Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic syndrome: a HARMONY Alliance study

Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic syndrome: a HARMONY Alliance study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic syndrome: a HARMONY Alliance study Elena Crisà, María Díez-Campelo, Ulrich Germing, Cécile Bally, and 40 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4257149/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Aug, 2024 Read the published version in Leukemia → Version 1 posted 9 You are reading this latest preprint version Abstract Lenalidomide (LEN) can induce RBC transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic syndrome (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN in RBC-TI. We enrolled 118 patients with an IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients in RBC-TI allows prolonged maintenance of TI in a large subset of patients. Health sciences/Medical research/Clinical trial design/Clinical trials Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome Figures Figure 1 Figure 2 Background Del(5q) is one of the most common cytogenetic abnormalities in de novo MDS, occurring in approximately 10–20% of MDS patients ( 1 – 3 ). Treatment with lenalidomide (LEN) can lead to red blood cell-transfusion independence (RBC-TI) in 60 to70% of patients with RBC-transfusion dependent (RBC-TD) MDS with lower-risk and isolated del(5q), and to complete cytogenetic response (CCyR) in 30–40% of them ( 4 – 7 ). Current practice in patients who attain RBC-TI is to continue LEN treatment indefinitely until loss of response or disease progression. However, the optimal duration of LEN treatment has never been formally addressed. Although LEN treatment in MDS with del(5q) does not appear to increase the risk of AML transformation ( 8 – 10 ), other long-term effects of immunomodulation have not been clearly elucidated and a possible intermittent use or discontinuation of LEN may benefit some patients. Moreover, although treatment with LEN is usually well tolerated, serious side effects may occur. Indeed, the most common grade 3/4 adverse events (AEs) reported in del(5q) MDS are cytopenias, which may be a result of direct cytotoxic effects of LEN on the del(5q) clone, and are more frequent and severe during the first cycles of treatment ( 11 ). Among extra-hematological toxicities, cutaneous rash and diarrhea are the most common AEs. More rarely thromboembolic events, in particular deep vein thrombosis, and hypothyroidism have also been reported ( 7 , 12 , 13 ). Furthermore, albeit a report by the Moffitt Cancer Center involving a large cohort of MDS patients did not show an increased risk of secondary malignancies in those treated with LEN, some concerns about its long-term cancerogenic potential still exist ( 14 , 15 ). Besides, despite the reduction in the cost of LEN in recent years, there is still concern about the healthcare resources utilization associated with the monitoring of potential side effects and the appearance or increase in clonal size of TP53 mutations. Indeed, LEN treatment in patients with TP53 mutations, present in 12–25% of del(5q) patients, could trigger disease progression, due to the selective expansion of TP53 mutant clones that are less sensitive to LEN ( 16 – 19 ). Some retrospective case reports or series involving a small number of patients have shown that most RBC-TI patients who stopped LEN maintained the hematological response. This finding was more evident in patients who had received at least 6–12 months of LEN and who were RBC-TI and had achieved a CCyR ( 20 – 22 ). This study, the largest to date, aimed to assess the outcome of patients with del(5q) MDS who discontinue LEN while in RBC-TI response based on a large international data set. Methods Within the MDS working group of the European Innovative Medicines Initiative HARMONY project, we included cases from centers and registries of seven European countries (Italy, Germany, Spain, France, Finland, Switzerland, and Sweden) and from one US center (Moffitt Cancer Center) with the diagnosis of MDS with isolated del(5q) according to 2016 WHO classification (blasts < 5%, presence of del(5q) alone or with 1 additional abnormality except − 7 or del(7q)), who discontinued therapy after achieving and maintaining RBC-TI, according to IWG criteria 2006 ( 23 – 25 ). Other inclusion criteria were age > 18 years, RBC-TD before LEN start, bone marrow (BM) blast percentage at diagnosis and at study entry < 5%, IPSS-R very low, low or intermediate risk at LEN treatment start and RBC-TI at LEN discontinuation ( 26 ). The main exclusion criteria were concomitant treatments for MDS in addition to LEN (excluding the use of growth factors), lack of response to LEN, disease progression, or death before LEN discontinuation. Clinical data were collected retrospectively and prospectively from January 2019 to June 2023. In some cases, molecular analysis by next generation sequencing (NGS) panel and isolated Sanger for TP53 mutation, were performed at diagnosis, at LEN start, at LEN discontinuation and in case of disease progression. The study complied with the declaration of Helsinki and all the patients signed an informed consent form before being included in the study. The primary endpoint of the study was RBC-TI duration after LEN discontinuation. Secondary end points were event-free survival (EFS) (events included for this endpoint were loss of transfusion independence, re-challenge with LEN therapy, disease progression, acute myeloid leukemia (AML) evolution or death), overall survival (OS), progression-free survival (PFS), time to AML transformation, response rate to LEN re-challenge, and identification of clinical or biological predictors of response duration after LEN discontinuation. Statistical methods The median value and range were used for reporting continuous variables and the absolute and relative frequency were reported for categorical variables. RBC-TI duration, EFS, PFS and OS survival curves were calculated using the Kaplan-Meier method. The comparison among groups for EFS, RBC-TI duration, PFS and OS curves was performed by the log-rank test. Cox proportional hazards regression models were performed to estimate hazard ratios (HR) with 95% confidence intervals (95% CI). All characteristics with a p-value < 0.10 at univariable analyses were selected to be considered in the multivariable model. Only those characteristics with a p-value < 0.1 in the multivariable model were retained. Cumulative incidence of RBC-TI loss was calculated considering death and lenalidomide retreatment as competing events. All statistical tests were two-tailed, and the significance level was set to 0.05. Stata software (v.16; StataCorp) was used for all statistical analyses. Results Patient population One hundred-eighteen patients (80% females) fulfilled the study criteria and were included in the analysis. LEN treatment had been started between December 2003 and September 2022 and this treatment had been discontinued between July 2004 and January 2023. At LEN treatment start patients were receiving a median of 4 RBC units per month. Of note, 21 (18%) patients were receiving less than 4 RBC units in the 8 weeks before starting treatment and could not be strictly defined as RBC-TD by 2006 IWG criteria. According to IPSS-R categories, 26 patients (22%), 68 (58%) and 24 (20%) were very low, low, and intermediate risk respectively. As per protocol eligibility criteria, all patients had achieved RBC-TI during LEN therapy. Cytogenetic analysis on bone marrow aspirate was evaluated after treatment in 95 patients and 15 (16%) had achieved partial CyR while 48 (51%) CCyR. The median number of LEN cycles received before discontinuation was 12 (range 1–72, median treatment duration 12 months) and 85 patients (71%) had experienced hematological or non-hematological treatment-related AEs during treatment. Seventy-nine (67%) AEs were grade1-2 and 59 (50%) grade 3–4, respectively. In 42 patients (35%) LEN dose had to be reduced due to toxicity. Median age at LEN discontinuation was 77 years (range, 33–93 years). The reason for stopping treatment was intolerance in 70 patients (59%), physician decision due to optimal response in 38 (32%), patient’s decision in nine (8%) and unknown in one patient (1%). Among the 70 patients who discontinued treatment for intolerance, 48 had a non-hematological toxicity (31/48 of grade 3/4). Patient characteristics at lenalidomide start/stop are summarized in Table 1 . Table 1 Patients main characteristics at lenalidomide start, over treatment and at lenalidomide discontinuation. Patients characteristics At lenalidomide start N° % Patients 118 Gender Male 24 20% Female 94 80% Age (years) median (range) 77 (42–93) Therapy related no 112 95% yes 6 5% IPSS low 59 56% intermediate I 46 44% IPSS-r very low 26 22% low 68 58% Intermediate I 24 20% Bone marrow blasts % median (range) 2 (0–5) RBC-transfusion burden > 4 units in 8 weeks no 21 17% yes 97 82% Best response to lenalidomide RBC-TI 55 47% RBC-TI + CCy 48 40% RBC-TI + PCy 15 13% Hematological toxicity Grade 1–2 36 30.5% Grade 3–4 27 23% Extra-hematological toxicity Grade 1–2 43 36% Grade 3–4 32 27% Dose reduction 42 36% N of lenalidomide cycles median (range) 12 (17–72 At lenalidomide discontinuation Age (years) median (range) 77 (33–97) Absolute Neutrophils Count x10 9 /µl median (range) 1.51 (0.19–5.1) Hemoglobin g/l median (range) 12 (7.8–15,5) Platelets x10 9 /µl median (range) 150 (3-386) Bone marrow blasts % median (range) 1(0–5) RBC transfusion-dependence 0 0% Cytogenetic response CCyR (95 evaluable patients) 45 47% PCyR (92 evaluable patients) 57 62% Reason for lenalidomide discontinuation intolerance 70 59% optimal response according to physician 38 32% patient decision 9 8% unknown 1 1% Abbreviations: RBC red blood cells; IPSS International Prognostic Scoring System ; IPSS-R International Prognostic Scoring System revised: CCyR Complete Cytogenetic Response; PCyR Partial Cytogenetic Response Follow-up after lenalidomide discontinuation Median observation time from diagnosis was 82 months (range 5-302) and median follow-up after LEN discontinuation was 49 months. Overall, 50 (42%) patients lost RBC-TI. Median duration of RBC-TI was 56.2 months (range 1-120, Fig. 1 A). When considering death or LEN restart as competing events for loss of RBC-TI, cumulative incidence of RBC-TI loss was 45% at 60 months. (Fig. 1 supplementary material) RBC-TI duration was longer for patients who had received > 12 LEN cycles (median, 85.8 vs 31 months; p = 0.001; Fig. 1 B) and for those who had received < 2 RBC units per month before LEN start (median 56.2 vs 44.1 p = 0.024, Fig. 1 C). LEN dose reduction did not impact on RBC-TI after LEN discontinuation. At multivariable analysis other prognostic factors for RBC-TI length were age ( p = 0.024) and hemoglobin level ( p = 0.092) at the time of LEN discontinuation (Table 2 ). Table 2 Prognostic factors for Red Blood Cell Transfusion Independence loss on multivariate analysis. Variables HR 95,0% CI Lower Upper p value Age * 1.04 1.00 1.07 0.024 RBC unit/8 weeks > 4 at lenalidomide start 3.34 1.18 9.47 0.024 Lenalidomide cycles ≥ 12 0.34 0.18 0.65 0.001 Hemoglobin level at lenalidomide stop* 0.86 0.71 1.03 0.092 *(continuous variable) Abbreviations: RBC red blood cells During study follow-up 23 patients (19%) progressed to higher-risk MDS (high or very high IPSS-R) or AML and 47 (39%) died. Median EFS was 40.8 months (range 1-130, Fig. 2A) and at multivariate analysis it was affected by age ( p = 0.019), transfusion burden (packed RBC units per month, p = 0.013), hemoglobin level ( p = 0.028), IPSS-R risk category at LEN start ( p = 0.004), as well as treatment duration (> or ≤ 12 cycles; p = 0.031), (Results shown in Table 3 ). Table 3 Prognostic factors for event-free survival on multivariate analysis Variables HR 95,0% CI Lower Upper p value Age at diagnosis* 1.04 1.01 1.07 0.005 RBC unit/8 weeks > 4 at lenalidomide start 1.28 1.05 1.56 0.013 IPSS-R very low vs low/intermediate 0.33 0.16 0.70 0.004 Lenalidomide cycles ≥ 12 0.55 0.32 0.95 0.031 Hemoglobin level at lenalidomide stop* 0.82 0.69 0.98 0.028 *(continuous variable) Abbreviations: RBC red blood cells;IPSS International Prognostic Scoring System; IPSS-R IPSS revised In particular, median EFS of patients who were treated with LEN for > 12 cycles was 58.0 months as compared with 18.8 months for patients who received ≤ 12 cycles (Fig. 2B) Patients who were in CCyR at LEN discontinuation had a longer EFS and RBC-TI at univariable analysis (median ,53.3 vs 31.0; p = 0.031 and 85.8 vs 50.4; p = 0.011, respectively), however these data were not confirmed in multivariable analysis. Moreover, patients who discontinued LEN for physician choice or for their own decision had a better outcome in terms of EFS and RBC-TI duration compared with patients who stopped treatment for toxicity (median EFS, 54.3 and 26.4 months, respectively, p = 0.006 and median RBC-TI, 85.8, and 59 months, respectively, p = 0.004, Fig. 2 Supplementary material). Of note, MDS del(5q) patients who discontinued LEN for toxicity in 39% had experienced of cases an adverse event grade 3/4, had received less LEN cycles (median 8 vs 16, p < 0.001), and did not achieve CCyR in most cases (30% vs 75% for the other patients, p < 0.001). After LEN discontinuation cytogenetic re-evaluation was performed in 30 patients, among these, 22 lost CCyR (73%). Twenty-three of 118 patients (19%) progressed to higher risk MDS (n = 15) or AML (n = 8) after a median time of 102 months (range 28–151) from diagnosis and of 29 months (range 1-125) from LEN discontinuation. Median PFS after LEN discontinuation was not reached and 5 years PFS rate was 83%. Twenty/23 patients progressed after having lost RBC-TI, of whom 4 progressed notwithstanding their response to LEN re-treatment; 3/23 patients underwent disease progression without losing TI, after 20, 28, and 40 months from LEN discontinuation. Median OS after LEN discontinuation was 78.4 months (range 2-186) and was affected by age, transfusion burden at LEN start, and number of LEN cycles. Moreover, patients who lost RBC-TI had a shorter survival (median 71.3 vs 102.1 months, p = 0.003) as 70% of them subsequently progressed as compared with 30% of patients maintaining RBC-TI ( p = 0.003). Finally, 48 patients were re-treated with LEN because of loss of response. Forty-two patients were evaluable for response and 28 of them (67%) achieved RBC-TI again. Cytogenetic analysis in these cases was rarely available. However, 3 and 2 patients attained CCyR and partial CyR, respectively. The efficacy of LEN re-challenge correlated with the length of RBC-TI after LEN suspension (median RBC-TI after LEN stop 52 months in patients responding to LEN rechallenge vs 12 months in non-responsive patients, p = 0.008). Molecular data Molecular data for a large number of somatic mutations by NGS were available for 30 patients whereas TP53 mutations by NGS or Sanger were available in 82 cases. Before LEN discontinuation, somatic mutations other than TP53 were detected by NGS in 20/30 (67%) patients (5/30 SF3B1 , 4/30 TET2 , 3/30 DNMT3A , ASXL1 and JAK2 , 1/30 BCOR , IKZF and SETBP1 ). TP53 mutations were present in 13 of 82 screened patients. A patient who presented a TP53 mutation with a variable allele frequency (VAF) of 7% at LEN discontinuation, experienced loss of RBC-TI after 4 months. This was accompanied by an increase to 26% in the TP53 mutation VAF and an acquisition of a new cytogenetic abnormality (del(20q)). This patient progressed to MDS with excess blasts after 22 months from LEN withdrawal. The presence of TP53 mutations did not impact on OS or AML transformation. Discussion In this study we present the largest series in our knowledge of MDS del(5q) cases who had discontinued LEN treatment while transfusion independent, with a long follow up (49 months). In large randomized prospective studies RBC-TI duration upon continued LEN therapy was around 2 years ( 4 – 7 ). In our cohort median duration of RBC-TI from LEN discontinuation was 56 months. In particular, 70% of the patients treated for > 12 LEN cycles were still RBC-TI at 5 years. Since its serendipitous demonstration of an exceptional efficacy in MDS with del(5q) almost 20 years ago, LEN has been largely and successfully employed in the clinics with erythroid and cytogenetic response, leading to prolongation of OS ( 27 ). With its activity in promoting erythropoiesis in MDS del(5q), LEN has demonstrated an acceptable profile of tolerability, but it is not completely devoid of toxicity. Although myelotoxicity induced in the first cycles of therapy is known to herald good response, still in rare cases is not self-resolving and may appear after several months of therapy, requiring use of growth factors or LEN dose reduction, facilitating infections or bleeding. Beside hematological toxicity, that may be acceptable in the majority of cases in the balance with benefits (transfusion independence), some patients experience extra-hematological toxicity as hypothyroidism or more frequently skin rash, renal insufficiency of various grade, as well as gastrointestinal symptoms like diarrhea, not always responding to symptomatic medications ( 5 – 7 ). LEN treatment is recommended to be continued until loss of response, therefore, the above-mentioned side effects can be an obstacle and impair quality of life of patients. LEN acts in MDS with del5q with a specific mechanism of action by inducing the proteasomal degradation of casein kinase 1, and it preferentially affects del(5q) cells because they express this gene at haplo-insufficient levels ( 28 ). This specific modulation of ubiquitin ligase function leads to elimination/reduction of the neoplastic clone ( 29 ). In this sense, one may envisage an interruption of treatment once the burden of disease is significantly diminished, in analogy to what has been demonstrated for imatinib therapy in chronic myeloid leukemia ( 30 ). In our study patients who were treated with LEN for at least 12 months showed the longest duration of RBC-TI after interruption, consistent with the hypothesis that reduction of the clone allowed achievement of stable response, as supported by the evidence that CCyR prolonged EFS at univariable analysis. Longitudinal cytogenetic analysis were available only in a minority of cases, reflecting clinical practice of avoiding repeated bone marrow evaluations in responding patients. However, 73% of the patients for whom CCyR was documented, lost it. On the other hand, 67% of the patients who were retreated with LEN at TI loss achieved it again. This data may suggest a potential strategy of intermittent administration of LEN, with possibly long period of time of interruption. Sequential cytogenetic data during follow up could help to better understand whether residual del(5q) clone size after LEN discontinuation is determinant for the duration of RBC-TI. In the past, it has been postulated that LEN treatment could select resistant clones and drive disease progression, particularly in case of TP53 mutation ( 16 – 19 ). More recently it has been shown that LEN treatment provides a selective advantage to TP53 -mutant hematopoietic stem and progenitor cells in vitro and in vivo ( 31 ). On the other hand, it has been shown that the presence of biallelic TP53 mutations has a negative impact on OS and response to LEN, therefore the evaluation of this molecular alteration needs to be interpreted carefully. In our cohort only 19% of patients progressed to higher risk MDS or AML, and mainly after a long disease history. This progression rate is comparable to what reported in patients responding to LEN and was not related to TP53 mutation ( 4 ). Establishing the optimal duration of lenalidomide treatment as well as its early inception to avoid clone expansion (Sintra-REV trial ( 32 ), could anyhow be relevant to define the risk of disease progression. Indeed, in our study patients who started LEN with a low transfusion burden, that could suggest lower burden of disease, had better outcome after LEN discontinuation. In conclusion, this is the largest series to date exploring the outcome of MDS del(5q) patients who discontinued LEN while in RBC-TI response. The main limitations of our study are the heterogeneity of the population (time from diagnosis and length of lenalidomide treatment differ profoundly among cases), the absence of sequential cytogenetic/molecular evaluations and the possible bias due to the lack of a matched cohort of patients continuing LEN until progression or loss of response. Our data suggest that stopping LEN in RBC-TI patients, particularly after more than one year of treatment, constitutes a possible option and may spare toxicities, likely improving patients’ quality of life, as well as reduce the economic impact on National Healthcare Systems. Some open issues remain, as whether CCyR achievement is a mandatory criterion to allow response maintenance after LEN discontinuation, although in our cohort patients who attained CCyR before treatment suspension seemed to have a more favorable outcome. This retrospective study may provide the needed background for building a prospective study assessing the optimal duration of LEN treatment, also exploring clone size variations and presence/acquisition of somatic mutations during LEN treatment and after its discontinuation. The possibility to discontinue LEN treatment in a substantial percentage of MDS del5q patients could be an innovative and cost-effective way to optimize available therapies. Declarations Acknowledgements This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under HARMONY Grant Agreement nº 116026. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA. VS was partially supported by AIRC IG-26537-2021 Investigator Research Grant M.D.C was partially supported by PI20/00970 Authors’ Contributions EC designed the study, collected and analyzed data, performed statistical analysis and wrote the paper; VS designed the study and wrote the paper; AS performed statistical analysis and wrote statistical methods of the paper; all the authors treated the patients, collected data, reviewed and approved the manuscript. Competing Interests U.P. declares research support and Honoraria from Geron, BMS and Janssen. M.D.C. declares Honoraria from BMS None of the other Authors has competing interest related to this study. 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The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30(8):1638-47. Sperling AS, Guerra VA, Kennedy JA, Yan Y, Hsu JI, Wang F, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood. 2022;140(16):1753-63. López Cadenas F, Lumbreras E, González T, Xicoy B, Sánchez-García J, Coll R, et al. Evaluation of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent Low Risk Del(5q) MDS Patients. Final Results of Sintra-REV Phase III International Multicenter Clinical Trial. Blood. 2022;140(Supplement 1):1109-11. Additional Declarations Yes there is potential conflict of interest. Supplementary Files Supplementarymaterial.pdf Supplementary material Cite Share Download PDF Status: Published Journal Publication published 05 Aug, 2024 Read the published version in Leukemia → Version 1 posted Editorial decision: revise 29 Apr, 2024 Review # 1 received at journal 28 Apr, 2024 Review # 2 received at journal 24 Apr, 2024 Reviewer # 2 agreed at journal 24 Apr, 2024 Reviewer # 1 agreed at journal 20 Apr, 2024 Reviewers invited by journal 12 Apr, 2024 Editor assigned by journal 12 Apr, 2024 Submission checks completed at journal 12 Apr, 2024 First submitted to journal 12 Apr, 2024 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-4257149","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":290591921,"identity":"63f35872-8d29-4ab8-834f-5b081df4bd3f","order_by":0,"name":"Elena Cris\u0026#x00E0","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDACdijNxsDA+CABxGImpAWmAKiF2QCihZAeJHk2CQwhbICfmfnYgx8Mdvl8/IefVTzcYyfPwM5/AK8WyWa2dMMehmTLNok0sxsJz5INGwg5zOAwj5kED8MBA6CrgFoOHEgg6Bf7w/zfJP+AtPAf/1ZAlBYDZh42abAtDDlmDERpkTjMZiYtY5AMdFhOsUTCgWTDNmZmA7xa+Nubn0m+qbAzkO8/vvHjjwN28vz8Bx/gtwbiPCQ2GxHqR8EoGAWjYBQQAAC5NzSU00hvYQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-1912-0574","institution":"Candiolo Cancer Institute, FPO-IRCCS","correspondingAuthor":true,"prefix":"","firstName":"Elena","middleName":"","lastName":"Cris\u0026#x00E0","suffix":""},{"id":290591922,"identity":"127acf8e-c38e-4a9a-bf8b-840802b06d95","order_by":1,"name":"María Díez-Campelo","email":"","orcid":"","institution":"Hospital Universitario y Centro de Investigación del Cáncer","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"","lastName":"Díez-Campelo","suffix":""},{"id":290591923,"identity":"f0c6b5a5-5710-4c17-8e1d-1f1ef7587932","order_by":2,"name":"Ulrich Germing","email":"","orcid":"","institution":"Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University","correspondingAuthor":false,"prefix":"","firstName":"Ulrich","middleName":"","lastName":"Germing","suffix":""},{"id":290591924,"identity":"a8ea1ac4-610d-4b41-8c51-4ec26112c6f9","order_by":3,"name":"Cécile Bally","email":"","orcid":"","institution":"Saint-Louis Hospital, AP-HP, Paris","correspondingAuthor":false,"prefix":"","firstName":"Cécile","middleName":"","lastName":"Bally","suffix":""},{"id":290591925,"identity":"3f5ae831-75ca-4418-a03f-3dfa42d052b6","order_by":4,"name":"Mikko Myllymäki","email":"","orcid":"","institution":"Hematology research unit Helsinki, University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Mikko","middleName":"","lastName":"Myllymäki","suffix":""},{"id":290591926,"identity":"5da1baae-bbe2-475e-8755-a7bb24660976","order_by":5,"name":"Martin Jädersten","email":"","orcid":"","institution":"Karolinska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Jädersten","suffix":""},{"id":290591927,"identity":"b2b164d5-e192-4118-9409-ffd353f005eb","order_by":6,"name":"Rami Komrokji","email":"","orcid":"https://orcid.org/0000-0002-1876-5269","institution":"H. 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A Overall. B. By N° of lenalidomide cycles. C. By transfusion burden before lenalidomide start\u003c/p\u003e","description":"","filename":"Figure1AB.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4257149/v1/034a10bedcacda6f57dc8f88.jpg"},{"id":55008200,"identity":"18961b1e-74e5-4ff3-9617-1d46a2c48f15","added_by":"auto","created_at":"2024-04-19 19:04:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":281392,"visible":true,"origin":"","legend":"\u003cp\u003eEvent free survival (EFS) after lenalidomide discontinuation. A Overall. B. By N° of lenalidomide cycles\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4257149/v1/3aaf607e0bb32dac2cb6bd4a.jpg"},{"id":61843148,"identity":"1f71c989-95e1-46be-91e4-5530e93d48e6","added_by":"auto","created_at":"2024-08-06 07:10:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1649478,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4257149/v1/75dc1e27-56b4-4fe0-98a5-8ceea37fbee1.pdf"},{"id":55008203,"identity":"2704aa0f-9a3f-40bd-ab17-220e3184595f","added_by":"auto","created_at":"2024-04-19 19:04:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":251990,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary material\u003c/p\u003e","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4257149/v1/043a4b2e3feb9d140c4305a0.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic syndrome: a HARMONY Alliance study","fulltext":[{"header":"Background","content":"\u003cp\u003eDel(5q) is one of the most common cytogenetic abnormalities in \u003cem\u003ede novo\u003c/em\u003e MDS, occurring in approximately 10\u0026ndash;20% of MDS patients (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Treatment with lenalidomide (LEN) can lead to red blood cell-transfusion independence (RBC-TI) in 60 to70% of patients with RBC-transfusion dependent (RBC-TD) MDS with lower-risk and isolated del(5q), and to complete cytogenetic response (CCyR) in 30\u0026ndash;40% of them (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Current practice in patients who attain RBC-TI is to continue LEN treatment indefinitely until loss of response or disease progression. However, the optimal duration of LEN treatment has never been formally addressed. Although LEN treatment in MDS with del(5q) does not appear to increase the risk of AML transformation (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), other long-term effects of immunomodulation have not been clearly elucidated and a possible intermittent use or discontinuation of LEN may benefit some patients. Moreover, although treatment with LEN is usually well tolerated, serious side effects may occur. Indeed, the most common grade 3/4 adverse events (AEs) reported in del(5q) MDS are cytopenias, which may be a result of direct cytotoxic effects of LEN on the del(5q) clone, and are more frequent and severe during the first cycles of treatment (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Among extra-hematological toxicities, cutaneous rash and diarrhea are the most common AEs. More rarely thromboembolic events, in particular deep vein thrombosis, and hypothyroidism have also been reported (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Furthermore, albeit a report by the Moffitt Cancer Center involving a large cohort of MDS patients did not show an increased risk of secondary malignancies in those treated with LEN, some concerns about its long-term cancerogenic potential still exist (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Besides, despite the reduction in the cost of LEN in recent years, there is still concern about the healthcare resources utilization associated with the monitoring of potential side effects and the appearance or increase in clonal size of \u003cem\u003eTP53\u003c/em\u003e mutations. Indeed, LEN treatment in patients with \u003cem\u003eTP53\u003c/em\u003e mutations, present in 12\u0026ndash;25% of del(5q) patients, could trigger disease progression, due to the selective expansion of \u003cem\u003eTP53\u003c/em\u003e mutant clones that are less sensitive to LEN (\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome retrospective case reports or series involving a small number of patients have shown that most RBC-TI patients who stopped LEN maintained the hematological response. This finding was more evident in patients who had received at least 6\u0026ndash;12 months of LEN and who were RBC-TI and had achieved a CCyR (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study, the largest to date, aimed to assess the outcome of patients with del(5q) MDS who discontinue LEN while in RBC-TI response based on a large international data set.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWithin the MDS working group of the European Innovative Medicines Initiative HARMONY project, we included cases from centers and registries of seven European countries (Italy, Germany, Spain, France, Finland, Switzerland, and Sweden) and from one US center (Moffitt Cancer Center) with the diagnosis of MDS with isolated del(5q) according to 2016 WHO classification (blasts\u0026thinsp;\u0026lt;\u0026thinsp;5%, presence of del(5q) alone or with 1 additional abnormality except \u0026minus;\u0026thinsp;7 or del(7q)), who discontinued therapy after achieving and maintaining RBC-TI, according to IWG criteria 2006 (\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOther inclusion criteria were age\u0026thinsp;\u0026gt;\u0026thinsp;18 years, RBC-TD before LEN start, bone marrow (BM) blast percentage at diagnosis and at study entry\u0026thinsp;\u0026lt;\u0026thinsp;5%, IPSS-R very low, low or intermediate risk at LEN treatment start and RBC-TI at LEN discontinuation (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe main exclusion criteria were concomitant treatments for MDS in addition to LEN (excluding the use of growth factors), lack of response to LEN, disease progression, or death before LEN discontinuation.\u003c/p\u003e \u003cp\u003eClinical data were collected retrospectively and prospectively from January 2019 to June 2023. In some cases, molecular analysis by next generation sequencing (NGS) panel and isolated Sanger for \u003cem\u003eTP53\u003c/em\u003e mutation, were performed at diagnosis, at LEN start, at LEN discontinuation and in case of disease progression.\u003c/p\u003e \u003cp\u003e The study complied with the declaration of Helsinki and all the patients signed an informed consent form before being included in the study.\u003c/p\u003e \u003cp\u003eThe primary endpoint of the study was RBC-TI duration after LEN discontinuation. Secondary end points were event-free survival (EFS) (events included for this endpoint were loss of transfusion independence, re-challenge with LEN therapy, disease progression, acute myeloid leukemia (AML) evolution or death), overall survival (OS), progression-free survival (PFS), time to AML transformation, response rate to LEN re-challenge, and identification of clinical or biological predictors of response duration after LEN discontinuation.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eThe median value and range were used for reporting continuous variables and the absolute and relative frequency were reported for categorical variables.\u003c/p\u003e \u003cp\u003eRBC-TI duration, EFS, PFS and OS survival curves were calculated using the Kaplan-Meier method.\u003c/p\u003e \u003cp\u003eThe comparison among groups for EFS, RBC-TI duration, PFS and OS curves was performed by the log-rank test. Cox proportional hazards regression models were performed to estimate hazard ratios (HR) with 95% confidence intervals (95% CI). All characteristics with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 at univariable analyses were selected to be considered in the multivariable model. Only those characteristics with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the multivariable model were retained.\u003c/p\u003e \u003cp\u003eCumulative incidence of RBC-TI loss was calculated considering death and lenalidomide retreatment as competing events.\u003c/p\u003e \u003cp\u003eAll statistical tests were two-tailed, and the significance level was set to 0.05. Stata software (v.16; StataCorp) was used for all statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eOne hundred-eighteen patients (80% females) fulfilled the study criteria and were included in the analysis. LEN treatment had been started between December 2003 and September 2022 and this treatment had been discontinued between July 2004 and January 2023.\u003c/p\u003e \u003cp\u003eAt LEN treatment start patients were receiving a median of 4 RBC units per month. Of note, 21 (18%) patients were receiving less than 4 RBC units in the 8 weeks before starting treatment and could not be strictly defined as RBC-TD by 2006 IWG criteria. According to IPSS-R categories, 26 patients (22%), 68 (58%) and 24 (20%) were very low, low, and intermediate risk respectively.\u003c/p\u003e \u003cp\u003eAs per protocol eligibility criteria, all patients had achieved RBC-TI during LEN therapy. Cytogenetic analysis on bone marrow aspirate was evaluated after treatment in 95 patients and 15 (16%) had achieved partial CyR while 48 (51%) CCyR.\u003c/p\u003e \u003cp\u003eThe median number of LEN cycles received before discontinuation was 12 (range 1\u0026ndash;72, median treatment duration 12 months) and 85 patients (71%) had experienced hematological or non-hematological treatment-related AEs during treatment. Seventy-nine (67%) AEs were grade1-2 and 59 (50%) grade 3\u0026ndash;4, respectively. In 42 patients (35%) LEN dose had to be reduced due to toxicity.\u003c/p\u003e \u003cp\u003eMedian age at LEN discontinuation was 77 years (range, 33\u0026ndash;93 years). The reason for stopping treatment was intolerance in 70 patients (59%), physician decision due to optimal response in 38 (32%), patient\u0026rsquo;s decision in nine (8%) and unknown in one patient (1%).\u003c/p\u003e \u003cp\u003eAmong the 70 patients who discontinued treatment for intolerance, 48 had a non-hematological toxicity (31/48 of grade 3/4).\u003c/p\u003e \u003cp\u003ePatient characteristics at lenalidomide start/stop are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients main characteristics at lenalidomide start, over treatment and at lenalidomide discontinuation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003ePatients characteristics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eAt lenalidomide start\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026deg;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatients\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e77 (42\u0026ndash;93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eTherapy related\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eIPSS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eintermediate I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eIPSS-r\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003every low\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntermediate I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone marrow blasts %\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRBC-transfusion burden\u0026thinsp;\u0026gt;\u0026thinsp;4 units in 8 weeks\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBest response to lenalidomide\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRBC-TI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRBC-TI\u0026thinsp;+\u0026thinsp;CCy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRBC-TI\u0026thinsp;+\u0026thinsp;PCy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHematological toxicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtra-hematological toxicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDose reduction\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN of lenalidomide cycles\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e12 (17\u0026ndash;72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAt lenalidomide discontinuation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e77 (33\u0026ndash;97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsolute Neutrophils Count x10\u003c/b\u003e\u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e/\u0026micro;l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1.51 (0.19\u0026ndash;5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemoglobin g/l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e12 (7.8\u0026ndash;15,5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlatelets x10\u003c/b\u003e\u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e/\u0026micro;l\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e150 (3-386)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone marrow blasts %\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e1(0\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRBC transfusion-dependence\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCytogenetic response\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCCyR (95 evaluable patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePCyR (92 evaluable patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReason for lenalidomide discontinuation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eintolerance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eoptimal response according to physician\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epatient decision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: RBC red blood cells; IPSS International Prognostic Scoring System ; IPSS-R International Prognostic Scoring System revised: CCyR Complete Cytogenetic Response; PCyR Partial Cytogenetic Response\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eFollow-up after lenalidomide discontinuation\u003c/h2\u003e \u003cp\u003eMedian observation time from diagnosis was 82 months (range 5-302) and median follow-up after LEN discontinuation was 49 months. Overall, 50 (42%) patients lost RBC-TI. Median duration of RBC-TI was 56.2 months (range 1-120, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). When considering death or LEN restart as competing events for loss of RBC-TI, cumulative incidence of RBC-TI loss was 45% at 60 months. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e supplementary material)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRBC-TI duration was longer for patients who had received\u0026thinsp;\u0026gt;\u0026thinsp;12 LEN cycles (median, 85.8 vs 31 months; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB) and for those who had received\u0026thinsp;\u0026lt;\u0026thinsp;2 RBC units per month before LEN start (median 56.2 vs 44.1 \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). LEN dose reduction did not impact on RBC-TI after LEN discontinuation.\u003c/p\u003e \u003cp\u003eAt multivariable analysis other prognostic factors for RBC-TI length were age (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024) and hemoglobin level (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.092) at the time of LEN discontinuation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for Red Blood Cell Transfusion Independence loss on multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e95,0% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUpper\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge *\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRBC unit/8 weeks\u0026thinsp;\u0026gt;\u0026thinsp;4 at lenalidomide start\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLenalidomide cycles\u0026thinsp;\u0026ge;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin level at lenalidomide stop*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*(continuous variable)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations:\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eRBC red blood cells\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring study follow-up 23 patients (19%) progressed to higher-risk MDS (high or very high IPSS-R) or AML and 47 (39%) died.\u003c/p\u003e \u003cp\u003eMedian EFS was 40.8 months (range 1-130, Fig.\u0026nbsp;2A) and at multivariate analysis it was affected by age (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.019), transfusion burden (packed RBC units per month, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.013), hemoglobin level (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028), IPSS-R risk category at LEN start (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.004), as well as treatment duration (\u0026gt;\u0026thinsp;or \u0026le;\u0026thinsp;12 cycles; \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.031), (Results shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrognostic factors for event-free survival on multivariate analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e95,0% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUpper\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRBC unit/8 weeks\u0026thinsp;\u0026gt;\u0026thinsp;4 at lenalidomide start\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPSS-R very low vs low/intermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLenalidomide cycles\u0026thinsp;\u0026ge;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin level at lenalidomide stop*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*(continuous variable)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: RBC red blood cells;IPSS International Prognostic Scoring System; IPSS-R IPSS revised\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn particular, median EFS of patients who were treated with LEN for \u0026gt;\u0026thinsp;12 cycles was 58.0 months as compared with 18.8 months for patients who received\u0026thinsp;\u0026le;\u0026thinsp;12 cycles (Fig.\u0026nbsp;2B)\u003c/p\u003e \u003cp\u003ePatients who were in CCyR at LEN discontinuation had a longer EFS and RBC-TI at univariable analysis (median ,53.3 vs 31.0; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031 and 85.8 vs 50.4; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011, respectively), however these data were not confirmed in multivariable analysis.\u003c/p\u003e \u003cp\u003eMoreover, patients who discontinued LEN for physician choice or for their own decision had a better outcome in terms of EFS and RBC-TI duration compared with patients who stopped treatment for toxicity (median EFS, 54.3 and 26.4 months, respectively, p\u0026thinsp;=\u0026thinsp;0.006 and median RBC-TI, 85.8, and 59 months, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, Fig.\u0026nbsp;2 Supplementary material). Of note, MDS del(5q) patients who discontinued LEN for toxicity in 39% had experienced of cases an adverse event grade 3/4, had received less LEN cycles (median 8 vs 16, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and did not achieve CCyR in most cases (30% vs 75% for the other patients, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eAfter LEN discontinuation cytogenetic re-evaluation was performed in 30 patients, among these, 22 lost CCyR (73%). Twenty-three of 118 patients (19%) progressed to higher risk MDS (n\u0026thinsp;=\u0026thinsp;15) or AML (n\u0026thinsp;=\u0026thinsp;8) after a median time of 102 months (range 28\u0026ndash;151) from diagnosis and of 29 months (range 1-125) from LEN discontinuation. Median PFS after LEN discontinuation was not reached and 5 years PFS rate was 83%. Twenty/23 patients progressed after having lost RBC-TI, of whom 4 progressed notwithstanding their response to LEN re-treatment; 3/23 patients underwent disease progression without losing TI, after 20, 28, and 40 months from LEN discontinuation.\u003c/p\u003e \u003cp\u003eMedian OS after LEN discontinuation was 78.4 months (range 2-186) and was affected by age, transfusion burden at LEN start, and number of LEN cycles. Moreover, patients who lost RBC-TI had a shorter survival (median 71.3 vs 102.1 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003) as 70% of them subsequently progressed as compared with 30% of patients maintaining RBC-TI (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.003).\u003c/p\u003e \u003cp\u003eFinally, 48 patients were re-treated with LEN because of loss of response. Forty-two patients were evaluable for response and 28 of them (67%) achieved RBC-TI again. Cytogenetic analysis in these cases was rarely available. However, 3 and 2 patients attained CCyR and partial CyR, respectively. The efficacy of LEN re-challenge correlated with the length of RBC-TI after LEN suspension (median RBC-TI after LEN stop 52 months in patients responding to LEN rechallenge vs 12 months in non-responsive patients, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMolecular data\u003c/h2\u003e \u003cp\u003eMolecular data for a large number of somatic mutations by NGS were available for 30 patients whereas \u003cem\u003eTP53\u003c/em\u003e mutations by NGS or Sanger were available in 82 cases. Before LEN discontinuation, somatic mutations other than \u003cem\u003eTP53\u003c/em\u003e were detected by NGS in 20/30 (67%) patients (5/30 \u003cem\u003eSF3B1\u003c/em\u003e, 4/30 \u003cem\u003eTET2\u003c/em\u003e, 3/30 \u003cem\u003eDNMT3A\u003c/em\u003e, \u003cem\u003eASXL1\u003c/em\u003e and \u003cem\u003eJAK2\u003c/em\u003e, 1/30 \u003cem\u003eBCOR\u003c/em\u003e, \u003cem\u003eIKZF\u003c/em\u003e and \u003cem\u003eSETBP1\u003c/em\u003e). \u003cem\u003eTP53\u003c/em\u003e mutations were present in 13 of 82 screened patients. A patient who presented a \u003cem\u003eTP53\u003c/em\u003e mutation with a variable allele frequency (VAF) of 7% at LEN discontinuation, experienced loss of RBC-TI after 4 months. This was accompanied by an increase to 26% in the \u003cem\u003eTP53\u003c/em\u003e mutation VAF and an acquisition of a new cytogenetic abnormality (del(20q)). This patient progressed to MDS with excess blasts after 22 months from LEN withdrawal.\u003c/p\u003e \u003cp\u003eThe presence of \u003cem\u003eTP53\u003c/em\u003e mutations did not impact on OS or AML transformation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study we present the largest series in our knowledge of MDS del(5q) cases who had discontinued LEN treatment while transfusion independent, with a long follow up (49 months). In large randomized prospective studies RBC-TI duration upon continued LEN therapy was around 2 years (\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In our cohort median duration of RBC-TI from LEN discontinuation was 56 months. In particular, 70% of the patients treated for \u0026gt;\u0026thinsp;12 LEN cycles were still RBC-TI at 5 years.\u003c/p\u003e \u003cp\u003eSince its serendipitous demonstration of an exceptional efficacy in MDS with del(5q) almost 20 years ago, LEN has been largely and successfully employed in the clinics with erythroid and cytogenetic response, leading to prolongation of OS (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). With its activity in promoting erythropoiesis in MDS del(5q), LEN has demonstrated an acceptable profile of tolerability, but it is not completely devoid of toxicity. Although myelotoxicity induced in the first cycles of therapy is known to herald good response, still in rare cases is not self-resolving and may appear after several months of therapy, requiring use of growth factors or LEN dose reduction, facilitating infections or bleeding. Beside hematological toxicity, that may be acceptable in the majority of cases in the balance with benefits (transfusion independence), some patients experience extra-hematological toxicity as hypothyroidism or more frequently skin rash, renal insufficiency of various grade, as well as gastrointestinal symptoms like diarrhea, not always responding to symptomatic medications (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). LEN treatment is recommended to be continued until loss of response, therefore, the above-mentioned side effects can be an obstacle and impair quality of life of patients.\u003c/p\u003e \u003cp\u003eLEN acts in MDS with del5q with a specific mechanism of action by inducing the proteasomal degradation of casein kinase 1, and it preferentially affects del(5q) cells because they express this gene at haplo-insufficient levels (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). This specific modulation of ubiquitin ligase function leads to elimination/reduction of the neoplastic clone (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In this sense, one may envisage an interruption of treatment once the burden of disease is significantly diminished, in analogy to what has been demonstrated for imatinib therapy in chronic myeloid leukemia (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study patients who were treated with LEN for at least 12 months showed the longest duration of RBC-TI after interruption, consistent with the hypothesis that reduction of the clone allowed achievement of stable response, as supported by the evidence that CCyR prolonged EFS at univariable analysis. Longitudinal cytogenetic analysis were available only in a minority of cases, reflecting clinical practice of avoiding repeated bone marrow evaluations in responding patients. However, 73% of the patients for whom CCyR was documented, lost it. On the other hand, 67% of the patients who were retreated with LEN at TI loss achieved it again. This data may suggest a potential strategy of intermittent administration of LEN, with possibly long period of time of interruption. Sequential cytogenetic data during follow up could help to better understand whether residual del(5q) clone size after LEN discontinuation is determinant for the duration of RBC-TI.\u003c/p\u003e \u003cp\u003eIn the past, it has been postulated that LEN treatment could select resistant clones and drive disease progression, particularly in case of \u003cem\u003eTP53\u003c/em\u003e mutation (\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). More recently it has been shown that LEN treatment provides a selective advantage to \u003cem\u003eTP53\u003c/em\u003e-mutant hematopoietic stem and progenitor cells in vitro and in vivo (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). On the other hand, it has been shown that the presence of biallelic \u003cem\u003eTP53\u003c/em\u003e mutations has a negative impact on OS and response to LEN, therefore the evaluation of this molecular alteration needs to be interpreted carefully.\u003c/p\u003e \u003cp\u003eIn our cohort only 19% of patients progressed to higher risk MDS or AML, and mainly after a long disease history. This progression rate is comparable to what reported in patients responding to LEN and was not related to \u003cem\u003eTP53\u003c/em\u003e mutation (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Establishing the optimal duration of lenalidomide treatment as well as its early inception to avoid clone expansion (Sintra-REV trial (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), could anyhow be relevant to define the risk of disease progression. Indeed, in our study patients who started LEN with a low transfusion burden, that could suggest lower burden of disease, had better outcome after LEN discontinuation.\u003c/p\u003e \u003cp\u003eIn conclusion, this is the largest series to date exploring the outcome of MDS del(5q) patients who discontinued LEN while in RBC-TI response. The main limitations of our study are the heterogeneity of the population (time from diagnosis and length of lenalidomide treatment differ profoundly among cases), the absence of sequential cytogenetic/molecular evaluations and the possible bias due to the lack of a matched cohort of patients continuing LEN until progression or loss of response. Our data suggest that stopping LEN in RBC-TI patients, particularly after more than one year of treatment, constitutes a possible option and may spare toxicities, likely improving patients\u0026rsquo; quality of life, as well as reduce the economic impact on National Healthcare Systems.\u003c/p\u003e \u003cp\u003eSome open issues remain, as whether CCyR achievement is a mandatory criterion to allow response maintenance after LEN discontinuation, although in our cohort patients who attained CCyR before treatment suspension seemed to have a more favorable outcome.\u003c/p\u003e \u003cp\u003eThis retrospective study may provide the needed background for building a prospective study assessing the optimal duration of LEN treatment, also exploring clone size variations and presence/acquisition of somatic mutations during LEN treatment and after its discontinuation.\u003c/p\u003e \u003cp\u003eThe possibility to discontinue LEN treatment in a substantial percentage of MDS del5q patients could be an innovative and cost-effective way to optimize available therapies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under HARMONY Grant Agreement n\u0026ordm; 116026. This Joint Undertaking receives support from the European Union\u0026rsquo;s Horizon 2020 Research and Innovation Programme and EFPIA.\u003c/p\u003e\n\u003cp\u003eVS was partially supported by AIRC IG-26537-2021 Investigator Research Grant\u003c/p\u003e\n\u003cp\u003eM.D.C was partially supported by PI20/00970\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEC designed the study, collected and analyzed data, performed statistical analysis and wrote the paper; VS designed the study and wrote the paper; AS performed statistical analysis and wrote statistical methods of the paper; all the authors treated the patients, collected data, reviewed and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eU.P. declares research support and Honoraria from Geron, BMS and Janssen.\u003c/p\u003e\n\u003cp\u003eM.D.C. declares Honoraria from BMS\u003c/p\u003e\n\u003cp\u003eNone of the other Authors has competing interest related to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHaase D, Germing U, Schanz J, Pfeilst\u0026ouml;cker M, N\u0026ouml;sslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110(13):4385-95.\u003c/li\u003e\n\u003cli\u003eSchanz J, T\u0026uuml;chler H, Sol\u0026eacute; F, Mallo M, Lu\u0026ntilde;o E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(8):820-9.\u003c/li\u003e\n\u003cli\u003eSol\u0026eacute; F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Lu\u0026ntilde;o E, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Espa\u0026ntilde;ol de Citogen\u0026eacute;tica Hematol\u0026oacute;gica. British Journal of Haematology. 2000;108(2):346-56.\u003c/li\u003e\n\u003cli\u003eList AF, Bennett JM, Sekeres MA, Skikne B, Fu T, Shammo JM, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia. 2014;28(5):1033-40.\u003c/li\u003e\n\u003cli\u003eFenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011;118(14):3765-76.\u003c/li\u003e\n\u003cli\u003eSchuler E, Giagounidis A, Haase D, Shirneshan K, B\u0026uuml;sche G, Platzbecker U, et al. Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5). 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Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia. 2013;27(5):1072-9.\u003c/li\u003e\n\u003cli\u003eKomrokji RS, List AF. Short- and long-term benefits of lenalidomide treatment in patients with lower-risk del(5q) myelodysplastic syndromes. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2016;27(1):62-8.\u003c/li\u003e\n\u003cli\u003eFigaro MK, Clayton W, Usoh C, Brown K, Kassim A, Lakhani VT, et al. Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review. American Journal of Hematology. 2011;86(6):467-70.\u003c/li\u003e\n\u003cli\u003eZeidan AM, Gore SD, McNally DL, Baer MR, Hendrick F, Mahmoud D, et al. Lenalidomide performance in the real world: patterns of use and effectiveness in a Medicare population with myelodysplastic syndromes. Cancer. 2013;119(21):3870-8.\u003c/li\u003e\n\u003cli\u003eDimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood. 2012;119(12):2764-7.\u003c/li\u003e\n\u003cli\u003eRollison DE, Shain KH, Lee J-H, Hampras SS, Fulp W, Fisher K, et al. Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide. Cancer Medicine. 2016;5(7):1694-701.\u003c/li\u003e\n\u003cli\u003eScharenberg C, Giai V, Pellagatti A, Saft L, Dimitriou M, Jansson M, et al. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations. Haematologica. 2017;102(3):498-508.\u003c/li\u003e\n\u003cli\u003eJ\u0026auml;dersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, G\u0026ouml;hring G, et al. 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Leukemia. 2016;30(8):1638-47.\u003c/li\u003e\n\u003cli\u003eSperling AS, Guerra VA, Kennedy JA, Yan Y, Hsu JI, Wang F, et al. Lenalidomide promotes the development of TP53-mutated therapy-related myeloid neoplasms. Blood. 2022;140(16):1753-63.\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez Cadenas F, Lumbreras E, Gonz\u0026aacute;lez T, Xicoy B, S\u0026aacute;nchez-Garc\u0026iacute;a J, Coll R, et al. Evaluation of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent Low Risk Del(5q) MDS Patients. Final Results of Sintra-REV Phase III International Multicenter Clinical Trial. Blood. 2022;140(Supplement 1):1109-11.\u003c/li\u003e\n\u003c/ol\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":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4257149/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4257149/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLenalidomide (LEN) can induce RBC transfusion independence (RBC-TI) in 60\u0026ndash;70% of del(5q) myelodysplastic syndrome (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN in RBC-TI. We enrolled 118 patients with an IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment\u0026thinsp;\u0026ge;\u0026thinsp;12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients in RBC-TI allows prolonged maintenance of TI in a large subset of patients.\u003c/p\u003e","manuscriptTitle":"Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic syndrome: a HARMONY Alliance study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 19:04:19","doi":"10.21203/rs.3.rs-4257149/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-04-29T11:43:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-29T00:52:25+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-24T20:22:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-24T19:39:34+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-20T12:06:34+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-04-12T15:05:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-12T14:48:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-12T14:47:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2024-04-12T10:30:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1d899e49-2933-42ee-b048-33ef2beacc85","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":30612632,"name":"Health sciences/Medical research/Clinical trial design/Clinical trials"},{"id":30612633,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome"}],"tags":[],"updatedAt":"2024-08-06T07:10:33+00:00","versionOfRecord":{"articleIdentity":"rs-4257149","link":"https://doi.org/10.1038/s41375-024-02360-1","journal":{"identity":"leukemia","isVorOnly":false,"title":"Leukemia"},"publishedOn":"2024-08-05 04:00:00","publishedOnDateReadable":"August 5th, 2024"},"versionCreatedAt":"2024-04-19 19:04:19","video":"","vorDoi":"10.1038/s41375-024-02360-1","vorDoiUrl":"https://doi.org/10.1038/s41375-024-02360-1","workflowStages":[]},"version":"v1","identity":"rs-4257149","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4257149","identity":"rs-4257149","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}