Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL)

Abstract Single-agent ibrutinib has been approved by the FDA for patients with mantle cell lymphoma (MCL) who received at least one prior therapy based on a phase II clinical trial in which ibrutinib elicited a response rate of 68% (Wang et al, NEJM, 2013). In this clinical study we found a transient increase in circulating MCL lymphocytes during the initial phase of tumor reduction. We hypothesized that targeting the circulating MCL cells with intravenous rituximab will further improve the efficacy of ibrutinib. We conducted a single-center phase II clinical trial with ibrutinib in combination with rituximab for relapsed MCL with no upper limit for prior lines of therapy. Among 50 patients with MCL, 100% received prior rituximab, 77% received prior Hyper-CVAD, 75% received prior bortezomib, and 20% received prior lenalidomide. Rituximab was dosed at 375 mg/m2 iv weekly X 4 during cycle 1 (cycle = 28 days), then on day 1 of every cycle from 3-8, and thereafter once every other cycle up to 2 years. Ibrutinib was dosed at 560 mg orally daily continuously. With a median follow up time of 6.5 months (range 1-10), 45 patients are evaluable for toxicity and efficacy as of July 21, 2014. Thirty three patients (73% of evaluable patients) have Ki-67 < 50%. Seventeen (17) patients are now off study including 2 patients with secondary malignancies (AML and lung cancer). One (1) patient in CR withdrew consent due to social issues and continued on commercial ibrutinib. Two (2) patients in remission withdrew consent due to their concerns that rituximab-ibrutinib might worsen their atrial fibrillation and both continued on single-agent commercial ibrutinib. One patient was off study due to bleeding. Three (3) patients in remission went off to stem cell transplantation. Eight (8) patients are off study due to progressive MCL (4 never responded: 4 responded then progressed), all of them had Ki-67 greater than 50% (range 50-100%). There were no toxic deaths due to therapy. Grade 3 hematologic toxicity events included neutropenia (1) and thrombocytopenia (1). The most common (≥ 20%) grade 1-2 non-hematologic toxicity events regardless of its relationship with study therapy included fatigue (18), diarrhea (11), myalgia (11), dyspnea (11), blurred vision (10), nausea (9),dry eye (9) and atrial filbrillation (6). The efficacy data is listed in Table 1. The ORR to date is 87% with CR in 17 patients (38%) and PR in 22 patients (49%). The CR rate is high in this study in the context of historical data (21% by single-agent ibrutinib). Median duration of response and PFS has not been reached. Notably, all 10 patients with SD (2) and PD (8) have Ki-67’s ≥ 50%. Excluding the 12 out of 45 evaluable patients with Ki-67 ≥ 50%, the ORR for 33 patients with lower Ki-67 (< 50%) is 100% (48% for CR and 52% for PR) in patients with relapsed/refractory MCL. While this trial is ongoing, preliminary data indicated that Ibrutinib-rituximab combination is well-tolerated and is efficacious, especially in patients with Ki-67 less than 50%. Table 1 The best response related to Ki-67 All n (%) Ki-67 < 50% Ki-67 ≥ 50% Evaluable patients 45 33 12 ORR 39 (87%) 33 (100%) 6 (50%) CR 17 (38%) 16 (48%) 1 (8%) PR 22 (49%) 17 (52%) 5 (42%) SD 2 (4%) 0 2 (17%) PD 4 (9%) 0 4 (33%) Duration of response NR NR NR PFS NR NR NR Disclosures Wang: Pharmacyclics and Janssen: Honoraria, Research Funding. Off Label Use: Ibrutinib and Rituximab for mantle cell lymphoma clinical trial. Westin:Pharmaciclics and Janssen: Honoraria, Research Funding. Fayad:Pharmacyclics and Janssen: Research Funding. Samaniego:Pharmacyclics and Janssen: Research Funding. Romaguera:Pharmacyclics and Janssen: Research Funding.

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Bendamustine plus rituximab for previously untreated patients with indolent B-cell non-Hodgkin lymphoma or mantle cell lymphoma: a multicenter Phase II clinical trial in Japan

International Journal of Hematology ◽

10.1007/s12185-016-2146-4 ◽

2016 ◽

Vol 105 (4) ◽

pp. 470-477 ◽

Cited By ~ 6

Author(s):

Michinori Ogura ◽

◽

Kenichi Ishizawa ◽

Dai Maruyama ◽

Naokuni Uike ◽

...

Keyword(s):

Clinical Trial ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Hodgkin Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Phase Ii Clinical Trial ◽

Non Hodgkin Lymphoma ◽

Multicenter Phase ◽

Mantle Cell

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Durable Responses with Bendamustine Monotherapy In Patients with Relapsed/Refractory Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL) and Mantle-Cell Lymphoma (MCL): Updated Follow-up Data From a Japanese Multicenter Phase II Study

Blood ◽

10.1182/blood.v116.21.4884.4884 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4884-4884 ◽

Cited By ~ 1

Author(s):

Kuniaki Itoh ◽

Kiyoshi Ando ◽

Michinori Ogura ◽

Kenichi Ishizawa ◽

Takashi Watanabe ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Group Performance ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Multicenter Phase ◽

Short Period ◽

Mantle Cell

Abstract Abstract 4884 Background: Bendamustine is an alkylating agent with a unique mechanism of action and has demonstrated efficacy as a single agent for the treatment of relapsed or refractory indolent B-NHL or MCL. We conducted a multicenter, phase II study of bendamustine in Japanese patients with indolent B-cell NHL or MCL, reporting an overall response rate of 91% (90% in indolent B-NHL and 100% in MCL) according to International Workshop Response Criteria after a median follow-up of 12.6 months (Ohmachi et al. Cancer Sci 2010 [Epub ahead of print]). Here we report the updated progression-free survival (PFS) data, including median PFS, which had not been reached at the time of previous reports. Patients and Methods: Eligible patients (aged 20–75 years; Eastern Cooperative Oncology Group performance status of 0 or 1) with measurable, pathologically confirmed indolent B-NHL or MCL that failed to respond to, or relapsed after, prior therapy were enrolled. Bendamustine 120 mg/m2 was administered intravenously over 60 minutes on days 1 and 2 every 21 days for up to 6 cycles. PFS was assessed 3 months after completion of the last cycle, and then at 3-month intervals. Results: A total of 69 patients, aged 33–75 years, were enrolled: 58 with indolent B-NHL, mainly follicular lymphoma (n = 52), and 11 with MCL. Patients had primarily stage III or IV disease. The median number of prior regimens was 2 (range, 1–9) for patients with indolent B-NHL and 4 (range, 1–16) for those with MCL. A median of 5 (range, 1–6) bendamustine cycles were administered, with 72% of patients completing 3 or more cycles. The median follow-up time for all patients is 20.6 months (range, 2.5–27.2 months). The median PFS was 21.1 months (95% CI, 15.8-NA; NA = not available due to short period of observation): 20.0 months (95% CI, 12.3-NA) in indolent B-NHL, and 21.7 months (95% CI, 16.5-NA) in MCL. Estimated 2-year PFS rates were 45.2% and 34.1% in indolent B-NHL and MCL, respectively. Conclusions: Bendamustine monotherapy is highly effective in patients with relapsed or refractory indolent B-NHL and MCL. The durable responses observed in this study strongly support the use of bendamustine in these patients and are particularly encouraging in the relapsed or refractory MCL population. Disclosures: Off Label Use: Bendamustine is a novel alkylator that has shown efficacy and safety in patients with indolent lymphomas, and particularly encouraging is the activity in patients with mantle cell lymphoma, which is difficult to treat. Although bendamustine is currently investigational in Japan, approval for relapsed/refractory indolent NHL and mantle cell lymphoma is anticipated in October 2010.

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Lenalidomide and Rituximab Are a Promising Combination in Vitro, in Vivo Preclinically and in a Phase I/II Clinical Trial in Relapsed/Refractory Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v112.11.3058.3058 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3058-3058

Author(s):

Michael Wang ◽

Liang Zhang ◽

Luis Fayad ◽

Fredrick Hagemeister ◽

Sattva Neelapu ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Phase 1 ◽

Dosage Level ◽

Toxicity Profile ◽

Mantle Cell ◽

Grade 3

Abstract Relapsed/refractory mantle cell lymphoma (MCL) is difficult to treat. Rituximab (R) targets CD20 antigen on the surface of MCL cells while lenalidomide (Len) may target the microenvironment of MCL cells and enhance the antibody-dependent cellular cytotoxicity (ADCC) activity of R. To test this hypothesis, we initiated preclinical studies and a phase I/II clinical trial. In the preclinical study we found that Len and R induced growth inhibition and apoptosis of both cultured and fresh primary MCL cells. Len enhanced R-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Daily treatment with Len increased NK cells by 10 times in SCID mice. The combination of Len and R decreased tumor burden and prolonged survival of MCL-bearing SCID mice. In the phase I/II clinical trial, Eligible patients (pts) with MCL had 1–4 lines of prior therapies. Treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m2 by IV infusion weekly for 4 weeks only during the first cycle with the first dose on Day 1 in Cycle 1. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. Detailed toxicity profile in phase I was reported previously (Wang et al, ASH 2007). Two DLT s occurred at 25 mg including 1 grade 3 hypercalcemia and 1 grade 4 non-neutropenic fever during the first cycle. Six patients from phase 1 were at 20 mg dosage level. One patient from phase 1 was initially at 25 mg dosage level and was subsequently reduced to 20 mg dosage level due to DLT. Eight patients have been enrolled in the phase II trial at MTD. In the 14 patients evaluated at 20 mg dosage level in phase II, median age was 68 (51–77); median prior therapies were 2 (1–4); median cycles received to date were 4 (range 2–26). Grade 3/4 hematologic toxic events included neutropenia (35), febrile neutropenia (2), and thrombocytopenia (11). There was no grade 3–4 anemia. Grade 3 non-hematologic toxic events included fatigue (2) and myalgia (1). Fourteen pts at MTD (20 mg) including 7 in phase I plus 7 in phase II were evaluable for response. Eight out of 14 pts achieved responses including 4 CRs, 4 PR s, 2 SD and 4 PD s. Conclusions: Lenalidomide in combination with rituximab provided a synergistically therapeutic effect on mantle cell lymphoma cells by enhancement of apoptosis and R-dependent NK cell-mediated cytotoxicity preclinically. Lenalidomide plus rituximab showed early evidence of response with a very favorable toxicity profile in a phase I/II clinical trial. Updated information will be presented at the conference.

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RCHOP and RDHAP Followed by Autologous Stem Cell Transplantation (ASCT) in Mantle Cell Lymphoma (MCL) : Final Results of a Phase II Study from the GELA

Blood ◽

10.1182/blood.v112.11.581.581 ◽

2008 ◽

Vol 112 (11) ◽

pp. 581-581 ◽

Cited By ~ 11

Author(s):

Richard Delarue ◽

Corinne Haioun ◽

Vincent Ribrag ◽

Pauline Brice ◽

Alain Delmer ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Mantle Cell Lymphoma ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Phase Ii ◽

Cell Lymphoma ◽

High Dose ◽

Mantle Cell

Abstract Introduction: Treatment of mantle cell lymphoma (MCL) in younger patients (pts) is still a challenge, with questions about best induction regimen before autologous stem cell transplantation (ASCT) and impact of Rituximab. We report here the final results with extended follow-up of a prospective phase II trial. Methods: Patients under 66 years with histologically proven, stage III-IV, MCL were included. Treatment consisted of three courses of CHOP with Rituximab at the third one and three courses of RDHAP. Peripheral blood stem cells harvest was performed and responding pts were eligible for an ASCT after high dose radio-chemotherapy with TAM6 (TBI 10 Gy, Aracytine 6 g/m², Melphalan 140 mg/m²) or BEAM if TBI could not be performed. Results: From May 2000 to September 2003, 60 pts were included. Median age was 57 years. Characteristics of patients were as follow : bone marrow involvement 85%, leukemic disease 48%, gastrointestinal involvment 52%, PS>1 6%, LDH > 1N 38%. Overall response rate was high with 93% after (R)CHOP and 95% after RDHAP. Interestingly, CR was uncommon after (R)CHOP (12%), whereas high proportion of patients (61%) were in CR after RDHAP, suggesting higher efficacy of high dose AraC. Forty-nine pts were autografted (41 with TAM6) : all patients but two (96%) were in CR. With a median follow-up of 67 months, median EFS was 83 months and median OS was not reached. Five years OS was 75%. Neither toxic death nor unexpected toxicities were observed. The comparison with our previous French oligocentric study using the same regimen but without Rituximab (Lefrere, Hematologica 2007) suggests a better outcome when Rituximab is added (median EFS : 51 months). Conclusion: This study confirms that regimens containing Aracytine and Rituximab are safe and prolong survival and may even induce cure in MCL patients. Thus, they should be used in induction treatment before ASCT. This regimen is currently compared with the classical RCHOP induction in a multicentric European protocol within the EMCL network.

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Updated Analysis of a Prospective Phase II Trial of R-MACLO-IVAM Followed by Maintenance for Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1622.1622 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1622-1622

Author(s):

Jose D Sandoval-Sus ◽

Peter J Hosein ◽

Deborah Goodman ◽

Alexandra Stefanovic ◽

Joseph D Rosenblatt ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Maintenance Phase ◽

Induction Phase ◽

Rituximab Maintenance ◽

Mantle Cell

Abstract Abstract 1622 Background: Contemporary therapy for mantle cell lymphoma (MCL) in fit patients usually consists of an induction phase followed by autologous stem cell transplantation (SCT). We previously reported a phase II trial of intensive chemotherapy induction with R-MACLO-IVAM followed by thalidomide maintenance and demonstrated promising progression-free survival (PFS) and overall survival (OS) rates without SCT (Lossos et al, Leuk Lymph 2010). We subsequently modified the protocol to utilize rituximab maintenance instead of thalidomide. Herein we present updated results and follow-up for the patients treated on this trial. Methods: This was a prospective single-arm phase II trial conducted at the University of Miami with IRB approval. Eligible patients were chemotherapy-naïve and had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS 0–2, adequate organ function and no history of HIV or prior cancer. Pretreatment staging include CT and PET scans, endoscopy, colonoscopy and bone marrow biopsy. Cycle 1 consisted of R-MACLO (rituximab, methotrexate, doxorubicin, cyclophosphamide and vincristine) followed by G-CSF. When the ANC was >1.5×109/L, cycle 2 with R-IVAM (rituximab, ifosfamide, mesna, etoposide and cytarabine) was begun, followed by G-CSF, as previously reported. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, patients were re-staged and responses were assessed by standard criteria. Patients who achieved complete responses (both radiologically and pathologically) were eligible for the maintenance phase. The first 22 patients were treated with thalidomide maintenance (target daily dose of 200mg); the protocol was subsequently modified to utilize rituximab maintenance at a dose of 375 mg/m2 IV weekly × 4 weeks, repeated every 6 months. Maintenance therapy was continued until MCL relapse or intolerable toxicity. OS was calculated from the date of diagnosis to the date of death or last follow up. PFS was calculated from date of diagnosis until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics and survival was analyzed using the Kaplan-Meier method. Results: Between June 2004 and June 2012, 32 patients were enrolled, 22 on the first phase and 10 after the amendment to rituximab maintenance. All patients were evaluable for toxicity and 31 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage III disease with bone marrow involvement in 84% and gastrointestinal involvement in 38%. Distribution according to MIPI: low 28%; intermediate 38%; high 34%. All patients had diffuse variant except 2 with blastic variant. Twenty-eight patients completed all 4 cycles of therapy; treatment was stopped in 2 after 3 cycles, and in one after 2 cycles, and 1 died during cycle 1. Of the 31 patients completing 2 cycles of chemotherapy, 29 (94%) achieved a complete response (CR) and 2 had a partial response (PR). After a median follow-up of 54.9 months, the 5-year PFS was 69% (95% CI 51% – 82%) and the 5-year OS was 88% (95% CI 72% – 95%) [Fig 1 & 2]. Lower MIPI group (low vs intermediate vs high) was associated with longer PFS (log rank p = 0.007) and longer OS (log rank p = 0.036) [Fig 3 & 4]. Nine patients relapsed and 5 died; 1 died from sepsis on cycle 1; 1 died in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL and the other 3 died from relapsed MCL after 22, 24 and 60 months respectively. Seven of the 9 patients who relapsed were treated with rituximab and bendamustine and one underwent an allogeneic SCT. Toxicities during the chemotherapy phase for the last 10 patients were similar to what was previously published for the first 22 patients, with the exception of lower renal toxicity since the dose of methotrexate was reduced to a total of 4.2 g/m2 instead of 6.7 g/m2 prior to the amendment. The toxicities during the thalidomide maintenance phase were similar to what was previously reported. For the 10 patients who received rituximab maintenance, there were no unexpected toxicities during the maintenance phase. Conclusions: R-MACLO-IVAM results in a high overall response rate (94% CR and 6% PR) and a low relapse rate after over 4.5 years of median follow-up. The median PFS and OS still have not been reached. These results compare favorably with regimens that include upfront SCT. Disclosures: No relevant conflicts of interest to declare.

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The Combination of Weekly Infusion of Rituximab and Bortezomib Is Effective in Relapsed or Refractory Indolent and Mantle Cell Lymphoma: Long-Term Results of Phase II BRIL06 Study of the Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood.v126.23.2735.2735 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2735-2735 ◽

Cited By ~ 2

Author(s):

Annalisa Chiappella ◽

Patrizia Pregno ◽

Pier Luigi Zinzani ◽

Amalia De Renzo ◽

Andrea Evangelista ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Long Term Results ◽

High Dose ◽

Treatment Schedule ◽

Weekly Infusion ◽

Mantle Cell

Abstract Background. Bortezomib, an inhibitor of the proteasome, is effective in relapsed mantle cell lymphoma (MCL) and indolent lymphomas and it is synergistic with Rituximab to enhance apoptosis and NFkB depletion. On these basis, the FIL conducted a phase II multicenter study aimed to evaluate safety and efficacy of Bortezomib in association with Rituximab in relapsed/refractory non-follicular Lymphoma (Linfocytic, LL and Marginal Zone Lymphoma, MZL) and MCL, not eligible to high dose chemotherapy with stem cell transplantation. Patients and methods. The study was a prospective single arm phase II trial, designed on Simon two-stage Optimal Design. Primary end-point was to obtain an Overall Response Rate (ORR) > 40%. The aim of this analysis is to evaluate long term follow-up of Bortezomib and Rituximab combination. A central histological revision was planned in all the patients at the enrollment. Inclusion criteria were: 18-75 years, relapsed/refractory LL, MZL, MCL after 1-4 lines. Treatment schedule was: one course of 1.6 mg/sqm Bortezomib weekly in combination with standard 375 mg/sqm Rituximab on days 1, 8, 15, 22 followed by two courses of four weekly intravenous bolus of Bortezomib alone; patients with complete (CR), partial remission and stable disease at the intermediate evaluation were planned to be given three further courses with the same schedule. Results. From September 2006 to March 2008, 55 patients were enrolled and six were excluded at central histological revision. Clinical characteristics were: median age 68 (50-74); 16 (33%) LL, 8 (16%) MZL, 25 (51%) MCL; 42 (86%) stage III/IV; 33 (67%) bone marrow involvement. Median number of previous treatments was 2 (range 1-7); 34 (69%) were Rituximab pretreated; 21 (43%) had refractory disease. Thirty (61%) patients completed the treatment and 233 courses were delivered (median: 4.7 courses/patient); 19 (39%) patients did not because of no response in 13, adverse events in five, with only one toxic death due to interstitial pneumonia. ORR was 53% (CR 26.5%); no response was seen in 43% and 4% were not evaluable for response. ORRs by clinical subgroup were: LL 37%, MZL 50%, MCL 64%; Rituximab pretreated 62%, Rituximab naïve 33%; relapsed 64% and refractory 38%. With a median follow-up of 85 months, median Overall Survival (OS) was 61.5 months (95%CI: 35.0-81.5), with 5-years OS 51% (95% CI: 36-65) and median Progression Free Survival (PFS) was 8.9 months (95%CI: 5.3-18.3), with 5-years PFS 16% (95% CI: 7-28%). Five-years PFS by histology was: 12% (95% CI: 2-31) for LL, 17% (95% CI: 5-34) for MCL and 19% (95% CI: 11-53) for MZL. PFS rates were not different between Rituximab pretreated versus naïve nor international prognostic index 1-2 versus 3-4-5 nor refractory versus relapsed. By number of previous therapies, 5-years PFS for 1 previous therapy versus 2 versus 3 or more was: 24%, 14% and 13%, respectively, p=0.36. Conclusions. Weekly infusion of Bortezomib in combination with Rituximab is effective in relapsed/refractory indolent and MCL and represents a treatment option in this setting of patients. Disclosures No relevant conflicts of interest to declare.

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Vorinostat (SAHA), Cladribine, and Rituximab in Previously Untreated Mantle Cell Lymphoma: Updated Results From a Phase I/II Trial

Blood ◽

10.1182/blood.v120.21.3675.3675 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3675-3675 ◽

Cited By ~ 1

Author(s):

Stephen E Spurgeon ◽

Kamal Sharma ◽

David F. Claxton ◽

Christopher W. Ehmann ◽

Carla Gallagher ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Response Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Significant Activity ◽

Free Survival ◽

Mantle Cell ◽

Upregulated Genes

Abstract Abstract 3675 Background: Mantle cell lymphoma (MCL) remains incurable and little consensus exists on the best standard initial therapy. However, improved understanding of disease biology has the potential to lead to novel treatment approaches including new perspectives on older drugs. For example, epigenetic modifications including altered DNA methylation and histone acetylation previously identified in MCL has provided the rationale for using the combination of a hypomethylating agent and a histone deactylase inhibitor. Here we show that agents with differing mechanisms have significant activity in previously untreated MCL. In addition to its cytotoxic effects in lymphoid malignancies, cladribine has hypomethylating properties. Vorinostat (SAHA) is a histone deacetylase inhibitor (HDACi) FDA approved in cutaneous T cell lymphoma with modest single agent activity in MCL. Preclinically, the combination of these agents has been shown to activate silenced genes. Since cladribine inhibits DNA methylation via a unique mechanism, it could also potentially inhibit histone methylation. We previously reported initial results of our Phase I/II trial combining SAHA, cladribine, and rituximab (SCR) for the treatment of B-cell non-Hodgkin's Lymphoma (NHL) [Spurgeon et al, ASH, 2012]. Here we present the updated results from the Phase II portion of the trial in the untreated MCL cohort including response rate, overall and progression free survival, and correlative studies. Methods: The achieved phase II starting dose was vorinostat 400 mg po (days 1–14) combined with cladribine 5mg/m2 IV (days 1–5), and Rituximab 375 mg/m2 IV (weekly × 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Response evaluation occurs after 2 cycles and at the completion of therapy. Responding patients are eligible to receive maintenance rituximab. Phase II eligibility includes relapsed NHL as well as previously untreated MCL. The primary outcome is response rate (ORR); secondary endpoints include progression-free survival (PFS) and overall survival (OS). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray, qRT-PCR and HELP methylation analysis. To evaluate the possible effects of SAHA metabolism on toxicity and response, UDP-glucuronosyltransferase 2B17 (UGT2B17) genotyping is also performed. This study continues to enroll patients. Results: 28 previously untreated MCL patients have been enrolled on the phase II portion of the study. 7 have not yet completed the planned 6 cycles; however, 26 patients have completed ≥ 2 cycles and are evaluable for response. The majority of responding patients have received maintenance rituximab. The overall response rate (ORR) is 100% (26/26) with 69% (18/26) achieving CR. Of those patients not attaining CR, 2 had blastic MCL and died, 3 have not yet completed active treatment, and 1 withdrew consent after two cycles. At a median follow up of 14.7 months (.07 – 25 months) 4 patients have relapsed and 3 have died. Of the relapsing patients, two had blastic MCL. None of the patients achieving a CR has relapsed. The estimated PFS curve (shown in the Kaplan-Meier curve below) did not reach the 0.5 level and therefore, median PFS could not be estimated. Toxicities were defined using CTCAE 4 and primarily include neutropenia, thrombocytopenia, fatigue, anorexia, and dehydration. We found that cladribine hypomethylates DNA in vivo (8/8 pts) and inhibits histone methylation in vitro. There were no upregulated genes common to untreated leukemic MCL patients; however, a number of changes in gene expression were observed. For example, upregulated genes after treatment included DUSP2 (3 patients), FOXO3 (2 patients), NOXA1 (2 patients), CEBPb (2 patients) and p53 (3 patients). Conclusions: The SCR regimen has significant activity and shows epigenetic activity in previously untreated MCL. Initial follow up results are promising, especially in patients without blastic MCL who continue with maintenance rituximab. The SCR regimen should be studied further in NHL. Disclosures: Spurgeon: Merck : Research Funding. Off Label Use: vorinostat: off label use mantle cell lymphoma. Epner:Merck: Research Funding, Speakers Bureau.

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