Association of CD34+ cell dose on outcome after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation (PBSCT) for adults with Acute Myeloid Leukemia (AML) in measurable residual disease (MRD)-negative remission Free

BACKGROUND:

Reduced-intensity conditioning (RIC) has expanded access of allogeneic hematopoietic cell transplantation (HCT) for adults with AML. Relative to myeloablative conditioning, RIC regimens rely more heavily on graft-versus-leukemia (GVL) effects to prevent AML relapses. Prior studies reported inconclusive results regarding a possible relationship between graft CD34⁺ cell doses and outcomes in the setting of RIC HCT. Here, we studied this relationship in a large cohort of adults with AML or MDS/AML in first or second morphologic remission who underwent 10/10-HLA matched sibling donor (MSD) or matched unrelated donor (MUD) RIC PBSCT between 6/2006 and 7/2024 at our center, with a particular focus on pre-HCT MRD as a possible modulating factor.

METHODS:

Pre-HCT MRD status was determined by 10-color multiparameter flow cytometry (MFC). For CD34⁺ cell doses, graft sample aliquots were evaluated by MFC based on patients' actual body weight. Point estimates of relapse, relapse-free survival (RFS), overall survival (OS) and non-relapse mortality (NRM) were summarized at selected time-points and compared using the Wald test. NRM was defined as death without prior relapse and was considered a competing risk for relapse, while relapse was a competing risk for NRM.

RESULTS: We identified 357 patients (median age: 66 [range: 19-80] years) for study inclusion, 63 (18%) of whom had pre-HCT MFC MRD (MRD^pos). Median infused graft CD34⁺ cell dose was 8.06 x 10⁶/kg (range=0.02-30 x 10⁶/kg). To evaluate the association of CD34⁺ cell doses on post-HCT outcomes, cell doses were transformed into a dichotomous variable (CD34⁺ cell dose^lowvs. CD34⁺ cell dose^high) after determining the optimal cutoff value (6.07 x 10⁶CD34⁺ cells/kg) by maximally selected rank statistic (accounting for multiple comparisons). After adjusting for adverse cytogenetic risk, pre-HCT MRD status, residual cytogenetic abnormalities at time of HCT, donor age, and time of HCT, recipients of CD34⁺ cell dose^low grafts had a significantly higher risk of relapse (hazard ratio [HR]=1.93 [95% confidence interval: 1.22-2.80], p<0.001) than recipients of CD34⁺ cell dose^high grafts. This increase in risk was more marked among MRD^neg patients (2-year relapse incidence, MRD^neg/CD34⁺ cell dose^lowvs. MRD^neg/CD34⁺ cell dose^high: 42% [31-53%, n=82] vs. 25% [19-31%, n=210], p=0.0092). Indeed, relapse incidences in MRD^neg/CD34⁺ cell dose^low patients approached those of MRD^pos patients (at 2 years: 54% [41-66%, n=65], p=0.14). While limited by small sample sizes, there was no difference in 2-year relapse incidence in patients who were MRD^pos when stratified by CD34⁺ cell dose (p=0.35). Of note, the association of CD34⁺ cell dose on RFS among MRD^negpatients became more apparent over time (at 6 months: 66% [56-77%] vs 76% [71-82%], p=0.085); at 2-years: 45% [35-57%] vs. 59% [53-67%], p=0.024). On the other hand, there was no apparent impact of CD34⁺ cell dose on 2-year OS (p=0.29) or 100-day NRM (p=0.84).

To examine the interaction with conditioning intensity, we then compared the RIC cohort to a similar cohort of 448 AML and MDS/AML patients who received allografts after myeloablative conditioning (MAC) and had CD34⁺ graft dose data available. These patients differed regarding regards to age, performance status, rates of secondary AML, and receipt of related vs. unrelated donor graft. Importantly, however, when stratified into CD34⁺ cell dose^low vs. CD34⁺ cell dose^high subgroups using the same cutoff as the RIC cohort, CD34+ graft dose had no impact on relapse incidence in the entire cohort (HR=1.27 [0.90-1.79], p=0.17; n=448) or the MRD^neg subset (HR=1.36 [0.86-2.14], p=0.19; n=353).

CONCLUSION:

With RIC HCT for AML or MDS/AML, lower graft CD34⁺ cell doses were associated with significantly higher relapse risk and reduced RFS. This effect was particularly pronounced in the MRD^neg cohort, with MRD^neg recipients of low CD34⁺ grafts having post-HCT outcomes similar to those of MRD^pos patients. In contrast, CD34⁺ cell dose had no significant impact on outcomes of MAC HCT recipients. These findings suggest that a low CD34⁺ cell dose may yield reduced graft-versus-leukemia effects and worse outcomes when the disease burden is low in the setting of RIC– an adverse effect that can be overcome with increased conditioning intensity. These findings offer a potential strategy to optimize outcomes for RIC HCT patients through graft composition.