A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation

Abstract

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.

Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

“…Eleven patients (39%) developed GVHD; two patients developed aGVHD (7%), eight patients (29%) developed cGVHD and one patient (4%) developed both. 7 Patients enrolled in that study had undergone alloHCT ≥6 months prior to study enrolment to minimize GVHD risk, which is believed to be increased with early initiation of ICI therapy after alloHCT. 27 However, because many patients with AML/MDS relapse within a few months of alloHCT and require prompt initiation of salvage therapy, it is often not feasible to wait for an extended period to initiate ICI therapy after alloHCT.…”

“…Of the 19 evaluable patients who received nivolumab at a dose of 0.5 mg/kg, the response rate was 16% (one patient with AML achieved partial response). 7 Irrespective of the use of ICIs, several pretransplantation and post-transplantation factors are known to play a crucial role in inciting GVHD, including the type of GVHD prophylaxis that is used. Several reports have established the efficacy of post-transplantation cyclophosphamide (PTCy) in GVHD prophylaxis to selectively deplete alloreactive T cells after T cell-replete alloHCT, [8][9][10] including after haploidentical alloHCT.…”

“…Of the 19 evaluable patients who received nivolumab at a dose of 0.5 mg/kg, the response rate was 16% (one patient with AML achieved partial response). 7 …”

Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

“…58,66 However, as Davids and colleagues demonstrated, increased risk of immune-related adverse events and fatal graft versus host disease is a serious concern in this setting and biomarkerbased approaches may help better select appropriate patients. 64 The effect of PD-1/PD-L1 inhibition is also thought to synergize with CAR-T therapy by decreasing T-cell exhaustion. However data are limited to case series which report significant off-target immune effects.…”

Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation

“…GVHD occurred in only 14%. The PD-1 inhibitor nivolumab has also been studied in the post–transplant setting, though fatal immune-related toxicities have limited the potential of this strategy [ 129 ]. Notably, patients treated with checkpoint inhibitors prior to HCT may also experience post-HCT immune effects including higher rates of GVHD [ 130 ].…”