Romidepsin Induces Durable Responses in Patients with Peripheral T-Cell Lymphoma: GPI-06–0002 Study Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3641-3641 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
Miles Prince ◽  
Francine M. Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Prior Therapy ◽  
Prior Systemic Therapy ◽  
Systemic Therapies

Abstract Abstract 3641 Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative disorders, and most subtypes have a poor prognosis even with aggressive chemotherapy. Romidepsin is a potent class 1 histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with PTCL who have received at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. A phase 2, single-arm, open-label registration study (GPI-06–0002) demonstrated the clinical benefit and tolerability of romidepsin in patients with relapsed or refractory PTCL (data cutoff: Oct 2010). Here, we present an update of the efficacy of GPI-06–0002 and characterize patients who achieved long-term responses (≥ 12 months) as of Dec 2011 (median follow-up: 22.3 months). Methods: Patients with histologically confirmed PTCL (N = 130) who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for responding patients. The primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee (IRC) based on the International Workshop Response Criteria. Secondary endpoints included objective response rate (ORR: CR/CRu + partial response), duration of response (DOR), and time to progression. Disease response was assessed every 2 treatment cycles. Baseline patient characteristics by DOR (≥ 12 months vs < 12 months) were examined. Results: The majority of the 130 patients had stage III or IV disease (70%); 28% had bone marrow involvement. PTCL not otherwise specified (53%) and angioimmunoblastic T-cell lymphoma (21%) were the most common subtypes. Patients received a median of 2 prior systemic therapies (range, 1–8); 38% of patients were refractory to their last line of therapy. The ORR was 25% (33 of 130 patients), including CR/CRu in 15% (19 of 130) of patients. The median duration of objective response was 28 months, with the longest response ongoing at 48 months (Figure). Of the 19 patients who achieved CR/CRu, 13 (68%) had not experienced disease progression per the IRC at a median follow-up of 25.8 months. The median duration of CR had not yet been reached (range, 1–48+ months; Figure). Of the 19 patients who achieved CR/CRu, 10 were long-term responders (responses ≥ 12 months). Interestingly, heavy pretreatment (≥ 4 prior systemic therapies) did not preclude patients from achieving long-term CR/CRu: 5 of 10 patients (50%) who maintained CR/CRu for ≥ 12 months were heavily pretreated vs 1 of 9 (11%) patients with CR/CRu maintained for < 12 months. Long-term CR/CRu was achieved regardless of response to last prior therapy; only 2 of 10 (20%) long-term responders had an objective response on their last treatment. In contrast, 6 of 9 (67%) patients with CR/CRu for < 12 months responded to their last prior therapy. Furthermore, advanced disease did not preclude long-term response to romidepsin: all 10 patients (100%) who maintained CR/CRu for ≥ 12 months had stage III/IV disease vs 55.5% of those who maintained CR/CRu for < 12 months. Other characteristics, such as Eastern Cooperative Oncology Group performance status, International Prognostic Index score, age, sex, and race, were similar among patients achieving CR/CRu for ≥ 12 months or < 12 months. Conclusions: Single-agent romidepsin induced durable responses in patients with relapsed/refractory PTCL, with responses ongoing at 48 months. None of the examined patient and disease characteristics predicted failure to achieve long-term remissions. These results support the use of romidepsin in relapsed/refractory PTCL. Disclosures: Coiffier: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pro:Allos: Honoraria; Spectrum : Honoraria; Seattle Genetics : Research Funding; Celgene: Honoraria, Research Funding. Prince:Celgene : Consultancy, Honoraria, Research Funding. Foss:Celgene : Consultancy. Sokol:Celgene : Honoraria, Speakers Bureau. Morschhauser:Celgene : Consultancy, Honoraria. Pinter-Brown:Celgene : Consultancy; Allos : Consultancy. Shustov:Celgene : Honoraria, Research Funding, Speakers Bureau. Nielsen:Celgene: Employment, Equity Ownership. Nichols:Celgene: Consultancy, Employment, Equity Ownership. Horwitz:Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Allos: Consultancy, Research Funding; Genzyme: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding.

scholarly journals Romidepsin Induces Durable Responses in Patients with Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1742-1742 ◽  
Author(s):  
Barbara Pro ◽  
Steven M. Horwitz ◽  
H. Miles Prince ◽  
Francine M. Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Prior Systemic Therapy ◽  
Line Of Therapy

Abstract Background: AITL is a common subtype of peripheral T-cell lymphoma (PTCL) that typically presents with lymphadenopathy and extranodal disease and is associated with frequent infections due to immune dysregulation. Patients with AITL generally have a poor prognosis, even with aggressive chemotherapy. Romidepsin is a structurally unique, potent, bicyclic, class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with PTCL who have received at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. A phase 2, single-arm, open-label registration study (GPI-06-0002) demonstrated durable clinical benefit and long-term tolerability of romidepsin in patients with relapsed or refractory PTCL. Here, we present updated data for patients with AITL from GPI-06-0002. Methods: Patients with histologically confirmed PTCL (N = 130) who experienced failure with or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for patients with stable disease (SD) or response. The protocol was amended to allow for (but not mandate) maintenance dosing of twice per cycle for patients treated for ≥ 12 cycles; dosing could be further reduced to once per cycle at ≥ 24 cycles in patients who had received maintenance dosing for ≥ 6 months. The primary endpoint was the rate of confirmed/unconfirmed complete response (CR/CRu) as determined by an independent review committee based on International Working Group criteria. Secondary endpoints included objective response rate (ORR: CR/CRu + partial response [PR]), duration of response (DOR), and time to progression; progression-free survival and overall survival (OS) were also assessed. Disease response was assessed every 2 treatment cycles. The analysis herein is focused on updated data (median follow-up, 22.3 months) in patients with AITL. Results: Of 27 patients with AITL, most had advanced disease (96% stage III/IV; 44% with bone marrow involvement; 52% with elevated lactate dehydrogenase) and heavy pretreatment (median, 2 [range, 1-8] prior therapies) and 37% were refractory to their last line of therapy. The ORR for patients with AITL was 33% (9 of 27 patients), with most responders achieving CR/CRu (6 of 27 patients; 22%). Most responses were noted at the first response assessment, with a median time to response of 52 days. Furthermore, an additional 8 patients with AITL achieved SD (30%), 3 of whom had disease stabilization for ≥ 90 days. The median DOR has not been reached, with the longest response ongoing at 56 months (Figure). Five patients with AITL and DOR of ≥ 12 months with romidepsin had either 1 (n = 2) or 2 (n = 3) prior therapies, and 3 of the 5 were refractory to their last line of therapy (CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], GVD [gemcitabine, vinorelbine, doxorubicin], or pralatrexate). All 5 responding patients who remained on treatment for ≥ 12 cycles received maintenance dosing of twice per cycle. Dosing for the 3 patients with the most durable responses was also later amended to 1 dose per cycle. For all patients with AITL treated with romidepsin, the median OS was 18 months (range, 2-58 months). Grade 3/4 infections (all types pooled, regardless of relationship to study drug) were reported in 6 patients (22%), and no discontinuations due to infection occurred. Conclusions: Single-agent romidepsin induced rapid, complete, and durable responses in some patients with relapsed/refractory AITL, with several responses ongoing for > 3 years. Patients with long-term responses to romidepsin received maintenance dosing. These results support the use of romidepsin in relapsed/refractory AITL. Figure. Patients With AITL Who Achieved a Response to Romidepsin Figure. Patients With AITL Who Achieved a Response to Romidepsin Disclosures Pro: Celgene: Honoraria. Horwitz:Bristol Myers Squibb,: Consultancy; Amgen: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Kiowa Kirin: Research Funding; Infinity: Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jannsen: Consultancy. Prince:Celgene: Honoraria, Research Funding. Foss:Celgene: Consultancy, Research Funding, Speakers Bureau. Sokol:Celgene: Consultancy. Morschhauser:Spectrum: Honoraria; Bayer: Honoraria; Mundipharma: Honoraria; Genentech: Honoraria; Gilead: Honoraria. Pinter-Brown:Celgene: Consultancy. Padmanabhan Iyer:Janssen Biotech, Inc.: Honoraria; Celgene: Speakers Bureau; Houston Methodist Cancer Center: Employment. Shustov:Celgene: Consultancy, Honoraria, Research Funding. Balser:Celgene: Consultancy. Coiffier:Celgene: Honoraria.

scholarly journals Long Term Outcomes of Patients with Aggressive T-Cell Non-Hodgkin Lymphoma Undergoing Allogeneic Stem Cell Transplantation: Retrospective Results from a Single Center

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4623-4623
Author(s):  
Amandeep Salhotra ◽  
Liana Nikolaenko ◽  
Lu Chen ◽  
NI-Chun Tsai ◽  
Diane Lynne Smith ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Chronic Gvhd ◽  
T Cell Lymphoma ◽  
Long Term Follow Up

Background: Mature T cell and NK cell neoplasms collectively known as peripheral T-cell lymphomas (PTCL) comprise 15-20% of Non-Hodgkin lymphomas in adults and have a poor prognosis with a 5-year survival of less than 30% for the most aggressive subtypes. Allogeneic HCT (allo-HCT) is offered to eligible patients as a potentially curative modality in the salvage setting or in high risk patients to consolidate an initial response to frontline therapy. There are few studies that report clinical outcomes derived from large sample size and long-term follow up data. Methods: We retrospectively reviewed medical records of 87 consecutive patients with PTCL including transformed mycosis fungoides and NK/T-cell lymphoma without prior autologous transplant who underwent allo-HCT at City of Hope from January 2000 to June 2018 after IRB approval was obtained. Descriptive statistics were used to summarize baseline patient demographic, treatment, and disease characteristics. Kaplan-Meier curves and the log-rank test were used to evaluate the overall survival (OS) and progression-free survival (PFS). Cumulative incidences of time to relapse and time to non-relapse mortality (NRM) were calculated with relapse and NRM as competing risks. Cumulative incidences of acute and chronic GVHD were calculated as time to onset of GVHD with relapse and death as competing events for GVHD. Results: 87 patients were included for the analysis. Median age at the time of allo-HCT was 49 years (range 2-70 years). Histologies were PTCL-NOS (n=21); transformed CTCL (n=19); NK T-cell lymphoma (n=17); AITL (n=15), ALCL (n=7); gamma delta T-cell lymphoma (n=6) and other rare subtypes (n=2). None of the patients had a prior auto transplant. 42 patients (48%) received myeloablative conditioning, with the majority of patients receiving FTBI based conditioning (n=39) and three patients received BEAM regimen for conditioning. 45 patients (52%) received reduced intensity conditioning; fludarabine/melphalan based-conditioning was the most common regimen used (n=39). Sibling HCT was performed in 47 patients (54%), while MUD HCT was performed in 36 patients (41%) with fully matched HLA unrelated donor in 15 (17%) and HLA mismatched in 21 (24%) patients; 4 (5%) received haploidentical HCT. GVHD prophylaxis consisted of tacrolimus/sirolimus (n=54), tacrolimus/sirolimus/MTX (n=11), tacrolimus or cyclosporine/MTX (n=7), tacrolimus or cyclosporine/MMF (n=7), post-transplant cyclophosphamide/tacrolimus/MMF (n=5) and other (n=3). Source of stem cells was PBSC in 77 (88%), bone marrow in 5 (6%), and cord blood in 5 (6%) patients. At the time of allo-HCT, there were a total of 25 (29%) patients in complete remission (CR1 n=15, CR2+ n=10), 25 (29%) patients in partial remission 22 (25%) with induction failure and 14 (16%) with relapsed disease. The median follow-up among survivors was 6.9 years (range 1.1-15.5). The 5- and 10-year PFS was 47% (95% CI: 36%-58%) and 38% (95% CI: 26%-50%), respectively. The 5- and 10-year OS was 53% (95% CI: 41%-63%) and 42% (95% CI: 29%-54%), respectively (Fig.1). Relapses at 5 and 10 years were both 24% (95% CI: 16%-34%), while NRM at 5 and 10 years was 28% (95% CI: 19%-39%) and 37% (95% CI: 25%-50%), respectively. At day 100 after allo-HCT, the rates of acute GVHD grade II-IV were 41% (95% CI: 30%-51%) and grade III-IV of 16% (95%CI: 9%-25%). Chronic GVHD rates at 3 years were 62% (95% CI: 51%-72%), with extensive GVHD of 55% (95% CI: 44%-65%). On univariate analysis, age (> 60 or not), sex, TBI-based conditioning, donor type (MSD vs MUD), stem cell source or remission status prior to allo-HCT did not predict for overall survival in our study. Conclusions: Our results constitute the largest reported single-institution series with a long-term follow-up on allo-HCT outcomes in patients with aggressive T-cell NHL. The 5-year PFS and OS of 47 and 53%, respectively, are encouraging for the high-risk T-cell NHL patients with limited treatment options. Disclosures Salhotra: Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Popplewell:City of Hope: Employment. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Mei:Seattle Genetics, Inc.: Research Funding. Zain:spectrum: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau.

Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Clinical Benefit to Advanced Cutaneous T-Cell Lymphoma Patients: Updated Results of the Phase IIb Multicenter Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 399-399 ◽  
Author(s):  
Madeleine Duvic ◽  
Youn H. Kim ◽  
Timothy M. Kuzel ◽  
Theresa R. Pacheco ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Systemic Therapies

Abstract Purpose: To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat in advanced cutaneous T-cell lymphoma (CTCL) patients (pts). Patients and Methods: Advanced CTCL pts received oral vorinostat 400 mg daily until disease progression (PD) or intolerable toxicity in this open label Phase IIb trial. Eligible pts must have received ≥ 2 prior systemic therapies which included bexarotene unless intolerable. The planned sample size was ≥ 50 evaluable pts with stage ≥ IIB. The primary endpoint was the objective response rate (ORR) as measured by a modified skin severity weighted assessment tool (SWAT). The study would be positive if the ORR in ≥ stage IIB pts was ≥ 20%. Time to response, time to progression (TTP), response duration (DOR, from time of first response), pruritus relief, safety and gene expression changes were also evaluated. Results: Seventy-four pts (median age, 60 y [range, 39–83]; median 3 prior systemic therapies) were enrolled (61 pts ≥ stage IIB) at 18 centers. Data cut-off was 5/06 with a median follow-up of 10 m. Efficacy data are shown (Table 1). The ORR was 29.5% in ≥ stage IIB pts. The median DOR and TTP were not reached but estimated to be at least 6.1 m and 9.8 m, respectively, for ≥ stage IIB responders. Median TTP was 4.9 m for all pts. Overall, 32% of pts had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%) and anorexia (26%), and were mostly ≤ grade 2. Seven pts discontinued and 10 had dose modification due to drug-related AE. Drug-related AE ≥ grade 3 included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%) and nausea (4%). Fifteen pts, including 9 responders, were receiving treatment as of 11/05. Three of these pts discontinued due to PD (n = 2) or unacceptable toxicity (n = 1), and 12 have received vorinostat for &gt; 1 y. A pharmacodynamic signature of vorinostat exposure based on gene expression changes was detected. Conclusion: These updated results with additional follow-up continue to demonstrate that oral vorinostat remains effective in advanced CTCL with an acceptable safety profile. Table 1. Efficacy of Vorinostat in Advanced CTCL Population n Objective Response* Median (range) n Pruritus Relief† *Objective response = confirmed complete or partial response. †Sustained pruritus reduction of ≥ 3 points or complete resolution for ≥ 4 wks; 2 pts with missing baseline scores were excluded. ‡Kaplan-Meier estimates were not reached but DOR was ≥ 165, 185 and 165 d, respectively, with a median follow-up of 10 m. §Stages IIB, III, IVA or IVB. CI = confidence interval n (%) (95% CI) TTR, d DOR, d n (%; 95% CI) All pts 74 22 (29.7) (19.7, 41.5) 55 (28–171) NR‡ (34+, 441+) 72 23 (31.9; 21.4, 44.0) Stage IB or IIA 13 4 (30.8) (9.1, 61.4) 42.5 (30–57) 80.5 (48+, 418+) 13 5 (38.5; 13.9, 68.4) ≥Stage IIB§ 61 18 (29.5) (18.5, 42.6) 56 (28–171) NR‡ (34+, 441+) 59 18 (30.5; 19.2, 43.9) Sezary syndrome 30 10 (33.3) (17.3, 52.8) 56 (28–171) NR‡ (34+, 244+) 30 9 (30.0; 14.7, 49.4)

Three-Year Survival Results From An Ongoing Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory Systemic Anaplastic Large Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1809-1809 ◽  
Author(s):  
Barbara Pro ◽  
Ranjana H. Advani ◽  
Pauline Brice ◽  
Nancy L. Bartlett ◽  
Joseph D. Rosenblatt ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
Observation Time ◽  
Board Membership ◽  
Equity Ownership

Abstract Background Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented. Methods Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results In this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Conclusions After a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Disclosures: Pro: Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.

Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin In Progressive or Relapsed Peripheral T-Cell Lymphoma (PTCL) Following Prior Systemic Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 114-114 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
H. Miles Prince ◽  
Francine M Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Open Label ◽  
Advisory Committees ◽  
Prior Systemic Therapy

Abstract Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.

Favorable Outcome In ALK-Negative Anaplastic Large-Cell Lymphoma Following Intensive Induction Chemotherapy and Autologous Stem Cell Transplantation (ASCT): a Prospective Study by the Nordic Lymphoma Group (NLG-T-01)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3566-3566 ◽  
Author(s):  
Thomas Relander ◽  
Grete Fossum Lauritzsen ◽  
Esa Jantunen ◽  
Hans Hagberg ◽  
Harald Anderson ◽  
...  
Keyword(s):  
T Cell ◽  
Induction Chemotherapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Serum Lactate Dehydrogenase ◽  
Term Survival

Abstract Abstract 3566 Primary systemic T-cell lymphoma of anaplastic large cell type (ALCL) is an aggressive and predominantly nodal subtype of lymphoma, further subdivided based on expression of the ALK-protein, with ALK-pos ALCL occurring predominantly in younger patients and associated with a favourable prognosis. ALK-neg ALCL is believed to carry a prognosis similar to that of other nodal peripheral T-cell lymphomas and previous studies have shown long-term survival rates below 50%. There is retrospective data suggesting a benefit from ASCT in first-line treatment of this lymphoma subtype. We analyzed the outcome of ALK-neg ALCL patients included in a prospective phase II trial, NLG-T-01, conducted by the Nordic Lymphoma Group. The NLG T-01 trial enrolled 160 patients aged 18–67 years from the Nordic countries with systemic ALK-neg peripheral T-cell lymphoma within the period 2002–2007. The treatment schedule consisted of 6 courses of CHOEP-14 followed by ASCT (BEAM or BEAC) in responding patients. Patients >60 years received CHOP-14 as induction. Altogether, the trial included 31 patients with ALK-neg ALCL (19% of the study population). Median age was 56 years (22-65) with a male:female ratio of 2.4. Stage III-IV was found in 18 patients (58%), B-symptoms in 19 patients (61%) and 6 patients (19%) had a bulky lesion (>10cm). Pre-therapeutic serum lactate dehydrogenase was elevated in 18 patients (58%) and performance score was 2–4 in 10 patients (32%). After 3 and 6 courses of chemotherapy, response status was CR or CRu in 29% and 58% of the patients, respectively. In total, 24 out of 31 patients (77%) underwent BEAM/BEAC therapy followed by ASCT. Four patients did not respond or had disease progression during induction chemotherapy. The remaining 3 patients did not undergo ASCT for other reasons (mobilization failure, lung insufficiency, patient decision, respectively). Overall response rate after ASCT was 74% for the entire initial population and 96% for those undergoing ASCT. Median follow-up was 45 months. Six patients relapsed after ASCT. There was a total of nine deaths (29%): six due to lymphoma, two due to toxicity and one from second malignancy (colon cancer). With a median follow-up of 45 months, 3-year overall and progression-free survival values were 73% and 64%, respectively. Intensive chemotherapy followed by ASCT was feasible in the majority of the patients included in this prospective trial. Long-term outcome appears promising when compared to previously published data, with the survival curve suggesting a plateau. In ASCT eligible patients, intensive induction chemotherapy consolidated by upfront ASCT is an effective treatment that yields outcome results at least as good as those obtained in age-comparable patients with diffuse large B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

Bortezomib (BTZ) and Panobinostat (PAN) Combination Is Effective in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL) and Maintenance Treatment May Be Essential for Sustained Response

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3669-3669
Author(s):  
Daryl Tan ◽  
William YK Hwang ◽  
Colin Phipps Diong ◽  
Wee Lee Goh ◽  
Lionel K.Y See ◽  
...  
Keyword(s):  
T Cell ◽  
Stable Disease ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Response Rate ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Objective Response ◽  
T Cell Lymphoma

Abstract Abstract 3669 Background: Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. Inhibition of HDAC6 by PAN abrogates BTZ-induced protective aggreosome formation and accentuates BTZ induced endoplasmic reticulum stress, leading to further apoptosis. Primary end point of this ongoing phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. Methods: Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. Preliminary response data were available for all 11 pts recruited for stage 1 of the study. A response rate of >25% will allow the study to proceed to stage 2. Results: Among pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=4, PTCL (unspecified) n=4, ALK+ Anaplastic large cell lymphoma n=1 and NKL, nasal type n=2. The median age was 52 (35–72) years, and 70% were male. The ORR was 54.5% with 18% attaining a complete response. Four pts (36%) had a partial response, and stable disease was noted in 2 (18%). Pts received a median of 2 prior therapies (range 1–3); 27% received an autogous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (36%), neutropenia (27%), diarrhoea (18%) and fatigue (9%). Peripheral neuropathy of any grade was observed in 35%. Among pts who responded or had stable disease, the median PFS was 6 months and disease progression occurred at a median of 2.5 months after stopping trial drugs. Two deaths have occurred: 1 due to progressive disease and 1 associated with an unrelated cardiac event. 3 pts successfully underwent subsequent allogeneic SCT. Conclusions: The study regimen shows activity across T/NK-cell lymphomas and ORR greatly exceeds the predefined threshold of 25% allowing, together with early tolerability data, continuation of study enrolment in stage 2. The early progression of the disease after stopping trial drugs albeit the high initial ORR suggests that the novel combination provides a tonic suppression of tumor proliferation and ongoing treatment will be beneficial for pts without option for subsequent alternative treatment like SCT. An extended phase of maintenance treatment will be incorporated into stage 2 of the study to allow pts to optimally benefit from the combination. Our interim findings may have implications on the design of future studies seeking proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/co-regulators known to be modified by acetylation. Disclosures: Tan: Novartis: Research Funding; Janssen: Equity Ownership, Honoraria, Research Funding. Goh:Novartis: Honoraria, Research Funding; Jansen: Honoraria, Research Funding.

Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with Peripheral T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1501-1501
Author(s):  
Matthew J Maurer ◽  
Fredrik Ellin ◽  
James Cerhan ◽  
Stephen Ansell ◽  
Brian K Link ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
T Cell Lymphomas

Abstract Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

scholarly journals Central Nervous System Involvement in Peripheral T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5293-5293
Author(s):  
Sangeetha Gandhi ◽  
N. Nora Bennani ◽  
Sonia Fortin ◽  
Thomas M. Habermann ◽  
Patrick Johnston ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
T Cell Lymphoma ◽  
High Dose ◽  
Cns Involvement ◽  
Advisory Committees ◽  
Genetics Research

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document