The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed ...death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.
Bone marrow transplantation (BMT) is a potentially curative treatment for patients with leukemia and lymphoma. Tumor eradication is promoted by the anti-tumor activity of donor T cells contained in ...the transplant; however, donor T cells also mediate the serious side effect of graft-versus-host disease (GVHD). Separation of GVHD from graft anti-tumor activity is an important goal of research in improving transplant outcome. One approach is to take advantage of the immunomodulatory activity of regulatory NKT cells and CD4⁺CD25⁺ Treg of host and/or donor origin. Both host and donor NKT cells and donor Treg are able to prevent GVHD in murine models. In this review, we summarize the mechanisms of NKT cell- and Treg-mediated protection against GVHD in mice while maintaining graft anti-tumor activity. In addition, we also examine the interactions between NKT cells and Treg in the context of BMT, and integrate the data from murine experimental models with the observations made in humans.
Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T‐cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous ...group of disorders. However, a significant number of patients will experience post‐AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow‐up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post‐AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3‐year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%–87%). Our report details the pattern of post‐AHCT relapse and the management of relapsed disease using different therapeutic modalities.
Brentuximab vedotin and allogeneic transplant provides long term survival in relapsed PTCL patients after AHCT.
The immune modulatory effects of total lymphoid irradiation (TLI) for graft-versus-host disease (GVHD) protection and transplantation tolerance following allogeneic bone marrow and organ ...transplantation have been studied for years in animal models. In preclinical models nonmyeloablative TLI conditioning alters residual host T cell subsets to favor regulatory natural killer T cells that suppress GVHD and prevent organ allograft rejection. These preclinical models have been recently adapted to human transplantation.
Patients receiving allogeneic hematopoietic cell transplantation for hematological malignancies conditioned with TLI and depletive T cell antibodies showed sustained donor chimerism, a reduced incidence of acute GVHD yet retained graft antitumor activity. As in the preclinical models, nonmyeloablative TLI conditioning significantly altered residual host T cell subsets favoring natural killer T cells, and the low incidence of GVHD was associated with increased IL-4 secretion by chimeric donor T cells. The TLI regimen used in cancer patients was modified to determine conditions for stable mixed chimerism and tolerance induction following combined hematopoietic cell and kidney transplantation.
This review summarizes the evolution of the preclinical TLI protocols and their recent translation to clinical trials, and discusses the mechanisms involved in protection from GVHD and the induction of tolerance following mixed chimerism.
Allogeneic stem cell transplantation (SCT) can be curative for high-risk (HR) hematologic malignancies, but until recently, access was limited to fully matched donors. The introduction of ...post-transplant cyclophosphamide (PTCy) has enabled patients to receive SCT using haploidentical (haplo) related donors; however, outcomes remain disappointing. Orca-Q, an investigational precision engineered cell therapy, represents an alternative strategy. The cellular composition of Orca-Q consists of enriched CD34+ stem cells, combined with specific T-cell subsets, manufactured from mobilized peripheral blood, and is intended to reconstitute the blood and immune systems.
Adults (18 to 65) with HR hematologic malignancies were enrolled on the haplo arm of a multicenter phase 1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received MAC and single agent GVHD prophylaxis with tacrolimus.
21 patients (11 AML, 8 ALL, 2 CML in blast crisis), all 4/8 HLA matched, were enrolled between 1/2019 to 7/2022. Orca-Q was successfully manufactured centrally and delivered to all patients with vein-to-vein time of < 72 hours. Median age was 44 (range, 21 – 63) years, 57% were male. Median follow-up was 333 (range, 39 – 1020) days. DRI score was high/very-high in 5; intermediate in 13 (low-risk, 2; N/A, 1). All patients engrafted; median time of 13 (range, 8 – 25) and 16 (range, 12 – 25) days for neutrophil and platelet engraftment, respectively. Gr 3-4 aGvHD was rare with only 1 event of gr 3 aGvHD. Of 16 patients who had > 3 months follow-up, only 1 developed mild cGvHD. No patients had moderate-tosevere cGvHD. Estimated incidence of BMTCTN MOP3 infections was 27% at 1yr. 2 patients died from relapsed disease during the study period. The 1-year GvHD-and-relapse free survival (GRFS) was 71%.
Our findings suggest encouraging safety and efficacy outcomes using Orca-Q cell therapy for haplo-SCT, without PTCy, and only single agent tacrolimus. Patients treated with Orca-Q experienced a low adverse event profile, low incidence of overall and severe aGvHD/cGvHD, and improved GRFS. This phase 1 study continues to enroll patients across the US.
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