Key Points TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT. Addition of a CD28 costimulatory domain to the CAR, plus changes to T-cell product manufacturing, resulted in improved T-cell expansion.

Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically delivers the potent cytotoxic drug MMAE to CD30-positive cells. BV is FDA-approved for treatment of relapsed/refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV resistant disease. We selected for BV-resistant HL (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (HL) exposure to BV. We confirmed drug resistance by MTS assay, and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. Additionally, tissue biopsy samples from 10 HL and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the HL cell line, demonstrated downregulated CD30 expression compared to the parental cell line. In contrast, the HL cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared to the parental line. For both HL and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One HL patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for HL both in vitro and in patients.

Post-transplant thrombotic microangiopathy (TMA) is a multi-factorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased when using a sirolimus plus tacrolimus regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. Donors were either sibling (n=82) or matched unrelated (n=95). Within the first 100 days post-HCT, 30 (17%) patients were diagnosed with TMA, and an additional nine patients (5%) were classified as probable TMA cases. The median time to TMA onset was 4.6 weeks (range: 1.6-10.6). Thirty-four patients developed both TMA and aGVHD, with the majority of patients (81%) developing aGVHD first. By multivariable analysis, the following factors were found to be associated with increased risk of TMA: day 14 serum sirolimus: ≥9.9 ng/ml (HR: 2.19, 95% CI: 1.13-4.27, p=0.02), presence of prior aGVHD grades II-IV (HR: 3.04, 95% CI: 1.38-6.71, p<0.01), and fully myeloablative conditioning (HR: 3.47, 95% CI: 1.60-7.53, p<0.01). The risk factors for TMA suggest that when using sirolimus/tacrolimus for GVHD prophylaxis, careful monitoring and adjustment of sirolimus dosages is critical, particularly in patients with active aGVHD.

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.

Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT. (Blood. 2012;119(26):6379-6381)