A phase II trial of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for patients with refractory or relapsed non-Hodgkin's lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8559-8559
Author(s):  
B. Park ◽  
W. Kim ◽  
H. Eom ◽  
J. Kim ◽  
S. Oh ◽  
...  
Keyword(s):  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Salvage Regimen ◽  
Non Hodgkin Lymphoma ◽  
Lymphoma Treatment ◽  
Mantle Cell ◽  
Grade 3

8559 Background: Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in salvage setting. However, this regimen has the modest response with severe nephrotoxcity and neurotoxicity, especially to heavily treated patients. We investigated the response rate and toxicity of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOx) for recurrent or refractory aggressive B-cell non-Hodgkin lymphoma (NHL), looking for the more effective and less toxic therapy. Methods: Patients with recurrent or refractory diffuse large B-cell NHL or mantle cell lymphoma, measurable disease, and more than one previous chemotherapy regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m2 intravenously (i.v.) on Days 1 and 8, ifosfamide 2000 mg/m2 i.v. on Day 1, dexamethasone 40 mg orally on Days 1–4, and oxaliplatin 130mg/m2 i.v. on Day 2, every 21 days. The primary end point was a response after three cycles. Patients could then proceed to stem cell transplantation (SCT) or receive up to six treatment cycles. Results: Twenty-seven eligible patients were evaluable for toxicity and response. The median age of the patients was 54 years (range, 18–75 years) and most had diffuse large-cell lymphoma. After 3 cycles, there were 4 complete responses (CR; 15%) and 10 partial responses (PR; 37%). There was an overall response rate (RR) of 52%. The RR after completion of all protocol chemotherapy including SCT was 44% (10 CR, 2 PR). In total 88 cycles of GIDOx, grade 3 and 4 neutropenia occurred in 33% and 16% of cycles, respectively. Grade 3 and 4 thrombocytopenia occurred in 14% and 16% of cycles, respectively. Tow patients (2%) experienced febrile neutropenia. Seven patients (26%) proceeded to SCT. Conclusions: GIDOx is an active salvage regimen in aggressive B-cell NHL and can be administered with acceptable toxicity. No significant financial relationships to disclose.

Phase II Trial of Lenalidomide - Dexamethasone - Rituximab In Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3962-3962
Author(s):  
Tahamtan Ahmadi ◽  
Elise A. Chong ◽  
Amanda Gordon ◽  
Leah Leinbach ◽  
Nicole A. Aqui ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Marginal Zone ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Response Assessment ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 3962 Introduction: Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods: Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continues during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results: As of May 16, 2010, 27 pts have started therapy; diagnoses include: follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas; median age is 60 years (range: 35–85); male: female ratio is 4:5; median number of prior therapies is 3 (range: 1 – 7); LDH is increased in 22% of pts. There were 2 deaths during protocol therapy: 1 death due to myocarditis during Part I treatment and 1 death due to lymphoma in a patient removed from study due to grade 3 rash, which subsequently resolved. One patient was removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. One patient has not completed Part II response assessment. For 23 pts completing Parts I and II, median follow-up is 12 months (range: 3.1 – 25.3) with a progression-free survival of 78% (95% CI: 50 – 91) [Figure below]. Overall response rate (ORR) after Part I is 22% (3 CR; 2 PR; 16 SD; 2 PD); ORR after Part II is 57% (7 CR; 6 PR; 8 SD; 2 PD). After Part II, the ORRs by histology were follicular lymphoma 60% (9/15 pts), mantle cell lymphoma 50% (2/4 pts), small lymphocytic lymphoma 67% (2/3 pts), and marginal zone lymphoma 0% (0/1 pt). Grade 3 or 4 non-hematologic adverse events possibly related to lenalidomide include hypokalemia (4 pts), hypophosphatemia (3 pts), pneumonia (3 pts), fatigue (1 pt), elevated ALT (1 pt), elevated AST (1 pt), tumor flare (1 pt), pulmonary embolism (1 pt), and hyperuricemia (1 pt). Conclusions: These data indicate that the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with durable responses in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas. Disclosures: Off Label Use: Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab. Schuster:Celgene: Research Funding.

Rituximab Increases Response to ESHAP in Relapsed, Refractory, and Transformed Aggressive B-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3067-3067 ◽  
Author(s):  
Lisa Hicks ◽  
Rena Buckstein ◽  
Joy Mangel ◽  
Eugenia Piliotis ◽  
Kevin Imrie ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Indolent Lymphoma ◽  
Overall Response ◽  
Grade 3 ◽  
Aggressive B Cell Lymphoma

Abstract Background: Patients with relapsed or refractory aggressive B-cell lymphoma, or transformed indolent lymphoma can achieve long-term survival with high dose therapy and autologous stem cell transplant (HDT/ASCT), provided their disease is sensitive to salvage chemotherapy. Unfortunately, approximately 50% of patients are insensitive to standard salvage regimens. Objectives: This trial investigated whether adding Rituximab to ESHAP (etoposide, solumedrol, cytosine arabinoside, cisplatin) induction improved chemosensitivity. The primary outcome was overall response rate (CR + CRu + PR) to R-ESHAP. Secondary outcomes were toxicity, ability to undergo ASCT, progression free survival (PFS) and overall survival (OS). Methods: The protocol was approved by the local ethics review board and all patients provided informed consent. Eligible patients received ESHAP every 28 days with GCSF support until < 15% bone marrow involvement was achieved (2–4 cycles). Rituximab was given weekly x 8 weeks concurrent with the first 2 cycles of ESHAP. GCSF mobilized stems cells were collected on day 10–11 of cycle 1 or 2. Results: The trial was stopped early after the complete response (CR) rate at a planned interim analysis exceeded 40% (a pre-specified criteria for stopping the trial). Final results of 26 patients are presented. Median age was 55.5 years (range 42–64). Twelve patients had relapsed aggressive lymphoma, 2 had refractory disease and 12 had transformed indolent lymphoma. Twenty-two of 26 patients were stage III/IV. The overall response rate to R-ESHAP was 92% (95% CI 82% to 100%). Twelve patients (46%; 95% CI 27% to 65%) had a CR or unconfirmed CR. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 57%, 40%, and 15% of R-ESHAP cycles respectively. Grade 3–4 infections complicated 7% of cycles. Median follow-up was 17 months (range 2.9 to 43.2) from enrollment. Twenty-three of 26 patients (88%) were transplanted. Notable post-transplant toxicity included 5 cases of herpes zoster, 2 cases of bacterial pneumonia, 1 case of pulmonary aspergillosis, and 1 fatal case of pneumocystis carnii pneumonia (PCP). Three patients did not proceed to HDT/ASCT; 2 were refractory to R-ESHAP and 1 died of a myocardial infarction after induction chemotherapy but prior to ASCT. Fifteen of 23 patients who received ASCT remain in remission, 6 have relapsed. Seven patients have died, 4 of progressive disease, 1 of myocardial infarction, 1 of PCP, and 1 of accelerated Parkinson’s Disease. Median PFS and median OS have not yet been reached. Conclusions: In this single-arm, phase II study of relapsed or refractory aggressive B-cell lymphoma and transformed indolent B-cell lymphoma, R-ESHAP induction therapy resulted in a very high ORR (92%) and enabled a large percentage of patients (88%) to proceed to HDT/ASCT. Toxicity of the R-ESHAP regimen was acceptable, and its efficacy compared favorably with other salvage regimens reported in the literature, including R-ICE.

Flavopiridol, Fludarabine and Rituximab (FFR): An Active Regimen in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1571-1571 ◽  
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Kristie A. Blum ◽  
Pierluigi Porcu ◽  
Eric H. Kraut ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) induces p53-independent apoptosis and may be able to eliminate tumor cells resistant to fludarabine and rituximab. Study Design and Treatment: We report final results of a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with mantle cell lymphoma (MCL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL). Pts had ANC 3 1500, hemoglobin 3 9.0, platelets 3 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. Flavopiridol was administered 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1, n=15) or day 1 and 2 (cohort 2, n=6) of each cycle. Based on promising results with a novel single agent dosing schedule in CLL, the study was amended to give flavopiridol by 30-min IV bolus followed by 4-hr IV infusion at a dose of 20 mg/m2 + 20 mg/m2 (cohort 3, n=3) or 30 mg/m2 + 30 mg/m2 (cohort 4, n=14) beginning with cycle 2. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was allowed in cohorts 3 and 4. Results: Thirty-eight pts were enrolled. Median age was 62 years (range, 38–81), and 22 pts were male (58%). Pts had CLL (11), MCL (10), follicular (FL, 9), small lymphocytic (3), marginal zone (4) or lymphoplasmacytic lymphoma (1). Sixteen pts had received 1 or 2 prior therapies; 22 pts were previously untreated. Two of 6 pts in cohort 2 developed dose limiting toxicity; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Fifteen pts were enrolled in cohort 1 and 14 pts were enrolled in cohort 4, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 16 of 38 pts completed all 6 planned cycles. Cytopenias (10), fatigue (3), fever (2) and progression (2) were the most common reasons for early discontinuation of therapy. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 82% (CR 50%, CRu 5%, PR 26%). Median progression-free survival (PFS) of responders was 25.5 months. ORR (82% vs. 81%), CR (50% vs. 50%) and median PFS (25.7 vs. 25.1 months) were similar for previously untreated and relapsed pts. Thirteen pts remain in remission with a median PFS of 33.5 months (range, 17.5–59.5), and 3 other pts died of unrelated causes. Eight of 10 MCL pts (median age 68, range 62–81) responded (7 CR, 1 PR). Two responders with blastoid variant MCL relapsed within 1 year, but median PFS of the other 6 responding MCL pts was 33.5 months. All 9 FL pts responded (5 CR, 2 CRu, 2 PR) with a median PFS of 25.1 months (range, 4.0–46.3). Conclusions: FFR exhibited significant clinical activity in indolent B-NHL, MCL and CLL. FFR was effective in both relapsed and previously untreated pts and showed promising clinical activity in older MCL pts. Changing from 1-hr IV bolus dosing to 30- min IV bolus followed by 4-hr IV infusion did not improve the response rate, suggesting that 1-hr IV bolus dosing may be effective when flavopiridol is given as part of combination chemotherapy. This regimen warrants further study.

Clinical Efficacy of the Rivbd Combination for Refractory/Relapsed (R/R) Mantle Cell Lymphoma (MCL) Patients: A Retrospective Study of the French Lysa Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1111-1111
Author(s):  
Caroline Régny ◽  
Sandra Malak ◽  
Guillaume Manson ◽  
Clementine Sarkozy ◽  
Aline Clavert ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Salvage Therapy ◽  
Older Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Background There is no standard treatment for R/R MCL that fail first line treatment. Non cross resistant regimens are usually used, which provided sometimes good overall response rate (until 93%) but with a minor disease control (PFS<2years). [1] The main objective of these salvage regimens is to bypass disease resistance, to obtain more profound ( deep or durable) response and to ensure, in younger patients, the option of performing autologous or allogenic stem cell transplantation. For older patients prolonging disease free survival is the aim. The new combination RiVBD (Rituximab-Bendamustine-Bortezomib-Dexametasone) has recently shown to be an effective regimen in frontline for eldery patients with a good tolerability profile (NCT 01457144). [2] Many French centers have also used this association for the R/R patients. Aim To explore the efficacy of the RiBVD regimen in the salvage therapy setting following failure of one, two or more prior treatments. Methods We proposed to all French LYSA partner centers a survey to retrospectively evaluate the efficacy of the RiBVD regimen in R/R MCL patients, regardless of prior treatments used. The RiBVD regimen comprises : Rituximab 375mg/sqm D1, Bendamustine 90mg/sqm D1 and D2, bortezomib 1,3mg/sqm D1, D4, D8, D11 and dexamethasone 40 mg D2. Analysis was performed in June 2016. Results From January 2012 to December 2015, 49 patients from 17 French hematological centers were recruited to the study. The median age was 72 years (50-91y) with 14 young (<65y) and 35 older patients (> 65y). Thirty eight cases presented with classic MCL variant and 11 had a blastoid variant. All patients but one were CD20+, CD5+, CD10- and were positive CYCLIN D1 expression and/or the t(11;14)(q13;q32). Eighteen patients presented a t(11;14) (q13;q32).The CYCLIN D1 negative patient had a t(11;14). Treatment history: Twenty seven patients received RiBVD in second line, 12 in third line and 10 patients after the third lines. Twenty two patients were refractory to their previous line and 27 were in relapse. Before RiBVD 44/49 patients (90%) had received high dose cytarabine, 3 Ibrutinib and 14 patients were intensified (11 at diagnosis, 3 in relapse). Efficacy: The global overall response rate (ORR) was 75% (37/49, 23 CR and 14 PR). For patients treated in 2nd line, the ORR was 85% (23/27, 16 CR and 7 PR), in 3nd line 58% (7/12, 4 CR and 3 PR), and 70% (7/10) for the others (3 CR and 4 PR). Young patients had an ORR of 64% (9/14, 8 CR, 2 RP) and elderly pts 77% (27/35, 15 CR, 12 PR). For relapsed and refractory pts the ORR was respectively 85% (23/27, 15 CR and 8 PR) and 63% (14/22 with 8 CR and 6 PR). For Classic and blastoid variants the ORR was 81.5% (31/38, 20 CR and 11 PR) and 54% (6/11, 3 CR and 3 PR) respectively. Note that 2/3 pts receiving RiBVD regimen post Ibrutinib failure, reached PR (n=2) and showed stable disease (n=1). Major toxicities were seen in 31 pts (63%) with grade 3/4 hematological toxicity in 22 pts, grade 3 neurotoxicity in 3 pts, grade 3/4 cardiotoxicity in 3 pts, grade 3/4 infectious complications in 8 pts, grade 4 fatigue in 3 pts and grade 3 digestive-tract or cutaneous toxicity in one pt each. At the update point, 17 pts had died, 15 for lymphoma progression, 2 for TRM while experiencing a CR (infectious and leukemia). The follow-up of the 32 surviving pts was 14.5 month. The median PFS was 9 months for the 49 pts. The PFS was statistically affected by the pathologic type (classic vs Blastoid, p=0.03), the number of prior treatment (one vs >one, p=0.04) and response to RiBVD (CR vs PR vs no response, p<0.0001 with a median PFS not reached for CR pts, 6 months for PR and 2 months for no response. The age (<65 vs >65) or the state (relapse or refractory) at the time of RiBVD had no impact on PFS. Conclusion The RiBVD regimen which shows remarkable efficacy in frontline treatment of elderly MCL pts, shows potential as a salvage therapy for refractory or relapsed MCL following cytarabine based treatment. This is particularly true for the 47% of patients achieving CR for which 2 years PFS was 71% regardless of their age. 1. Cheah CY, Seymour JF, Wang ML. Mantle Cell Lymphoma. J Clin Oncol 2016; 34: 1256-1269. 2. Gressin R, Callanan M, Daguindau N et al. Frontline therapy with the RiBVD regimen elicits high Clinical and Molecular Response Rates and long PFS in elderly patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II trial by the LYSA group. Blood 2014. Disclosures No relevant conflicts of interest to declare.

Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study

2016 ◽  
Vol 34 (10) ◽  
pp. 1104-1111 ◽  
Author(s):  
Maria-Elisabeth Goebeler ◽  
Stefan Knop ◽  
Andreas Viardot ◽  
Peter Kufer ◽  
Max S. Topp ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Phase I Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bispecific T Cell Engager

Purpose Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m2/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m2/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m2/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m2/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). Conclusion In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m2/day. Single-agent blinatumomab showed antilymphoma activity.

Cladribine Plus Rituximab Is An Effective Therapy for Newly Diagnosed Mantle Cell Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4910-4910
Author(s):  
Stephen Spurgeon ◽  
Talia Pindyck ◽  
Marc M Loriaux ◽  
Craig Okada ◽  
Kamal Abbi ◽  
...  
Keyword(s):  
Complete Remission ◽  
B Cell ◽  
Initial Treatment ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Treatment Strategies ◽  
Newly Diagnosed ◽  
Mantle Cell

Abstract Abstract 4910 Background: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is incurable with standard chemotherapy and remains a therapeutic challenge. Despite improved outcomes in MCL there is no consensus on the best initial treatment. Options vary from aggressive treatment strategies that incorporate multi-agent induction chemotherapy and consolidative transplant to less intensive treatment strategies that utilize alkylators, purine nucleoside analogues, and the monoclonal antibody rituximab. Although, higher response rates have been seen with aggressive approaches, their impact on overall survival is not yet fully appreciated and many patients are not candidates for such approaches. Thus, finding less intensive induction regimens is imperative. The combination of rituximab plus cladribine has shown activity across a number of B-cell malignancies and the NCCN treatment guidelines currently include this regimen for the initial treatment of MCL; noting that there are few data available to substantiate this recommendation. The largest prospective experience (n=29) with R-cladribine for the initial treatment of MCL comes from the North Central Cancer Group. They reported an overall response rate (ORR) of 66% with a 52% complete remission (CR) rate and a 2 year progression free survival (PFS) of 43%. Given its therapeutic potential and increasing popularity, more data are needed to verify the benefits of the R-cladribine regimen. Therefore, to explore the role of R-cladribine in the treatment of newly diagnosed MCL, we performed a retrospective chart review of patients with newly diagnosed MCL treated with R-cladribine. Methods: We reviewed the charts of 31 patients with newly diagnosed MCL initially seen at two university hospitals and at an associated VA that were treated with R-cladribine. One patient had been previously treated with 2 cycles of R-CHOP;, all other patients were untreated. All patients had measurable disease and follow up imaging (CT and/or PET/CT scans) before and at the completion of therapy. Post treatment bone marrow biopsies were not available for all patients. Chemotherapy included: cladribine 5mg/m2 given over two hours on days 1–5; and rituximab given on days 1, 8, 15, and 22 with the first cycle and then on day 1 with subsequent cycles. Each cycle was 28 days for up to a total of 6 cycles. Patients with an initial response received maintenance rituximab. Results: The median age of our cohort was 67 years (48-86) with 42% of patients ≥ 65 years. All patients had advanced stage disease (stage ≥ 3) and the majority of patients had poor risk disease. For example, 20/31 (65%) of patients had high FLIPI (≥ 3) and11/31 (37%) had high MIPI (≥ 6). Of the 24 patients in whom beta2-microglobulin was available, 11 (46%) had levels ≥ 3.5 mg/L. The overall response rate (ORR) was 87% with 19/31(61%) of patients achieving a complete remission (CR/CRu). At a median follow up of 21.5 months (2-85 months) the 2 year PFS rate is 65% and the OS rate is 74%. For those subjects achieving a CR/CRu with a median follow up of 23 months, 1/19 (5.3%) has relapsed. No significant trends were seen regarding response rate and pre-treatment disease defining parameters including Ki67, beta2-microglobulin, FLIPI, or MIPI. However, CR was associated with improved survival (p = <.0001) while high MIPI was associated with worse survival (p=0.0317). There was one toxic death (neutropenic sepsis) related to treatment. Conclusion: The combination of rituximab plus cladribine appears to be an effective initial therapy in MCL. The higher response rates seen in this series may be the result of patient selection and/or increased rituximab exposure. Rituximab maintenance may also be an important component of ongoing disease control in responding patients. These data support the ongoing evaluation of rituximab plus cladribine in combination with novel agents. Prospective single arm studies incorporating R-cladribine with other novel agents such as vorinostat, bortezomib, or temsirolimus are ongoing. Disclosures: No relevant conflicts of interest to declare.

Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1700-1700
Author(s):  
Tahamtan Ahmadi ◽  
Elise A. Chong ◽  
Amanda Gordon ◽  
Nicole A. Aqui ◽  
Lisa H. Downs ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Disease Progression ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1700 Poster Board I-726 Introduction Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond to or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continue during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results To date, 22 pts have started therapy; diagnoses included: follicular (n = 17), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 72); male: female ratio was 5:6; median number of prior therapies was 3 (range: 1 - 7); LDH was increased in 23%. For 21 pts with at least one follow-up visit, there were 2 deaths and 2 episodes of disease progression. One death due to myocarditis occurred during Part I treatment; one death due to lymphoma occurred in a patient removed from study due to grade 3 rash, which subsequently resolved. Both episodes of disease progression occurred in pts with follicular lymphoma, one of whom had been removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. For all patients, at a median follow-up of 5.0 months (range: 0.3 - 12.3), progression-free survival (PFS) is 81% (95% CI: 51-94). For 10 pts with response assessments after Parts I and II, overall response rate (ORR) after Part I was 30% (3 CR; 6 SD; 1 PD) and ORR after Part II was 70% (5 CR; 2 PR; 2 SD; 1 PD). At a median follow-up of 7.8 months (range: 5.0 - 11.9), PFS is 89% (95% CI: 43-98) for these 10 pts. For pts who completed Parts I and II, grade 3 or 4 non-hematologic toxicities included hypokalemia (2/10 pts), hypophosphatemia (1/10 pts), and hypocalcemia (1/10 pts); grade 1 tumor flare occurred in one pt with follicular lymphoma. Conclusions Based on these preliminary data in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with relatively durable responses. Additional follow-up and correlative studies will be presented. Disclosures Off Label Use: Lenalidomide is used in this trial for treatment of lymphoma.. Downs:Genentech: Honoraria; Celgene: Honoraria. Nasta:Genentech: Speakers Bureau. Schuster:Celgene: Consultancy, Research Funding.

Results of GROC-rev salvage regimen: Gemcitabine, rituximab, and oxaliplatin chemotherapy with revlimid for relapsed/refractory aggressive non-Hodgkin lymphoma (NHL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7556-7556 ◽  
Author(s):  
Fernando Cabanillas ◽  
Idalia Liboy ◽  
Alexis Cruz ◽  
Pedro Gil Solivan ◽  
Noridza Rivera ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Regimen ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Best Response ◽  
Grade 3 ◽  
Clinical Trial Information

7556 Background: Currently there is no optimal salvage regimen for relapsed/refractory NHL (R/R NHL). Prognosis of pts who fail to achieve CR to salvage therapy is dismal. We sought to improve the CR rate by adding Lenalidomide (L) to GROC (ASCO #8530, 2008). Methods: Primary endpoint was rate of conversion to CR after switch to L for pts whose best response to GROC was <CR. Secondary endpoint was progression free survival (PFS) of all pts as well as those who achieve <CR on chemotherapy and were crossed over to L.Pts who failed to achieve at least PR after GROC x2 and those who didn’t achieve CR after GROC x6, were crossed over to L 25 mg x 3 weeks q 28 days. CRs were maintained on L x 2 yrs. Results: 34 pts were enrolled of which 32 are evaluable. Median age: 61 and 56% males. Histologies included DLBCL (81%), PTCL (9%), follicular grade 3-B (9%). Stage was III-IV in 75% and median IPI=2. Best overall response rate (ORR) at any point during treatment= 19/32 (59%) and CR 13/32 (41%). ORR before crossover to L=13/32 (41%) and CR= 8/32 (25%). There were 24 who failed to achieve CR on GROC (19 who didn’t respond at all and 5 whose maximum response was PR). Of these, 21 crossed over to L and 7 (33%) responded (CR in 5, PR in 2). The fact that 5 pts attained a CR to L thus improving the CR rate from 25% to 41% after exhibiting refractoriness to GROC is noteworthy. Of the 7 responders to L, all are alive and only 1 relapsed. At 2 yrs., overall survival (OS) was 48% and PFS 35%. This compares favorably with our previous GROC study without L in which 2 yr. OS= 33% and PFS 29%. In total, 11 pts were eligible for ASCT after chemo plus L and 8 were transplanted (3 refused). Of these eight, 6 remain in CR at 11, 18, 21, 22, 52, 74 mos. At 2 yrs, PFS for transplanted pts is 73% and for those whose response to GROC before crossover to L was <CR, it is 27 mos. Toxic events included 2 neutropenic fevers, 1 MDS (34 mos. after ASCT) and 1 AML (11 mos. after ASCT). Both of these remain continuously in CR after allo SCT. Conclusions: 2 yrOS=48% and PFS=35% with GROC-Rev are the best observed with any salvage regimen we have tested. L is active as a single agent in 29% of cases whose best response to GROC was <CR. A larger study is desirable to confirm these data. Clinical trial information: NCT01307592.

Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma

2021 ◽  
Author(s):  
Preetesh Jain ◽  
Shuangtao Zhao ◽  
Hun Ju Lee ◽  
Holly A. Hill ◽  
Chi Young Ok ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Older Patients ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Ki 67 ◽  
Overall Response ◽  
Mantle Cell ◽  
Grade 3

PURPOSE Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial ( NCT01880567 ). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

scholarly journals Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: First Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 148-148 ◽  
Author(s):  
Mats Jerkeman ◽  
Martin Hutchings ◽  
Riikka Räty ◽  
Karin Fahl Wader ◽  
Anna Laurell ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Molecular Remission ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL) over the last 10-15 years, this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, with an overall response rate (ORR) of 68% as a single agent in the relapse situation. In vitro, ibrutinib has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. A phase I trial with this combination has been performed in 22 patients with untreated follicular lymphoma (Alliance 051103). In this trial, rash was the most common adverse event (AE), occuring in 73% of pts, with grade 3 rash in 32%. Methods: Eligibility criteria were: patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing was performed on frozen tumor cells from bone marrow at time of relapse, including the following genes: ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment. Given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in 12 months, June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. In total, 17/50 pts have discontinued treatment (n=9 due to PD, n=4 due to AE, n=2 withdrew consent, n=1 proceeded to alloSCT and n=1 due to other cause). Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). One event of laboratory tumor lysis syndrome was reported, and two events of atrial fibrillation, without reduction or discontinuation of ibrutinib. With a median follow up time of 7 months, 29 patients were evaluable for efficacy as of July 14, 2016. The ORR to date is 83% with 12 patients achieving CR (41%) and 12 PR (41%). Median duration of response and PFS has not been reached. One of three evaluable patients with progression on single agent ibrutinib responded with a PR, with ongoing response at 9 months. Of the 13 patients evaluable for MRD at 6 months, 7/12 patients have achieved molecular remission in blood and 7/13 in bone marrow. Conclusions: So far, the combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in patients with R/R MCL, associated with molecular remission. Cutaneous toxicity was manageable, in contrast to what has been reported with a similar combination in untreated patients with follicular lymphoma. Up-dated results will be presented at the annual meeting, including data on mutational profile as biomarker for efficacy. This trial was registered at http://clinicaltrials.gov as NCT02460276. Disclosures Jerkeman: Gilead: Research Funding; Mundipharma: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Geisler:Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy.

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