Population Based Analysis of Mantle Cell Lymphoma in Texas: Are Outcomes Any Different in Hispanics?

Introduction: Mantle cell lymphoma (MCL) is a rare type of incurable B-cell lymphoma with an incidence rate of ~0.8/100,000 in the United States (US) (Blood, PMID: 30154113; CA Cancer J Clin, PMID: 27618563). Recent advances in understanding of MCL biology, development of new therapeutic modalities such as Bruton tyrosine kinsase inhibitors (BTKi), and advancement of treatment strategy incorporating chemotherapy and non-chemotherapy treatment modalities have improved survival (Am J Hematol, PMID: 30963600; Blood, PMID: 26059948; Blood, PMID: 28899853). However, prognosis for MCL remains poor overall (Blood, PMID: 30154113). Although variations in incidence in MCL by race has been reported in the literature (CA Cancer J Clin, PMID: 27618563), there is currently limited data available on differences in demographics, treatment patterns, and outcomes in Hispanic (H) MCL patients. Methods: In this retrospective cohort study, de-identified data was obtained from the Texas Cancer Registry (TCR) database for those diagnosed with MCL between 2006-2016. Standard demographic variables collected include gender, race, ethnicity, birthplace, dates at diagnosis and death, primary payer at diagnosis, stage, type of treatment, poverty index, and vitality status among others. The significance of variation in the distribution of outcomes with ethnicity [H, non-Hispanic (NH)] was assessed with Fisher's Exact test, Pearson's Chi-square test, T-test, or Wilcoxon test as appropriate. Survival time was measured in years from date of primary diagnosis to date of death. Patients not coded as dead were considered censored on survival time at the date last seen. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. All statistical testing was two-sided with a significance level of 0.05. Results: A total of 1852 (296 H, 1556 NH) patients were included in the final analysis. Median age at diagnosis were 65.5 (H) and 68.0 (NH). 72.6% of H and 72.7% of NH cohorts were male. Of the NH cohort, 92.5% were White, 5.3% Black, 1.5% Asian, 0.4% Native American and 0.1% with unknown race. There was a statistically significant difference between the cohorts in the poverty index. Most H (50.5%) were in the 20-100% bracket, while the majority of NH (36.2%) were in the 10-19.9%. The majority of the cohort were from metro areas (90.2% H and 82.6% NH) and non-border counties (72.6% H and 97.2% NH). There was a statistically significant difference in insurance status at diagnosis between the cohorts. Medicare was the most common type for both H (41.1%) and NH (50.2%), while 13.4% of H and 4.0% of NH were uninsured. The majority of H (66.2%) and NH (64.0%) were diagnosed with stages 3-4 MCL; for H, stage 1 10.5%, stage 2 6.1%, stages 3-4 66.2%; for NH, stage 1 10.4%, stage 2 6.6%, stages 3-4 64.0%. The most common treatment received was combination chemotherapy (43.2% H, 38.8% NH); for H, combination chemotherapy (CC) 43.2%, single agent chemotherapy (SAC) 7.4%, chemotherapy not otherwise specified (CNOS) 14.5%, died prior to recommended treatment (PRI) 1%, refused recommended treatment (REF) 0.7%, treatment recommended but not given (NG) 0.3%, treatment contraindicated (CI) 0.7%, no treatment (NT) 18.6% and unknown treatment status (UTS) 13.5%; for NH, CC 38.8%, SAC 10.5%, CNOS 14.5%, PRI 0.2%, REF 1.3%, NG 0.3%, CI 0.8%, NT 23.0% and UTS 10.4%. Regarding BMT/stem cell infusion, 3.1% H and 3.6 NH were confirmed to have received it; 2.5% H and 2.1% NH were confirmed to have received treatment involving radiation. Median survival was 3.7 years (y) and 3.8 y for H and NH respectively; the survival probability at 2 y was 0.65 (0.59-0.71) vs 0.65 (0.62-0.68), 5 y 0.40 (0.33-0.48) vs 0.41 (0.38-0.44) and 10 y 0.19 (0.12-0.30) vs 0.14 (0.09-0.21) for H and NH respectively. There was no statistically significant differences between the cohorts on stage of disease at diagnosis, types of treatment received or overall survival probability. Conclusions: In Texas residents diagnosed with mantle cell lymphoma between 2006-2016, there were statistically significant differences in the level of poverty and insurance coverage between H and NH cohorts but no differences in stage at diagnosis, type of treatment received, or survival. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Molecular Templates: Research Funding; AstraZeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Seattle Genetics: Speakers Bureau; Verastem: Speakers Bureau; AbbVie: Speakers Bureau.

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Disparities in Mantle Cell Lymphoma Outcomes in Hispanics: A Population Based Analysis in Texas and Florida

Blood ◽

10.1182/blood-2021-145937 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4081-4081

Author(s):

Brian Warnecke ◽

Daniel Rosas ◽

Alexandra Wehbe ◽

Qianqian Liu ◽

Joel E Michalek ◽

...

Keyword(s):

Survival Time ◽

Median Survival ◽

Survival Probability ◽

Median Survival Time ◽

Research Funding ◽

Cell Lymphoma ◽

Poverty Index ◽

Significant Difference ◽

Mantle Cell ◽

Age Of Diagnosis

Abstract Introduction: Mantle cell lymphoma (MCL) is a rare, aggressive type of B-cell non-Hodgkin lymphoma (NHL) that accounts for approximately 7% of adult NHL's in the United States. (JCO PMID: 9704731)Although recent advancements in treatment have improved survival, prognosis remains poor. (Blood PMID: 30154113) There have been several recent studies demonstrating ethnic disparities in MCL, however, there is a paucity of survival outcome data in Hispanic (H) patients with MCL. (CLMLPMID: 31029647) The purpose of this study was to compare the demographics, treatment patterns, and survival outcomes of H and Non-Hispanic (NH) patients diagnosed with MCL, and to contrast Hispanic cohorts between Texas (TX) and Florida (FL). Methods: This is a retrospective cohort study of patients diagnosed with lymphoma (Hodgkin and Non-Hodgkin) from the Texas Cancer Registry (TCR) and the Florida Cancer Data System (FCDS) from 2006-2017. This particular analysis focuses on patients with diagnosis of MCL. Key variables included gender, race, ethnicity, birthplace, dates of diagnosis and death, primary payer at diagnosis, poverty index, stage at diagnosis, and type of treatment. The significance of variation in distribution of categorical outcomes with ethnicity [H, NH] was assessed with Fisher's Exact tests or Pearson's Chi-square as appropriate; age was assessed with T-test or Wilcoxon. Survival time was measured in years from date of primary diagnosis to date of death. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. All statistical testing was two-sided with a significance level of 0.05. Results: We identified a total 4619 (2078 TX, 2541 FL) patients with MCL. 669 (15%) were H and 3950 (85%) were NH. In TX, the median age of diagnosis was 65.6 years (y) in H and 68.3 y in NH (p < 0.001). In FL, the median age of diagnosis was 67.56 in H and 70.06 in NH (p < 0.001). There was a statistically significant difference in poverty index between the cohorts in both TX and FL. The majority of H (50%) in TX were in the 20-100% bracket while the majority of NH (36%) in TX were in the 10-19.9% bracket (p < 0.001). The majority of H (39%) in FL were in the 10-19.9% bracket, and the majority of NH (35%) were also in the 10-19.9% bracket (p < 0.001). Interestingly, there were only 30% of H in FL in the 20-100% bracket. There was a statistically significant difference in insurance status with the most frequent insurance being government-sponsored insurance for H in TX (48%), NH in TX (58%), H in FL (48%), and NH in FL (62%). Patients were without insurance at time of diagnosis in 14% of H in TX and 9% of H in FL, in contrast to 4% of NH in TX and 2% NH in FL. The most common stage at diagnosis in both cohorts in TX and FL was Stage III/IV with 68% H in TX vs 65% NH in TX (p = 0.746) and 69% H in FL vs 67% NH in FL (p = 0.316). The most frequent chemotherapy regimen included multiple agents for all cohorts, 43% H in TX vs 37% NH in TX (p = 0.063), and 48% H in FL vs 42% NH in FL (p = 0.695). Median survival time was 3.4 y H in TX, 3.5 y NH in TX, 4.1 y H in FL, and 4.3 y NH in FL. The survival probability at 2 years was 0.636, 0.640, 0.707, 0.675 for H in TX, NH in TX, H in FL, and NH in FL, respectively. The survival probability at 5 years was 0.371, 0.379, 0.445, 0.459 for H in TX, NH in TX, H in FL, and NH in FL, respectively. The survival probability at 10 years was 0.147, 0.118, 0.276, 0.245 for H in TX, NH in TX, H in FL, and NH in FL, respectively. There was no statistically significant difference in survival probability at 2, 5, or 10 years between H and NH in TX (p = 0.68) and FL (p = 0.72). Conclusions: Our study of patients diagnosed with MCL demonstrated statistically significant differences between H and NH patients in median age of diagnosis, poverty index, and insurance status at diagnosis. These disparities were observed in patients between the cancer registries in both states. Although there were no statistically significant differences in median survival time or survival probability at 2, 5, and 10 years among the H cohorts within each state, we observed intriguing data when the two states were compared. Strikingly, H in TX had much lower survival probability at 2, 5, and 10 years compared to H in FL. In addition, H in TX were noted to have a shorter median survival time compared to H in FL. These disparities may be a direct reflection of the significantly higher rates of poverty and lack of insurance among H in TX compared to H in FL. Figure 1 Figure 1. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Astra Zeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Epizyme: Research Funding.

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Biweekly Bendamustine Monotherapy for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma and Mantle Cell Lymphoma: A Rabbit-14 Trial

Blood ◽

10.1182/blood.v128.22.5325.5325 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5325-5325

Author(s):

Tadahiko Igarashi ◽

Hisashi Wakita ◽

Hideki Tsujimura ◽

Nobuyuki Aotsuka ◽

Shinichi Masuda ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Complete Response ◽

Median Number ◽

Treatment Schedule ◽

Random Allocation ◽

Significant Difference ◽

Mantle Cell

Abstract [Background] Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702). [Methods] Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point. [Results] A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (>6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm.　After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months. [Conclusions] Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population. Disclosures Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

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Limited stage mantle cell lymphoma: Results of overall survival based on treatment modality using SEER database.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19566 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19566-e19566

Author(s):

Apoorva Jayarangaiah ◽

Shuai Wang ◽

Tarek N. Elrafei ◽

Lewis Steinberg ◽

Abhishek Kumar

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Stage I ◽

Close Monitoring ◽

Seer Database ◽

Limited Stage ◽

Number Of Patients ◽

Significant Difference ◽

Mantle Cell

e19566 Background: Limited stage mantle cell lymphoma (MCL) (stage I-II) is rare and occurs in 5-15% of patients. The ideal treatment approach among radiation (RT), chemotherapy (CT), chemoradiotherapy (CRT) or close monitoring (NT) has not been defined. Methods: A retrospective analysis of SEER database (1975 to 2018) was conducted for patients with stage I-II MCL to compare overall survival (OS) among the various treatment modalities in patients >18 years. We excluded patients lacking information on demographic characteristics and survival. Patients were analyzed in 4 groups; RT only, CT only, CRT and no treatment groups. ANOVA test and Chi-square test were used to evaluate parametric and non-parametric variables between groups, respectively. Cancer specific survival (CSS) and OS were assessed by Kaplan-Meier. SPSS 26.0 was used for data analysis. Results: There were in total 2266 patients with limited stage MCL. Median age was 71 years (61-78.25) and predominantly male (65.7%). Stage I MCL was noted in 55.6% and stage II in 44.4% of the patients. The number of patients in each group; RT only, CT only, CRT and NT along with the OS are presented in Table. CSS among these four groups showed no statistically significant differences (p <0.26). OS showed that CT only group has worse survival compared to RT only and CRT groups (p <0.001). CRT has no significant difference in survival compared to RT only (p<0.001). NT was associated with poorest survival rates (p<0.001). Conclusions: In limited stage MCL, RT only and CRT resulted in superior OS compared to CT only. Results suggest a role for incorporation of RT in treatment regimens. One limitation of the study is that the SEER database lacks the ability to distinguish between no receipt of therapy versus lack of availability of data.[Table: see text]

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Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

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

Blood ◽

10.1182/blood-2020-133298 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Mats Jerkeman ◽

Martin Hutchings ◽

Riikka Räty ◽

Karin Fahl Wader ◽

Anna Laurell ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Molecular Remission ◽

Mantle Cell ◽

Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

Author(s):

Luhua Wang ◽

Luis Fayad ◽

Fredrick B. Hagemeister ◽

Sattva Neelapu ◽

Felipe Samaniego ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Progression Free Survival ◽

Phase 2 ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽

10.1182/blood.v116.21.110.110 ◽

2010 ◽

Vol 116 (21) ◽

pp. 110-110 ◽

Cited By ~ 20

Author(s):

Olivier Hermine ◽

Eva Hoster ◽

Jan Walewski ◽

Vincent Ribrag ◽

Nicole Brousse ◽

...

Keyword(s):

Treatment Failure ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

High Dose ◽

Advisory Committees ◽

Overall Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

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LFB-R603, a Third-Generation Monoclonal Anti-CD20 Antibody Displays An Additive Antitumor Activity with Antileukemic Chemotherapeutic Agents in Mouse Xenograft Models

Blood ◽

10.1182/blood.v118.21.1660.1660 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1660-1660 ◽

Cited By ~ 3

Author(s):

Isabel Tourais Esteves ◽

Charles Dumontet ◽

Stéphanie Herveau ◽

Lina Reslan ◽

Frédérique Brune ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Mantle Cell Lymphoma ◽

Subcutaneous Injection ◽

Research Funding ◽

Cell Lymphoma ◽

Chemotherapeutic Agents ◽

Mantle Cell ◽

Cd20 Antibody ◽

Anti Cd20

Abstract Abstract 1660 LFB-R603, a next generation anti-CD20 antibody currently in clinical development, is characterized by a specific glycosylation pattern containing a high percentage of non fucosylated antibodies molecules at the Fc site. This pattern of glycosylation increases the affinity of antibodies for human FcγRIIIa, resulting in an increased antibody dependent cell-mediated cytotoxicity (ADCC) by human FcγRIIIa-expressing effector cells. This antibody is currently in a phase I clinical trial in B-CLL patients and its use is planned to be expanded to other non-hodgkin's lymphomas (NHL) such as follicular and mantle cell lymphoma, as a single agent and in combination with chemotherapeutic agents. The antitumor efficacy of LFB-R603 was studied in comparison with rituximab in combination with conventional chemotherapeutic agents in two models of NHL developed in immuno-deficient mice. The RL cell line, derived from a patient with follicular lymphoma (FL), was xenografted in mice by subcutaneous injection. Tumor-bearing mice were treated intravenously during 4 weeks with the anti-CD20 antibodies used alone or in combination with suboptimal doses of cyclophosphamide 50 mg/kg or bendamustine 30 mg/kg. LFB-R603 and rituximab displayed a dose-related antitumor activity. The tumor growth inhibition (TGI) was at day 30, 64% at 10 mg/kg, 84% at 30 mg/kg and 100% at 100 mg/kg for LFB-R603 compared with the untreated-group. For rituximab, the TGI was 84% at 30 mg/kg and 99% at 100 mg/kg. More interestingly, LFB-R603 at 100 mg/kg dose showed a significantly superior antitumor activity as a delay of 21 days in tumor growth was observed compared to rituximab (p=0.00001). The combination of LFB-R603 or rituximab at 60 mg/kg with cyclophosphamide enhanced the effect observed with the antileukemic agent only and the additive effect was similar for the two antibodies as a delay of 13 days in tumor growth was observed for both combination-treated groups compared with the cyclophosphamide-treated group (p=0.00001). However, LFB-R603 displayed a significant higher antitumor activity against RL xenografts than rituximab when combined with bendamustine as a tumor growth delay of 7 days was observed between the two treated-groups (p=0.00001). The NCEB cell line, derived from a patient with mantle cell lymphoma (MCL), was xenografted in mice by subcutaneous injection. In this model, LFB-R603 and rituximab injected once weekly up to 3 weeks displayed a dose-related TGI activity. A higher activity of LFB-R603 compared to rituximab was observed at all tested doses (3, 10, 30 and 60 mg/kg). TGI values at day 51 were 91% for LFB-R603 at 3 mg/kg versus 40% for rituximab, 88% for LFB-R603 at 10 mg/kg versus 57 % for rituximab and 100% for LFB-R603 at 30 and 60 mg/kg versus 66% for rituximab when compared with untreated-group. In conclusion, LFB-R603 displayed a greater antitumor activity as compared to rituximab in two different non-clinical in vivo models of NHL, namely follicular and mantle cell lymphoma. Moreover, additive effects were obtained when LFB-R603 was combined with chemotherapeutic agents such as cyclophosphamide and bendamustine in the FL model. Disclosures: Tourais Esteves: LFB Biotechnologies: Employment. Dumontet:LFB Biotechnologies: Research Funding. Herveau:LFB Biotechnologies: Research Funding. Reslan:LFB Biotechnologies: Research Funding. Brune:LFB Biotechnologies: Employment. Van Overtvelt:LFB Biotechnologies: Employment. Salcedo:LFB Biotechnologies: Employment. Fournès:LFB Biotechnologies: Employment.

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Whole Transcriptome Sequencing Reveals Recurrent NOTCH1 Mutations in Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.436.436 ◽

2011 ◽

Vol 118 (21) ◽

pp. 436-436 ◽

Cited By ~ 3

Author(s):

Robert Kridel ◽

Barbara Meissner ◽

Sanja Rogic ◽

Merrill Boyle ◽

Adele Telenius ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Line ◽

Cell Lines ◽

Research Funding ◽

Cell Lymphoma ◽

The Other ◽

Mantle Cell ◽

Whole Transcriptome ◽

Notch1 Mutations

Abstract Abstract 436 Background: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma that is characterized by the hallmark t(11;14)(q13;q32) translocation, as well as a high number of secondary chromosomal alterations. Further, a small number of genes such as TP53, ATM and CCND1 have been reported to be recurrently mutated in MCL, but do not fully explain the biology and do not adequately account for the wide spectrum of clinical manifestations, response to treatment and prognosis. The aim of this study was to discover new somatic mutations that could contribute to our understanding of the pathogenesis of MCL. Methods: In our discovery cohort, we sequenced the transcriptomes of 18 clinical samples (11 diagnostic and 7 progression biopsies) and 2 mantle cell lymphoma-derived cell lines (Mino and Jeko-1). For this purpose, whole transcriptome shotgun sequencing was performed on RNA extracted from fresh frozen tissue. We assembled an extension cohort of 103 diagnostic patient samples and 4 additional cell lines (Rec-1, Z-138, Maver-1, JVM-2), and performed Sanger sequencing of NOTCH1 exons 26, 27 and 34 on genomic DNA. We further exposed the 6 cell lines to 1 μM of the γ-secretase inhibitor XXI (compound E) for 7 days and measured cellular proliferation with an EdU incorporation assay. Survival analysis was carried out in the 113 patients with diagnostic biopsies and available outcome data. Results: NOTCH1 mutations were found in 14 out of 121 patient samples (11.6%) and in 2 out of 6 cell lines, Mino and Rec-1 (33.3%). The majority of these mutations (12 out of 14) lie in exon 34 that encodes the PEST domain of NOTCH1 and consist of either small frameshift-causing indels (10 cases) or nonsense mutations (2 cases). These mutations are predicted to cause truncations of the C-terminal PEST domain. To gain further insight into functional relevance, we treated 6 cell lines with compound E, an inhibitor of the γ-secretase complex that plays a critical role in the release of the intracellular domain of NOTCH1 after ligand-induced activation. In Rec-1, that harbours a NOTCH1 mutation, we observed a significant decrease in proliferation (mean percentage of cells in culture incorporating EdU decreasing from 47.5% to 1.4%, p<.001). No effect of compound E was observed in Mino, the other cell line with a NOTCH1 mutation, nor in the 4 cell lines that are wild type for NOTCH1. Outcome correlation analysis showed that NOTCH1 mutations are associated with poor overall survival (1.56 versus 3.86 years respectively, p=.001), but not with significantly shortened progression-free survival (0.88 versus 1.73 years respectively, p=.07). Discussion: We have identified recurrent mutations in NOTCH1 in a subset of patients with MCL (11.6%). The frequency and the pattern of mutations are strikingly similar to what has recently been reported in chronic lymphocytic leukemia, the other major CD5 positive B-cell malignancy (Nature, 2011 Jun 5, 475:101–105 and J Exp Med, 2011 Jul 4, 208:1389–1401). NOTCH1 mutations are associated with adverse prognosis as evidenced by shortened overall survival. This latter finding, however, should ideally be validated in a larger and uniformly treated cohort. Finally, the sensitivity of the Rec-1 cell line to compound E suggests that NOTCH1 mutations could serve as the target for tailored therapy in mantle cell lymphoma. Disclosures: Sehn: Roche/Genentech: Consultancy, Honoraria, Research Funding. Connors:Roche: 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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