Ibrutinib and Rituximab Are an Efficacious and Safe Combination in Relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 627-627 ◽  
Author(s):  
Michael (Luhua) Wang ◽  
Fredrick Hagemeister ◽  
Jason R. Westin ◽  
Luis Fayad ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Phase Ii Clinical Trial ◽  
Hematologic Toxicity ◽  
Ki 67 ◽  
Mantle Cell

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.

scholarly journals 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)

2018 ◽  
Vol 182 (3) ◽  
pp. 404-411 ◽  
Author(s):  
Preetesh Jain ◽  
Jorge Romaguera ◽  
Samer A. Srour ◽  
Hun J. Lee ◽  
Frederick Hagemeister ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Phase Ii Clinical Trial ◽  
Mantle Cell

Ibrutinib in combination with Rituximab for Relapsed Mantle Cell Lymphoma: An Update for a Phase II Clinical Trial

2015 ◽  
Vol 15 ◽  
pp. S65 ◽  
Author(s):  
Michael (Luhua) Wang ◽  
Hun Lee ◽  
Hubert Chuang ◽  
Nicolaus Wagner-Bartak ◽  
Fredrick Hagemeister ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Phase Ii Clinical Trial ◽  
Mantle Cell

scholarly journals Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi

Haematologica ◽  
2017 ◽  
Vol 102 (5) ◽  
pp. e203-e206 ◽  
Author(s):  
Francesco Zaja ◽  
Simone Ferrero ◽  
Caterina Stelitano ◽  
Angela Ferrari ◽  
Flavia Salvi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Phase Ii Clinical Trial ◽  
Second Line ◽  
Mantle Cell

Phase II Multicenter Study of Single-Agent Lenalidomide in Subjects with Mantle Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: The MCL-001 “EMERGE” Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 905-905 ◽  
Author(s):  
Andre Goy ◽  
Rajni Sinha ◽  
Michael E. Williams ◽  
Sevgi Kalayoglu Besisik ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Board Member ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Advisory Board ◽  
Safety And Efficacy ◽  
Mantle Cell ◽  
Heavily Pretreated

Abstract Abstract 905 Introduction: Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin's lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods: This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results: 134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions: The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib. Disclosures: Goy: Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

scholarly journals Ofatumumab-Bendamustine As First Line Treatment for Elderly Patients with Mantle Cell Lymphoma: A Phase II Risk Adapted Design with Comprehensive Geriatric Assessment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1751-1751
Author(s):  
Carla Casulo ◽  
Augustine Iannotta ◽  
Jannelle Walkley ◽  
Craig H. Moskowitz ◽  
Alison J Moskowitz ◽  
...  
Keyword(s):  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Line Treatment ◽  
First Line ◽  
Mantle Cell ◽  
First Line Treatment

Abstract Introduction: Mantle cell lymphoma (MCL) is a heterogeneous disease and risk-stratification of patients (pts) for treatment is not performed routinely. For older pts ineligible for aggressive treatments, comprehensive geriatric assessments (CGA) are recommended but not routinely implemented into practice. Commonly used chemo-immunotherapeutic options result in low rates of complete remission (CR) (40%-50% bendamustine-rituximab; Rummel et al Lancet 2013; Flinn et al Blood 2014), with frequent relapses. Risk-stratification of older MCL pts through biological and clinical characteristics may improve treatment outcomes and reduce toxicity. Ofatumumab may have an advantage over rituximab given more efficient complement activation and complement dependent cytotoxicity. To test this we designed a phase II risk-stratified study of ofatumumab alone or in combination with bendamustine as first line treatment for elderly MCL with the goal of improved remission rates and extended survival. Methods: This was a single-institution phase II study. The primary objective was response. Eligible pts were 65 years of age or older with untreated MCL and/or ineligible for aggressive treatments such as high dose chemotherapy/autologous stem cell transplant. Patients were risk-stratified for therapy. Low risk pts with no GELF/NCCN criteria, low/intermediate risk MIPI, Ki-67 index < 30% and no blastic morphology received single agent ofatumumab weekly for 4 doses. High risk pts with GELF/NCCN criteria present, high risk MIPI, Ki-67 index > 30% or blastic morphology received ofatumumab and bendamustine (O-B) every 28 days for 6 cycles. A simon-two stage design was implemented requiring 6 of 12 pts to have a CR in the O-B arm to proceed. Pts receiving ofatumumab only were permitted to cross over to O-B for less than a partial response (PR) at restaging. Survival probability was estimated by the Kaplan-Meier method. CGA was performed prior to each cycle, and correlation to treatment toxicity was evaluated as a secondary endpoint. Results: Twenty pts in total were enrolled. Median age was 73 (range: 44-83). Seven pts (35%) were classified as low risk and received single agent ofatumumab. Thirteen pts (65%) were classified as high risk and received O-B. All patients in the O-B arm completed 6 cycles of treatment, all met GELF/NCCN criteria. Of these, 54% had high risk MIPI, 54% had Ki67 ≥30%. Among pts receiving single agent ofatumumab, 71% (5 pts) had < PR (stable disease), 1 had CR (14%), and 1 pt was not evaluable. Three pts with < PR crossed over to the O-B arm. Among 12/16 evaluable pts (3 too early, 1 withdrew) in the O-B arm; overall response rate was 92%; CR rate was 67%, PR rate 25%. One patient had stable disease (8%). After median follow-up of 1.8 years (range 0.1-2.6 years), overall survival in the entire group is 100%. Progression free survival at 2 yrs for the O-B arm is estimated at 68%. Both regimens were safe and well tolerated. Incidence of grade 3/4 serious adverse effects was 15% (3 of 22 patients), all in the O-B group. Baseline CGA identified patients as low (n=15) and medium risk (n=3) for grade 3/4 toxicity, with all three SAE (pneumonia, UTI, SVT) occurring in medium risk patients (p=0.001). Baseline timed-up and go showed a trend for anticipated toxicity for patients in the worst quartile (p=0.11). Conclusions: The combination of ofatumumab and bendamustine has promising activity in elderly pts with high risk MCL, with superior CR rates compared to historical chemo-immunotherapeutic regimens. Single agent ofatumumab had modest activity, but was safe in low risk pts and did not impact responses to chemoimmunotherapy. CGA assessment may help predict toxicity. Ofatumumab-bendamustine is effective as first line treatment for older pts with MCL and holds promise as a platform for combination with novel agents in prospective trials of untreated MCL. Figure 1 Figure 1. Disclosures Off Label Use: Ofatumumab is an anti CD20 monocloncal antibody not approved for use in mantle cell lymphoma. Moskowitz:Genentech: Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Zelenetz:Foundation Medicine, Inc: Consultancy. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding.

scholarly journals A Phase II Clinical Trial of Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone (R-CyBor-D) in Relapsed Low Grade and Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4410-4410
Author(s):  
Allison C. Rosenthal ◽  
Amylou Constance Dueck ◽  
Katherine Gano ◽  
Craig Nichols ◽  
Daniel Johnson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Combination Therapy ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Sensory Neuropathy ◽  
Low Grade ◽  
Best Response ◽  
Mantle Cell

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Updated Efficacy and Safety, and Exploratory Ki-67 Results For The MCL-001 Study Of Lenalidomide In Mantle Cell Lymphoma Patients Who Relapsed Or Were Refractory To Bortezomib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3057-3057 ◽  
Author(s):  
Andre Goy ◽  
Michael E. Williams ◽  
Sevgi Kalayoglu Besisik ◽  
Johannes Drach ◽  
Radhakrishnan Ramchandren ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
High Dose ◽  
Efficacy And Safety ◽  
High Dose Therapy ◽  
Ki 67 ◽  
Mantle Cell ◽  
Heavily Pretreated

Abstract Introduction Patients with mantle cell lymphoma (MCL) typically respond to initial therapy and almost inevitably relapse with frequent chemoresistance over time and poor outcome. Multiple phase II studies have established the efficacy and safety of lenalidomide, an immunomodulatory agent with tumoricidal and antiproliferative properties, in relapsed/refractory MCL. The prospective phase II multicenter MCL-001 “EMERGE” study led to FDA approval of lenalidomide for patients with relapsed/refractory MCL after 2 prior treatments, that included bortezomib. The activity of lenalidomide was seen regardless of MIPI, number of prior therapies, prior high dose therapy, bulky disease or high tumor burden. One of the most established prognostic factors in MCL is the proliferation index Ki67 (MIB1), now confirmed both in standard and dose-intensive high-dose therapy strategies. We present here longer follow-up of efficacy and safety from the MCL-001 study in patients relapsed/refractory to bortezomib and the potential relationship between Ki-67 and efficacy outcomes. Methods Patients with heavily pretreated MCL, that included prior bortezomib, received lenalidomide 25 mg/day PO, days 1-21 in 28-day cycles until disease progression or intolerability. Primary study endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety. Response rates and time-to-event data were analyzed by independent central reviewers per modified IWG criteria and Kaplan-Meier estimates respectively (data cut-off March 20, 2013). Ki-67 was examined as an exploratory endpoint by immunohistochemistry for 81/134 patients (60%) either performed on biopsy samples for 24 patients, or based on the Ki-67 scores reported in local pathology reports for 57 patients. Results Median age for the enrolled intent-to-treat patient population (N=134) was 67 years (range, 43-83; 63% ≥65 years). The median number of previous therapies was 4 (range, 2-10; 78% received ≥3), 93% stage III/IV, and 72% were <6 months from last prior treatment. At a median follow-up of 13.2 months, the ORR was 28% (CR/CRu 8%), with a median DOR of 16.6 months (95% CI, 9.2-26.7; median not reached in patients with CR/CRu) by central review. Median TTR was 2.3 months (95% CI, 1.7-13.1), with a median time to CR/CRu of 4.1 months (95% CI, 1.9-13.2). Median PFS was 4.0 months (95% CI, 3.6-6.9), and median OS was 20.9 months (95% CI, 13.7-24.4). The average dose intensity of lenalidomide was 20 mg/day, for a median duration of 94.5 days (range, 1-1,256). Dose reductions or interruptions due to adverse events (AEs) occurred in 40% and 58% of patients, respectively. Neutropenia (44%), thrombocytopenia (28%), and anemia (11%) were the most common treatment-related grade 3/4 AEs. Ki-67 results were available in 81/134 patients, and efficacy data were categorized using 30% and 50% cut-off thresholds for Ki-67 expression (Table 1). Although patient numbers were limited, the ORR was similar in both lower and higher Ki-67 group, but those with lower Ki-67 levels demonstrated better CR rates, DOR and survival outcomes compared with patients with elevated Ki-67. Conclusions Single-agent lenalidomide in heavily pretreated patients with relapsed/refractory MCL post-bortezomib showed durable long-term efficacy with a consistent safety profile. Consistent with what is reported in the literature, high Ki-67 is associated with poor outcome in our cohort with shorter OS. Though based on retrospective evaluation and subsets of patients, the ORR to lenalidomide was similar in both low and high Ki-67 groups, suggesting lenalidomide can be active in patients expressing high levels of Ki67. Prospective studies are needed to confirm these findings. Disclosures: Goy: Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Williams:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Drach:Celgene: Honoraria. Ramchandren:Celgene: Research Funding. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Heise:Celgene: Employment, Equity Ownership. Witzig:Celgene: Research Funding.

Outcome of Observation As Initial Strategy in Patients with Mantle Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2699-2699 ◽  
Author(s):  
Pau Abrisqueta ◽  
Graham W Slack ◽  
David W Scott ◽  
Randy D. Gascoyne ◽  
Joseph M. Connors ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Early Treatment ◽  
Peripheral Blood ◽  
Research Funding ◽  
Treatment Initiation ◽  
Clinical Presentation ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Ki 67 ◽  
Mantle Cell

Abstract Background Patients with mantle cell lymphoma (MCL) follow a heterogeneous clinical course ranging from very indolent to very aggressive. While patients with MCL generally require treatment initiation shortly after diagnosis, it is unclear whether deferring treatment in patients with "indolent" MCL affects their overall outcome. Because it is difficult to identify such patients at the time of diagnosis, their course can only be retrospectively described as indolent after a prolonged period of observation. The aim of this study was to describe the subgroup of patients with MCL who underwent observation as their initial management, including their clinical and biological characteristics and outcomes. Methods Patients diagnosed with MCL from 1998-2015 who were initially observed for ≥3 months from the date of definitive diagnosis were identified in the BCCA Lymphoid Cancer and Pharmacy Databases. Pathology was centrally reviewed at the time of diagnosis, and only cases positive for CCND1 by immunohistochemistry and/or t(11;14) by FISH were included. During the study period, there were no predefined criteria guiding observation or active treatment. Eventual treatment indications included high tumor burden, disease associated symptoms or peripheral blood cytopenias. Clinical-biological features at diagnosis, treatment and outcomes, were analyzed. Results A total of 725 patients with MCL were initially identified, but 286 were excluded: missing data (n=179), treatment refusal (n=7), no treatment due to frailty (n=16), or absence of CCDN1 or t(11;14) confirmation (n=84). 365 (83%) patients received early treatment (ET) and 74 (17%) were observed >3 months (OBS), as shown in Table 1. In the OBS group, 52 (71%) patients had measurable lymph nodes at presentation, 16 (22%) a non-nodal presentation (defined as peripheral blood, bone marrow, and/or spleen only), and 5 (7%) only had gastro-intestinal involvement. Patients in the OBS group were older, with favorable presenting features including good performance status, less frequent B symptoms or increased LDH, and lower Ki67 (<30% vs ≥ 30%) than the ET group. However, MIPI scores were similar between both groups. The majority of patients received rituximab-containing chemotherapy (most commonly R-CHOP or R-bendamustine) at the time of initial treatment in both the ET group (70%) and the OBS group (72%). In the OBS cohort, with a median follow-up of 47 months (range 3.4 - 158 months) in living patients, the median time to treatment (TtT) was 35.5 months (range 5 - 79 months). 10 patients (14%) were observed for > 5 years without requiring treatment. Factors associated with longer TtT included clinical presentation (non-nodal vs nodal, median not reached vs 29 months; P=.005) and Ki-67 (<30% vs ≥ 30%, median 59 vs 20 months, P=.033). Median OS was significantly longer in the OBS group than in the ET group (66 vs 50 months, respectively, P=.024) reflecting the more favorable disease characteristics of the OBS group. Clinical presentation (ie, non-nodal vs nodal) was the only factor associated with OS (median 123 vs 47 months, P=.003) in the OBS group. Finally, the median OS from date of treatment initiation for patients eventually requiring therapy in the OBS group was 34.4 months. With a median age at treatment initiation of 71 yrs (range 40 - 91 yrs) in the OBS group, OS was not significantly different in comparison with the ET group when the analysis was adjusted by age at treatment. Conclusions A subgroup of patients with MCL may be safely observed at diagnosis of the disease without negatively impacting their outcomes, including not only those patients with non-nodal presentation but also asymptomatic patients with low burden nodal presentation, particularly those with a low proliferative rate. Table 1. Patients characteristics by treatment group Observation (n=74) Early treatment (N=365) p-value Median age, years (range) 68 (39 - 90) 66 (22 - 94) 0.05 Male sex 47/74 (64%) 262/365 (72%) 0.16 Performance status >1 7/71 (10%) 97/337 (29%) <.001 B symptoms 1/73 (1%) 116/353 (33%) <.001 Elevated LDH 5/66 (8%) 110/310 (36%) <.001 Ann Arbor Stage I/II 7/73 (10%) 40/357 (11%) 0.80 Ki-67 ≥30% 6/24 (25%) 89/151 (59%) 0.002 Blastoid morphology 0/74 (0) 44/365 (12%) <.001 Nodular pattern 30/58 (52%) 139/304 (46%) 0.40 MIPI 0.73 -   Low risk 20/64 (31%) 83/288 (29%) -   Intermediate risk 19/64 (30%) 77/288 (27%) -   High risk 25/64 (39%) 128/288 (44%) Disclosures Scott: Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Villa:Roche: Research Funding.

scholarly journals Ofatumumab Plus Hypercvad/MA Induction Leads to High Rates of Minimal Residual Disease (MRD) Negativity in Patients with Newly Diagnosed Mantle Cell Lymphoma, Results of a Phase 2 Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2817-2817
Author(s):  
Pallawi Torka ◽  
Nishitha Reddy ◽  
Adrienne Groman ◽  
Angela Kader ◽  
Jenna Nichols ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Survival Outcomes ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Mantle Cell ◽  
Minimal Residual

Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

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