A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma

A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma | 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 Research Article A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma Jeffrey J. Pu, Kristin N. Berger, Chunlei Zheng, Nhan Do, Mary T. Brophy, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4139215/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Cladribine indirectly downregulates methylations of DNA, RNA and histone by blocking transferring methyl groups from S-adenosyl-methionine. Cladribine and Rituximab combination showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is a FDA approved proteasome inhibitor for treating mantle cell lymphoma (MCL). In this single arm phase I study, we evaluated the safety, dose limiting toxicity, and efficiency of Bortezomib, Cladribine, and Rituximab (VCR) combination treatment in elderly MCL patients. We also proposed potential DNA methylation biomarkers for VCR treatment. A standard 3+3 dose escalation scheme was designed to determine the maximum tolerable cladribine dose. The therapy consisted of 6 28-day cycles. Most patients tolerated this regimen well. The overall responding (OR) rate was 84.6% and complete remission (CR) rate was 84.6%. In newly diagnosed subject cohort, the OR and CR was 100% respectively, 1 year overall survival rate was 90%, and progression free survival rate was 80%. Low grade hematological toxicity and mild fatigue were observed. No severe systemic toxicity was observed. Five hypermethylated regions located at gene promoters were identified as potential biomarkers for an effective treatment response. In conclusion, VCR combination is a well-tolerated, low toxicity and effective regimen for elderly untreated MCL. Clinicaltrials.gov #: NCT01439750. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Mantle cell lymphoma (MCL) is a malignancy of monomorphically small to medium-sized B lymphocytes. The majority of MCL cells are CD5+, CD23-, and exhibit the t(11;14) chromosomal translocation leading to deregulated expression of cyclin D1. 1,2 MCL is considered incurable with current available chemotherapies. Median survival estimates are three to seven years, with even shorter survival times in patients with blastoid variant type disease and with higher lymphoma cell proliferation rates. 3–5 In the last decade, a multitude of innovative therapeutic strategies, which employ hypomethylatic modulation, signal transduction pathway intervention, or immunotherapeutic suppression, have been emerging in managing MCL. 1,2 However, chemotherapy is still considered as the backbone for first line treatment. Several chemotherapy regimens have been used for MCL management, including aggressive regimens such as high dose cyclophosphamide, vincristine, doxorubicin, dexamethasone plus rituximab (R-hyper-CVAD), as well as cyclophosphamide, doxorubicin, vincristine, and prednisone in combination with rituximab (R-CHOP). In a study by Romaguera et al. 6 which employed R-hyper-CVAD, the complete response (CR) rate was found to be 87% after the completion of six cycles of chemotherapy, with a failure free survival (FFS) rate of 64% and overall survival (OS) of 82% at 3 years. Despite generating high overall response (OR) rates, these regimens are not curative. In addition, the regimens are highly toxic. Of the 97 patients in Romaguera trial, there were eight toxic deaths (8.3%), as well as four cases of treatment-related acute leukemia, three of which were fatal. As a result, many patients with MCL are not eligible to undergo treatments with these aggressive regimens due to either advanced age or comorbidities. In an effort to find less toxic treatment regimens, the North Central Cancer Treatment Group used the combination of rituximab and cladribine in previously untreated MCL patients. 7 The study resulted in an OR rate of 66% and a CR rate of 52%. Only 3 of 15 patients, who achieved CR, developed recurrent disease at a median follow-up time of 21.5 months. The high response rates and long response duration of this well-tolerated regimen were promising, which raises the question of whether responses could be improved by inclusion of an additional agent targeting a MCL related signal pathway. Bortezomib (Velcade), a small molecular proteasome inhibitor, is currently FDA approved for the treatment of MCL. 8,9 Literature demonstrated that adding Bortezomib to standard immunochemotherapy regimens could benefit those newly diagnosed MCL patients. 10 Most recently, data from our laboratory and other laboratories showed the hypomethylatic agents synergistically increase the treatment efficacy. 11–14 We herein present the data of a phase I study conducted to evaluate the safety and efficacy of, Bortezomib, cladribine, and rituximab (VCR) combination regimen in treating MCL, especially for those newly diagnosed elderly patients as the first line therapy. Cladribine dose limiting toxicity (DLT) also was evaluated and maximum tolerated dose (MTD) was identified. Methods Patient Eligibility Patients with relapsed or refractory MCL who met the following criteria were eligible for participation in this study: diagnosed as MCL, either treatment naïve, relapsed, or refractory MCL; had received no treatment in the 14 days prior to study entry; had an Eastern Cooperative Oncology Group (ECOG) performance status score of 3 or less; had a platelet count of at least 50x10 9 cells per litter (L) within 14 days before enrollment if not related to disease; had an absolute neutrophil count of at least 1x10 9 cells per L within 14 days before enrollment if not related to disease; had a calculated or measured creatinine clearance of > 35mL/minute within 14 days before enrollment; had less than grade 2 peripheral neuropathy within 14 days before enrollment; and had less than 1.5 times the upper limit of normal bilirubin. This study was approved by Institutional Review Board (IRB) and was compliant with institutional guidelines and the Declaration of Helsinki. Informed written consent was obtained prior to patient enrollment. Study Design We performed a single-arm, open-label, investigator-initiated phase 1 clinical trial to assess the safety and efficacy of combination treatment using bortezomib, cladribine, and rituximab in MCL patients. This study employed a standard 3 + 3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of cladribine within this regimen. The therapy consisted of 6 cycles, with 28 days in each cycle. During the first cycle, rituximab 375 mg/m 2 infusion was administered on day 5 of the first week, and was then given weekly for 3 weeks. In the next 5 cycles, rituximab was given on day 5 of each cycle, and then once every 2 months as the maintenance therapy. Cladribine 3–5 mg/m 2 (3 mg/m 2 for dose escalation scale 1, 4 mg/m 2 for scale 2, and 5 mg/m 2 for scale 3) infusion was given on days 1 to 5 for 6 cycles. If the patient’s age was older than 70 years, cladribine was only given on days 1 to 3 of each cycle. Bortezomib 1.6 mg/m 2 subcutaneous injection was administered on days 12, 19 and 26 for cycles 1 to 3, days 5 and 19 during cycles 4 to 6, and then once per month as maintenance therapy until toxicity or progression of the disease. Dosing and duration of growth factor support with filgrastim or peg-filgrastim was determined by the treating physician for neutropenia. The primary endpoint of this study was to investigate the DLT and safety of this regimen in patients with MCL. The secondary endpoints included OR and CR rates, response duration, PFS and OS rates. This study is registered with clinicaltrials.gov (NCT01439750). Post Study Analysis Following completion of the clinical trial a DNA methylation assay was performed on 4 patients, 2 good responders and 2 poor responders, to assess the biological factors involved in treatment response. The samples of bone marrow aspiration derived mononuclear cells before and after treatments were obtained from these patients for study. Table 1 shows the details of sample group information. The specific method used in study was the reduced representation bisulfate sequencing (RRBS) assay to measure DNA methylation at CpG sites. Table 1 information for patient response and treatment Patient 1 Patient 2 Patient 3 Patient 4 JP01 JP02 JP03 JP04 JP05 JP06 JP07 JP08 Response good good poor poor poor poor good good Treatment before after before after before after before after All DNA methylation analyses were performed using R (version 4.2.1). 15 Principal Component Analysis (PCA) was used to obtain overall methylation profiles for patients. There are several analytic tools available for differentially methylated regions (DMRs) analysis. BSseq package was used in this study since its capacity in dealing with the small sample size and taking biological variability into account. 16 The small sample size also caused difficulty in statistically identifying genomic regions with small difference. To increase the statistical power and reliability, only promoter regions that were identified using GenomicFeatures, 17 was considered in our analysis. DMR was defined as a region that has at least two measured loci and mean difference in methylation level between two groups is bigger than 0.3. Quantile cutoff (lower: 0.025, upper: 0.075) of t-statistic was used for DMR identification. These DMRs were further mapped to specific genes using Ensembl in biomaRt. 18,19 Statistical Methods All patients who enrolled for this study were assessed to determine OR, CR, responding duration, PFS, and OS. The duration of response to treatment was measured from the date of the first observed remission until the time at which relapse was noted. PFS was measured between the time of first treatment to the time of disease progression, relapse, or death. OS was measured from the time of first treatment to the time of death or last known survival date. The Kaplan-Meier method was used to estimate times to events (in months). Results Patient Characteristics Thirteen patients were enrolled in this 24-week dose escalation study (Table 2). Most patients were male (11/13), with a median age of 64 years (range 54-81 years). Of 13 patients, 9 (69%) had low-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) scores and 4 (31%) had intermediate-risk MIPI scores. In terms of individual MIPI risk factors, 8 (62%) patients were >60 years old, all patients were identified as ECOG performance status from 0 to 3, 13 (100%) patients had elevated levels of lactate dehydrogenase, and 8 (62%) patients had elevated white blood cells counts. Most patients (10/13) never received prior treatment for MCL. Of the relapsed MCL patients who previously received treatment, 2 patients were experiencing their first relapse following previous treatment with rituximab and bendamustine. The 3rd patient was experiencing 3rd relapse following previous treatment with R-CHOP, RDHAP, hyper-CVAD, and allogeneic SCT therapy. The dose escalation study tested cladribine in doses ranging from 3 to 5 mg/m 2 on days 1 through 5 of 6 28-day cycles. Of the 13 patients, 3 received 3 mg/m 2 of cladribine in dose scale 1, 3 received 4 mg/m 2 of cladribine in dose scale 2, and 7 received 5 mg/m 2 of cladribine in dose scale 3. Of the 13 patients, 4 completed the 24-week dose-escalation study and followed with rituximab maintenance therapy as described at study design section. Two patients withdrew from therapy due to disease progression after each completing 2 cycles. One chose to withdraw from active therapy after completing 3 cycles of treatment and achieving CR status citing personal reasons, though he did continue with maintenance therapy. Another one also chose to withdraw after 4 cycles and instead to undergo rituximab maintenance after achieving partial remission with one persistently FDG avid lymph node, who ultimately achieved CR. One patient withdrew due to prolonged bone marrow suppression, though she suffered anemic, thrombocytopenic, and neutropenic prior to participating this study. Safety No subject experienced DLT while receiving cladribine dose scales 1 or 2. One subject who was receiving cladribine dose scale 3 suffered infectious colitis during the second cycle of therapy and was labeled as possibly experiencing DLT. The patient died 7 months later as a result of multiple organ failure after experiencing disease progression. Additional patients were recruited to the cladribine dose scale 3 cohort, and no one experienced DLT. Table 3 summarizes the most frequently reported adverse events (AEs). All AEs were grade 1 or 2 in severity other than single patient reports of cellulitis, diarrhea, neuropathy, fatigue, and hyperglycemia. The most common non-hematological AEs of any grade were neuropathy, fatigue, diarrhea, constipation, and hyponatremia. No patient experienced tumor lysis syndrome. Only one patient discontinued the treatment due to prolonged bone marrow suppression caused pancytopenia as previously mentioned. Of the 5 patients who discontinued treatment prior to completion of all 6 cycles, the median number of treatment cycles prior to discontinuation was 2 (range 2-4). Efficacy Table 4 summarizes each cohort’s best response to therapy. Of the 13 patients in this study, the OR rate was 11/13 patients (84.6%, 95% confidence interval 57.8-95.7). Complete remission (CR) was reported in 11/13 patients (84.6%, 95% confidence interval 57.8-95.7). In the newly diagnosed subject cohort, the OR and CR rates were both 100% (10/10). The 2-year overall survival (OS) rate in this cohort was 85% (11/13). The 1-year and 2-year progression-free survival (PFS) in this same cohort were 77% (10/13) and 60% (9/13), respectively. The median duration of response, PFS, and OS had not been reached at the time of the current report. Two patients are deceased during the period of the study due to disease progression. Patients on the overall survival curve (Figure 1a) are censored at time of last known survival. Four patients experienced disease progression, including two deceased patients with relapsed disease who didn’t respond to treatment, and two patients who experienced relapse following complete remissions (Figure 1b). One patient’s death was not preceded by disease progression. Of the two patients who experienced disease progression without achieving remission, both suffered progression within two months of beginning this treatment, and both bore the blastoid variant type of MCL and suffered from relapsed disease at the time enrolled to this study. Of the patients who achieved a response, only 2 experienced disease relapses, with response durations of 7.6 and 11.2 months. The remaining patients on the response duration curve (Figure 1c) were censored, with one patient’s remission times currently lasting longer than 50 months after first reaching CR. Biological Differences An initial attempt to determine whether there were any overall differences in methylation values between the subjects using principal components analysis (PCA). Figure 2A showed that the high-dimension data can be represented by the first seven components. Although the first two components only explained around 40% of variance of our data, which prevented us to visualize them in a two-dimension space efficiently (Figure 2B), we can still see the treatment-induced methylation changes. Prior to the treatment, a sample from a good responder (JP07) showed difference compared to the other three patients. After the treatment, the methylation from this patient has a big change (JP08). We can also see the methylation from one poor responder has a large change after treatment in the opposite direction (JP04 vs JP03). Differentially Methylated Regions (DMRs) analysis was then performed between good responders and poor responders before treatment and a total of 50 DMRs within gene promoter regions were identified, including both hypermethylated and hypomethylated regions (Figure 3). In this study, the methylation biomarkers for treatment response should meet two criteria: 1) they are differentially methylated between good and poor responders before treatment; 2) they respond to treatment differently between good and poor responders after treatment. We identified nine candidate DMRs (Figure 4A). All these regions are hypermethylated before treatment and demethylated after treatment in good responders (Figure 4B). When we examine their methylation profiles in poor responders, five of nine DMRs showed demethylated status before treatment while increased methylation or no change after treatment (subpanel 1, 2, 5, 8 and 9 in Figure 4C); the remaining four DMRs showed opposite trend (subpanel 3, 4, 6 and 7 in Figure 4C). Thus, the five DMRs differentially response to treatment between good and poor responders, indicating that they are potential methylation biomarkers for treatment response. Discussion The current most utilized regimens to initiate MCL treatment, including R-CHOP and R-hyper-CVAD, produce high overall response rates, though they oftentimes result in late relapse and are exceedingly toxic. 6, 20–22 Due to the toxicity of these regimens, it is challenging to treat elderly patients with MCL, particularly those with comorbidities. Prior trials have demonstrated the capabilities of both rituximab and cladribine as monotherapies in treating. 23–25 In addition to patients treated by Inwards et al. 7 (2008), rituximab and cladribine combination therapy also was used to treat 9 MCL patients by Robak et al. 26 (2006), resulting in an OR rate of 67% and a CR rate of 22%. One report also notes a CR by colonic MCL treated with rituximab and cladribine. 27 It is suggested that hypomethylatic agent is one of several molecules synergistically enhance the MCL therapy efficacy. 11–14 In this study we demonstrated that the combination of Bortezomib, cladribine, and rituximab is a well-tolerated regimen, despite the elderly study population (median age of 64 years). No severe systemic toxicity was observed during this trial. The most common AEs resulted from bone marrow suppression. The therapy was not associated with a significant rate of opportunistic infections. Antiviral and antifungal prophylaxis was not used. Only one patient receiving cladribine dose scale 3 of 5 mg/m 2 was considered as possibly experiencing DLT. A previous study which also utilized this dosing of cladribine in combination with rituximab reported one death on therapy from cerebrovascular accident. 7 This toxicity profile is much preferable to those of more intensive R-CHOP or R-hyper-CVAD regimens. This trial resulted in OR and CR rates of 84.6%, including OR and CR rates of 100% in the newly diagnosed subject cohort. In addition, the newly diagnosed subject cohort’s 2-year PFS rate was 90%. In the study comparing MCL patients who were treated with cladribine and rituximab versus cladribine alone, the most striking difference occurred between the duration of responses in these two groups. The 2-year PFS rate was 43% in the group that received combination therapy versus 21% in the group that received cladribine alone. 7 We believe that the PFS rate is higher in this trial due to the use of an additional agent, Bortezomib. 28,29 Rituximab maintenance therapy (in 4 cases, rituximab and Bortezomib maintenance therapy) also played a rule in maintaining CR in long term. 30 Our previous SCR study results confirmed importance of maintenance therapy. 12 The efficacy of Bortezomib, cladribine, and rituximab (VCR) combination regimen within the much smaller cohort of relapsed MCL patients in this study was not as impressive as in the cohort of newly diagnosed MCL patients. The relapsed MCL cohort includes two patients who suffered disease progression while receiving VCR treatment. Furthermore, both patients bored the feature of blastoid variant of MCL, and one of the patients contained additional poor prognostic cytogenetic mutation. Our result on treating relapsed MCL patents is consistent with the results from a multicenter phase 2 PINNACLE study that utilized bortezomib to treat relapsed or refractory MCL, which resulted in an OR rate of 33% and a CR rate of 8%. 8,31,32 Other trials have also studied therapies for newly diagnosed MCL. Ruan et al. 33 (2015) evaluated the combination of lenalidomide plus rituximab in this patient population. Of a total of 38 patients at the median follow-up of 30 months, the OR rate among participants with newly diagnosed MCL was 92%, with a CR rate of 64% and a 2-year PFS estimated to be 85%. A separate study by Rummel et al. 34 (2013), also for newly diagnosed disease, showed that a combination of bendamustine and rituximab significantly improved PFS of elderly patients with indolent MCL compared with R-CHOP, with a median PFS of 69.5 months but a CR rate of only 40%. Prior studies of this drug combination in patients with rituximab-refractory, indolent and transformed non-Hodgkin’s lymphoma showed a high relapse rate, with a median duration of response of 6.7 months. 35 Tremendous efforts have been making in searching for more effective MCL treatment target. 36–39 Cladribine is a promising hypomethylatic agent in MCL combination therapy. 1 We conducted methylation assay on 2 good-responders and 2 poor-responders. PCA analysis data showed that there is difference between good-responders and poor- responders in methylation status change after receiving VCR regimen treatment. Furthermore, the DMR methylation status change patterns between good- and poor-responders in promoter regions of five genes raise the possibility of biomarkers and potential treatment target. However, these DMR methylation data needs to be verified via conducting study in a larger patient population. Our data suggests that the VCR combination therapy is effective in treating MCL patients with minimal toxicity. VCR should be considered as a viable option of first line therapy for elderly MCL patients, or patients who opt for less aggressive regimens. A phase II/III study will further confirm the efficacy of this VCR regimen and help us to narrow the list of treatment-response biomarker candidates identified in this study, which also potentially could be the novel treatment target. Declarations Funding Declaration This study is supported by: Takeda Pharmaceutical’s investigator-initiated study grant, AA & MDSIF research grant to JJP (146818), American Cancer Society research grant to JJP (124171-IRG-13-043-02) and Paige’s Cancer Researcher Fund to JJP (Pu33860). Acknowledgements The authors would like to thank Dr. Yuka Imamura Kawasawa and her molecular core laboratory for conducting methylation assay on those patient samples. Authorship Contributions: JJP and EME designed this study. JJP and KNB collected data and wrote this manuscript. JJP, WCE, DFC, and EME provided patient care. JJP and JJD directed correlative study. CZ and HL conducted biostatistics and bioinformatics analyses. CZ wrote bioinformatics interpretation in the manuscript. All authors participated in manuscript edition and finalization. Conflict-of-interest disclosure: All authors declare no competing financial interests. Data availability statement : All data is available to share for research purpose. References Pu JJ, Savani M, Huang N, Epner EM. Mantle cell lymphoma management trends and novel agents: where are we going? Ther Adv Hematol. 2022 Feb 26;13:20406207221080743. doi: 10.1177/20406207221080743. PMID: 35237397; PMCID: PMC8882940. Ladha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its management: where are we now? Exp Hematol Oncol. 2019 Jan 30;8:2. doi: 10.1186/s40164-019-0126-0. PMID: 30733891; PMCID: PMC6354396. 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Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Kahl BS, Longo WL, Eickhoff JC, Zehnder J, Jones C, Blank J, McFarland T, Bottner W, Rezazedeh H, Werndli J, Bailey HH. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Annals of oncology. 2006 Jun 9;17(9):1418-23. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, De Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Journal of clinical oncology. 2006 Oct 20;24(30):4867-74. Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, De Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Annals of oncology. 2008 Dec 12;20(3):520-5. Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. New England Journal of Medicine. 2015 Nov 5;373(19):1835-44. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. The Lancet. 2013 Apr 6;381(9873):1203-10. 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PMID: 19228923; PMCID: PMC4969050. Corcione A, Arduino N, Ferretti E, Raffaghello L, Roncella S, Rossi D, Fedeli F, Ottonello L, Trentin L, Dallegri F, Semenzato G, Pistoia V. CCL19 and CXCL12 trigger in vitro chemotaxis of human mantle cell lymphoma B cells. Clin Cancer Res. 2004 Feb 1;10(3):964-71. doi: 10.1158/1078-0432.ccr-1182-3. PMID: 14871974. Long ME, Koirala S, Sloan S, Brown-Burke F, Weigel C, Villagomez L, Corps K, Sharma A, Hout I, Harper M, Helmig-Mason J, Tallada S, Chen Z, Scherle P, Vaddi K, Chen-Kiang S, Di Liberto M, Meydan C, Foox J, Butler D, Mason C, Alinari L, Blaser BW, Baiocchi R. Resistance to PRMT5-targeted therapy in mantle cell lymphoma. Blood Adv. 2024 Jan 9;8(1):150-163. doi: 10.1182/bloodadvances.2023010554. PMID: 37782774. Tables Table 1: information for patient response and treatment Patient 1 Patient 2 Patient 3 Patient 4 JP01 JP02 JP03 JP04 JP05 JP06 JP07 JP08 Response good good poor poor poor poor good good Treatment before after before after before after before after Table 2: Patient baseline characteristics. Characteristic N = 13 Median age (range), years 64 (53-81) Sex, male/female 11/2 ECOG performance score, n (%) 0 1 (7.7) 1 6 (46.2) 2 4 (30.8) 3 2 (15.3) MIPI score, n (%) Low (6.2) 0 (0) Risk Factors, n (%) Age >60 years 8 (62) ECOG >/= 2 0 (0) LDH/ULN > 6.7 13 (100) WBC > 6.7 8 (62) Table 3: Common adverse events (n=13) on patients participating in the trial. Data are number of patients (%). Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Hematological Events Anemia 4 (31) 3 (23) 0(0) 0 (0) Neutropenia 5 (0) 6 (15) 0 (0) 0 (0) Febrile Neutropenia 1 (8) 0 (0) 0 (0) 0 (0) Thrombocytopenia 3 (23) 1 (8) 0 (0) 0 (0) Leukopenia 3 (23) 5 (38) 0 (0) 0 (0) Lymphopenia 2(15) 10 (77) 0 (0) 0 (0) Non-hematological Events Fever 1 (8) 1 (8) 0 (0) 0 (0) Chills 3 (23) 0 (0) 0 (0) 0 (0) GFR decrease 1 (8) 0 (0) 0 (0) 0 (0) Cellulitis 0 (0) 0 (0) 1 (8) 0 (0) Diarrhea 4 (31) 1 (8) 0 (0) 0 (0) Dyspnea on exertion 3 (23) 0 (0) 0 (0) 0 (0) Hyperuricemia 2 (15) 0 (0) 0 (0) 0 (0) Increased alkaline phosphatase 1 (8) 0 (0) 0 (0) 0 (0) Increased ALT 1 (8) 1 (8) 0 (0) 0 (0) Increased AST 4 (31) 0 (0) 0 (0) 0 (0) Increased total bilirubin 2 (15) 0 (0) 0 (0) 0 (0) Increased LDH 1 (8) 0 (0) 0 (0) 0 (0) Hives 1 (8) 0 (0) 0 (0) 0 (0) Watery Eyes 1 (8) 0 (0) 0 (0) 0 (0) Bone pain 0 (0) 1 (8) 0 (0) 0 (0) Neuropathy 2 (15) 4 (31) 1 (8) 0 (0) Myalgia 3 (23) 0 (0) 0 (0) 0 (0) Fatigue 3 (23) 3 (23) 1 (8) 0 (0) Stye 0 (0) 1 (8) 0 (0) 0 (0) Loss of balance 1 (8) 0 (0) 0 (0) 0 (0) Joint/Back pain 0 (0) 3 (23) 0 (0) 0 (0) Bradycardia 1 (8) 0 (0) 0 (0) 0 (0) Constipation 3 (23) 2 (15) 0 (0) 0 (0) Upper respiratory infection 0 (0) 1 (8) 0 (0) 0 (0) Weight loss 0 (0) 1 (8) 0 (0) 0 (0) Abdominal pain 2 (15) 1 (8) 0 (0) 0 (0) Tonsillitis 0 (0) 1 (8) 0 (0) 0 (0) Hypocalcemia 2 (15) 0 (0) 0 (0) 0 (0) Nausea 4 (31) 0 (0) 0 (0) 0 (0) Mouth sores 1 (8) 0 (0) 0 (0) 0 (0) Cold intolerance 1 (8) 0 (0) 0 (0) 0 (0) Insomnia 1 (8) 1 (8) 0 (0) 0 (0) Loss of appetite 1 (8) 1 (8) 0 (0) 0 (0) Vomiting 3 (23) 0 (0) 0 (0) 0 (0) Lower extremity edema 1 (8) 1 (8) 0 (0) 0 (0) Hypoalbuminemia 1 (8) 0 (0) 0 (0) 0 (0) Hypomagnesemia 1 (8) 0 (0) 0 (0) 0 (0) Hyponatremia 5 (38) 0 (0) 0 (0) 0 (0) Hyperglycemia 2 (15) 1 (8) 1 (8) 0 (0) Hypernatremia 1 (8) 0 (0) 0 (0) 0 (0) Weakness 1 (8) 3 (23) 0 (0) 0 (0) Lightheadedness 1 (8) 0 (0) 0 (0) 0 (0) Rash 2 (15) 0 (0) 0 (0) 0 (0) Avascular necrosis 0 (0) 1 (8) 0 (0) 0 (0) Table 4: Response rates in newly diagnosed and relapsed MCL patients receiving bortezomib, cladribine, and rituximab. Dose cohorts received 3-5mg/m 2 of cladribine. PR: Partial Remission; DP: Disease Progression Receiving 3mg/m 2 (n=3) Receiving 4mg/m 2 (n=3) Receiving 5mg/m 2 (n=7) Newly Diagnosed (n=10) Overall (n=13) Patients with relapsed MCL 1 (33) 0 (0) 2 (29) 0 (0) 3 (23) ORR 3 (100) 3 (100) 4 (57) 9 (90) 10 (77) Best Response CR 3 (100) 3 (100) 5 (71) 10 (100) 11 (85) PR 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) DP 0 (0) 0 (0) 2 (29) 0 (0) 2 (15) Median time to first response (range, months) 2.5 (2.1-3.2) 6.8 (2.2-7.4) 3.0 (2.4-6.8) 3.1 (2.1-7.4) 3.0 (2.1-7.4) 1-year PFS 2 (67) 3 (100) 5 (71) 9 (90) 10 (77) 2-year PFS 1 (33) 3 (100) 4 (57) 8 (80) 8 (62) 4-year PFS 1/2 2/2 0/2 3/3 3/6 1-year OS 3 (100) 3 (100) 5 (71) 10 (100) 11 (85) 2-year OS 3 (100) 3 (100) 4 (57) 9 (90) 10 (77) 4-year OS 2/2(100) 2/2 (100) 0/2(0) 3/3(100) 4/6 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 22 Mar, 2024 Submission checks completed at journal 22 Mar, 2024 First submitted to journal 20 Mar, 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4139215","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":282657337,"identity":"9dd4eff2-e738-45ec-84fb-19504065289e","order_by":0,"name":"Jeffrey J. Pu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACxgbGBx/ALPYGIGFgQYwWZsMZYBbPAZAWCWLsgWmRSACTRGhob2Zsrqg4nGdw8/nVDT8KJBj427sT8Dus5zBj45kzh4sNbueU3ewBOkzizNkN+LXMyD/+sLHtcOKG2zlpN3iAWgwkcglomf+YsbHxH1DLzTNpN/8QpWUGM1BLA1DLDfZjt4mzpSeZsbHhWHqx5JkcttsyBhI8BP1i2A70fkONdR7f8ePPbr75YyPH395LQEsDmGpOAMalAYjFg1c5CMhDqDqgFvYHBFWPglEwCkbByAQAGQBQA78sZbUAAAAASUVORK5CYII=","orcid":"","institution":"VA Boston Healthcare system","correspondingAuthor":true,"prefix":"","firstName":"Jeffrey","middleName":"J.","lastName":"Pu","suffix":""},{"id":282657338,"identity":"33a176da-46c0-4b33-9d52-0c887cca81a1","order_by":1,"name":"Kristin N. Berger","email":"","orcid":"","institution":"New York Presbyterian Hospital, Weill Cornell Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kristin","middleName":"N.","lastName":"Berger","suffix":""},{"id":282657339,"identity":"3b95d78e-679e-4fb7-ad17-6bc29c226c40","order_by":2,"name":"Chunlei Zheng","email":"","orcid":"","institution":"VA Boston Healthcare system","correspondingAuthor":false,"prefix":"","firstName":"Chunlei","middleName":"","lastName":"Zheng","suffix":""},{"id":282657341,"identity":"1284b935-9642-4a07-b445-5e008052573e","order_by":3,"name":"Nhan Do","email":"","orcid":"","institution":"VA Boston Healthcare system","correspondingAuthor":false,"prefix":"","firstName":"Nhan","middleName":"","lastName":"Do","suffix":""},{"id":282657343,"identity":"0485da5d-b377-47fa-a9d6-3ea0116e53e5","order_by":4,"name":"Mary T. Brophy","email":"","orcid":"","institution":"VA Boston Healthcare system","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"T.","lastName":"Brophy","suffix":""},{"id":282657345,"identity":"14615c29-ea24-4442-905f-35b03d865a95","order_by":5,"name":"David F. Claxton","email":"","orcid":"","institution":"Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"F.","lastName":"Claxton","suffix":""},{"id":282657347,"identity":"bc89ed6e-a8ff-482d-82fc-ce79448a7fb3","order_by":6,"name":"W Christopher Ehmann","email":"","orcid":"","institution":"Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"W","middleName":"Christopher","lastName":"Ehmann","suffix":""},{"id":282657348,"identity":"566c869a-ad67-4881-8110-a799aed08e60","order_by":7,"name":"Joseph J. Drabick","email":"","orcid":"","institution":"Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Joseph","middleName":"J.","lastName":"Drabick","suffix":""},{"id":282657350,"identity":"35ff9698-f0d5-4966-a75b-76880f15c5a4","order_by":8,"name":"Haiquan Li","email":"","orcid":"","institution":"University of Arizona","correspondingAuthor":false,"prefix":"","firstName":"Haiquan","middleName":"","lastName":"Li","suffix":""},{"id":282657352,"identity":"857e3c6a-8459-42d1-bcab-b70631e11e89","order_by":9,"name":"Thomas P. Loughran","email":"","orcid":"","institution":"University of Virginia NCI Designated Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"P.","lastName":"Loughran","suffix":""},{"id":282657354,"identity":"95478bf5-da9d-40b1-9c88-b42c799845d0","order_by":10,"name":"Elliot M. Epner","email":"","orcid":"","institution":"Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Elliot","middleName":"M.","lastName":"Epner","suffix":""}],"badges":[],"createdAt":"2024-03-20 19:29:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4139215/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4139215/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53579935,"identity":"705dfb27-8768-4134-9349-3a2047b13ae0","added_by":"auto","created_at":"2024-03-27 17:27:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":156323,"visible":true,"origin":"","legend":"\u003cp\u003ePatients’ overall survival (OS), and progression-free survival (PFS), and response duration (RD) are presented in Panel a, b, and c, respectively. OS or PFS months count from the treatment starting date to the event happening date, which were death for OS curve, and relapse, progression, or death for PFS curve. RD count similarly as PFS curve, except the starting point is from the first response date when remission happened.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4139215/v1/d15b6da2013bd53d4c7bdc4e.png"},{"id":53579978,"identity":"e77fe2e3-8240-4253-9213-d64d4f55517d","added_by":"auto","created_at":"2024-03-27 17:27:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57583,"visible":true,"origin":"","legend":"\u003cp\u003ePCA analysis of DNA methylation. (A) Proportion of variance plot shows the percentage of variance explained by first eight components. (B) PCA plot shows the first and second components for each sample. Samples were grouped by response and treatment (see Table 1) and presented in different shapes. For example, JP01 and JP07 are represented as triangle, indicating they are from good responders before treatment.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4139215/v1/1d9bfd34643e9667141289f6.png"},{"id":53580046,"identity":"71cee24f-21b2-45a1-ad81-89a24a726fc7","added_by":"auto","created_at":"2024-03-27 17:27:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1232252,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap shows differentially methylated regions (DMRs) between samples from good responders (JP01 and JP07) and poor responders (JP03 and JP05). Each DMR is labeled with its genomic location and mapped to individual gene. Note: Several DMRs are unable to mapped to genes.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4139215/v1/c69a5b921f27adc36646a7a5.png"},{"id":53579926,"identity":"30652225-91f4-4b88-a21c-aab59c3cbfbb","added_by":"auto","created_at":"2024-03-27 17:27:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":191790,"visible":true,"origin":"","legend":"\u003cp\u003eMethylation profiles of candidate DMRs in different groups. (A) good and poor responders before treatment. (B) before and after treatment in good responders. (C) before and after treatment in poor responders\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4139215/v1/9ba8b59124ca13c479fa8aa8.png"},{"id":53581386,"identity":"0e9cdbd2-9fae-41f6-91d7-244b085e4941","added_by":"auto","created_at":"2024-03-27 17:35:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1005001,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4139215/v1/e8b8a58d-c7f4-402b-b34e-09b3918f680a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMantle cell lymphoma (MCL) is a malignancy of monomorphically small to medium-sized B lymphocytes. The majority of MCL cells are CD5+, CD23-, and exhibit the t(11;14) chromosomal translocation leading to deregulated expression of cyclin D1.\u003csup\u003e1,2\u003c/sup\u003e MCL is considered incurable with current available chemotherapies. Median survival estimates are three to seven years, with even shorter survival times in patients with blastoid variant type disease and with higher lymphoma cell proliferation rates.\u003csup\u003e3\u0026ndash;5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the last decade, a multitude of innovative therapeutic strategies, which employ hypomethylatic modulation, signal transduction pathway intervention, or immunotherapeutic suppression, have been emerging in managing MCL.\u003csup\u003e1,2\u003c/sup\u003e However, chemotherapy is still considered as the backbone for first line treatment. Several chemotherapy regimens have been used for MCL management, including aggressive regimens such as high dose cyclophosphamide, vincristine, doxorubicin, dexamethasone plus rituximab (R-hyper-CVAD), as well as cyclophosphamide, doxorubicin, vincristine, and prednisone in combination with rituximab (R-CHOP). In a study by Romaguera et al.\u003csup\u003e6\u003c/sup\u003e which employed R-hyper-CVAD, the complete response (CR) rate was found to be 87% after the completion of six cycles of chemotherapy, with a failure free survival (FFS) rate of 64% and overall survival (OS) of 82% at 3 years. Despite generating high overall response (OR) rates, these regimens are not curative. In addition, the regimens are highly toxic. Of the 97 patients in Romaguera trial, there were eight toxic deaths (8.3%), as well as four cases of treatment-related acute leukemia, three of which were fatal. As a result, many patients with MCL are not eligible to undergo treatments with these aggressive regimens due to either advanced age or comorbidities.\u003c/p\u003e \u003cp\u003eIn an effort to find less toxic treatment regimens, the North Central Cancer Treatment Group used the combination of rituximab and cladribine in previously untreated MCL patients.\u003csup\u003e7\u003c/sup\u003e The study resulted in an OR rate of 66% and a CR rate of 52%. Only 3 of 15 patients, who achieved CR, developed recurrent disease at a median follow-up time of 21.5 months. The high response rates and long response duration of this well-tolerated regimen were promising, which raises the question of whether responses could be improved by inclusion of an additional agent targeting a MCL related signal pathway.\u003c/p\u003e \u003cp\u003eBortezomib (Velcade), a small molecular proteasome inhibitor, is currently FDA approved for the treatment of MCL.\u003csup\u003e8,9\u003c/sup\u003e Literature demonstrated that adding Bortezomib to standard immunochemotherapy regimens could benefit those newly diagnosed MCL patients.\u003csup\u003e10\u003c/sup\u003e Most recently, data from our laboratory and other laboratories showed the hypomethylatic agents synergistically increase the treatment efficacy.\u003csup\u003e11\u0026ndash;14\u003c/sup\u003e We herein present the data of a phase I study conducted to evaluate the safety and efficacy of, Bortezomib, cladribine, and rituximab (VCR) combination regimen in treating MCL, especially for those newly diagnosed elderly patients as the first line therapy. Cladribine dose limiting toxicity (DLT) also was evaluated and maximum tolerated dose (MTD) was identified.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Eligibility\u003c/h2\u003e \u003cp\u003ePatients with relapsed or refractory MCL who met the following criteria were eligible for participation in this study: diagnosed as MCL, either treatment na\u0026iuml;ve, relapsed, or refractory MCL; had received no treatment in the 14 days prior to study entry; had an Eastern Cooperative Oncology Group (ECOG) performance status score of 3 or less; had a platelet count of at least 50x10\u003csup\u003e9\u003c/sup\u003e cells per litter (L) within 14 days before enrollment if not related to disease; had an absolute neutrophil count of at least 1x10\u003csup\u003e9\u003c/sup\u003e cells per L within 14 days before enrollment if not related to disease; had a calculated or measured creatinine clearance of \u0026gt;\u0026thinsp;35mL/minute within 14 days before enrollment; had less than grade 2 peripheral neuropathy within 14 days before enrollment; and had less than 1.5 times the upper limit of normal bilirubin. This study was approved by Institutional Review Board (IRB) and was compliant with institutional guidelines and the Declaration of Helsinki. Informed written consent was obtained prior to patient enrollment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eWe performed a single-arm, open-label, investigator-initiated phase 1 clinical trial to assess the safety and efficacy of combination treatment using bortezomib, cladribine, and rituximab in MCL patients. This study employed a standard 3\u0026thinsp;+\u0026thinsp;3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of cladribine within this regimen. The therapy consisted of 6 cycles, with 28 days in each cycle. During the first cycle, rituximab 375 mg/m\u003csup\u003e2\u003c/sup\u003e infusion was administered on day 5 of the first week, and was then given weekly for 3 weeks. In the next 5 cycles, rituximab was given on day 5 of each cycle, and then once every 2 months as the maintenance therapy. Cladribine 3\u0026ndash;5 mg/m\u003csup\u003e2\u003c/sup\u003e (3 mg/m\u003csup\u003e2\u003c/sup\u003e for dose escalation scale 1, 4 mg/m\u003csup\u003e2\u003c/sup\u003e for scale 2, and 5 mg/m\u003csup\u003e2\u003c/sup\u003e for scale 3) infusion was given on days 1 to 5 for 6 cycles. If the patient\u0026rsquo;s age was older than 70 years, cladribine was only given on days 1 to 3 of each cycle. Bortezomib 1.6 mg/m\u003csup\u003e2\u003c/sup\u003e subcutaneous injection was administered on days 12, 19 and 26 for cycles 1 to 3, days 5 and 19 during cycles 4 to 6, and then once per month as maintenance therapy until toxicity or progression of the disease. Dosing and duration of growth factor support with filgrastim or peg-filgrastim was determined by the treating physician for neutropenia.\u003c/p\u003e \u003cp\u003eThe primary endpoint of this study was to investigate the DLT and safety of this regimen in patients with MCL. The secondary endpoints included OR and CR rates, response duration, PFS and OS rates. This study is registered with clinicaltrials.gov (NCT01439750).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePost Study Analysis\u003c/h2\u003e \u003cp\u003eFollowing completion of the clinical trial a DNA methylation assay was performed on 4 patients, 2 good responders and 2 poor responders, to assess the biological factors involved in treatment response. The samples of bone marrow aspiration derived mononuclear cells before and after treatments were obtained from these patients for study. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the details of sample group information. The specific method used in study was the reduced representation bisulfate sequencing (RRBS) assay to measure DNA methylation at CpG sites.\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\u003einformation for patient response and treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003ePatient 4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJP01\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eJP02\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJP03\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eJP04\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eJP05\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eJP06\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eJP07\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eJP08\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003epoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003epoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003egood\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ebefore\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eafter\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAll DNA methylation analyses were performed using R (version 4.2.1).\u003csup\u003e15\u003c/sup\u003e Principal Component Analysis (PCA) was used to obtain overall methylation profiles for patients. There are several analytic tools available for differentially methylated regions (DMRs) analysis. BSseq package was used in this study since its capacity in dealing with the small sample size and taking biological variability into account.\u003csup\u003e16\u003c/sup\u003e The small sample size also caused difficulty in statistically identifying genomic regions with small difference. To increase the statistical power and reliability, only promoter regions that were identified using GenomicFeatures,\u003csup\u003e17\u003c/sup\u003e was considered in our analysis. DMR was defined as a region that has at least two measured loci and mean difference in methylation level between two groups is bigger than 0.3. Quantile cutoff (lower: 0.025, upper: 0.075) of t-statistic was used for DMR identification. These DMRs were further mapped to specific genes using Ensembl in biomaRt.\u003csup\u003e18,19\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Methods\u003c/h2\u003e \u003cp\u003eAll patients who enrolled for this study were assessed to determine OR, CR, responding duration, PFS, and OS. The duration of response to treatment was measured from the date of the first observed remission until the time at which relapse was noted. PFS was measured between the time of first treatment to the time of disease progression, relapse, or death. OS was measured from the time of first treatment to the time of death or last known survival date. The Kaplan-Meier method was used to estimate times to events (in months).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThirteen patients were enrolled in this 24-week dose escalation study (Table 2). Most patients were male (11/13), with a median age of 64 years (range 54-81 years). Of 13 patients, 9 (69%) had low-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) scores and 4 (31%) had intermediate-risk MIPI scores. In terms of individual MIPI risk factors, 8 (62%) patients were \u0026gt;60 years old, all patients were identified as ECOG performance status from 0 to 3, 13 (100%) patients had elevated levels of lactate dehydrogenase, and 8 (62%) patients had elevated white blood cells counts. \u003c/p\u003e\n\n\u003cp\u003eMost patients (10/13) never received prior treatment for MCL. Of the relapsed MCL patients who previously received treatment, 2 patients were experiencing their first relapse following previous treatment with rituximab and bendamustine. The 3rd patient was experiencing 3rd relapse following previous treatment with R-CHOP, RDHAP, hyper-CVAD, and allogeneic SCT therapy.\u003c/p\u003e\n\n\u003cp\u003eThe dose escalation study tested cladribine in doses ranging from 3 to 5 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1 through 5 of 6 28-day cycles. Of the 13 patients, 3 received 3 mg/m\u003csup\u003e2\u003c/sup\u003e of cladribine in dose scale 1, 3 received 4 mg/m\u003csup\u003e2\u003c/sup\u003e of cladribine in dose scale 2, and 7 received 5 mg/m\u003csup\u003e2\u003c/sup\u003e of cladribine in dose scale 3. Of the 13 patients, 4 completed the 24-week dose-escalation study and followed with rituximab maintenance therapy as described at study design section. Two patients withdrew from therapy due to disease progression after each completing 2 cycles. One chose to withdraw from active therapy after completing 3 cycles of treatment and achieving CR status citing personal reasons, though he did continue with maintenance therapy. Another one also chose to withdraw after 4 cycles and instead to undergo rituximab maintenance after achieving partial remission with one persistently FDG avid lymph node, who ultimately achieved CR. One patient withdrew due to prolonged bone marrow suppression, though she suffered anemic, thrombocytopenic, and neutropenic prior to participating this study. \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo subject experienced DLT while receiving cladribine dose scales 1 or 2. One subject who was receiving cladribine dose scale 3 suffered infectious colitis during the second cycle of therapy and was labeled as possibly experiencing DLT. The patient died 7 months later as a result of multiple organ failure after experiencing disease progression. Additional patients were recruited to the cladribine dose scale 3 cohort, and no one experienced DLT. \u003c/p\u003e\n\n\u003cp\u003eTable 3 summarizes the most frequently reported adverse events (AEs). All AEs were grade 1 or 2 in severity other than single patient reports of cellulitis, diarrhea, neuropathy, fatigue, and hyperglycemia. The most common non-hematological AEs of any grade were neuropathy, fatigue, diarrhea, constipation, and hyponatremia. No patient experienced tumor lysis syndrome. Only one patient discontinued the treatment due to prolonged bone marrow suppression caused pancytopenia as previously mentioned. Of the 5 patients who discontinued treatment prior to completion of all 6 cycles, the median number of treatment cycles prior to discontinuation was 2 (range 2-4).\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eEfficacy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTable 4 summarizes each cohort\u0026rsquo;s best response to therapy. Of the 13 patients in this study, the OR rate was 11/13 patients (84.6%, 95% confidence interval 57.8-95.7). Complete remission (CR) was reported in 11/13 patients (84.6%, 95% confidence interval 57.8-95.7). In the newly diagnosed subject cohort, the OR and CR rates were both 100% (10/10). The 2-year overall survival (OS) rate in this cohort was 85% (11/13). The 1-year and 2-year progression-free survival (PFS) in this same cohort were 77% (10/13) and 60% (9/13), respectively. The median duration of response, PFS, and OS had not been reached at the time of the current report.\u003c/p\u003e\n\n\u003cp\u003eTwo patients are deceased during the period of the study due to disease progression. Patients on the overall survival curve (Figure 1a) are censored at time of last known survival.\u003c/p\u003e\n\n\u003cp\u003eFour patients experienced disease progression, including two deceased patients with relapsed disease who didn\u0026rsquo;t respond to treatment, and two patients who experienced relapse following complete remissions (Figure 1b). One patient\u0026rsquo;s death was not preceded by disease progression. Of the two patients who experienced disease progression without achieving remission, both suffered progression within two months of beginning this treatment, and both bore the blastoid variant type of MCL and suffered from relapsed disease at the time enrolled to this study. \u003c/p\u003e\n\n\u003cp\u003eOf the patients who achieved a response, only 2 experienced disease relapses, with response durations of 7.6 and 11.2 months. The remaining patients on the response duration curve (Figure 1c) were censored, with one patient\u0026rsquo;s remission times currently lasting longer than 50 months after first reaching CR.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eBiological Differences\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn initial attempt to determine whether there were any overall differences in methylation values between the subjects using principal components analysis (PCA). Figure 2A showed that the high-dimension data can be represented by the first seven components. Although the first two components only explained around 40% of variance of our data, which prevented us to visualize them in a two-dimension space efficiently (Figure 2B), we can still see the treatment-induced methylation changes. Prior to the treatment, a sample from a good responder (JP07) showed difference compared to the other three patients. After the treatment, the methylation from this patient has a big change (JP08). We can also see the methylation from one poor responder has a large change after treatment in the opposite direction (JP04 vs JP03).\u003c/p\u003e\n\n\u003cp\u003eDifferentially Methylated Regions (DMRs) analysis was then performed between good responders and poor responders before treatment and a total of 50 DMRs within gene promoter regions were identified, including both hypermethylated and hypomethylated regions (Figure 3). \u003c/p\u003e\n\n\u003cp\u003eIn this study, the methylation biomarkers for treatment response should meet two criteria: 1) they are differentially methylated between good and poor responders before treatment; 2) they respond to treatment differently between good and poor responders after treatment. We identified nine candidate DMRs (Figure 4A). All these regions are hypermethylated before treatment and demethylated after treatment in good responders (Figure 4B). When we examine their methylation profiles in poor responders, five of nine DMRs showed demethylated status before treatment while increased methylation or no change after treatment (subpanel 1, 2, 5, 8 and 9 in Figure 4C); the remaining four DMRs showed opposite trend (subpanel 3, 4, 6 and 7 in Figure 4C). Thus, the five DMRs differentially response to treatment between good and poor responders, indicating that they are potential methylation biomarkers for treatment response.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current most utilized regimens to initiate MCL treatment, including R-CHOP and R-hyper-CVAD, produce high overall response rates, though they oftentimes result in late relapse and are exceedingly toxic. \u003csup\u003e6, 20\u0026ndash;22\u003c/sup\u003e Due to the toxicity of these regimens, it is challenging to treat elderly patients with MCL, particularly those with comorbidities.\u003c/p\u003e \u003cp\u003ePrior trials have demonstrated the capabilities of both rituximab and cladribine as monotherapies in treating.\u003csup\u003e23\u0026ndash;25\u003c/sup\u003e In addition to patients treated by Inwards et al.\u003csup\u003e7\u003c/sup\u003e (2008), rituximab and cladribine combination therapy also was used to treat 9 MCL patients by Robak et al.\u003csup\u003e26\u003c/sup\u003e (2006), resulting in an OR rate of 67% and a CR rate of 22%. One report also notes a CR by colonic MCL treated with rituximab and cladribine.\u003csup\u003e27\u003c/sup\u003e It is suggested that hypomethylatic agent is one of several molecules synergistically enhance the MCL therapy efficacy.\u003csup\u003e11\u0026ndash;14\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn this study we demonstrated that the combination of Bortezomib, cladribine, and rituximab is a well-tolerated regimen, despite the elderly study population (median age of 64 years). No severe systemic toxicity was observed during this trial. The most common AEs resulted from bone marrow suppression. The therapy was not associated with a significant rate of opportunistic infections. Antiviral and antifungal prophylaxis was not used. Only one patient receiving cladribine dose scale 3 of 5 mg/m\u003csup\u003e2\u003c/sup\u003e was considered as possibly experiencing DLT. A previous study which also utilized this dosing of cladribine in combination with rituximab reported one death on therapy from cerebrovascular accident.\u003csup\u003e7\u003c/sup\u003e This toxicity profile is much preferable to those of more intensive R-CHOP or R-hyper-CVAD regimens.\u003c/p\u003e \u003cp\u003eThis trial resulted in OR and CR rates of 84.6%, including OR and CR rates of 100% in the newly diagnosed subject cohort. In addition, the newly diagnosed subject cohort\u0026rsquo;s 2-year PFS rate was 90%. In the study comparing MCL patients who were treated with cladribine and rituximab versus cladribine alone, the most striking difference occurred between the duration of responses in these two groups. The 2-year PFS rate was 43% in the group that received combination therapy versus 21% in the group that received cladribine alone.\u003csup\u003e7\u003c/sup\u003e We believe that the PFS rate is higher in this trial due to the use of an additional agent, Bortezomib.\u003csup\u003e28,29\u003c/sup\u003e Rituximab maintenance therapy (in 4 cases, rituximab and Bortezomib maintenance therapy) also played a rule in maintaining CR in long term.\u003csup\u003e30\u003c/sup\u003e Our previous SCR study results confirmed importance of maintenance therapy.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe efficacy of Bortezomib, cladribine, and rituximab (VCR) combination regimen within the much smaller cohort of relapsed MCL patients in this study was not as impressive as in the cohort of newly diagnosed MCL patients. The relapsed MCL cohort includes two patients who suffered disease progression while receiving VCR treatment. Furthermore, both patients bored the feature of blastoid variant of MCL, and one of the patients contained additional poor prognostic cytogenetic mutation. Our result on treating relapsed MCL patents is consistent with the results from a multicenter phase 2 PINNACLE study that utilized bortezomib to treat relapsed or refractory MCL, which resulted in an OR rate of 33% and a CR rate of 8%.\u003csup\u003e8,31,32\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOther trials have also studied therapies for newly diagnosed MCL. Ruan et al.\u003csup\u003e33\u003c/sup\u003e (2015) evaluated the combination of lenalidomide plus rituximab in this patient population. Of a total of 38 patients at the median follow-up of 30 months, the OR rate among participants with newly diagnosed MCL was 92%, with a CR rate of 64% and a 2-year PFS estimated to be 85%. A separate study by Rummel et al.\u003csup\u003e34\u003c/sup\u003e (2013), also for newly diagnosed disease, showed that a combination of bendamustine and rituximab significantly improved PFS of elderly patients with indolent MCL compared with R-CHOP, with a median PFS of 69.5 months but a CR rate of only 40%. Prior studies of this drug combination in patients with rituximab-refractory, indolent and transformed non-Hodgkin\u0026rsquo;s lymphoma showed a high relapse rate, with a median duration of response of 6.7 months.\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTremendous efforts have been making in searching for more effective MCL treatment target. \u003csup\u003e36\u0026ndash;39\u003c/sup\u003e Cladribine is a promising hypomethylatic agent in MCL combination therapy.\u003csup\u003e1\u003c/sup\u003e We conducted methylation assay on 2 good-responders and 2 poor-responders. PCA analysis data showed that there is difference between good-responders and poor- responders in methylation status change after receiving VCR regimen treatment. Furthermore, the DMR methylation status change patterns between good- and poor-responders in promoter regions of five genes raise the possibility of biomarkers and potential treatment target. However, these DMR methylation data needs to be verified via conducting study in a larger patient population.\u003c/p\u003e \u003cp\u003eOur data suggests that the VCR combination therapy is effective in treating MCL patients with minimal toxicity. VCR should be considered as a viable option of first line therapy for elderly MCL patients, or patients who opt for less aggressive regimens. A phase II/III study will further confirm the efficacy of this VCR regimen and help us to narrow the list of treatment-response biomarker candidates identified in this study, which also potentially could be the novel treatment target.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study is supported by: Takeda Pharmaceutical\u0026rsquo;s investigator-initiated study grant, AA \u0026amp; MDSIF research grant to JJP (146818), American Cancer Society research grant to JJP (124171-IRG-13-043-02) and Paige\u0026rsquo;s Cancer Researcher Fund to JJP (Pu33860).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Dr. Yuka Imamura Kawasawa and her molecular core laboratory for conducting methylation assay on those patient samples.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContributions: JJP and EME designed this study. JJP and KNB collected data and wrote this manuscript. JJP, WCE, DFC, and EME provided patient care. JJP and JJD directed correlative study. CZ and HL conducted biostatistics and bioinformatics analyses. CZ wrote bioinformatics interpretation in the manuscript. All authors participated in manuscript edition and finalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict-of-interest disclosure:\u003c/strong\u003e All authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e: All data is available to share for research purpose.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePu JJ, Savani M, Huang N, Epner EM. Mantle cell lymphoma management trends and novel agents: where are we going? Ther Adv Hematol. 2022 Feb 26;13:20406207221080743. doi: 10.1177/20406207221080743. PMID: 35237397; PMCID: PMC8882940.\u003c/li\u003e\n\u003cli\u003eLadha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its management: where are we now? Exp Hematol Oncol. 2019 Jan 30;8:2. doi: 10.1186/s40164-019-0126-0. PMID: 30733891; PMCID: PMC6354396.\u003c/li\u003e\n\u003cli\u003eMatutes E, Parry-Jones N, Brito-Babapulle V, Wotherspoon A, Morilla R, Atkinson S, Elnenaei MO, Jain P, Giustolisi GM, A\u0026apos;hern RP, Catovsky D. The leukemic presentation of mantle-cell lymphoma: disease features and prognostic factors in 58 patients. Leukemia \u0026amp; lymphoma. 2004 Oct 1;45(10):2007-15.\u003c/li\u003e\n\u003cli\u003eMartin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, Elstrom R, Niesvizky R, Ely S, DiLiberto M, Melnick A. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009 Mar 10;27(8):1209-13.\u003c/li\u003e\n\u003cli\u003eHerrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, Reiser M, Forstpointner R, Metzner B, Peter N, Wormann B. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009 Feb 1;27(4):511-8.\u003c/li\u003e\n\u003cli\u003eRomaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005 Oct 1;23(28):7013-23.\u003c/li\u003e\n\u003cli\u003eInwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. 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The hyper-CVAD\u0026ndash;rituximab chemotherapy programme followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma. Annals of hematology. 2007 Feb 1;86(2):101-5.\u003c/li\u003e\n\u003cli\u003eLenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). Journal of Clinical Oncology. 2005 Mar 20;23(9):1984-92.\u003c/li\u003e\n\u003cli\u003eHoward OM, Gribben JG, Neuberg DS, Grossbard M, Poor C, Janicek MJ, Shipp MA. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. Journal of Clinical Oncology. 2002 Mar 1;20(5):1288-94.\u003c/li\u003e\n\u003cli\u003eRummel MJ, Chow KU, J\u0026auml;ger E, Hossfeld DK, Bergmann L, Peter HD, Hansmann ML, Meyer A, Hoelzer D, Mitrou PS. Treatment of mantle-cell lymphomas with intermittent two-hour infusion of cladribine as first-line therapy or in first relapse. Annals of oncology. 1999 Jan 1;10(1):115-7.\u003c/li\u003e\n\u003cli\u003eGhielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, Betticher DC, Schefer H, Pichert G, Stahel R, Ketterer N. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). Journal of clinical oncology. 2005 Feb 1;23(4):705-11.\u003c/li\u003e\n\u003cli\u003eForan JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M, Coiffier B, Johnson PW, Gisselbrecht C, Reyes F, Radford JA. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. Journal of Clinical Oncology. 2000 Jan 1;18(2):317-24.\u003c/li\u003e\n\u003cli\u003eInwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long‐term results of the treatment of patients with mantle cell lymphoma with cladribine (2‐CDA) alone (95‐80‐53) or 2‐CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16.\u003c/li\u003e\n\u003cli\u003eRobak T, Smolewski P, Cebula B, Szmigielska‐Kaplon A, Chojnowski K, Blonski JZ. Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma. Cancer. 2006 Oct 1;107(7):1542-50.\u003c/li\u003e\n\u003cli\u003eWatanabe T, Homma N, Ogata N, Saito H, Kanefuji T, Hasegawa K, Soga K, Shibasaki K, Endo T, Ajioka Y. Complete response in a patient with colonic mantle cell lymphoma with multiple lymphomatous polyposis treated with combination chemotherapy using anti-CD20 antibody and cladribine. Gut. 2007 Mar 1;56(3):449-50.\u003c/li\u003e\n\u003cli\u003eForstpointner R, Unterhalt M, Dreyling M, B\u0026ouml;ck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, H\u0026auml;nel A, Lehmann T. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8.\u003c/li\u003e\n\u003cli\u003eKahl BS, Longo WL, Eickhoff JC, Zehnder J, Jones C, Blank J, McFarland T, Bottner W, Rezazedeh H, Werndli J, Bailey HH. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network. Annals of oncology. 2006 Jun 9;17(9):1418-23.\u003c/li\u003e\n\u003cli\u003eFisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, De Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Journal of clinical oncology. 2006 Oct 20;24(30):4867-74.\u003c/li\u003e\n\u003cli\u003eGoy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, De Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Annals of oncology. 2008 Dec 12;20(3):520-5.\u003c/li\u003e\n\u003cli\u003eRuan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. New England Journal of Medicine. 2015 Nov 5;373(19):1835-44.\u003c/li\u003e\n\u003cli\u003eRummel MJ, Niederle N, Maschmeyer G, Banat GA, von Gr\u0026uuml;nhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. The Lancet. 2013 Apr 6;381(9873):1203-10.\u003c/li\u003e\n\u003cli\u003eFriedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, Van der Jagt RH. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin\u0026apos;s lymphoma: results from a phase II multicenter, single-agent study. Journal of Clinical Oncology. 2008 Jan 10;26(2):204-10.\u003c/li\u003e\n\u003cli\u003ePeng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, Cho K, Hensley-Alford S, Munkarah A, Liu R, Zou W. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015 Nov 12;527(7577):249-53. doi: 10.1038/nature15520.\u003c/li\u003e\n\u003cli\u003eKurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009 May 7;113(19):4604-13. doi: 10.1182/blood-2008-10-185827. Epub 2009 Feb 19. PMID: 19228923; PMCID: PMC4969050.\u003c/li\u003e\n\u003cli\u003eCorcione A, Arduino N, Ferretti E, Raffaghello L, Roncella S, Rossi D, Fedeli F, Ottonello L, Trentin L, Dallegri F, Semenzato G, Pistoia V. CCL19 and CXCL12 trigger in vitro chemotaxis of human mantle cell lymphoma B cells. Clin Cancer Res. 2004 Feb 1;10(3):964-71. doi: 10.1158/1078-0432.ccr-1182-3. PMID: 14871974.\u003c/li\u003e\n\u003cli\u003eLong ME, Koirala S, Sloan S, Brown-Burke F, Weigel C, Villagomez L, Corps K, Sharma A, Hout I, Harper M, Helmig-Mason J, Tallada S, Chen Z, Scherle P, Vaddi K, Chen-Kiang S, Di Liberto M, Meydan C, Foox J, Butler D, Mason C, Alinari L, Blaser BW, Baiocchi R. Resistance to PRMT5-targeted therapy in mantle cell lymphoma. Blood Adv. 2024 Jan 9;8(1):150-163. doi: 10.1182/bloodadvances.2023010554. PMID: 37782774.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: information for patient response and treatment\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.635859519408502%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.147874306839185%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.072088724584102%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.256931608133087%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePatient 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.88724584103512%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePatient 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.053097345132743%\" valign=\"top\"\u003e\n \u003cp\u003eJP01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.061946902654867%\" valign=\"top\"\u003e\n \u003cp\u003eJP02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.274336283185841%\" valign=\"top\"\u003e\n \u003cp\u003eJP03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\" valign=\"top\"\u003e\n \u003cp\u003eJP04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.168141592920353%\" valign=\"top\"\u003e\n \u003cp\u003eJP05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.274336283185841%\" valign=\"top\"\u003e\n \u003cp\u003eJP06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.274336283185841%\" valign=\"top\"\u003e\n \u003cp\u003eJP07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.946902654867257%\" valign=\"top\"\u003e\n \u003cp\u003eJP08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.605166051660518%\" valign=\"top\"\u003e\n \u003cp\u003eResponse\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.885608856088561%\" valign=\"top\"\u003e\n \u003cp\u003egood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.22509225092251%\" valign=\"top\"\u003e\n \u003cp\u003egood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.96309963099631%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.14760147601476%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003egood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.96309963099631%\" valign=\"top\"\u003e\n \u003cp\u003egood\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.605166051660518%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.885608856088561%\" valign=\"top\"\u003e\n \u003cp\u003ebefore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.22509225092251%\" valign=\"top\"\u003e\n \u003cp\u003eafter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003ebefore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.96309963099631%\" valign=\"top\"\u003e\n \u003cp\u003eafter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.14760147601476%\" valign=\"top\"\u003e\n \u003cp\u003ebefore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003eafter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.07011070110701%\" valign=\"top\"\u003e\n \u003cp\u003ebefore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.96309963099631%\" valign=\"top\"\u003e\n \u003cp\u003eafter\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Patient baseline characteristics.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eN = 13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMedian age (range), years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e64 (53-81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSex, male/female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e11/2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eECOG performance score, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e1 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e6 (46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e4 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eMIPI score, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Low (\u0026lt;5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;9 \u0026nbsp; \u0026nbsp; (69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Intermediate (5.7-6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;4 \u0026nbsp; \u0026nbsp; (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; High (\u0026gt;6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;0 \u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eRisk Factors, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Age \u0026gt;60 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;8 \u0026nbsp; \u0026nbsp; (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ECOG \u0026gt;/= 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;0 \u0026nbsp;(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; LDH/ULN \u0026gt; 6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e13 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; WBC \u0026gt; 6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;8 \u0026nbsp; \u0026nbsp; (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3: Common adverse events (n=13) on patients participating in the trial. Data are number of patients (%). \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003eGrade 4 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHematological Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e4 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNeutropenia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e5 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e6 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eFebrile Neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e5 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLymphopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2(15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e10 (77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNon-hematological Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eChills\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eGFR decrease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eCellulitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e4 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eDyspnea on exertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHyperuricemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased alkaline phosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased ALT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased AST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e4 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased total bilirubin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eIncreased LDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHives\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eWatery Eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eBone pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNeuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e4 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eMyalgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eStye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLoss of balance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eJoint/Back pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eBradycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eUpper respiratory infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eWeight loss\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eTonsillitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHypocalcemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e4 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eMouth sores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eCold intolerance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLoss of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLower extremity edema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHypomagnesemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e5 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHyperglycemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eHypernatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eWeakness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eLightheadedness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.757575757575758%\" valign=\"top\"\u003e\n \u003cp\u003eAvascular necrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e1 (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.560606060606062%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4: Response rates in newly diagnosed and relapsed MCL patients receiving bortezomib, cladribine, and rituximab. Dose cohorts received 3-5mg/m\u003csup\u003e2\u003c/sup\u003e of cladribine. PR: Partial Remission; DP: Disease Progression\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003eReceiving 3mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003eReceiving 4mg/m\u003csup\u003e2\u003c/sup\u003e (n=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003eReceiving 5mg/m\u003csup\u003e2\u003c/sup\u003e (n=7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003eNewly Diagnosed (n=10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003eOverall (n=13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003ePatients with relapsed MCL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e1 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003eORR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e4 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e10 (77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003eBest Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;CR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e5 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e11 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;PR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;DP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003eMedian time to first response (range, months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2.5 (2.1-3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e6.8 (2.2-7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3.0 (2.4-6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3.1 (2.1-7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3.0 (2.1-7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e1-year PFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2 (67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e5 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e10 (77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e2-year PFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e1 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e4 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e8 (62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e4-year PFS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3/3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e1-year OS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e5 (71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e11 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e2-year OS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e4 (57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e10 (77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.599320882852293%\" valign=\"top\"\u003e\n \u003cp\u003e4-year OS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2/2(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e2/2 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e0/2(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e3/3(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.280135823429541%\" valign=\"top\"\u003e\n \u003cp\u003e4/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"experimental-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"exho","sideBox":"Learn more about [Experimental Hematology \u0026 Oncology](http://ehoonline.biomedcentral.com)","snPcode":"40164","submissionUrl":"https://submission.nature.com/new-submission/40164/3","title":"Experimental Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4139215/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4139215/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCladribine indirectly downregulates methylations of DNA, RNA and histone by blocking transferring methyl groups from S-adenosyl-methionine. Cladribine and Rituximab combination showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is a FDA approved proteasome inhibitor for treating mantle cell lymphoma (MCL).\u003c/p\u003e\n\u003cp\u003eIn this single arm phase I study, we evaluated the safety, dose limiting toxicity, and efficiency of Bortezomib, Cladribine, and Rituximab (VCR) combination treatment in elderly MCL patients. We also proposed potential DNA methylation biomarkers for VCR treatment. A standard 3+3 dose escalation scheme was designed to determine the maximum tolerable cladribine dose. The therapy consisted of 6 28-day cycles.\u003c/p\u003e\n\u003cp\u003eMost patients tolerated this regimen well. The overall responding (OR) rate was 84.6% and complete remission (CR) rate was 84.6%. In newly diagnosed subject cohort, the OR and CR was 100% respectively, 1 year overall survival rate was 90%, and progression free survival rate was 80%. Low grade hematological toxicity and mild fatigue were observed. No severe systemic toxicity was observed. Five hypermethylated regions located at gene promoters were identified as potential biomarkers for an effective treatment response.\u003c/p\u003e\n\u003cp\u003eIn conclusion,\u003cstrong\u003e \u003c/strong\u003eVCR combination is a well-tolerated, low toxicity and effective regimen for elderly untreated MCL.\u003c/p\u003e\n\u003cp\u003eClinicaltrials.gov #: NCT01439750.\u003c/p\u003e","manuscriptTitle":"A Phase I Study using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Elderly Patients with Mantle Cell Lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-27 17:26:55","doi":"10.21203/rs.3.rs-4139215/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-03-22T11:12:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-22T05:10:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Experimental Hematology \u0026 Oncology","date":"2024-03-20T19:15:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"experimental-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"exho","sideBox":"Learn more about [Experimental Hematology \u0026 Oncology](http://ehoonline.biomedcentral.com)","snPcode":"40164","submissionUrl":"https://submission.nature.com/new-submission/40164/3","title":"Experimental Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f0301cd8-f796-4fdb-8b3e-580ca8654731","owner":[],"postedDate":"March 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-03-27T17:26:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-27 17:26:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4139215","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4139215","identity":"rs-4139215","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}