Refractory Indolent B-cell Lymphoma Research Articles

Six-year safety and efficacy results from the CHRONOS-1 study of the PI3K inhibitor copanlisib in patients with relapsed or refractory follicular lymphoma.

7555 Background: The efficacy of copanlisib, an intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, was demonstrated in the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma (Dreyling et al. J Clin Oncol 2017). Copanlisib was approved by the US Food and Drug Administration in 2017 for the treatment of patients with follicular lymphoma (FL) who have received ≥2 therapies. Here, we describe updated efficacy and safety data from patients with FL at the 6-year follow-up of CHRONOS-1. Methods: CHRONOS-1 included patients with relapsed or refractory indolent FL (grades 1-3a) who had received ≥2 lines of therapy. Copanlisib 60 mg was administered via intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Objective tumor response rate (ORR) was assessed by independent radiologic review (Cheson et al. J Clin Oncol 2007) as the primary efficacy endpoint. Safety analysis included adverse events graded using CTCAE v4.03. Results: 104 patients with FL were treated in CHRONOS-1, of whom 99.0% ( n= 103) discontinued treatment at the time of database cut-off on June 30, 2022. 72% of patients ( n= 75) received ≥1 line of subsequent systemic anti-cancer therapy during follow-up, with 40% receiving a rituximab-based regimen. At the cut-off, ORR (primary endpoint) was 57.7% ( n= 60), with 19.2% ( n= 20) of patients achieving a complete response. Median duration of response was 12.2 months (range 1.1-48.1). Median progression-free survival (PFS) was 11.2 months (range 0.2-51.5) with a median follow-up of 20.7 months (95% confidence interval [CI] 11.5, 31.5); PFS rate was 32% at 2 years. Median overall survival was 46.3 months (range 0.7-82.9) with a total of 56 events and a median follow-up of 82.4 months (95% CI 79.3, 84.9); survival rate was 43% at 6 years. Median duration of treatment was 6.0 months (range 0.23-80.9). No patients experienced transformation to aggressive lymphoma (diffuse large B-cell lymphoma). The primary reasons for stopping treatment included radiologic disease progression (42.3%; n= 44) and adverse events not associated with clinical disease progression (29.8%; n= 31). The safety profile was consistent with the reported 2-year follow-up data (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent adverse events (all grades/grades 3-4) were infusion-related hyperglycemia (50.0%/39.5%), diarrhea (36.5%/8.7%), hypertension (28.8%/23.1%), pyrexia (27.9%/4.8%), and neutropenia (26.0%/23.0%). Conclusions: Copanlisib continued to induce robust response and durable survival in patients with relapsed or refractory indolent FL at 6 years of follow-up. Copanlisib was well tolerated, with no new safety signals and no evidence of malignant transformation. These results further support the long-term use of copanlisib in this patient population. Clinical trial information: NCT01660451 .

Updated Safety and Efficacy from the Copanlisib CHRONOS-1 Trial in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma: Low Incidence of Late-Onset Severe Toxicities

Updated Safety and Efficacy from the Copanlisib CHRONOS-1 Trial in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma: Low Incidence of Late-Onset Severe Toxicities

Efficacy of Copanlisib Monotherapy in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Subset Analysis from the CHRONOS-1 Trial

Efficacy of Copanlisib Monotherapy in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Subset Analysis from the CHRONOS-1 Trial

Long-Term Efficacy and Safety from the Copanlisib CHRONOS-1 Study in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma

Long-Term Efficacy and Safety from the Copanlisib CHRONOS-1 Study in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma

Outcomes for Patients with Pre-Existing Diabetes or Hypertension Treated with Copanlisib from the CHRONOS-1 Study in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma

Outcomes for Patients with Pre-Existing Diabetes or Hypertension Treated with Copanlisib from the CHRONOS-1 Study in Patients with Relapsed or Refractory Indolent B-Cell Lymphoma

Outcomes for Patients with High-Risk Relapsed or Refractory Indolent B-Cell Lymphoma Treated with Copanlisib in the CHRONOS-1 Study

Outcomes for Patients with High-Risk Relapsed or Refractory Indolent B-Cell Lymphoma Treated with Copanlisib in the CHRONOS-1 Study

1006O - Copanlisib monotherapy activity in relapsed or refractory indolent B-cell lymphoma: Combined analysis from phase I and II studies

1006O - Copanlisib monotherapy activity in relapsed or refractory indolent B-cell lymphoma: Combined analysis from phase I and II studies

Copanlisib treatment in patients with relapsed or refractory indolent B-cell lymphoma: Subgroup analyses of diabetic patients from the phase II CHRONOS-1 study.

7570Background: Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity recently approved in the US for treatment of relapsed follicul...

Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma.

This corrects the article DOI: 10.1038/bcj.2015.86.

1000PD - Copanlisib treatment in patients with relapsed or refractory indolent B-cell lymphoma: Subgroup analyses from the CHRONOS-1 study

1000PD - Copanlisib treatment in patients with relapsed or refractory indolent B-cell lymphoma: Subgroup analyses from the CHRONOS-1 study

Abstract CT149: Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study

Abstract Introduction: There are limited treatment options for patients with indolent B-cell lymphoma who have relapsed or are refractory to standard therapies. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. We report here the primary results from a pivotal phase II study (NCT01660451, part B). Methods: Patients with indolent B-cell non-Hodgkin lymphoma (4 subtypes: follicular [FL], marginal zone [MZL], small lymphocytic [SLL] and lymphoplasmacytoid/Waldenström macroglobulinemia [LPL-WM]) and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective tumor response rate (ORR) as assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: The full analysis set comprised 142 patients, of which 141 patients had indolent lymphoma (FL/MZL/SLL/LPL-WM: 104/23/8/6). At the time of primary analysis, median duration of treatment was 22 weeks (range 1-105); 46 patients remained on treatment. The most common treatment-related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs of interest included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). No colonic perforations occurred. There were two non-fatal opportunistic infections. Laboratory toxicities of interest were principally grade-1, including alanine aminotransferase (23% all-grade/19% grade-1) and aspartate aminotransferase (28%/25%). There were 6 deaths, 3 of which were attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with stable disease in 29.6% of patients and progressive disease in 2.1% of patients. In the FL subset, the ORR was 58.7%, including 14.4% CR and 44.2% PR. In the MZL subset, the ORR was 69.6%, including 8.7% CR and 60.9% PR. The estimated Kaplan-Meier (KM) median duration of response in the full analysis set was 687 days (range 0-687) and 370 days (range 0-687) in the FL subset. The KM-estimate of median PFS was 340 days (range 0-736). Median overall survival had not yet been reached. Conclusions: Treatment of patients with relapsed or refractory indolent B-cell lymphoma with copanlisib resulted in durable tumor responses. Administration of copanlisib had a manageable safety profile, with low rates of severe hepatic enzymopathy, diarrhea or inflammatory events, as well as low rates of opportunistic infections, fatal infections or other fatal serious adverse events. Citation Format: Martin Dreyling, Armando Santoro, Luigina Mollica, Sirpa Leppä, George A. Follows, Georg Lenz, Won Seog Kim, Arnon Nagler, Panayiotis Panayiotidis, Judit Demeter, Muhit Özcan, Marina Kosinova, Krimo Bouabdallah, Franck Morschhauser, Don A. Stevens, David Trevarthen, Marius Giurescu, Lisa Kupit, Shuxin Yin, Florian Hiemeyer, Jose Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT149. doi:10.1158/1538-7445.AM2017-CT149

Prolonged Lymphocytepenia after Bendamustine with or without Rituximab Treatment in Patients with Relapsed or Refractory Indolent B-Cell and Mantle Cell Lymphoma

Introduction:Although bendamustine with or without rituximab has demonstrated remarkable efficacy in patients with relapsed or refractory indolent B-cell lymphoma (B-NHL) and mantle cell lymphoma (MCL), previous reports showed that the incidence of lymphocytopenia was higher in patients receiving bendamustine with or without rituximab than in those receiving other conventional cytotoxic chemotherapies such as R-CHOP regimen. However, the length of time until recovery of the decreased lymphocytes and CD4-positive T cells to the baseline upon bendamustine treatment is still unclear.Patients and Methods:We retrospectively analyzed 56 consecutive patients with relapsed or refractory B-NHL and MCL who received bendamustine with or without rituximab at our institution between 2011 and 2014. We analyzed their peripheral blood lymphocytes and CD4-positive T-cell counts at baseline, during, and after bendamustine treatment, the details of infectious events, and their correlations.Results:Thirty-one (55%) patients were male and 25 (45%) female, with a median age of 63 years (range: 36-86). Twenty (35%) patients had follicular lymphoma, 14 (25%) MCL, nine (16%) transformed lymphoma, five (9%) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, four (7%) small lymphocytic lymphoma, two (4%) nodal marginal zone lymphoma, and one (2%) each had lymphoplasmacytic lymphoma and low-grade B-NHL, unclassifiable. The median number of prior regimens administered was two (range: 1-9). Twenty-three (41%) of the 56 patients received rituximab in combination with bendamustine. The median number of bendamustine cycles was four (range: 1-6). The median follow-up period was nine months (range: 0-33 months). At baseline, median lymphocyte and CD4-positive T-cell counts were 1,025/µL (range: 270-3,420/µL) and 282/µL (range: 83-645/µL), respectively. After the first cycle, they immediately decreased to 545/µL (range: 60-2,900/µL) and 190/µL (range: 116-635/µL), respectively. The median lymphocyte and CD4-positive T-cell count nadirs during observation were 365/µL (range: 20-1,310/µL) and 93/µL (range: 7-178/µL), respectively. Significantly decreased lymphocyte counts (median: 260 vs. 410/µL) were detected in the patients who received bendamustine with rituximab compared with those who received bendamustine alone (p=0.03). Recovery of lymphocyte and CD4-positive T-cell counts to those at baseline was observed at 7-9 months after the completion of bendamustine with or without rituximab, and median lymphocyte and CD4-positive T-cell counts were 1,045/µL (range: 170-2,580/µL) and 223/µL (range: 47-709/µL), respectively (Figures A, B). The numbers of patients who received prophylaxis against pneumocystis pneumonia (PCP), varicella zoster virus (VZV), and fungal infection were 44 (78%), 37 (66%), and four (7%), respectively, at the physician’s discretion. Infectious events were observed in 32 (57%) patients during follow-up. Cytomegalovirus antigenemia was detected in 15 (27%) patients, VZV infection in two (3%), cytomegalovirus colitis in one (2%), and other infectious complications such as sepsis or febrile neutropenia in 20 (35%) patients. Interestingly, all infectious events occurred within nine months after the completion of bendamustine with or without rituximab in patients who received no treatment after bendamustine during follow-up.Conclusion:The results of this analysis revealed that the majority of relapsed or refractory patients with indolent B-NHL and MCL showed prolonged lymphocytopenia and low CD4-positive T-cell counts, for at least 7-9 months, after the completion of bendamustine with or without rituximab. Because lymphocytopenia, especially low CD4-positive T-cell counts, may increase the risk of opportunistic infections, the prophylaxis against PCP and VZV deserves consideration for at least 7-9 months after bendamustine treatment. Further investigations, especially a prospective study, are needed to confirm our results. [Display omitted] [Display omitted] Box plots of lymphocyte counts (Figure A) and CD4-positive T-cell counts (Figure B) among patients who were treated with bendamustine with or without rituximab. DisclosuresMaruyama:Eisai Co., Ltd: Honoraria. Kobayashi:Boehringer Ingelheim GmbH: Research Funding; ARIAD Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Tobinai:Eisai Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding.

FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan Therapy Predicts Outcome in Relapsed or Refractory Indolent B-Cell Lymphoma

AbstractAbstract 3648 Background:Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan has been used for the treatment of relapsed or refractory indolent B-cell lymphoma. Early prediction of response to the therapy may offer the potential to identify patients who will benefit this therapy. We evaluated the efficacy of fluorine 18 fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (FDG-PET/CT) imaging for assessment of therapy and predicting outcome in 90Y-ibritumomab tiuxetan radioimmunotherapy. Methods:Radioimmunotherapy with 90Y-ibritumomab tiuxetan was preformed in 52 patients with relapsed or refractory indolent B cell lymphoma (follicular lymphoma, 45; mucosa-associated lymphoid tissue lymphoma, 5; lymphoplasmacytic lymphoma, 2) at Hyogo College of Medicine Hospital from June 2009 through August 2012. FDG-PET/CT scanning was performed at two weeks and the later after 90Y-ibritumomab tiuxetan therapy. Results:In FDG-PET at 2 weeks after 90Y-ibritumomab therapy, 26 (50%) showed complete response (defined as early CR), 20 (38%) showed partial response (PR-2W) and 6 (12%) showed non response (NR-2W). Further follow-up revealed 10 later CR (8 CR out of 20 PR-2W and 2 CR out of 6 NR-2W), showing 69 %(36) of overall CR rate. Relapse was occurred in 4(17%) of 26 early CR and in 6 (60%) of 10 later CR, indicating significantly low relapse late in early CR (P= 0.0074, by Chi-square test). Patients with early CR (CR in 2 weeks after the RIT) showed significantly better progression free survival than those with later CR (P=0.0046, by Logrank test). In contrast, analysis at six weeks after the RIT showed 36 CR patients (10 of which eventually relapse), but failed to discriminate patients who had high risk of relapse. Conclusion:Our results suggest that CR assessed by FDG-PET/CT at 2 weeks after 90Y-ibritumomab tiuxetan therapy discriminates good responder to the RIT and predicts better progression free survival in relapsed or refractory indolent B cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Japanese phase II study of 90Y‐ibritumomab tiuxetan in patients with relapsed or refractory indolent B‐cell lymphoma

There is no data about the efficacy and safety of radioimmunotherapy with 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma pretreated with rituximab-containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with 90Y-ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100-149x10(9) and >150x10(9) platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with 90Y-ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty-five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab-containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67-93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51-81%). The overall response rates in patients pretreated with rituximab-containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression-free survival time of the 40 patients who received 90Y-ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non-hematological toxicity was observed. In conclusion, radioimmunotherapy with 90Y-ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B-cell lymphoma, including those pretreated with rituximab-containing chemotherapy. (ClinicalTrials.gov number NCT00220285).

Cladribine Treatment in Two-Hour Intravenous Infusion for Previously-Treated Low Grade B-Cell Lymphoma : A Pilot Study

Cladribine is approved to be used in 24-hour continuous infusion for the treatment of low-grade lymphoma by the Ministry of Health, Labor and Welfare in Japan. Pharmacokinetic studies showed that the antitumor activity of cladribine by 2-hour infusion should be comparable to that given by continuous infusion. The safety and anti-tumor activity of short infusion of cladribine was shown in hairy cell leukemia, chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma in Europe. We therefore underwent a pilot study to confirm the safety and efficacy of cladribine given by 2-hour infusion for Japanese patients with relapsed or refractory indolent B-cell lymphoma. Cladribine at a dose of 0.09 mg/kg was administered in 2-hour intravenous infusion for 5 consecutive days. The treatment was repeated at a 28-day interval for at least 2 cycles, and its efficacy and toxicity were investigated. Fourteen patients were entered into this study. Eight patients (57%) responded to cladribine, including 2 (14%) complete response (CR) and 6 (43%) partial response (PR). The median duration of response was 20+ and 21+ months for CR, and 12 months ranging from 3 to 34 months for PR, respectively. Grade 3 or 4 neutropenia and lymphocytopenia occurred in 43% and 71% of patients, respectively, but there was no febrile neutropenia or opportunistic infection associated with cladribine treatment. No other adverse events greater than grade 3 were encountered. The tumor response and degree of toxicity were comparable with those observed in cladribine treatment given by continuous infusion at a same dose. Cladribine can be administered in 2-hour infusion in an outpatient clinic and is therefore quite convenient for patients.

Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells

AbstractAdoptive immunotherapy with T cells expressing a tumor-specific chimeric T-cell receptor is a promising approach to cancer therapy that has not previously been explored for the treatment of lymphoma in human subjects. We report the results of a proof-of-concept clinical trial in which patients with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma were treated with autologous T cells genetically modified by electroporation with a vector plasmid encoding a CD20-specific chimeric T-cell receptor and neomycin resistance gene. Transfected cells were immunophenotypically similar to CD8+ effector cells and showed CD20-specific cytotoxicity in vitro. Seven patients received a total of 20 T-cell infusions, with minimal toxicities. Modified T cells persisted in vivo 1 to 3 weeks in the first 3 patients, who received T cells produced by limiting dilution methods, but persisted 5 to 9 weeks in the next 4 patients who received T cells produced in bulk cultures followed by 14 days of low-dose subcutaneous interleukin-2 (IL-2) injections. Of the 7 treated patients, 2 maintained a previous complete response, 1 achieved a partial response, and 4 had stable disease. These results show the safety, feasibility, and potential antitumor activity of adoptive T-cell therapy using this approach. This trial was registered at www.clinicaltrials.gov as #NCT00012207.

Phase I study of radioimmunotherapy with an anti‐CD20 murine radioimmunoconjugate (90Y‐ibritumomab tiuxetan) in relapsed or refractory indolent B‐cell lymphoma

We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium-90-ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B-cell lymphoma. Indium-111-labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma-camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non-hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non-hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non-hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903-910).

Bortezomib: clinical profile in lymphoproliferative malignancies

In addition to its efficacy in the treatment of multiple myeloma, the proteasome inhibitor bortezomib appears to be active against a variety of other haematological malignancies. In a phase II trial, bortezomib, given twice weekly for 2 weeks of a 3 week cycle to patients with relapsed, refractory or untreated indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL), produced durable responses in 2/7 MCL patients and stable disease in five. Six of eight patients with follicular NHL achieved a durable response (1 CR, 5 PR). In another study, bortezomib was administered to patients with relapsed or refractory indolent or aggressive B-cell lymphoma. Durable responses were seen in 7/12 MCL patients, including three CR. This apparent activity in MCL is particularly encouraging, given its poor prognosis. These early trial results demonstrate that further clinical testing of bortezomib and additional exploration of the multiple biologic effects of proteasome inhibition are warranted in lymphoproliferative malignancies.

Bortezomib: clinical profile in lymphoproliferative malignancies

In addition to its efficacy in the treatment of multiple myeloma, the proteasome inhibitor bortezomib appears to be active against a variety of other haematological malignancies. In a phase II trial, bortezomib, given twice weekly for 2 weeks of a 3 week cycle to patients with relapsed, refractory or untreated indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL), produced durable responses in 2/7 MCL patients and stable disease in five. Six of eight patients with follicular NHL achieved a durable response (1 CR, 5 PR). In another study, bortezomib was administered to patients with relapsed or refractory indolent or aggressive B-cell lymphoma. Durable responses were seen in 7/12 MCL patients, including three CR. This apparent activity in MCL is particularly encouraging, given its poor prognosis. These early trial results demonstrate that further clinical testing of bortezomib and additional exploration of the multiple biologic effects of proteasome inhibition are warranted in lymphoproliferative malignancies.