Allogeneic hematopoietic stem cell transplantation (alloHCT) remains a curative approach for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) owing to the antileukemic properties of T cells, which leads to a graft-versus-leukemia effect. However, up to 50% of AML/MDS patients relapse after alloHCT,1 and therapy options for these patients remain limited. Among patients with relapsed AML, the 1-year postrelapse overall survival (OS) rate is less than 20% despite subsequent therapies.2 Thus, novel therapeutic strategies for these patients are urgently needed.

AML relapse after alloHCT is mediated through several unique mechanisms. Toffalori et al demonstrated that disease relapse may occur after alloHCT owing to the ability of the AML cells to escape immune control by expressing inhibitory immune checkpoint proteins B7-1/B7-2 and programmed death ligand 1/2 (PD-L1/PD-L2), which impair antitumor immunity by inducing T cell exhaustion and downregulating the activity of cytotoxic T cells that are mediating the graft-versus-leukemia effect.3–5 Given these findings, immune checkpoint inhibitors (ICIs) are now being tested in patients who have undergone alloHCT to reverse the immune dysfunction that is driving the AML to relapse, and to augment the graft-versus-leukemia effect. However, a major concern with using ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD).

A phase I/Ib study highlighted the efficacy of cytotoxic T lymphocyte-associated antigen 4 receptor (CTLA-4) blockade following alloHCT for patients with relapsed AML.6 In that study, 28 patients with relapsed hematological malignancies after alloHCT (12 patients with AML, including 3patients with leukemia cutis) were treated with single-agent ipilimumab. Of the 22 patients who received the higher ipilimumab dose (10 mg/kg), complete responses were reported in five patients (23%), including three patients with leukemia cutis and two patients with AML. In the remaining six patients, who received the lower dose of ipilimumab (3 mg/kg), no clinical responses were reported. Immune-related adverse events (irAEs) of grades 2–4 were reported in six patients (21%), including one death, and acute GVHD (aGVHD) and chronic GVHD (cGVHD) following ipilimumab administration was reported in four patients (14%).

Programmed cell death protein 1 (PD-1) receptor blockade after alloHCT has also been tested as a therapeutic strategy. In a phase I clinical trial of nivolumab in 28 patients with relapsed hematological malignancies after alloHCT (11 patients with AML), two of the six patients who were treated with nivolumab at a dose of 1 mg/kg developed irAEs. Moreover, among patients who received nivolumab at a dose of 0.5 mg/kg, four patients had dose-limiting toxicity, including two cases of grade 3 aGVHD resulting in death. 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,8–10 including after haploidentical alloHCT.11 12 PTCy use after alloHCT is associated with a lower incidence of grades 3–4 aGVHD and cGVHD, and some studies have even reported lower rates of GVHD in patients who underwent haploidentical alloHCT with PTCy compared with those who underwent alloHCT from matched related or matched unrelated donors using GVHD prophylaxis that omitted PTCy.9 13–16 We, therefore, hypothesize that using PTCy for GVHD prophylaxis will reduce the incidence of GVHD in patients who receive ICI therapy for AML/MDS relapse after alloHCT.

In this retrospective analysis, we describe our experience with ICI therapy after alloHCT in AML/MDS patients. We analyzed the association between GVHD prophylaxis and frequency of GVHD in this cohort of patients, and we observed reduced incidence of GVHD in patients who received PTCy for GVHD prophylaxis.

The use of ICIs in patients with hematological malignancies is increasing. However, ICI use after alloHCT has been hampered owing to the fear of eliciting GVHD, which is unique to alloHCT recipients.20–24 A variety of pretransplantation and post-transplantation factors can play a crucial role in exacerbating GVHD, including the dose of ICIs administered, allograft donor source, conditioning intensity, prior history of GVHD and GVHD prophylaxis. We performed a retrospective analysis to report our experience with ICI use after alloHCT in AML/MDS patients treated at our institution, with a focus on the impact of PTCy GVHD prophylaxis. Our analysis shows that the use of ICIs for AML/MDS relapse after alloHCT is a safe and feasible option, and that PTCy appears to decrease the frequency of aGVHD in this patient population.

Activation of graft immunity after alloHCT through ICIs carries a risk of triggering GVHD. A few phases I clinical trials have investigated the efficacy and safety of ICIs in patients with relapsed disease after alloHCT.6 7 25 26 In a phase I/Ib trial of 28 patients with relapsed hematological malignancies, including AML/MDS (n=14), Hodgkin lymphoma (n=7), non-Hodgkin’s lymphoma (n=4), multiple myeloma (n=1), myeloproliferative neoplasm (n=1) and acute lymphoblastic leukemia (n=1), who were treated with ipilimumab (3 mg/kg or 10 mg/kg) after alloHCT, four patients (14%) developed GVHD, including three with cGVHD and one with aGVHD.6 More recently, Davids et al reported the first prospective clinical trial of nivolumab (0.5 mg/kg or 1 mg/kg) for relapsed hematological malignancies in 28 patients, including those with AML/MDS (n=17), Hodgkin lymphoma (n=5), non-Hodgkin's lymphoma (n=3), chronic lymphocytic leukemia (n=1), myeloproliferative disorder (n=1) and leukemia of unspecified type (n=1), after alloHCT. 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. Our results showed that early initiation of ICI therapy after alloHCT was safe, particularly in patients who had received PTCy GVHD prophylaxis. In our cohort, patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (5.1 months compared with 26.6 months). Despite early initiation of ICI therapy in our cohort, patients who received PTCy had a lower incidence of GVHD than did patients who did not receive PTCy. Because of the small number of patients and the retrospective nature of our study, prospective studies are needed to definitively confirm this observation.

In our entire cohort, 19% of patients developed aGVHD following ICI therapy initiation, and no deaths were attributed to GVHD. Not only was the rate of aGVHD in our cohort of patients lower than what has been reported in previous studies, but also none of the patients in our cohort developed cGVHD. Although the pathology reports confirmed GVHD, we recognize that it may be difficult to distinguish GVHD from some forms irAEs. However, based on clinical data and overall clinical assessment of the patients, in addition to pathology, we strongly believe that the reported events were more likely GVHD than irAEs. Two retrospective studies reported the outcomes of PD-1 inhibition in patients with Hodgkin lymphoma after alloHCT. In the first study, which included 20 patients, aGVHD occurred in six patients (30%), including two deaths due to aGVHD.28 In the second study, which included 31 patients, aGVHD occurred in 10 patients (32%), including four deaths attributed to aGVHD.29 Consistent with our data, in the latter study, Haverkos et al made the observation that of the five patients who received PTCy GVHD prophylaxis, none developed aGVHD following initiation of nivolumab.29 More recently, Ijaz et al analyzed the use of ICIs in patients with relapsed hematological malignancies after alloHCT in a comprehensive literature review of 24 articles (13 case reports and 11 research articles).30 Of the 176 patients who received ICIs after alloHCT, 44 patients (25%) developed GVHD; 25 patients (14%) developed aGVHD and 19 patients (11%) developed cGVHD. Furthermore, the investigators reported 10 GVHD-related deaths. The authors did not report any association between GVHD prophylaxis regimen and GVHD.

Use of PTCy after HLA‐matched alloHCT has been shown to be safe and efficacious,16 and is now a standard for GVHD prophylaxis at our institution in patients deemed to be medically fit to receive PTCy. At the time of this study, patients received PTCy based on the clinical judgment of their primary stem cell transplant physician, considering their HCT-CI score, performance status and the risk of GVHD. PTCy was first used for GVHD prophylaxis in recipients of haploidentical alloHCT11 12 31 and has since been adopted in patients receiving grafts from matched related and matched unrelated donors.32–34 Recently, a randomized phase II clinical trial compared the efficacy of three GVHD prophylaxis regimens, including PTCy, in patients who had undergone alloHCT with matched related and matched unrelated donors.31 Of the three regimens compared, only the PTCy-containing regimen attenuated the risk of severe aGVHD and cGVHD. There are multiple studies that showed that PTCy does not increase relapse rate in the matched or mismatched setting, For instance, our group had previously compared PTCy to traditional GVHD prophylaxis in 7/8 mismatched unrelated donor donors and reported encouraging results in patients receiving PTCy, showing no difference in non-relapse mortality compared with patients who did not receive PTCy.35

Efficacy of PTCy in reducing GVHD was also shown in patients who received ICI therapy prior to alloHCT. In a retrospective analysis of 43 patients with AML/MDS who were treated at our institution with ICIs prior to alloHCT, Oran et al reported that patients who received PTCy had a lower incidence of grades 3–4 aGVHD than did patients who did not receive PTCy (5% compared with 22%).36 Similar findings also were reported by Schoch et al, who reported no grades 3–4 aGVHD with the use of PTCy in a series of 14 patients who received ICI therapy prior to alloHCT.37 Our data corroborate these reports and support the use of PTCy to reduce GVHD after ICI therapy. Although we recognize that the conditioning regimens used in lymphoid malignancies prior to alloHCT differ from the conditioning regimens used in myeloid malignancies, our study may be applicable primarily to patients with AML/MDS who receive myeloablative or non-myeloablative conditionings that incorporates PTCy as GVHD prophylaxis.

Several mechanisms may be mediating the decrease in aGVHD incidence following PTCy. In patients who undergo haploidentical alloHCT, a preferential increase in the frequency of regulatory T cells was reported in those who received PTCy.38 This was also validated in murine models, in which PTCy successfully restored T cell homeostasis and reduced GVHD induced by PD1^−/− donor T cells, rescuing PD-1^−/− regulatory T cells from apoptosis.39 The use of PTCy for GVHD prophylaxis therefore may be abrogating ICI-induced T cell-mediated GVHD by selectively abolishing alloreactive T cells, stimulating regulatory T cells and promoting long-term tolerance.39–42 Therefore, PTCy GVHD prophylaxis may increase the safety of using ICI therapy in patients who experience relapse after alloHCT.

Even with the limitations of the retrospective nature of our analysis, ours is the first study to investigate the effects of PTCy on outcomes of AML/MDS patients who receive ICI therapy for disease relapse after alloHCT. Our data suggest that irAEs associated with the use of ICI therapy after alloHCT may be lessened in patients who receive PTCy as GVHD prophylaxis. Given the small number of patients in our study, further prospective investigation with a larger number of patients is needed to determine the magnitude of the effect of PTCy on reducing aGVHD following ICI therapy.