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Homeostatic T-cell activation involves a network of stimulatory and inhibitory responses. Immune checkpoint protein interaction helps to avoid out-of-control immune responses and autoimmune conditions. Immune checkpoint proteins include programmed death receptor 1 (PD-1), its corresponding ligand (PD-L1), and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).1,2 Dysregulation of immune checkpoint proteins has been observed in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), resulting in a number of clinical trials investigating the efficacy of immune checkpoint inhibitors (CPI).3 However, observations in patients with non-Hodgkin lymphoma (NHL) have suggested an increased incidence of severe acute graft-versus-host disease (aGvHD) following allogeneic hematopoietic stem cell transplant (allo-HSCT) in patients previously treated with CPIs.4
Betül Oran and colleagues recently conducted a retrospective study of patients with AML and/or MDS that had been treated with CPI(s) prior to HSCT. The study pays particular attention to a subset of patients receiving post-transplant cyclophosphamide (PTCy), and the impact of GvHD prophylaxis on patient outcome was evaluated. The data was recently published in Cancer, and we hereby present a summary.3
Retrospectively investigate transplantation outcomes after previous CPI treatment and correlate it with different GVHD prophylaxis (PTCy vs no PTCy) in patients with AML/MDS. Patient data from four investigational clinical trials (NCT02530463, NCT02397720, NCT02464657, and NCT02532231) were evaluated
Overall survival (OS), progression free survival (PFS), disease progression, nonrecurrence mortality (NRM), and aGVHD.
Table 1. CPI treatment prior to HSCT3
CPI, checkpoint inhibitor; 5-AC, 5-azacytidine |
|
CPI |
Patients (N = 43), n |
---|---|
Nivolumab Single agent + 5-AC + chemotherapy* |
34 2 11 19 |
Ipilimumab Single agent + 5-AC |
9 3 6 |
Nivolumab + ipilimumab + 5-AC |
2 |
Table 2. Baseline patient characteristics by GvHD prophylaxis3
AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; PBSCs, peripheral blood stem cells; PTCy, post-transplant cyclophosphamide |
||||
Characteristics |
Patients, % |
p |
||
---|---|---|---|---|
All patients |
No PTCy |
PTCy |
||
N = 43 |
N = 21 |
N = 22 |
||
Disease type AML MDS |
67 33 |
81 19 |
55 45 |
0.1 |
Hematopoietic stem cell source PBSCs Bone marrow Cord blood |
53 40 7 |
57 29 14 |
50 50 0 |
0.1 |
Donor type Matched related donor Matched unrelated donor Haploidentical donor Cord blood donor |
16 58 19 7 |
14 71 0 14 |
18 45 36 0 |
0.01 |
Table 3. Incidence of Grade 3–4 aGvHD in patients receiving HSCT3
aGvHD, acute graft-versus-host disease; CI, confidence interval; CPI, checkpoint inhibitor; GvHD, graft-versus-host disease; PBSCs, peripheral blood stem cells; PTCy, post-transplant cyclophosphamide |
||
Treatment |
Patients developing Grade 3–4 aGvHD, % |
p |
---|---|---|
GvHD prophylaxis PTCy No PTCy |
5 22 |
0.2
|
Hematopoietic stem cell source (95% CI) PBSCs Bone marrow |
20 (8–48) 6 (1–42) |
0.3 |
Matched unrelated donor (n = 25) PBSCs · + PTCy · − PTCy Bone marrow · + PTCy · − PTCy |
0 44
0 0 |
0.048
|
> 4 CPI treatments · + PTCy · − PTCy |
12 43 |
0.01 |
Table 4. Patient survival outcomes by GvHD prophylaxis3
CI, confidence ratio; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PTCy, post-transplant cyclophosphamide; TRM, transplant-related mortality |
|||||
|
Patients |
|
|||
---|---|---|---|---|---|
All patients |
No PTCy |
PTCy |
|||
Outcome, % (95% CI) |
N = 43 |
n = 21 |
n = 22 |
HR |
p |
6-month OS |
71 (53–83) |
60 (36–78) |
81 (51–94) |
0.3 (0.1–1.3) |
0.1 |
1-year OS |
54 (34–70) |
33 (13–55) |
81 (51–94) |
0.2 (0.1–0.8) |
0.02 |
6-month PFS |
66 (49–79) |
50 (27–69) |
81 (51–94) |
0.2 (0.1–0.9) |
0.03 |
1-year PFS |
39 (21–57) |
25 (8–46) |
56 (20–81) |
0.3 (0.1–0.8) |
0.02 |
6-month TRM |
19 (9–36) |
25 (12–53) |
14 (4–51) |
0.4 (0.1–1.9) |
0.2 |
1-year TRM |
23 (12–43) |
31 (16–61) |
14 (5–51) |
0.3 (0.1–1.6) |
0.2 |
Cumulative incidences of disease recurrence |
13 (6–29) |
— |
— |
— |
— |
Table 5. Cause of death at one year3
aGvHD, acute graft-versus-host disease |
|||
|
Patients |
||
---|---|---|---|
All patients |
No PTCy |
PTCy |
|
|
N = 43 |
n = 21 |
n = 22 |
Cause of death at one year, n |
15 |
12 |
3 |
Disease recurrence and/or progression |
7 |
6 |
1 |
aGvHD |
3 |
2 |
1 |
Infections |
4 |
3 |
1 |
Graft failure |
1 |
1 |
- |
The findings from this study are consistent with those previously published — highlighting the impact of CPIs on aGvHD establishment. Immune checkpoint blockade prior to HSCT increased the incidence of Grade 3–4 aGvHD, in addition to the impact of stem cell source and donor type in patients with AML/MDS. GvHD prophylaxis treatment with PTCy appears to reduce the incidence of CPI induced aGvHD establishment considerably. A more substantial study cohort is required to determine the significance of the findings, but the results from this study ought to be considered should CPIs emerge into the routine treatment programs of patients with AML/MDS.
Parry RV et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol.2005 Nov; 25(21): 9543–53 DOI: 1128/MCB.25.21.9543-9553.2005
Keir ME et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol.2008; 26:677–704. DOI: 1146/annurev.immunol.26.021607.090331
Betül Oran et al. Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors. Cancer. 2020 Mar 3. DOI: 10.1002/cncr.32796
Merryman RW et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017 Mar 9; 129(10):1380–1388. DOI: 10.1182/blood-2016-09-738385
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