Marked Activity of Bortezomib, Rituximab, and Dexamethason in Relapsed and Refractory Mantle Cell Lymphoma.

Abstract Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. We have now enrolled 14 pts at a median age of 69 years (range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 12 pts, high-dose therapy in 4 pts, and thalidomide in 7 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts), vasculitic skin infiltrates in 3 pts, and hyponatremia in 1 pt. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 12 pts evaluable for efficacy, 9 have achieved a response (3 CR, 6 PR), and 2 pts experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. All 3 pts who achieved a CR are still progression-free at 12 months after treatment initiation. Among pts in PR, 3 pts have relapsed (progression-free survival 14, 11, and 6 months, respectively), and 3 pts are still progression-free beyond 6 months from initiation of treatment. In summary, the BORID treatment regimen has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable and durable response.

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Marked activity of bortezomib, rituximab, and dexamethasone (BORID) in heavily pretreated patients with mantle cell lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.17522 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 17522-17522 ◽

Cited By ~ 2

Author(s):

J. Drach ◽

H. Kaufmann ◽

O. Pichelmayer ◽

V. Sagaster ◽

S. Seidl ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Proteasome Inhibitors ◽

High Dose ◽

Synergistic Activity ◽

Mantle Cell ◽

Heavily Pretreated ◽

Mucosal Candidiasis ◽

Line Of Therapy

17522 Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. Methods: We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. Results: Up to now, we have enrolled 10 pts (median age, 69 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 8 pts, high-dose therapy in 3 pts, and thalidomide in 5 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 8 pts evaluable for efficacy, 7 have achieved a response (3 CR, 4 PR), and 1 pt experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. 6 of 6 pts are still progression-free at 6 months after treatment initiation. Recruitment of patients is ongoing, and updated results will be presented. Conclusions: Data obtained thus far indicate that BORID has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable response. [Table: see text]

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Bortezomib, Rituximab, and Dexamethason (BORID) as Salvage Treatment in Relapsed/Refractory Mantle Cell Lymphoma: Sustained Disease Control in Patients Achieving a Complete Remission.

Blood ◽

10.1182/blood.v110.11.2578.2578 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2578-2578 ◽

Cited By ~ 2

Author(s):

Johannes Drach ◽

Hannes Kaufmann ◽

Oskar Pichelmayer ◽

Verena Sagaster ◽

Sonja Holzer ◽

...

Keyword(s):

Adverse Events ◽

Disease Control ◽

Mantle Cell Lymphoma ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

High Dose ◽

Synergistic Activity ◽

Overall Response ◽

Mantle Cell

Abstract Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We therefore evaluated the activity and safety of B in combination with R and dexamethasone (BORID) in patients with relapsed and refractory MCL (phase II trial). Methods: A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) achieving a response received 4 additional doses of R as maintenance (every 8 weeks). Pts with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) were eligible. Results: We have completed enrollment of 16 pts (median age, 67 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6, prior rituximab in 88%; thalidomide in 50%; high-dose therapy in 31%; a fludarabine-containing regimen in 31%). Median time between start of frontline therapy and study inclusion was 42 months (range, 11 to 98 months). Severe adverse events (> grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (< 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Overall response rate was 69% (11 of 16 pts), with 6 pts achieving a CR (38%; confirmed by PET-scan in 5 pts) and 5 pts reaching a PR. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. Remission status appeared to be associated with progression-free survival (PFS): Patients in CR had longer PFS (29+, 24+, 21+, 12+, 12, and 10+ months) compared to patients in PR (median 8.5 months, range 6 – 15). Conclusions: BORID has promising activitiy (69% overall response rate; CR rate 38%) and managable toxicity in this patient population with predominantly heavily pretreated MCL. Achievement of a CR emerged as an important factor for sustained disease control. Further evaluation of this regimen, in particular in pts at an earlier phase of the disease, is warranted.

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Promising Activity of Bortezomib, Rituximab, and Dexamethason (BORID) in Patients with Relapsed Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v106.11.4799.4799 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4799-4799

Author(s):

Johannes Drach ◽

Sonja Seidl ◽

Oskar Pichelmayer ◽

Hannes Kaufmann ◽

Christoph Zielinski ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Autologous Transplantation ◽

High Dose ◽

Synergistic Activity ◽

Phase Ii Studies ◽

Mantle Cell

Abstract Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma. Moreover, recent data indicate that B is also effective in other B-cell malignancies, most notably in mantle cell lymphoma (MCL). Phase II studies revealed remission rates between 40 and 55% of patients with relapsed or refractory MCL. Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of such a treatment combination. We have therefore initiated a phase II study in relapsed/chemotherapy refractory MCL in order to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. Up to now, we have enrolled 7 patients at a median age of 65 years (range, 52 to 74 years); they had received one to 6 lines of prior therapy including R in 5 of them and high-dose chemotherapy followed by autologous stem cell transplantation in 2 patients. Severe adverse events (> grade II) included 3 infections (herpes zoster, bacterial pneumonia, pneumonia of potential viral origin), grade III peripheral neuropathy in one patient, and nodular skin infiltrates in one patient. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. No severe hematological toxicity has yet been encountered. Of 6 patients evaluable for efficacy, 5 have achieved a response (1 CR, 4 PR), and 1 patient experienced stable disease. The patient in CR (previously treated by R-CHOP, autologous transplantation, and R plus thalidomide) was also negative for disease activity by PET scanning. None of the patients has yet progressed at 4 to 9 months after initiation of BORID. Recruitment of patients is ongoing, and updated results will be presented. Data obtained thus far indicate that BORID has promising activitiy and managable toxicity in patients with relapsed MCL, which warrants further investigation not only in MCL but also in other B-cell lymphomas.

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The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2010-11-314708 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2807-2812 ◽

Cited By ~ 134

Author(s):

Jonathan W. Friedberg ◽

Julie M. Vose ◽

Jennifer L. Kelly ◽

Faith Young ◽

Steven H. Bernstein ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Cell Lymphoma ◽

Objective Response ◽

Synergistic Activity ◽

Significant Activity ◽

Serious Adverse Events ◽

Non Hodgkin Lymphoma ◽

Mantle Cell

AbstractGiven the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m2 days 1 and 4; rituximab 375 mg/m2 day 1, and bortezomib 1.3 mg/m2 days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.

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Rituximab/Chemotherapy Induction Treatment Followed by High-Dose Therapy and Autologous Transplantation in Patients with Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1389.1389 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1389-1389

Author(s):

C. Thieblemont ◽

D. Antal ◽

L. Lacotte-Thierry ◽

V. Delwail ◽

F. Bouafia ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Median Time ◽

Cell Lymphoma ◽

Performance Status ◽

Autologous Transplantation ◽

Progression Free Survival ◽

Induction Treatment ◽

High Dose ◽

Chemotherapy Induction ◽

Mantle Cell

Abstract Between September 1998 and September 2003, 25 patients with Mantle Cell Lymphoma (MCL) were treated in our centres with a treatment combining rituximab + chemotherapy at induction with subsequent consolidation high-dose chemo/radiotherapy (HDT) and autologous PBSC-transplantation. Twenty-two (80%) patients received this treatment in first line therapy. Median age of patients was 53 (range: 41–65). All patients had a disseminated disease with a bone marrow (BM) involvement in 23 (92%) patients. Elevated LDH was present in 11 patients. All patients except one had a good performance status. IPI score was low in 5 patients, low-intermediate in 10 patients, high-intermediate in 7 patients and high in 3 patients. Chemotherapy induction regimens were: R-CHOP (n=7 pts), R-ACVB (n=4 pts), R-ESHAP (n=1 pts), R-DHAP (n=1pts), or sequential CHOP+DHAP/ESHAP+Rituximab (n=12pts) regimens. Rituximab was giving simultaneously with the chemotherapy in 13 patients or just before harvest in 12 patients. Number of rituximab injections was four in all patients except one that received 5 injections. PBSC harvest was done after cyclophosphamide or cyclophosphmide + etoposide followed by G-CSF and was successful in all patients with a median number of CD34+ cells at 6.44 106/kg. HDT included TBI in 21 patients. After induction therapy, all patients were in response: 16 (64%) reached a CR and 9 (36%) a PR because of persistence of a weak (<5%) BM involvement. Evaluation three months after transplant showed a CR in 17 (68%) patients and a PR in 7 (24%) patients because of weak BM involvement. At 3 years, 80% (20/25) of the patients are still alive (Figure). With a median follow-up at 4 years, median time to progression was 3.3 years. Four patients died from progressive disease. Transplantation toxicities were similar to those observed with regular induction treatment without rituximab with a median time of achievement of a PN count > 0.5GI/L at 10 days. One patient died before neutrophil recovery because of undocumented pulmonary infection. No patient presented late neutropenia. In conclusion, combined induction chemotherapy with rituximab followed by HDT dramatically improved the overall survival and the progression free survival in MCL patients, without adding hematological toxicities and infectious complications. Figure Figure

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Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2019001355 ◽

2020 ◽

Vol 4 (5) ◽

pp. 858-867 ◽

Cited By ~ 3

Author(s):

Reid W. Merryman ◽

Natasha Edwin ◽

Robert Redd ◽

Jad Bsat ◽

Matthew Chase ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Residual Disease ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Complete Response ◽

Pooled Analysis ◽

High Dose ◽

Phase 2 ◽

Mantle Cell ◽

High Dose Cytarabine

Abstract The addition of high-dose cytarabine to rituximab/bendamustine (RB) induction could improve outcomes for transplant-eligible patients with mantle cell lymphoma (MCL). We conducted a pooled analysis of 2 phase 2 trials and an off-trial cohort each testing 3 cycles of RB and 3 cycles of rituximab/high-dose cytarabine (RC) followed by autologous stem cell transplantation (ASCT) among untreated, transplant-eligible patients with MCL. Dana-Farber Cancer Institute (DFCI) and Washington University in St. Louis (WUSTL) led separate phase 2 trials testing sequential and alternating cycles of RB/RC, respectively. Patients treated at DFCI with sequential RB/RC off trial were retrospectively identified. Minimal residual disease (MRD) was assessed in the DFCI trial. A total of 88 patients (23 DFCI trial, 18 WUSTL trial, and 47 off trial) received RB/RC; 92% of patients completed induction, and 84% underwent planned consolidative ASCT. Grade 3 or 4 adverse events among trial patients included lymphopenia (88%), thrombocytopenia (85%), neutropenia (83%), and febrile neutropenia (15%). There were no treatment-related deaths during induction and 2 following ASCT. Among 87 response-evaluable patients, the end-of-induction overall and complete response rates were 97% and 90%, respectively. After a median follow-up of 33 months, 3-year progression-free survival and overall survival were 83% and 92%, respectively. Patients undergoing MRD testing experienced prolonged MRD negativity after ASCT with emergence of MRD occurring in only 1 patient who subsequently relapsed. RB/RC followed by ASCT achieves high rates of durable remissions in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT01661881 (DFCI trial) and #NCT02728531 (WUSTL trial).

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Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database

Blood ◽

10.1182/blood-2011-07-369629 ◽

2012 ◽

Vol 119 (9) ◽

pp. 2093-2099 ◽

Cited By ~ 59

Author(s):

Ann S. LaCasce ◽

Jonathan L. Vandergrift ◽

Maria A. Rodriguez ◽

Gregory A. Abel ◽

Allison L. Crosby ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Initial Therapy ◽

Outcome Data ◽

High Dose ◽

Stem Cell Rescue ◽

Non Hodgkin Lymphoma ◽

Mantle Cell ◽

Cancer Network

AbstractFew randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role of aggressive induction is unclear. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Database, a prospective cohort study collecting clinical, treatment, and outcome data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial therapies in MCL. Patients younger than 65 diagnosed between 2000 and 2008 were included if they received RHCVAD (rituximab fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone), RCHOP+HDT/ASCR (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone + high-dose therapy/autologous stem cell rescue), RHCVAD+HDT/ASCR, or RCHOP. Clinical parameters were similar for patients treated with RHCVAD (n = 83, 50%), RCHOP+HDT/ASCR (n = 34, 20%), RCHOP (n = 29, 17%), or RHCVAD+HDT/ASCR (n = 21, 13%). Overall, 70 (42%) of the 167 patients progressed and 25 (15%) expired with a median follow-up of 33 months. There was no difference in progression-free survival (PFS) between aggressive regimens (P > .57), which all demonstrated superior PFS compared with RCHOP (P < .004). There was no difference in overall survival (OS) between the RHCVAD and RCHOP+HDT/ASCR (P = .98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR, which had similar PFS and OS. Despite aggressive regimens, the median PFS was 3 to 4 years. Future trials should focus on novel agents rather than comparing current approaches.

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Daily Alternating of Immunomodulating Agents and Rituximab in Therapy for Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, and Mantle Cell Lymphoma: The THRIL (Thalidomide [TH], Rituximab [RI], and Lenalidomide [L]) Regimen

Blood ◽

10.1182/blood.v112.11.4203.4203 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4203-4203

Author(s):

Morton Coleman ◽

Peter Martin ◽

Jia Ruan ◽

Ruben Niesvizky ◽

John P. Leonard ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Adverse Events ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Synergistic Activity ◽

Small Lymphocytic Lymphoma ◽

Color Flow ◽

Mantle Cell ◽

Continuous Use

Abstract Introduction: Immunomodulatory drugs thalidomide and lenalidomide, alone or in combination with other agents, have shown activity in treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). Lenalidomide when used as part of the 21 day on, 7 day off schedule, may be limited by marrow toxicity, whereas continuous use of thalidomide is often limited by neurologic toxicity. Interestingly, lenalidomide is not associated with neurologic toxicity, and thalidomide is not associated with marrow toxicity. By alternating thalidomide and lenalidomide daily, adverse events seen with each drug may be attenuated, as total dosage of either drug is reduced. Preliminary data suggest that thalidomide and lenalidomide are not cross-resistant. The two agents may have synergistic activity, resulting in improved responses. This phase II study aims to assess efficacy and safety of THRIL (thalidomide [TH] rituximab [RI], and lenalidomide [L]) combination therapy in patients with CLL/SLL, or MCL. Methods: Patients were treated with the THRIL regimen, which consists of a 50 mg/day thalidomide oral dose, alternated with oral lenalidomide 10 mg/day. Rituximab 375 mg/m2/week was given intravenously for 4 weeks, every 6 months, for up to 4 courses. Patients received 162 mg/day aspirin prophylaxis against venous thromboembolism. Results: Of the 14 patients enrolled, 11 had CLL/SLL, and 3 had MCL; most had received at least 3 prior treatments. Median patient age was 71 years (range 58–9). Four patients had a complete response (CR) as seen by 4-color flow cytometry (n = 2) or bone marrow/computed tomography criteria (n = 2). Three patients had a partial response, and 3 had stable disease. With a median follow-up of 8 months (range 2–27), the median response duration was over 12 months (range 3–27+). The 2 patients with MCL who had a CR, relapsed after 6 and 9 months of therapy, respectively. Disease regressed with increased dosing to 100 mg/day thalidomide and 25 mg/day lenalidomide. Treatment was discontinued in 8 patients due to lack of response (n = 4), progressive disease (n = 2, including 1 patient who initially responded), and rash (n = 2). The THRIL regimen was associated with few adverse events; the only grade 3–4 adverse events were neutropenia and rash, each occurring in 2 patients. Four grade 2 tumor flare reactions were recorded, all in CLL patients, and each successfully treated with steroids. In each case the flares announced a response. No significant neurological adverse events or thromboembolic events were observed. Lenalidomide therapy was paused briefly due to cytopenias in 4 cases. Conclusion: Alternating thalidomide and lenalidomide in the THRIL regimen may be an effective method of reducing adverse events, while achieving responses in patients by enabling longer continuous use of immunomodulating agents. Further investigation is needed to assess whether enhanced responsiveness results from combined sequential use of thalidomide and lenalidomide. Exploration of this regimen may be beneficial in other diseases that respond to lenalidomide and thalidomide, particularly myeloma and myelodysplasia.

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Single-Agent Lenalidomide in Patients With Mantle-Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: Phase II MCL-001 (EMERGE) Study

Journal of Clinical Oncology ◽

10.1200/jco.2013.49.2835 ◽

2013 ◽

Vol 31 (29) ◽

pp. 3688-3695 ◽

Cited By ~ 211

Author(s):

Andre Goy ◽

Rajni Sinha ◽

Michael E. Williams ◽

Sevgi Kalayoglu Besisik ◽

Johannes Drach ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Single Agent ◽

Progression Free Survival ◽

Complete Response ◽

The United States ◽

High Dose ◽

End Points ◽

Mantle Cell

Purpose Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib. Patients and Methods Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease progression or intolerance. Primary end points were overall response rate (ORR) and duration of response (DOR); secondary end points included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Results In all, 134 patients were enrolled with a median age of 67 years and a median of four prior therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% CI, 7.7 to 26.7 months). Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months), and median OS was 19.0 months (95% CI, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). Conclusion The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were refractory to bortezomib.

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Immunochemotherapy As Induction (R-CHOP and R-HyperC-VAD/R-MA) in Mantle Cell Lymphoma, a Hungarian Multicenter Open Label Phase II Study (Rituximab [MabThera®] in Mantle Cell Lymphoma, REMENY)

Blood ◽

10.1182/blood.v120.21.4889.4889 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4889-4889

Author(s):

Miklos Udvardy ◽

Andras Rosta ◽

Zoltan Gasztonyi ◽

Zita Borbenyi ◽

Gaspar Radvanyi ◽

...

Keyword(s):

Adverse Events ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Septic Complication ◽

High Dose ◽

Open Label ◽

Number Of Patients ◽

Mantle Cell ◽

Initial Staging

Abstract Abstract 4889 Background: Considering the especially poor outcome of mantle cell lymphoma with traditional induction chemotherapies, the Hungarian working group initiated a Hungarian Mantle Cell Lymphoma Study (REMENY) using rituximab (MabThera) based immunochemotherapy. The structure of the trial: National, multicenter, open label trial rituximab based immunochemotherapy induction in mantle cell lymphoma. Two therapies were available according to investigators' choice: R-CHOP-21 (8x) or R-HyperC-VAD/R-MA according to the MD Anderson protocol. High dose therapy + autologous stem cell support (ASCT) was allowed, according to the investigators decision. Diagnosis was based upon standard histology. Initial staging included the standard protocols, imaging techniques, bone marrow evaluation and gastrointestinal endoscopy (not compulsory at initial staging). Recruitment period was planned to be 3 years, the follow-up 2 years. Remission was evaluated according to Cheson (IWC) criteria,CR was qualified only after completion of gastroscopy and colonoscopy, which did not reveal any mantle cell related abnormality. In some cases FDG PET-CT was allowed to substitute for endoscopy. Primary endpoints: OS and PFS, safety Results: Recruitment started in June 2007 and completed unexpectedly early (Nov 2008). 48 patients were included, per protocol Patients were 31 (64.58%), follow-up (24 months) was completed for 15 (31.25%) patients. Ann Arbor III-IV B 43 (89.58%) was dominant. Median PFS for all patients was 30.4 months (SD 5.839, 95% CI: 19–41.9). PFS median for those patients who reached a CR has not been reached while it was 23.7 months in PR (p=0.031). Safety: One hundred-thirteen adverse events occurred in 31 (64.58%) patients; 53 serious adverse events in 15 (31.25%) patients: 17 cytopenia, including fever with neutropenia 7, transient bronchospasm during rituximab (MabThera) infusion 1, hyperglycemia 1 which may be treatment related. There were 20 death cases, 13 of them due to progression of disease, two due to septic complication, three heart failures and one second malignancy (breast cancer). Significantly more patients on the R-HyperC-VAD/R-MA arm experienced adverse events (11/12 patients, 91.6%) compared to R-CHOP (20/36, 55.5%, p=0.035). Conclusion: This trial further confirmed the value of adding rituximab to standard induction therapies in mantle cell lymphoma. The results are conforming to data published in literature. Higher percentage of patients completed R-CHOP regimen. R-HyperC-VAD/R-MA was more effective in inducing CR, but could be completed only in one third of patients. However, in those patients who adhered to R-HyperC-VAD/R-MA therapy, it resulted in 80% CR, vs. 42.3% in the R-CHOP group. This difference is not statistically significant (p=0.172) possibly due to low case numbers. Those patients who reached CR had significantly longer PFS. PFS obtained in this trial is comparable to international data, and could be further improved by adding immunotherapy maintenance. Planned total number of patients (48) entered the trial during the first 12 months. This was surprising, as the expected number of mantle cell lymphoma based on the international incidence data is cca. 30–35 yearly. The unexpectedly high patient numbers need further explanation. Disclosures: Off Label Use: Rituximab is not authorized for Mantle Cell Lymphoma in Hungary.

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