The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation.

Acute myeloid leukemia (AML) is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter gene SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione, and multiple tricarboxylic acid (TCA) cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, which binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed patients and patients who have experienced relapse while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.

Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine.

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.

Risk of transfusion-related iron overload varies based on oncologic diagnosis and associated treatment: Retrospective analysis from a single pediatric cancer center.

BACKGROUND: Transfusion-related iron overload (TRIO) is a widely acknowledged late effect of antineoplastic therapy in pediatric cancer survivors, but firm guidelines as to screening protocols or at-risk populations are lacking in the literature. PROCEDURE: We performed retrospective analysis of all oncology patients diagnosed at our center from 2014 to 2019, who underwent TRIO screening as part of an internal quality improvement project. Correlations of MRI-confirmed TRIO with patient-, disease-, and treatment-specific features were evaluated. RESULTS: We show that a tiered screening algorithm for TRIO, when followed as intended, led to the identification of the highest proportion of patients with TRIO. We confirm that cardiac TRIO is quite rare in the oncology patient population. However, accepted surrogate markers including red blood cell transfused volume and ferritin only modestly correlated with TRIO in our patient cohort. Instead, we found that older age, leukemia diagnosis, anthracycline exposure, and receipt of stem cell transplant were most strongly associated with risk for TRIO. CONCLUSIONS: We describe associations between TRIO and patient, disease, and treatment characteristics in a multivariate risk model that could lead to an improved risk stratification of off-therapy patients, and which should be validated in a prospective manner.

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

Digital polymerase chain reaction strategies for accurate and precise detection of vector copy number in chimeric antigen receptor T-cell products.

BACKGROUND AIMS: Vector copy number (VCN), an average quantification of transgene copies unique to a chimeric antigen receptor (CAR) T-cell product, is a characteristic that must be reported prior to patient administration, as high VCN increases the risk of insertional mutagenesis. Historically, VCN assessment in CAR T-cell products has been performed via quantitative polymerase chain reaction (qPCR). qPCR is reliable along a broad range of concentrations, but quantification requires use of a standard curve and precision is limited. Digital PCR (dPCR) methods were developed for absolute quantification of target sequences by counting nucleic acid molecules encapsulated in discrete, volumetrically defined partitions. Advantages of dPCR compared with qPCR include simplicity, reproducibility, sensitivity and lack of dependency on a standard curve for definitive quantification. In the present study, the authors describe a dPCR assay developed for analysis of the novel bicistronic CD19 × CD22 CAR T-cell construct. METHODS: The authors compared the performance of the dPCR assay with qPCR on both the QX200 droplet dPCR (ddPCR) system (Bio-Rad Laboratories, Inc, Hercules, CA, USA) and the QIAcuity nanoplate-based dPCR (ndPCR) system (QIAGEN Sciences, Inc, Germantown, MD, USA). The primer-probe assay was validated with qPCR, ndPCR and ddPCR using patient samples from pre-clinical CAR T-cell manufacturing production runs as well as Jurkat cell subclones, which stably express this bicistronic CAR construct. RESULTS: ddPCR confirmed the specificity of this assay to detect only the bicistronic CAR product. Additionally, the authors' assay gave accurate, precise and reproducible CAR T-cell VCN measurements across qPCR, ndPCR and ddPCR modalities. CONCLUSIONS: The authors demonstrate that dPCR strategies can be utilized for absolute quantification of CAR transgenes and VCN measurements, with improved test-retest reliability, and that specific assays can be developed for detection of unique constructs.

Identifying patterns of neurocognitive dysfunction through direct comparison of children with leukemia, central nervous system tumors, and sickle cell disease.

PURPOSE: To quantify and compare the magnitude and type of neurocognitive dysfunction in at-risk children with central nervous system (CNS) tumors, acute lymphoblastic leukemia (ALL), and sickle cell disease (SCD) using a common instrument and metric to directly compare these groups with each other. METHODS: Fifty-three participants between the ages of 7 and 12 years (n = 27 ALL, n = 11 CNS tumor, n = 15 SCD) were enrolled and assessed using the NIH Toolbox Cognition Battery (NIHTCB). Participants with ALL or CNS tumor were 0-18 months posttherapy, while participants with SCD possessed the SS or Sß0 genotype, took hydroxyurea, and had no known history of stroke. RESULTS: Independent sample t-tests showed that participants with ALL and CNS tumor experienced greatest deficits in processing speed (ALL d = -0.96; CNS tumor d = -1.2) and inhibitory control and attention (ALL d = -0.53; CNS tumor d = -0.97) when compared with NIHTCB normative data. Participants with SCD experienced deficits in cognitive flexibility only (d = -0.53). Episodic memory was relatively spared in all groups (d = -0.03 to -0.32). There were no significant differences in function when groups were compared directly with each other by analysis of variance. CONCLUSIONS: Use of a common metric to quantify the magnitude and type of neurocognitive dysfunction across at-risk groups of participants by disease shows that participants perform below age-expected norms in multiple domains and experience dysfunction differently than one another. This approach highlights patterns of dysfunction that can inform disease- and domain-specific interventions.

Assessing the Feasibility, Acceptability, and Effectiveness of a Pilot Hepatitis C Screening Program at Food Distribution Sites in Cherokee Nation, Oklahoma.

Compared with other racial and ethnic groups in the United States, American Indian and Alaska Native (AI/AN) people experience the highest incidence of acute hepatitis c (HCV). Cherokee Nation Health Services (CNHS) implemented a pilot health screening program from January through May 2019 to assess whether conducting HCV and other preventive health screenings at food distribution sites is a feasible, acceptable, and effective strategy to increase health screening among underserved community members. Data were collected among 340 eligible participants. Most (76%) participants reported being very comfortable receiving health screenings at food distribution sites and that getting screened at food distribution sites is very easy (75.4%). Most (92.1%, n = 313) participants received HCV screening, with 11 (3.5%) individuals testing positive for HCV antibodies. Of the 11 HCV seropositive individuals, six were confirmed to have active HCV infection of which four initiated treatment. Most (55.7%) participants exhibited a body mass index in the obese range, 33.1% exhibited high hemoglobin A1C (> 6.0), 24.5% exhibited high (> 200) cholesterol, 44.6% exhibited high blood pressure ( > = 140/90), and 54.8% did not have a current primary care provider. This project demonstrated that conducting HCV and other health screenings at food distribution sites within Cherokee Nation was an effective strategy to engage AI/AN people in preventive health screenings. Future programs are needed to scale-up preventive health screenings outside of traditional medical facilities as these types of screenings may help to decrease the HCV disparities among AI/AN people.

N-terminus DUX4-immunohistochemistry is a reliable methodology for the diagnosis of DUX4-fused B-lymphoblastic leukemia/lymphoma (N-terminus DUX4 IHC for DUX4-fused B-ALL).

B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain "not otherwise specified."

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia.

BACKGROUND: The BCL-2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single-center experience with venetoclax in combination with the hypomethylating agent 5-azacitidine (aza) in pediatric patients with MDS or AML. PROCEDURE: We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high-grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy. RESULTS: Eight patients received ven/aza, two for high-grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza. CONCLUSIONS: Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late-phase clinical trials.

Metastatic angiosarcoma arising in malignant peripheral nerve sheath tumor in a young patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome with an incidence of approximately one in 3,000 and a lifetime risk of malignancy estimated at 8-13%. Here, we report the case of a patient with NF1 who developed synchronous malignant peripheral nerve sheath tumors, one with a focus of angiosarcoma. He succumbed to metastatic angiosarcoma despite local resection and adjuvant chemotherapy. This case highlights the need for monitoring for malignancy in NF1 patients, the risks of sampling error during tumor biopsy, and the clinical decision - making involved in choosing a therapeutic plan for a patient with multiple simultaneous malignancies.

The relationship between sleep disturbance in pregnancy and persistent common mental disorder in the perinatal period (sleep disturbance and persistent CMD).

BACKGROUND: Common mental disorder (CMD) and sleep disturbance are two common conditions among women in late pregnancy, affecting up to 20% and 63% of women, respectively, and may adversely affect their quality of life. AIM: The aim of this study is to examine the relationship between sleep disturbance in pregnancy and persistent CMD among low-income pregnant women living in Brazil. METHODS: This was a prospective cohort study conducted with pregnant women recruited from public primary care clinics in São Paulo, Brazil. We performed a longitudinal analysis of 219 women who had CMD from the Self-Report Questionnaire during the 20-30 weeks of pregnancy. Two groups were examined: (1) those who had CMD remission in the postpartum and (2) those who had persistent CMD in the postpartum (measured once in the postpartum period). Poisson regression was used to estimate the degree of association between sleep disturbance in pregnancy and the risk for persistent CMD postpartum. RESULTS: After adjusting for sociodemographic and clinical factors, sleep disturbance during pregnancy is associated with persistent CMD (RR = 1.36, 95% confidence interval: 1.01-1.84). CONCLUSION: In this sample of low-income pregnant women living in Brazil, the presence of sleep disturbance during pregnancy was associated with persistent common mental disorder in the postpartum period. Identification of sleep disturbance in pregnant women with CMD will be important in order to recognize those women at higher risk of persistent CMD in the postpartum period.

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.

Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells.

Acute myeloid leukemia (AML) is a rare subtype of acute leukemia in the pediatric and adolescent population but causes disproportionate morbidity and mortality in this age group. Standard chemotherapeutic regimens for AML have changed very little in the past 3-4 decades, but the addition of targeted agents in recent years has led to improved survival in select subsets of patients as well as a better biological understanding of the disease. Currently, one key paradigm of bench-to-bedside practice in the context of adult AML is the focus on leukemia stem cell (LSC)-targeted therapies. Here, we review current and emerging immunotherapies and other targeted agents that are in clinical use for pediatric AML through the lens of what is known (and not known) about their LSC-targeting capability. Based on a growing understanding of pediatric LSC biology, we also briefly discuss potential future agents on the horizon.

Implementing Opt-Out HIV Testing in the Alameda County Jails.

Incorporating routine opt-out HIV testing in correctional settings is a critical component of an effective strategy to end the HIV/AIDS epidemic. Between 2012 and 2017, Alameda County jails implemented opt-out HIV testing to identify new cases, link those who were newly diagnosed to care, and reengage those who were previously diagnosed but not in care. Over a 6-year period, 15,906 tests were conducted, with a positivity rate of 0.55% for both newly diagnosed cases and previously diagnosed but out of care. Nearly 80% of those who tested positive were linked to care within 90 days. The high positivity and successful linkage and reengagement with care underscores the need to support HIV testing programs in correctional settings.

A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy.

The BCL2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances, m-LSC and p-LSC subtypes can co-reside in the same patient with AML and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlight the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens. SIGNIFICANCE: These studies identify and characterize a new type of human acute myeloid LSC that is responsible for monocytic disease progression in patients with AML treated with venetoclax-based regimens. Our studies describe the phenotype, molecular properties, and drug sensitivities of this unique LSC subclass. This article is featured in Selected Articles from This Issue, p. 1949.

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.

Outcomes Are Similar After Allogeneic Hematopoietic Stem Cell Transplant for Newly Diagnosed Acute Myeloid Leukemia Patients who Received Venetoclax + Azacitidine Versus Intensive Chemotherapy.

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age.