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

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.

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Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2011.37.4223 ◽

2012 ◽

Vol 30 (6) ◽

pp. 631-636 ◽

Cited By ~ 362

Author(s):

Bertrand Coiffier ◽

Barbara Pro ◽

H. Miles Prince ◽

Francine Foss ◽

Lubomir Sokol ◽

...

Keyword(s):

T Cell ◽

Phase Ii ◽

Systemic Therapy ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Complete Response ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Prior Systemic Therapy

Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Conclusion Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

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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 ◽

10.1182/blood.v116.21.114.114 ◽

2010 ◽

Vol 116 (21) ◽

pp. 114-114 ◽

Cited By ~ 7

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.

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

Blood ◽

10.1182/blood.v120.21.3641.3641 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3641-3641 ◽

Cited By ~ 1

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.

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Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽

10.1182/blood.v114.22.919.919 ◽

2009 ◽

Vol 114 (22) ◽

pp. 919-919

Author(s):

Steven M. Horwitz ◽

Madeleine Duvic ◽

Youn Kim ◽

Jasmine M Zain ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Dose Reduction ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Single Agent ◽

Optimal Dose ◽

T Cell Lymphoma ◽

Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

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A Phase II Study of Nivolumab in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood-2019-126194 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 467-467 ◽

Cited By ~ 4

Author(s):

N. Nora Bennani ◽

Levi D Pederson ◽

Pamela Atherton ◽

Ivana Micallef ◽

Joseph P. Colgan ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Interim Analysis ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Board ◽

T Cell Lymphoma ◽

Number Of Patients ◽

Hyperprogressive Disease

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin lymphomas. They carry a worse prognosis for most subtypes compared with their B-cell counterparts. Despite the recent approval of newer therapies, the response rate and duration of clinical benefit is short and the outlook for patients with relapsed/refractory (RR) PTCL remains poor. There is therefore a need for novel effective therapies in PTCL. Targeting the profoundly immunosuppressive tumor microenvironment (TME) in PTCL is one such approach. Preclinical data show that malignant cells in PTCL overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal further suppressing antitumor immunity. PD-1/PD-L1/2 interactions in PTCL are particularly complicated as both the receptor and ligands can be expressed on the malignant T-cell. While the use of anti-PD-1 blocking antibodies has shown remarkable efficacy particularly in relapsed Hodgkin lymphoma, only a small number of patients with PTCL have been treated with checkpoint blockade. We conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here the results of the prespecified interim analysis. Study design and patient selection: Nivolumab was given at a flat dose of 240 mg intravenously (IV) every 2 weeks for 8 cycles then 480 mg IV every 4 weeks starting cycle 9. The primary objective was to assess the overall response rate (ORR) defined as proportion of subjects achieving either a partial response (PR) or complete response (CR) within 12 cycles of treatment. Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Pre-planned sample size was 39, assuming that an ORR of 10% or less would be considered negative and an ORR of 30% or greater would warrant further study. We used a one-stage design with an interim analysis (upon enrolling 12 subjects) based on a Simon optimal design to assess efficacy. This design had a 90% power with a 1-sided 10% level test. The Duffy and Santner method was utilized to determine confidence intervals for the ORR. Kaplan-Meier methods were used to assess PFS, OS, and DOR. This study was sponsored by Bristol-Myers Squibb (NCT03075553). Results: Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Patient characteristics are illustrated in table 1. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified (NOS), one had ALK negative anaplastic large cell lymphoma (ALK- ALCL). Most (11/12) were advanced stage (stage 4), had extranodal disease and half of the patients had received a prior autologous transplant. The ORR was 33% (4/12) (95% CI: 12.3 - 63.7%): 1 CR seen in ALK-ALCL; 2 PR, 1 in PTCL, NOS and 1 in enteropathy associated T-cell lymphoma; 1 CR in AITL. The median DOR was 3.6 months (95% CI: 1.9-6.9). The median PFS for all 12 patients was short at 1.9 months (95% CI: 1.5-8.7); median OS was 7.9 months (95% CI: 3.4-10.8) (Panel A). Hyperprogressive disease (defined as dramatic progression within 1 cycle of treatment) occurred in 4 patients. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 5/12 (41.7%), while hematologic AEs were seen in 3/12 (25%) patients. Conclusions: Nivolumab had modest clinical activity in patients with R/R PTCL and the study met the criteria at interim analysis to continue accrual. However, due to the high number of patients with hyperprogressive disease, the moderate activity of the drug, and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases. Further studies are indicated using nivolumab in combination (rather than a single-agent) and use of biomarkers to better predict the responders. Disclosures Bennani: Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; 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. Ansell:Merck: Other: research funding for clinical trials; Seattle Genetics: Other: research funding for clinical trials; Takeda: Other: research funding for clinical trials; Bristol Myers Squibb: Other: research funding for clinical trials; Regeneron: Other: research funding for clinical trials; Affimed: Other: research funding for clinical trials; Pfizer: Other: research funding for clinical trials; AI Therapeutics: Other: research funding for clinical trials.

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

Blood ◽

10.1182/blood-2019-131357 ◽

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.

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The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis

Blood ◽

10.1182/blood-2019-128352 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3328-3328 ◽

Cited By ~ 1

Author(s):

Lorenz Selberg ◽

Peter Stadtherr ◽

Sascha Dietrich ◽

Thomas Luft ◽

Andrea Bondong ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

The Other ◽

Advisory Committees ◽

Unrelated Donors ◽

The Impact

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

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Bexarotene Is Highly Active in the Treatment of Subcutaneous Panniculitis-Like T-Cell Lymphoma.

Blood ◽

10.1182/blood.v106.11.3344.3344 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3344-3344 ◽

Cited By ~ 1

Author(s):

Ana M. Molina ◽

Ranjana Advani ◽

Sunil Reddy ◽

Richard Hoppe ◽

Jonathan W. Friedberg ◽

...

Keyword(s):

T Cell ◽

Combination Chemotherapy ◽

T Cell Receptors ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

Single Agent ◽

Response To Therapy ◽

T Cell Lymphoma ◽

Cell Transplant ◽

Cell Receptors

Abstract Background: Subcutaneous Panniculitis-like T-cell lymphoma (SPTCL) is a rare, often aggressive T-cell lymphoma. Recently it has been appreciated that there are two clinical courses, whereby some patients have rapidly progressive disease and others have a chronic course. The likelihood of an aggressive course may be dependent on the T-cell receptor phenotype expressed by the tumor, with γ/δ expression portending a worse outcome than α/β expression. In the WHO-EORTC classification γ/δ expressing cases of SPTCL are provisionally renamed as Primary Cutaneous γ/δ T-cell lymphoma. Although most reported cases have been treated with combination chemotherapy, there are no prospective trials for the treatment of SPTCL. With chemotherapy, only a minority of patients have durable remissions; the majority have either primarily refractory disease or relapses. Bexarotene is an oral retinoid used for the treatment of mycosis fungoides and other T cell lymphomas. Patients and methods: We treated eight SPTCL patients with bexarotene. There were four women and four men, with a median age of 56 years (range 23–80). All patients presented with disseminated subcutaneous nodules, Stage IV, but without extracutaneous involvement. Three patients presented with pancytopenia, without bone marrow involvement, suggestive of hemophagocytic syndrome. Four patients had an elevated LDH and four had ECOG PS > 2. Five patients received bexarotene as primary treatment. Three patients had progression of disease after previous combination chemotherapy. Doses of bexarotene ranged from 100mg/m2 – 450 mg/m2. All patients received at least one month of therapy. Results: Overall 5/8 (63%) patients responded. Two patients progressed at one and three months. One of these patients could only tolerate 100mg/m2. One patient had stable disease for four months. Two patients had partial responses (PR) lasting 10 and 18 months. One of the PR patients was given chemotherapy to induce a remission prior to a planned allogeneic stem cell transplant. They progressed on CHOP and ICE and then responded again to bexarotene. Three patients achieved a complete response (CR). Two remain in CR at 14 and 26 months on bexarotene. The other patient had a CR lasting 33 months. Bexarotene was then discontinued due to hypertriglyceridemia, and the patient developed new lesions within three months. As expected with bexarotene, toxicities of treatment were limited to hypertriglycerides and hypothyroidism. IPI was not predictive of response to therapy. Both patients with documented γ/δ T-cell receptors achieved a PR. Conclusion: Bexarotene showed a high response rate in SPTCL, which characteristically responds poorly to chemotherapy. These responses included patients with both γ/δ and α/β T-cell receptors. Given bexarotene’s favorable toxicity profile and demonstrated activity, it represents an excellent treatment option for patients with this rare T-cell lymphoma. Further study is required to determine whether bexarotene is best used as a single agent, or as part of combination or sequential therapies.

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Gemcitabine as single agent in pretreated T-cell lymphoma patients: evaluation of the long-term outcome

Annals of Oncology ◽

10.1093/annonc/mdp508 ◽

2010 ◽

Vol 21 (4) ◽

pp. 860-863 ◽

Cited By ~ 130

Author(s):

P.L. Zinzani ◽

F. Venturini ◽

V. Stefoni ◽

M. Fina ◽

C. Pellegrini ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Single Agent ◽

T Cell Lymphoma ◽

Term Outcome ◽

Long Term Outcome

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A Meta-Analysis of Pivotal Pralatrexate Studies in Relapsed/Refractory Mature T-Cell Lymphoma (r/r TCL)

Blood ◽

10.1182/blood-2021-145580 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2450-2450

Author(s):

Owen A. O'Connor ◽

Bor-Sheng Ko ◽

Ming-Chung Wang ◽

Dai Maruyama ◽

Yuqin Song ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Meta Analysis ◽

T Cell Lymphoma ◽

New Drugs ◽

Publicly Traded ◽

Advisory Committees ◽

Prior Therapy ◽

Line Of Therapy

Abstract Introduction While patients with r/r TCL have a poor prognosis, significant progress has been made over the past decade in developing new drugs and regimens for the disease. All of the approved agents have their own distinct advantages and issues, making it essential to critically assess the merits and limitations of each. It is well accepted that the development of acquired drug resistance to conventional chemotherapy reduces efficacy with each subsequent line of therapy. However in the era of novel single agents, less is known about the role of these new drugs in patients with chemo-sensitive and chemo-refractory disease. Based on results of the PROPEL trial in 111 treated patients, pralatrexate was the first drug approved as a novel single agent in the US for r/r TCL (O'Connor et al. J Clin Oncol. 2011). Drug registration and approval of pralatrexate was subsequently attained in many healthcare ministries around the world, including Japan, China and Taiwan based on the results of PROPEL and/or locally conducted studies (Maruyama et al. Cancer Sci 2017; Hong et al. Target Oncol 2019; Wang et al. EHA 2019). A meta-analysis of these four trials was undertaken to better understand those factors influencing efficacy and safety of pralatrexate in this patient population. Methods Patient- or summary-level data presented in the individual clinical study reports from the four regulatory-mandated prospective clinical trials of pralatrexate monotherapy in patients with r/r TCL were included in this meta-analysis. Pooled studies (phase 2 PDX-008 [PROPEL], phase 3 FOT12-CN-301, phase 4 FOT14-TW-401, phase 2 part of PDX-JP1) collected data on the primary efficacy endpoint of objective response rate (ORR) as assessed by central review. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Data were collected in accordance with the original protocol and updated with longer survival follow-up where available. Relapse was defined as achieving a complete response (CR) or partial response (PR) on prior therapy lasting for > 3 months, and refractory was defined as stable disease or progressive disease on prior therapy or relapsed disease <3 months of achieving CR or PR. Both the fixed effect model (includes within study variations) and random effects model (includes within study and between study variations) were considered in this meta-analysis. Results A total of 221 patients were included in the efficacy analysis set for this meta-analysis. The median age was 59 years (range 21-89) and 67% were male. Histological subtypes as assessed by the central review included PTCL-not otherwise specified (108 pts, 49%), angioimmunoblastic T-cell lymphoma (47 pts, 21%), anaplastic large cell lymphoma (ALK-negative; 26 pts, 12%), transformed mycosis fungoides (12 pts, 5%), extranodal NK/T cell lymphoma, nasal type (7 pts, 3%), and other/missing (10/11 pts, 5% each). Patients had a median of 2 prior lines of systemic therapies (range 1-14). At the most recent line of therapy prior to pralatrexate, 68 (31%) and 103 (47%) patients were classified as relapsed and refractory respectively, with the remaining 50 (23%) unable to be determined due to response to the prior therapy being unavailable or not evaluable. Ten percent (n=24) of patients had stem cell transplant prior to receiving pralatrexate. Pooled ORR of the entire cohort was 40.7% (95% CI, 34.2, 47.5), including 30 in CR (13.6%) and 60 in PR (27.2%). The median DOR was 9.1 months (95% CI, 7.4-10.8). Median PFS was 4.6 months (95% CI, 4.0-5.2) while median OS was 16.3 months (95% CI, 13.1-22.6). Conclusions This meta-analysis confirms significant clinical activity of pralatrexate in heavily treated patients with r/r TCL, with an ORR of 40.7% at a median of two lines of prior therapy. These findings meaningfully bolster the original observations from PROPEL with 3 additional regulatory mandated clinical studies and suggest that earlier use may be associated with improved outcome. Further details on the efficacy by prior lines of systemic therapy as well as safety data will be presented. Disclosures O'Connor: TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; BMS: Research Funding; Astex: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Mundipharma: Honoraria; Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Maruyama: Novartis: Research Funding; Chugai: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Otsuka: Research Funding; MSD: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yeoh: Mundipharma: Current Employment. Tobinai: Celgene: Consultancy, Honoraria; Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria; Solasia Pharma: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria; Yakult: Honoraria; Zenyaku Kogyo: Consultancy, Honoraria.

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