Salvage Therapy with Bortezomib Plus Lenalidomide for Relapsed/Refractory Mantle Cell Lymphoma: Initial Results of a Phase II Trial (Alliance/CALGB 50501)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3696-3696
Author(s):  
Vicki A. Morrison ◽  
Sin-Ho Jung ◽  
Jeffrey Johnson ◽  
Ann LaCasce ◽  
Kristie A. Blum ◽  
...  

Abstract Abstract 3696 Introduction: The majority of patients (pts) with mantle cell lymphoma (MCL) respond to initial treatment, yet most pts relapse and die from disease. Although stem cell transplantation (SCT) is a treatment option, it is not always curative and many pts are not eligible. Based upon single agent activity of thalidomide and bortezomib in MCL (overall response rates [ORR] approximately 30%), CALGB designed a phase II trial of bortezomib + lenalidomide therapy for pts with relapsed/refractory MCL. Methods: Eligibility criteria included: histologically confirmed MCL (CD5+, CD 23-, cyclin D1+); measurable disease; prior therapy with >1 regimen that may include autologous (not allogeneic) SCT, now with relapsed/refractory disease; no prior radioimmunotherapy, bortezomib, or lenalidomide; ECOG performance status (PS) 0–2; no >grade (gr) 3 peripheral neuropathy. Induction therapy was lenalidomide (20 mg po qd, days [D] 1–14) plus bortezomib (1.3 mg/m2 IV, D 1, 4, 8, 11), given every 21 D for 8 cycles. Pts were restaged at 3 & 6 mos; responding patients (complete and partial responses; [CR+PR]) at 6 mos received maintenance with lenalidomide (15 mg po D 1–14) and bortezomib (1.3 mg/m2 IV, D 1, 8), until disease progression (PD). In 9/09, the protocol was modified to have separate toxicity-related dose reductions for each agent (myelosuppression, decrease lenalidomide; neuropathy, decrease bortezomib). Primary endpoints were ORR (=CR+PR), CR rate; secondary endpoints were event-free- (EFS) (time to progression, all-cause death, or initiation of non-protocol therapy), progression-free- (PFS) (time to progression or all-cause death), and overall survival (OS) (time to death from any cause). The study design considered an ORR <45% too low, and >65% of strong interest. Response and toxicity data were summarized using frequency tables; Kaplan-Meier method was used to analyze survival parameters. The study was activated in 11/07. It temporarily closed for planned interim analysis after accrual of 19 pts, and closed in 7/11, when it reached the accrual goal of 54 pts. Results: Median pt age was 67 (range, 39–83) yrs; 83% were male. 47 (89%) pts had relapsed, and 6 (11%) refractory, disease. 79% of pts had stage IV disease; 21% had B-symptoms; lactate dehydrogenase was elevated in 17 (32%). PS was 0 (62%), 1 (36%), and 2 (2%). Number of prior chemotherapy regimens was: one (60% of pts), 2 (25%), 3 (12%), 4 (2%), and 5 (2%). Prior therapy included rituximab in 46 (85%), radiotherapy in 14 (26%), and SCT in 21 (40%). Median number of protocol therapy cycles received was 4 (range, 1–64); 20 pts (37%) received <2 cycles. Reasons for treatment discontinuation included: PD in 20 pts (38%); no response in 1 (2%); toxicity in 17 (32%); pt refusal in 4 (8%); rising lymphocyte count in 1; physician decision in 1; other treatment in 6 (8%). Best response for the 53 eligible pts was 8 (15%) CR, 13 (25%) PR, 8 (15%) stable disease (SD), 17 (32%) PD; 7 (13%) unevaluable pts were taken off treatment after cycle one. Among the responding pts, 5/8 CR pts and 4/13 PR pts went onto maintenance therapy. Of the responders, 6 CR and 1 PR pts remain in remission. 27 (51%) pts have died (1 treatment-related, 24 with PD, 2 with infections). Median follow-up in the 26 living eligible pts is 2.3 (range, 0.1–3.8) yrs. One-yr EFS, PFS, and OS are 25%, 41%, and 67%, respectively. Gr 3/4 toxicities (% gr 3/% gr 4) were: anemia (8/0), leukopenia (6/0), thrombocytopenia (13/21), fatigue/aesthenia (21/0), dyspnea (9/0), infection (6/0), motor neuropathy (9/0), sensory neuropathy (8/0; gr 2 36%), hypotension (8/0), and thrombosis (6/0). During induction therapy (cycles 1–8), at least >1 lenalidomide or bortezomib dose reduction occurred in 24 (44%) and 29 (54%) pts, respectively, due to adverse events; 21 (39%) pts had dose reductions in both drugs. Conclusion: The ORR of 40% for the combination of lenalidomide + bortezomib was disappointing given the high single agent response rates reported with lenalidomide. The lower than anticipated ORR may be due to inadequate lenalidomide dosing, initial simultaneous dose reductions in both agents for toxicity, or the limited protocol therapy administered in 37% of pts. Due to the small number of pts receiving maintenance therapy, one cannot assess its impact. Future studies with this dose and schedule of lenalidomide + bortezomib are not warranted. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3028-3028 ◽  
Author(s):  
Hyebin Park ◽  
Donglu Zhao ◽  
George Tsourdinis ◽  
Zhishuo Ou ◽  
Archito T. Tamayo ◽  
...  

Abstract Introduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor outcome and therapeutic challenge. Oral single-agent ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, elicited a response rate of 68% in phase II clinical trial and has been approved by FDA for the treatment of MCL patients who received at least one prior therapy. To increase the possibility of therapeutic potential, the investigation of BTK-dependent/independent signaling pathways is needed. Methods and Results Using both established MCL cell lines and primary MCL cells as a model system, our data demonstrated that ibrutinib effectively inhibited BTK phosphorylation along with quick STAT3 inactivation within 30 minutes of ibrutinib incubation at a dose lower than 100nM. Since the results clearly indicated that ibrutinib inhibited both BTK and STAT3 activation in MCL cells, we next elucidated the function and action between BTK and STAT3. Using a validated BTK-specific siRNA, we knocked down BTK to test the legitimacy of the relationship between BTK and STAT3. The results showed that transient knockdown of BTK significantly inhibited STAT3 phosphorylation in MCL cells. Next, the results from both immunoprecipitation and confocal microscopy showed that STAT3 was BTK-associated transcription protein indicating that BTK could function as a kinase upstream of STAT3, in a similar manner to the JAK/STAT pathway. Since STAT3 is predominately known as the downstream protein of the IL-6/JAK pathway, we examined whether there is a cross-talk between the BTK-STAT3 and the JAK-STAT3 pathways in MCL cells. After stimulation of MCL cells with IgM or IL-6, ibrutinib only inhibited IgM-induced STAT3 activation but not IL-6-induced STAT3 activation. Even with an increased dose of ibrutinib, the basal level of STAT3 phosphorylation remains detectable in MCL cells due to IL-6 autocrine. However, ibrutinib plus JAK inhibitor completely inactivated STAT3 and synergistically inhibited the growth of MCL cells. These data indicate that there are two independent pathways, BCR-BTK and IL6-JAK, which lead to STAT3 activation without cross-talk in MCL cells. Conclusions Our results may lead to the development of more effective combination therapy to block both BCR-BTK and IL-6-JAK signaling pathways for relapsed or refractory MCL. Disclosures Wang: Pharmacyclics: Honoraria, Research Funding.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8534-8534 ◽  
Author(s):  
Michael E. Williams ◽  
Andre Goy ◽  
Rajni Sinha ◽  
Sevgi Kalayoglu Besisik ◽  
Johannes W. Drach ◽  
...  

8534 Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Single-agent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N=134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio=0.193; p=0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. [Table: see text]


Haematologica ◽  
2012 ◽  
Vol 97 (7) ◽  
pp. 1085-1091 ◽  
Author(s):  
C. Renner ◽  
P. L. Zinzani ◽  
R. Gressin ◽  
D. Klingbiel ◽  
P.-Y. Dietrich ◽  
...  

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 262-262 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Thomas E. Witzig ◽  
Julie M. Vose ◽  
Craig B. Reeder ◽  
Rena Buckstein ◽  
...  

Abstract Introduction: Mantle-cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) that typically responds to initial chemo-immunotherapy, but with a relatively short duration of response (DR) and progression-free survival (PFS) when treated with conventional chemotherapy agents. Although the overall survival (OS) of MCL has improved, most patients are not cured and new agents are needed. A sub-analysis of a recent phase II trial (NHL-002) investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL, demonstrated a promising overall response rate (ORR) of 53% with a median DR of 11.9 months. A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory aggressive NHL that had received at least one prior treatment and had measurable disease. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: This report focuses on the 39 MCL patients that were enrolled and evaluable for response assessment. Median age was 66 (33–82) years and 29 (74%) patients were male. Median time from diagnosis to lenalidomide treatment was 3.4 (0.4–9) years. Patients had received a median of 3 (1–8) prior treatments, and 23% (9/39) of patients had received prior bortezomib treatment. The ORR with lenalidomide was 41% (16/39), including 13% (5/39) complete response (CR)/unconfirmed CR, and 28% (11/39) partial responses. Ten (26%) patients had stable disease. The most common grade 3 or 4 adverse events were neutropenia (51%) and thrombocytopenia (25%), anemia (13%), fatigue (10%) and febrile neutropenia (10%). Conclusion: These results confirm that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects.


ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.


2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Marco Gunnellini ◽  
Lorenzo Falchi

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.


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