Conditioning regimens and transplant outcomes in MF

Allogeneic hematopoietic cell transplantation (allo-HCT) is the prevailing curative treatment for myelofibrosis (MF).¹ The MPN Hub has previously reported on factors influencing allo-HCT outcomes. However, optimal conditioning regimens and comparative outcomes with reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC) are not well known.¹

To address this knowledge gap, Murthy et al.¹ recently published a study in Haematologica that evaluated the outcomes of allo-HCT for MF based on the choice of RIC or MAC conditioning regimens.¹ Here we summarize key findings from the study.

Study design

• Patients aged ≥18 years with MF who underwent allo-HCT between 2008 and 2019 from the Center for International Blood and Marrow Transplant Research database were included.
• The cohort was selected based on the most common conditioning regimens used in RIC (fludarabine/busulfan vs fludarabine/melphalan) and MAC (fludarabine/busulfan vs busulfan/cyclophosphamide).
• The donor groups included:
  • matched related donors;
  • 8/8 (HLA-A, -B, -C, and -DRB1) matched unrelated donors; and
  • 7/8 matched unrelated donors.
• The key exclusion criteria included allo-HCT from a haploidentical donor, syngeneic donor, cord blood, and ex vivo T-cell depleted or CD34 selected grafts.

Outcomes were compared separately in the RIC and MAC cohorts based on conditioning regimen, with multivariate Cox regression analysis used to evaluate factors that could influence outcomes.

The key objectives were to compare the overall survival (OS), disease-free survival, non-relapse mortality, relapse, incidence of Grade 2–3 and 3–4 acute graft-versus-host disease (GvHD), chronic GvHD, and GvHD-free relapse-free survival (GRFS) based on the choice of the conditioning regimen used with RIC or MAC.

Results

Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/busulfan, n = 166; fludarabine/melphalan, n = 327) and 379 using MAC (fludarabine/busulfan, n = 247; busulfan/cyclophosphamide, n = 132). The key baseline characteristics are presented in Table 1.

Table 1. Key baseline characteristics*

ATG, antithymocyte globulin; Bu, busulfan; Cy, cyclophosphamide; DIPSS, dynamic international prognostic scoring system; ET, essential thrombocytosis; Flu, fludarabine; HCT, hematopoietic cell transplantation; Mel, melphalan; PV, polycythemia vera. *Adapted from Murthy, et al.1
Characteristic, % (unless otherwise stated)	RIC			MAC
	Flu/Bu (n = 166)	Flu/Mel (n = 327)	p value	Flu/Bu (n = 247)	Bu/Cy (n = 132)	p value
Median age (range), years	63 (44–75)	63 (38–78)	0.88	60 (27–74)	55 (24–67)	<0.01
Disease type			0.22			0.85
Primary	80	74		77	76
Post ET	8	14		8	10
Post PV	12	12		15	14
Median time from diagnosis to HCT (range), months	22 (3–393)	37 (3–594)	0.02	25 (2–490)	38 (3–377)	0.41
DIPSS score			0.07			0.03
Low/intermediate-1	43	33		54	61
Intermediate-2/high	42	51		38	26
Missing	16	16		8	14
Donor type			0.75			0.15
HLA-identical sibling	29	29		32	40
8/8-matched               unrelated	64	63		57	47
7/8 matched               unrelated	7	9		11	13
ATG/alemtuzumab use			<0.01			<0.01
No	48	75		55	95
Yes	52	25		45	5
Graft type			0.84			<0.01
Bone marrow	4	4		4	12
Peripheral blood	96	96		96	88
Pre-transplant ruxolitinib			0.03			<0.01
No	51	38		41	57
Yes	49	61		59	43
Missing	0	1		0	0

In the RIC setting, fludarabine/melphalan was associated with significantly poorer outcomes compared with fludarabine/busulfan (Figure 1), including the following:

• Significantly worse 2-year adjusted OS (54.4% vs 60.9%)
• Higher risk of early non-relapse mortality (17.4% vs 4.3%)
• Higher risk of Grade 2–4 (40% vs 35.3%) and Grade 3–4 (21.8% vs 12.1%) acute GvHD
• Worse rate of 30-day neutrophil engraftment (92.4% vs 95.1%)
• Lower 100-day platelet engraftment (73.9% vs 84.4%)

In the MAC setting, busulfan/cyclophosphamide was associated with significantly higher risk of Grade 2–4 and 3–4 acute GvHD and inferior GRFS compared with fludarabine/busulfan (Figure 1).

Disease-free survival and risk of relapse were not significantly different based on the conditioning regimen used in both settings (Figure 1).

Bu, busulfan; CI, confidence interval; Cy, cyclophosphamide; Flu, fludarabine; GRFS, GvHD-free relapse-free survival; GvHD, graft-versus-host disease; Mel, melphalan; NRM, non-relapse mortality.
*Adapted from Murthy, et al.^1
†≤2 months.
^‡≤6 months.

Conclusion

The study suggested that fludarabine/busulfan conditioning in allo-HCT for MF was associated with superior OS, lower early non-relapse mortality and lower acute GvHD with RIC, and lower acute GvHD and superior GRFS with MAC. The results provide directions for tailoring the conditioning strategies to improve allo-HCT outcomes in MF. Further studies are warranted to validate these results and identify the ideal conditioning regimen in MF.