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

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*

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.
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

Table 2. BMT outcomes*

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
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)

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*

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.
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

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*

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
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

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.