This multicenter prospective phase II study examines the activity and tolerability of brentuximab vedotin as second-line therapy in patients with Hodgkin lymphoma that was relapsed or refractory after induction therapy. Brentuximab vedotin (1.8 mg/kg) was administered intravenously on day 1 of a 21-day cycle for a total of 4 cycles. Patients then proceeded to autologous hematopoietic cell transplantation (AHCT), if eligible, with or without additional salvage therapy, based on remission status post brentuximab vedotin. The primary endpoint was overall response rate (ORR). Secondary endpoints were safety, stem cell mobilization/collection, AHCT outcomes and association of CD68+ with outcomes. Of 37 patients, the ORR was 68% (13 complete remission, 12 partial remission). The regimen was well tolerated with few grade 3/4 adverse events including lymphopenia (1), neutropenia (3), rash (2), and hyperuricemia (1). Thirty-three (89%) patients were able to proceed to AHCT, with 24 (65%) in CR at time of AHCT. Thirteen patients in CR, 4 in PR and 1 in SD (49%) received AHCT without salvage combination chemotherapy. CD 68 expression did not correlate with response to brentuximab vedotin. The median number of stem cells mobilized was 6.0 × 106 (2.6–34) and median number of days to obtain minimum collection (2 × 106) was 2 (1–6). Brentuximab vedotin as second-line therapy is active, well tolerated, and allows adequate stem cell collection and engraftment. For Hodgkin lymphoma patients with relapsed/refractory disease post-induction therapy, second-line brentuximab vedotin, followed by combination chemotherapy for residual disease, can effectively bridge patients to AHCT.

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Among non-Hodgkin lymphoma subtypes, T-cell phenotype confers a poor clinical prognosis. For more aggressive histologies, patients frequently present with advanced disease that is inherently chemoresistant. For cutaneous histologies, disease progresses less rapidly, but is debilitating and often incurable long term. Here we report the retrospective analysis of data from 27 patients with mature T-cell lymphoma treated with salvage allo-HCT at the City of Hope using a reduced-intensity fludarabine/melphalan conditioning regimen between the years 2001 and 2008. Eleven of the twenty-seven patients had cutaneous T-cell lymphoma (CTCL). The majority of patients had advanced disease at the time of transplant (17/27 or 63%). Median followup was 36 months. We observed 2-year overall survival (OS) of 55%, progression-free survival (PFS) of 47%, and cumulative incidence of relapse/progression and non-relapse mortality (NRM) of 30% and 22%, respectively. For CTCL, patients had a 2-yr PFS of 45% and NRM of 27% compared to patients with other histologies, who had PFS of 62% and NRM of 19%. Overall, our results suggest that meaningful long term survival rates and disease control can be achieved with acceptable non-relapse mortality in patients with mature T-cell lymphomas, including CTCL using reduced intensity conditioning with melphalan and fludarabine.

Background: Brentuximab vedotin (BV), an antibody drug conjugate, selectively induces apoptosis of CD30+ cells. A phase II trial demonstrated an overall response rate (ORR) of 75%, with 34% CR, and a favorable toxicity profile in Hodgkin Lymphoma (HL) patients post autologous hematopoietic cell transplantation (AHCT). Standard first line salvage regimens such as ICE have similar response rates but more serious toxicities. We report results of a phase II trial evaluating BV as first line salvage therapy in relapsed/refractory HL prior to AHCT. Patients and Methods: This is a prospective, multicenter (City of Hope, Cornell Weill Medical College), phase II trial in patients with relapsed/refractory HL. All patients had biopsy proven HL post induction therapy with ABVD, BEACOPP or a combination +/- consolidative XRT. Patients were treated with 1.8 mg/kg of BV intravenously every 3 weeks for a maximum of 4 cycles. The primary endpoint was the best response rate according to Revised Cheson Criteria assessed at end of cycles 2 and 4. Secondary endpoints were toxicities, stem cell mobilizations, and engraftment analysis. Immunohistochemical (IHC) staining was performed on pre-treatment tumor specimens for biological correlates. Results: 37 patients were accrued with 36 evaluable for response. See table for baseline characteristics. The overall best response (CR+PR) rate was 69%, CR rate was 33%, SD was 28%, and PD was 3%. When stratified by stage at diagnosis, the ORR was 68% for stage I/II patients and 70% for stage III/IV patients. When stratified by response to induction therapy, the ORR was 75% for primary refractory disease and 66% for relapsed disease. Univariate analysis did not yield any significant differences in response rates in terms of age, gender, stage, and response to induction. There was no correlation between CD68 expression levels by IHC and response rates. Additional IHC for drug exporters and B-tubulin isomers are pending. Treatment was well tolerated. Grade 4 possibly-related toxicities included lymphopenia (n=1), neutropenia (n=1), and hyperuricemia (n=1). Grade 3 possibly-related toxicities >5% included rash (n=2), neutropenia (n=2). Grade I/II possibly related toxicities >25% included peripheral sensory neuropathy (n=19), AST elevation (n=14), ALT elevation (n=14), rash (n=13) fatigue (n=11), and generalized muscle weakness (n=11). There were no transfusions required and no neutropenic fevers. 30/36 patients were evaluable for AHCT thurs far (6 had not finished 4 cycles of BV or salvage chemotherapy). 27/30 (90%) successfully proceeded to AHCT (2 went to alloHCT, 1 could not be salvaged). Among the 12 CR patients, all proceeded to AHCT without additional chemotherapy. Among the 13 PR patients, 2 proceeded to AHCT directly while 11 received additional chemotherapy (ICE/DICE/IGEV, GND). All patients with SD/PD received additional chemotherapy. Among the 27 patients who received AHCT, 13 received additional chemotherapy (48%) and 14 received BV only (52%). Three patients who achieved PR after 2 cycles had progressed by 4 cycles of therapy. All patients who achieved CR did so after 2 cycles of therapy. All patients were primed with cyclophosphamide/G-CSF; 8 patients received plerixafor. The median cell dose collected was 5.6x 10^6 CD34 cells (2.6-22.4). The median days of collection was 3 (1-6). Patients received BEAM, CBV, or BEAM plus yttrium-90 labeled anti-CD25 as AHCT conditioning. The median time to neutrophil engraftment (ANC≥500) was 11 days (10-11) and platelet engraftment (≥20K) was 14 days (9-22) Conclusion: BV as first line salvage therapy is efficacious, well tolerated, and does not hinder stem cell collection or engraftment. 90% of patients were effectively bridged to AHCT and 52% did not require multiagent chemotherapy. For Hodgkin lymphoma patients with relapsed/refractory disease after induction therapy, BV can be considered as first line salvage. Table Characteristics N (%)or Median (Range) Gender Female Male 16 (44%) 20 (56%) Age 34 (11-59) Institution City of Hope Cornell 31 (84%) 6 (16%) Stage at Diagnosis I-II III-IV 19 (53%) 17 (47%) Prior XRT 9 (25%) B symptoms 22 (61%) Bulky Disease 31 (86%) Best Response to Induction Primary Refractory Relapsed (within 7 months) 23 (64%) 13 (36%) Disclosures Chen: Seattle Genetics: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Results of a phase II clinical trial on the use of brentuximab vedotin as first line salvage therapy in relapsed/refractory Hodgkin lymphoma. Siddiqi:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Leonard:Seattle Genetics: Consultancy.

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