Abstract
Young adults (YAs) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) represent a unique population with distinct medical and psychosocial needs. Optimizing graft-versus-host disease (GvHD) prophylaxis in this population remains critical to improving outcomes.
We performed a retrospective analysis of YAs undergoing unrelated donor HSCT using a contemporary Center for International Blood and Marrow Transplant Research (CIBMTR) dataset. GvHD-free, relapse-free survival (GRFS) at 24 months was evaluated across three GvHD prophylaxis strategies: Group A (PTCy + CNI + MMF), Group B (CNI + MTX/MMF), and Group C (CNI + MTX/MMF + ATG). A propensity score–matched (PSM) analysis was conducted to adjust for baseline differences.
A total of 1,387 YA patients were included. In the total cohort, 24-month GRFS was 58.9% (95% CI, 53–64) in Group A, 32.2% (95% CI, 29–36) in Group B, and 44.2% (95% CI, 39–49) in Group C (p < 0.001). On MVA, both Group A (HR = 0.44; 95% CI, 0.35–0.54) and C (HR = 0.79; 95% CI, 0.70–0.90) showed improved GRFS compared to Group B.
In the propensity score matched cohort, GRFS at 24 months remained higher in the PTCy group (58.2%, 95% CI, 52–64) versus the CNI-MTX/MMF ± ATG group (32.9%, 95% CI, 27–39; p < 0.001), with PTCy independently associated with improved GRFS (HR = 0.48; 95% CI, 0.40–0.60; p < 0.001). PTCy-based prophylaxis also reduced non-relapse mortality (NRM), with no significant differences in relapse or overall survival (OS) between groups.
In this large, retrospective analysis, PTCy was associated with significantly improved GRFS and reduced NRM in YAs undergoing unrelated donor HSCT. These findings support the use of PTCy-based regimens in this population and warrant prospective evaluation.
Keywords: GvHD prophylaxis, PTCy, young adults, allogeneic transplant
Graphical Abstract
Introduction
Young adults (YA) represent a distinct population within oncology (1). Hematologic malignancies are among the most common cancers in this age group, and adolescent and young adults (AYAs) frequently present with more aggressive disease biology (1–3). This group is also more vulnerable to treatment-related toxicity, highlighting the need for tailored therapeutic strategies (1). Despite therapeutic advances, survival improvements in YAs have lagged behind those seen in children across several hematological malignancies (4).
Beyond disease biology, YAs face profound psychosocial challenges (5–8). A cancer diagnosis during this transitional life stage can disrupt education, employment, financial stability, and family planning (7–9). Many YAs are in the process of establishing careers, forming long-term partnerships, or raising young children (5,6). Treatment-related morbidity can result in prolonged functional limitations and emotional distress (5,6,9,10).
Allogeneic hematopoietic stem cell transplantation (HSCT) continues to evolve (11). A major advance has been the introduction of post-transplant cyclophosphamide (PTCy), which has reduced the incidence of both acute and chronic graft-versus-host disease (GvHD), broadened donor availability, and improved survival across donor types (12–14). Transplant survivors have historically experienced considerable morbidity that adversely impact quality of life (11,15). Up to 50% of patients develop chronic GVHD, which may cause disfigurement, physical disability, emotional stress, and social isolation (15,16).
Endpoints such as overall survival (OS), while important, are no longer sufficient in isolation to define the therapeutic success of HSCT. GvHD-free, relapse-free survival (GRFS) is an increasingly recognized composite endpoint that more accurately reflects the outcomes that matter most to YA patients, namely, freedom from both disease and debilitating transplant-related morbidity (17).
While there is growing evidence on the use of PTCy in older adults, outcomes in young adults are rarely reported separately. Most data on PTCy come from studies using reduced-intensity conditioning, whereas myeloablative conditioning is more commonly used in younger patients. To address this gap, we performed a retrospective analysis using a contemporary Center for International Blood and Marrow Transplant Research (CIBMTR) dataset to evaluate GRFS in YAs undergoing HSCT from unrelated donors, focusing on the impact of different GvHD prophylaxis strategies. A propensity score-matched analysis was also performed to account for differences in baseline characteristics across groups.
Methods
Patients
We utilized a publicly available CIBMTR dataset (P-5891, Shaffer et al) (18). Patients aged 18 to 39 years were identified for inclusion. The cohort consisted of recipients of matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HSCT. The graft source was either peripheral blood stem cells (PBSC) or bone marrow (BM). GVHD prophylaxis regimens were categorized into three groups. Group A: PTCy with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) (PTCy-CNI-MMF), Group B: CNI with methotrexate (MTX)/MMF (CNI-MTX/MMF), and Group C: CNI with MTX/MMF plus anti-thymocyte globulin (CNI-MTX/MMF+ATG).
Definitions
YAs were defined as individuals aged 18 to 39 years at the time of HSCT. Conditioning regimen intensity, acute, and chronic GVHD, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), and Disease Risk Index (DRI) were defined as per previously published criteria (19–23). GRFS was defined as a composite end-point of the occurrence of any of the following: grade III-IV acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death, whichever occurred earlier (17). NRM was defined as death after HSCT not preceded by disease relapse, and OS as the time from transplantation to death due to any cause.
Statistical analysis
The primary objective was to compare GRFS across the three GvHD prophylaxis groups. Categorical variables were summarized as counts and percentages and compared using the chi-square test. Continuous variables were presented as medians with interquartile ranges (IQR; 25th–75th percentiles) and compared using the Mann–Whitney U test.
The cumulative incidences of acute and chronic GvHD were evaluated using competing risk methods, accounting for relapse and death before GvHD onset as competing events. Relapse and NRM were also analyzed within a competing risk framework, considering NRM as a competing event for relapse and vice versa. OS and GRFS were estimated using the Kaplan–Meier method, and differences between groups were assessed with the log-rank test.
To account for imbalances in baseline characteristics, we conducted a 1:1 propensity score-matched (PSM) analysis comparing patients who received PTCy-CNI-MMF (Group A) to those who received other GvHD prophylaxis strategies (CNI-MTX/MMF ± ATG) (Groups B and C). Propensity scores were estimated using binary logistic regression, incorporating donor types (MUD vs. MMUD), patient age, sex, underlying diagnosis (AML, ALL, or MDS), DRI, HCT-CI, CMV serostatus (recipient/donor), and conditioning regimen intensity (myeloablative vs. reduced intensity vs non-myeloablative). Matching was performed without replacement using a caliper width of 0.3 standard deviations of the logit of the propensity score. Baseline covariate balance after PSM was assessed using standardized mean differences (SMD), with all variables achieving an SMD <0.1 (Supplement Figure 1).
Outcomes were then compared within the matched cohorts to provide a more robust estimate of the effect of GvHD prophylaxis on GRFS and other endpoints. Variables with a p-value <0.1 in univariate analyses and those deemed clinically relevant were included in the multivariable model. cGVHD was included as a time-dependent covariate. All p-values were two-sided, with values <0.05 considered statistically significant. Statistical analyses were performed using Easy R (version 1.62, Saitama Medical Center, Jichi Medical University, Saitama, Japan) (24).
Results
Baseline characteristics
A total of 1,387 YA patients with a median age of 30 years (IQR: 23 – 34) were included in the analysis. GvHD prophylaxis consisted of PTCy-CNI-MMF in 306 patients (22%; Group A), CNI-MTX/MMF in 686 (50%; Group B), and CNI-MTX/MMF + ATG in 395 (28%; Group C).
The overall cohort included 749 (54%) males. Acute myeloid leukemia (AML) was the most common indication for HSCT (n=730, 53%). Most patients received grafts from MUD (n = 1,209, 87%) and underwent myeloablative conditioning (MAC) (n = 1,229, 89%).
Patients in Group A were marginally older at the time of transplant and more likely to have received MMUD grafts and reduced intensity conditioning (RIC). The baseline characteristics for the overall cohort and the PSM population are summarized in Tables 1 and 2, respectively.
Table 1:
Baseline characteristics
| PTCy-Cni-MMF (Group A) (n=306) | Cni-MTX /MMF(Group B) (n=686) | Cni-MTX/MMF-ATG (Group C) (n=395) | p-value | |
|---|---|---|---|---|
| Age, years, median (Interquartile range) | ||||
| • Recipient | 31 (26 – 37) | 29 (23 – 35) | 29 (23 – 35) | 0.01 |
| • Donor | 30 (23 – 35) | 29 (21 – 34) | 30 (22 – 36) | 0.13 |
| Male, n (%) | 169 (55) | 356 (52) | 224 (57) | 0.27 |
| Indication for HSCT | ||||
| • Acute Myeloid Leukemia | 154 (50) | 359 (52) | 217 (55) | 0.55 |
| • Acute Lymphoblastic Leukemia | 121 (40) | 275 (40) | 147 (37) | |
| • Myelodysplastic syndrome | 31 (10) | 52 (8) | 31 (8) | |
| Graft source | ||||
| • Peripheral blood | 258 (84) | 486 (71) | 311 (79) | 0.01 |
| Donor | ||||
| • HLA Matched unrelated (8/8) | 222 (73) | 644 (94) | 343 (87) | <0.001 |
| • HLA Mismatched unrelated (7/8) | 84 (27) | 42 (6) | 52 (13) | |
| HCT-CI >=3, n (%) | 135 (44.1) | 287 (41.8) | 168 (42.5) | 0.79 |
| Disease-risk index | ||||
| • Low | 24 (8) | 35 (5) | 27 (7) | |
| • Intermediate | 190 (65) | 445 (67) | 234 (62) | 0.12 |
| • High | 72 (25) | 169 (25) | 98 (26) | |
| • Very-high | 6 (2) | 20 (3) | 20 (5) | |
| Conditioning intensity, n (%) | ||||
| • Myeloablative | 246 (80) | 623 (91) | 360 (91) | <0.001 |
| • Reduced Intensity | 43 (14) | 53 (8) | 31 (8) | |
| • Non-myeloablative | 17 (6) | 10 (1) | 4 (1) | |
| CMV serostatus, n (%) | ||||
| • Donor+/Recipient+ | 67 (22) | 180 (26) | 78 (20) | |
| • Donor+/Recipient− | 38 (13) | 92 (14) | 37 (10) | 0.03 |
| • Donor−/Recipient+ | 102 (34) | 225 (33) | 139 (36) | |
| • Donor−/ Recipient− | 67 (22) | 180 (26) | 78 (20) |
Abbreviations: ATG: anti-thymocyte globulin; Cni: Calcineurin inhibitor; CMV: cytomegalovirus; GvHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; PTCy: post-transplantation cyclophosphamide; MTX: methotrexate; MMF: mycophenolate mofetil; Tac: tacrolimus
Table 2:
Baseline characteristics of the propensity score matched population
| Cni-MTX/MMF ± ATG (n=277) | PTCy-Cni-MMF (n=277) | p-value | |
|---|---|---|---|
| Age, years, median (Interquartile range) | |||
| • Recipient | 31 (25 – 34) | 31 (25 – 35) | 0.75 |
| • Donor | 30 (23 – 34) | 30 (23 – 34) | 0.46 |
| Male, n (%) | 156 (56) | 153 (55) | 0.86 |
| Indication for HSCT | |||
| • Acute Myeloid Leukemia | 143 (52) | 149 (54) | 0.90 |
| • Acute Lymphoblastic Leukemia | 118 (43) | 113 (41) | |
| • Myelodysplastic syndrome | 16 (5) | 15 (5) | |
| Graft source | |||
| • Peripheral blood | 236 (85) | 233 (84) | 0.81 |
| Donor | |||
| • HLA Matched unrelated (8/8) | 211 (76) | 212 (76) | 1.0 |
| • HLA Mismatched unrelated (7/8) | 66 (24) | 65 (24) | |
| HCT-CI >=3, n (%) | 111 (40) | 119 (43) | 0.54 |
| Disease-risk index | |||
| • Low | 22 (8) | 23 (8) | |
| • Intermediate | 178 (64) | 182 (66) | 0.69 |
| • High | 66 (24) | 66 (24) | |
| • Very-high | 11 (4) | 6 (2) | |
| Conditioning intensity, n (%) | |||
| • Myeloablative | 225 (81) | 227 (82) | 0.93 |
| • Reduced Intensity | 40 (14) | 37 (13) | |
| • Non-myeloablative | 12 (5) | 13 (5) | |
| ATG used, n (%) | 109 (39) | 0 (0) | <0.001 |
| CMV serostatus, n (%) | |||
| • Donor+/Recipient+ | 84 (31) | 81 (30) | |
| • Donor+/Recipient− | 25 (9) | 33 (12) | 0.69 |
| • Donor−/Recipient+ | 99 (36) | 100 (37) | |
| • Donor−/ Recipient− | 66 (24) | 60 (22) |
Abbreviations: ATG: anti-thymocyte globulin; Cni: Calcineurin inhibitor; CMV: cytomegalovirus; GvHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; PTCy: post-transplantation cyclophosphamide; MTX: methotrexate; MMF: mycophenolate mofetil; Tac: tacrolimus
GRFS
The GRFS at 24 months was 58.9% (95% CI: 53 – 64) in Group A, 32.2% (95% CI: 29 – 36) in Group B, and 44.2% (95% CI: 39 – 49) in Group C (p<0.001) (Figure 1a). On MVA, both Group A (HR = 0.44; 95% CI, 0.35–0.54) and Group C (HR = 0.79; 95% CI, 0.70–0.90; p < 0.001) were associated with significantly improved GRFS compared to Group B. The use of MUD (vs MMUD) (HR: 0.78, 95% CI: 0.6 – 0.9; p=0.02) was also associated with better GRFS while increasing donor age (continuous variable) (HR: 1.02, 95% CI: 1 – 1.04; p<0.001), and the use of non-myeloablative conditioning (HR: 2.5, 95% CI: 1.6 – 3.8; p<0.001) adversely impacted GRFS.
Figure 1.
(Total Cohort) (a) Graft-versus-host-disease free/Relapse-free survival; (b) grade II-IV acute graft-versus-host-disease; (c) grade III-IV acute graft-versus-host-disease; (d) moderate-severe graft-versus-host-disease
Acute and chronic GvHD
At D+100, the cumulative incidence of grade II-IV acute GvHD was 28.1% (95% CI: 23 – 33) in Group A, 39.9% (95% CI: 36 – 44) in Group B, and 39.7% (95% CI: 35 – 45) in group C (p<0.001) (Figure 1b). The corresponding incidence of grade III-IV acute GvHD was 7.2% (95% CI: 5 – 10), 13.4% (95% CI: 11 – 16), and 12.4% (95% CI: 9 – 16) in Groups A, B, and C, respectively (p<0.001) (Figure 1c)
At 12 months, the incidence of moderate-severe cGvHD was significantly lower in Group A (8.1%; 95% CI, 5–11) compared to Group B (31%; 95% CI, 28–35) and Group C (20.8%; 95% CI, 17–25) (p < 0.001) (Figure 1d).
NRM
At 12 months, NRM was 5.9% (95% CI, 4–9) in Group A, 11.3% (95% CI, 9–14) in Group B, and 11.7% (95% CI, 9–15) in Group C (p = 0.01) (Figure 3a). On MVA, PTCy-based GvHD prophylaxis was associated with significantly reduced NRM (HR = 0.50; 95% CI, 0.3–0.8; p = 0.004), as was use of MUD vs MMUD (HR = 0.57; 95% CI, 0.3–0.8; p = 0.001). HCT-CI score ≥3 (HR: 1.63, 95% CI: 1.2 – 2.2, p=0.001) and moderate-severe chronic GvHD (HR: 2.32, 95% CI: 1.5 – 3.6; p=0.001) were associated with increased NRM.
Figure 3.
(a) Non-relapse mortality; (b) relapse; (c) Non-relapse mortality in the propensity score matched cohort; (d) Relapse in the propensity score matched cohort
Relapse
The cumulative incidence of relapse at 24 months was comparable across GvHD prophylaxis groups (Group A: 25.7%, Group B: 20.5%, Group C: 24.1%; p = 0.24) (Figure 3b). On MVA, increasing recipient age (HR = 1.01; 95% CI, 1.00–1.10; p = 0.05) and high/very high DRI (p < 0.001) were independently associated with increased relapse risk.
OS
The 24-month OS was similar across groups: 73.9% (95% CI: 68–79) in Group A, 73% (95% CI: 69–76) in Group B, and 70.5% (95% CI: 66–75) in Group C (p = 0.61). On MVA, NMA conditioning (HR: 2.3; 95% CI: 1.3–3.9; p = 0.002), increasing donor age (HR: 1.02; 95% CI: 1.00–1.10; p = 0.001), and recipient CMV seropositivity (HR: 1.36; 95% CI: 1.10–1.80; p = 0.01) were associated with inferior OS.
MVA
To adjust for potential confounders, we performed an MVA including GvHD prophylaxis regimens (CNI-MTX/MMF as reference), donor and recipient age (as continuous variables), conditioning regimen intensity (MAC vs RIC and NMA), stem cell source (PBSC vs BM), donor type (MUD vs MMUD), donor-recipient CMV serostatus, moderate-severe chronic GvHD (as a time-dependent covariate), DRI (low vs intermediate/high/ very-high), and HCT-CI (≥3 vs <3). PTCy-based prophylaxis was independently associated with improved GRFS (HR: 0.44; 95% CI: 0.35–0.54; p<0.001), reduced grade II-IV acute GvHD (HR: 0.76, 95% CI: 0.68 – 0.85; p<0.01), grade III-IV acute GvHD (HR: 0.65, 95% CI: 0.53 – 0.80; p<0.01), moderate-severe chronic GvHD (HR: 0.20, 95% CI: 0.12 – 0.30; p<0.01), and lower NRM (HR: 0.50, 95% CI: 0.3 – 0.8; p=0.004). GvHD prophylaxis had no significant impact on relapse or OS. Full results of the MVA are summarized in Table 3.
Table 3:
Multivariable Analysis (total cohort)
| Variable | HR | 95% CI | p |
|---|---|---|---|
| GvHD-free/Relapse-free survival | |||
| • PTCy | 0.44 | 0.35 – 0.54 | <0.001 |
| • NMA | 2.50 | 1.60 – 3.80 | <0.0001 |
| • Very high | 2.69 | 1.74 – 4.16 | <0.001 |
| Age (continuous variable) | 1.01 | 0.99 – 1.02 | 0.18 |
| Donor age (continuous variable) | 1.02 | 1.01 – 1.02 | <0.001 |
| PBSC (vs BM) | 1.10 | 0.99 – 1.40 | 0.05 |
| MUD (vs MMUD) | 0.78 | 0.63 – 0.96 | 0.02 |
| Non-relapse Mortality | |||
| • PTCy | 0.50 | 0.31 – 0.81 | 0.004 |
| • NMA | 1.72 | 0.74 – 4.01 | 0.20 |
| Chronic GvHD (time dependent) | 2.32 | 1.50 – 3.58 | 0.001 |
| Age (continuous variable) | 0.98 | 0.95 – 1.00 | 0.11 |
| Donor age (continuous variable) | 1.00 | 0.98 – 1.01 | 0.90 |
| PBSC (vs BM) | 0.85 | 0.61 – 1.18 | 0.34 |
| MUD (vs MMUD) | 0.57 | 0.33 – 0.76 | 0.001 |
| HCT-CI score ≥ 3 | 1.63 | 1.20 – 2.22 | 0.001 |
| Relapse | |||
| • PTCy | 1.20 | 0.89 – 1.61 | 0.21 |
| • NMA | 1.65 | 0.82 – 3.31 | 0.15 |
| • Very high | 3.39 | 1.71 – 6.72 | 0.0004 |
| Chronic GvHD (time dependent) | 0.85 | 0.61 – 1.18 | 0.33 |
| Age (continuous variable) | 1.01 | 0.99 – 1.03 | 0.05 |
| Donor age (continuous variable) | 1.001 | 0.98 – 1.01 | 0.90 |
| PBSC (vs BM) | 0.98 | 0.75 – 1.24 | 0.81 |
| MUD (vs MMUD) | 1.23 | 0.87 – 1.75 | 0.23 |
| HCT-CI score ≥ 3 | 1.16 | 0.93 – 1.44 | 0.16 |
| Acute GvHD grade III-IV | |||
| • PTCy | 0.65 | 0.53 – 0.80 | 0.00003 |
| • NMA | 1.18 | 0.84 – 1.52 | 0.59 |
| Age (continuous variable) | 0.99 | 0.96 – 1.02 | 0.94 |
| Donor age (continuous variable) | 1.01 | 0.99 – 1.03 | 0.12 |
| PBSC (vs BM) | 1.45 | 0.97 – 2.13 | 0.05 |
| MUD (vs MMUD) | 0.51 | 0.34 – 0.77 | 0.001 |
| Chronic GvHD moderate – severe | |||
| • PTCy | 0.20 | 0.12 – 0.29 | <0.001 |
| • NMA | 0.63 | 0.23 – 1.72 | 0.59 |
| Acute GvHD grade III-IV (time dependent) | 2.08 | 1.59 – 2.71 | <0.001 |
| Age (continuous variable) | 1.01 | 0.99 – 1.02 | 0.21 |
| Donor age (continuous variable) | 1.01 | 0.99 – 1.01 | 0.14 |
| PBSC (vs BM) | 1.36 | 1.05 – 1.77 | 0.02 |
| MUD (vs MMUD) | 1.05 | 0.72 – 1.53 | 0.77 |
Abbreviations: ATG: anti-thymocyte globulin; BM: bone marrow; Cni: Calcineurin inhibitor; GvHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; MTX: methotrexate; MMF: mycophenolate mofetil; MAC: myeloablative; MUD: matched unrelated donor; MMUD: mismatched unrealted donor; NMA: non-myeloablative; PTCy: post-transplantation cyclophosphamide; PBSC: peripheral blood stem cells; RIC: reduced intensity conditioning; Tac: tacrolimus
PSM
In the PSM cohort, the 24-month GRFS was 58.2% (95% CI: 52 – 64) in patients receiving PTCy-based prophylaxis and 32.9% (95% CI: 27 – 39) in the CNI-MTX/MMF ± ATG group (p<0.001) (Figure 2 a, b, c, d). On MVA, PTCy remained independently associated with improved GRFS (HR: 0.48; 95% CI: 0.40–0.60; p<0.001). PTCy-based prophylaxis was also associated with reduced incidence of grade II-IV acute GvHD (HR: 0.54, 95% CI: 0.4 – 0.7; p<0.01), grade III-IV acute GvHD (HR: 0.36, 95% CI: 0.2 – 0.6; p=0.002), moderate-severe chronic GvHD (HR: 0.28, 95% CI: 0.17–0.46; p,0.01), and NRM (HR: 0.52, 95% CI: 0.31 – 0.88; p=0.01) (Figure 3 c, d), (Figure 4). These findings were consistent with those in the overall cohort.
Figure 2.
(Propensity score matched cohort) (a) Graft-versus-host-disease free/Relapse-free survival; (b) grade II-IV acute graft-versus-host-disease; (c) grade III-IV acute graft-versus-host-disease; (d) moderate-severe graft-versus-host-disease
Figure 4:
Multivariable analysis of transplantation outcomes. Forest plot demonstrating hazard ratios (HRs) and 95% confidence intervals (CIs) for key clinical variables.
Discussion
YAs are a unique population with distinct medical, psychological, and social needs (1,3,5–9). This study included a large contemporary cohort of 1,387 YA patients undergoing HSCT, the majority of whom received PBSC grafts and MAC. Using PSM to balance baseline characteristics and reduce confounding, we confirmed that PTCy-based GVHD prophylaxis was independently associated with improved GRFS, lower rates of acute and chronic GVHD, and reduced non-relapse mortality, without affecting relapse or overall survival.
AYAs undergoing HSCT experience poorer outcomes when compared to children (25,26). Grain et al. reported significantly lower 5-year OS in AYAs compared to children under 15 years, with the excess mortality primarily attributed to higher NRM. Most NRM events in AYAs were related to chronic GVHD, which occurred more frequently in this group, even when bone marrow was used as the graft source. Consequently, the GRFS was lower in AYAs compared to children (26). Similarly, a large CIBMTR registry study reported that AYAs had a 1.5-fold higher risk of mortality compared to children, largely due to increased NRM from higher rates of chronic GVHD (27). This may be partly explained by the greater use of PBSC in AYAs, particularly among those transplanted at adult centers, where PBSC use was significantly more common than at pediatric centers (27).
The increased incidence of chronic GvHD in this population is particularly concerning due to its impact on long-term health outcomes and quality of life (15). Chronic GVHD imposes considerable socioeconomic burdens, including high rates of disability leave, reduced work hours, job loss, and income reduction. Dependence on caregiver support is common, with caregivers frequently experiencing employment disruptions, thereby exacerbating the overall impact on patients and their families (16). These effects are especially detrimental for YAs navigating critical life stages such as education, career development, and identity formation (5,6,9,15). Chronic GvHD also contributes to increased healthcare resource utilization, placing additional strain on the healthcare system (28).
Historically, the development of chronic GvHD has been regarded as a surrogate for enhanced graft-versus-leukemia activity, contributing to reduced relapse rates after HSCT (29,30). As a result, higher rates of chronic GvHD have often been accepted as a necessary trade-off in patients with high-risk disease. However, this perspective underestimates the significant morbidity and long-term burden imposed by chronic GvHD, which often necessitates prolonged immunosuppressive therapy that increases the risk of life-threatening infections and disease relapse (31). This highlights the importance of effective GvHD prophylaxis. PTCy has been associated with a reduced risk of GVHD and has been shown to lower the global immunosuppressive burden, potentially mitigating these complications (32). In this study, we observed a reduced incidence of chronic GvHD without a corresponding increase in relapse risk, a finding consistently reported in the literature (13,14,33–35). This may indicate that effective disease control can be achieved without the potentially life-altering complication of chronic GvHD.
Our findings support the routine consideration of PTCy-based GvHD prophylaxis in YA patients, without concern for increased relapse risk. As transplant outcomes continue to improve, GRFS should be increasingly recognized as a clinically meaningful endpoint, particularly in this population. Living with chronic GvHD poses a significant burden for all patients, but it is especially detrimental to the long-term quality of life and functional outcomes of YA survivors.
The advantages of PTCy-based prophylaxis may extend beyond the prevention of GvHD. Recent reports suggest that PTCy is associated with lower rates of second primary malignancies, most likely as a consequence of reduced chronic GvHD and the attendant decrease in prolonged immunosuppressive therapy (36). This may be particularly relevant for YA patients, who have a long life expectancy after transplant and are therefore more susceptible to developing late complications.
Optimizing the dosing of PTCy remains an important future direction to ensure an optimal balance between efficacy and toxicity (37). Identifying the ideal combination with PTCy is also crucial to improve GRFS. We have previously reported promising GRFS using anti-thymocyte globulin in combination with PTCy. This approach warrants further investigation in prospective trials.
To the best of our knowledge, this is the first study to specifically assess GRFS in the YA population across different GvHD prophylaxis regimens in the unrelated donor setting. Strengths include the use of a large, contemporary registry dataset and propensity score matching to reduce confounding. However, as a retrospective registry-based analysis, the study has inherent limitations. These include potential selection bias, missing data, lack of granular clinical details, and variable center-specific practices. Despite these, the findings provide important insights and lay the groundwork for future prospective studies. In conclusion, PTCy-based GVHD prophylaxis improves GRFS in the YA population undergoing MUD/MMUD HSCT, the majority of whom received PBSC grafts and myeloablative conditioning. Prospective trials are needed to validate these findings and further optimize transplant strategies for this group.
Supplementary Material
Key Points:
Young adults represent a distinct population with unique medical, psychological, and social needs that make graft-versus-host disease-free/relapse-free survival (GRFS) a particularly relevant outcome.
Post-transplant cyclophosphamide (PTCY)-based graft-versus-host disease prophylaxis significantly improves GRFS compared to non-PTCY strategies in this population undergoing unrelated donor allogeneic hematopoietic cell transplantation.
Funding source:
This dataset was collected by the Center for International Blood and Marrow Transplant Research (CIBMTR) which is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute; the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; 75R60222C00011 from the Health Resources and Services Administration; N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research; the National Marrow Donor Program; and the Medical College of Wisconsin
Footnotes
Conflict of interest disclosure: The authors have no conflict of interest to declare.
Data availability statement:
This study used a publicly available dataset from the Center for International Blood and Marrow Transplant Research (CIBMTR). The dataset can be accessed at https://www.cibmtr.org following their terms of use.
References
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Associated Data
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Supplementary Materials
Data Availability Statement
This study used a publicly available dataset from the Center for International Blood and Marrow Transplant Research (CIBMTR). The dataset can be accessed at https://www.cibmtr.org following their terms of use.