1898–1908 Luo D, Liu H, Lin D, Lian K, Ren H (2019) The clinicopathologic and prognostic value of hypoxia-inducible factor-2α in cancer patients: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 28(5):857–866 Moreno Roig E, Yaromina A, Houben R et al (2018) Prognostic role of hypoxia-inducible factor-2α tumor cell expression in cancer patients: a meta-analysis. Front Oncol 8:224 Tables Table 1 is available in the Supplementary Files section. Table (2): The adverse effects among both groups Historical Control N=52 Study group N=26 p Allergy N (%) 0 (0%) 0 (0%) - Edema N (%) 12 (9.6%) 22 (76.9%) <0.001 Cytopenia N (%) 23 (44.2%) 12 (46.2%) 0.872 Muscle aches N (%) 10 (19.2%) 0 (0%) 0.026 GIT symptoms N (%) 5 (9.6%) 3 (11.5%) 0.256 Hepatotoxicity N (%) 11 (21.2%) 7 (26.9%) 0.569 Table (3): The BCR/ABL expression level across time among both groups % BCR-ABL expression level median(range) Historical group The Study group P1 Baseline 88 (26-365) 81 (32-380) 0.215 3 months 7 (0.02-67) 3.65 (0.05-20) 0.046 6 months 2.0 (0.01-122) 0.75 (0.002-46) 0.049 12 months 0.25 (0-121) 0.1 (0.002-0.6) 0.056 18 months 0.06 (0-2) 0.02 (0-0.8) 0.317 24 months 0.01 (0-4.6) 0.02 (0-22) 0.586 3 years 0.01 (0-1) 0.009 (0-0.06) 0.410 4 years 0.009 (0-62) 0.0095 (0-0.07) 0.640 5 years 0.01 (0-37) 0.0095 (0-0.06) 0.163 Table (4): The response milestones and efficacy among both groups Historical N (%) 52 (100%) Study N (%) 26(100%) P Achieved milestones N (%) HR at 3 months 41/52 (78.8%) 26/26 (100%) 0.013 ≥ CCYR at 6 months 23/50 (46%) 17/26 (65.4%) 0.108 ≥ CCYR at 12 months 26/35 (74.2%) 22/22 (100%) 0.009 ≥ MMR at 6 months 9/50 (18%) 6/26 (23%) 0.598 ≥ MMR at 12 months 19/35 (54.3 %) 17/22 (77.3%) 0.080 ≥ MMR at 18 months 19/31 (61.3%) 20/22 (91%) 0.01 6 ≥ MMR at 2 years 25/29 (86.2%) 17/22 (77.2%) 0.407 ≥ MMR at 3 years 21/27 (77.7%) 17/17 (100%) 0.036 ≥ MMR at 4 years 19/22 (86.3%) 16/16 (100%) 0.124 ≥ MMR at 5 years 18/19 (94.7%) 14/14 (100%) 0.383 Depth of molecular response N (%) EMR 3 months 31/52 (59.6%) 24/26 (92.3%) 0.00 3 EMR 6 months 35/50 (70%) 22/26 (84.6%) 0.163 CMR 1y 0/35 (0) 0/22 (0) x CMR 2y 3/29 (10.3%) 3/22 (13.6%) 0.718 CMR 3y 4/27 (14.8%) 0/17 (0) 0.147 CMR 4y 5/22 (22.7%) 5/16 (31.2%) 0.556 CMR 5y 5/19 (26.3%) 4/16 (25%) 0.929 Median Time to CMR (months) 36 (18-48) 48 (18-60) 0.670 DMR (M4, M4.5, M5) 1 y 6/35 (17%) 6/22 (27.3%) 0.361 DMR (M4, M4.5, M5) 2 y 16/29 (55%) 9/22 (41%) 0.313 DMR (M4, M4.5, M5) 3 y 15/27 (55.5%) 15/17 (88.2%) 0.023 DMR (M4, M4.5, M5) 4 y 13/22 (59%) 11/16 (68.7%) 0.542 DMR (M4, M4.5, M5) 5 y 13/19 (68.4%) 13/16 (81.2%) 0.387 Median Time to DMR ( Months) 21 (6-48) 18 (6-36) 0.152 Failing/progression to advanced stages Failing patients (5ys) 27/52 (51.9%) 7/26(26.9%) 0.036 Median(range) Time to Failure (Months) 12(6-72) 6(6-24) 0.243 Progressed patients (4ys) 3/52(5.7%) 1/26(3.8%) 0.717 Median (range) Time to Progression (Months) 48(48-60) 18 0.157 Table (5): Comparison between CITED2, HIF2a gene expression level between healthy group and study group patients Gene expression Healthy Control (N=12) Study N=25 p1 p2 p3 Pre treatment Post treatment CITED 2 Median 0.96 276.3 2.6 <0.001 0.005 0.119 range 0.082-2.2 1-241221.7 0.006-86475.3 HIF2 Median 0.38 2.7 1 0.004 0.026 0.082 range 0.03-4.68 0.041-1255647.4 0.006-47.2 P1 : comparing the gene expression between the healthy control and the study group patients pretreatment, P2 : comparing the gene expression pre and post treatment within the study group patients. P3 : comparing the gene expression between the healthy control and the study group patients posttreatment Table (6): Comparison the CITED2, HIF2a post- treatment gene expression level among responders and non-responders Gene expression Study N=25 P Responders N=21 Non responders N=4 CITED 2 Pre-treatment expression Median 261.4 3145 0.630 Range 1-241221.7 1-14972.2 Post-treatment expression Median 2.2 92.6 0.235 Range 0.01-103.25 0.01-86475.27 HIF2α Pre-treatment expression Median 1.6 19.7 0.373 Range 0.041-32768 1-1255647.4 Post-treatment expression Median 1 0.8 0.232 Range 0.01-47.18 0.02-1 Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Published Journal Publication published 25 Feb, 2026 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 12 Sep, 2025 Reviews received at journal 29 Aug, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviews received at journal 16 Aug, 2025 Reviewers agreed at journal 01 Aug, 2025 Reviewers invited by journal 01 Aug, 2025 Editor assigned by journal 21 Jul, 2025 Submission checks completed at journal 21 Jul, 2025 First submitted to journal 16 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7140724","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":494304302,"identity":"c1710133-2e8f-4adb-b0fc-2d19732d49d7","order_by":0,"name":"Basma Atef","email":"","orcid":"","institution":"Mansoura University","correspondingAuthor":false,"prefix":"","firstName":"Basma","middleName":"","lastName":"Atef","suffix":""},{"id":494304303,"identity":"06ca2f7e-4b01-4b81-986f-49b675e01614","order_by":1,"name":"Shaimaa El-Ashwah","email":"","orcid":"","institution":"Mansoura University","correspondingAuthor":false,"prefix":"","firstName":"Shaimaa","middleName":"","lastName":"El-Ashwah","suffix":""},{"id":494304304,"identity":"a2ac2f80-44d0-4dc3-b143-e15b88666c08","order_by":2,"name":"Layla M. Saleh","email":"","orcid":"","institution":"Mansoura University","correspondingAuthor":false,"prefix":"","firstName":"Layla","middleName":"M.","lastName":"Saleh","suffix":""},{"id":494304305,"identity":"6b8f4d5f-2c5e-414f-a452-49d263e6869c","order_by":3,"name":"Hanan Gawish","email":"","orcid":"","institution":"Mansoura University","correspondingAuthor":false,"prefix":"","firstName":"Hanan","middleName":"","lastName":"Gawish","suffix":""},{"id":494304306,"identity":"3a79e409-b6f0-4b7a-af81-f154f75cc47b","order_by":4,"name":"Mohamed Mabed","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACHgYGxgYGxn4oF8gmVsvMBpK1bDhArBbd9t6jG37usJHdfO3ws4c/GGxkNxxgPvwCnxazM+fSbvaeSTPedjvN3JiHIc14wwG2NAu8Wm7kmN3gbTucuO12gpk0A8PhxA0HeMwMCGm5+bftf+Lm2enfJH8w/Adq4f9GUMtt3rYDiRukc8wkeBgOgGxhfoDfL2fMbsueSTaecTunTJrHINl45mE2M3w6GMyO95jdfLvDTrZ/dvo2yR8VdrJ9x5sff8CrBxWAPMHMwCZBghYIYCbFllEwCkbBKBj+AAAAaVSRANzJkAAAAABJRU5ErkJggg==","orcid":"","institution":"Mansoura University","correspondingAuthor":true,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Mabed","suffix":""}],"badges":[],"createdAt":"2025-07-16 13:53:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7140724/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7140724/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-026-06795-7","type":"published","date":"2026-02-25T15:58:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88410168,"identity":"c0581a98-3f1f-4d12-92fc-cbaa7111c76a","added_by":"auto","created_at":"2025-08-06 08:22:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":19236,"visible":true,"origin":"","legend":"\u003cp\u003eCITED2 gene expression among healthy control and within study group.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7140724/v1/53c7658641b3a960a0c4fe52.png"},{"id":88410169,"identity":"b51eabd6-266c-4d53-9540-78f3fb8e41f2","added_by":"auto","created_at":"2025-08-06 08:22:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37590,"visible":true,"origin":"","legend":"\u003cp\u003eHIF2α expression among study group and healthy control\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7140724/v1/ef9e06a3e9645b188370a640.png"},{"id":103765940,"identity":"3a04653f-061b-48f7-ac96-c3b1f2535c0f","added_by":"auto","created_at":"2026-03-02 16:11:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2323133,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7140724/v1/a6aab21b-373c-4be5-b444-a11e11351a59.pdf"},{"id":88410170,"identity":"72e7ebea-74be-4127-8dd5-ab5b34d8242e","added_by":"auto","created_at":"2025-08-06 08:22:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18157,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7140724/v1/5282c7442d3e45e16124cd28.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Potential Utility of PPARγ Agonists in the Eradication of Chronic Myeloid Leukemia Stem Cells","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic myeloid leukemia (CML) is a myeloproliferative disorder that is characterized by the cytogenic hallmark \"Philadelphia chromosome (Ph+)\". The use of tyrosine kinase inhibitors (TKIs) has revolutionized the treatmentof CML and improved the patients\u0026rsquo; survival dramatically [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Moreover, the obtained deep molecular responses have encouraged starting the treatments free remission (TFR) trials. However 50% of the patients relapse [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Researches owed this relapse mainly to the presence of quiescent/therapy resistant leukemic stem cells (LSCs) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. They also proved that LSCs are \u0026ldquo;Not oncogene-addicted\u0026rdquo; i.e. their survival is not strictly dependent on BCR-ABL1 kinase activity alone but on many other signaling pathways [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Studies have reported how strong the extra-activated STAT5 can regulate the quiescence/proliferation of LSCs through many target genes for example: Hypoxia inducible factor genes and \u003cem\u003eCITED2\u003c/em\u003e genes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePeroxisome proliferator-activated receptor gamma (PPARγ) is one of nuclear-hormone receptors that regulate cellular differentiation, proliferation and apoptosis. Combining pioglitazone (PPARγ agonist) with imatinib has increased the anti-leukemic effect in vitro [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and in vivo studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This was explained by its ability to down regulate the STAT5 target genes and subsequently impact the LSC cell cycle and increase their sensitivity to therapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAim of the study\u003c/strong\u003e\u003cp\u003eThe objective of this study was to assess the therapeutic impact of combining glitazones with tyrosine kinase inhibitors (TKIs) in the treatment of newly diagnosed patients with chronic phase chronic myeloid leukemia (CML-CP). The primary endpoint was to evaluate the safety profile of the combination regimen. Secondary endpoints included assessment of short-term (at 3, 6, and 12 months) and long-term treatment responses and efficacy, based on molecular response milestones. The tertiary endpoint involved evaluating changes in the expression levels of the \u003cem\u003eCITED2\u003c/em\u003e and \u003cem\u003eHIF2α\u003c/em\u003e genes before treatment and after 6 months of therapy.\u003c/p\u003e\u003c/p\u003e"},{"header":"Study Design and Methodology","content":"\u003cp\u003e\u003cb\u003eStudy Design\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis was a prospective, non-randomized interventional study conducted at the Oncology Center, Mansoura University (OCMU), Egypt, from January 2017 to January 2022. Ethical approval was obtained from the Faculty of Medicine Ethical Committee (MD/17.12.30), and the study was registered as a clinical trial (NCT04883125).\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe study included 26 newly diagnosed patients with chronic phase Philadelphia chromosome\u0026ndash;positive chronic myeloid leukemia (CML), with the sample size calculated to detect a 25% absolute increase in major molecular response (MMR) at 12 months (from 25\u0026ndash;50%), assuming a significance level (α) of 0.05 and a statistical power of 80% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Eligible participants were adults aged 18 to 60 years of both sexes, diagnosed with de novo chronic phase CML, and who provided written informed consent in accordance with the Declaration of Helsinki. Exclusion criteria included advanced disease stages (accelerated or blast phase), atypical CML, and any significant organ dysfunction.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiagnosis and Treatment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCML diagnosis was confirmed via real-time quantitative PCR (RT-qPCR) for the BCR/ABL gene. Bone marrow examination and flow cytometry were performed to evaluate cellularity and rule out advanced stages. Patients received a combination of pioglitazone 15 mg and imatinib 400 mg, both once daily, for 6 months, with close clinical monitoring. All clinical data, adverse effects, and treatment responses were recorded in OCMU\u0026rsquo;s electronic medical records. BCR/ABL transcript levels were monitored by real-time quantitative PCR (RT-qPCR) at 3, 6, 12, 24, 36, 48, and 60 months to evaluate treatment response. Molecular responses were categorized according to log reductions on the International Scale (IS) as follows: Early Molecular Response (EMR) was defined as BCR/ABL IS\u0026thinsp;\u0026le;\u0026thinsp;10% at 3 months; Complete Cytogenetic Response (CCyR) corresponded to the absence of Philadelphia chromosome\u0026ndash;positive metaphases in \u0026ge;\u0026thinsp;20 bone marrow cells, approximated by BCR/ABL IS\u0026thinsp;\u0026lt;\u0026thinsp;1%; Major Molecular Response (MMR) was defined as BCR/ABL IS\u0026thinsp;\u0026le;\u0026thinsp;0.1%; Deep Molecular Response (DMR) as BCR/ABL IS\u0026thinsp;\u0026le;\u0026thinsp;0.01%; and Complete Molecular Response (CMR) as undetectable BCR/ABL transcripts on the IS.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes and Evaluation\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eI. Safety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTreatment safety was defined by the absence of grade 3\u0026ndash;4 hematologic or non-hematologic toxicities at any time [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eII. Efficacy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEfficacy was assessed via achievement of molecular response milestones. Any progression to accelerated or blast phase during follow-up was documented.\u003c/p\u003e\u003cp\u003eA \u003cb\u003ehistorical control group\u003c/b\u003e of 52 age- and gender-matched chronic phase CML (Ph+) patients treated with imatinib 400 mg alone was used for comparison of clinical and molecular outcomes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eIII. Gene Expression Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eExpression levels of \u003cb\u003eCITED2\u003c/b\u003e and \u003cb\u003eHIF2α\u003c/b\u003ewere evaluated by RT-qPCR before treatment and at 6 months. These were compared with levels in a third group of 12 age- and gender-matched healthy blood donors.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis was performed using SPSS Version 25.0. Normality was tested using the Kolmogorov-Smirnov test (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 considered normal). Normally distributed variables were compared using the \u003cb\u003eStudent\u0026rsquo;s t-test\u003c/b\u003e, while non-parametric variables were analyzed using the \u003cb\u003eMann\u0026ndash;Whitney U test\u003c/b\u003e. \u003cb\u003eChi-square\u003c/b\u003e or \u003cb\u003eFisher\u0026rsquo;s exact test\u003c/b\u003e was used for categorical variables, as appropriate.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eDemographic data of both groups\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe study group comprised 15 males (57.7%) and 11 females (42.3%), with a mean age of 43.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7 years. The historical control group included 27 males (51.9%) and 25 females (48.1%), with a mean age of 44.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3 years. No statistically significant differences were observed between the two groups in terms of demographic characteristics, clinical parameters, laboratory findings, or the various risk scoring systems \u003cb\u003e[Table\u0026nbsp;1]\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSafety of imatinib and pioglitazone combination\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOver the follow up time, edema was the most frequently reported complaint among patients in the study group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas muscle aches were more commonly reported in the historical group (p\u0026thinsp;=\u0026thinsp;0.026). Lower limb edema was observed in 85% (n\u0026thinsp;=\u0026thinsp;22) of patients in the study group, compared to 23% (n\u0026thinsp;=\u0026thinsp;11) in the historical group. Additionally, patients in the study group exhibited a significant increase in body weight over time. The mean (\u0026plusmn;\u0026thinsp;SD) body weight was 78.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6 kg at baseline, 80\u0026thinsp;\u0026plusmn;\u0026thinsp;11.05 kg at 3 months, and 83.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.17 kg at 6 months, with a median weight gain of 5 kg (range: 0\u0026ndash;10 kg). During follow-up, none of the patients in the study group exhibited abnormal elevations or reductions in random blood glucose (RBG) or fasting blood glucose (FBG) levels. Cytopenic episodes\u0026mdash;including neutropenia, anemia, and thrombocytopenia\u0026mdash;were observed in both groups; however, there were no significant differences in the severity grades of these hematologic abnormalities between the two groups \u003cb\u003e[Table\u0026nbsp;2]\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResponse and efficacy evaluation of imatinib and pioglitazone combination\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eQ- PCR of\u003c/b\u003e \u003cb\u003eBCR/ABL\u003c/b\u003e \u003cb\u003egene evaluation [table 3]\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eAt baseline, the median \u003cem\u003eBCR/ABL\u003c/em\u003e gene expression level was 81% (range\u0026thinsp;=\u0026thinsp;32\u0026ndash;380) in the study group compared to 88% (range\u0026thinsp;=\u0026thinsp;26\u0026ndash;365) in the historical cohort \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.215)\u003c/b\u003e. The median \u003cem\u003eBCR/ABL\u003c/em\u003e gene expression was downregulated in pioglitazone group compared to the historical group significantly at the 3rd (\u003cb\u003e3.65% vs 7%; P\u0026thinsp;=\u0026thinsp;0.046)\u003c/b\u003e and the 6th month\u003cb\u003e(0.75% vs 0.2%; P\u0026thinsp;=\u0026thinsp;0.049)\u003c/b\u003e, though it was marginallyinsignificant at 12th month\u003cb\u003e(0.25% vs0.1%: P\u0026thinsp;=\u0026thinsp;0.056).\u003c/b\u003eHowever, starting from 18th month the difference between both groups was statistically insignificant \u003cb\u003e(0.02% vs 0.06%; P\u0026thinsp;=\u0026thinsp;0.317).\u003c/b\u003e This insignificant difference remained through the 24th, 36th, 48th and 60th months among both groups \u003cb\u003e[Table\u0026nbsp;3].\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eThe achieved milestones/depth of molecular response [Table\u0026nbsp;4]\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eEMR was significantly obtained in 92.3% of the study group patients \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.003)\u003c/b\u003eat 3 months while at 6 months the difference between both groups was not significant \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.163).\u003c/b\u003eCCYR was achieved in 65.4% (N\u0026thinsp;=\u0026thinsp;17), 100% (N\u0026thinsp;=\u0026thinsp;22) of the study group patients and 46% (N\u0026thinsp;=\u0026thinsp;23), 74.2% (N\u0026thinsp;=\u0026thinsp;26) of the historical group patients at 6, 12 months respectively with a highsignificant difference only at 12 months \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.009)\u003c/b\u003e. MMR was achieved in 23% (N\u0026thinsp;=\u0026thinsp;6), 77.3% (N\u0026thinsp;=\u0026thinsp;17) of the patients of the study group and 18% (N\u0026thinsp;=\u0026thinsp;9), 54.3% (N\u0026thinsp;=\u0026thinsp;19) of the other group at 6, 12 months respectively \u003cb\u003e(P\u003c/b\u003e\u0026thinsp;=\u0026thinsp;0.598, \u003cb\u003e0.08\u003c/b\u003e). However, MMR was attained significantly among patients of the study group at 18 months \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.016\u003c/b\u003e) and 36 months \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.03)\u003c/b\u003e. The other time points (24 months, 48 months and 60 months) did not show any further statistical significance \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.407, 0.124, 0.383)\u003c/b\u003e respectively.\u003c/p\u003e\u003cp\u003eComplete molecular response (CMR) was not significantly achieved at any time point in either group, with median times to CMR of 48 months (range: 18\u0026ndash;60) in the study group and 36 months (range: 18\u0026ndash;48) in the control group \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.929).\u003c/b\u003e Deep molecular response (DMR) was significantly different between the groups only at the 36-month time point \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.023)\u003c/b\u003e, while no significant differences were observed at other time points. The median time to DMR was 18 months (range: 6\u0026ndash;36) in the study group and 21 months (range: 6\u0026ndash;48) in the control group \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.152).\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTreatment failure and transformation to advanced stages\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eDuring the study period, first-line treatment failure occurred in 7 patients (26.9%) in the study group compared to 27 patients (51.9%) in the control group, with a statistically significant difference \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.036).\u003c/b\u003e The median time to treatment failure was 6 months (range: 6\u0026ndash;24) in the study group and 12 months (range: 6\u0026ndash;72) in the historical group \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.243).\u003c/b\u003e Regarding disease progression, only one patient (3.8%) in the study group progressed to the accelerated phase (AP) after 18 months of therapy, compared to three patients (5.8%) in the control group, with no statistically significant difference \u003cb\u003e(P\u0026thinsp;=\u0026thinsp;0.717).\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eDetection of the\u003c/b\u003e \u003cb\u003eCITED2and HIF2\u003c/b\u003e\u003cb\u003eα genes expression levels (pre-treatment, post-treatment in the study group and in the healthy control group) [tables 5,6]\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eCITED2 gene expression was measured in study group patients prior to treatment, revealing a median expression level of 276.3 (range: 1\u0026ndash;241,221.7). This baseline level was significantly elevated\u0026mdash;approximately 288-fold\u0026mdash;compared to age- and gender-matched healthy controls \u003cb\u003e(\u003c/b\u003e\u003cb\u003eP₁\u003c/b\u003e\u003cb\u003e\u0026lt; 0.001)\u003c/b\u003e. Following the combined treatment regimen, \u003cem\u003eCITED2\u003c/em\u003e expression decreased significantly to a median of 2.6 (range: 0.006\u0026ndash;86,475.3) \u003cb\u003e(\u003c/b\u003e\u003cb\u003eP₂\u003c/b\u003e \u003cb\u003e= 0.005)\u003c/b\u003e, with no statistically significant difference compared to the control group\u003cb\u003e(\u003c/b\u003e\u003cb\u003eP₃\u003c/b\u003e \u003cb\u003e= 0.119)[Figure 1].\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eHIF2α\u003c/em\u003e gene expression was assessed in patients before treatment revealing a median of 2.7 (range\u0026thinsp;=\u0026thinsp;0.041-1255647). This pretreatment expression level is significantly higher (7 folds) when compared to the healthy control group \u003cb\u003e(\u003c/b\u003e\u003cb\u003eP1\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.004)\u003c/b\u003e. The gene expression level also decreased significantly after receiving the combined treatment to a median of 1 (range\u0026thinsp;=\u0026thinsp;0.006\u0026ndash;47.2) \u003cb\u003e(\u003c/b\u003e\u003cb\u003eP2\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.026)\u003c/b\u003e that was not significantly different from the normal subject\u0026rsquo;s level \u003cb\u003e(\u003c/b\u003e\u003cb\u003eP3\u003c/b\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;0.082)[Figure 2]\u003c/b\u003e.No significant associations were found between the median pretreatment genes expression level with demographic, and laboratory data among study groups. No significant difference between the pre-treatment and the post-treatment levels among responders and non-responders.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough the quantum leap in the response spectrum after using TKIs in treating CML, TKIs alone (even the new generations) are still unable to completely eliminate the LSCs and cure CML [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. LSCs act as the game player in TKIs resistance and disease relapse [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Combining pioglitazone (FDA approved PPARγagonist in treating T2DM) with imatinib was reported to push LSCs out of their quiescence that can deplete theCML stem cell pool [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].To our knowledge, there are no population-based studies of this combination therapy in newly diagnosed CML patients. We aimed -in the study- to evaluate the safety and efficacy of this combination as upfront treatment line whether it could help to obtain deeper and may be faster molecular responses or not.\u003c/p\u003e\u003cp\u003eIn the present study, 26 newly diagnosed chronic phase Philadelphia chromosome-positive (Ph\u0026thinsp;+\u0026thinsp;CP) chronic myeloid leukemia (CML) patients\u0026mdash;without advanced disease or organ dysfunction\u0026mdash;were treated with a combination of imatinib (400 mg) and pioglitazone (15 mg) daily. The pioglitazone dose was chosen to minimize potential adverse effects. Consistent with most other studies, the treatment duration was set at six months [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRegarding the safety profile of the combination therapy, pioglitazone was generally well tolerated among the majority of patients. No episodes of hypoglycemia or grade 3\u0026ndash;4 adverse events were observed. The most commonly reported adverse effects were edema and increased body weight. Edema of varying severity was observed in 84.6% of patients, predominantly presenting as grade 2 pedal edema. This was effectively managed with furosemide (40 mg), and no patient discontinued treatment due to adverse effects. In comparison, a clinical trial conducted at Emory University (\u003cb\u003eNCT02730195\u003c/b\u003e) reported pedal edema in 55% and facial edema in 11.1% of participants. In the ACTIM trial, one patient withdrew due to grade 2 edema [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], while another study reported discontinuation of pioglitazone in two patients due to pedal edema [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The EDI-PIO trial noted a need to reduce the pioglitazone dose to 30 mg on alternate days in response to worsening periorbital and limb edema [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWith respect to weight gain, a median increase of 5 kg (range: 1\u0026ndash;10 kg) was observed in 88.4% of patients. Due to the absence of body weight data in the control group's retrospective records, direct comparison was not feasible. In the EDIPIO trial, a statistically significant increase in mean body weight was reported following pioglitazone treatment (83.7\u0026thinsp;\u0026plusmn;\u0026thinsp;22 kg; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), likely attributable to the higher doses used (30\u0026ndash;45 mg daily) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, the French study reported a non-significant weight increase in 50% of patients (N\u0026thinsp;=\u0026thinsp;12) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], while Goyal et al. observed no weight gain in their cohort [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These discrepancies may be influenced by ethnic and dietary differences across study populations.\u003c/p\u003e\u003cp\u003eAnemia and neutropenia were observed in 57.6% and 53.8% of patients, respectively, while thrombocytopenia was reported in 38.4%. These hematologic toxicities were managed effectively by temporarily withholding treatment for up to 1\u0026ndash;2 weeks [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In comparison, Rousselot et al. reported a statistically significant incidence of anemia (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) after 12 months of therapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], whereas the Emory University trial (\u003cb\u003eNCT02730195\u003c/b\u003e) documented only a single case of anemia over a 6-month period. Goyal et al. did not observe any reduction in hemoglobin levels in their study population [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn terms of efficacy, a significant reduction in \u003cem\u003eBCR-ABL1\u003c/em\u003e transcript levels was observed in both groups at 3 and 6 months. Despite comparable clinicopathological characteristics and risk profiles between the groups, the study cohort demonstrated a 12-month complete cytogenetic response (CCyR) rate of 100% (N\u0026thinsp;=\u0026thinsp;22), which was significantly higher than that of the imatinib-only group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). Additionally, a greater proportion of patients in the study group achieved a 12-month major molecular response (MMR) (65.3%) compared to 50% in the historical control group, although this difference did not reach statistical significance \u003cb\u003e[table 4].\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt 6 months, 23% of patients in the combination therapy group achieved MMR, a rate that was not statistically significant compared to the control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.598). This finding is consistent with Goyal et al., who reported a 22.5% MMR rate when pioglitazone was used as an adjunctive therapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Notably, previous in vivo studies assessing the efficacy of the imatinib\u0026ndash;pioglitazone combination were conducted in CML patients who had already received treatment but had not yet achieved MMR or complete molecular response (CMR), aiming to deepen their molecular response [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In contrast, our study employed pioglitazone as part of the initial, upfront treatment strategy.\u003c/p\u003e\u003cp\u003eTo evaluate the potential benefit of using the combination as upfront therapy, we compared our findings with outcomes from various imatinib trials. Studies using standard-dose imatinib (400 mg/day) have reported 12-month CCyR and MMR rates ranging from 55\u0026ndash;66% and 22\u0026ndash;38%, respectively, while high-dose imatinib (600\u0026ndash;800 mg/day) achieved rates of approximately 65% for CCyR and 45\u0026ndash;55% for MMR. Additionally, the three largest trials employing second-generation TKIs as first-line treatment\u0026mdash;ENESTnd, DASISION, and BEFORE\u0026mdash;reported 12-month CCyR rates of 80%, 77%, and 77%, and corresponding MMR rates of 44%, 46%, and 47%, respectively [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Notably, the 12-month MMR rate observed in our study is also comparable to that reported in the EPIC trial [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA detailed analysis of molecular responses demonstrated that a significantly greater proportion of patients treated with the combination therapy achieved early molecular response (EMR) at 3 months compared to the imatinib-only group (92.3% vs. 59.6%, P\u0026thinsp;=\u0026thinsp;0.003). These results are comparable to EMR rates reported in major frontline TKI trials\u0026mdash;ENESTnd (91%), DASISION (84%), and BEFORE (75%) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Moreover, although not statistically significant, 9% of patients in the combination group achieved MR^4.5 at 12 months. This rate aligns with previously reported 12-month MR^4.5 rates of 9% for high-dose imatinib, 11% for nilotinib, 5% for dasatinib, and 8% for bosutinib [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. While these trials involved larger patient cohorts, achieving similar molecular outcomes with fewer adverse effects and lower treatment costs highlights the potential of this combination as a viable therapeutic option, particularly in resource-limited settings [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese promising early results encouraged us to monitor long-term outcomes with the aim of identifying a potentially accelerated path to \u003cb\u003etreatment-free remission\u003c/b\u003e (TFR). However, the findings did not meet these expectations. Beyond the first year, the decline in \u003cem\u003eBCR-ABL1\u003c/em\u003e transcript levels was not statistically significant in either cohort \u003cb\u003e[Table\u0026nbsp;3].\u003c/b\u003e Similarly, the proportions of patients achieving complete molecular response (CMR) and deep molecular response (DMR) over time were largely comparable between the groups, with the exception of a statistically significant difference in the 3-year DMR rate (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) \u003cb\u003e[table 4].\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe 5-yearfollow up results were not different among the two groups as well. The M4.5 rate was 37.5% that is less than 42% and 54% reported results from DASISION andENESTnd [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].These responses may not persist due to the short duration of pioglitazone treatment or the small sample size (after excluding non-responders). The potential efficacy may be enhanced with higher doses, extended duration or by implying pulsed (on/off) therapeutic cycles. Consideringan alternative perspective \u003cb\u003e'TreatmentFailure,'\u003c/b\u003e the study group demonstrated significantly fewer failing (p\u0026thinsp;=\u0026thinsp;0.03) and non-significant less progressed patients. This may suggest a potential hidden benefit of the combination therapy thatpossibly improving long-term disease control and eligibility for treatment-free remission planning.\u003c/p\u003e\u003cp\u003eThe early results were supportingthe suggested proposal about the synergism between the PPARγagonists and TKIs in affecting the CML LSCs through inhibition of STAT5 and its target genes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Therefore, \u003cb\u003ew\u003c/b\u003ee tested the pretreatment and post treatment gene expression levels of \u003cem\u003eCITED2\u003c/em\u003e and \u003cem\u003eHIF2α\u003c/em\u003e. Both genes were found to be significantly overexpressed in the pretreatment samples. The over expression has been already detected in many pretreated CML and AML patients for CITED2 gene [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] \u003cb\u003eand for the\u003c/b\u003e HIF2α in myeloid leukemia cell lines U937, HL60 and THP1 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These studies emphasizetheir role in regulating the oncogene-induced quiescent LSCs poolimplying a worse prognosis [\u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNotably, the expression levels of both genes significantly decreased in post-treatment samples (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026, respectively), and were not significantly different from those observed in the healthy control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.11 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08, respectively). These findings suggest a potential effect of the combination therapy on leukemic stem cells (LSCs). This observation aligns with the results reported by Stephan Prost et al. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In contrast, Lopes et al. found no significant changes in \u003cem\u003eHIF2α\u003c/em\u003e and \u003cem\u003eCITED2\u003c/em\u003e expression before and after pioglitazone treatment at 3 and 6 months following imatinib discontinuation [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFurther analysis revealed no significant associations between pretreatment median levels of \u003cem\u003eCITED2\u003c/em\u003e and \u003cem\u003eHIF2α\u003c/em\u003e gene expression and the demographic, clinical, or laboratory parameters within the study group. These findings are consistent with previous reports showing a lack of correlation between the expression of these genes and clinical or laboratory characteristics in both myeloid leukemia and various solid tumors [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Additionally, no significant differences were observed in post-treatment gene expression levels between responders and non-responders. This may suggest a limited prognostic value of these genes and highlights the need for further investigation in larger patient cohorts [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our study, adding pioglitazone to imatinib in newly diagnosed CML showed short-term benefit but lacked long-term durability.These responses may not persist due to the short duration of pioglitazone treatment or the small sample size. The potential efficacy may be enhanced with higher doses, extended duration or by implying pulsed (on/off) therapeutic cycles. Although \u003cem\u003eCITED2\u003c/em\u003e and \u003cem\u003eHIF2α\u003c/em\u003e expression decreased with treatment, these changes did not align with BCR-ABL1 transcript levels, suggesting limited utility as molecular markers. Their potential prognostic value, however, warrants further investigation in larger studies.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThis study has several limitations that should be acknowledged. First, the small sample size (n\u0026thinsp;=\u0026thinsp;26) limits the statistical power and generalizability of the findings. Additionally, the use of a historical control group rather than a randomized, contemporaneous control introduces potential selection and information biases, and the lack of randomization and blinding increases the risk of bias in outcome assessment.Moreover, although short-term responses appeared promising, the long-term outcomes did not align, indicating a lack of durability in response. The wide variability observed in \u003cem\u003eCITED2\u003c/em\u003eand \u003cem\u003eHIF2a\u003c/em\u003e gene expression levels may reflect inter-patient differences or inconsistencies in measurement techniques, and the clinical relevance of the gene expression changes remains unclear, as the study did not directly assess leukemic stem cell burden. Finally, the study's focus on newly diagnosed chronic phase patients limits the applicability of results to broader CML populations.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical and genetic data supporting the findings of this study are not publicly available due to institutional restrictions. However, the data do not contain identifiable human subject information, and there are no legal or ethical limitations preventing their use. Data may be made available to qualified researchers upon reasonable request and subject to approval by the corresponding institutional review board and data access committee. Requests for access to the data can be submitted through the \u003cem\u003eAnnals of Hematology\u003c/em\u003e journal in accordance with its data access policies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eFunding Declaration:\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMohamed Mabed: Conceptualized and designed the study, supervised patient recruitment, and contributed to data interpretation and manuscript writing.Basma Atef: Collected clinical data, coordinated sample collection and processing, and performed follow-up evaluations and response assessments.Shaimaa El-Ashwah: Performed follow-up evaluations and response assessments and contributed to data interpretation and manuscript writing.Layla M. Saleh Carried out molecular analyses, including gene expression assays for CITED2 and HIF2\u0026alpha;, performed statistical analysis, and contributed to drafting the results section.Hanan Gawish: Contributed to the literature review, data interpretation, reporting side effects of the drug, manuscript editing, and critically revised the work for important intellectual content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSampaio MM, Santos MLC, Marques HS (2021) Chronic myeloid leukemia\u0026mdash;from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol \u0026ndash;02(2):69\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5306/wjco.v12.i2.69\u003c/span\u003e\u003cspan address=\"10.5306/wjco.v12.i2.69\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharf G, Marin C, Bradley JA et al (2020) Treatment-free remission in chronic myeloid leukemia: the patient perspective and areas of unmet needs. Leukemia 34(8):2102\u0026ndash;2112\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhai X, Jiang X (2022) Properties of leukemic stem cells in regulating drug resistance in acute and chronic myeloid leukemias. Biomedicines 10(8):1841\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMojtahedi H, Yazdanpanah N, Rezaei N (2021) Chronic myeloid leukemia stem cells: targeting therapeutic implications. Stem Cell Res Ther 12(1):603\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eProst S, Relouzat F, Spentchian M et al (2015) Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists. Nature 525(7569):380\u0026ndash;383\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang J, Ma W, Huang J et al (2024) HIF-2α inhibition disrupts leukemia stem cell metabolism and impairs vascular microenvironment to enhance chronic myeloid leukemia treatment. Cancer Lett. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.canlet.2024.217435\u003c/span\u003e\u003cspan address=\"10.1016/j.canlet.2024.217435\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZang C, Liu H, Waechter M et al (2006) Dual PPARα/γ ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines. Cell Cycle 5(19):2237\u0026ndash;2243\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBertz J, Zang C, Liu H et al (2009) Compound 48, a novel dual PPARα/γ ligand, inhibits the growth of human CML cell lines and enhances the anticancer-effects of imatinib. Leuk Res 33(5):686\u0026ndash;692\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang L, Giannoudis A, Austin G, Clark RE (2012) Peroxisome proliferator activated receptor activation increases imatinib uptake and killing of chronic myeloid leukemia cells. ExpHematol 40(10):811\u0026ndash;819\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRousselot P, Prost S, Guilhot J et al (2017) Pioglitazone together with imatinib in chronic myeloid leukemia: a proof of concept study. Cancer 123(10):1791\u0026ndash;1799\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eA\u0026rsquo;Hern RP (2001) Sample size tables for exact single-stage phase II designs. Stat Med 20(6):859\u0026ndash;866\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBasch E, Becker C, Rogak LJ et al (2021) Composite grading algorithm for the National Cancer Institute\u0026rsquo;s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Clin Trials 18(1):104\u0026ndash;114\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShah NP, Bhatia R, Altman JK et al (2024) Chronic myeloid leukemia, version 2.2024, NCCN clinical practice guidelines in oncology. J NatlComprCancNetw 22(1):43\u0026ndash;69\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen Y, Zou J, Cheng F, Li W (2021) Treatment-free remission in chronic myeloid leukemia and new approaches by targeting leukemia stem cells. Front Oncol 11:769730\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTanaka Y, Fukushima T, Mikami K et al (2020) Efficacy of tyrosine kinase inhibitors on a mouse chronic myeloid leukemia model and chronic myeloid leukemia stem cells. ExpHematol 90:46\u0026ndash;51\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoyal S, Babu G, Lokanatha D et al (2020) A study to assess the efficacy and feasibility of adding pioglitazone to imatinib in patients of CML with suboptimal response in a resource-limited setting.\u003cem\u003eAnnOncol\u003c/em\u003e. 31(Suppl 10):S10\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePagnano KB, Lopes ABP, Miranda EC et al (2020) Efficacy and safety of pioglitazone in a phase 1/2 imatinib discontinuation trial (EDI-PIO) in chronic myeloid leukemia with deep molecular response. Am J Hematol 95(12):E321\u0026ndash;E323\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYanamandra U, Yadav N, Pramanik S et al (2023) Supplemental pioglitazone to patients of CML with suboptimal TKI response: a pragmatic pilot study. Indian J Hematol Blood Transfus 39(1):71\u0026ndash;76\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBraun TP, Eide CA (2020) DrukerBJ.Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell 37(4):530\u0026ndash;542\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCortes J, Lang F (2021) Third-line therapy for chronic myeloid leukemia: current status and future directions. J HematolOncol 14(1):44\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLipton JH, Chuah C, Guerci-Bresler A et al EPIC: A phase III trial of ponatinib (PON) versus imatinib (IM) in patients with newly diagnosed CP-CML. [Journal or Abstract Book Needed]\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOehler VG (2020) First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia? Hematol Am SocHematolEduc Program 2020(1):228\u0026ndash;236\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalhotra H, Radich J, Garcia-Gonzalez P (2019) Meeting the needs of CML patients in resource-poor countries. Hematol Am SocHematolEduc Program 2019(1):433\u0026ndash;442\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLambert J, Saliba J, Calderon C et al (2021) PPARγ agonists promote the resolution of myelofibrosis in preclinical models. J Clin Invest 131(11):e145953\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRadich JP, Dai H, Mao M et al (2006) Gene expression changes associated with progression and response in chronic myeloid leukemia. ProcNatlAcadSci U S A 103(8):2794\u0026ndash;2799\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDiaz-Blanco E, Bruns I, Neumann F et al (2007) Molecular signature of CD34\u0026thinsp;+\u0026thinsp;hematopoietic stem and progenitor cells of patients with CML in chronic phase. Leukemia 21(3):494\u0026ndash;504\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMattes K, Berger G, Geugien M, Vellenga E, Schepers H (2017) CITED2 affects leukemic cell survival by interfering with p53 activation. Cell Death Dis 8(10):e3132\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eForristal CE, Brown AL, Helwani FM et al (2015) Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML. Leukemia 29(10):2075\u0026ndash;2085\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNg KP, Manjeri A, Lee KL et al (2014) Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood 123(21):3316\u0026ndash;3326\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKorthuis PM, Berger G, Bakker B et al (2015) CITED2-mediated human hematopoietic stem cell maintenance is critical for acute myeloid leukemia. Leukemia 29(3):625\u0026ndash;635\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSontakke P, Koczula KM, Jaques J et al (2016) Hypoxia-like signatures induced by BCR-ABL potentially alter the glutamine uptake for maintaining oxidative phosphorylation. PLoS ONE 11(4):e0153226\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLawson H, van de Lagemaat LN, Barile M et al (2021) CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation. Stem Cell Rep 16(11):2784\u0026ndash;2797\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLop\u0026egrave;s A, Miranda E, P\u0026oacute;voa V et al (2019) Pioglitazone did not affect PPARG, STAT5, HIF2α and CITED2 gene expression in chronic myeloid leukemia patients with deep molecular response. Blood 134(Suppl 1):1637\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMinemura H, Takagi K, Sato A et al (2016) CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance. Cancer Sci 107(12):1898\u0026ndash;1908\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuo D, Liu H, Lin D, Lian K, Ren H (2019) The clinicopathologic and prognostic value of hypoxia-inducible factor-2α in cancer patients: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 28(5):857\u0026ndash;866\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoreno Roig E, Yaromina A, Houben R et al (2018) Prognostic role of hypoxia-inducible factor-2α tumor cell expression in cancer patients: a meta-analysis. Front Oncol 8:224\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 is available in the Supplementary Files section.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (2): The adverse effects among both groups\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHistorical Control\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eN=52\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eStudy group\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eN=26\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eAllergy N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0 \u0026nbsp; \u0026nbsp;(0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0 \u0026nbsp; \u0026nbsp;(0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eEdema N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e12 (9.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e22 (76.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCytopenia N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e23 (44.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e12 (46.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.872\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMuscle aches N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e10 (19.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0 \u0026nbsp; (0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.026\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eGIT symptoms N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e5 \u0026nbsp; (9.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e3 \u0026nbsp; (11.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.256\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHepatotoxicity N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e11 (21.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e7 \u0026nbsp; (26.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.569\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003eTable (3): The BCR/ABL expression level across time among both groups\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e% BCR-ABL expression level median(range)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHistorical group\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eThe Study group\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003eP1\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eBaseline\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e88 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (26-365)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e81 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(32-380)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.215\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e7 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(0.02-67)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3.65 \u0026nbsp; \u0026nbsp; (0.05-20)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.046\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003e2.0 \u0026nbsp; \u0026nbsp; \u0026nbsp; (0.01-122)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003e0.75 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(0.002-46)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003e0.049\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e12 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003e0.25 \u0026nbsp;(0-121)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.1 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(0.002-0.6)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003e0.056\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e18 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.06 \u0026nbsp;(0-2)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.02 \u0026nbsp; \u0026nbsp; \u0026nbsp;(0-0.8)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.317\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003e24 months\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.01 \u0026nbsp;(0-4.6)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.02 \u0026nbsp; \u0026nbsp; \u0026nbsp;(0-22)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.586\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.01 \u0026nbsp;(0-1)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.009 \u0026nbsp; \u0026nbsp;(0-0.06)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.410\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e4 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.009 (0-62)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.0095 \u0026nbsp;(0-0.07)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.640\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e5 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.01 \u0026nbsp;(0-37)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 177px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.0095 \u0026nbsp; \u0026nbsp; (0-0.06)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 52px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.163\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eTable (4): The response milestones and efficacy among both groups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHistorical N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e52 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eStudy N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e26(100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;Achieved milestones N (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHR at 3 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e41/52 \u0026nbsp; \u0026nbsp; \u0026nbsp;(78.8%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e26/26 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.013\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; CCYR at 6 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e23/50 \u0026nbsp; (46%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e17/26 (65.4%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.108\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; CCYR at 12 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e26/35 \u0026nbsp; \u0026nbsp; \u0026nbsp;(74.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e22/22 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.009\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 6 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e9/50 \u0026nbsp; \u0026nbsp; (18%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6/26 \u0026nbsp; (23%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.598\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 12 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e19/35 \u0026nbsp; (54.3 %)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e17/22 (77.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.080\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 18 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e19/31 \u0026nbsp; (61.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e20/22 (91%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.01\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 2 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e25/29 \u0026nbsp; \u0026nbsp; \u0026nbsp;(86.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e17/22 (77.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.407\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 3 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e21/27 \u0026nbsp; \u0026nbsp; \u0026nbsp;(77.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e17/17 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.036\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 4 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e19/22 \u0026nbsp; \u0026nbsp; \u0026nbsp;(86.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e16/16 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.124\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026ge; MMR at 5 years\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e18/19 \u0026nbsp; \u0026nbsp; \u0026nbsp;(94.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e14/14 (100%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.383\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e Depth of molecular response \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eN (%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eEMR 3 months\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e31/52 \u0026nbsp; \u0026nbsp; (59.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e24/26 \u0026nbsp; \u0026nbsp; (92.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.00\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eEMR \u0026nbsp;6 months\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e35/50 \u0026nbsp; \u0026nbsp; (70%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e22/26 (84.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.163\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCMR 1y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0/35 \u0026nbsp; \u0026nbsp; \u0026nbsp; (0)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0/22 \u0026nbsp; (0)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ex\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCMR 2y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3/29 \u0026nbsp; \u0026nbsp;(10.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3/22 \u0026nbsp; \u0026nbsp; \u0026nbsp;(13.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.718\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCMR \u0026nbsp;3y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e4/27 \u0026nbsp; \u0026nbsp; \u0026nbsp;(14.8%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0/17 \u0026nbsp; \u0026nbsp; \u0026nbsp;(0)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.147\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCMR \u0026nbsp;4y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e5/22 \u0026nbsp; \u0026nbsp; \u0026nbsp;(22.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e5/16 \u0026nbsp; \u0026nbsp; \u0026nbsp;(31.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.556\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCMR \u0026nbsp;5y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e5/19 \u0026nbsp; (26.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e4/16 \u0026nbsp; (25%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.929\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian Time to CMR\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e (months)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e36 \u0026nbsp; \u0026nbsp; \u0026nbsp; (18-48)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e48 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(18-60)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.670\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eDMR (M4, M4.5, M5) 1 y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6/35 \u0026nbsp; \u0026nbsp; \u0026nbsp;(17%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6/22 \u0026nbsp; \u0026nbsp; \u0026nbsp;(27.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.361\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eDMR (M4, M4.5, M5) 2 y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e16/29 (55%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e9/22 \u0026nbsp; \u0026nbsp; \u0026nbsp;(41%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.313\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eDMR (M4, M4.5, M5) 3 y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e15/27 (55.5%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e15/17 (88.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.023\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eDMR (M4, M4.5, M5) 4 y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e13/22 (59%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e11/16 (68.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.542\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eDMR (M4, M4.5, M5) 5 y\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e13/19 (68.4%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e13/16 (81.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.387\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian Time to DMR (\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMonths)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e21 \u0026nbsp;(6-48)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e18 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (6-36)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.152\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eFailing/progression to advanced stages\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"LTR\" style=\"text-align: left;\"\u003e\u003cstrong\u003eFailing patients (5ys)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e27/52 \u0026nbsp; \u0026nbsp; \u0026nbsp;(51.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e7/26(26.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.036\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian(range) Time to Failure (Months)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e12(6-72)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e6(6-24)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.243\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eProgressed patients (4ys)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e3/52(5.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e1/26(3.8%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.717\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 228px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian (range) Time to Progression (Months)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e48(48-60)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e18\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.157\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eTable (5): Comparison between CITED2, HIF2a gene expression level between healthy group and study group patients\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"108%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 22px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eGene expression\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHealthy\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eControl (N=12)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 36px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eStudy N=25\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003ep1\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003ep2\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003ep3\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ePre treatment\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ePost treatment\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCITED 2\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.96\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e276.3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e2.6\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.005\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.119\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003erange\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.082-2.2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e1-241221.7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.006-86475.3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eHIF2\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.38\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e2.7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 10px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.004\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.026\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.082\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003erange\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.03-4.68\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.041-1255647.4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e0.006-47.2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003cstrong\u003e\u003cem\u003eP1\u003c/em\u003e\u003c/strong\u003e: comparing the gene expression between the healthy control and the study group patients pretreatment,\u0026nbsp;\u003c/p\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003eP2\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e:\u003c/span\u003e\u003c/strong\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;comparing the gene expression pre and post treatment within the study group patients.\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003eP3\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003cspan dir=\"LTR\"\u003e: comparing the gene expression between the healthy control and the study group patients posttreatment\u003c/span\u003e\u003c/p\u003e\n\u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eTable (6): Comparison the CITED2, HIF2a post- treatment gene expression level among responders and non-responders\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e \u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 31px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eGene expression\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eStudy N=25\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cem\u003e\u003cspan dir=\"LTR\"\u003eP\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eResponders\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eN=21\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eNon responders\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eN=4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 12px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eCITED 2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003ePre-treatment expression\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eMedian\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e261.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e3145\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.630\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n 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dir=\"LTR\"\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.232\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eRange\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.01-47.18\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp dir=\"RTL\" style=\"text-align: left;\"\u003e\u003cspan dir=\"LTR\"\u003e0.02-1\u003c/span\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic myeloid leukemia, Leukemic stem cells, PPARγ agonists, pioglitazone, CITED2 gene, HIF2α gene","lastPublishedDoi":"10.21203/rs.3.rs-7140724/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7140724/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML), yet persistent leukemia stem cells (LSCs) remain a barrier to cure. PPARγ agonists like pioglitazone have been proposed to enhance eradication of LSCs when used alongside TKIs. This study investigated the impact of adding pioglitazone to imatinib therapy in 26 newly diagnosed chronic-phase CML patients. Patients received imatinib (400 mg) plus pioglitazone (15 mg) daily for six months, with follow-up extending to 60 months. Treatment responses and adverse events were recorded, and expression levels of \u003cem\u003eCITED2\u003c/em\u003e and \u003cem\u003eHIF2α\u003c/em\u003e genes were measured before and after therapy, compared to a control group of 52 matched patients treated with imatinib alone. The combination therapy showed improved early cytogenetic and molecular responses, though long-term outcomes were not significantly different. Significant reductions in median \u003cem\u003eCITED2\u003c/em\u003e (from 276.3 to 2.6; p\u0026thinsp;=\u0026thinsp;0.005) and \u003cem\u003eHIF2α\u003c/em\u003e (from 2.7 to 1; p\u0026thinsp;=\u0026thinsp;0.026) expression were observed post-treatment. These results suggest that pioglitazone may enhance early molecular response and suppress LSC-associated genes, but further research is needed to confirm its long-term benefit and clarify the role of PPARγ modulation in CML management.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Trial Number\u003c/b\u003e: NCT04883125.\u003c/p\u003e","manuscriptTitle":"Potential Utility of PPARγ Agonists in the Eradication of Chronic Myeloid Leukemia Stem Cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 08:22:11","doi":"10.21203/rs.3.rs-7140724/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-12T19:13:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-29T08:42:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197012584249608871903999630708613947782","date":"2025-08-17T21:35:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-16T18:01:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"281300921745198571506772535742266356782","date":"2025-08-01T12:23:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-01T07:56:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-21T11:26:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-21T11:23:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-07-16T13:48:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"71f88d15-78a8-4d82-97b1-01ad7e5391c7","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:08:15+00:00","versionOfRecord":{"articleIdentity":"rs-7140724","link":"https://doi.org/10.1007/s00277-026-06795-7","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2026-02-25 15:58:56","publishedOnDateReadable":"February 25th, 2026"},"versionCreatedAt":"2025-08-06 08:22:11","video":"","vorDoi":"10.1007/s00277-026-06795-7","vorDoiUrl":"https://doi.org/10.1007/s00277-026-06795-7","workflowStages":[]},"version":"v1","identity":"rs-7140724","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7140724","identity":"rs-7140724","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}