Haploidentical hematopoietic cell transplantation: A preferred approach for adult patients with ALL

There is limited evidence supporting the use of haploidentical hematopoietic cell transplantation (HCT) as an alternative to traditional matched sibling donor (MSD) and matched unrelated donor (MUD) allogeneic HCT for acute lymphoblastic leukemia (ALL). The existing retrospective, comparative studies have found no differences in the overall survival (OS) between haploidentical HCT and MSD, MUD, or mismatched MUD (MMUD) HCT, and there is a lack of data to establish a superior donor approach among haploidentical HCT with posttransplant cyclophosphamide (PTCy), 7/8 human leukocyte antigen-matched unrelated donor (7/8 HLA-matched-UD) HCT, and umbilical cord blood (UCB) HCT for adult patients with ALL.¹

Wieduwilt and colleagues recently published in Blood Advances, a retrospective study comparing outcomes between adult patients with ALL undergoing haploidentical HCT using PTCy versus MSD HCT, MUD HCT, 7/8-HLA-matched-UD HCT, or UCB HCT.¹ Here we summarize the key findings.

Study design

This was a retrospective, cohort study using patient data generated from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Eligible patients were aged >18 years, were in complete remission (CR) 1, 2, or 3+ undergoing their first allogeneic HCT from a haploidentical, HLA-matched sibling, 8/8 HLA-matched unrelated, 7/8 HLA-matched unrelated, or UCB donor.

• The primary outcome was OS after HCT between the donor-transplant cohorts: haploidentical HCT using PTCy, MSD HCT, MUD HCT, 7/8 HLA-matched-UD HCT, and UCB HCT.
  • OS was defined as the time from transplant to death from any cause with surviving patients censored when last reported alive.

Secondary outcomes included:

• Leukemia-free survival (LFS): Time to leukemia relapse or death from any cause
• Relapse: Cumulative incidence estimates with treatment-related mortality
• Nonrelapse mortality (NRM): Cumulative incidence estimates of death in CR with relapse
• Grade 2–4 and Grade 3–4 acute graft-versus-host disease (aGvHD) and chronic GvHD (cGvHD) rates.

Results

Baseline characteristics

A total of 4,201 patients were included in the five cohorts and the baseline characteristics were well balanced for age, sex, Karnofsky performance status, HCT-comorbidity index (HCT-CI), immunophenotype, cytogenetic risk, Philadelphia chromosome (Ph)/BCR-ABL1 status, disease status, minimal residual disease (MRD) status at transplantation, and recipient cytomegalovirus (CMV) serostatus (Table 1).

There were, however, some notable differences between the cohorts as summarized in Table 1. The haploidentical HCT cohort had the lowest percentage of non-Hispanic white patients, and included patients who were more likely to use reduced intensity conditioning (RIC) and bone marrow as graft source.

Table 1. Baseline characteristics*

CMV, cytomegalovirus; CNI, calcineurin inhibitor; CR, complete remission; F, female; HCT, hematopoietic cell transplant; HLA-matched-UD, human leukocyte antigen-matched unrelated donor; M, male; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MRD, minimal residual disease; MSD, matched sibling donor; MTX, methotrexate; MUD, matched unrelated donor; NA, not applicable; NMA, non-myeloablative; PTCy, posttransplant cyclophosphamide; RIC, reduced intensity conditioning; TBI, total body irradiation; UCB, umbilical cord blood. *Adapted from Wieduwilt et al.1 †Native American (n = 30), Pacific Islander (n = 20), Non-resident of the US (n = 291), not specified (n = 156), Hispanic – excluding white Hispanic (n = 213). ‡Not reported.
Characteristic, % (unless otherwise stated)	Donor/HCT cohort
	Haploidentical (n = 393)	MSD (n = 1,627)	MUD (n = 1,646)	7/8 HLA-matched-UD (n = 230)	UCB (n = 305)
Median donor age, range	35 (10–74)	41 (9–75)	28 (18–60)	31 (19–60)	NA‡
Race
Hispanic white	22	15	8	18	21
Non-Hispanic white	43	52	74	49	49
Black	15	5	3	8	9
Asian	6	7	4	4	7
Other/not specified†	14	22	10	20	14
Time from diagnosis to HCT (CR1-only)
0–5 months	48	65	59	38	44
6–11 months	43	30	37	54	48
≥12 months	9	6	5	8	8
Conditioning regimen
MAC, TBI-based	41	60	58	60	71
MAC, chemotherapy-based	16	20	19	22	4
RIC/NMA	42	19	23	17	25
Graft source
Bone marrow	41	14	19	29	—
Peripheral blood	59	86	81	71	—
GvHD prophylaxis
CNI + MTX ± others	0	68	71	70	2
CNI + MMF ± others	0	15	12	8	87
CNI + others	0	7	9	6	2
CNI alone	0	4	4	2	5
PTCy + CNI ± MMF	100	5	4	13	<1
Other prophylaxis	0	1	<1	<1	3
In vivo T-cell depletion
Antithymocyte globulin	1	5	34	50	13
Alemtuzumab	0	2	4	3	0
None	99	93	61	46	87

Overall and leukemia-free survival

In multivariate analysis, compared to haploidentical HCT:

• MSD HCT and MUD HCT had similar OS (p = 0.18 and p = 0.11, respectively) and LFS (p = 0.71 and p = 0.73, respectively)
• 7/8 HLA-matched-UD HCT showed an inferior OS (p = 0.01; Table 2).
• UCB HCT had inferior OS and LFS (p < 0.001 and p = 0.007, respectively) at 18 months but similar after 18 months (p = 0.19 and p = 0.08, respectively) (Table 2).
• MSD HCT showed inferior OS for the following factors: HCT in complete remission 2+ (CR2+) (p < 0.001), older age of 50–69 years (p < 0.001), female donor to male recipient (p = 0.002), Ph/BCR-ABL1-positive status (p = 0.003), and CMV-seronegative donor to CMV-seropositive recipient (p = 0.007).
• MUD HCT showed inferior OS for the following factors: CR2+ (p < 0.001), older age of 50–69 years (p < 0.001), Asian (p = 0.002), HCT-CI 3+ (p = 0.02), and Ph/BCR-ABL1-positive status (p = 0.02).
• 7/8 HLA-matched-UD HCT had inferior OS for CR2+ patients (p < 0.001).
• UCB HCT had inferior OS for CR2+ and MAC chemotherapy (p < 0.001, each).

Relapse and nonrelapse mortality

• NRM was significantly higher for MUD HCT (p = 0.02), 7/8 HLA-matched-UD HCT, and UCB HCT (p < 0.001, each) versus haploidentical HCT (Table 2).
• Myeloablative conditioning using total body irradiation significantly reduced the risk of relapse across all donor HCT cohorts.

GvHD

• Higher cumulative incidence of cGvHD was observed for MSD HCT versus haploidentical HCT (p < 0.001 for female/male donor/recipient sex match, and p < 0.003 for other donor/recipient sex match; Table 2).
• MUD HCT showed a higher cumulative incidence of Grade 2–4 aGvHD (p = 0.09) and cGvHD (p = 0.001) compared with haploidentical HCT (Table 2).
• Higher cumulative incidences of Grade 2–4 aGvHD (p = 0.04), Grade 3–4 aGvHD (p = 0.003), and cGvHD (p < 0.001) were observed for 7/8 HLA-matched-UD versus haploidentical HCT (Table 2).
• Higher cumulative incidences of Grade 2–4 and Grade 3–4 aGvHD (p < 0.001, each) were observed for UCB HCT versus haploidentical HCT (Table 2).

Table 2. Multivariate analysis for outcomes*

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; CI, confidence interval; D, donor; F, female; HCT, hematopoietic cell transplantation; HR, hazard ratio; LFS, leukemia-free survival; M, male; MSD, matched sibling donor; MUD, matched unrelated donor; NRM, nonrelapse mortality; OS, overall survival; R, recipient; UCB, umbilical cord blood. *Adapted from Wieduwilt et al.1 †Values in bold are statistically significant.
Outcome	HR (95% CI), p value†
	MSD HCT vs Haploidentical HCT	MUD HCT vs Haploidentical HCT	7/8 HLA-matched-UD HCT vs Haploidentical HCT	UCB HCT vs Haploidentical HCT
OS	1.13 (0.94–1.36), 0.18	1.17 (0.96–1.41), 0.11	1.38 (1.08–1.78), 0.01	—
≤18 months	—	—	—	1.93 (1.45–2.56), < 0.001
>18 months	—	—	—	0.68 (0.38–1.21), 0.19
LFS	1.03 (0.88–1.22) 0.71	1.03 (0.87–1.22) 0.73	1.21 (0.95–1.54), 0.12	—
≤18 months	—	—	—	1.40 (1.09–1.79), 0.007
>18 months	—	—	—	0.58 (0.31–1.07), 0.08
NRM	1.06 (0.81–1.41), 0.66	1.42 (1.07–1.89), 0.02	2.13 (1.50–3.01), < 0.001	2.08 (1.45–2.99), < 0.001
Relapse	0.99 (0.81–1.21), 0.93	0.83 (0.67–1.03), 0.09	0.81 (0.57–1.13), 0.22	0.83 (0.60–1.13), 0.23
aGvHD Grade 2–4	0.92 (0.77–1.11), 0.40	1.17 (0.98–1.41), 0.09	1.33 (1.02–1.73), 0.04	1.83 (1.46–2.30), < 0.001
aGvHD Grade 3–4	1.09 (0.79–1.50), 0.59	1.59 (1.15–2.20), 0.005	1.86 (1.23–2.80), 0.003	1.97 (1.35–2.88), < 0.001
cGvHD	—	—	1.72 (1.34–2.20), < 0.001	1.13 (0.86–1.47), 0.38
D/R sex match = F/M	2.59 (1.68–3.99), < 0.001	2.91 (1.87–4.52), < 0.001	—	—
D/R sex match = other	1.37 (1.12–1.69), 0.003	1.38 (1.14–1.68), 0.001	—	—

Deaths

• A total of 1,554 deaths occurred in the haploidentical (n = 132), MSD (n = 564), MUD (n = 625), 7/8 HLA-matched-UD (n = 103), and UCB (n = 130) cohorts.
• The most common causes of death included ALL, graft failure, GvHD, and infection.
  • Death from ALL was more common with haploidentical HCT (48%) and MSD HCT (52%) compared with other HCT cohorts (31–38%).
  • Death from GvHD caused 5% of deaths in the haploidentical HCT cohort compared with 12%–24% in other HCT cohorts.

Conclusion

This retrospective study demonstrated that haploidentical HCT using PTCy could be a preferred alternative donor HCT approach in adult patients with ALL, with superior OS compared with 7/8-HLA-matched-UD and UCB HCT. Although the OS was similar with haploidentical HCT compared to traditional MDS and MUD HCT, the risk of GvHD was reduced in the haploidentical HCT cohort. Further research aiming to prevent relapse, reduce death by infections, and establishing the role of haploidentical HCT using PTCy at different stages of ALL remission with a longer-term follow-up are warranted.