aGvHD

Post-transplant cyclophosphamide for the management of GvHD in patients receiving immune checkpoint inhibitors for AML/MDS

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

Study design

Aim: to 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

Primary endpoints: overall survival (OS), progression free survival (PFS), disease progression, nonrecurrence mortality (NRM), and aGVHD

Patients characteristics

  • Between April 2015 and December 2017, 188 patients with AML/MDS had received CPI therapy at The University of Texas MD Anderson Cancer Center (MDACC), Houston, US. Of these, 43 underwent subsequent HSCT and were investigated in this study (Table 1)

Table 1. CPI treatment prior to HSCT3

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

CPI, checkpoint inhibitor; 5-AC, 5-azacytidine

*Chemotherapy regimens included cytarabine and idarubicin

Previous response to CPI therapy

  • Responses to CPI therapy were achieved in 36 (84%) of the 43 patients investigated, with 24 patients achieving CR and six patients CR with incomplete hematologic recovery
  • Patient characteristics were balanced between GvHD prophylaxis groups for age (median age, 57 years), number of CPI doses prior to transplantation (median number, 4), conditioning intensity (~50:50, myloblative:reduced intensity), and HSC comorbidity index (median HSC CI, 3)
  • Other relevant patient characteristics according to GvHD prophylaxis (± PTCy) are illustrated in Table 2

Table 2. Baseline patient characteristics by GvHD prophylaxis3

 

Patients, %

 

 

p

All patients

No PTCy

PTCy

Characteristics

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

AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; PBSCs, peripheral blood stem cells; PTCy, post-transplant cyclophosphamide

 Results

Incidence of aGvHD

  • PTCy prophylaxis, the number of CPI treatments prior to HSCT, stem cell source, and donor type all had an impact on the numerical frequency of Grade 3–4 aGvHD (Table 3)
  • The time between CPI treatment and HSCT had no effect on aGvHD establishment in any treatment group
  • Patients with more than four CPI treatments had a higher incidence of aGvHD if they were not treated with PTCy

Table 3. Incidence of Grade 34 aGvHD in patients receiving HSCT3

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

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

Patient outcomes

  • 6-month and 1-year OS, PFS, and NRM rates were significantly superior in patients receiving prophylaxis with PTCy vs without PTCy (Table 4)
  • Multivariate regression analyses adjusted age, disease type, disease status, cytogenetic risk classification, stem cell source, donor type, and conditioning intensity, and HSC CI confirmed the improved 1-year PFS with the use of PTCy compared with no PTCy
  • The cause of death at one year was dependent on prophylaxis (Table 5)

Table 4. Patient survival outcomes by GvHD prophylaxis3

 

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)

CI, confidence ratio; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PTCy, post-transplant cyclophosphamide; TRM, transplant-related mortality

Table 5. Cause of death at one year3

 

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

-

aGvHD, acute graft-versus-host disease

Matched case control study

  • A case control matching analysis was conducted with a matching ratio 2:1 (controls:cases) and the following matching criteria:
    • Age at HSCT
    • Stem cell source
    • Donor type
    • Conditioning intensity
    • GvHD prophylaxis
    • HSC CI
  • Eighty-two patients who had received HSCT without previous CPI treatment were suitable for matching and were compared to 41 patients who had previously received CPI therapy
  • No significant difference was detected between both cohorts in the incidence of Day 100 Grade 24 aGvHD, 1-year PFS, and 1-year OS
  • In contrast, the risk of Grade 3­4 aGVHD by Day 100 was higher for those patients who had prior CPI treatment (HR, 5.2; 95% CI, 0.9–27; p = 0.05) but was limited to patients with prior CPI who had not received PTCy prophylaxis

Conclusion

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 34 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.

References
  1. 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

  2. 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

  3. Betül Oran et al. Posttransplantation cyclophosphamide improves transplantation outcomes in patients with AML/MDS who are treated with checkpoint inhibitors. Cancer2020 Mar 3. DOI: 10.1002/cncr.32796

  4. Merryman RW et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood2017 Mar 9; 129(10):1380–1388. DOI: 10.1182/blood-2016-09-738385

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