Prior Hematopoietic Stem Cell Transplantation Research Articles

P-377 Understanding the interplay between multiple sclerosis patterns and ovarian reserve, which influences the other?

Abstract Study question Is multiple sclerosis (MS) associated with diminished ovarian reserve in women? Does ovarian reserve influence multiple sclerosis progression patterns? Summary answer AntiMüllerian Hormone (AMH) is not diminished in MS patients compared to healthy matched controls. Ovarian reserve predicts multiple sclerosis patterns independently from chronological age. What is known already Population registries indicate increased childlessness in individuals with MS, but the influence of MS on ovarian reserve and the need for fertility preservation counseling are topics of ongoing debate. Notably, MS research highlights the concept of immunosenescence: with age the disease shifts from high relapse rates to disability accumulation and fewer relapses. It is uncertain whether ovarian aging, assessed through AMH, could serve as a marker of immunosenescence, offering more precise predictions of MS patterns compared to chronological age alone. Study design, size, duration This prospective observational study enrolled all female MS patients aged 18 to 50 presenting to the neurology service between June and November 2023, matching them in a 1:2 ratio with controls of similar age and BMI. The controls were healthy females, without known causes of female infertility. Exclusion criteria were: postmenopausal state, prior neoplasm requiring gonadotoxic therapy or prior hematopoietic stem cell transplantation. Participants/materials, setting, methods The study was conducted in an academic hospital, regional referral for neurology and fertility preservation. Detailed neurological and gynecological anamnesis was collected for 73 patients and 146 controls. AMH measurements were performed by the same laboratory with the Roche Elecsys AMH system. Multiple generalized linear models were carried out to explore the correlation between AMH and neurological data. All results were adjusted for age and use of hormonal contraception. Bonferroni corrected post-hoc analyses were performed. Main results and the role of chance Cases and controls were matched for age (33.6±6.1 vs. 34.4±4.5 years) and BMI (22.3±3.4 vs. 22.2±3.5 Kg/m2). The AMH values were not significantly different between cases and controls (2.7±3.5 vs. 2.7±1.6 ng/ml, p = 0.7) and showed no correlation with MS duration (p = 0.3) and disability measured with EDSS score (p = 0.9). Interestingly, higher AMH levels correlated with both having relapsed in the prior year (yes: 4.9±5.3 vs. no: 1.7±1.6 p = 0.008) and with the number of relapses in the 2 previous years (zero: 1.9±1.8, one: 2.3±2.9, more than 2: 5.8±6.2 ng/ml, p = 0.02). Consequently, patients with “No Evidence of Disease Activity”(NEDA) in the previous year showed lower AMH levels (1.68±1.3 vs. 4.1±4.7 ng/ml, p = 0.01), since absence of relapses is one of the components to define NEDA. In summary, patients with higher ovarian reserve showed a MS pattern typical of young age (higher relapse rates) independently from the actual chronological age. Limitations, reasons for caution The results should be confirmed by larger/multicenter datasets, powered to properly assess the possible influence of the different disease modifying therapies. Further research is warranted to understand the biological link behind the observed results. Wider implications of the findings Ovarian aging, measured through AMH, may provide a better indicator of a patient’s biological age than chronological age only. This may help neurologists in predicting MS patterns and treating it accordingly, providing a unique perspective on the mechanisms that link immunosenescence to the ovarian reserve reduction. Trial registration number Not Applicable

Evolution of tisagenlecleucel use for the treatment of pediatric and young adult relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL): Center for International Blood & Marrow Transplant Research (CIBMTR) registry results.

10016 Background: Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy indicated for patients (pts) up to 25 y of age with B-ALL that is refractory or in second or later relapse. Since the pivotal ELIANA trial, pt characteristics now include pts < 3 y, pts with isolated central nervous system relapse, and pts with leukemia burden < 5%. Here we examine the impact of tisagenlecleucel on the pt treatment journey since FDA approval in 2017. Methods: Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. Pts were treated in the United States, Canada, Korea, or Taiwan. Results: As of May 4, 2023, 974 pts received tisagenlecleucel. Primary disease history has evolved since 2017. Notably, disease burden prior to infusion has decreased (≥50% blasts: 18% in 2018, 4% in 2022) and a higher proportion of pts received tisagenlecleucel while in morphological complete remission (34% in 2018, 51% in 2022). Between 2018 and 2022, the proportion of pts who were in third or greater relapse decreased (14% vs 2%, respectively). Pts ≥18 y had more prior exposure to blinatumomab and inotuzumab compared with pts < 18 y: 27% vs 16% and 17% vs 7%, respectively. The proportion of pts undergoing ≥1 hematopoietic stem cell transplantation (HSCT) before tisagenlecleucel infusion decreased (37% in 2018, 15% in 2022), coinciding with the use of tisagenlecleucel in earlier lines of therapy. Reporting of B-cell recovery was suboptimal. In total, 34.5% (314/911) of pts received postinfusion HSCT (reasons for HSCT were not captured for most pts); 8.5% (77/911) of pts received postinfusion HSCT to treat relapse, persistent/progressive disease, or positive minimal residual disease. Although the overall rate of postinfusion HSCT did not change, pts with high-risk cytogenetics showed a decrease in HSCT frequency. Previously, most pts < 3 y with KMT2A rearrangement received a HSCT. Since 2017, only 16% (12/75) of pts < 3 y received a prior HSCT despite 72% (54/75) having a KMT2A rearrangement. Furthermore, of the pts with rearrangement, only 43% (23/53) received a HSCT postinfusion. With censoring for HSCT, median RFS improved: 18 mo in 2018, 27 mo in 2020, and not estimable in 2021. OS was not substantially affected by HSCT censoring; 36-mo probabilities (95% CI) with and without censoring were 66 (61-71) and 62 (57-66), respectively. Conclusions: Pediatric and young adult pts with r/r B-ALL are receiving tisagenlecleucel earlier in the course of their disease treatment, reducing the use of HSCT for r/r disease, and prolonging RFS. As both real-world and clinical trial data supporting the curative potential of tisagenlecleucel grow, the use of HSCT in pts with remission after CAR-T should be carefully evaluated.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors

Background aimsThe success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. ObjectiveWe compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. MethodsA retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. ResultsOf 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. ConclusionsImmune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory tointensive chemotherapy.

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML

Background Leukemic stem cells have high expression of CD123 compared to normal hematopoietic stem cells and is therefore a therapeutic target in multiple leukemias including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has shown clinical activity in relapsed/refractory AML, particularly in low-blast disease. We therefore sought to evaluate vibecotamab in other low-blast states, including MDS or CMML after hypomethylating agent failure and MRD-positive AML. Methods In this two-arm, open-label, phase II study, adults with either MDS (IPSS-R intermediate or higher risk) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents or AML in first or second morphologic remission with detectable MRD at a level of ≥0.1% by flow cytometry were eligible. CD123 expression ≥20% on aberrant myeloid blasts was required for enrollment. Vibecotamab was given IV in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7µg/kg. Patients (pts) received up to 4 cycles of vibecotamab in 28-day cycles. The primary endpoint of the MDS/CMML cohort was response rate (CR + mCR + PR + HI + clinical benefit) within 4 cycles. The primary endpoint of the AML MRD cohort was the MRD negativity rate within 4 cycles. Results Between May 2022 and July 2023, 23 pts were treated (11 MDS/CMML, 12 AML MRD). Baseline characteristics are shown in Table 1. In the MDS/CMML cohort, 7 pts (63%) had received two or more prior lines of therapy, 8 pts (73%) had prior venetoclax exposure, and 2 pts (18%) had prior hematopoietic stem cell transplant (HSCT). Six MDS pts (66%) were IPSS-R high or very high risk. In the AML cohort, 6 pts (50%) had received two or more lines of prior therapy, 11 pts (92%) had prior venetoclax exposure, and 5 pts (42%) had prior HSCT. Ten pts (83%) were ELN 2022 adverse risk. The baseline CD123 expression was 72% (range, 43%-99%) in the MDS/CMML cohort and 89% (range, 55%-99%) in the AML MRD cohort. The baseline MRD by flow cytometry in the AML MRD cohort was 1.1% (range, 0.1%-3.9%). Responses are shown in Table 2. In the MDS/CMML cohort, 7 pts responded (64%), with 6 pts (56%) achieving marrow complete remission (mCR) and 1 pt (9%) achieving hematologic improvement (HI) per International Working Group (IWG) 2006 criteria. Among the 9 MDS pts, 4 (44%) achieved mCR + HI (2 HI-N, 1 HI-P, and 1 HI-P + HI-N), and 1 (11%) achieved HI (HI-N + HI-P). Per revised IWG 2023 MDS response criteria, 5 of the 9 MDS pts (56%) achieved complete remission with limited count recovery (CR L). Two of 4 MDS pts (50%) with TP53 mutations achieved CR L. Both CMML pts achieved mCR, with one pt also achieving HI-N. Among 9 pts with baseline bone marrow blasts =&amp;gt;5% at trial enrollment, 6 (67%) achieved a mCR, with or without HI. Best response occurred after the first cycle in all pts. CD123 expression was not associated with likelihood of response. Of the 7 responders, 5 are in ongoing response (range 0.3-6.9 months), one died in CR L from non-hematologic complications (heart failure), and one relapsed 5 months after achieving CR L. Of the 12 pts in the AML MRD cohort, 3 (25%) achieved MRD negativity, all of which occurred after 1 cycle of vibecotamab. Among the 3 responders, all were ELN adverse risk and had prior venetoclax exposure, 2 had prior HSCT, and 1 had inv(3). The median MRD and CD123 expression in responders was 0.2% (range 0.1%-0.2%) and 98% (range 95%-99%) vs 1.8% (range 0.5%-3.9%) and 87% (range 66%-96%) in non-responders, respectively. At last follow-up, all 3 responders are still in MRD-negative remission (range 3.2-12.8 months). Vibecotamab was well-tolerated with no pts requiring dose reductions or being taken off study due to adverse events. Ten pts (44%) experienced grade 2 infusion reactions and 1 pt (4%) experienced a grade 3 infusion reaction. Myelosuppression was minimal, consistent with previous studies of vibecotamab. Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemias: Efficacy and Safety Results from the Augment-101 Phase 1/2 Study

Background: Revumenib (SNDX-5613), a potent, selective small-molecule inhibitor of the menin-histone-lysine N-methyltransferase 2A (KMT2A) interaction, is being investigated in patients (pts) with relapsed/refractory (R/R) KMT2A-rearranged ( KMT2Ar) and nucleophosmin 1-mutated ( NPM1m) acute leukemias. An initial analysis of the phase 1 of AUGMENT-101 (NCT04065399) has been reported ( Nature. 2023;615:920-924). Here we report an update of &amp;gt;1 year additional experience in the phase 1 portion of the study, which has completed enrollment, with safety data from 131 treated pts and efficacy data in 80 pts with R/R KMT2Ar leukemia. Demographic data from pivotal phase 2 cohorts are included; safety and efficacy data of a preplannedanalysis will be reported at the meeting. Methods: In phase 1, pts aged ≥30 days with R/R acute leukemias were assigned to 1 of 6 dose-escalation arms designed to identify a recommended phase 2 dose (RP2D) for concomitant administration of weak, moderate, or strong cytochrome P450 3A4 inhibitor (CYP3A4i) azole antifungal or no CYP3A4i. Pts received revumenib every 12 hours (q12h) or 3 times a day at a flat dose (≥40 kg) or a body surface area-based dose (&amp;lt;40 kg). Safety was assessed in all pts who received ≥1 dose of revumenib; responses are reported for all treated pts with KMT2Ar. In pts who underwent hematopoietic stem cell transplant (HSCT), responses reported are those achieved before HSCT. The Phase 2 study was initiated following identification of an RP2D of 163 mg (95 mg/m 2 if &amp;lt;40 kg) q12h with a strong CYP3A4i in 28-day cycles until unacceptable toxicity, lack of at least morphological leukemia-free state (MLFS) by end of cycle 4, or progressive disease without clinical benefit as defined by the investigator. The phase 2 primary objectives are evaluation of safety and tolerability of revumenib and assessment of the complete remission (CR) + CR with partial hematologic recovery (CRh) rate. The safety and efficacy of revumenib at an RP2D is being explored in 3 expansion cohorts: Cohort 2A, KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia; Cohort 2B, KMT2Ar acute myeloid leukemia (AML); and Cohort 2C, NPM1m AML. A preplanned pooled analysis of adult and pediatric pts with KMT2Ar acute leukemia will be conducted when a subset of Cohorts 2A+2B pts have completed a minimum of 4 cycles or have discontinued therapy. Results: Phase 1: As of June 19, 2023, 80 pts with R/R KMT2Ar acute leukemia were treated with revumenib in the 6 dose-escalation arms (Table 1). In adults with AML (n=51), the largest KMT2Ar subgroup, CR+CRh was 28% and overall response rate (ORR) was 59%. Responses were consistent in ALL/other leukemia subtype (n=15), with 27% CR+CRh and 53% ORR. ORR (61%) was similar in pediatric pts (&amp;lt;18 years, n=18), with 22% proceeding to HSCT. Although similar percentages of adult and children proceeded to transplant, consistent with common clinical practice in pediatrics, 75% of children transplanted went on to HSCT prior to achieving a CR/CRh (2 MLFS, 1 CRp) versus 17% of adults. In the safety population (n=131), 24% of pts had a ≥Grade 3 treatment-related adverse event (TRAE), with Grade 3 QTc prolongation in 8% and differentiation syndrome in 2% (Table 1). QTc prolongation remained as the only dose-limiting toxicity; no patients experienced ventricular arrhythmias. In addition, based on updated phase 1 pharmacokinetics, clinical activity, and safety data, an RP2D of 276 mg q12h without a strong CYP3A4i was established. Phase 2: In a preliminary analysis of Cohorts 2A and 2B (June 19, 2023), 88 pts with KMT2Ar acute leukemia were enrolled and treated with revumenib at an RP2D (Table 2). Ages ranged from 1.3 to 75 years (22 aged &amp;lt;18 y; Table 2). Leukemia subtypes included ALL (15%), AML (81%), and other (3%). Pts were heavily pretreated, having received a median of 3 prior lines of therapy (range 1-12); 38% received ≥4 prior lines and 48% had prior HSCT. Conclusions: These phase 1 data continue to demonstrate deep responses to revumenib and a manageable safety profile in heavily pretreated patients with R/R KMT2Ar acute leukemia across ages and subtypes. The lack of targeted therapies approved for KMT2Ar leukemia indicate the need for further investigation of novel, potentially transformative therapies such as revumenib. Enrollment in the AUGMENT-101 trial is ongoing. Pivotal Phase 2 safety and efficacy data for the KMT2Ar population will be reported at the meeting.

Higher CD34+ Cell Doses Correlate with Reduced Incidence of Relapse and Better Event-Free Survival after KIR-Ligand Mismatch Cord Blood Transplantation for Childhood Acute Myeloid Leukemia

Introduction In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) is an important treatment, and cord blood units from unrelated donors provide a well-established source of stem cells for HSCT. The main advantages of using cord blood include rapid availability, allowance of greater HLA disparities due to a relatively low risk of severe graft-versus-host disease (GVHD), and possibly a greater graft-versus-leukemia (GVL) effect. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer cells that play an important role in GVL after HSCT. Previous studies on the effects of KIR-ligand (KIR-L) incompatibility in unrelated cord blood transplantation (CBT) for leukemia have resulted in conflicting results, and in some studies, this has led to an increased incidence of acute GVHD. Furthermore, the impact of KIR-L mismatch on outcomes in children with AML remains poorly understood. In this study, we explored the association of KIR-L incompatibility and other clinical factors with patient outcomes in children with AML who received CBT. Methods Data were collected from the Transplant Registry Unified Management Program sponsored by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. The patients were selected according to the following criteria: (1) de novo non-M3 AML, (2) age &amp;lt; 16 years and CR1 or CR2 at the time of receiving HSCT, (3) no prior HSCT, and (4) HSCT performed between 2000 and 2021. Patients without information on survival and disease recurrence or those with Down syndrome were excluded. KIR-L mismatch in the graft-versus-host direction was defined as lacking a donor KIR-L group (HLA-C1, C2, Bw4, or A3/A11) in a recipient. A myeloablative conditioning regimen was defined as total-body irradiation (TBI) at &amp;gt; 8 Gy, melphalan at &amp;gt; 140 mg/m 2, or busulfan at ≥ 9 mg/kg. All other regimens were analyzed as reduced-intensity conditioning regimens. Adverse cytogenetics were defined as previously described [Creutzig et al. Blood, 2012]. Results A total of 299 patients were included. The median age at HSCT was 5 years (range, 0-15), and the median follow-up period for survivors was 7.2 years (range, 0.1-22.4). The median total nucleated cell and CD34+ cell doses were 6.7 x 10 7/kg (range 0.01-12.3) and 1.9 x 10 5/kg (range 0.01-59.4), respectively. The study cohort consisted of 240 patients in the KIR-L match group and 59 patients in the KIR-L mismatch group. The background characteristics of these two groups did not differ significantly, except for a trend indicating that the KIR-L mismatch group received CBT more recently ( p = 0.063). The cumulative incidence rates of neutrophil recovery at Day 42 were 93.3% (95% CI, 89.3-95.9%) and 91.5% (95% CI, 80.0-96.5%) ( p = 0.980), and the cumulative incidence rates of platelet engraftment at 6 months were 91.5% (95% CI, 87.1-94.5%) and 89.8% (95% CI, 77.9-95.5%) ( p = 0.314) for the KIR-L match and mismatch groups, respectively. The cumulative incidence rates of grade II-IV acute GVHD at Day 100 were 40.9% (95% CI, 34.6-47.1%) and 40.7% (95% CI, 28.0-52.9%) ( p = 0.709), whereas those of chronic GVHD at one year after transplantation were 15.6% (95% CI, 11.2-20.6%) and 15.9% (95% CI, 7.8-26.6%) ( p = 0.914) for the KIR-L match and mismatch groups, respectively. In univariate analyses, the 5-year event-free survival (EFS) was 70.1% (95% CI, 63.6-75.6%) for the KIR-L match group and 72.9% (95% CI, 59.0-82.8%) for the KIR-L mismatch group ( p = 0.609). Stratification by CD34+ cell doses showed a significant correlation between higher CD34+ cell doses and better EFS in the KIR-L mismatch group (Figure 1), attributed not only to reduced nonrelapse mortality but also to a lower incidence of relapse. In multivariate analysis of EFS, KIR-L mismatch with high CD34+ cell doses (&amp;gt; the median doses) was identified as an independent favorable prognostic factor (Table 1; hazard ratio = 0.21, p = 0.037). Conclusion Our study demonstrates that higher CD34+ cell doses were associated with a lower relapse rate and better EFS in KIR-L mismatch CBT for childhood AML. This finding is noteworthy, as previous literature has primarily emphasized the role of higher CD34+ cell doses in reducing nonrelapse mortality. Our results suggest that higher CD34+ cell doses are also crucial for achieving a high GVL effect in the context of KIR-L mismatch CBT.

A Phase 2, Open-Label Study to Assess the Pharmacokinetics, Pharmacodynamics and Safety of Orally Administered Epeleuton in Patients with Sickle Cell Disease

Background. Sickle cell disease (SCD) is a rare hereditary multi-system disorder that is caused by a single mutation in the beta allele of the hemoglobin gene, leading to the production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, resulting in red blood cell (RBC) sickling and membrane damage, ultimately leading to a cascade of events which include hemolysis, chronic anemia, inflammation, and vaso-occlusion. Despite recent progress, there is a need for additional disease-modifying therapeutic options. Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester, a novel synthetic second generation w-3 fatty acid which targets key drivers of hemolysis and multicellular adhesion. In preclinical studies in Townes humanized SCD mice and SCD patient RBCs, epeleuton acts as a disease-modifying agent by simultaneously decreasing (a) systemic and local inflammatory activation, (b) endothelial adhesion, (c) organ damage and (d) intravascular hemolysis and sickling. Epeleuton has been administered to 343 subjects in clinical trials, with a favorable safety and tolerability profile. Objective To evaluate the pharmacokinetics, pharmacodynamics and safety of orally administered epeleuton in patients with SCD. Study Design and Methods. This open-label, phase 2, multicenter study (NCT05861453) will enroll approximately 30 adult patients with a confirmed diagnosis of SCD (HbSS and HbSß0-thalassemia). Participants must have hemoglobin levels of 5.0-9.5g/dL at screening, 2-10 vaso-occlusive crises (VOCs) in the past 12 months, and a high adhesion index at screening defined as RBC laminin adhesion &amp;gt; 400 cells. Concomitant treatment with a stable dose of hydroxyurea is permitted during the study. Key exclusion criteria include receiving an RBC transfusion within three months of enrolment, receiving voxelotor, crizanlizumab or l-glutamine within six weeks of enrolment and, prior hematopoietic stem cell transplant. The trial has a 28-day screening period, followed by a 16-week treatment phase and a 30-day post-treatment follow-up period. Study participants will attend the clinic on 6 occasions at screening, baseline, weeks 4, 8 and 16 (end-of-treatment) and the week 20 post-treatment follow-up visit. Enrolled patients will receive epeleuton 2g BID (4g daily) for 16 weeks. Study endpoints include change from baseline in hemoglobin levels, hemolytic markers, assessments of RBC health, soluble adhesion molecules, RBC adhesion, whole blood adhesion and rates of VOC. Conclusion: Treatments that can simultaneously target hemolysis and cellular adhesion may have an important disease-modifying utility for patients with SCD. The results of this study are anticipated to confirm the potential of epeleuton to address multiple aspects of SCD and to guide the design and conduct of future studies in patients with SCD.

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial

Background: Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419). Methods: Module 1, Part A of NIMBLE is a dose-escalation study of AZD0466 monotherapy investigating its preliminary safety and tolerability, pharmacokinetics (PK), and preliminary efficacy. Dose escalation and de-escalation of AZD0466 follow a modified toxicity probability interval (mTPI-2) design. Eligible pts are ≥18 years old with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome. AZD0466 is administered IV with a dose ramp-up on Days (D) 1, 4, and 8, reaching the target dose on D8 of Cycle 1, with weekly administrations thereafter. Cycle duration is 35 days for Cycle 1 and 28 days for subsequent cycles. Pts remain on study until disease progression, unacceptable toxicity, or withdrawal of consent. Resul ts: As of May 31, 2023, 31 pts (n=25 AML, n=6 ALL; median age 69 years) had received ≥1 dose of AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), 1200 mg (n=7), 2400 mg (n=5), 3600 mg (n=9), and 5400 mg (n=2). Median treatment duration was 4.1 weeks (range 0.1−29.6). Twenty-two pts (71%) had prior VEN and 11 (35%) had prior hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of any grade reported in &amp;gt;10% of pts are displayed in Table 1. One Grade 5 intracranial hemorrhage unrelated to AZD0466 was reported. Four pts experienced a serious adverse event (SAE) possibly related to AZD0466 (alanine aminotransferase [ALT] increase, pneumonia, troponin T increase, and uncoded SAE). Grade ≥3 TEAEs possibly related to AZD0466, reported in 12 pts (39%), included febrile neutropenia (n=3), platelet count decrease (n=2), diarrhea, thrombocytopenia, ALT increase, blood creatinine phosphokinase increase, pneumonia, gamma-glutamyltransferase increase, lipase increased, and troponin T increase (n=1, each). DLTs of asymptomatic troponin increase were observed in two pts (3600 mg [n=1], 5400 mg [n=1]). Evaluation of maximum concentration and area under the concentration-time curve revealed dose-proportional exposure to AZD4320. Released AZD4320 represented 1-5% of total AZD4320 and had a longer half-life than total AZD4320. Preclinical modeling and PK data predicted that 5400 mg may be required to drive efficacy. As a surrogate of BCL-xL on-target activity, transient aggravation of thrombocytopenia post-dosing was observed across all dose cohorts followed by platelet recovery prior to the next dose. Platelet reduction was in line with preclinical models showing a substantial reduction at lower doses with a ceiling effect at higher doses. As of July 6, 2023, no complete responses have been observed. However, preliminary bone marrow (BM) blast reductions of &amp;gt;50% were observed in four pts (1200 mg [n=1], 2400 mg [n=2], 3600 mg [n=1]), indicating antileukemia activity of AZD0466. Conclusions: Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated.

Results from the Phase 1 Portion of a Trial of Oral Ixazomib Combined with Chemotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoma in Children, Adolescents and Young Adults: A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

ACKNOWLEDGEMENT Proteasome inhibitors potentiate anti-tumor effects of standard cytotoxic chemotherapy in childhood leukemia. Ixazomib is an oral proteasome inhibitor that has a shorter proteasome dissociation half-life than bortezomib, which leads to a higher tumor-to-blood ratio inhibition. We performed a phase 1 trial to determine the dose limiting toxicities (DLT), Recommended Phase 2 Dose (RP2D) of ixazomib in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoma (LL). Patients ≤ 21 years of age with relapsed or refractory ALL (with ≥ 5% detectable disease in the marrow) or LL were eligible. Ixazomib was combined with 28-day blocks of well-established, relapsed ALL backbone chemotherapy. Block 1 contained vincristine (1.5 mg/m 2/dose IV Days 1, 8, 15, 22), dexamethasone (5 mg/m 2/dose IV or oral twice daily Days 1-14), PEG-asparaginase (2500 IU/m 2/dose IV Days 2, 15) and daunorubicin (60 mg/m 2/dose IV Day 1) (VXLD). An optional Block 2 contained vincristine (1.5 mg/m 2/dose IV Day 1), dexamethasone (3 mg/m 2/dose oral twice daily Days 1-5), methotrexate (1000 mg/m 2/dose IV over 36 hours Day 8), PEG-asparaginase (2500 IU/m 2/dose IV Day 9), cyclophosphamide (440 mg/m 2/dose IV Days 15-19) and etoposide (100 mg/m 2/dose IV Days 15-19). An additional optional Maintenance Block contained vincristine (1.5 mg/m 2/dose IV Day 1), prednisone (20 mg/m 2/dose oral twice daily Days 1-5), mercaptopurine (75 mg/m 2/dose oral daily) and methotrexate (20 mg/m 2/dose oral weekly). Intrathecal therapy was given throughout with agents and dosing based on the patient's CNS disease status upon study entry. Ixazomib was given orally and tested at two dose levels (DL) (DL1: 1.6 mg/m 2/dose; DL2: 2 mg/m 2/dose) using a 3+3 design and was given during Block 1 on Days 1, 4, 8 and 11; during Block 2 on Days 1, 4, 8, 15 and 18 and during Maintenance on Days 1, 8 and 15. DLTs during Block 1 only were utilized to make DL escalation decisions and determine the RP2D. Patients without Down Syndrome (DS) entered Cohort A, used to determine the P2RD. Patients with DS were eligible for a 1 DL lagging descriptive-only Cohort B. Ten patients were treated; nine in Cohort A (n = 3 at DL1 and n = 6 at DL2) and one in Cohort B (DL1). Median age (range) at study entry was 10.5 years (5 - 20 years). Nine patients had B-ALL and one had T-ALL. Most were heavily pretreated with a median (range) of 3.4 (1 - 7) previous remission attempts with six having had prior immunotherapy and three patients having had at least one prior hematopoietic stem cell transplant. After Block 1, two patients received Block 2 and one received Maintenance. In Block 1 of Cohort A, non-hematological Grade 3/4 adverse events (AE) possibly, probably or definitely related to ixazomib or the backbone chemotherapy were limited and included neutropenic fever (n = 7), increased AST (n = 3), increased ALT (n = 2) and hypokalemia (n = 2). Two septic events occurred (n = 1 in Cohort A (Grade 3) and n = 1 in Cohort B (Grade 4)). Block 2 and Maintenance AEs were not significantly different than those seen in Block 1. No deaths or DLTs occurred. Response assessment showed that at DL1 two of three patients had a Complete Remission (CR) both of whom were Minimal Residual Disease (MRD) negative (-) and at DL2 three of six patients had a CR, two of whom were MRD- and two patients had a CR with incomplete count recovery (CRi). The overall response rate (CR + CRi) was 78% (7 of 9 patients). With a minimum of 20 months of follow-up six of nine patients in Cohort A and the single patient in Cohort B are still alive. All three deceased patients died of disease progression. Ixazomib can be combined with standard chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric relapsed ALL including those with DS. The RP2D of Ixazomib combined with chemotherapy is 2 mg/m 2/dose, which is being used in the ongoing phase 2/expansion cohort of the study. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Takeda Pharmaceuticals Company provided the investigative drug and funding in support of this trial.

Olutasidenib for the Treatment of mIDH1 Acute Myeloid Leukemia in Patients Relapsed or Refractory to Hematopoietic Stem Cell Transplant, Prior mIDH1 Inhibitor, or Venetoclax

Introduction. Olutasidenib is a small molecule, oral, mutated-IDH1 (mIDH1) inhibitor approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). In the pivotal cohort of the registrational phase 1/2 trial, 51/147 (35%) patients achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) to olutasidenib, with a duration of response of 25.9 months and an overall response rate (ORR) of 48%. The phase 1/2 study included 10 cohorts for a total of 335 patients, and there were patient subsets that were R/R to previous hematopoietic stem cell transplant (HSCT), ivosidenib (IVO) or venetoclax (VEN). We conducted post hoc analyses to better understand the response to olutasidenib in these poor-prognosis subgroups of mIDH1 AML. Methods. This Phase 1/2, open-label, multi-center study enrolled patients with confirmed AML or intermediate, high-, or very high-risk myelodysplastic syndromes/neoplasms (MDS). Patients received olutasidenib 100mg QD, 150mg QD or 150mg BID monotherapy or the combination of olutasidenib 150mg BID plus azacitidine. Patients were grouped by prior therapy. Baseline demographics and disease characteristics are shown in Table 1. The study was not powered to statistically evaluate subpopulations; descriptive statistics are provided. Data cutoff date is June 2021. Results. The post-HSCT group (n=31) had a relatively high median baseline bone marrow blast count (58%) and a median of 4 prior treatment regimens ( Table 1). Six (19%) of these patients had a CR (including the 1 patient with MDS), and 3 (10%) patients had a CR with incomplete count recovery (CRi) resulting in a 29% composite complete remission (CRc) rate. One patient had a morphologic leukemia-free status, resulting in a 32% ORR. Half the responders received monotherapy, and half received a combination of olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CR to prior HSCT; one of these patients maintained a CR for 13 months before progressing, and the other patient progressed and discontinued due to a new central nervous system disease ( Table 2). For the 10 patients with responses (ORR), the median duration of response was 7.1 months (range 1-23.4+). At data cutoff, 2 patients were ongoing responders, 3 patients proceeded to a second HSCT, and 3 to donor lymphocyte infusion (DLI). The post-IVO group (n=9) had a high median baseline bone marrow blast count (83%) and a median of 4 prior treatment regimens ( Table 1). Two patients (22%) achieved a CR; both CRc and ORR were 22% ( Table 2). Both responders had received olutasidenib in combination with azacitidine. One responder proceeded to HSCT after 3.1 months, and one responded for 5.6 months and then had disease progression. Response rates in the post-VEN group (n=20) included CR in 6 patients (30%), CRh in 1 (5%), and CRi in 2 (10%) resulting in a CRc of 9 (45%) and an ORR of 45% ( Tables 1 and 2). One responder received combination olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CRi to prior treatment; both improved their response to a CR. Median duration of response was not reached and ongoing at 28.5 months. At data cutoff, 5 patients continued treatment, and 15 had discontinued. Conclusions. This descriptive analysis suggests that olutasidenib alone or in combination with azacitidine may induce complete remissions in patients with mIDH1 AML or MDS that is R/R to VEN, IVO or even HSCT. Further investigation of these difficult-to-treat subpopulations is needed. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.

Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study

Background: Most patients (pts) with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia, relapse after conventional chemotherapy and hematopoietic stem cell transplant (HSCT). Remission rates after relapse (complete remission [CR], 5%) and median overall survival (2.4 mo) in ≥2nd salvage therapies in adults remain low (Blood Cancer J. 2021;11[9]:162). In KMT2Ar leukemia, interaction of menin with KMT2A fusion proteins is a key driver of leukemogenesis. However, no therapies targeting the menin-KMT2A interaction have been approved. Revumenib (SNDX-5613; rev), a small-molecule inhibitor of menin-KMT2A interactions, demonstrated preliminary efficacy and safety in a phase 1 study of R/R KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. We report topline efficacy and safety for pts with R/R KMT2Ar acute leukemia treated with rev in a pivotal phase 2 study (AUGMENT-101; NCT04065399). Methods: Pts aged ≥30 days with R/R KMT2Ar acute leukemia were enrolled in cohort A (acute lymphoblastic leukemia [ALL]/mixed phenotype acute leukemia [MPAL]) and B (acute myeloid leukemia [AML]); cohort C continues to enroll pts with NPM1m and is not included in this analysis. Pts received rev (163 mg or 95 mg/m2 if body weight &amp;lt;40 kg) q12h with a strong cytochrome P450 3A4 inhibitor orally in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state (MLFS) after 4 cycles of treatment. Phase 2 primary objectives were safety and tolerability of rev and CR+CR with partial hematologic recovery (CRh) rate. Key secondary endpoints included composite CR rate (CRc, CR+CRh+CR with incomplete platelet recovery [CRp]+CR with incomplete count recovery [CRi]) and overall response rate (ORR, CRc+MLFS+partial remission). A planned interim analysis (IA) of pooled adult and pediatric pts with KMT2Ar acute leukemia was conducted. Results:As of July 24, 2023, 94 pts with R/R KMT2Ar acute leukemia received ≥1 dose of study drug and were included in the safety analysis (Table 1). Median age was 37.0 y (range, 1.3-75.0). Of the 94 pts, 23 (24.5%) were aged &amp;lt;18 y and 13 (13.8%) were aged ≥65 y. Seventy-eight (83%) had AML and 16 (17.0%) had ALL or MPAL. Over half of pts were female; 17.5% of pts were non-White. Pts were heavily pretreated (median 2 [range, 1-11] prior lines of therapy), with 41 pts (43.6%) having received ≥3 prior lines. Fifty-four pts (57.4%) had refractory relapse disease (unresponsive to most recent salvage treatment), and 47 pts (50%) had prior HSCT. Treatment-related adverse events (TRAEs) were reported in 81.9% of the safety population. Most common TRAEs (≥20%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Grade ≥3 TRAEs were observed in 51 pts (54.3%), the most common being differentiation syndrome (16.0%), febrile neutropenia (13.8%), and QTc prolongation (13.8%) (Table 2). Overall, 6.4% of pts discontinued therapy due to TRAEs; none discontinued rev due to differentiation syndrome or QTc prolongation. The pooled efficacy population for the IA (n=57) included all phase 2 pts with centrally confirmed KMT2Ar and ≥5% blasts in bone marrow at baseline who had received ≥1 dose of study drug and started treatment on or before the 38th adult AML efficacy evaluable patient. The IA was specified to occur when the 57 patients have had the opportunity to be followed for 6 months. After median follow-up of 6.1 mo, 13 pts (22.8% [95% confidence interval (CI), 12.7-35.8]) achieved CR+CRh, surpassing the predefined IA efficacy boundary for the pooled KMT2Ar population; CR+CRh rate was similar in adult and pediatric pts. Median duration of CR+CRh was 6.4 mo (95% CI, 3.4-not reached). CRc was 43.9% (95% CI, 30.7-57.6); ORR was 63.2% (95% CI, 49.3-75.6). Most pts with a CR or CRh response, and for whom measurable residual disease (MRD) status was reported, achieved MRD negativity (7/10, 70.0%); most pts with CRc and MRD reported also achieved MRD negativity (15/22, 68.2%). Fourteen of 36 responders (38.9%) proceeded to HSCT, with half resuming rev post HSCT. Conclusions: Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.

Neighborhood Socioeconomic Disadvantage and Distance from Treatment Center Do Not Impact Survival Outcomes of Patients with Non-Hodgkin Lymphoma and Multiple Myeloma Treated with CAR T-Cell Therapies

Introduction: Chimeric antigen receptor (CAR) T-cell therapies have radically changed the treatment paradigm of patients (pts.) with relapsed/refractory (r/r) hematologic malignancies. Despite their remarkable efficacy, health care disparities can impact outcomes of pts. in the real-world setting. Living in a disadvantaged neighborhood has been associated with inferior outcomes after allogenic hematopoietic stem cell transplantation (HSCT), independent from individual-level socioeconomic (SE) factors. Our study aimed to identify the impact of neighborhood adversity on survival outcomes of recipients of CAR T-cell therapies, as this has not been yet described. Methods: We retrospectively identified consecutive adult pts. with r/r B-cell non-Hodgkin lymphoma (B-NHL) and multiple myeloma (MM) who received CAR T-cell therapies at our center from May 2018- January 2023. Neighborhood disadvantage was defined by Area Deprivation Index (ADI), a validated tool that allows for ranking of census block groups based on SE domains (income, education, employment, and housing quality) at a national level. The 2021 national ADI percentile ranks (1-100) were obtained for each pt. using the 9-digit zip code of place of residence, with a higher rank corresponding to higher level of disadvantage. We compared overall survival (OS) and progression free survival (PFS) between pts. with high vs. low ADI. We also examined survival outcomes in relation to estimated distance from place of residence to treatment center (DTC). Time dependent outcomes were calculated from date of CAR T infusion. Pts. with B-NHL and MM were analyzed separately. Baseline variables were compared between groups using chi-squared, t-test, and Wilcoxon rank sum tests as appropriate. Survival estimates were calculated with Kaplan-Meier method, and hazard ratios were generated using cox proportional hazards model. Results: CAR T therapy was administered in 124 and 45 pts. with B-NHL and MM, respectively. Median ages were 65 and 62 yrs., 68% and 51% were male, 94% and 84% were White, 47% and 20% had high-risk disease (based on IPI/MIPI for B-NHL, and FISH for MM), 30% and 69% had prior HSCT, and median number of prior therapies were 3 (range 1-6) and 6 (range 4-14), among pts. with B-NHL and MM, respectively. B-NHL subtypes included DLBCL (84%), MCL (6%), FL (5%), and PMBCL (5%), and CAR T products for B-NHL were axi-cel (52%), tisa-cel (24%), liso-cel (18%) and brexu-cel (6%). Ide-cel (82%) and cilta-cel (18%) were used in pts. with MM. We treated pts. from 169 census block groups over 8 states, although 89% pts. were from Ohio. For the entire cohort, median ADI rank was 62.5 (range 1-100) and median DTC was 42.5 (range 1-4559) miles (m). Pts. were categorized (based on median) as having high (&amp;gt; 62.5) or low (≤ 62.5) ADI, and long (&amp;gt; 42.5m) or short (≤ 42.5m) DTC. Longer DTC was significantly associated with higher ADI ( p&amp;lt;0.001). Baseline characteristics (age, sex, prior therapies, prior HSCT, high risk disease, CAR T product) were similar across groups with low vs. high ADI and short vs. long DTC. Median follow up time up was 12 (range 4-60) and 9 (range 4-22) months for living pts. with B-NHL and MM, respectively. For pts. with B-NHL, objective response rates (ORR) (85% vs. 80%; p=0.4), relapse rates (RR) (66% vs. 66%; p=0.9), median OS (19 vs. 14 months; HR of death: 1.2; 95% CI 0.7-1.8; p=0.5) ( Fig.1), and median PFS (10 vs. 5 months, HR of relapse: 1.1, 95% CI 0.7-1.7; p=0.6) were similar for pts. with low vs. high ADI. For pts. with MM, there were no differences in ORR (77% vs. 87%; p=0.3), RR (77% vs. 70%; p=0.5), median OS (14 vs. 18 months; HR of death: 0.8; 95% CI: 0.3-2; p=0.6) ( Fig.2), and median PFS (7 vs. 9 months, HR of relapse: 0.7, 95% CI 0.3-1.4; p=0.3) between those with low vs. high ADI. There were no differences in median OS of pts. with short vs. long DTC for NHL (19 vs. 14 months; HR: 1.2, 95% CI 0.7-1.9, p=0.4) or MM (14 vs. 20 months; HR: 0.9, 95% CI 0.3-2.5; p=0.9), or when DTC was analyzed as a continuous variable. Conclusion: In patients with r/r B-NHL and MM who received CAR T-cell therapies, response rates and survival outcomes were comparable regardless of neighborhood disadvantage level or distance to treatment center. Pts. living in more disadvantaged neighborhoods travelled longer distances for treatment. These findings prompt future investigation into referral patterns and access barriers to cellular immunotherapy, especially in disadvantaged neighborhoods.

Early Results of the Phase I/II Study Investigating the All-Oral Combination of the Menin Inhibitor Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax in Acute Myeloid Leukemia (SAVE)

Background: The interaction of menin with lysine methyltransferase 2A (KMT2A) is a dependency in acute leukemia caused by either rearrangement of the KMT2A (KMT2Ar) or Nucleoporin 98 ( NUP98r) genes, or mutation of the Nucleophosmin 1 gene ( NPM1mt). The menin inhibitor revumenib (previously SNDX-5613), is a potent, oral, selective inhibitor of the menin-KMT2A interaction with demonstrated safety and clinical activity in highly refractory acute leukemias (Issa GC, Nature 2023). KMT2Ar or NPM1mt leukemias are highly susceptible to induction of apoptosis through BCL2 inhibition, and dual Bcl-2 and menin inhibition led to synergistic activity in KMT2Ar or NPM1mt leukemia models (Carter BZ, Blood 2021). Therefore, we designed a phase I/II, investigator-initiated trial of the all-oral combination of revumenib, venetoclax and the hypomethylating agent ASTX727 in children and adults with relapsed/refractory (R/R) acute myeloid leukemia (AML) (NCT05360160). Methods: Patients (pts) with R/R AML or myeloid mixed-lineage acute leukemia (MPAL) aged 12 years and older were eligible.Dose escalation followed a 3+3 design. ASTX727 (decitabine/ cedazuridine) was administered at 35 mg/100 mg PO daily days 1-5, venetoclax at 400 mg (target dose) PO daily days 1-14, and revumenib 113 mg PO Q12h (dose level [DL] 0) or 163 mg PO Q12h (DL 1, used in phase II monotherapy), days 1-28 with either posaconazole or voriconazole (strong CYP3A4 inhibitors, for antifungal prophylaxis). Maintenance with revumenib monotherapy is planned following hematopoietic stem cell transplant (HSCT) for 1 year. For the first pt cohort, bone marrow examination was performed on cycle 1 day 14 and at the end of the cycle to assess for early morphologic remission and to inform future dose adjustments. Results: As of 7/20/2023, 8 pts were enrolled, 6 at DL0, and 2 at DL1. The median age was 27 years (range, 12-62 years), including 2 children (ages 12 and 16), 5 with KMT2Ar, 2 with NUP98r and 1 with NPM1mt. One pt had MPAL, and one had bone marrow and extramedullary disease. The median prior lines of therapy was 2.5 (range 1-4), 5 pts (63%) had prior venetoclax, 5 pts (63%) had a prior hypomethylating agent, 5 pts (63%) had prior HSCT, and one had prior menin inhibitor. The most common all-grade treatment-related adverse events (TRAEs) in ≥25% of pts were febrile neutropenia (63%), hyperphosphatemia (63%), nausea (63%), and AST/ALT elevation (25%). Grade ≥ 3 TRAEs were febrile neutropenia (63%), decreased platelets count (25%), and decreased neutrophil count (25%). There was 1 dose-limiting toxicity (DLT), grade 4 prolonged thrombocytopenia and neutropenia, at DL0 (resolved after dose hold), prompting enrollment of 3 additional pts, and escalation to DL1 when no additional DLTs were noted (1/6 pts with DLT). Pts at DL1 (N=2) have not completed the DLT period. There were no deaths due to TRAEs. No grade 3 or higher QTc prolongation occurred. Two pts had grade 2 differentiation syndrome (bone pain only), resolved with steroids. One pt ( NUP98r) had asymptomatic leukocytosis at the end of cycle 1 with neutrophilia, monocytosis, decrease in peripheral blasts, decrease in bone marrow blasts from 66% to 8%, and persistence of NUP98r by fluorescence in situ hybridization at 90% indicating differentiation. Seven of 8 pts are response-evaluable, and all 7 attained a morphologic remission (overall response rate of 100%) (Figure 1). Best responses achieved included a complete remission (CR) in 1 pt (including resolution of extramedullary disease), CR with partial hematologic recovery (CRh) in 1 pt, CR with incomplete platelet count recovery (CRp) in 3 pts, partial response (PR) in 1 pt, and 1 pt with morphologic leukemia free state (MLFS). Measurable residual disease was undetectable by flow (sensitivity at 10 -4) in 3 of 7 pts (43%). Three pts transitioned to HSCT following response, 2 are in continued remission, 1 has started maintenance and 1 pt died of transplant complications prior to starting maintenance. Enrollment is ongoing and updated data will be presented. Conclusions: Early results indicate acceptable safety and high efficacy of this combination in R/R myeloid leukemias with either KMT2Ar or NPM1mt or NUP98r. This study is ongoing with plans to establish the recommended phase 2 dose and optimize delivery of this combination.

First-in-Human Study of the CD123 NK Cell Engager SAR443579 in Relapsed or Refractory Acute Myeloid Leukemia, B-Cell Acute Lymphoblastic Leukemia or High Risk-Myelodysplasia: Updated Safety, Efficacy, Pharmacokinetics and Pharmacodynamics

Introduction: SAR443579 (SAR'579) is a trifunctional anti-CD123 NKp46xCD16 natural killer cell engager, facilitating the formation of a cytolytic synapse between natural killer (NK)-cells and CD123-positive tumor cells leading to NK-cell activation and tumor cell killing. Herein, we report data of SAR'579 from TCD17197, an on-going phase 1/2 trial in patients (pts) with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia or high risk-myelodysplasia (HR-MDS) (NCT05086315). Methods: TCD17197 is a first-in human, open-label, multicenter study designed to characterize the overall safety and tolerability profile of SAR'579 and to assess preliminary anti-leukemic activity per International Working Group criteria. SAR'579 was administered intravenously for three 28-day induction cycles, either twice weekly or once weekly (QW), depending on the dose level (DL) for the first 2 weeks and then weekly for the remainder of the induction cycles. Pts achieving a complete remission (CR) or incomplete hematologic recovery (CRi) transitioned to maintenance with dosing approximately once every four weeks. Bone marrow and peripheral blood samples were taken at various time points to assess treatment response, pharmacokinetics, and pharmacodynamics. Results: As of July 05, 2023, 43 pts (42 R/R AML and 1 HR-MDS) across 8 DLs at 10 - 6000 µg/kg/dose (3 in DL1, 4 each in DL2 - DL5 and 8 each in DL6 - DL7 and DL1mg) were included. The median age was 68 years (21 - 81). Pts had received a median of 2.0 (1.0 -10.0) prior lines of treatment with 13 pts (30.2%) reporting prior hematopoietic stem cell transplantation and 36 pts (83.7%) withprior exposure to venetoclax. Median white blood cell count at screening was 2.8 × 10 9/L (0.2 - 12.2 × 10 9/L). Median bone marrow blast burden at study entry was 50% (2.8 - 90.0) and 7 (16.28%) pts had extramedullary disease. Pts received a median of 2 cycles (1 - 9) with a median treatment duration of 7.9 weeks (1 - 49). No dose limiting toxicities (DLTs) were observed up to the highest dose of 6000 µg/kg QW. TEAEs were reported in 42 pts (97.7%) with grade ≥3 adverse events (AEs) in 28 pts (65.1%). No TEAE lead to the permanent discontinuation of SAR'579. The most common treatment-emergent adverse events (TEAEs) were infusion-related reactions (n = 29 [67.4%]) and constipation (n = 11 [25.6%]) all being ≤ grade 2 events. Treatment-related AEs occurred in 32 pts (74.4%), with one (2.3%) grade 4 neutropenia. There were 2 cases of grade 1 cytokine release syndrome at DL4 and DL5, and no case of immune effector cell-associated neurotoxicity syndrome. The composite complete remission rate (CR+CRi) was 12.0% (5/42 R/R AML). In DLs with a highest dose of 1000 µg/kg QW, (DL3, DL4, DL1mg) 5/15 (33.3%) pts achieved a CR (4 CR/1 CRi) as of the cut-off date. Complete remissions were observed upon completion of 1 (CR &amp; CRi), 2, 3 and 4 cycles of treatment, and the median duration of CR/CRi is not estimable. Data from updated PK/PD and in vitro mechanistic analyses studying dose-response relations will be presented. Conclusions: SAR'579 was well tolerated up to doses of 6000 µg/kg QW with observed clinical benefit in pts with R/R AML. The results are consistent with the predicted favorable safety profile.

Intensive Chemotherapy (IC) Followed By Oral Azacitidine (AZA) Maintenance Versus Venetoclax (VEN) Plus AZA for Patients (pts) with Acute Myeloid Leukemia (AML): Retrospective Analysis of an Electronic Medical Record (EMR) Database in the United States

Introduction:Frontline therapy with IC is usually recommended for eligible pts with newly diagnosed (ND) AML. Pts who achieve remission with induction and are transplant-ineligible can receive oral AZA (Oral-AZA) maintenance. For pts ineligible for IC, VEN with injectable AZA (VEN-AZA) is the recommended treatment. Selection of frontline therapy can be challenging for pts considered reasonable candidates for either IC or VEN-AZA. A prior analysis suggested that survival outcomes may be comparable in matched pts with ND AML treated with either IC or VEN-AZA (Zeidan AM, et al, Annal Hematol 2023;102:749-754). However, the impact of Oral-AZA maintenance was not accounted for. In this analysis, we compare the survival outcomes of pts who received IC followed by Oral-AZA maintenance (IC-Oral-AZA) versus those who received frontline VEN-AZA and achieved remission, before and after matching for baseline and clinical characteristics Methods:In this retrospective, observational, study using Flatiron Health's database, de-identified data from adult pts with ND AML who received either frontline IC-Oral-AZA or frontline VEN-AZA and achieved remission were analyzed. Exclusion criteria included diagnosis of acute promyelocytic leukemia, treatment with arsenic trioxide/tretinoin, clinical trial participation, or prior hematopoietic stem cell transplant (HSCT). Treatment with Oral-AZA for IC-Oral-AZA pts had to commence prior to a 2nd line of therapy or disease relapse, and after Sept 1, 2020. Cohorts were matched 1:1 on baseline demographic and clinical characteristics using propensity scores to minimize differences. Matched characteristics included sex, age at diagnosis (18-64, 65-74, ≥ 75 years), race/ethnicity, region, ECOG performance status (PS), BMI, previous diagnosis of myelodysplastic syndromes or myeloproliferative neoplasm, cytogenetic risk category, whether AML is treatment-related or was diagnosed as mixed phenotype. Baseline molecular data were insufficient. Relapse-free survival (RFS) and overall survival (OS) were estimated for unmatched and matched cohorts using Kaplan-Meier analysis from date of remission, censoring pts at the time of HSCT/end of follow-up. Cox regression analyses were conducted for RFS and OS, both on an unadjusted basis and after adjusting for any remaining differences in age between the matched cohorts. Confirmatory landmark analysis is being conducted. Results:In total, 50 IC-Oral-AZA and 403 VEN-AZA pts met the selection criteria prior to matching. The matching process yielded 33 pts in each cohort, with median follow-up from start of therapy of 13.1 and 11.2 months for IC-Oral-AZA and VEN-AZA cohorts, respectively. The cohorts matched well on median age at diagnosis (63 years for both), sex (54.5%, 51.5% males), ECOG PS 2+ (18.2%, 21.2%), cytogenetic risk (46.7% poor, 26.7% intermediate, 26.7% favorable risk for both groups, among those with known risk status), whether AML was treatment-related (12.1%, 21.2%), race/ethnicity, region, and BMI. Three pts (9.1%) in the IC-Oral-AZA cohort and 8 (24.2%) in the VEN-AZA cohort received HSCT during follow-up. Median time from remission to start of Oral-AZA for the IC-Oral-AZA cohort was 128 days. For the unmatched cohorts, median RFS was significantly longer for IC-Oral-AZA (20.0 months [95% CI, 13.4-not reached (NR)]) than for VEN-AZA (9.3 months [8.3-10.7]; P&amp;lt;0.001) as was median OS (IC-Oral-AZA, NR [15.5-NR]) versus VEN-AZA (13.4 months [10.7-15.5]; P &amp;lt; 0.001). For the matched cohorts, median RFS was significantly longer for IC-Oral-AZA (20.0 months [95% CI, 9.9-NR]) than for VEN-AZA (8.7 months [4.1-15.5]; P = 0.002) as was median OS (IC-Oral-AZA, NR [14.6-NR] versus VEN-AZA, 15.2 months [7.4-19.7]; P = 0.002) (Figures A and B). The Cox analyses confirmed the superior outcomes of the IC-Oral-AZA cohort for both RFS (unadjusted HR, 0.33 [95% CI, 0.17-0.65]; P &amp;lt; 0.01, adjusted HR, 0.34 [0.17-0.70]; P &amp;lt; 0.01) and OS (unadjusted HR, 0.28 [0.11-0.68]; P &amp;lt; 0.01, adjusted HR, 0.29 [0.11-0.74]; P &amp;lt; 0.01). Conclusion:Pts treated with frontline IC followed by Oral-AZA as maintenance had significantly better survival outcomes than pts who were treated and achieved remission with frontline VEN-AZA. These results suggest that pts with ND AML eligible for frontline IC should receive this regimen followed by Oral-AZA maintenance, if they are not candidates for transplant at remission.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of &amp;gt;24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

Komet-008: A Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-Rearranged or NPM1-Mutant Relapsed/Refractory Acute Myeloid Leukemia

Background and Significance: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) remain a high unmet need. Ziftomenib is a potent and selective inhibitor of the interaction between menin and mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A), which drives leukemogenesis in these subtypes. Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. An ongoing Phase 1/2 study (KOMET-001) in R/R AML has demonstrated that ziftomenib monotherapy is safe and well tolerated and that the clinical activity at the recommended phase 2 dose (RP2D) is robust, as the rates of response were not affected by the presence of downstream co-mutations, such as FLT3 and IDH1 or IDH2. Given the monotherapy activity seen to date, the development of ziftomenib in combination with standard-of-care (SOC) chemotherapies or FLT3 inhibitors may provide increased clinical benefit for R/R AML patients with KMT2A-r or with NPM1-m with or without concurrent FLT3-mutations ( FLT3-m) and warrants further investigation. Study Design and Methods: KOMET-008 (NCT# 05735184) is an open-label, dose escalation and expansion study to determine the safety, tolerability, and preliminary efficacy of ziftomenib when combined with SOC regimens for the treatment of either NPM1-m (Arm A) or KMT2A-r (Arm B) R/R AML. Each genetically defined arm will evaluate ziftomenib in combination with various SOC treatments in separate and independent cohorts, as outlined below: Arm A:NPM1-m R/R AML Cohort A-1: Ziftomenib plus FLAG-IDACohort A-2: Ziftomenib plus LDACCohort A-3: Ziftomenib plus gilteritinib (for NPM1-m + FLT3-m R/R AML) Arm B: KMT2A-r R/R AML Cohort B-1: Ziftomenib plus FLAG-IDACohort B-2: Ziftomenib plus LDAC The Part 1a dose escalation uses a i3+3 design, followed by dose expansion/validation in Part 1b. Key eligibility criteria include adults (≥18 years) with documented NPM1-m (±co-occurring FLT3-m) or KMT2A-r R/R AML, ECOG ≤2, prior hematopoietic stem cell transplant (HSCT) allowed, if recovered and prior gilteritinib allowed. Patients who receive an HSCT during study participation will be allowed to receive ziftomenib maintenance therapy upon recovery. The primary objectives are to establish the safety and tolerability of ziftomenib when combined with SOC therapies (ie, dose limiting toxicities, AEs per CTCAE v5.0) and to identify the RP2D of ziftomenib for each SOC combination in each genetically defined cohort. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.

Utilizing a best practice advisory (BPA) to increase pneumocystis jirovecii pneumonia (PJP) prophylaxis prescribing for patients with cancer on high dose corticosteroids.

391 Background: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that can cause severe respiratory infection in immunocompromised patients. Corticosteroid use is a common risk factor for developing PJP in non-human immunodeficiency virus (HIV) patients. Corticosteroids are commonly prescribed medications for cancer patients to help with symptom control from cancer treatment (e.g. nausea, vomiting, and pain) as well as for immunotherapy related adverse events. The risk of developing PJP is significantly increased for patients on prednisone equal to or greater than 20 mg per day x 1 month or equivalent. Steroid related PJP (srPJP) is associated with a 30-50% mortality in non-HIV patients. Methods: We conducted an IRB-approved retrospective chart review of individuals diagnosed with PJP at an academic medical center and 6 partner hospitals between 2016-2022. Patients were excluded if they had a diagnosis of HIV or prior hematopoietic stem cell transplant (HSCT). We then created a best practice advisory (BPA) built into the electronic health record to notify clinicians if a patient is at risk of developing srPJP based on their outpatient corticosteroid prescription. The BPA is triggered system-wide if a clinician signs an outpatient prescription for a prednisone or equivalent steroid dose of 20 mg or more for a duration of at least 3 weeks. The BPA will suggest PJP prophylaxis and link to an order for the clinician to select. Results: There were 96 identified cases of srPJP in non HIV/HSCT patients. None of these patients received antibiotic prophylaxis. Among these cases, 32 patients died from ARDS due to PJP, a mortality of 33.3%. 45% of identified cases were related to steroids prescribed for cancer management, and 68% of these received dexamethasone as the primary steroid. The BPA launched in April 2023 system wide across UC Health. Since launching the BPA in April 2023, it has been triggered 911 times with action taken by selecting an order for PJP prophylaxis 24.5% of the time. Conclusions: Despite the efficacy of prophylaxis, many patients at risk of developing srPJP do not receive prophylaxis. Since launching the BPA, preliminary data shows that the BPA has increased the orders placed for concurrent PJP prophylaxis. Further work must be done to determine if these orders for concurrent PJP prophylaxis were signed and if the BPA can increase PJP prophylaxis prescribing for patients on high dose corticosteroids and ultimately decrease srPJP cases and deaths.

Risk factors for nosocomial rectal colonisation with carbapenem-resistant Gram-negative bacilli in children with haematological malignancies: a case-control study

BackgroundRectal colonisation with carbapenem-resistant Gram-negative bacilli (CR-GNB) may cause CR-GNB infection in children with haematological malignancies (HMs) haematological. To date, information on its epidemiology is limited. This study aimed to assess the the risk factors for rectal colonisation with CR-GNB in children with HMs.MethodsA case–control study in a tertiary children’s hospital in Hangzhou City, was conducted between July 2019, and September 2021. Based on the hospitalisation date, children in the CR-GNB colonisation group and control groups were matched at a ratio of 1:2. Conditional logistic regression models were used to compute the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of the risk factors for CR-GNB rectal colonisation in children with HMs.ResultsA total of 85 non-duplicated CR-GNB isolates were collected from rectal swab samples of 69 children with HMs. The 30-day mortality rates were 5.8% in the CR-GNB colonisation group and 0% in the control group (P = 0.020).colonisation In the conditional logistic regression model, the aORs were 6.84 (95% CI 1.86–25.20) for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), 4.16 (95% CI 1.17–14.84) for prior concomitant infections within the last 1 month, 2.33 (95% CI 1.16–4.69) for prior carbapenems usage within the last 1 month and 7.46 (95% CI 1.81–30.67) for prior hematopoietic stem-cell transplantation (HSCT).ConclusionAML/ALL, prior concomitant infections within the last 1 month, prior carbapenems usage within the last 1 month, and prior HSCT are associated with an increased risk of rectal colonisation with CR-GNB in children with HMs.