Checkpoint Inhibitor Therapy and Graft Versus Host Disease in Allogeneic Bone Marrow Transplant Recipients of Haploidentical and Matched Products with Post-Transplant Cyclophosphamide.

Abstract

Background: Concerns have been raised whether immune checkpoint inhibitor therapy in the alloBMT setting will result in graft versus host disease (GvHD) and transplant related mortality (TRM). We report our experience with a variety of checkpoint inhibitors used before or after allogeneic bone marrow transplantation (alloBMT). Our series comprises patients who received T cell-replete hematopoietic stem cells from HLA-haploidentical or -matched donors and is limited to those treated with post-transplant cyclophosphamide (PTCy) as primary GvHD prophylaxis. Patient selection: We retrospectively reviewed the records of alloBMT recipients who received PTCy and received checkpoint inhibitor therapy before or after alloBMT. GvHD was assessed using the CIBMTR GVHD index. Results: Eleven patients received checkpoint inhibitor therapy prior to alloBMT: anti-PD-1: Nivolumab n=6, anti-CTLA4: Ipilimumab n=8 (3 patients received both nivolumab and ipilimumab). These patients received a median of 4 (range 1 - 18) cycles of therapy. The median interval from last checkpoint inhibitor treatment to day of transplant was 43 (range 18-302) days. All patients received nonmyeloablative conditioning; 6 received partially mismatched allografts (5 were HLA haploidentical). Four patients developed Grade II aGvHD: Three patients who had received partially mismatched allografts (haplo-2, 9/10 unrelated-1) experienced stage 3 cutaneous GvHD only; one patient who received a 10/10 unrelated donor allograft developed stage 3 cutaneous GvHD with stage 1 liver involvement. Three patients were on immunosuppression when GvHD developed, the fourth patient with cutaneous and liver GvHD had been taken off tacrolimus on day 68 due to concerns of graft failure. GvHD resolved with treatment in each case. None of these patients developed chronic GvHD and none have died [median follow-up of 0.66 (range 0.91 - 2.0) years post alloBMT]. Nine patients received checkpoint therapy following alloBMT: anti-PD-1: Pembrolizumab n = 1, Nivolumab n= 6, anti-CTLA4: Ipilimumab n= 3 (one patient received nivolumab and ipilimumab). Eight patients had received nonmyeloablative conditioning; 5 received haploidentical allografts. Six received treatment for relapse of their hematologic malignancy, 1 for relapsed pediatric sarcoma, and 2 for newly diagnosed lung cancer. The median time to initiation of checkpoint inhibitor therapy was 1.2 (range: 0.8 - 5.8) years post alloBMT. Patients received a median of 5 (range 1 - 24) cycles of therapy. There was 1 case of Grade II aGvHD; stage 3 cutaneous GvHD when DLI from a 10/10 matched unrelated donor was given for relapsed disease after ipilimumab. This resulted in GvHD which was not accompanied by the desired graft-vs-leukemia effect. There were no other cases of acute or chronic GvHD in this group. There were 4 tumor-related deaths: pediatric sarcoma (1), lung cancer (1), and AML (2). The median follow-up for this group is 2 years (range 0.85 - 8.0) post alloBMT. Conclusions: In this small series, the incidence and severity of GvHD seen in patients who received checkpoint inhibitors was similar to that seen in patients treated with PTCy as GvHD prophylaxis without checkpoint inhibitors. GvHD was seen in patients treated with checkpoint inhibitors prior to alloBMT, but was generally mild and readily controlled and there were no associated deaths. In patients treated with checkpoint inhibitors after alloBMT, the only case of GvHD occurred after the patient received DLI. We caution that use of checkpoint inhibitors in closer temporal proximity to transplant might well be associated with increased risk of GvHD or severity of GvHD. Disclosures Borrello: WindMIL Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding. Wagner-Johnston:Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Other: member of DSMB.

Transplant strategies in relapsed/refractory Hodgkin lymphoma

“…Similarly, Schoch et al found that prior CPI exposure (nivolumab or ipilimumab) did not alter the incidence or severity of GVHD for lymphoma patients who had received posttransplant cyclophosphamide for GVHD prophylaxis after haploidentical or matched donor allo-HCT. 74 Eight of the 19 patients in this study had HL, and most (12/19) had received CPI .90 days before or .90 days after allo-HCT. Grade 2 aGVHD was seen in 4/11 patients with CPI before allo-HCT (3 with stage III skin involvement and 1 with stage III skin and stage I liver involvement).…”

PD-1 blockade for relapsed lymphoma post–allogeneic hematopoietic cell transplant: high response rate but frequent GVHD

“…Prior case reports and a case series with varying allograft donor sources, histories of GVHD, immunosuppression at time of anti-PD-1 administration, and dosing schedules (including starting at lower doses of anti-PD-1) report no cases of treatment-refractory GVHD when treated with anti-PD-1 mAbs after allograft. [20][21][22][23][24][27][28][29]45 In a French cohort, treatment-emergent aGVHD occurred in 6 patients (30%) after anti-PD-1 treatment, including 2 deaths attributed to GVHD, although GVHD only occurred in patients with a history of GVHD. 30 In our study, the majority of treatment-emergent GVHD occurred in patients with a prior history of GVHD; however, we observed treatment-emergent GVHD in 5 patients without a prior…”

“…19 Less is known about the safety and efficacy of anti-PD-1 mAbs when administered after allo-HCT. To date, most case reports [20][21][22][23][24][25][26][27][28] and 2 case series 29,30 suggest it can be given safely and is effective. However, due to concerns about small numbers of patients and the possibility of reporting bias, we conducted a large multicenter retrospective study to better characterize the risks and benefits of PD-1 blockade after allo-HCT.…”

Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil

“…However, a recent retrospective analysis of 11 patients who underwent allogeneic allogenic hematopoietic stem cell transplantation with PtCy GVHD prophylaxis after treatment with a checkpoint inhibitor demonstrated low rates of both aGVHD and cGVHD. 44 Based on these results and the favorable anecdotal experience using this strategy at our centers, we consider transplantation using a bone marrow graft followed by a PtCy-based GVHD prophylactic regimen (eg, PtCy/tacrolimus/mycophenolate mofetil) for patients with previous exposure to immune checkpoint agents. We also use ursodiol for VOD prophylaxis in all patients.…”

“…Table 1 highlights the baseline patient characteristics and frequency of teGVHD from the 2 largest retrospective [1][2][3][4]57 In a separate retrospective series, Schoch et al reported no evidence of teGVHD in 7 patients treated with anti-PD-1 mAb's after allo-HCT. 44 Donor source varied but all 7 patients received PtCy. In the US retrospective series, there were 5 patients who received PtCy (4 haploidentical and 1 MUD); 1 patient (MUD) developed severe teGVHD 14 days after anti-PD-1.…”