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Haploidentical donor blood/marrow transplantation with PTCy for chronic phase myelofibrosis
By Claire Baker
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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 |
|
|
Time from diagnosis to BMT, months, median (range) |
20.5 (1.8–143.1) |
|
Year of BMT |
|
|
Disease |
|
|
Fibrosis grade at diagnosis |
|
|
DIPSS plus at BMT |
|
|
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 |
|
|
Donor – recipient gender |
|
|
Donor – recipient CMV status |
|
|
GvHD prophylaxis |
|
|
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. |
|
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 |
|
|
|
|
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. |
|
||
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† |
1.88 |
1.08–3.26 |
0.025 |
|
Relapse |
||||
|
Higher risk |
Spleen size at BMT (≥22 vs <22 cm) |
4.57 |
1.31–16.0 |
0.017 |
|
Lower risk |
Increased age at BMT |
0.36 |
0.16–0.81 |
0.014 |
|
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. |
||||
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 |
2.30 |
1.22–4.34 |
0.010 |
|
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. |
||||
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.
- 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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