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Haploidentical donor blood/marrow transplantation with PTCy for chronic phase myelofibrosis

Jan 13, 2022
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Despite recent advances in targeted agents for patients with myelofibrosis (MF), blood or marrow transplant represent the only chance of cure. Haploidentical donor blood or marrow transplant (haplo-BMT) offers a solution to the lack of suitable matched sibling donors observed in older patient populations. Haplo-BMT has been associated with increased incidences of graft failure and graft-versus-host disease (GvHD); however, the introduction of post-transplantation cyclophosphamide (PTCy) has helped to reduce GvHD occurrence.

A previous European Society for Blood and Marrow Transplantation (EBMT) analysis highlighted the feasibility of allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with PTCy in patients with MF. 2-year overall survival (OS) and progression-free survival (PFS) rates were 56% and 43%, respectively. The analysis reported a relapse incidence of 19%, graft failure of 9%, and NRM of 38% at 2 years. Despite these findings, there remains a lack of available literature around the value of haplo-BMT plus PTCy for patients with MF. A recent publication by Siddharth Kunte and colleagues1 reported the clinical outcomes of patients in North America who have received haplo-BMT with PTCy for the treatment of chronic phase MF.

For some background information on the role of allo-HSCT in patients with MF, including information on risk stratification, and considerations around several aspects of transplantation, click here.

Study design1

Retrospective analysis of patients aged ≥18 years who received haplo-BMT plus PTCy for chronic phase MF across 13 centers in North America, between January 1, 2000, and December 31, 2019. The analysis included patients with primary or post-essential thrombocythemia (ET) or polycythemia vera (PV) MF who had received haplo-BMT.

Results1

  • Sixty-nine patients were eligible for this analysis; baseline patient characteristics are presented in Table 1.
  • At a median follow-up of 23.1 months, 71% of patients remained alive; BMT outcomes are presented in Table 2.

Table 1. Baseline patient characteristics*

Characteristic

% (unless otherwise stated)

Age at diagnosis, years, median (range)

59 (33–71)

Age at BMT, years, median (range)

63 (41–74)

Gender
              M
              F


64
36

Time from diagnosis to BMT, months, median (range)

20.5 (1.8–143.1)

Year of BMT
              2010–2015
              2016–2019


20
80

Disease
              Primary MF
              Post-ET MF
              Post-PV MF


51
28
22

Fibrosis grade at diagnosis
              MF 1
              MF 2
              MF 3


12
46
39

DIPSS plus at BMT
              Low
              Intermediate-1
              Intermediate-2
              Hight


3
3
69
25

High-risk cytogenetics (N = 66)

15

Prior splenectomy (N = 67)

7

Spleen size at BMT (N = 62), cm, median (range)

18.0 (9.4–28.1)

JAK inhibitor use prior to BMT (N = 68)

87

HCT-CI ≥3 (N = 64)

44

Graft source
              Peripheral blood
              Bone marrow


86
14

Donor – recipient gender
              F–F
              F–M
              M–F
              M–M


17
17
19
46

Donor – recipient CMV status
              D+/R+
              D+/R−
              D−/R+
              D−/R−


42
9
22
28

GvHD prophylaxis
              CNI/MMF/PTCy
              CSA/ATG/PTCy
              mTORi/MMF/PTCy


74
14
12

ATG, antithymocyte globulin; BMT, blood or marrow transplantation; cGy, centigrays; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CSA, cyclosporine A; DIPSS, Dynamic International Prognostic Scoring System; D/R, donor/recipient; ET, essential thrombocythemia; F, female; GvHD, graft-versus-host disease; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; HMA, hypomethylating agent; JAK, Janus kinase; M, male; MF, myelofibrosis; MMF mycophenolate mofetil; mTORi, mTOR inhibitor; PTCy, posttransplantation cyclophosphamide; PV, polycythemia vera.
*Data from Kunte et al.1
Defined as a complex karyotype or abnormalities including +8, −7/7q−, i(17q), −5/5q−, 12p, inv(3) or 11q23 rearrangement.

Table 2. BMT outcomes*

Outcome, % (95% CI)

1 year post-BMT

3 years post-BMT

OS

74 (61–83)

72 (59–81)

RFS

72 (60–82)

44 (29–59)

GRFS

55 (42–66)

30 (17–43)

NRM

21 (12–32)

23 (14–34)

Relapse

5 (1–12)

31 (17–47)

Outcome, % (95% CI)

3 months post-BMT

6 months post-BMT

 

Acute GvHD
              All grades
              Grades 3–4


36 (25–48)
10 (4–19)


48 (36–60)
13 (6–22)

 

Outcome, % (95% CI)

1 year post-BMT

2 years post-BMT

 

Chronic GvHD, all grades

22 (13–33)

29 (17–41)

 

Outcome, % (95% CI)

1 and 2 years post-BMT

 

Chronic GvHD, extensive grade

8 (3–16)

 

Outcome, median (range)

 

Days to neutrophil engraftment (N = 65)

20 (14–70)

 

Days to platelet engraftment (N = 56)

34 (15–224)

 

BMT, blood or marrow transplantation; CI, confidence interval; GRFS, GvHD-free relapse-free survival; GvHD, graft-versus-host disease; NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival.
*Data from Kunte et al.1

 

Clinical factors: Univariate analysis

  • Variables found to significantly influence outcomes to BMT following univariate analysis are presented in Table 3.

Table 3. Clinical factors significantly affecting haplo-BMT outcomes by univariate analysis*

Outcome

Variable

HR

95% CI

p value

OS

              Inferior

HCT-CI ≥3

3.97

1.51–10.4

0.005

              Improved

Male donor

0.42

0.17–1.00

0.05

RFS

              Inferior

HCT-CI ≥3

2.16

1.04–4.52

0.04

              Improved

Recipient CMV+

0.46

0.22–0.96

0.038

GRFS

              Improved

Recipient CMV+

0.52

0.28–0.97

0.039

NRM

              Higher risk

Increased age
HCT-CI ≥3

1.88
4.07

1.08–3.26
1.32–12.5

0.025
0.014

Relapse

              Higher risk

Spleen size at BMT (≥22 vs <22 cm)
Spleen size at BMT (≥22 + splenectomy vs <22 cm)
BM grafts

4.57
6.37

4.92

1.31–16.0
2.02–20.1

1.68–14.4

0.017
0.002

0.004

              Lower risk

Increased age at BMT
Later year at BMT
Recipient CMV+

0.36
0.73
0.32

0.16–0.81
0.61–0.87
0.11–0.94

0.014
<0.001
0.038

CI confidence interval; CMV, cytomegalovirus; GRFS, GvHD-free relapse-free survival; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival.
*Data from Kunte et al.1
per 10-year increase.
vs peripheral blood.

Clinical factors: Multivariate analysis

Relapse

  • Following correction for recipient age, year of BMT, recipient CMV serostatus, and graft source, bone marrow (BM) vs peripheral blood (PB), splenomegaly ≥22 cm or pre-BMT splenectomy was significantly associated with increased risk of relapse.
  • Following correction for recipient age, year of BMT, and recipient CMV serostatus, BM grafts were significantly associated with increased risk of relapse

Following correction for recipient age, year of BMT, and recipient CMV serostatus, BM grafts were significantly associated with increased risk of relapse OS, RFS, and NRM

  • Variables found to significantly influence additional outcomes to BMT following multivariate analysis are presented in Table 4.

Table 4. Clinical factors significantly affecting haplo-BMT outcomes by multivariate analysis*

Outcome

Variable

HR

95% CI

p value

OS

              Inferior

HCT-CI ≥3

6.71

2.35–19.2

<0.001

              Improved

Male donor

0.21

0.08–0.56

0.002

RFS

              Inferior

HCT-CI ≥3

2.36

1.12–4.99

0.024

              Improved

Recipient CMV+

0.46

0.22–0.97

0.041

NRM

              Higher risk

Increased age
HCT-CI ≥3

2.30
5.11

1.22–4.34
1.55–16.9

0.010
0.007

CI confidence interval; CMV, cytomegalovirus; GRFS, GvHD-free relapse-free survival; HCT-CI, Hematopoietic Cell Transplantation-specific Comorbidity Index; NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival.
*Data from Kunte et al.1

Conclusion

This study is thought to represent the most extensive retrospective analysis of patients with MF undergoing haplo-BMT plus PTCy in North America. The data suggest that this approach results in low graft failure and encouraging survival outcomes, and, when combined with reduced intensity or nonmyeloablative conditioning and PTCy, haplo-BMT is feasible and effective in patients with MF. The incidence of acute Grade 3–4 GvHD was 10% at 3 months and the incidence of extensive chronic GvHD was 8%. Several factors were associated with transplant outcomes in this setting, and a higher incidence of relapse was observed in patients with splenomegaly ≥22 cm and those who received BM grafts.

The author notes a number of study limitations in relation to the sample size, retrospective nature of the analysis, and lack of direct comparison with matched sibling or unrelated donors.

  1. Kunte S, Rybicki L, Viswabandya A, et al. Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: A multicenter study. 2021. DOI: 10.1038/s41375-021-01449-1

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