Multi-target measurable residual disease assessed by error-corrected sequencing in patients with acute myeloid leukemia: An ALFA study.

The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.

Consensus-Based Guidelines for Acute Myeloid Leukemia Management in Gulf Cooperation Council Countries: Addressing Unmet Regional Needs and the Changing AML Landscape.

PURPOSE: AML is a heterogeneous hematologic malignancy. Region-specific recommendations for AML management can enhance patient outcomes. This article aimed to develop recommendations for the Gulf Cooperation Council (GCC) countries. METHODS: Ten AML panel members from Kuwait, Oman, Qatar, and the United Arab Emirates (KOQU) participated in a modified two-round Delphi process. The panel first identified the unmet regional needs and finalized a list of core variables. Next, they voted on iterative statements drawn from international recommendations and provided feedback via a questionnaire. Consensus voting ≤70% was discussed, and additional clinical decision making statements were suggested. At round closure, a consensus vote took place on revised statements. RESULTS: The panel reached ≥97.8% consensus on AML management. The panel agreed to use international risk stratification categories for personalized treatment of AML. The presence of ≥10% blasts for recurrent genetic abnormalities was required for a diagnosis of AML. Key consensus was reached for different treatment stages. The panel noted that older patients pose a challenge because of poor cytogenetics and genetic anomalies and require different treatment approaches. The panel recommended venetoclax-hypomethylating agents; fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor; and targeted therapy for AML relapsed/refractory disease. Supportive care is considered on the basis of prevailing organisms and drug resistance. CONCLUSION: The GCC KOQU's consensus-based recommendations for managing AML include an evidence-based and region-specific framework.

Chimeric antigen receptor T-cell therapy in childhood acute myeloid leukemia: how far are we from a clinical application?

Recurrent and/or refractory (R/R) pediatric acute myeloid leukemia (AML) remains a recalcitrant disease with poor outcomes. Cell therapy with genetically modified immune effector cells holds the promise to improve outcomes for R/R AML since it relies on cytotoxic mechanisms that are distinct from chemotherapeutic agents. While T cells expressing chimeric antigen receptors (CAR T cells) showed significant anti-AML activity in preclinical models, early phase clinical studies have demonstrated limited activity, irrespective of the targeted AML antigen. Lack of efficacy is most likely multifactorial, including: (i) a limited array of AML-specific targets and target antigen heterogeneity; (ii) the aggressive nature of R/R AML and heavy pretreatment of patients; (iii) T-cell product manufacturing, and (iv) limited expansion and persistence of the CAR T cells, which is in part driven by the immunosuppressive AML microenvironment. Here we review the results of early phase clinical studies with AML-specific CAR T cells, and avenues investigators are exploring to improve their effector function.

Navigating Treatment Options and Communication in Relapsed Pediatric AML.

Despite improved outcomes in newly diagnosed pediatric AML, relapsed disease remains a therapeutic challenge. Factors contributing to slow progress in improving outcomes include inherent challenges in pediatric clinical trial accrual and the scarcity of novel targeted/immunotherapy agents available for pediatric development. This paradigm is changing, however, as international collaboration grows in parallel with the development of promising targeted agents. In this review, we discuss the therapeutic landscape of relapsed pediatric AML, including conventional chemotherapy, targeted therapies, and the challenges of drug approvals in this patient population. We highlight current efforts to improve communication among academia, industry, and regulatory authorities and discuss the importance of international collaboration to improve access to new therapies. Among the therapeutic options, we highlight the approach to second hematopoietic stem cell transplant (HSCT) and discuss which patients are most likely to benefit from this potentially curative intervention. Importantly, we acknowledge the challenges in providing these high-risk interventions to our patients and their families and the importance of shared communication and decision making when considering early-phase clinical trials and second HSCT.

Implementation of and Systems-Level Barriers to Guideline-Driven Germline Genetic Evaluation in the Care of Patients With Myelodysplastic Syndrome and Acute Myeloid Leukemia.

PURPOSE: Knowledge of an inherited predisposition to myelodysplastic syndrome (MDS) and AML has important clinical implications for treatment decisions, surveillance, and care of at-risk relatives. National Comprehensive Cancer Network (NCCN) guidelines recently incorporated recommendations for germline genetic evaluation of patients with MDS/AML on the basis of personal and family history features, but the practicality of implementing these recommendations has not been studied. METHODS: A hereditary hematology quality improvement (QI) committee was formed to implement these guidelines in a prospective cohort of patients diagnosed with MDS/AML. Referral for germline genetic testing was recommended for patients meeting NCCN guideline criteria. Referral patterns and genetic evaluation outcomes were compared with a historical cohort of patients with MDS/AML. Barriers to evaluation were identified. RESULTS: Of the 90 patients with MDS/AML evaluated by the QI committee, 59 (66%) met criteria for germline evaluation. Implementation of the QI committee led to more referrals for germline evaluation in accordance with NCCN guidelines (31% v 14%, P = .03). However, the majority of those meeting criteria were never referred due to high medical acuity or being deceased or in hospice at the time of QI committee recommendations. Despite this, two (17%) of the 12 patients undergoing genetic testing were diagnosed with a hereditary myeloid malignancy syndrome. CONCLUSION: Current NCCN guidelines resulted in two thirds of patients with MDS/AML meeting criteria for germline evaluation. A hereditary hematology-focused QI committee aided initial implementation and modestly improved NCCN guideline adherence. However, the high morbidity and mortality and prolonged inpatient stays associated with MDS/AML challenged traditional outpatient genetic counseling models. Further improvements in guideline adherence require innovating new models of genetic counseling and testing for this patient population.

[Successful induction therapy for acute myeloid leukemia under management with extracorporeal membrane oxygenation].

A 53-year-old woman presented with shortness of breath and hyperleukocytosis and was admitted to our hospital. Shortly after, she went into cardiopulmonary arrest and was resuscitated. Her white blood cell count was 566,000/µl, with 94.5% cup-like blasts positive for MPO staining and FLT3-ITD positive, so she was diagnosed with acute myeloid leukemia (AML) M1. She also had disseminated intravascular coagulation and tumor lysis syndrome. Extracorporeal membrane oxygenation (ECMO) was started to manage bilateral pulmonary thromboembolism that had developed due to deep vein thrombosis, and induction therapy was performed under ECMO. On the third day of illness, the patient developed cerebral hemorrhage. Hematological remission was confirmed on the 39th day of illness. After consolidation therapy with chemotherapy and an FLT3 inhibitor, she underwent allogeneic hematopoietic stem cell transplantation, and remains alive. Case reports suggest strong evidence of mortality benefit from ECMO in patients with hematologic malignancies, particularly when ECMO served as a bridge through chemotherapy. Our patient suffered from cardiopulmonary arrest due to hyperleukocytosis and pulmonary thromboembolism, but was saved by induction of remission under ECMO. Improvements in supportive care should lead to reduction in early deaths during induction therapy.

Post-transplant de novo anti-HLA donor specific antibodies may contribute to poor graft function after haploidentical haematopoietic stem cell transplantation.

De novo anti-HLA donor-specific antibodies (DSAs) were rarely reported in stem cell transplantation patients. We present a case of 39-year-old acute myelogenous leukaemia patient who developed de novo DSAs only 16 days after transplantation with the highest mean fluorescence intensity (MFI) of 7406.23, which were associated with poor graft function (PGF). We used plasma exchange (PE) and intravenous immunoglobulin (IVIg) to reduce DSA level. A series of treatment including mesenchymal stem cells and donor cell transfusion were used to help recover graft function. On day 130, the patient achieved a successful engraftment.

Lysosome-related genes predict acute myeloid leukemia prognosis and response to immunotherapy.

Background: Acute myeloid leukemia (AML) is a highly aggressive and pathogenic hematologic malignancy with consistently high mortality. Lysosomes are organelles involved in cell growth and metabolism that fuse to form specialized Auer rods in AML, and their role in AML has not been elucidated. This study aimed to identify AML subtypes centered on lysosome-related genes and to construct a prognostic model to guide individualized treatment of AML. Methods: Gene expression data and clinical data from AML patients were downloaded from two high-throughput sequencing platforms. The 191 lysosomal signature genes were obtained from the database MsigDB. Lysosomal clusters were identified by unsupervised consensus clustering. The differences in molecular expression, biological processes, and the immune microenvironment among lysosomal clusters were subsequently analyzed. Based on the molecular expression differences between lysosomal clusters, lysosomal-related genes affecting AML prognosis were screened by univariate cox regression and multivariate cox regression analyses. Algorithms for LASSO regression analyses were employed to construct prognostic models. The risk factor distribution, KM survival curve, was applied to evaluate the survival distribution of the model. Time-dependent ROC curves, nomograms and calibration curves were used to evaluate the predictive performance of the prognostic models. TIDE scores and drug sensitivity analyses were used to explore the implication of the model for AML treatment. Results: Our study identified two lysosomal clusters, cluster1 has longer survival time and stronger immune infiltration compared to cluster2. The differences in biological processes between the two lysosomal clusters are mainly manifested in the lysosomes, vesicles, immune cell function, and apoptosis. The prognostic model consisting of six prognosis-related genes was constructed. The prognostic model showed good predictive performance in all three data sets. Patients in the low-risk group survived significantly longer than those in the high-risk group and had higher immune infiltration and stronger response to immunotherapy. Patients in the high-risk group showed greater sensitivity to cytarabine, imatinib, and bortezomib, but lower sensitivity to ATRA compared to low -risk patients. Conclusion: Our prognostic model based on lysosome-related genes can effectively predict the prognosis of AML patients and provide reference evidence for individualized immunotherapy and pharmacological chemotherapy for AML.

Developing a membrane-proximal CD33-targeting CAR T cell.

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking. METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice. RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy. CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.

Treatment outcomes of pediatrics acute myeloid leukemia (AML) and associated factors in the country's tertiary referral hospital, Ethiopia.

BACKGROUND: Pediatric Acute Myeloid Leukemia (AML) is a major cause of morbidity and mortality in children with cancer in Africa and other developing continents. Systemic chemotherapy and effective supportive care have significantly contributed to increased survival rates of pediatric AML in developed countries reaching approximately 70%. There is a paucity of contextual data regarding overall and event-free survival outcomes in children with acute myeloid leukemia in developing countries and most centers in Africa provide palliative care. The objective of this study was to assess the overall survival, event-free survival, and associated factors in pediatric AML patients treated in Ethiopia. METHODS: This retrospective study was conducted on Pediatric AML patients treated at Tikur Anbessa Hospital between January 1, 2015, and May 30, 2022. The socio-demographic profile of patients, the clinical characteristics, the biochemical and morphological subtypes of AML were analyzed using SPSS version 25. The Kaplan-Meier survival curve was used to estimate the probabilities of overall and event-free survival. Statistical significance was set at p < 0.05. RESULTS: A total of 92 children with AML were included in this study. The median age at diagnosis was 7 years (interquartile range: 5-10 years) with a slight male predominance. The median duration of symptoms was one month. Neutropenic fever (56, 86.2%) was the most common complication during treatment. About 29.3% of the patients succumbed to early death. The corresponding 1-year and 3-year OS probabilities were 28.2% and 23% respectively. The median event-free survival time for all pediatric AML patients was one-month (95% CI: 0.77-1.23). The determinants of poorer survival outcomes were FAB subtype, type of protocol used, and signs of CNS involvement (p < 0.05). CONCLUSION: The survival rates of children from AML were low in the study setting. More than 25% of AML patients succumbed to early death, and febrile neutropenia was the most common complication. Effective supportive and therapeutic measures should be taken to manage febrile neutropenia and to prevent early death in AML patients.

TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates.

TP53 mutations are found in 5%-10% of de novo myelodysplastic syndrome (MDS) and AML cases. By contrast, in therapy related MDS and AML, mutations in TP53 are found in up to 30%-40% of patients. The majority of inactivating mutations observed in MDS and AML are missense mutations localized in a few prevalent hotspots. TP53 missense mutations together with truncating mutations or chromosomal loss of TP53 determine a loss-of-function effect on normal p53 function. Clonal expansion of TP53-mutant clones is observed under the selection pressure of chemotherapy or MDM2 inhibitor therapy. TP53-mutant clones are resistant to current chemotherapy, and when responses to treatment have been observed, they have correlated poorly with overall survival. The most heavily investigated and targeted agent for patients with TP53-mutant MDS and AML has been APR-246 (eprenetapopt) a p53 reactivator, in combination with azacitidine, but also in triplets with venetoclax. Despite positive results in phase II trials, a phase III trial did not confirm superior response or improved survival. Other agents, like magrolimab (anti-CD47 antibody), failed to demonstrate improved activity in TP53-mutant MDS and AML. Agents whose activity is not dependent on a functional apoptosis system like anti-CD123 antibodies or cellular therapies are in development and may hold promises. Delivering prognostic information in a dismal disease like TP53-mutated MDS and AML is particularly challenging. The physician should balance hope and realism, describing the trajectory of possible treatments and at the same time indicating the poor outcome, together with promoting adaptive coping in patients and elaborating on the nature of the disease.

Comparison of allo-SCT, auto-SCT and chemotherapy for the treatment of patients with low- or intermediate-risk acute myeloid leukemia: a network meta-analysis.

BACKGROUND: The therapeutic status of allogeneic stem cell transplantation (allo-SCT) as a post-remission treatment for patients with high-risk acute myeloid leukemia (AML) was well-accepted. However, the optimal treatment for patients with low/favorable- or intermediate-risk AML who achieve complete remission has remained controversial. Therefore, we conducted a network meta-analysis to discuss this disputed problem. METHODS: We compared the effects of treatment strategies including allo-SCT, autologous stem cell transplantation (auto-SCT) and consolidation chemotherapy (CT) for patients with low/favorable- or intermediate-risk AML. The pooled HRs and 95% CIs for overall survival and disease-free survival were estimated with Stata12 and R software. Thirty clinical studies with 6682 patients were included in the meta-analysis. RESULTS: The results indicated that the treatment outcome of allo-SCT was the best, followed by auto-SCT, and CT was likely the worst in the total AML patients. In patients with low/favorable-risk AML, the treatment outcome of auto-SCT was likely ranked first, followed by allo-SCT, and CT was the worst. In patients with intermediate-risk AML, the treatment outcome of haploidentical stem cell transplantation (haplo-SCT) was the best, followed by allo-SCT (excluding haplo-SCT), and auto-SCT and CT were the worst. However, the median age of the haplo-SCT group was much younger than that of the control group, which may be one of the reasons for the better prognosis of the haplo-SCT group. CONCLUSIONS: Patients with low/favorable- and intermediate-risk (non-high-risk) AML should prioritize allo-SCT if they are eligible for transplantation, and auto-SCT is optional. However, in the subgroup analysis, auto-SCT was the optimal treatment choice for patients with low/favorable-risk AML, and allo-SCT was the priority selection for patients with intermediate-risk AML, especially young patients. These findings could provide references for clinical practice.

Effective delivery of anti-PD-L1 siRNA with human heavy chain ferritin (HFn) in acute myeloid leukemia cell lines.

Because of the high biocompatibility, self-assembly capability, and CD71-mediated endocytosis, using human heavy chain ferritin (HFn) as a nanocarrier would greatly increase therapeutic effectiveness and reduce possible adverse events. Anti-PD-L1 siRNA can downregulate the level of PD-L1 on tumor cells, resulting in the activation of effector T cells against leukemia. Therefore, this study aimed to produce the tumor-targeting siPD-L1/HFn nanocarrier. Briefly, the HFn coding sequence was cloned into a pET-28a, and the constructed expression plasmid was subsequently transformed into E. coli BL21. After induction of Isopropyl ß-D-1-thiogalactopyranoside (IPTG), HFn was purified with Ni-affinity chromatography and dialyzed against PBS. The protein characteristics were analyzed using SDS-PAGE, Western Blot, and Dynamic light scattering (DLS). The final concentration was assessed using the Bicinchoninic acid (BCA) assay. The encapsulation was performed using the standard pH system. The treatment effects of siPD-L1/HFn were carried out on HL-60 and K-562 cancer cell lines. The RT-PCR was used to determine the mRNA expression of PD-L1. The biocompatibility and excretion of siPD-L1/HFn have also been evaluated. The expression and purity of HFn were well verified through SDS-PAGE, WB, and DLS. RT-PCR analyses also showed significant siRNA-mediated PD-L1 silencing in both HL-60 and K-562 cells. Our study suggested a promising approach for siRNA delivery. This efficient delivery system can pave the way for the co-delivery of siRNAs and multiple chemotherapies to address the emerging needs of cancer combination therapy.

Multi-omics Analysis of a Fecal Microbiota Transplantation Trial Identifies Novel Aspects of Acute GVHD Pathogenesis.

Acute GVHD (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) associated with gut microbiota disruptions. However, whether therapeutic microbiota modulation prevents aGVHD is unknown. We conducted a randomized, placebo-controlled trial of third-party fecal microbiota transplantation (FMT) administered at the peak of microbiota injury in 100 patients with acute myeloid leukemia receiving induction chemotherapy and alloHCT recipients. Despite improvements in microbiome diversity, expansion of commensals, and shrinkage of potential pathogens, aGVHD occurred more frequently after FMT than placebo. Although this unexpected finding could be explained by clinical differences between the two arms, we asked whether a microbiota explanation might be also present. To this end, we performed multi-omics analysis of preintervention and postintervention gut microbiome and serum metabolome. We found that postintervention expansion of Faecalibacterium, a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, predicted a higher risk for aGVHD. Faecalibacterium expansion occurred predominantly after FMT and was due to engraftment of unique donor taxa, suggesting that donor Faecalibacterium-derived antigens might have stimulated allogeneic immune cells. Faecalibacterium and ursodeoxycholic acid (an anti-inflammatory secondary bile acid) were negatively correlated, offering an alternative mechanistic explanation. In conclusion, we demonstrate context dependence of microbiota effects where a normally beneficial bacteria may become detrimental in disease. While FMT is a broad, community-level intervention, it may need precision engineering in ecologically complex settings where multiple perturbations (e.g., antibiotics, intestinal damage, alloimmunity) are concurrently in effect. SIGNIFICANCE: Post-FMT expansion of Faecalibacterium, associated with donor microbiota engraftment, predicted a higher risk for aGVHD in alloHCT recipients. Although Faecalibacterium is a commensal genus with gut-protective and anti-inflammatory properties under homeostatic conditions, our findings suggest that it may become pathogenic in the setting of FMT after alloHCT. Our results support a future trial with precision engineering of the FMT product used as GVHD prophylaxis after alloHCT.

White blood cell count nadir to zero following intensive chemotherapy as a predictive factor for patients with acute myeloid leukemia.

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25-30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed. AREAS COVERED: This review provides a comprehensive overview of FLT3mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor. EXPERT OPINION: In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.

Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.