Multiple myeloma patients with a long remission after autologous hematopoietic stem cell transplantation.

Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies.

The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 (range, 18-72) years were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age>=55 was the only predictive factor in multivariable analysis for inferior PFS (HR 3.41, 95% CI: 1.21-9.60; p=0.020) and OS (HR 3.31, 95% CI: 1.08-10.18; p=0.037). Thirteen patients (9%) died in the long-term survivor group, only two of which died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n=4), followed by infection (n=2). For haplo-SCT with PTCy-based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

Impact of revised International Staging System 2 risk stratification on outcomes of patients with multiple myeloma receiving autologous haematopoietic stem cell transplantation.

The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 and 24.8 months, (p < 0.001) and the median OS was 130.8, 128.5, 94.2 and 61.4 months (p < 0.001) for patients with R2-ISS stages I, II, III and IV respectively. On multivariable analysis (MVA) for PFS, using R2-ISS stage I as reference, R2-ISS stages III (hazard ratio [95% confidence interval], 1.55 [1.05-2.29]; p = 0.028) and IV (2.04 [1.24-3.36]; p = 0.005) were associated with significantly inferior PFS. In the MVA of OS, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS (2.43 [1.18-5.01]; p = 0.017). Overall, we found that R2-ISS is a reliable prognostic tool for NDMM patients undergoing up-front auto-HCT.

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience.

OBJECTIVES: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. METHODS: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D-/R- group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. RESULTS: The analysis included 1071 consecutive allo-HCT recipients: 131 D-/R-, 557 R+/LTV-, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D-/R- group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV- and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV-, R+/LTV+, and D-/R- groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV- compared with D-/R- and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D-/R-. DISCUSSION: CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.

Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.

Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML). In a phase I clinical trial, we treated 12 patients (median age 60 years) with refractory AML (median 5 lines of prior therapy, median bone marrow blast count of 47%) with fludarabine/cytarabine followed by 6 infusions of NK-cells expanded from haploidentical donors using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL. Patients received 106-107/kg/dose. No toxicity or graft-versus-host disease (GVHD) was observed and MTD was not reached. Seven patients (58.3%) responded and achieved a complete remission (CR) with/without count recovery. Median time to best response was 48 days. Five responding patients proceeded to a haploidentical transplant from the same donor. After a median follow-up of 52 months, 1-year overall survival (OS) for the entire group was 41.7%, better for patients who responded with CR/CRi (57.14%), and for patients who responded and underwent transplantation (60%). Persistence and expansion of donor-derived NK-cells were identified in patients' blood, and serum IFNγ levels rose concurrently with NK cell infusions. A higher count-functional inhibitory KIR was associated with higher likelihood of achieving CR/CRi. In conclusion, we observed a significant response to ex vivo expanded NK-cell administration in refractory AML patients without adverse effects.

Hu8F4-CAR T cells with mutated Fc spacer segment improve target-specificity and mediate anti-leukemia activity in vivo.

Hu8F4 is a T cell receptor (TCR)-like antibody with high affinity for leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is comprised of the Hu8F4 scFv, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain, and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from AML patients in vitro. Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by mouse Fc gamma receptor (FcgR)-expressing cells. We generated Hu8F4-CAR(PQ) with mutated Fc receptor binding sites on the CH2 domain of Hu8F4-CAR to prevent unwanted interactions with FcgR-expressing cells in vivo. The primary human T cells transduced with Hu8F4-CAR(PQ) can specifically lyse HLA-A2+ PR1-expressing leukemia cell lines in vitro. Furthermore, both adult donor-derived and cord blood-derived Hu8F4-CAR(PQ)-T cells are active and can eliminate U937 leukemia cells in NSG mice. Herein, we demonstrate that modification of the IgG1-based spacer can eliminate Fc receptor-binding-induced adverse effects and Hu8F4-CAR(PQ)-T cells can kill leukemia in vivo.

Mycophenolate mofetil is associated with inferior overall survival in cytomegalovirus seropositive patients with acute myeloid leukemia undergoing hematopoietic cell transplantation.

Not available.

Safety and long-term survival results of the addition of inotuzumab ozogamicin to the conditioning regimen of allogeneic stem cell transplantation: A single-center phase 1,2 trial.

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Gene editing-based targeted integration for correction of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a severe X-linked primary immunodeficiency resulting from a diversity of mutations distributed across all 12 exons of the WAS gene. WAS encodes a hematopoietic-specific and developmentally regulated cytoplasmic protein (WASp). The objective of this study was to develop a gene correction strategy potentially applicable to most WAS patients by employing nuclease-mediated, site-specific integration of a corrective WAS gene sequence into the endogenous WAS chromosomal locus. In this study, we demonstrate the ability to target the integration of WAS2-12-containing constructs into intron 1 of the endogenous WAS gene of primary CD34+ hematopoietic stem and progenitor cells (HSPCs), as well as WASp-deficient B cell lines and WASp-deficient primary T cells. This intron 1 targeted integration (TI) approach proved to be quite efficient and restored WASp expression in treated cells. Furthermore, TI restored WASp-dependent function to WAS patient T cells. Edited CD34+ HSPCs exhibited the capacity for multipotent differentiation to various hematopoietic lineages in vitro and in transplanted immunodeficient mice. This methodology offers a potential editing approach for treatment of WAS using patient's CD34+ cells.

Azacitidine Post-transplant Maintenance Improves Disease Progression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome.

BACKGROUND: Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. MATERIALS AND METHODS: We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. RESULTS: The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). CONCLUSION: AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.

Incidence and risk factors of early onset VOD/SOS differ in younger vs older adults after stem cell transplantation.

ABSTRACT: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

Outcomes of patients with multiple myeloma and 1q gain/amplification receiving autologous hematopoietic stem cell transplant: the MD Anderson cancer center experience.

The prognostic impact of additional copies of chromosome 1q (1q + ) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008-2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p < 0.001), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, p = 0.030, 2.33, p = 0.023 and 3.00, p = 0.047, respectively). In conclusion, patients with 1q+ NDMM, especially 1q amplification, have inferior survival outcomes compared to standard-risk disease after upfront autoSCT, though outcomes are better than other high-risk cytogenetic abnormalities.

Development of a rabbit human glioblastoma model for testing of endovascular selective intra-arterial infusion (ESIA) of novel stem cell-based therapeutics.

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24). METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach. RESULTS: Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (107 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours. CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (eg, MSC-D24) in a clinically relevant fashion.

A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.

Stroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.

Effect of donor age in patients with acute myeloid leukemia undergoing haploidentical hematopoietic cell transplantation vary by conditioning intensity and recipient age.

We investigated the impact of donor age (younger [≤35 years] vs. older [>35 years]) after accounting for other non-HLA and HLA factors on outcomes of patients with acute myeloid leukemia undergoing HLA-haploidentical hematopoietic cell transplantation (n = 790). The effect differed by conditioning-partly related to the differences in the recipient age in myeloablative (MAC; median 46 years) versus reduced-intensity/non-myeloablative conditioning (RIC/NMA; median 61 years) groups. With MAC (n = 320), donor age had no impact on acute graft-versus-host disease (GVHD), but older donors were associated with a significantly higher risk of chronic GVHD (hazard ratio [HR]: 1.6, 95% confidence interval [CI]: 1.10-2.30, p = .02) independent of recipient age and other factors. Donor age had no impact on either relapse or non-relapse mortality (NRM). The impact of donor/recipient age on overall survival changed over time. Older donors were associated with significantly higher late overall mortality (>6 months) in younger recipients (≤ 50 years; HR: 2.2, 95% CI: 1.03-4.6, p = .04) but not older recipients. With RIC/NMA (n = 470), neither recipient's nor donor's age influenced the risk of GVHD. Donor age had no significant impact on the risk of relapse, but older donors were associated with a significantly higher risk of NRM (HR: 1.6, 95% CI: 1.02-2.6, p = .04) independent of recipient age. Older donor age was associated with significantly higher late overall mortality (>9 months) in older recipients (>50 years; HR: 1.66, 95% CI: 1.0-2.67; p = .049) but not in younger recipients. Donor selection based on donor age may require a tailored approach for a particular recipient.