
==== Front
J Clin Oncol
J Clin Oncol
jco
JCO
Journal of Clinical Oncology
0732-183X
1527-7755
Wolters Kluwer Health

39018507
JCO.24.00184
10.1200/JCO.24.00184
ORIGINAL REPORTS
Hematologic Malignancy
Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors
https://orcid.org/0000-0003-3433-9179
Shaffer Brian C. MD, MS 1
Gooptu Mahasweta MD 2
DeFor Todd E. MS 3
https://orcid.org/0000-0002-0198-2064
Maiers Martin MS 3
Bolaños-Meade Javier MD 4
https://orcid.org/0000-0001-7786-4155
Abboud Ramzi MD 5
Briggs Adrienne D. MD 6
https://orcid.org/0000-0003-4828-4711
Khimani Farhad MBBS 7
https://orcid.org/0000-0001-6525-8844
Modi Dipenkumar MD 8
https://orcid.org/0000-0002-8251-6961
Newcomb Richard MD 9
Shpall Elizabeth J. MD 10
https://orcid.org/0000-0003-0766-1162
Bupp Caitrin MPH 3
Spellman Stephen R. MBS 3
Stefanski Heather E. MD, PhD 3
https://orcid.org/0000-0003-3317-1896
Shaw Bronwen E. MD, PhD 11
https://orcid.org/0000-0002-1515-2141
Auletta Jeffery J. MD 3 12
https://orcid.org/0000-0001-7731-759X
Devine Steven M. MD 3
https://orcid.org/0000-0003-2817-6836
Jimenez Jimenez Antonio M. MD, MSc 13
https://orcid.org/0000-0001-8226-471X
Al Malki Monzr M. MD 14
1 Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
2 Department of Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA
3 CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN
4 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
5 Washington University School of Medicine, St Louis, MO
6 Cancer Transplant Institute at HonorHealth, Scottsdale, AZ
7 Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
8 Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI
9 Massachusetts General Hospital, Boston, MA
10 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
11 CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
12 Hematology/Oncology/BMT and Infectious Diseases, Nationwide Children's Hospital, Columbus, OH
13 Sylvester Comprehensive Cancer Center, Miller School of Medicine, Miami, FL
14 City of Hope National Medical Center, Duarte, CA
Steven M. Devine, MD; e-mail: sdevine2@nmdp.org.
1 10 2024
17 7 2024
17 7 2024
42 28 32773286
29 1 2024
2 4 2024
7 5 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

PURPOSE

Access to allogeneic hematopoietic cell transplantation (HCT) remains limited among persons of non-European ancestry if human leukocyte antigen (HLA) matching is required. We evaluated whether post-transplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis improved HCT outcomes with HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HCT when compared with calcineurin inhibitor (CNI)–based prophylaxis.

METHODS

Three-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were compared between adult recipients undergoing initial MUD or single HLA locus MMUD HCT with either PTCy- or CNI-based prophylaxis who were reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021.

RESULTS

Included were 10,025 HCT recipients (7,272 recipients of MUD with CNI, 1,681 MUD with PTCy, 613 MMUD with CNI, and 459 MMUD with PTCy) who underwent HCT for acute leukemia (70.9%) or myelodysplastic syndromes (29.2%). Median patient age was 60.7 years (range, 18.0-82.7) and median follow-up was 36.6 (range, 3.0-77.8) months. When compared with MUD HCT with PTCy, MMUD HCT with PTCy had similar OS (hazard ratio [HR], 0.96 [95% CI, 0.823 to 1.11]; P = .60) and GRFS (HR, 0.90 [0.79 to 1.02]; P = .1). When compared with MUD HCT with CNI, OS was improved after MUD HCT with PTCy (HR, 0.88 [0.80 to 0.96]; P = .004) and GRFS was improved with PTCy after either MUD (HR, 0.61 [0.57 to 0.66]; P < .0001) or MMUD (HR, 0.68 [0.60 to 0.76]; P < .0001) HCT. Benefit from PTCy was independent of patient ancestry. Global registry level analysis demonstrated that inclusion of MMUD increased donor availability regardless of recipient ancestry.

CONCLUSION

Use of PTCy results in comparable OS and GRFS using either MUD or MMUD HCT, expanding access to HCT for patients from all racial and ethnic ancestry groups.

OPEN-ACCESSTRUE
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pmcINTRODUCTION

Allogeneic hematopoietic cell transplantation (HCT) is an important consolidation strategy for many patients with hematologic malignancies. Optimal results are achieved with HLA matched related donor or matched unrelated donor (MUD), defined by allele resolution matching at HLA-A, -B, -C, and -DRB1.1,2 Sibling donors are available to approximately 30% of patients, necessitating use of unrelated donors in many patients.3 Population-level diversity in HLA haplotype frequencies result in variations in MUD availability on the basis of patient self-reported ancestry.4 For example, the probability of identifying an HLA-matched unrelated donor (URD) in the National Marrow Donor Program (NMDP) registry is approximately 75% for patients of non-Hispanic White (NHW) ancestry, but is significantly lower, varying from 15% to 45%, among individuals of non-White and Hispanic ancestry.5,6 Mismatched related donor (haploidentical) and mismatched unrelated donor (MMUD), including umbilical cord blood URDs, are frequently the sole graft source for patients without matched donor options.7 Historically, HCT using single-locus HLA MMUD resulted in inferior survival rates because of increased graft-versus-host disease (GVHD), infections, and graft failure when performed with standard calcineurin inhibitor (CNI)–based GVHD prophylaxis.8-10

CONTEXT

Key Objective

To determine whether differences in overall survival (OS) and other clinically meaningful outcomes exist between recipients of matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) hematopoietic cell transplantation when post-transplant cyclophosphamide (PTCy) is used to prevent graft-versus-host disease (GVHD).

Knowledge Generated

In adults with hematologic malignancies undergoing hematopoietic cell transplantation using PTCy to prevent GVHD reported to the Center for International Blood and Marrow Transplant Research from 2017 to 2021, there was no difference in OS between MUD and MMUD recipients. Other important clinical outcomes, including GVHD-free, relapse-free survival, were also similar.

Relevance (C.F. Craddock)

If confirmed in ongoing randomized trials, these data identify the possibility that adoption of a PTCy regimen has the potential to increase donor availability for allo-mandatory patients, particularly those from racial and ethnic minorities.*

*Relevance section written by JCO Associate Editor Charles F. Craddock, MD.

Administration of post-transplant cyclophosphamide (PTCy) improves outcomes after haploidentical donor HCT.11,12 Several studies suggest that a similar strategy is effective when used with MMUD.13-15 The NMDP-sponsored 15-MMUD study, using PTCy-based GVHD prophylaxis, demonstrated promising overall survival (OS) in adult patients receiving MMUD bone marrow grafts matched at ≤7/8 HLA alleles.16,17 Notably, a substantial proportion of patients with minority ancestries (48%) were enrolled, underscoring the potential of PTCy MMUD HCT to broaden donor options for all patients. There is a scarcity of contemporary, large-scale studies comparing matched and MMUD HCT outcomes using real-world data in the era of novel GVHD prophylaxis agents.18,19 Therefore, we conducted a cohort study using recent data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We sought to determine whether outcome gaps between MUD and MMUD recipients continue to exist and hypothesized that PTCy-based GVHD prophylaxis would result in acceptable OS and GVHD-free, relapse-free survival (GRFS) after MUD and MMUD HCT.

METHODS

Patient Eligibility and Inclusion

Patient, donor, disease, and transplant clinical data were obtained from the CIBMTR outcomes database. Informed consent for participation in retrospective research was obtained from recipients and donors according to the Declaration of Helsinki. Included were adult patients who underwent first allogeneic HCT from January 2017 through June 2021 with a diagnosis of AML, ALL, or myelodysplastic syndromes, with complete clinical data available. Patients receiving either CNI- or PTCy-based prophylaxis were included. CNI-based transplants included use of either cyclosporine or tacrolimus with other adjunctive agents including methotrexate or mycophenolate mofetil (MMF) with or without antithymocyte globulin (ATG). PTCy regimens included a CNI or sirolimus with or without MMF and ATG. Patients who received other GVHD prophylaxis programs (including single agent PTCy), had missing clinical data, or lacked follow-up reporting were excluded (Data Supplement, Table S1 [online only]). Patients were categorized by the receipt of either a MUD, defined as high resolution matching at HLA-A, -B, -C, and -DRB1 (8/8), or MMUD, defined as mismatched at any single locus (7/8). Analysis of donor existence in preliminary searches performed in world registries from 2022 to 2023 was performed as previously described.20

Biostatistical Methods

The primary study objectives were to compare OS and GRFS within and between MUD versus MMUD allogeneic HCT, on the basis of receipt of either CNI- or PTCy-based GVHD prophylaxis. OS was defined as the time from transplant to death from any cause. GRFS was defined as survival without grade III-IV acute GVHD, moderate or severe chronic GVHD requiring systemic treatment, or relapse.21,22 Secondary end points included incidences of relapse, nonrelapse mortality (NRM), grade II-IV and grade III-IV acute GVHD, and moderate/severe chronic GVHD. The HCT comorbidity index (HCT-CI) and the refined Disease Risk Index (DRI) were assigned as previously described.23,24 Kaplan-Meier curves were generated to determine the unadjusted probability of OS and GRFS through 3 years after transplant. Cox regression was used to examine the independent effect of HLA match/GVHD prophylaxis controlling for other clinical factors on OS and GRFS. A priori clinically selected factors were evaluated for univariable association with the end point of interest, with a backward elimination procedure used to remove variables if the P value was >.1 unless inclusion affected the hazard ratio (HR) of HLA match by more than 10%. Variables with a strong clinical rationale for inclusion in the model were retained regardless of significance. Martingale residuals were used to test against nonproportionality for continuous variables, and log of negative log plots were used to assess proportionality among categorical variables.25 Final models were stratified by factors violating the proportional hazards assumption. Interactions were tested against a P < .01. Factors included in the final Cox regression models were used to estimate adjusted survival curves for OS and GRFS.26 Similar methods were used for competing risk end points using cumulative incidence to estimate relapse, NRM, and GVHD, with NRM, relapse, and non-GVHD deaths as competing risks for each end point, respectively.27 Fine and Gray28 regression was used for multiple regression models of competing risk end points. The precision of estimates was measured with 95% CIs and P < .05 were considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R software version 4.3.1.

RESULTS

Patient Demographics and Donor Matching

The final patient cohort included 10,025 recipients from 153 centers (Table 1). Median follow-up of patients was 36.6 months (range, 3.0-77.8). Median time from diagnosis to HCT was 6.0 months (IQR, 4.4-9.9 months). MMUD recipients had slightly longer time from diagnosis to HCT compared with MUD recipients (6.7 months; IQR, 4.7-11.3; v 6.0 months; IQR, 4.4-9.8; P < .001). Patients were similar with respect to age, HCT-CI, and disease histology and risk. Recipients of MMUD were more likely to be of minority ancestry (defined as other than NHW): MMUD recipients 22% versus 8% in MUD recipients (P < .0001). Myeloablative conditioning (MAC) was more commonly used in the CNI-based prophylaxis group (47% v 40%; P < .001). Administration of ATG was most frequent in recipients of MMUD with CNI-based prophylaxis (48.1%), followed by 31.0% in MUD with CNI, 2.5% in MMUD with PTCy, and <1% in MUD with PTCy (global P < .001). Specific mismatched HLA locus among MMUD and the matching rates of HLA-DQB1 and HLA-DPB1 in all groups are provided in the Data Supplement (Table S2).

TABLE 1. Patient and Donor Demographics

Characteristic	PTCy URD 8/8	CNI URD 8/8	PTCy URD 7/8	CNI URD 7/8	Total	
No. of patients	1,681	7,272	613	459	10,025	
Patient age, years, median (range)	62.0 (18.0-82.2)	60.6 (18.0-82.7)	57.9 (18.0-78.8)	58.2 (18.1-81.4)	60.7 (18.0-82.7)	
Donor age, years, median (range)	27.6 (18.0-60.9)	26.8 (18.0-66.5)	28.8 (18.0-61.2)	28.3 (18.0-61.4)	27.1 (18.0-66.5)	
Female, No. (%)	674 (40.1)	3,173 (43.6)	335 (54.6)	197 (42.9)	4,379 (43.7)	
Race, No. (%)						
 White	1,526 (90.8)	6,674 (91.8)	467 (76.2)	367 (80.0)	9,034 (90.1)	
 Black or African American	44 (2.6)	127 (1.7)	68 (11.1)	37 (8.1)	276 (2.8)	
 Asian	37 (2.2)	194 (2.7)	34 (5.5)	22 (4.8)	287 (2.9)	
 Othera	11 (0.7)	59 (0.8)	10 (1.7)	7 (1.5)	87 (0.9)	
 Not reported	63 (3.7)	218 (3.0)	34 (5.5)	26 (5.7)	341 (3.4)	
Ethnicity, No. (%)						
 Hispanic or Latino	86 (5.1)	474 (6.5)	99 (16.2)	77 (16.8)	736 (7.3)	
 Non-Hispanic or non-Latino	1,518 (90.3)	6,606 (90.8)	487 (79.4)	369 (80.4)	8,980 (89.6)	
 Not reported	77 (4.6)	192 (2.6)	27 (4.4)	13 (2.8)	309 (3.1)	
Karnofsky, No. (%)						
 90%-100%	884 (52.6)	3,697 (50.8)	324 (52.9)	217 (47.3)	5,122 (51.1)	
 <90%	755 (44.9)	3,483 (47.9)	275 (44.9)	233 (50.8)	4,746 (47.3)	
 Not reported	42 (2.5)	92 (1.3)	14 (2.3)	9 (2.0)	157 (1.6)	
Comorbidity (HCT-CI), No. (%)						
 0-2	807 (48.0)	3,306 (45.4)	272 (44.4)	198 (43.1)	4,583 (45.6)	
 3+	874 (52.0)	3,966 (54.6)	341 (55.6)	261 (56.9)	5,442 (54.4)	
DRI, No. (%)						
 Low	59 (3.5)	241 (3.3)	18 (2.9)	8 (1.7)	326 (3.3)	
 Intermediate	952 (56.6)	4,126 (56.7)	369 (60.2)	239 (52.1)	5,686 (56.7)	
 High	449 (26.7)	2,100 (28.9)	156 (25.4)	168 (36.6)	2,873 (28.7)	
 Very high	31 (1.8)	197 (2.7)	17 (2.8)	11 (2.4)	256 (2.6)	
 Early MDS	138 (8.2)	388 (5.3)	36 (5.9)	24 (5.2)	586 (5.8)	
 Advanced MDS	52 (3.1)	220 (3.0)	17 (2.8)	9 (2.0)	298 (3.0)	
Disease, No. (%)						
 AML	909 (54.1)	3,937 (54.1)	330 (53.8)	243 (52.9)	5,419 (54.1)	
 ALL	250 (14.9)	1,209 (16.6)	128 (20.9)	93 (20.3)	1,680 (16.8)	
 MDS	522 (31.1)	2,126 (29.2)	155 (25.3)	123 (26.8)	2,926 (29.2)	
Disease status at HCT, No. (%)						
 AML categories						
  Primary induction failure	85 (5.1)	482 (6.6)	37 (6.0)	41 (8.9)	645 (6.4)	
  Complete remission	1,039 (61.8)	4,506 (61.9)	415 (67.7)	286 (62.4)	6,246 (62.3)	
  Relapse	35 (2.1)	159 (2.2)	6 (1.0)	9 (2.0)	209 (2.1)	
 MDS categories						
  Early MDS	242 (14.4)	818 (11.2)	68 (11.1)	45 (9.8)	1,173 (11.7)	
  Advanced MDS	274 (16.3)	1,289 (17.7)	87 (14.2)	75 (16.3)	1,725 (17.2)	
  MDS other	6 (0.4)	18 (0.2)	0	3 (0.7)	27 (0.3)	
Graft source, No. (%)						
 Bone marrow	127 (7.6)	931 (12.8)	102 (16.6)	64 (13.9)	1,224 (12.2)	
 Peripheral blood stem cells	1,554 (92.4)	6,341 (87.2)	511 (83.4)	395 (86.1)	8,801 (87.8)	
Donor/recipient CMV serostatus, No. (%)						
 +/+	464 (27.6)	2,030 (27.9)	205 (33.4)	168 (36.6)	2,867 (28.6)	
 +/–	174 (10.4)	798 (11.0)	91 (14.8)	42 (9.2)	1,105 (11.0)	
 –/+	593 (35.3)	2,475 (34.0)	190 (31.0)	146 (31.8)	3,404 (34.0)	
 –/–	440 (26.2)	1,935 (26.6)	125 (20.4)	100 (21.8)	2,600 (25.9)	
 Not reported	10 (0.6)	34 (0.5)	2 (0.3)	3 (0.7)	49 (0.5)	
Conditioning intensity, No. (%)						
 Myeloablative	667 (39.7)	3,445 (47.4)	244 (39.8)	219 (47.7)	4,575 (45.6)	
 Nonmyeloablative	307 (18.3)	746 (10.3)	103 (16.8)	49 (10.7)	1,205 (12.0)	
 Reduced intensity	707 (42.1)	3,081 (42.4)	266 (43.4)	191 (41.6)	4,245 (42.3)	
GVHD prophylaxis, No. (%)						
 CNIb + MTX or MMF	0	6,156 (84.7)	0	370 (80.6)	6,526 (65.1)	
 CNI + sirolimus ± MMF or MTX	0	1,116 (15.3)	0	89 (19.4)	1,205 (12.0)	
 PTCy + CNI + MMF	1,586 (94.4)	0	509 (83.1)	0	2,095 (20.9)	
 PTCy + sirolimus + MMF	95 (5.7)	0	104 (17.0)	0	199 (2.0)	
Antithymocyte globulin use, No. (%)	8 (<1.0)	2,258 (31.0)	15 (2.5)	221 (48.1)	2,502 (25.0)	
Abbreviations: CMV, cytomegalovirus; CNI, calcineurin inhibitor; DRI, Disease Risk Index; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HCT-CI, HCT comorbidity index; MDS, myelodysplastic syndromes; MMF, mycophenolate mofetil; MTX, methotrexate; PTCy, post-transplant cyclophosphamide; URD, unrelated donor.

a American Indian, Alaska Native, Native Hawaiian, or Pacific Islander.

b CNI includes tacrolimus or cyclosporin A.

Multivariable Analysis of OS and GRFS on the Basis of GVHD Prophylaxis

Univariable analyses for OS and GRFS are provided in the Data Supplement (Tables S3a and S3b). Results of the Cox regression models of OS are available in the Data Supplement (Table S3c). The final model for OS included patient and donor age, DRI, HCT-CI, race/ethnicity, sex, donor/recipient cytomegalovirus serostatus, and year of HCT. HCT recipients using PTCy had no difference in OS on the basis of degree of donor HLA matching (HR, 0.96 [95% CI, 0.82 to 1.18]; P = .60), whereas significant differences remained in OS between MUD and MMUD HCT recipients receiving CNI-based prophylaxis (HR for matched URD, 0.80 [0.70 to 0.92]; P = .016; Figs 1A and 1B). Compared with patients receiving MUD HCT with CNI-based prophylaxis, recipients of PTCy-based MUD HCT had better OS (HR, 0.88 [95% CI, 0.804 to 0.96]; P = .0041), and recipients of MMUD HCT with PTCy had similar OS (HR, 0.92 [95% CI, 0.80 to 1.05]; P = .2062).

FIG 1. Adjusted Kaplan-Meier estimates of GRFS and OS in recipients of (A) PTCy and (B) CNI. CNI, calcineurin inhibitor; GRFS, graft-versus-host disease-free, relapse-free survival; HLA, human leukocyte antigen; OS, overall survival; PTCy, post-transplant cyclophosphamide; URD, unrelated donor.

Cox regression model results for GRFS are provided in the Data Supplement (Table S3d). The final model for GRFS included refined DRI, patient and donor age, HCT-CI, patient race/ethnicity, graft source, and year of HCT. Compared with MUD recipients receiving CNI-based prophylaxis, patients who received MUD or MMUD with PTCy were less likely to experience a GRFS event. There was no difference in GRFS between recipients of MUD and MMUD HCT receiving either PTCy- (HR, 0.90 [95% CI, 0.79 to 1.02]; P = .11; Fig 1A) or CNI-based GVHD prophylaxis (Fig 1B). Patients receiving a MMUD HCT with PTCy were less likely to experience a GRFS event compared with MMUD recipients with CNI-based prophylaxis (HR, 0.65 [95% CI, 0.56 to 0.76]; P < .0001).

Similar results for the OS and GRFS multivariable models were found when the cohorts were subgrouped on the basis of conditioning intensity (Data Supplement, Tables S4 and S5) and among the subgroups that were treated without ATG (Data Supplement, Tables S6a and S6b). ATG exposure did not improve GRFS (HR, 1.20 [95% CI, 0.9-1.50]; P = .120) or OS (HR, 1.50 [95% CI, 1.14-1.97]; P < .001) in recipients of CNI-based MMUD HCT but was associated with improved GRFS (HR, 0.79 [95% CI, 0.75 to 0.84]; P < .001) without differences in OS (HR, 1.08 [95% CI, 1.00 to 1.16]; P = .059) in recipients of MUD HCT. Compared with recipients receiving CNI with ATG, GRFS was superior with PTCy (without ATG) in MUD recipients (HR, 0.71 [95% CI, 0.65 to 0.78]; P < .001) and MMUD recipients (HR, 0.57 [95% CI, 0.47 to 0.69]; P < .001). Similarly, compared with CNI with ATG recipients, PTCy resulted in superior OS after MUD (HR, 0.94 [95% CI, 0.76 to 0.94]; P = .002) and MMUD (HR, 0.57 [95% CI, 0.45 to 0.73]; P < .001). Full multivariable regression results for OS and GRFS in CNI with ATG versus PTCy recipients grouped by degree of donor matching are provided in the Data Supplement (Tables S6c-S6f).

In the subgroup of patients of minority ancestry who underwent MMUD HCT with PTCy, the 3-year OS was 60% (52%-67%), compared with 59% (53%-64%) in NHW patients. Similarly, the 3-year GRFS was 42% (34%-49%) in minority ancestry patients undergoing MMUD with PTCy compared with 42% (37%-47%) in NHW patients undergoing MMUD with PTCy. Considering MMUD recipients of minority ancestry, the use of PTCy resulted in improved OS (HR, 0.56 [95% CI, 0.40 to 0.79]; P = .001) and GRFS (HR, 0.57 [95% CI, 0.43 to 0.76]; P < .001) compared with CNI recipients.

Multivariable Analysis of Secondary Clinical End Points in Patients Receiving PTCy- and CNI-Based GVHD Prophylaxis

We then evaluated whether differences in GVHD, NRM, and relapse were apparent on the basis of donor HLA matching and GVHD prophylaxis. Adjusted cumulative incidence of secondary end points are provided in Figures 2 and 3 and results of multiple regression models for all end points in Figure 4 using MUD with CNI-based prophylaxis as the reference group. Compared with recipients of MUD HCT using CNI, the risk of 6-month grade III-IV acute GVHD was lower in recipients of MUD HCT with PTCy (HR, 0.44 [95% CI, 0.36 to 0.55]; P < .0001) and in recipients of MMUD HCT with PTCy (HR, 0.58 [95% CI, 0.43 to 0.78]; P = .014), but was greater in MMUD HCT with CNI (HR, 1.51 [95% CI, 1.21 to 1.88]; P = .0084; Fig 2). Similar results were noted considering grade II-IV 6-month acute GVHD (Data Supplement, Table S7a). Compared with recipients of MUD HCT with CNI, the 2-year risk of moderate-severe chronic GVHD was lower in recipients of MUD HCT with PTCy (HR, 0.29 [95% CI, 0.25 to 0.34]; P < .0001), MMUD HCT with PTCy (HR, 0.45 [95% CI, 0.37 to 0.56]; P < .0001), and MMUD HCT with CNI (HR, 0.77 [95% CI, 0.65 to 0.93]; P = .0058; Fig 2). Considering only recipients of PTCy, the use of MUD versus MMUD HCT resulted in no difference in grade III-IV acute GVHD (HR, 0.76 [95% CI, 0.54 to 1.08]; P = .12) but lower incidence of moderate-severe chronic GVHD (HR, 0.64 [95% CI, 0.49 to 0.82]; P = .0005). Full regression models for both acute and chronic GVHD are provided in the Data Supplement (Tables S7 and S8a). The cumulative incidence of chronic GVHD within the CNI-treated patients on the basis of ATG exposure and donor HLA matching is provided in the Data Supplement (Table S8b).

FIG 2. Cumulative incidence of (A) acute GVHD grades 2-4, (B) acute GVHD grades 3-4, and (C) moderate/severe chronic GVHD on the basis of the GVHD prophylaxis approach and donor/recipient HLA matching group. CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; PTCy, post-transplant cyclophosphamide; URD, unrelated donor.

FIG 3. Cumulative incidence of (A) relapse and (B) nonrelapse mortality; and (C) relative causes of death in each donor/GVHD prophylaxis group. CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; PTCy, post-transplant cyclophosphamide; URD, unrelated donor.

FIG 4. Forest plot results of the multivariable adjusted risk of primary and secondary end points compared with recipients of MUD HCT using CNI-based GVHD prophylaxis. CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HR, hazard ratio; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; PTCy, post-transplant cyclophosphamide.

Compared with recipients of MUD HCT with CNI, the risk of NRM was lower in recipients of MUD and MMUD HCT with PTCy and greater in recipients of MMUD HCT with CNI (Fig 3). Pairwise comparisons demonstrated that the risk of NRM was less in recipients receiving PTCy-based prophylaxis in both MUD HCT (HR, 0.77 [95% CI, 0.67 to 0.87]; P < .0001) and MMUD HCT (HR, 0.58 [95% CI, 0.45 to 0.75]; P < .0001). There was similar risk of NRM among MUD and MMUD HCT recipients using PTCy (HR, 0.96 [95% CI, 0.76 to 1.2]; P = .71). Compared with recipients of MUD with CNI-based prophylaxis, risk of relapse was greater in recipients of MUD with PTCy and similar among recipients of MMUD with PTCy and CNI (Fig 3). Pairwise group analysis demonstrated that the risk of relapse was similar between recipients of MUD and MMUD using PTCy (HR, 1.02 [95% CI, 0.85 to 1.22]; P = .81) and between MUD and MMUD HCT recipients using CNI (HR, 1.00 [95% CI, 0.83 to 1.21]; P = .97). Multivariable associations with relapse and NRM are given in the Data Supplement (Table S9).

Potential Impact to Donor Availability in the NMDP and World Marrow Donor Association Registries

To determine the impact of these results on donor availability in the NMDP and global (World Marrow Donor Association) registries when considering either MUDs alone versus MUDs or MMUDs as suitable donors, we analyzed 50,000 preliminary URD registry searches conducted between 2022 and 2023 on the basis of patient ancestry. We considered only donors age 35 years and younger with a >75% probability of matching at the specified degree. The proportion of recipients having at least one URD improved in all major ancestry groups (Fig 5A) if both MMUD and MUDs were considered (all pairwise P < .001). The median (IQR) number of donors available for all major ancestry groups (Fig 5B) improved if MMUDs were considered: African American ancestry two (1-8) if only MUDs were considered but 74 (26-218) if MMUDs were considered, NHW ancestry (29 [5-208]-1,226 [287-5,371]), Asian/Pacific-Islander (6 [2-27]-151 [48-629]), White/Hispanic (5 [2-24]-147 [43-787]), and Native American (6 [2-39]-362 [70-2,163]). Consideration of more highly mismatched donors (<7/8) suggests greater numbers of potential donors across all ancestry groups (Data Supplement, Fig S1).

FIG 5. Registry-level modeling using results from 50,000 preliminary unrelated donor searches. Donors age 35 years and younger with at least a 75% probability of HLA matching at the designated degree were considered. (A) The probability of at least one available donor existing on the basis of patient ancestry improves in all groups (global P < .001) if both MUD and MMUD are considered, and (B) the median number of existing donors in patients who had at least one available donor if only MUDs are considered versus MUDs and MMUDs are considered as suitable. AFA, African American; API, Asian/Pacific Islander; HIS, Hispanic/White; HLA, human leukocyte antigen; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; NAM, Native American; NHW, non-Hispanic/White; URD, unrelated donor.

DISCUSSION

We used the CIBMTR database to conduct a large cohort analysis of allogeneic HCT recipients to determine whether MMUD HCT using PTCy results in acceptable OS and GRFS when compared with MUD HCT. The results demonstrate comparable outcomes between MUDs and MMUDs when using PTCy, suggesting that MMUDs are a suitable donor option if a MUD is not available. Differences in OS between MUD and MMUD HCT continue to be observed after CNI-based GVHD prophylaxis without PTCy, suggesting the results are not simply because of recent changes in supportive care. We also demonstrate that consideration of MMUDs substantially expands the numbers of potential donors within large donor registries. The impact of these findings for all patients, particularly those of minority ancestry, is high, given the historical gaps in access to suitable donors for minority patients.

The comparable OS and GRFS between MUD and MMUD HCT with PTCy may be due to similar risks of acute GVHD, implying that PTCy effectively abrogates detrimental alloreactivity mediated by donor/recipient HLA disparity. Improvements in OS and GRFS for MUD HCT with PTCy relative to CNI, and in GRFS in MMUD with PTCy relative to MUD with CNI, are likely because of a combination of lower risks of both acute and chronic GVHD as well as NRM in both MUD and MMUD with PTCy. We did note a greater incidence of relapse in recipients of MUD HCT with PTCy when compared with CNI, similar to other retrospective cohort studies examining T-cell–modulating strategies.29 These results should be interpreted cautiously as they may be confounded by greater use of MAC in the CNI arm and competing risk of early NRM, which was greater in the CNI-based recipients. An unexpected finding was the lower incidence of chronic GVHD in MMUD using CNI compared with MUD with CNI. This result may be due to greater use of ATG in the MMUD cohort, and early mortality among MMUD, resulting in removal of patients with the most alloreactive donors. Taken together, these results suggest that PTCy is an acceptable alternative to CNI-based prophylaxis in MUD HCT recipients and superior to CNI-based prophylaxis that do not incorporate abatacept in MMUD HCT, extending recent findings of a randomized clinical trial similarly demonstrating improvement in GRFS with PTCy-based GvHD prophylaxis in the reduced intensity conditioning setting.30

There are limitations to the current study. First, this is a retrospective analysis of registry patients and as such there is potential selection bias for patients receiving certain allograft types on the basis of perceived urgency of HCT and disease risk. This limitation may be greater in the comparator groups of MMUD and MUD treated with PTCy, which are smaller. Second, we only evaluated HLA-7/8 matches in the MMUD group for this study and excluded donors who were mismatched at more than one locus. In the completed 15-MMUD study, 31/80 participants (39%) received HCT from a 4-6/8 MMUD, suggesting an ongoing need for these donors. The recently completed ACCESS (ClinicalTrials.gov identifier: NCT04904588) study includes greater numbers of more highly MMUD and will provide important context for outcomes in this group. Given the size of the MMUD recipient cohort, we lack here the power to examine the effects of specific HLA locuswise mismatching on HCT outcomes.

Alternative strategies to prevent GVHD in the setting of MUD and MMUD are undergoing evaluation in prospective clinical trials. Two important ongoing studies (ClinicalTrials.gov identifier: NCT05153226, NCT04888741) aim to compare recipients of PTCy-based versus ATG-based GVHD prophylaxis in unrelated donor recipients. Our results are similar to a recent European registry study; however, given the potential for patient selection bias, evaluation of ATG in a prospective study is important to identify optimal GVHD prophylaxis in both MUD and MMUD HCT.31 The combination of novel prophylaxis agents with either standard-dose or reduced-dose PTCy is a promising strategy that will be evaluated in existing or planned clinical trials. Favorable outcomes in patients with severe aplastic anemia treated with combinatorial ATG and PTCy after haplo-HCT suggest that this approach may be promising in selected patients.32 Other completed and ongoing studies exist to evaluate the use of abatacept in single-locus MMUD, a promising new approach.18,33 Taken together, these results and those of forthcoming clinical trials will represent a significant step forward in resolving barriers to transplantation. Increasing access to HCT is paramount to making this lifesaving procedure available to patients of all ancestries.

SUPPORT

AUTHOR CONTRIBUTIONS

Conception and design: Brian C. Shaffer, Mahasweta Gooptu, Javier Bolaños-Meade, Farhad Khimani, Caitrin Bupp, Jeffery J. Auletta, Steven M. Devine, Antonio M. Jimenez Jimenez, Monzr M. Al Malki

Provision of study materials or patients: Javier Bolaños-Meade, Adrienne D. Briggs, Farhad Khimani, Elizabeth J. Shpall, Stephen R. Spellman

Collection and assembly of data: Todd E. DeFor, Ramzi Abboud, Adrienne D. Briggs, Farhad Khimani, Caitrin Bupp, Jeffery J. Auletta, Steven M. Devine, Antonio M. Jimenez Jimenez, Monzr M. Al Malki

Data analysis and interpretation: Brian C. Shaffer, Mahasweta Gooptu, Todd E. DeFor, Martin Maiers, Javier Bolaños-Meade, Ramzi Abboud, Farhad Khimani, Dipenkumar Modi, Richard Newcomb, Elizabeth J. Shpall, Caitrin Bupp, Stephen R. Spellman, Heather E. Stefanski, Bronwen E. Shaw, Jeffery J. Auletta, Antonio M. Jimenez Jimenez, Monzr M. Al Malki

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

See accompanying Editorial, p. 3263

Supported by the Public Health Service U24CA076518 from the NIH/NCI, the NIH/National Heart, Lung, and Blood Institute (NHLBI), and the NIH/National Institute of Allergy and Infectious Diseases (NIAID), HHSH250201700006C from the Health Resources and Services Administration (HRSA), and N00014-20-1-2705 and N00014-20-1-2832 from the Office of Naval Research. Additional federal support is provided by R01AI128775, R01HL130388, and the Biomedical Advanced Research and Development Authority (BARDA). Support is also provided by the NMDP Foundation, the Medical College of Wisconsin, NMDP and from the following commercial entities: Actinium Pharmaceuticals, Inc; Adienne SA; Allovir, Inc; Amgen, Inc; Angiocrine Bioscience; Astellas Pharma US; bluebird bio, Inc; Bristol Myers Squibb Co; Celgene Corp; CSL Behring, CytoSen Therapeutics, Inc; Daiichi Sankyo Co, Ltd; ExcellThera; Fate Therapeutics; Gamida-Cell, Ltd; Genentech, Inc; Incyte Corporation; Janssen/Johnson & Johnson; Jazz Pharmaceuticals, Inc; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Merck Sharp & Dohme Corp; Millennium, the Takeda Oncology Co; Miltenyi Biotec, Inc; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc; Orca Biosystems, Inc; Pfizer, Inc; Pharmacyclics, LLC; Sanofi Genzyme; Stemcyte; Takeda Pharma; Vor Biopharma; and Xenikos BV.

* B.C.S., M.G., A.M.J.J., and M.M.A.M. contributed equally to this work.

Brian C. Shaffer

Consulting or Advisory Role: Hansa Biopharma

Mahasweta Gooptu

Consulting or Advisory Role: Syndax

Travel, Accommodations, Expenses: Syndax

Todd E. Defor

Employment: HealthPartners Institute

Javier Bolaños-Meade

Honoraria: Banner MD Anderson Colorado

Consulting or Advisory Role: MJH Healthcare Holdings, LLC, Avoro Capital Advisors

Travel, Accommodations, Expenses: Dictaforum Servicios

Ramzi Abboud

Consulting or Advisory Role: Rigel, Autolus

Research Funding: Incyte

Farhad Khimani

Research Funding: Bristol Myers Squibb (Inst), Incyte (Inst)

Dipenkumar Modi

Consulting or Advisory Role: Seagen, AstraZeneca, Genentech, Daiichi Sankyo/Lilly, ADC Therapeutics, Genmab

Speakers' Bureau: BeiGene

Research Funding: Karyopharm Therapeutics (Inst), Genentech (Inst), Genmab (Inst), AstraZeneca (Inst)

Richard Newcomb

Employment: Vertex

Stock and Other Ownership Interests: TimeDoc, Vertex

Elizabeth J. Shpall

Honoraria: Bayer

Consulting or Advisory Role: Adaptimmune, AXIO Research, Navan, Fibrobiologics, NY Blood Center, Celaid Therapeutics

Patents, Royalties, Other Intellectual Property: Takeda, Affimed Therapeutics, Syena

Travel, Accommodations, Expenses: Magenta Therapeutics, Novartis

Bronwen E. Shaw

Consulting or Advisory Role: Orca Bio (Inst), Mallinckrodt (Inst)

Jeffery J. Auletta

Employment: NMDP

Honoraria: Takeda, Ascella Health

Consulting or Advisory Role: Ascella Health, Cardinal Health

Steven M. Devine

Leadership: NMDP

Antonio M. Jimenez Jimenez

Research Funding: AbbVie

Monzr M. Al Malki

Consulting or Advisory Role: CareDX, T scan, TR1X

Research Funding: NexImmune, Incyte, Stemline Therapeutics

No other potential conflicts of interest were reported.

Brian C. Shaffer

Consulting or Advisory Role: Hansa Biopharma

Mahasweta Gooptu

Consulting or Advisory Role: Syndax

Travel, Accommodations, Expenses: Syndax

Todd E. Defor

Employment: HealthPartners Institute

Javier Bolaños-Meade

Honoraria: Banner MD Anderson Colorado

Consulting or Advisory Role: MJH Healthcare Holdings, LLC, Avoro Capital Advisors

Travel, Accommodations, Expenses: Dictaforum Servicios

Ramzi Abboud

Consulting or Advisory Role: Rigel, Autolus

Research Funding: Incyte

Farhad Khimani

Research Funding: Bristol Myers Squibb (Inst), Incyte (Inst)

Dipenkumar Modi

Consulting or Advisory Role: Seagen, AstraZeneca, Genentech, Daiichi Sankyo/Lilly, ADC Therapeutics, Genmab

Speakers' Bureau: BeiGene

Research Funding: Karyopharm Therapeutics (Inst), Genentech (Inst), Genmab (Inst), AstraZeneca (Inst)

Richard Newcomb

Employment: Vertex

Stock and Other Ownership Interests: TimeDoc, Vertex

Elizabeth J. Shpall

Honoraria: Bayer

Consulting or Advisory Role: Adaptimmune, AXIO Research, Navan, Fibrobiologics, NY Blood Center, Celaid Therapeutics

Patents, Royalties, Other Intellectual Property: Takeda, Affimed Therapeutics, Syena

Travel, Accommodations, Expenses: Magenta Therapeutics, Novartis

Bronwen E. Shaw

Consulting or Advisory Role: Orca Bio (Inst), Mallinckrodt (Inst)

Jeffery J. Auletta

Employment: NMDP

Honoraria: Takeda, Ascella Health

Consulting or Advisory Role: Ascella Health, Cardinal Health

Steven M. Devine

Leadership: NMDP

Antonio M. Jimenez Jimenez

Research Funding: AbbVie

Monzr M. Al Malki

Consulting or Advisory Role: CareDX, T scan, TR1X

Research Funding: NexImmune, Incyte, Stemline Therapeutics

No other potential conflicts of interest were reported.
==== Refs
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