-
1.
Prophylactic maintenance with venetoclax/azacitidine after reduced intensity conditioning allo-transplant for high risk MDS and AML
Garcia, J. S., Kim, H. T., Murdock, H. M., Ansuinelli, M., Brock, J., Cutler, C. S., Gooptu, M., Ho, V. T., Koreth, J., Nikiforow, S., et al
Blood advances. 2024
Abstract
We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) in patients with high risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic hematopoietic stem cell transplantation following venetoclax and FluBu2-conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% prior venetoclax exposure and 96% molecular measurable residual disease (MRD)-positive), 22 received maintenance therapy with azacitidine 36 mg/m2 intravenously on days 1-5 and venetoclax 400 mg by mouth on days 1-14 on one of two schedules (42-day cycles x 8 or 28-day cycles x 12). During maintenance, the most common grade 3/4 adverse events were leukopenia, neutropenia and thrombocytopenia, which were transient and manageable. Infections were uncommon (n=4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% CI, 0.3-18%) and 22% (95% CI, 9-40%). After a median follow-up of 25-months among survivors, median overall survival (OS) was not reached. In the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, non-relapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43-83%), 59% (95% CI, 36-76%), 0%, and 41% (95% CI, 20-61%), respectively. Immune monitoring demonstrated no significant impact on T cell expansion, but identified reduced B cell expansion compared to controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered in high risk MDS/AML patients, but a randomized study is required to properly assess any potential benefit. (NCT03613532).
-
2.
Opportunistic Infections in Patients Receiving Post-Transplant Cyclophosphamide: Impact of Haploidentical Versus Unrelated Donor Allograft
Little, J. S., Duléry, R., Shapiro, R. M., Aleissa, M. M., Prockop, S. E., Koreth, J., Ritz, J., Antin, J. H., Cutler, C., Nikiforow, S., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) is an effective strategy for graft-versus-host disease (GVHD) prophylaxis and is the standard of care for haploidentical hematopoietic cell transplantation (HCT). It is increasingly used for matched and mismatched unrelated donor (MUD/MMUD) HCT, but infections remain a concern. OBJECTIVE The objective of this study was to evaluate the characteristics and risk factors for infections in haploidentical and unrelated donor HCT recipients treated with PTCy-based GVHD prophylaxis. STUDY DESIGN This single-center retrospective study examined 354 consecutive adults undergoing HCT with PTCy-based GVHD prophylaxis (161 MUD/MMUD; 193 haploidentical) between 2015 and 2022. Opportunistic infections (OIs) including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), and invasive fungal disease (IFD) were assessed from day 0 through day +365. The one-year cumulative incidence function of OIs and non-relapse mortality were calculated using dates of relapse and repeat HCT as competing risks. Secondary analysis evaluated risk factors for OIs and NRM using univariate and multivariable Cox regression models. RESULTS Haploidentical HCT recipients had an increased risk of OIs compared to unrelated donor allograft recipients (39% haploidentical vs. 25% MUD/MMUD; HR 1.70; 95% CI 1.16 - 2.49; p=0.006). On multivariable analysis, haploidentical donor (HR 1.50; 95% CI 1.01 - 2.23; p=0.046), prior HCT (HR 1.99; 95% CI 1.29 - 3.09; p=0.002), and diagnosis of acute GVHD (HR 1.47; 95% CI 1.02 - 2.14; p=0.041) were associated with an increased risk of OIs. Non-relapse mortality within the first year was not significantly different between the two groups (HR 1.11; 95% CI 0.64 - 1.93; p=0.70). CONCLUSIONS Overall, haploidentical donor was a significant risk factor for OIs in patients receiving PTCy, although one-year NRM was not different between haploidentical and MUD/MMUD HCT recipients. CMV and adenovirus infections were significantly increased amongst haploidentical HCT recipients, while the incidence of EBV infection and IFD was similar between the groups. Our findings may have implications for infection monitoring and prophylaxis in the setting of PTCy, particularly in haploidentical HCT recipients.
-
3.
Systematic Evaluation of Donor-KIR/Recipient-HLA Interactions in HLA-matched Hematopoietic Cell Transplantation for AML
Fein, J. A., Shouval, R., Krieger, E., Spellman, S. R., Wang, T., Baldauf, H., Fleischhauer, K., Kröger, N., Horowitz, M. M., Maiers, M., et al
Blood advances. 2023
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
In acute myeloid leukemia (AML), donor NK-cell killer immunoglobulin-like receptors (KIR) and recipient HLA interactions may contribute to the graft-versus-leukemia effect of allogeneic hematopoietic cell transplantation (HCT). Analyses of individual KIR/HLA interactions however have yielded conflicting findings, and their importance in the HLA-matched unrelated donor (MUD) setting remains controversial. We systematically studied outcomes of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit. Adult AML patients (n=2025) transplanted in complete remission who received MUD grafts reported to the Center for International Blood and Marrow Transplantation were evaluated. Only the donor-2DL2present/recipient-HLA-C1present pair was associated with reduced relapse (hazard ratio 0.79 [95% confidence interval: 0.67, 0.93], p = 0.006) compared with donor-2DL2absent/recipient-HLA-C1present. However, no association were found when comparing HLA-C groups among KIR-2DL2present-graft recipients. We identified nine prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype (G)5 in all recipients and G3 in Bw4present recipients were associated with decreased relapse risk (HR 0.52 [0.35, 0.78], p = 0.002; 0.32 [0.14, 0.72], p = 0.006, respectively) and G2 (HR 1.63 [1.15, 2.29], p = 0.005) with increased relapse risk C1-homozygous recipients, compared to patients with the same ligand. However, we could not validate these findings in an external dataset of 796 AML transplants from the German transplantation registry. Neither a systematic evaluation of known HLA-KIR interactions nor an empiric assessment of prevalent KIR genotypes demonstrated clinically actionable associations, therefore not supporting these KIR-driven strategies for MUD selection in AML.
PICO Summary
Population
Adults with acute myeloid leukaemia who underwent matched unrelated donor (MUD) transplantation in complete remission, identified from the CIBMTR registry (n=2025)
Intervention
Evaluation of individual donor-KIR/recipient-HLA interactions for HCT outcomes and empirically evaluated prevalent KIR genotypes for clinical benefit.
Comparison
Independent validation cohort of 796 AML transplants from the German transplantation registry (n=796)
Outcome
Only the donor-2DL2+/recipient-HLA-C1+ pair was associated with reduced relapse (hazard ratio 0.79 [95% confidence interval: 0.67, 0.93]) compared with donor-2DL2-/recipient-HLA-C1+. However, no association were found when comparing HLA-C groups among KIR-2DL2+-graft recipients. We identified nine prevalent donor KIR genotypes in our cohort and screened them for association with relapse risk. Genotype (G)5 in all recipients and G3 in Bw4+recipients were associated with decreased relapse risk (HR 0.52 [0.35, 0.78]; 0.32 [0.14, 0.72], respectively) and G2 (HR 1.63 [1.15, 2.29]) with increased relapse risk C1-homozygous recipients, compared to patients with the same ligand.
-
4.
Posttransplant cyclophosphamide vs tacrolimus-based GVHD prophylaxis: lower incidence of relapse and chronic GVHD
Maurer, K., Ho, V. T., Inyang, E., Cutler, C. S., Koreth, J., Shapiro, R. M., Gooptu, M., Romee, R., Nikiforow, S., Antin, J. H., et al
Blood advances. 2023
-
-
-
Free full text
-
Full text
-
Editor's Choice
Abstract
The ability of post-transplant cyclophosphamide (PTCY) to facilitate stem cell transplantation using HLA-haplotype-mismatched donors has spurred interest in whether PTCY can improve clinical outcomes in patients with HLA-matched unrelated donors undergoing peripheral blood stem cell transplantation (PBSCT). We investigated our institutional experience with 8/8 or 7/8 HLA-matched unrelated donor PBSCT using PTCY-based GVHD prophylaxis compared to conventional tacrolimus-based regimens. We compared overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality, and acute and chronic GVHD in 107 adult patients receiving a PTCY-based regimen versus 463 patients receiving tacrolimus-based regimens for GVHD prophylaxis. All patients were transplanted for hematologic malignancies. The two cohorts were well balanced for baseline characteristics except that more patients in the PTCY cohort received 7/8 matched PBSCT. There was no difference in acute GVHD. All-grade chronic GVHD and moderate-severe chronic GVHD were substantially reduced in patients receiving PTCY compared to tacrolimus-based regimens (2-year moderate-severe chronic GVHD 12% vs 36%, p<0.0001). Recipients of PTCY-based regimens also had a lower incidence of relapse compared to recipients of tacrolimus-based regimens (25% vs. 34% at 2-years, p=0.027), primarily in patients who received reduced intensity conditioning. This led to improved PFS in the PTCY cohort (64% vs 54% at 2 years, p=0.02). In multivariable analysis, hazard ratio was 0.59 (p=0.015) for PFS and subdistribution hazard ratio was 0.27 (p<0.0001) for moderate-severe chronic GVHD and 0.59 (p=0.015) for relapse. Our results suggest that PTCY prophylaxis is associated with lower rates of relapse and chronic GVHD in patients who receive HLA-matched unrelated donor PBSCT.
PICO Summary
Population
Adults who underwent allogeneic peripheral blood HSCT from unrelated donor between 2018 and end of 2021 from a single centre in USA (n=570)
Intervention
Post-transplant cyclophosphamide (PTCY)-based GvHD prophylaxis regimen (n=107)
Comparison
Tacrolimus-based GVHD prophylaxis regimen (n=463)
Outcome
There was no difference in acute GVHD. All-grade chronic GVHD and moderate-severe chronic GVHD were substantially reduced in patients receiving PTCY compared to tacrolimus-based regimens (2-year moderate-severe chronic GVHD: 12% vs 36%). Recipients of PTCY-based regimens also had a lower incidence of relapse compared to recipients of tacrolimus-based regimens (25% vs. 34% at 2-years), primarily in patients who received reduced intensity conditioning. This led to improved progression-free survival (PFS) in the PTCY cohort (64% vs 54% at 2 years). In multivariable analysis, hazard ratio was 0.59 for PFS and subdistribution hazard ratio was 0.27 for moderate-severe chronic GVHD and 0.59 for relapse.
-
5.
Clinical Features of AKI in the Early Post-Transplant Period Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation
Vergara-Cadavid, J., Johnson, P. C., Kim, H. T., Yi, A., Sise, M. E., Leaf, D. E., Hanna, P. E., Ho, V. T., Cutler, C. S., Antin, J. H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplant (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). Few studies have examined risk factors for AKI at engraftment, or its relationship with clinical outcomes. OBJECTIVE The objective of this study was to examine the incidence and risk factors for peri-engraftment AKI, as well as the association between AKI and overall survival and non-relapse mortality. METHODS We conducted a retrospective analysis of adult patients receiving reduced intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Peri-engraftment (day 0 to day 30) AKI incidence and severity was defined using modified Kidney Disease: Improving Global Outcomes criteria. Factors associated with peri-engraftment AKI risk were examined using Cox regression analysis. The impact of peri-engraftment AKI on overall survival and non-relapse mortality (defined as death without recurrent disease after HCT), was evaluated using Cox regression and Fine and Gray's competing risk model, respectively. Kidney recovery, defined as a return of serum creatinine within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 in relation to HCT. RESULTS Peri-engraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days [IQR 4-30] post-transplant. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (HR: 1.56, 95% CI: 1.20-2.03; p<0.001), fludarabine/melphalan conditioning (HR: 1.35, 95% CI: 1.01-1.81; p=0.05; compared to fludarabine/busulfan and fludarabine, cyclophosphamide, total body irradiation), HCT-Comorbidity Index ≥4 (HR: 1.43, 95% CI: 1.14-1.79; p=0.002), albumin <3.4 g/dl (HR: 2.04, 95% CI: 1.33-3.12; p=0.001), hemoglobin ≤12 (HR 1.96, 95% CI 1.38-2.78; p<0.001), supratherapeutic tacrolimus (HR 1.45, 95% CI 1.07 - 1.95; p=0.02), and baseline serum creatinine >1.1 mg/dl (HR: 1.87, 95% CI: 1.48-2.35; p<0.001). Peri-engraftment AKI was associated with worse overall survival (HR 1.40, 95% CI: 1.16-1.71; p<0.001) and non-relapse mortality (subdistribution HR 2.10, 95% CI: 1.52-2.89; p<0.001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, 2, and 3 AKI without KRT, respectively, and 4 of 16 (25%) patients were liberated from KRT. CONCLUSION Peri-engraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for peri-engraftment AKI. Peri-engraftment AKI is associated with worse overall survival and non-relapse morality, highlighting the importance of timely recognition and management of AKI.
-
6.
Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse
Shapiro, R. M., Kim, H. T., Ansuinelli, M., Guleria, I., Cutler, C. S., Koreth, J., Gooptu, M., Antin, J. H., Kelkar, A. H., Ritz, J., et al
Blood advances. 2023
Abstract
Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles the CRS after chimeric antigen receptor (CAR)-T therapy. We conducted this single-center retrospective study evaluating the association of post-haploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction, and graded according to established criteria. The development of post-haploidentical HCT CRS was associated with a lower incidence of disease relapse (p=0.024) but with an increased risk of chronic GVHD (p=0.01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor TNC dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (p<0.0005), CD4+ Tcon (p<0.005) and CD8+ T-cells (p<0.005) were increased at 1 month following HCT compared to those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells at 1 month post HCT was most notable among patients with CRS who received a bone marrow graft (p<0.005). The development of post haploidentical HCT CRS is associated with a reduced incidence of disease relapse and with a transient effect on post HCT immune reconstitution of T cells and their subsets. Validation of these observations in a multicenter cohort is required.
-
7.
A Phase I-II Trial of Early Azacitidine after Matched Unrelated Donor Hematopoietic Cell Transplant
Xu, Z., Choi, J., Cooper, M., King, J., Fiala, M. A., Liu, J., Pusic, I., Romee, R., Cashen, A., Jacoby, M. A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic cell transplant (allo-HCT). Azacitidine (AZA) is a hypomethylating agent that has been shown to be effective in preclinical and clinical studies for the prevention of acute GvHD (aGvHD). OBJECTIVES We sought to determine the maximum tolerated dose (MTD) of AZA when given on day 1-5 in 28-day cycles for 4 cycles, starting from day 7 after allo-HCT, as well as its impact on acute and chronic GvHD, relapse, and overall survival in patients undergoing matched unrelated donor allo-HCT. STUDY DESIGN This study was a single-arm, single-center, open-label phase I-II study with a total of 15 and 38 patients enrolled in the phase I and II portions of the trial, respectively. A standard 3+3 study design was used in phase I, and all patients in phase II received AZA at MTD determined in phase I. RESULTS The MTD of AZA post-transplant starting at day 7 was 45mg/m(2). The phase II part of the study was halted after enrolling 38 out of the 46 planned patients following an interim analysis that suggested futility. Overall, AZA at 45mg/m(2) exhibited a side-effect profile consistent with prior reports and had minimal impact on engraftment. The cumulative incidence of clinically significant acute GvHD by day 180 was 39.9% (95% CI 22-53.7%). The incidence of all grades chronic GvHD was 61.4% (95% CI 40.3-75%). At one year, the overall survival was 73.7% (95% CI 60.9-89.1%), and the disease relapse rate was 11.4% (95% CI 0.2-21.3%). CONCLUSION Early post-allo-HCT AZA has limited efficacy in preventing acute and chronic GvHD but could have a beneficial effect in preventing disease relapse.
-
8.
Invasive Yeast Infection After Haploidentical Donor Hematopoietic Cell Transplantation Associated with Cytokine Release Syndrome
Little, J. S., Shapiro, R. M., Aleissa, M. M., Kim, A., Chang, J. B. P., Kubiak, D. W., Zhou, G., Antin, J. H., Koreth, J., Nikiforow, S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Use of haploidentical donor hematopoietic cell transplantation (haploHCT) has expanded but recent reports raise concern for increased rates of infectious complications. The incidence and risk factors for invasive fungal disease (IFD) after haploHCT have not been well elucidated. OBJECTIVE The objective of this study is to evaluate the incidence and risk factors for IFD after haploHCT. The identification of key risk factors will permit targeted prevention measures and may explain elevated risk for other infectious complications after haploHCT. STUDY DESIGN We performed a single-center retrospective study of all adults undergoing haploHCT between May 2011 and May 2021 (n=205). The 30-day and one-year cumulative incidence of proven or probable IFD and one-year non-relapse mortality (NRM) were assessed. Secondary analysis evaluated risk factors for invasive yeast infection (IYI) using univariate and multivariable Cox regression models. RESULTS Twenty-nine patients (14%) developed IFD following haploHCT. Nineteen (9.3%) developed IYI in the first year, 13 of which occurred early with a 30-day cumulative incidence of 6.3% (95% CI 2.9 - 9.6%) and increased NRM in patients with IYI (53.9% versus 10.9%). The majority of yeast isolates (17/20; 85%) were fluconazole susceptible. The incidence of IYI in the first 30 days after haploHCT was 10% among the 110 (54%) patients who developed cytokine release syndrome (CRS) and 21% among the 29 (14%) who received tocilizumab. On multivariable analysis, AML (HR 6.24; 1.66 - 23.37; p=0.007) and CRS (HR 4.65; 1.00 - 21.58; p=0.049) were associated with an increased risk of early IYI after haploHCT. CONCLUSION CRS after haploHCT is common and is associated with increased risk of early IYI. The identification of CRS as a risk factor for IYI raises questions about its potential association with other infections after haploHCT. Recognition of key risk factors for infection may permit individualized strategies for prevention and intervention and minimize potential side effects.
-
9.
Ibrutinib in Steroid-Refractory Chronic Graft-Versus-Host Disease, a Single-Center Experience
Chin, K. K., Kim, H. T., Inyang, E. A., Ho, V., Koreth, J., Romee, R., Gooptu, M., Shapiro, R., Antin, J., Soiffer, R., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogenic hematopoietic stem cell transplantation. Corticosteroid-based therapies are a mainstay of its initial treatment but there is no consensus in how to treat steroid-refractory cGVHD. Ibrutinib is a Bruton Tyrosine Kinase and Interleukin-2 Inducible Kinase inhibitor thought to affect pathways driving cGVHD, and it was approved for the treatment of refractory cGVHD by the Food and Drug Administration in August 2017 after a landmark Phase 1b/2 study. It was the first medication approved for this indication, but how to best treat refractory cGVHD remains an open question and there has been limited post-FDA approval literature studying ibrutinib. OBJECTIVE This study sought to characterize the utilization and outcomes associated with ibrutinib use in cGVHD via a retrospective single-center study. STUDY DESIGN 53 patients were identified as having been treated with ibrutinib for cGVHD following FDA approval between September 1(st), 2017, and December 31(st), 2020 using an institutional data repository. Their records were reviewed for demographics, cGVHD characteristics, and outcomes. RESULTS For the entire cohort, two-year overall survival was 76% (95% CI: 60%, 86%) with median follow-up among survivors 26 months (range 1.3-39.5). However, two-year failure free survival (FFS) after initiation of ibrutinib was 9% (95% CI: 2.6%, 20%) and median FFS was 4.5 months (95% CI: 2.8, 7.1). Events of FFS included treatment change due to lack of response or toxicity, malignant relapse, or non-treatment related mortality. 21% of patients (n=11) remain on ibrutinib. At time of FFS event or last follow-up, 12% (n=6) had a complete or partial response while 64% had stable disease (n=34) and 25% (n=13) had progressive disease. Ibrutinib use was associated with no reduction in corticosteroid dose between ibrutinib initiation and FFS event or last follow-up (mean difference 0.00, p=0.98). The most common non-corticosteroid cGVHD therapy used after ibrutinib was ruxolitinib (n=14, 33%). The most common adverse events associated with treatment discontinuation were infection (lung, skin, enterocolitis, n=6), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleed, n=5), and muscle aches (n=2). CONCLUSION In a real world setting, ibrutinib is associated with a modest response rate and FFS and its use in a narrower, more targeted, patient population may be indicated.
-
10.
Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide
Rambaldi, B., Kim, H. T., Reynolds, C., Chamling Rai, S., Arihara, Y., Kubo, T., Buon, L., Gooptu, M., Koreth, J., Cutler, C., et al
Blood advances. 2021;5(2):352-364
-
-
Free full text
-
Abstract
Administration of posttransplant cyclophosphamide (PTCy) has significantly expanded the number of patients undergoing HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). To examine immune reconstitution in these patients, we monitored T- and natural killer (NK)-cell recovery in 60 patients receiving bone marrow or peripheral blood stem cell (PBSC) grafts after haplo-HCT with PTCy and 35 patients receiving HLA-matched donor PBSC grafts with standard graft-versus-host disease (GVHD) prophylaxis. Compared with HLA-matched recipients, early T-cell recovery was delayed in haplo-HCT patients and skewed toward effector memory T cells with markedly reduced naive T cells. We found higher regulatory T (Treg)-cell/conventional T (Tcon)-cell ratios early after HCT and increased PD-1 expression on memory T cells. Within the haplo-HCT, patients who did not develop chronic GVHD (cGVHD) had higher PD-1 expression on central and effector memory CD4+ Treg cells at 1 month after transplant. These findings suggest an immunologic milieu that promotes immune tolerance in haplo-HCT patients. NK cells were decreased early after haplo-HCT with preferential expansion of immature CD56brightCD16- NK cells compared with matched donor transplants. One month after transplant, mass cytometry revealed enrichment of immature NK-cell metaclusters with high NKG2A, low CD57, and low killer-cell immunoglobulin-like receptor expression after haplo-HCT, which partially recovered 3 months post-HCT. At 2 months, immature NK cells from both groups were functionally impaired, but interleukin-15 priming corrected these defects in vitro. Increased immature/mature NK-cell ratios were associated with cytomegalovirus reactivation and increased incidence of cGVHD after haplo-HCT. These homeostatic imbalances in T- and NK-cell reconstitution after haplo-HCT reveal opportunities for early immune-based interventions to optimize clinical outcomes.