The outcome of peripheral t-cell lymphoma patients failing first-line therapy: A report from the prospective, international t-cell project

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation. (Registered at clinicaltrials.gov identifier: 01142674)

Response assessment in lymphoma: Concordance between independent central review and local evaluation in a clinical trial setting

Background: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known. Methods: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N=102) or systemic anaplastic large-cell lymphoma (N=58). Results: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa=0.68; anaplastic large-cell lymphoma: kappa=0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3months by independent central review (95% confidence interval: 6.9, -); 14.5months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8months by independent central review (95% confidence interval: 5.0, 9.0); 9.0months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review. Conclusion: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation

Prediction of Progression-Free Survival with Brentuximab Vedotin Therapy for Relapsed Hodgkin Lymphoma: A Retrospective Analysis

Introduction: The role of brentuximab vedotin (BV) in Hodgkin Lymphoma (HL) is expanding, but factors predicting progression-free survival (PFS) after BV therapy are poorly defined. Age, tumor bulk, presence of extranodal disease, neutrophil:lymphocyte ratio (ANC/ALC), and lymphocyte:monocyte ratio (ALC/AMC) predict outcome in HL patients (pts) treated with chemotherapy, but their impact on PFS after BV has not been well-studied. Also, among pts with relapsed/refractory HL (rel/ref HL) who progress after BV, efficacy of additional chemotherapy is undefined. To inform patient selection and future clinical trial design with BV, we undertook a retrospective study to identify factors predicting PFS with BV therapy in rel/ref HL, and explore chemotherapy efficacy as salvage after BV failure. Methods: Pts receiving BV since 2009 were identified through pharmacy and research records and studied with IRB approval. Those with rel/ref HL receiving BV before or after transplant without intervening therapy were excluded. Age ≥40 at time, sex, pre-BV PET findings (SUV max, extranodal [EN] involvement, bulk > 5cm), prior therapy (# lines of therapy> median; prior transplant, platinum-containing, radiotherapy), and lab findings (AMC/ALC³4.3, ALC/AMC ratio³1) at time of start of BV were examined for an impact on PFS and OS via log-rank testing of Kaplan-meier projections(JMP 11.0 software). PFS was defined as time from first BV dose to radiographic or clinical progression, initiation of post-BV salvage, or death from any cause. OS was measured from date of first BV dose to death from any cause. Efficacy of salvage therapy for those failing BV was recorded. Results: Of 90 patient receiving BV, 43 met above criteria. Median age was 34 yrs (range 17-80), median # of pre-BV therapies was 3 (range 1-7). 31 (73%) had failed autologous transplant, 10 (23%) had undergone allogeneic transplant, and 20 (46%) received radiotherapy prior to BV. Pre-BV PET staging data was available in 26 pts; post-BV PET was not analyzed in this dataset as response criteria were nonstandardized. BV was administered for a median 6 cycles (range 2-20). Median PFS after BV was 6 mo. (Figure 1) with 4 pts having PFS >4 yrs. At 31 mo. median follow-up, 71% of pts were alive with no plateau in the survival curve. On univariate analysis, age 40 or older at time of BV predicted inferior PFS (p=.03) and inferior OS though 95% confidence intervals were wide (OS by age: Figure 2, p=.02). HR for death for pts age 40 or older was 4 (98% CI .03-2.3, p=.05). No other factor predicted PFS or OS. Among 29 pts who failed BV, OS was 3.4 yrs. 40 chemotherapy regimens were given with 11 responses. Five of 11 pts responded to bendamustine, but median time to progression was 4 mo. Two of 4 responded to gemcitabine as did 3/8 receiving platinum chemotherapy. Conclusions: In this cohort of rel/ref HL pts treated with BV, PFS was 6 mo. overall and inferior among pts 40 yrs or older. OS was also worse in this group, although confidence intervals were wide in both univariate analyses. We confirm and expand upon prior data showing features predicting outcomes in HL after chemotherapy do not clearly apply after BV; and that most pts progress Disclosures Off Label Use: Brentuximab is approved in HL after failure of autologous stem cell transplant; in this series, some patients received Brentuximab before or when ineligible for an autologous stem cell transplant.. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Gilead: Research Funding; Spectrum: Research Funding; Teva: Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding

Minimal detectable disease confirmed by flow cytometry and poor outcome after autologous stem cell transplantation in peripheral T-Cell lymphomas.

Minimal detectable disease confirmed by flow cytometry and poor outcome after autologous stem cell transplantation in peripheral T-Cell lymphoma

Bone Marrow Involvement Detected By Multi-Parameter Flow Cytometry Predicts Poor Outcome after Autologous Stem Cell Transplantation for Peripheral T-Cell Lymphoma

BACKGROUND: Peripheral T-cell lymphomas (PTCL) encompass a heterogeneous group of neoplasms accounting for 10 to 15% of non-Hodgkin lymphomas worldwide. Prognosis for PTCL patients is poor and consolidation in first remission with autologous stem cell transplantation (ASCT) is widely used. Most patients though still relapse after transplant. We hypothesized that pre-ASCT bone marrow (BM) involvement detected by multi-parameter flow cytometry (FC) would identify patients with inferior outcome after ASCT. METHODS: We retrospectively analyzed the outcome of 29 consecutive PTCL patients who underwent ASCT at the Fred Hutchinson Cancer Research Center from April 2004 through July 2014. Pre-ASCT BM involvement by flow cytometry (FC) was defined as the presence of an abnormal T-cell population detected by multi-parameter FC analysis in a BM aspirate obtained within 30 days prior to ASCT. An abnormal T-cell population accounting for a percentage equal or greater than 0.01% of total leukocytes after red blood cell lysis was considered significant. RESULTS: Ten patients (34%) with angioimmunoblastic T cell lymphoma (AITCL), 8 (27%) with ALK-negative anaplastic large cell lymphoma (ALCL), 8 (27%) with peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) and 3 (12%) with other PTCL sub-types were included. Median age at transplant was 54 (range: 29-71). Twenty patients (76%) presented at ASCT in complete remission (CR) per 1999 Cheson criteria and 9 (31%) were in first CR (CR1). Fifteen patients (50%) underwent ASCT upfront. Pre-ASCT BM involvement was detected by FC analysis in 7 patients (24%, 3 patients with AITCL, 1 patient with ALCL and 3 patients with PTCL-NOS) and by morphology in 2 patients (7%, 2 patients with AITCL). The 7 patients with pre-ASCT BM involvement detected by FC experienced a significantly higher 4-year cumulative incidence of relapse (CIR) (85% versus 36%, p versus 89%, p versus 32%, p = 0.002) and lower OS (25 versus 94%, p CONCLUSION: Pre-ASCT BM involvement by FC correlated with dramatically higher relapse rates and an inferior OS in PTCL patients after ASCT. Furthermore, we demonstrate that residual disease, detected only in patients meeting Cheson 1999 criteria for CR at ASCT is capable of predicting a higher risk for relapse. These findings should encourage further evaluation of minimal residual disease in PTCL patients achieving complete remission as defined per Cheson 1999 and 2007 criteria. Disclosures Gopal: Merck: Research Funding; Emergent/Abbott: Research Funding; Cephalon/Teva: Research Funding; BioMarin: Research Funding; Sanofi-Aventis: Honoraria; Millenium: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Piramal: Research Funding; Biogen Idec, BMS: Research Funding. Maloney: Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria. Till: Roche-Genentech: Research Funding

Allogeneic Transplant Following Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma.

Brentuximab vedotin is an antibody drug conjugate that induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Fifteen of 160 patients who participated in two pivotal phase 2 studies received a consolidative allogeneic stem cell transplant (allo-SCT) following brentuximab vedotin treatment. This case series describes their experience. The studies were approved by Institutional Review Boards prior to patient enrollment. Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks for up to 16 cycles. The estimated 2-year progression-free survival (PFS) rate was 66%, and the median PFS has not yet been reached. Eleven of the 15 patients were alive and the estimated 2-year survival rate was 80%. The safety of brentuximab vedotin treatment in this series was consistent with the known safety profile in this setting. Brentuximab vedotin is a compelling option for reducing tumor burden to facilitate a consolidative allo-SCT

Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study.

PURPOSE: Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL. PATIENTS AND METHODS: Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches. RESULTS: After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%). CONCLUSION: Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152)