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

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.

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

Blood ◽

10.1182/blood.v124.21.1751.1751 ◽

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.

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Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years of Age (PrE0405): A Phase II Study

Blood ◽

10.1182/blood-2019-122759 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5243-5243 ◽

Cited By ~ 2

Author(s):

Craig A. Portell ◽

N. Nora Bennani ◽

Opeyemi Jegede ◽

Seema Naik ◽

Benjamin M Parsons ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Advisory Board ◽

Dose Titration ◽

Type I ◽

Mantle Cell

Background: Mantle Cell Lymphoma (MCL) is an aggressive form of Non Hodgkin Lymphoma (NHL) and typically presents in patients over the age of 60 years. Bendamustine and rituximab (BR) combination is one of the standard treatments for MCL and is given to patients for whom high dose chemotherapy with autologous stem cell rescue is planned in the first remission. Progression free survival (PFS) with BR is approximately 36 months (Rummel M Lancet 2013; Flinn IW Blood 2014) and the regimen is overall well tolerated. Venetoclax (VEN) is an orally available inhibitor of BCL2, an anti-apoptotic protein highly expressed in several NHL. Single agent activity has mostly been studied in a Phase I study (in various NHL histologies) where 28 MCL patients were enrolled. Overall response rate was 75% (21 of 28) but complete response (CR) rate was only 21% (6 of 28). Tumor lysis syndrome (TLS) has been associated with VEN and initial dosing requires a ramp up period (Davids MS JCO 2018). VEN has also been combined with other agents in MCL with promising activity (Tam CS NEJM 2018) VEN has been studied as a chemotherapy sensitizer and has shown pre-clinical synergy with chemotherapy. In Follicular lymphoma, BR+VEN was studied at 800mg PO continuous daily dosing and showed an excessive Grade 3-4 adverse event (AE) rate of 78% compared to historical studies of 46% (Zinzani ASH 2016). We hypothesize that, in MCL, VEN can be safely combined with BR at a lower dose and intermittent dosing with improvements to the response rate based on historical controls and maintain a better safety profile. Study Design: This Phase II single arm, multicenter study evaluates VEN at a max dose of 400mg with BR (Bendamustine 90mg/m2 IV day 1 and 2; rituximab 375mg/m2 IV or SQ equivalent day 1) for six 28-day cycles in untreated patients with MCL over the age of 60 years (NCT03834688). Cycle 1 will include a VEN dose titration over the 4 week course (20mg D1-7, 50mg D8-14, 100mg D15-21, and 200mg D22-28). For Cycles 2-6, VEN will be given at 400mg daily x 10 days starting with day 1. Participants are followed for 6 cycles, though will be followed for progression and survival afterward. Participants may receive maintenance rituximab at investigator's discretion. Eligible participants, age 60 years or older, must have biopsy proven untreated MCL with t(11;14) or cyclin D1 expression, though a short course of steroids is allowed for symptomatic MCL. They must have adequate organ function and not require any prohibited concomitant medications. Primary outcome is CR rate as assessed by the Lugano criteria. We estimate a historical CR rate of BR after induction of about 70%. A 15% increase in this rate, to 85% CR, is considered promising for the combination. To achieve this goal, the study will enroll 56 participants (53 eligible) to achieve a 90% power to detect the difference with a 10% Type I error rate. We will also evaluate PFS and overall survival. TLS is an AE of interest and will be evaluated after 19 participants have been enrolled and treated during cycle 1. Minimal residual disease (MRD) will be assessed throughout the study. MRD from peripheral blood will be compared to bone marrow aspirates in all participants undergoing bone marrow aspirate at the end of treatment. Tumor samples at screening and progression will be collected for future study. This study is conducted through PrECOG and is funded by Genentech, a member of the Roche Group. Venetoclax is co-developed by Genentech and AbbVie. The study is slated to open in Fall of 2019 at 10 US sites. Figure Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board. Naik:Celgene: Other: Advisory board. Parsons:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kahl:BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Venetoclax is not approved for use in MCL.

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

Blood ◽

10.1182/blood.v124.21.627.627 ◽

2014 ◽

Vol 124 (21) ◽

pp. 627-627 ◽

Cited By ~ 10

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.

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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 ◽

10.1182/blood.v122.21.3057.3057 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3057-3057 ◽

Cited By ~ 2

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.

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A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.150.150 ◽

2016 ◽

Vol 128 (22) ◽

pp. 150-150 ◽

Cited By ~ 7

Author(s):

Peter Martin ◽

Kristie Blum ◽

Nancy L. Bartlett ◽

Steven I. Park ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hematological Toxicity ◽

Mantle Cell ◽

Previously Treated ◽

Grade 3 ◽

Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

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Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8533 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8533-8533

Author(s):

Thomas E. Witzig ◽

Julie Vose ◽

Pier Luigi Zinzani ◽

Thomas Matthew Habermann ◽

Joseph M. Tuscano ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Single Agent ◽

Pooled Analysis ◽

Prior Treatment ◽

Second Primary ◽

Phase Ii Studies ◽

Venous Thromboembolic Events ◽

Mantle Cell

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]

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The Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Mantle Cell Lymphoma Previously Treated with Bortezomib: Pooled Data from Two Phase II Studies (NHL-002 and NHL-003).

Blood ◽

10.1182/blood.v112.11.1560.1560 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1560-1560 ◽

Cited By ~ 4

Author(s):

Craig B. Reeder ◽

T.E. Witzig ◽

Julie M. Vose ◽

Pier Luigi Zinzani ◽

Rena Buckstein ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Prior Treatment ◽

Cell Transplant ◽

Phase Ii Trials ◽

Phase Ii Studies ◽

Mantle Cell

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.

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The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Blood ◽

10.1182/blood.v118.21.442.442 ◽

2011 ◽

Vol 118 (21) ◽

pp. 442-442 ◽

Cited By ~ 12

Author(s):

Luhua Wang ◽

Peter Martin ◽

Kristie A. Blum ◽

Brad S. Kahl ◽

Lauren S. Maeda ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Single Agent ◽

Employment Equity ◽

Mantle Cell ◽

Previously Treated ◽

Equity Ownership

Abstract Abstract 442 Introduction: Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL. Methods and Patients: Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria. Results: A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62–72). The median number of prior treatment regimens is 2 (1–5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1). Conclusions: Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned. Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial. Martin:Pharmacyclics: Research Funding. Blum:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Maeda:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. Williams:Pharmacyclics: Research Funding. Rule:Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang:Pharmacyclics: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Goy:Pharmacyclics: Research Funding.

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A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma

Haematologica ◽

10.3324/haematol.2011.053173 ◽

2012 ◽

Vol 97 (7) ◽

pp. 1085-1091 ◽

Cited By ~ 71

Author(s):

C. Renner ◽

P. L. Zinzani ◽

R. Gressin ◽

D. Klingbiel ◽

P.-Y. Dietrich ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Single Agent ◽

Multicenter Phase ◽

Mantle Cell

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Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL

Blood ◽

10.1182/blood-2019-126175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2815-2815 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Shuangtao Zhao ◽

Rashmi Kanagal-Shamanna ◽

Lucy Navsaria ◽

Holly Hill ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Board ◽

Advisory Committees ◽

Ki 67 ◽

Mantle Cell ◽

Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

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