Cytotoxic and Gamma-Delta Subtypes Of Peripheral T-Cell Lymphoma: A Single Center Experience

Abstract Background Peripheral T-cell lymphomas (TCLs) are uncommon neoplasms. TCLs in which gamma-delta T-cell receptors are expressed are extremely aggressive and rare, accounting for less than 1% of lymphoid neoplasms. The two main types of CTLs recognized in the 2008 WHO classification of lymphoid neoplasms are hepatosplenic T-cell lymphoma (HSTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL). Although rare, these diseases are associated with an aggressive clinical course, refractoriness to conventional therapies, and poor prognosis. Methods Patients with newly diagnosed cytotoxic or gamma-delta TCLs treated from 2005-2012 were retrospectively identified. Analyses included patient characteristics, clinical presentation, pathology, treatment and outcome. Results Twenty-two patients (11 cutaneous gamma-delta TCL, 5 primary cutaneous aggressive epidermotropic CD8+TCL, 4 hepatosplenic gamma-delta TCL, 2 cytotoxic TCL involving the intestine) were identified. Median age was 48 (range: 18-70), 12% (12/22) were male, and 54.5% (12) presented with B symptoms. Initial therapy included CHOP based chemotherapy in 6, denileukin difititox with CHOP in 5, and single agent denileukin diftitox in 4. One patient died with hemophagocytosis prior to initiation of chemotherapy. Fifteen of 21 pts responded to initial therapy but 10 of 15 required more than one regimen containing either etoposide or gemcitabine to achieve remission. The median number of regimens was 2 (range 0-4). In the salvage setting, two patients had partial responses with romidepsin, one had a PR with pralatrexate and one had a CR after pralatrexate salvage therapy. Thirteen patients underwent stem cell transplantation in first remission: autologous in 5 pts who had no donor, and allogeneic in 8 pts. At a median follow up of 3 years, 60% relapsed, and 14 (63%) are still alive. Of the patients who underwent transplant, one auto pt died from hemophagocytosis, 2 alloBMT patients died from acute GVHD, and 2 alloBMT pts died from disease progression. One alloBMT patient with cutaneous gamma delta TCL relapsed and responded to salvage therapy. Conclusions Cytotoxic and gamma-delta TCLs are rare diseases that have traditionally responded poorly to treatment. In our experience, many patients have a suboptimal response to CHOP alone and require additional therapy to achieve remission. We report a favorable outcome after stem cell transplantation and with implementation of novel agents. Advances in understanding biology and international collaborative efforts are required to improve outcome in these rare entities. Disclosures: Off Label Use: sorafenib in t cell nhl. Foss:merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding.

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Patterns of Treatment for Newly Diagnosed and Relapsed/Refractory Peripheral T-Cell Lymphoma in the Community Setting

Blood ◽

10.1182/blood.v126.23.3952.3952 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3952-3952

Author(s):

Tatyana Feldman ◽

Michael McGuire ◽

Claudio Faria ◽

Andre Goy ◽

Charles M. Farber ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Retrospective Review ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

Initial Therapy ◽

T Cell Lymphoma ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Background: Peripheral T-Cell lymphomas (PTCL) are an uncommon, heterogeneous group of disorders that are difficult to treat due a lack of a consensus standard of care algorithms. Conventional B-cell lymphoma chemotherapy regimens have been adapted for use in PTCL but have shown low response rates, short durations of response and generally poor outcomes. Mature T/NK cell lymphoma-specific therapies are now available, however their sequencing into treatment algorithms is not defined. The objective of this study was to determine which regimens are currently being used and the associated outcomes for PTCL patients (pts) in community settings. Patients & methods: A retrospective review was performed of newly diagnosed and relapsed/refractory pts with PTCL, including anaplastic large cell lymphoma (ALCL), PTCL not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL) treated by Regional Cancer Care Associates between January 1, 2010 and April 30, 2015. Pts were identified using the COTA software platform, which extracts data from electronic health records and permits real-time observational database analysis. Results: 93 pts with ALCL (n=30), PTCL-NOS (n=44), or AITL (n=19) treated by 30 physicians throughout New Jersey were identified. Median age at diagnosis was 61 (range: 19-91), with ALCL pts younger than other subtypes (53 years, 65 years, 62 years, respectively). Pts were predominantly male (63%). 55 pts (81% of assessed pts) had an Ann Arbor stage of III/IV and 34 pts (41% of assessed pts) had an international prognostic index (IPI) score >3. ALK positivity was identified in 40% of assessed ALCL pts. Median time to the 1st oncology visit from pathologic diagnosis was 29 days; time to treatment initiation was 15 days later. The analysis demonstrated significant variation in the treatment of newly diagnosed pts. As initial 1st line therapy, there were 13 different regimens used among 21 pts with ALCL, 18 different regimens among 29 pts with PTCL-NOS, and 7 regimens used in the 16 pts with AITL. CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) was the most frequently prescribed 1st line chemotherapy regimen, used by 37 pts (56%) and an additional 12 pts (18%) were prescribed a CHOP-like regimen. The complete response rates and duration of response for first line CHOP plus CHOP-like regimens (excluding pts consolidated by transplant n=38) was 39% / 33.7 months for all PTCL subtypes (75% CR/37.8 months for ALCL, 24% CR/26.5 months for PTCL-NOS, and 22%CR/36.9 months for AITL). The 4-year PFS and OS for these 1st line CHOP/CHOP-like pts was 50% and 50% respectively. Transplants were performed as part of initial therapy in 12 pts (2 allo; 10 auto) with a 4-year PFS 57% and 4-year OS 55% (p=0.29 and p=0.63; log-rank, compared to CHOP without BMT). Relapsed/refractory PTCL show similar variability in treatment regimens. There were 7 different salvage regimens for the 7 ALCL pts, 15 different regimens for the 15 PTCL-NOS pts, and 5 different regimens for the 5 AITL pts. Across all patient types there were 29 unique regimens used to treat relapsed/refractory PTCL pts. Romidepsin monotherapy (n=6) and brentuximab monotherapy (n=6) were the most common regimens. Salvage transplants were performed in 6 pts (3 allo & 3 auto). From date of diagnosis ALCL (ALK positive) pts had a 4-year PFS 68% and an OS at 4-years 100%. ALCL (ALK negative) pts had a 4-year PFS of 73% and an OS 80%. PTCL-NOS pts had a 4-year PFS of 32% and OS 42% (median PFS 13 months and a median OS 30 months). AITL pts had a 4-year PFS 48% and OS 42% (median PFS 12 months and a median OS 25 months). Conclusion: This retrospective review demonstrated significant variability in the regimens used to treat PTCL pts outside of protocol settings. Although CHOP / CHOP-like therapy was the most common initial therapy (used in 74% of pts) with transplant up-front consolidation in 12 pts (26%), there appears to be no consensus on the optimal management approach for the PTCL subtypes and in each line of therapy. No benefit was noted in our series for upfront transplant. The survival outcomes in this community based cohort are comparable with recent multi-center institutional studies (COMPLETE and Abramson et al) and demonstrate improving survival for AITL pts versus historical control. There is a need to assess the comparative effectiveness of available treatment options in these diseases to better inform future treatment decisions. Disclosures Feldman: Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. McGuire:Celgene: Employment. Faria:Celgene: Employment. Goy:Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees. Farber:Jansen Pharmacyclics: Honoraria, Speakers Bureau; Gilead Sciences: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Choi:COTA: Employment. Connors:COTA: Employment. Paramanathan:COTA: Employment. Schultz:COTA: Employment. Goldberg:Ariad: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Novartis: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Pfizer: Research Funding.

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Autologous Stem Cell Transplantation for Angioimmunoblastic T-Cell Lymphoma

Blood ◽

10.1182/blood-2020-142889 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Samer A. Srour ◽

Yago Nieto ◽

Swaminathan P Iyer ◽

Roberto N. Miranda ◽

Farzaneh Maadani ◽

...

Keyword(s):

Stem Cell ◽

Prognostic Factors ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Angioimmunoblastic T Cell Lymphoma ◽

Grant Support

Introduction: Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of rare neoplasms, the majority characterized by an aggressive course and short survival. Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype (19%) of PTCLs, with generally poor long-term prognosis. The outcomes for most reported cases of AITL are derived from cohorts which include other PTCL subtypes. There is limited data for the role of autologous stem cell transplantation (ASCT) in AITL, and the associated predictive factors for prognosis. We present the largest single center cohort of AITL patients who underwent ASCT either upfront or at time of relapse. Methods: We included consecutive patients with AITL who had confirmed diagnosis and underwent ASCT at our institution from May 2000 to November 2019. Primary endpoints: progression free survival (PFS) and overall survival (OS). Secondary endpoints were cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and to identify prognostic factors associated with PFS and OS. Kaplan-Meier method was used to estimate OS and PFS. CIR and NRM were determined using the competing risks method. Cox regression analyses were used to determine prognostic factors. Results: The study included 54 patients with a median age of 63 (range, 37-77) years and male predominance (57%). All patients had advanced stage III/IV at diagnosis. Additional patient and disease characteristics are outlined in Table 1. Carmustine, etoposide, cytarabine, and melphalan (BEAM) with (30%) or without (57%) rituximab (R; used at the discretion of treating physician for EBER-positive AITL) were the most commonly used preparative regimens. With a median follow-up of 47.4 (range, 7.1-142.2) months, the median PFS and OS of all study patients were 41 and 108 months, respectively. The 2- and 4-year PFS/OS were 58%/83% and 46%/65%, respectively. CIR of relapse at 1, 2, and 4 years were 30%, 34%, and 44%, respectively. NRM at 1, 2, and 4 years were 7.5%, 7.5%, and 10%, respectively. All variables listed in Table 1 were assessed for their prognostic impact in univariate analysis (UVA) for PFS and OS. Of those, transplant for relapsed AITL (HR 3.716 95% CI: 1.728-7.991; p=0.0008) and high LDH at transplant (HR 2.139, 95% CI: 1.023-4.471; p=0.0433) were significantly associated with worse PFS (Figure 1A, C). There was a tendency for improved PFS for women (HR 0.56, 95% CI: 0.259-1.209; p=0.1398) and patients who received R-BEAM conditioning (HR for BEAM 1.99, 95% CI: 0.808-4.899; p=0.1344). Similar UVA results were noted for OS, where transplant for relapsed AITL (HR 2.943, 95% CI: 1.173-7.382; p=0.0214) and high LDH at transplant (HR 2.771, 95% CI: 1.076-7.138; p=0.0348) were significantly associated with worse OS (Figure 1B, D). On multivariable analysis (MVA), transplant at relapse (HR 3.716 95% CI: 1.728-7.991; p=0.0008) was associated with inferior PFS (HR 3.038, 95% CI: 1.386-6.659; p=0.0055) and OS (HR 2.291, 95% CI: 1.054-4.979; p=0.0364). High LDH at transplant was associated with worse PFS (HR 2.291, 95% CI: 1.054-4.979; p=0.0364), and with a trend for inferior OS (HR 2.259, 95% CI: 0.838-6.093; p=0.1073). Only 10 (19%) patients were transplanted with active disease at transplant; disease status at transplant didn't have a significant impact on outcomes in UVA and MVA. A subset analysis subgrouping patients by 1 (n=33) vs 2 (n=16) vs >2 (n=5) prior lines of therapy showed no significant difference in outcomes between 2 vs >2 prior lines of therapy. Conclusions: Upfront ASCT is associated with significantly improved and durable survival in patients with AITL. Receiving more than one prior line of therapy (transplant for relapsed AITL) and elevated LDH at transplant are associated with very poor prognosis, for which allogeneic transplant and alternative novel therapies should be further explored. Disclosures Nieto: Secura Bio: Other: Grant Support; Astra Zeneca: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Janssen: Research Funding; Bioline: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy. Shpall:Takeda: Other: Licensing Agreement; Novartis: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Cancer Prevention and Research Institute of Texas: Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Burroughs Wellcome Fund: Research Funding; TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Acerta: Research Funding; Spectrum: Consultancy; National Cancer Institute: Research Funding; V Foundation: Research Funding; Kite: Research Funding; Bayer: Consultancy; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; OptumRx: Consultancy. Champlin:Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Cytonus: Consultancy; Omeros: Consultancy; Takeda: Patents & Royalties; Actinium: Consultancy. Hosing:NKARTA Inc.: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Outcomes of Patients with Refractory Peripheral T-Cell Lymphoma, Angioimmunoblastic and Other Nodal Lymphomas of T Follicular Helper-Cell Origin (OPerA)

Blood ◽

10.1182/blood-2019-124447 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2854-2854

Author(s):

Joanna M Rhodes ◽

Suchitra Sundaram ◽

Adam Zayac ◽

Adam J Olszewski ◽

Paolo Caimi ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Initial Therapy ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Line Therapy

Introduction: T cell lymphomas are heterogenous with an overall poor prognosis. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T cell lymphoma (AITL) are the two most common subtypes in the US accounting for 45% of diagnoses. Based on overlapping recurrent molecular and cytogenetic abnormalities, the WHO created an umbrella category of nodal T-cell lymphomas with T-follicular helper phenotype (TFH lymphoma), which includes AITL and PTCL with TFH phenotype (Swerdlow SH, et al. Blood. 2016). 25-30% of patients (pts) are refractory to initial therapy and even amongst responders to initial therapy, relapse is common. Survival after relapse or progression (R/P) is typically measured only in months. Outcomes have not changed significantly even with the introduction of several new agents in the last 10 years (Chihara D, et al. Br J Haematol. 2017). There remains no standard 2nd line therapy or guidance on sequencing of therapies as interpretation of clinical data in T-cell lymphoma is frequently hampered by the heterogeneity of the patient population and small sample size. The aim of our study was to determine outcomes in a large, well-defined group of pts with either primary refractory PTCL-NOS or TFH lymphoma. Methods: We performed a multi-center retrospective study to determine outcomes to 2nd line therapy for adult pts diagnosed between 1.1.09-6.30.18 with PTCL-NOS or TFH lymphoma, who were primary refractory defined by either induction failure, less than CR to initial therapy, or relapse within 6 months (mo) of completion of initial therapy. We performed time to event analysis using Kaplan-Meier method and compared groups using log-rank test. All other statistics were descriptive. Results: Patient and disease characteristics at diagnosis and relapse are summarized in Table 1. We identified 80 eligible pts from 7 US academic centers. Median FU was 17.2 mo from diagnosis (0.5-70). Overall, pts had mostly advanced stage with multiple high-risk features including bone marrow (BM) or extranodal (EN) involvement and B symptoms at diagnosis and R/P. Most pts received CHOP (52%) or CHOEP (24%) as initial therapy. 60% of patients did not attain a CR, while 40% of pts relapsed after initial CR.14% had received a consolidative transplant in 1st CR prior to relapse (almost all autologous hematopoietic cell transplant [HCT]). At R/P, 48% received single agent therapy [mostly romidepsin (15/38)], while 36% received multi-agent salvage therapy [mostly ICE (9/29)]. 13/80 pts were placed on hospice or only received local therapy after R/P. Median OS from diagnosis and following R/P was 19 mo/12.9 mo respectively. Median PFS2 (defined as time from 2nd line therapy to 2nd progression) for pts receiving systemic therapy was 73 days (d) (range 41-175). On univariate and multivariate analysis, there was no significant difference in PFS2 by histologic subtype (74 d for PTCL and 73 d for TFH lymphoma; p=0.29), platelet count <150,000 (75 d vs 59 d; p=0.37), presence of B symptoms at R/P (78 d vs. 63 d, p=.16), ECOG PS ≥2 (75 d vs 57 d, p=0.62), elevated LDH (63 d vs 75 d, p=0.31) and EN disease at R/P (59 d vs 75 d, p=0.72). There was a trend towards longer PFS2 with single agent salvage therapy compared to combination salvage therapy (97 d vs. 51 d; p=0.09). There was no statistically significant difference in survival if pts had relapsed disease or induction failure (75 d vs. 50 d, p=0.97). Although numerically longer, OS did not differ statistically if pts underwent HCT as consolidation after 2nd line therapy (allogeneic HCT 29.1 mo, autologous HCT 48.5 mo vs. 16.1mo for no HCT; p=0.61, n=8). Median number of therapies after salvage was 1 (range 1-6). Conclusions: Outcomes in this large, well-defined population of primary refractory PTCL-NOS and TFH lymphoma were poor, but better compared to most other retrospective series in R/R T-cell lymphoma. EN disease and advanced stage were common in this cohort of primary refractory pts. Relapse after HCT in CR1 had a particularly poor prognosis. Our findings suggest that single agent therapy following R/P in primary refractory pts and transplant may be beneficial, though our statistical power was limited due to small sample size. In a next step, we plan to expand the cohort and perform genetic/molecular characterization of available biospecimens following central pathology review. Disclosures Rhodes: DAVA Oncology: Honoraria. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Ghosh:TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Dwivedy Nasta:Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding; Celgene: Honoraria; ATARA: Research Funding; Aileron: Research Funding; Debiopharm: Research Funding; Millenium/Takeda: Research Funding; Pharmacyclics: Research Funding. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding.

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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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Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE): First Detailed Report of Primary Treatment

Blood ◽

10.1182/blood.v120.21.1614.1614 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1614-1614 ◽

Cited By ~ 5

Author(s):

Francine M. Foss ◽

Kenneth R. Carson ◽

Lauren Pinter-Brown ◽

Steven M. Horwitz ◽

Steven T. Rosen ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Treatment ◽

T Cell Lymphoma ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees

Abstract 1614 Background: Registries can be invaluable for describing patterns of care for a population of patients. COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients designed to identify the lymphoma-directed treatments and supportive care measures that PTCL patients receive. We report here the first detailed findings of initial therapy. Methods: This is a prospective, longitudinal, observational registry that is led by a global steering committee. Patients with newly diagnosed PTCL and providing written informed consent are eligible. Patients are entered into the registry from time of initial diagnosis and followed for up to 5 years. Only locked records are reported. Results: As of July 2012, 330 patients have been enrolled from the United States. The first patient was enrolled in February 2010. Locked baseline and treatment records are available for 124 and 81 patients, respectively. Of the 124 patients with locked baseline records, 67 patients (54%) were male, the mean age was 59 (range: 19–89), and race/ethnicity was recorded as: White (87 patients; 70%), Black (19; 15%), Asian (5; 4%) and other/unknown (13; 11%). Histology was reported as follows: PTCL-not otherwise specified (27%), anaplastic large cell lymphoma-primary systemic type (18%), angioimmunoblastic T-cell lymphoma (17%), transformed mycosis fungoides (7%), T/NK-cell lymphoma-nasal and nasal type (6%), adult T-cell leukemia/lymphoma, HTLV 1+ (6%) and other (19%). 25 patients (20%) had received another diagnosis, including B-cell lymphoma, Hodgkin's disease and other T-cell lymphomas, prior to their current diagnosis of PTCL. 49 patients (40%) had B symptoms, 102 patients (82%) had an Ann Arbor stage of III/IV, 116 patients (94%) had ECOG performance status of 0–1, and international prognostic index (IPI) score was distributed as follows: IPI 0 (7% of patients), 1 (15%), 2 (43%), 3 (26%), and 4 (9%). Of the 81 patients with locked treatment records, details on initial treatment can be found in table below. Conclusions: This first detailed analysis of primary treatment of PTCL indicates that this disease is still largely being treated with regimens derived primarily from studies of B-cell lymphomas and that a single standard of care does not exist. The fact that a meaningful proportion of patients were initially diagnosed with something other than their current diagnosis of PTCL points out the challenges of diagnosing the disease. While the intent of initial treatment for most patients is to affect a cure, more than 20% of patients were noted as deceased at the end of initial treatment, underscoring the need for more effective, disease-specific therapy. Disclosures: Foss: Merck: Study Grant, Study Grant Other; Celgene: Study Grant, Study Grant Other; Eisai: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Allos: Honoraria; Seattle Genetics: Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding.

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Tolinapant (ASTX660), a Non-Peptidomimetic Antagonist of cIAP1/2 and XIAP, and the HDAC Inhibitor Romidepsin Are Synergistic in in Vitro Models of T Cell Lymphoma

Blood ◽

10.1182/blood-2021-153451 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4356-4356

Author(s):

John S Manavalan ◽

Ipsita Pal ◽

Aidan Pursley ◽

George A. Ward ◽

Tomoko Smyth ◽

...

Keyword(s):

T Cell ◽

Cell Line ◽

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Tnf Alpha ◽

Sensitive Cell ◽

Advisory Committees

Abstract Background: The PTCL are a heterogeneous group of non-Hodgkin lymphomas originating from mature T-lymphocytes. They are aggressive diseases, often resistant to conventional chemotherapy. Despite the fact that a number of new agents have been approved, treatment paradigms tailored to the biology of the disease have yet to emerge. Tolinapant (ASTX660) is a potent antagonist of both cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), and is presently in phase I/II trials in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis (Ward GA, et al. Mol Cancer Ther. 2018), are potent anti-tumor immune enhancers and induce markers of immunogenic cell death such as damage associated molecular patterns (DAMPs; Ye W, et al, Oncoimmunology, 2020). Objectives: We explored the sensitivity of a range of T-cell lymphoma (TCL) cell lines to tolinapant. We establish the synergy coefficient between tolinapant and the HDAC inhibitor, romidepsin, and interrogated the molecular basis of their synergistic interaction. Methods: A panel of human T-cell lymphoma cell lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10ng/ml of TNF alpha. For combination studies, with tolinapant and romidepsin, each drug was tested at the IC10 and IC40 concentrations in the presence or absence of TNF alpha. Synergy scores using the Excess over Bliss (EOB) model were calculated using SynergyFinder (Aleksandr Ianevski et al; Nucleic Acids Research, 2020). Additionally, the effects of tolinapant and romidepsin on the IAPs and caspases were analyzed by western blots. TNFR1 receptor expression and induction of DAMPs were also analyzed by flow cytometry. Results: TCL Lines demonstrated varying sensitivities to tolinapant in the presence or absence of TNF alpha. The most sensitive cell lines, ALK+ ALCL and SUP-M2, had IC50 concentrations ranging from 200nM ± 100nM to 20nM ± 1nM in the absence or presence of TNF alpha, respectively, at 24, 48 and 72hrs, while a resistant CTCL cell line HH had an IC50 concentration of over 20mM, even in the presence of TNF alpha. Interestingly, using western blot analysis, we found that the presence of TNF alpha increased the levels of cIAP1 in the tolinapant sensitive SUP-M2 cell line, but not in the resistant HH cell line. However, there was a concentration dependent decrease in cIAP1 but not in XIAP in both cell lines treated with tolinapant. Flow cytometry analysis demonstrated that tolinapant increases the expression of TNFR1 and DAMPs in a dose dependent manner on the sensitive SUP-M2, but not in the resistant HH cells. In combination experiments, using the EOB model, tolinapant plus romidepsin was found to be synergistic in the absence of TNF alpha, at 36hrs, in both the sensitive cell line SUP-M2 and the resistant cell line HH. In the presence of TNF alpha, synergism was seen only in the sensitive cell line SUP-M2 and antagonistic in the HH cell line (Fig. 3). In the tolinapant plus romidepsin treated samples, cIAP1 levels decreased in the SUP-M2 cell line, in the absence of TNF alpha, however, addition of TNF alpha did not alter the levels of cIAP1 in the SUP-M2 cells. The cIAP1 levels decreased in the HH cells treated with the combination, in both the presence or absence of TNF alpha (Figure). Our findings indicate that the synergy of the tolinapant plus romidepsin is not dependent on the presence of TNF alpha. Conclusion: Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha. These data provide the rationale to continue to explore the combination of tolinapant and romidepsin in vivo and to investigate additional combinations with T-cell specific agents (e.g. pralatrexate, belinostat, azacitidine and decitabine). Figure 1 Figure 1. Disclosures Smyth: Astex Pharmaceuticals: Current Employment. Sims: Astex Pharmaceuticals: Current Employment. Loughran: Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioniz Therapeutics: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Marchi: Kyowa Kirin: Honoraria; Myeloid Therapeutics: Honoraria; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; Kymera Therapeutics: Other: Scientific Advisor.

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Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽

10.1182/blood-2021-152603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 623-623

Author(s):

Bradley M. Haverkos ◽

Onder Alpdogan ◽

Robert Baiocchi ◽

Jonathan E Brammer ◽

Tatyana A. Feldman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

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Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

Blood ◽

10.1182/blood-2018-99-116277 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2937-2937

Author(s):

Thomas E. Witzig ◽

Lubomir Sokol ◽

Eric D Jacobsen ◽

Won-Seog Kim ◽

Francine M. Foss ◽

...

Keyword(s):

Medical Education ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Board ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Cxcl12 Expression ◽

Phase 2 Study

Abstract Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

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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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A Phase Ib Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma (PTCL): The Ro-CHOP Study

Blood ◽

10.1182/blood.v120.21.1617.1617 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1617-1617 ◽

Cited By ~ 1

Author(s):

Jehan Dupuis ◽

Rene-Olivier Casasnovas ◽

Herve Ghesquieres ◽

Franck Morschhauser ◽

Herve Tilly ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Phase Ib ◽

Overall Response ◽

Phase Ii Studies

Abstract Abstract 1617 Background: Romidepsin is a selective class 1 histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 phase II studies with overall response rates of 25–38% (Piekarz, Blood 2011;117:5827; Coiffier, J Clin Oncol 2012;30:631). Toxicity was mainly hematologic and digestive. The aim of the present study was to evaluate the safety, tolerability and efficacy of different doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods: Patients with biopsy-proven PTCL were planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1 – 5) in association with varying doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 was chosen. The dose-variation scheme follows a traditional “3+3” design. Dose-limiting toxicity (DLT) were considered during the first 2 cycles. Results: Eighteen patients (11 male, 7 female, aged 31 to 78) have been included and are analyzable for toxicity during the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=10), angioimmunoblastic TCL (n=4), other PTCL (n=4). ECOG performance status was good (0–1) in all but one patient; 17/18 had stage III-IV disease; LDH levels were elevated in 11/18. The age-adjusted IPI score was 0 (n=1), 1 (n=14), 2 (n=3). Significant, albeit tolerable haematological toxicity having been observed in the first two cohorts, the definition of DLT was modified during the course of the study. The study diagram is shown in the figure. Accrual of the phase Ib part of the study is now completed and the phase II part is ongoing with a dose of 12 mg/m2 D1&8. Serious adverse events of interest included: One episode of acute pulmonary edema after course 1 in 1 patient, acute coronary syndrome (n=1), deep venous thrombosis (n=1) and cardiac arrhythmia (n=1). Among 14 evaluable patients, 3 progressed during treatment or shortly after end of treatment; and 11 responded (partial response 3/14, complete response 8/14) for an overall response rate of 78%. The 4 other patients have not yet reached the 8 cycles. Conclusion: Romidepsin can be combined with CHOP at the price of foreseeable hematological toxicity. Some cardiovascular events have been observed but the relationship with romidepsin is questionable. The dose of 12 mg/m2 on days 1& 8 is currently evaluated in the phase 2 part of the study. Response rates seem promising, but longer follow-up is needed. Updated results will be presented at the meeting. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding. Coiffier:Celgene: Consultancy.

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