European LeukemiaNet Research Articles

Dynamics of Response and Response Factors in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) after ≥2 Prior Tyrosine Kinase Inhibitors (TKIs) in the Phase 3 Ascembl Study

Introduction: Asciminib is the 1st BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). Based on the phase 3 ASCEMBL trial, asciminib was FDA approved for the treatment of adult pts with Philadelphia chromosome-positive CML-CP after ≥2 TKIs and for pts with the T315I mutation. In ASCEMBL, after ≥2 years of follow-up, asciminib continues to demonstrate superior efficacy, safety, and tolerability compared with bosutinib (BOS), with more pts on asciminib remaining on treatment and continuing to benefit from therapy over time. In a preplanned subgroup analysis, major molecular response (MMR; BCR::ABL1IS ≤0.1%) rates were consistently higher with asciminib than BOS across major demographic and prognostic subgroups. Here we describe exploratory analyses aimed to characterize the efficacy of asciminib over time and compared with BOS (data cutoff for ASCEMBL wk 96 analysis: October 6, 2021). Methods: Eligible pts with intolerance or treatment failure (lack of efficacy) per European LeukemiaNet (ELN) 2013 recommendations were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by baseline major cytogenetic response status. Per ELN 2013, pts with BCR::ABL1IS >10% at wk 24 were considered to have lack of efficacy and discontinued therapy. Analyses included molecular response at different time points according to baseline BCR::ABL1IS, cumulative incidence of MMR/BCR::ABL1IS ≤1% in nonresponder pts by wk 24, and logistic regression to assess baseline characteristics as predictive factors of MMR achieved early (by wk 24) vs late (after wk 24). MMR rate at wk 96 according to prior TKIs and reason of discontinuation was analyzed with asciminib and BOS. Results: Of 60 pts on asciminib with BCR::ABL1IS ≤10% at baseline, 18 (30.0%), 24 (40.0%), and 36 (60.0%) reached MMR at wk 12, 24, and 96, respectively, and 38 (63.3%), 45 (75.0%), and 47 (78.3%) reached BCR::ABL1IS ≤1% at wk 12, 24, and 96, respectively. Of 97 pts with BCR::ABL1IS >10% at baseline, 10 (10.3%), 16 (16.5%), and 23 (23.7%) reached MMR at wk 12, 24, and 96, respectively, and 28 (28.9%), 32 (33.0%), and 29 (29.9%) reached BCR::ABL1IS ≤1% at wk 12, 24, and 96 (Table 1). Per protocol, twenty-one (21.6%) pts had BCR::ABL1IS >10% at wk 24 and discontinued treatment per protocol. Of 18 pts on asciminib with BCR::ABL1IS >1% by wk 24, the estimated cumulative incidence of BCR::ABL1IS ≤1% (95% CI) was 22.2% (6.5%-43.6%) by 1 year and 38.9% (16.4%-61.0%) by 2 years. Of 56 pts on asciminib without MMR by wk 24 and who were still on asciminib after wk 24, the estimated cumulative incidence of MMR (95% CI) was 17.9% (9.1%-29.0%) by 1 year and 37.9% (25.1%-50.6%) by 2 years. No baseline characteristics were identified as independent predictive factors of early vs late MMR. Overall MMR rates at wk 96 were higher with asciminib than BOS regardless of the last prior TKI received (imatinib, 55.6% vs 14.3%; nilotinib, 40.9% vs 35.7%; dasatinib, 37.1% vs 10.5%; radotinib, 50.0% vs 0%; ponatinib, 20.0% vs 11.8%) and higher in pts who discontinued their last TKI due to intolerance (asciminib, n=59; BOS, n=22) vs resistance (asciminib, n=95; BOS, n=54). A higher proportion of pts who were resistant to the prior lines of 2nd-generation (2G) TKIs received before randomization, achieved MMR with asciminib vs BOS, respectively, at wk 96: 34.3% vs 7.7% with 1 prior 2G TKI; 35.0% vs 16.7% with ≥2 prior 2G TKIs (Table 2). Conclusions: Responses continued to deepen over time with asciminib in pts with CML-CP after ≥2 prior TKIs, with additional pts achieving MMR at later time points. Pts on asciminib achieved MMR regardless of the last TKI and reason for discontinuation (resistance/intolerance), and overall MMR rates at wk 96 were higher with asciminib than BOS across all last prior TKIs. In pts with resistance to all prior lines of 2G TKIs, MMR rates at wk 96 were higher with asciminib than BOS and comparable to the previously published MMR rate of all pts randomized to receive asciminib (37.6 %). Overall, these results demonstrate that pts who continued asciminib therapy beyond wk 24 have a considerable probability of achieving MMR at later time points. The efficacy of asciminib after treatment failure on 2G TKIs supports a new standard of care for pts with CML-CP for whom ≥2 prior TKIs have failed. This study is sponsored by Novartis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Chronic Myeloid Leukemia with No Major Molecular Response within 2 Years of Tyrosine Kinase Inhibitor Therapy

Introduction: Achieving a major molecular response (MMR) defined as BCR::ABL1 ≤ 0.1% IS, is an important milestone for optimal response in patients with chronic myeloid leukemia (CML), and decreased risk of transformation to advanced CML. However, the long-term clinical impact of not achieving this milestone is unknown, especially whether it affects chances of survival in older patients. Therefore, we sought to examine responses and outcomes associated with BCR::ABL1 > 0.1% IS after 2 years of treatment with tyrosine kinase inhibitors (TKI). Methods: In a retrospective analysis, we screened our databases for CML patients treated at our institution between 2001 and 2020 and identified those who never achieved MMR within 2 years of TKI therapy. Overall survival (OS) was measured from treatment start date to death from any cause or censored at last follow-up, whereas CML-specific OS assessed only death due to CML complications as events. Progression-free survival (PFS) was measured from TKI start date to progression to either accelerated or blast phase or death. The role of various prognostic factors on survival was evaluated in a multivariate analysis Results: We identified 131 patients who never achieved MMR within 2 years (Table 1). Among them, 79 (60%) eventually achieved MMR at a median of 49.4 months from time of TKI start (range 27-187 months). 24 (30%) of these patients achieved MMR by continuing the same TKI, 48 (61%) by switching to a different therapy and 9 (11%) by undergoing stem cell transplant (Table 1). The remaining 52 patients had different levels of cytogenetic response as highlighted in (Table 1). The 10-year CML-specific OS of this cohort was 89%, with a 10-year OS of 76% and 10-year PFS of 74%. Patients who achieved only minor or no cytogenetic response (BCR::ABL1 > 10%) within the first two years had worse 10-year OS (64%) compared to those who achieved major cytogenetic response (BCR::ABL1 ≤ 10% - MCyR) (88%, P=0.01) or complete cytogenetic response (BCR::ABL1 ≤ 1% - CCyR) (85%, P=0.05) within the same period. These trends were similar when evaluating CML-specific OS (Figure 1). In patients aged ≥ 60 years at CML diagnosis, the 10-year OS was 55%; however, none of these deaths were attributed to CML complications (10-year CML-specific OS of 100%) and only 1 (4%) patient progressed to blast phase. In a multivariate analysis of patients included in this cohort, MCyR within 2 years was identified as the only independent prognostic factor associated with improved CML-specific OS with a hazard ratio of 0.19 (95% CI 0.04 - 0.89; P=0.04). Conclusion: CML related mortality remains low among patients who do not achieve MMR within the first 2 years of TKI therapy. Favorable outcomes were seen even among patients with BCR:ABL1 levels between 1% to 10% IS. This is particularly evident for those above the age of 60, where mortality is mainly due to CML-unrelated comorbidities. These findings may help the new considerations in European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Activity of Azacitidine and Venetoclax Compared to Other Therapies in Adults with Refractory or Relapsed Acute Myeloid Leukemia, a Retrospective Study

Introduction: Primary refractory or relapsed (R/R) acute myeloid leukemia (AML) is associated with poor prognosis. Therapeutic resistance is the principal cause of treatment failure. Despite recent advances in therapeutics, there are still unmet needs in R/R AML. With VIALE-A study (DiNardo et al., 2020), azacitidine-venetoclax (AZA-VEN) has been used more frequently in current practice for R/R disease without strong evidence to support its use after first induction. The purpose of this study was to report patient selection and outcomes in adults who received AZA-VEN compared to other therapies (NO-AZA-VEN cohort) during the same time period. Methods: Between January 1st 2019 and January 1st 2021, we retrospectively analyzed the charts of 84 consecutive patients who had R/R AML, of whom 68 (81%) received at least one line of chemotherapy for R/R disease. Nine patients were excluded because they previously received an hypomethylating agent. Of the 59 patients analyzed, 20 (34%) received AZA-VEN and 39 (66%) received other therapies. Results: The baseline characteristics are described in Table 1. Median age of patients was 60 years old and 51% were males. Second line of treatment (first line for R/R setting) for the NO-AZA-VEN cohort was either NOVE (51%), FLAG-IDA (10%), IDAC (13%), Sorafenib (15%), HDAC-12 (5%), CPX-351 (3%) or Gilteritinib (3%). In the AZA-VEN cohort, 6 (30%) patients received it in second line, 10 (50%) patients in third line and 4 (20%) in fourth line. There was significantly more European LeukemiaNet (ELN) 2017 adverse risk patients in the AZA-VEN cohort compared to the NO-AZA-VEN cohort (55% vs 5%, p<0.001). However, there was no FLT3-ITD mutations in the AZA-VEN cohort compared to 11 patients (28%) in the other cohort, p=0.01. For those who achieved a complete response (CR) after first induction (n=40), the median time to relapse was 21 months in the AZA-VEN cohort and 17 months in the NO-AZA-VEN cohort, p=0.229. There were 9 (45%) patients in the AZA-VEN cohort who received an allogenic hematopoietic stem cell transplant in first remission compared to 25 (64%) patients in the NO-AZA-VEN cohort, p=0.177. Median follow up was comparable in both groups with 8 months in the AZA-VEN cohort compared to 7 months in the NO-AZA-VEN cohort, p=0.521. From the date of relapse or the date of refractory disease after first line therapy, the AZA-VEN cohort had a median overall survival (OS) of 8 months compared to 9 months in the NO-AZA-VEN cohort, p=0.854. Receiving AZA-VEN in second, third and fourth line was associated with an overall response rate (ORR), composed of CR and CR with incomplete hematologic recovery (CRi), of 67% (n=6), 50% (n=10) and 50% (n=4), respectively and a median progression free survival (PFS) of 4.7, 1.4 and 3.6 months, p=0.747 (Figure 1). Most frequent causes of death for both AZA-VEN and NO-AZA-VEN cohorts were leukemia progression (64% vs 54%, p=0.739) and infection (21% vs 42%, p=0.299). There was no statistical difference in complications of treatment such as number of hospitalization days (median 38 days vs 32 days, p=0.637), febrile neutropenia (85% vs 90%, p=0.680), intensive care unit stay (5% vs 8%, p=1.00), septic shock (10% vs 5%, p=0.560) and total parenteral nutrition (0% vs 13%, p=0.156). Although the cohort is small for subgroup analyses, age, Eastern Cooperative Oncology Group (ECOG) performance status score, line of treatment, ELN 2017 risk categories, AML subtype and previous allogenic hematopoietic stem cell transplant did not impact ORR, PFS and OS in the AZA-VEN cohort. Conclusion: Use of AZA-VEN was associated with good ORR despite being used in later line of treatment, but with a short mean of PFS. Even though AZA-VEN was used with more adverse risk R/R AML, the overall survival was comparable to the NO-AZA-VEN cohort. Further randomized studies are needed to advise on the usage of AZA-VEN in the R/R setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Occurrence of Thrombosis during Intensive Chemotherapy Treatment for Acute Myeloid Leukemia Patients Does Not Impact on Long-Term Survival

Introduction A thrombotic event is seen in 10% of newly diagnosed acute myeloid leukemia (AML) patients and has been shown to be associated with disseminated intravascular coagulation (Libourel et al. Blood. 2016). As of yet, the association of developing thrombosis during intensive chemotherapy with AML risk models such as the Medical Research Council (MRC) cytogenetics-based assessment and the European LeukemiaNet (ELN) 2017 molecular based risk model has not been rigorously evaluated. In addition, there is a paucity of data pertaining to the long-term prognostic impact of thrombosis in AML patients. Aiming to investigate these prognostic facets of thrombosis in AML, we performed an analysis of patients with AML diagnosed with thrombosis during treatment with intensive chemotherapy. Methods For this analysis, we collected data on baseline clinical, laboratory, cytogenetic and molecular characteristics of patients with newly diagnosed AML who were treated with intensive chemotherapy and were diagnosed with venous thrombosis. These data were compared with intensively treated patients who did not experience thrombosis to assess for clinical parameters associated with a higher likelihood of developing thrombosis, and to determine whether overall survival was affected by thrombosis. Results The analyzed cohort consisted of 335 newly diagnosed AML patients diagnosed and treated between 2007 through 2021 at the Sheba Medical Center. Median patient age at diagnosis was 55 years. At the time of data analysis 162 patients were alive (48%). Two hundred and eighty-three patients were classified as de novo AML (85%) and the remainder were categorized as secondary disease (15%). Ninety patients harbored the FLT3-ITD mutation (28%) and 117 patients harbored NPM1 mutations (39%). Of evaluable patients, 7 were found to have biallelic CEBPA mutations (8%). In terms of MRC cytogenetic risk, 35 patients (11%) were classified as favorable risk, 219 (66%) patients as intermediate risk, 58 patients (17%) as adverse risk and 21 patients had technically insufficient cytogenetic studies. Using the ELN 2017 risk stratification model, 132 patients (40%) had favorable risk disease, 122 patients (36%) intermediate risk, and 80 patients (24%) adverse risk disease. Venous thrombosis was seen in 33 patients (9.9%) with 28 patients diagnosed with central catheter related thrombosis and 5 patients with lower extremity deep vein thrombosis. In 23 patients (70%) thrombosis occurred during the initial induction chemotherapy phase, in 5 patients (15%) during the first consolidation treatment phase, in 3 patients (9%) during the second consolidation treatment phase, and in 2 patients (6%) during admission for salvage chemotherapy. Following diagnosis of thrombosis, the central catheter was taken out in 9 patients (28%), and 3 patients (8.8%) experienced a recurrence of thrombosis. At the time of thrombosis diagnosis, 14 patients (42%) were found to have a concurrent blood stream bacterial infection. Nineteen patients (58%) were started on anticoagulation following the diagnosis of thrombosis. In univariate analysis, patient age, initial levels of white blood cells, hemoglobin, platelets, creatinine, uric acid, lactate dehydrogenase, INR, albumin, and liver function tests were not significantly different between patients who developed thrombosis and those who did not. Disease type (de novo versus secondary), FLT3-ITD and NPM1 mutational status, achievement of remission, and ELN 2017 risk category also not did not differ to a significant degree between groups. However, MRC intermediate risk group patients were significantly more likely to experience thrombosis compared to favorable risk and adverse risk patients (12.8% versus 5.7% and 1.7%, respectively; p=0.049). Overall survival was not significantly impacted by the diagnosis of thrombosis with an estimated median overall survival of 3.7 years seen in patients without thrombosis compared with 2.2 years in patients with thrombosis (p=0.47). Leukemia-free survival was also comparable between groups (2.4 years versus 1 year; p=0.15). Conclusion Venous thrombosis is seen mostly during the initial induction phase of AML patients receiving intensive therapy with a tight association with the MRC intermediate risk category, however long-term survival and leukemia related outcomes are not significantly impacted by the diagnosis of thrombosis.

ASC4OPT: A Phase 3b Open-Label Optimization Study of Oral Asciminib in Chronic Myelogenous Leukemia in Chronic Phase Previously Treated with 2 or More Tyrosine Kinase Inhibitors

Introduction Tyrosine kinase inhibitors (TKIs) are the standard of care in the treatment of chronic myeloid leukemia (CML). However, patients (pts) may experience resistance or intolerance to successive lines of TKI therapy. Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). It is approved in the United States for the treatment of adults with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP) previously treated with ≥2 TKIs (at 40 mg twice daily [BID] or 80 mg once daily [QD]), and also Ph+ CML-CP with the T315I mutation (at 200 mg BID). This was based on the Phase 3 ASCEMBL trial (Rea et al. Blood 2021) and a Phase 1 study (Cortes et al. ASH 2020). The ASC4OPT (NCT04948333) trial was initiated to investigate the potential optimization of treatment with asciminib in adult pts with CML-CP previously treated with ≥2 TKIs (≥3rd-line). ASC4OPT will explore 3 aspects of treatment optimization: 1. Pt population, ASCEMBL inclusion criteria were based on the European LeukemiaNet (ELN) treatment recommendations from 2013. ASC4OPT will re-evaluate asciminib in an expanded ≥3rd-line population using the ELN 2020 treatment recommendations for warning and failure criteria. 2. Simplified posology, asciminib dosing in ASCEMBL was 40 mg BID. BID dosing may affect optimal compliance for pts and ASC4OPT will investigate both asciminib 40 mg BID and 80 mg QD. 3. Dose escalation, with limited treatment options in the ≥3rd-line setting, ASC4OPT will explore whether pts not in major molecular response (MMR) at ≥48 weeks (wks) could benefit from a potential dose escalation to 200 mg QD. Methods ASC4OPT is an international, multi-center, non-comparative, Phase 3b study in pts aged ≥18 years with CML-CP previously treated with ≥2 TKIs. The trial will enroll approximately 156 pts who are in treatment failure or warning (ELN 2020) or intolerant to the last prior TKI and not in MMR at baseline. Up to 30 additional pts in MMR at baseline and intolerant to their most recent TKI treatment will also be enrolled; these pts will not be included in the primary endpoint analysis, however all assessments will be performed. Pts are excluded if they have had previous or planned hematopoietic stem cell transplantation, second CP after previous progression to accelerated phase/blast crisis, or known presence of the BCR::ABL1 T315I mutation at any time prior to study entry. Pts will be randomized 1:1 to receive asciminib 40 mg BID or 80 mg QD. In pts not achieving MMR at 48 wks or losing response after wk 48 and up to wk 108, asciminib dose may be escalated to 200 mg QD if in the investigator's opinion the pt may benefit from the escalation. In addition, for dose escalation there must not be any grade 3 or 4 toxicity while on therapy, or persistent grade 2 toxicity, possibly related to asciminib and unresponsive to optimal management (Figure). The primary endpoint is MMR rate (BCR::ABL1IS ≤0.1%) at wk 48 in pts not in MMR at baseline. Secondary endpoints include MMR rate at wks 12, 24, 36, 72, 96 and 144 in pts not in MMR at baseline, MMR rate at wk 48 for pts in MMR at baseline, time to MMR, rate of early responses of BCR::ABL1IS ≤10% and ≤1% at wks 12, 24, 36 and 48, deep molecular responses (rates of MR4.0 [BCR::ABL1IS ≤0.01%] and MR4.5 [BCR::ABL1IS ≤0.0032%] at wks 12, 24, 36, 48, 72, 96 and 144), rate of cytogenetic response at wk 48 and at end of treatment (up to 144 wks), and patient-reported outcomes and quality of life. Current status As of July 2022, 77 patients have been enrolled in the study. This study is sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MO-TRANS: A Phase 2b Placebo-Controlled Study of Mocravimod As Adjunctive and Maintenance Treatment in AML Patients Undergoing Allogeneic Hematopoietic Cell Transplant

Introduction: Mocravimod is a sphingosine 1-phosphate receptor (S1PR) immunomodulator that blocks lymphocyte egress from lymphoid organs via its phosphorylated active metabolite. Allogeneic hematopoietic cell transplant (allo-HCT) is a common treatment in AML, which is indicated as consolidation therapy for intermediate/high risk AML. The therapeutic benefit includes graft-versus-leukemia (GvL) effect of the donor's T cells against the leukemic cells of the patient. One of the major risks of allo-HCT is graft-versus-host disease (GvHD) and is regarded as the off-target effect of the desirable GvL effect, in which the donor T cells respond to and attack normal host cells other than the leukemic cells. The major causes of post-transplant mortality, morbidity and quality of life impairment, remain disease relapse and GvHD. S1PR modulation does not interfere with T cell cytotoxicity, hence function is maintained, and anti-leukemia response remains potent. Since mocravimod is not immunosuppressive, alloreactive T cells can retain anti-leukemia reactivity to boost GvL while being sequestered in the lymphatic organs and thus not promoting peripheral GvHD. Therefore, treatment with mocravimod as an adjunctive and maintenance therapy to allo-HCT may trigger two positive effects: 1) increase the GvL effect through the eradication of residual malignant cells by alloreactive T cells sequestered in the lymphoid tissues such as lymph nodes, the bone marrow, and the spleen white pulp, and 2) reduce the GvHD because alloreactive T cells are retained in the lymphoid tissues and thus do not migrate into peripheral tissues. Both effects will ultimately result in improving overall survival (OS). Based on the encouraging results of a phase Ib study with mocravimod in the allo-HCT setting, a phase 2b trial is planned. Study Design and Methods: In this multicenter, double-blind, phase 2b study, approximately 249 pts will be randomized 1:1:1 to receive mocravimod 1mg or mocravimod 3mg or placebo. Patients will be stratified by the complete remission status (CR1 versus CR2), the treatment used for GvHD prophylaxis cyclosporine A (CsA) versus tacrolimus (TAC), and the measurable residual disease (MRD) status (MRD pos versus MRD neg). Key eligibility criteria include age (> 18 years and < 75 years), diagnosis of AML (excluding acute promyelocytic leukemia) with European LeukemiaNet (ELN) high risk disease in CR1, intermediate risk in CR1 if MRD pos, or AML of any risk in CR2. Patients need to be planned to undergo allo-HCT, with either fully matched related or unrelated donor. The planned use of GvHD prophylaxis needs to be either methotrexate (MTX) plus CsA or MTX plus TAC. Treatment in all arms will consist of 28-day cycles with daily administration of either 1mg mocravimod or 3mg mocravimod or placebo. Treatment will start 2 days before conditioning treatment and will be ongoing for 12 cycles or until relapse, unacceptable toxicity, or consent withdrawal. Patients will be observed for overall survival after end of treatment. Primary efficacy endpoint is relapse free survival (RFS), which is calculated as the time from randomization to relapse or death. It will be assessed once 46 events are reached in one mocravimod arm and the placebo arm and will be observed by an unblinded independent data monitoring committee. The first key secondary objective is to assess the effect of mocravimod relative to placebo on Overall Survival (OS). A second key objective is the comparison of the effect on RFS between the second mocravimod arm and the placebo arm and it will be assessed once the primary endpoint analysis timepoint will be reached. The FDA activated the IND #127312 on 22 Apr 2022, and five European Health Authorities approved the study to date: France, the UK, Spain, Switzerland and Germany. Enrollment is expected to begin in Q3, 2022. The ClinicalTrials.gov identifier is NCT05429632.

Efficacy and Safety of Long-Term Ropeginterferon Alfa-2b Treatment in Patients with Low-Risk and High-Risk Polycythemia Vera (PV)

Introduction: Patients with "low-risk” (LR) PV are managed conservatively despite higher risk of vascular events and impaired quality of life compared to a population without PV. Acknowledging new evidence (LOW-PV study, Barbui et al 2021), recent treatment guidelines (European LeukemiaNet [ELN] 2021) recommend ropeginterferon alfa-2b (BESREMi®) as a cytoreductive treatment in LR PV patients meeting specific criteria as well as in high-risk (HR) PV patients. Final data from the phase 3 PROUD-PV and CONTINUATION-PV trials (NCT01949805; NCT02218047) demonstrated the long-term efficacy and safety of ropeginterferon alfa-2b compared with hydroxyurea/best available treatment (HU/BAT); here we report results in the ropeginterferon alfa-2b arm by risk stratum. Methods: PV patients were randomized 1:1 and received ropeginterferon alfa-2b or HU/BAT for ≥6 years. In the ropeginterferon alfa-2b arm, subgroup analyses were performed post-hoc by risk stratum (LR: age ≤60 years and no history of thrombosis; all others HR). Complete hematologic response (CHemR) and molecular response defined by modified ELN criteria were assessed in the full analysis set for CONTINUATION-PV (N=95); safety analyses included all data regardless of roll-over (N=127). Results: CONTINUATION-PV enrolled 46 LR and 49 HR patients in the ropeginterferon alfa-2b arm. At baseline, mean age was 50.7 vs 63.7 years respectively, and median duration since PV diagnosis was 1.9 months vs 1.5 months. HR patients had higher platelet and leukocyte counts at baseline and more frequently presented with clinically significant splenomegaly or PV-related symptoms. Median JAK2V617F allele burden was similar for LR and HR patients (37.0% vs 39.4%), however LR patients were less likely to harbor additional non-driver mutations (11.4% vs 24.4%). The median 4-weekly ropeginterferon alfa-2b dose was comparable in LR and HR patients throughout the study (in the 6th year, 499 µg and 489µg respectively) as was the use of an extended 3-4 weekly dose regimen (6th year: 59.5% vs 65.4%). LR patients achieved a significantly higher CHemR rate than HR patients during long-term treatment (Month 72: 73.2% vs 38.3% in LR and HR respectively [RR: 2.41; 95% CI: 1.50 to 3.90; p=0.0003]). Higher CHemR among LR patients was confirmed in a sensitivity analysis including discontinued patients (last observation carried forward [LOCF]; 80.4% in LR vs 65.3% in HR patients at Month 72) indicating that in the HR group, more patients discontinued despite CHemR. In general, discontinued patients were older than those who completed the study (mean age 62.8 years vs 55.2 years) but did not have a longer duration of PV or markedly greater symptom burden at baseline. Importantly, regardless of risk stratum, most patients receiving ropeginterferon alfa-2b did not require any phlebotomy for the entire 6th year (85.7% of LR patients and 75.0% of HR patients entering the 6th year [p=0.3]). LR patients had a higher molecular response rate than HR patients (LOCF at Month 72: 84.4% vs 49.0% respectively, RR: 2.15 [95% CI: 1.37 to 3.37]; p=0.0009) and achieved molecular response more rapidly (median time to first response: 12 months [95% CI: 12 to 18] vs 18 months [95% CI: 12 to 24]; Log-rank test p=0.03). The median JAK2V617F allele burden was 5.6% for LR and 17.9% for HR patients at Month 72 (p<0.0001). During the entire PROUD-PV/CONTINUATION-PV studies (≥6 years exposure), adverse drug reactions (ADRs) to ropeginterferon alfa-2b led to withdrawal of treatment in 1 (1.8%) LR patient (due to sarcoidosis), and in 13 (18.3%) HR patients (due to thrombocytopenia [n=1], elevated transaminases [n=1], psychiatric disorders [n=2], autoimmune disorders [n=6], hypothyroidism [n=2] and dyspnea/pneumonitis [n=1]). LR patients were also less likely than HR patients to experience ADRS of grade ≥3 severity (5.4% vs 23.9%). Conclusion: These results demonstrate the benefit of ropeginterferon alfa-2b therapy in both HR and LR patient populations. LR patients may have a greater potential benefit: higher hematologic and molecular response rates can be safely achieved, and the patients are more likely to remain on long-term treatment. These data provide further evidence for an early treatment start as recently outlined by the updated ELN guidelines.

Prognostic Discrimination within a Heterogeneous Population of TP53-Aberrant Myelodysplastic Syndromes and Acute Myeloid Leukemia

Background:TP53-aberrant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) constitute the highest risk molecular subgroup of myeloid neoplasms, and there are currently no FDA-approved targeted therapies for this subset of patients. We have recently explored the reasons for these distinctly adverse outcomes using clonal dynamic modeling. However, prognostic discrimination within this heterogeneous group of patients has not been validated in large-scale efforts. More recently, efforts to gain clarity on this disease subset include the IPSS-M model for MDS, the European LeukemiaNet (ELN) 2022 classification for AML, and the 2022 International Consensus Classification (ICC) for both MDS and AML. For example, the IPSS-M model has shown an adjusted hazard ratio of 3.27 (95% CI 2.38 - 4.48) for multi-hit TP53 aberration; the ELN 2022 classification now includes a new category termed "AML with mutated TP53" for patients with TP53 variant allele frequency (VAF) ≥ 10%; and the 2022 ICC has designated categories for MDS and AML with TP53 mutation. However, these systems do not discern among the subtypes of TP53 genomic aberrations with regard to clinical outcomes. Methods: Identification of patients from the UMass Chan Leukemia Registry was performed via UMass Clarity, a Microsoft SQL Server database comprised of 23,000 tables, in conjunction with the main reporting environment in EPIC. The Registry identified patients harboring one or more aberrations in TP53 and with ICD-10 code of either D46.9 (MDS, including its subentities) or C92.00 (AML, including its subentities) between 2011-2022. A total of 63 patients were identified. Patients with TP53-aberrant MDS or AML were stratified by the presence or absence of multi-hit status and/or TP53 VAF >50%. Multi-hit status was defined as per the 2022 ICC: two or more distinct TP53 mutations with VAF ≥ 10%, or a single TP53 mutation plus one of the following abnormalities: (1) del(17p13.1), (2) TP53 VAF >50%, (3) copy-neutral loss-of-heterozygosity, or (4) any complex karyotype. Monoallelic status was defined as non-multi-hit. Kaplan-Meier survival with log rank p value analysis was performed on subgroups based on the TP53 genomic state. Results: Median age of the UMass cohort (n = 63) was 69.8 ± 11.3 years. There were 35 patients (55.6%) with AML. We identified 58 patients who met the 2022 ICC definition for myeloid neoplasm with mutated TP53 (after exclusion of 5 patients with VAF < 10%) then stratified patients based on hit status and VAF. Median overall survival (OS) was similar among patients with monoallelic TP53-mutant MDS, multi-hit TP53-mutant MDS, and monoallelic TP53-mutant AML (median OS 440 days vs. 437 days vs. 440 days, respectively) (Panel A). In contrast, patients with multi-hit TP53-mutant AML had distinctly shorter survival (median 46 days) (Panel A). For patients with multi-hit status MDS or AML per the 2022 ICC (n = 41), we sub-stratified patients based on TP53 VAF. OS for patients with MDS with VAF ≤ 50% and VAF > 50% was similar (median 376 days vs. 435 days, respectively) (Panel B). Patients with AML with TP53 VAF > 50% had significantly inferior OS (median 43 days) (Panel B). Twelve (19.0%) of 63 patients underwent allogeneic hematopoietic cell transplant (allo-HCT) (2 had VAF >50%). Allo-HCT significantly improved median OS (732 days with allo-HCT vs. 161 days for n = 51 without allo-HCT; p = 0.0033) (data not shown). Only 3 (25%) of the 12 allo-HCT recipients achieved MRD-free remission lasting beyond 1000 days; VAF was ≤ 10% in all of these long-term survivors with TP53-mutant MDS or AML. Conclusion:TP53-aberrant MDS and AML comprise a prognostically heterogeneous group of patients with inferior clinical outcomes, though the highest risk subgroup appears to be AML with multi-hit TP53 status or AML with TP53 VAF > 50%. There is high value in determining the allelic state and hit status at the time of diagnosis to help prognosticate and develop a long-term management plan. Allo-HCT improves median OS, though durable MRD-negative remission is rare. Our data suggest that there may be a limited window of VAF ≤ 10% for the success of allo-HCT for TP53-aberrant myeloid neoplasm. We acknowledge that there is a selection bias for proceeding with allo-HCT. Large-scale systematic studies are needed to comprehensively profile patients classified as myeloid neoplasm with mutated TP53 such that risk-adapted management strategies can implemented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Q-TWiST in Venetoclax-Based Regimens in Elderly Patients with AML: A Quality-Adjusted Analysis

Introduction: Non-intensive venetoclax-based regimens are the current standard of treatment for acute myeloid leukemia (AML) in the elderly. Phase 3 VIALE-C (LDAC vs. LDAC+Ven) and VIALE-A (Aza vs. Aza+Ven) trials showed improved median overall survival (OS) from 4.1 to 7.2 months (VIALE-C) and from 9.6 to 14.7 months (VIALE-A), with serious adverse events (SAEs) in 73% low-dose AraC (LDAC), 83% (Aza + Ven), 66% (LDAC + Ven). Quality of the time gained with these regimens is particularly important in this population. Q-TWiST is a useful tool to adjust the OS to quality time without symptoms or toxicity. This kind of analysis has been previously published in newly diagnosed AML in glasdegib + LDAC vs LDAC trials (Solem CT, 2020), and in the CPX-352 vs 7+3 (Cortes JE, 2021) trial. However, venetoclax-based non-intensive regimens have not been analyzed with this method. Methods: We performed a retrospective, longitudinal analysis of data gathered from a single-center cohort. All newly diagnosed, >60 years old patients with upfront management with venetoclax-based non-intensive chemotherapy combined with LDAC or hypomethylating agents (HMA) at our institution were included. TOX time was defined as the period of time before remission and/or time with serious adverse events (SAE) as defined by Office for Human Research Protections (OHRP) guidance (2007). REL time was defined as time from relapse until death, last follow-up or the start of a second line treatment, TWiST was defined as the time in remission and without SAEs. Q-TWiST analysis was performed as previously described (Solem CT, 2020). Results: We included 17 patients, 58.8% were male, mean age was 74 (70-78) years. The diagnosis was de novo AML in 52.9%, and secondary AML in 46.9%. European LeukemiaNet (ELN) risk was favorable in 5.8%, intermediate in 11.7% and adverse in 41.1%, 35.2% was unknown, FLT3-ITD mutations were present in 23.5%. 25% of the population had basal ECOG performance status ≥3, HCT-CI score was ≥3 in 47%. Considering the patients with baseline geriatric assessment: 14.2% were frail, 42.8% pre-frail and 42.8% robust. Venetoclax was combined with azacitidine in 35.2% and LDAC in 64.7%, 11.7% received additional midostaurin. Venetoclax dose was 100 mg/day in combination with strong CYP3A4 inhibitors (mainly itraconazole) in all patients. By last cycle, venetoclax was adjusted to <28 days in 76.6% of patients. Azacitidine dose was adjusted in 60% of patients, and LDAC in 9%. 76% of patients achieved complete remission (CR) or complete remission with incomplete hematological recovery (CRi) with the treatment, 23.5% had no response and 28% relapsed. With a mean follow up of 42.4 (25.7-59.1), mean OS was 43.1 (95% IC 26.6-59.6), progression free survival (PFS) 37 (95% IC 19.1-54.8), Q-TWiST 36.3 (95% IC 19.7-53), and TWiST 30.3 (95% IC 13.5-47.1) weeks. Other variables related to toxicity are shown in table 1. Comparison with previously reported Q-TWiST with LDAC and 7+3 as frontline therapy in the elderly is described in Figure 1. Conclusions: the Q-TWiST in our unselected population was better than the Q-TWiST described for LDAC arm in the glasdegib trial, this is striking considering the comparison between real world data in a low-income setting with clinical trial population. This suggests that venetoclax-based non intensive chemotherapy not only offers longer OS but also longer quality-adjusted time compared to previous standard to this vulnerable population. When compared to 7+3 regimens the Q-TWiST was slightly shorter in our cohort,probably associated with the inclusion criteria of the trial, including ability to tolerate 7+3 regimen and an age limit of 75 years, which different from our population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia

Background Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine approved for the treatment of myelodysplastic syndrome (MDS). Herein we report the interim results of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML. Methods Eligible patients were > 18 years old with relapsed/refractory (R/R) IDH1 or IDH2 mutated AML, or newly diagnosed (ND) AML not eligible for intensive chemotherapy. For the R/R AML cohort, prior VEN, HMA or IDHi use was not exclusionary. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with ivosidenib (Arm A) or enasidenib (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2]. Results A total of 32 patients have enrolled, with 3 screen failures and 2 patients ongoing first cycle of therapy. There are currently 27 evaluable patients (arm A: 10, arm B: 17) with median follow up of 5.7 months. Median age at enrollment was 73 (50 - 81). 44% (n=12) had ND AML and 56% (n=15) had R/R AML. European LeukemiaNet (ELN) risk was intermediate or adverse in 52% and 44%, respectively. Patients received a median of 4 treatment cycles (ND: 5, R/R: 3). The CRc rate in the overall population was 72% (ND: 100%, R/R: 53%). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved in 64% (ND: 83%, R/R: 42%). (Table 1) In the R/R cohort, 78% (n=11) patients had received prior treatment with either an HMA (azacitidine or decitabine), BCL2i and/or IDHi, with a median of 2 prior treatments. (Table 2) 5 patients did not have prior VEN exposure of which 4 (80%) achieved an MRD negative CRc. Four patients transitioned to stem cell transplant (ND: 2, R/R: 2). The most common non-hematologic grade 3/4 AEs in the overall population included hyperbilirubinemia (n=2, 7%), representing indirect bilirubin in enasidenib-treated patients and mucositis (n=2, 7%) with one considered a residual effect of prior cytoreduction. There were two patients with possible/probable differentiation syndrome which resolved with medical management (dexamethasone and diuresis). Two episodes of reversible grade 1 tumor lysis syndrome were also reported. 60-day mortality within the ND and R/R cohort was 8% (n=1) and 0%, respectively. The ND patient withdrew from the study and went home on hospice after an admission for febrile neutropenia. Conclusions The combination of ASTX727 + VEN with IDH1 or IDH2 inhibition appears to be an effective regimen for the treatment of IDH mutated AML with high response rates including MRD-negative CRc, most notably in de novo patients and R/R pts without prior VEN exposure. AEs are anticipated and tolerable. Enrollment to this study is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Protection Against Breakthrough Delta/Omicron Variants in Vaccinated Patients with Myeloproliferative Neoplasms (MPN)

Background Information on breakthrough SARS-CoV-2 infections in MPN vaccinated patients (pts) is very limited. In these diseases, effectiveness of coronavirus disease 2019 (Covid-19) vaccines may be influenced not only by the MPN phenotype and the intrinsic reduced immunological competence, but also by the prior Covid-19 infection that can elicit a natural immunity against reinfections. Patients In the European LeukemiaNet (ELN) observational registry, 863 MPN pts with Covid-19 have been enrolled since February 2020 and in 649 of them, information on the vaccination status is now available. To ensure that well characterized reinfections were considered, diagnosis of breakthrough Covid-19 included a positive naso-pharyngeal swab and symptoms highly suggestive for SARS CoV-2 infection. ResultsBreakthrough infections in vaccinated patients with previous Covid-19 infection The effectiveness of previous Covid-19 infection in preventing reinfections was tested in a group of 131 and 287 unvaccinated and vaccinated MPN pts, respectively. Prior Covid-19 occurred during the first and second wave in 74% and 98% pts, respectively and the interval between Covid-19 and the breakthrough infection in unvaccinated and in vaccinated was similar (8.5 months). Administered vaccine doses (Pfizer in 71%) were 1-2 and 3-4 in 77% and 23% of vaccinated cases, respectively. The proportion of PV, ET, pre-PMF was similar in the two groups while the number of MF pts was lower (19%) than in the unvaccinated group (28%) (p=0.024). Reinfections occurred during delta (n=4) or omicron variants period (n=14) in 8 (6.1%) and 10 (3.5%) unvaccinated and vaccinated pts (p=ns) and hospitalization was required in 0 and 2 pts, respectively. Severity of the acute infection was variable and 1 death was registered.Breakthrough infections in vaccinated patients without previous Covid-19 infection Breakthrough infections were reported in 231 vaccinated cases (ET=89, PV=75, MF=54 and pre-PMF=13) without prior Covid-19. In 51% of pts the administered vaccine doses were 1-2 and 3-4 in 49%. No relevant vaccine related side effects were registered. Time interval from vaccination to Covid-19 was 8.1 months. Twenty-six pts (11%) required hospitalization and 205 (89%) were managed at home. Hospitalized pts were older (median age 76), males (69%) with MF (39%), and prior exposure to ruxolitinib (42%, 7 MF and 4 PV). Of note, values of C-reactive protein (CRP) and neutrophil/lymphocyte ratio (NLR) were significantly more elevated in hospitalized cases (CRP=33.1 vs. 2.0 and NLR=5.9 vs. 3.3, p<0.001). Although some infections occurred in the second wave, corresponding to alpha/beta/gamma coronavirus infection (6%), the majority of breakthrough episodes occurred in delta and omicron variant periods (41% and 53%). Three deaths were registered in hospitalized pts. We explored the risk of hospitalization and evaluated the marginal effect of gender, age and ruxolitinib exposure in a logistic model fitted to predict this event. We found that the risk of hospitalization was substantially higher only in males on ruxolitinib and increased with age (Figure). We also found that the inflammatory status measured with NLR could explain these results (data not shown). Conclusion The effectiveness of previous Covid-19 in preventing reinfection occurring during the delta and omicron variants of SARS-CoV-2 was robust (94% and 97% in unvaccinated and vaccinated pts, respectively). This is good news for MPN patients who recovered from Covid-19 and the hope is that this effectiveness can work against any future SARS-CoV-2 variant. In the cohort of vaccinated pts without prior Covid-19, we identified a subgroup of patients with more severe delta and omicron disease, at high risk of hospitalization, consisting of males who were on ruxolitinib and had elevated inflammatory biomarkers. Subsequent studies are needed to interpret these latest results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Regularized Mixture Cure Models Identify a Gene Signature That Improves Risk Stratification within the Favorable-Risk Group in 2017 European Leukemianet (ELN) Classification of Acute Myeloid Leukemia (Alliance 152010)

Introduction: The 2017 ELN Favorable-risk group comprises specific recurrent cytogenetic and molecular alterations. Assignment to this group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients (pts) receiving chemotherapy and transplant-associated mortality. However, not all Favorable-risk pts experience long-term survival and their outcomes are affected by co-occurring genetic features making recognition of pts who would most likely be cured of high importance. Thus, we used our regularized mixture cure model (MCM) that embeds false discovery rate control to identify prognostically relevant transcripts that can distinguish pts cured from pts susceptible to lower- or higher-risk of relapse. Methods: We analyzed 312 pts <60 years with de novo AML classified in the 2017 ELN Favorable-risk group excluding APL who achieved a CR, had RNA-seq data available, and treated on one of 8 CALGB/Alliance frontline protocols with intensive 7+3-based induction chemotherapy. No pt received an allogeneic stem cell transplant in first CR. MCMs assume the population consists of 2 subgroups, cured and susceptible, thus there are 2 regression components, which permit identification of features associated with cure and/or latency of susceptible pts. 'Cured' is synonymous with attaining long-term relapse-free survival and thus pts have a survival probability of 1. We fit univariable MCMs to identify baseline demographic, clinical features, or selected gene mutations related to the probability of being cured and/or to the latency distribution (time to relapse). RNA-seq expression values were candidate covariates in a regularized MCM to identify a parsimonious list of transcripts associated with cure or latency. We then used 2017 ELN Favorable pts in an independent dataset (GSE37642) for validation. Results: The estimated proportion cured (39.5%) was significant (P < 0.001) indicating that a MCM should be fit. Other than % of bone marrow blasts (P = 0.009) and % of blood blasts (P = 0.048), no other pretreatment features were significant in univariable MCMs. CEBPAdouble and TET2 mutations were the only ones significantly associated with latency (P = 0.008 and P = 0.013, respectively), but neither was associated with cure (P = 0.881 and P = 0.507, respectively). Our regularized MCM identified 101 transcripts associated with cure and 71 transcripts associated with latency. Kaplan-Meier curves of cured vs susceptible pts as well as of those susceptible with lower vs higher risk of relapse or death were well separated. We mapped the 168 unique transcripts to GSE37642 Affymetrix HG-U133Plus2 GeneChip for validation and found that 65 cure-related probe sets and 57 latency probe sets mapped to 34 and 32 unique genes, respectively. The validation data yielded AUC=0.788 and C-statistic=0.887, indicating good predictive ability of the selected genes. As desired, the predicted cured group had a survival probability of 1 throughout the observation period (Fig 1), with good separation between predicted susceptibles in the lower- versus higher-risk groups (Fig 2). Cell death and survival was the top molecular/cellular function for both the cure and latency portions of the model with 22 and 20 transcripts involved, respectively, with only BRD2, HLA-A, HLA-B, NAIP, and TXNIP in common. Cell death and survival molecules unique to the latency portion of the model included CD300A, CRNDE, DDX39B, FAS, GPI, HLA-DRA, KLF13, LAT, let-7, LMO2, LSP1, NOTCH1, PLCG2, PSMB8, and U2AF1; those unique to the cure portion included ARID5B, BAG6, BMI1, CCL5, CDK7, DPPA4, ELOVL5, HLA-DRB1, IL18, INTS6, MAP4K4, mir-25, mir-491, NOMO1, NR1H3, RPS16, and TUBB. Conclusion: Our regularized MCM identified important subsets of genes associated with cure and latency in the 2017 ELN Favorable-risk pts. Our results suggest that the Favorable-risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this risk category by identification of pts who might be cured with chemotherapy alone. Given similar treatment with 7+3-based cytotoxic chemotherapy, the identified subgroups (cured, susceptible lower risk, susceptible higher risk) seem to have different sensitivities to 7+3-based therapy. Support: R01LM013879, U10CA180821, U10CA180882, U24CA196171 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Impact of Day 14 Bone Marrow (D14 BM Bx) in Acute Myeloid Leukemia (AML) in the Setting of European Leukemianet (ELN) Risk Classification

Prognostic Impact of Day 14 Bone Marrow (D14 BM Bx) in Acute Myeloid Leukemia (AML) in the Setting of European Leukemianet (ELN) Risk Classification

A Suboptimal Response in CML Is Associated with Expression of the Immune Checkpoint VISTA

Introduction: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) leading to molecular remission in most patients. The next challenges are decreasing resistance and improving the odds of treatment-free remission. Understanding determinants of disease persistence and suboptimal responses is critical for improving these probabilities. The role of the immune system in the control or eradication of CML has been demonstrated in multiple settings including successful graft-vs-leukemia effect and the requirement of active T-cells and natural killer (NK) cells for sustained remission prior to therapy discontinuation. Herein, we aim to demonstrate a comparison of immune determinants of response in CML in those who achieve a deep molecular response (MR4.5) compared to suboptimal responders. Methods: We prospectively collected longitudinal blood and bone marrow samples from patients receiving treatment for CML and characterized them using cytometry by time of flight (CyTOF). 20 patients that achieved MR4.5 at any time during their treatment were compared to a cohort of 32 patients with suboptimal response to therapy according to the European LeukemiaNet (ELN) response milestones (Table 1). We custom-designed this CyTOF panel (36-plex) to include markers of leukemia/stem progenitor cells, lineage defining, intracellular signaling, immune exhaustion and activation markers. Samples were barcoded, pooled and processed simultaneously to overcome technical variations and batch effects. CD45hi cells (leukocytes) were grouped using PhenoGraph clustering, based on expression of these markers in the earliest samples available, collected at various timepoints during treatment. Results: Analysis of differential expression patterns revealed 25 distinct clusters. Patients with suboptimal response to therapy had a higher proportion of CD45hiCD3+ cells (T-cells) compared to those with an optimal response (median of 59% vs 53%, P=0.04). Notably, this included a higher proportion of exhausted CD8+ cytotoxic T-cells in patients with suboptimal response characterized by high Eomes and low Tbet expression (median of 8.0% vs 1.9%, P=0.04). In contrast, CD56+ NK-cells were more prevalent in the optimal response group (median of 5.5% vs 3.2%, P=0.04), particularly an interferon gamma releasing (CD56hiCD16loTbet+) subpopulation (median of 4.1% vs 2.5%, P=0.04). While CD68+ cells (macrophages) were detected at similar rates in both the optimal and suboptimal response groups (median of 16.5% vs 15.5%, P=0.07), the phagocytic subpopulation (CD16-CD14+CD68+HLA-DRlo) was more prevalent in those who achieved an optimal response (median of 15.1% vs 13.2%, P=0.02). Patients with suboptimal response had a higher proportion of CD68+HLA-DRloVISTAhi cells (median of 5.6% vs 1.8%, P=0.004), referring to macrophages expressing the immune regulatory ligand V-domain immunoglobulin suppressor of T cell activation (VISTA). Like PD-L1 and other B7 family ligands, VISTA attenuates T-cells response to antigens and VISTA overexpression has been associated with resistance to immune checkpoint inhibitors in solid tumors. Furthermore, cells characterized by CD66b+CXCR4+VISTAlo were increased in patients with optimal response (median of 20.6% vs 0.6%, P=0.01), indicating a higher proportion of mature granulocytes with low expression of VISTA in the optimal response group (Figure 1). Conclusion: We found that higher expression of the immune checkpoint VISTA, in addition to markers of T-cells exhaustion is associated with suboptimal response to therapy in CML. These findings highlight the importance of the immune microenvironment in response to targeted therapies such as TKIs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prediction of Resistance to Hydroxyurea Therapy in Patients with Polycythemia Vera: A Machine Learning Study (PV-AIM)

Introduction: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Thromboembolic events (TEs) are a common complication in patients (pts) with PV but can be reduced by controlling hematocrit (HCT) levels (<45%) with phlebotomy and/or hydroxyurea (HU), a first-line treatment (tx) for PV. However, in some pts HU can fail due to resistance and alternative tx options are needed, such as ruxolitinib. Machine learning was utilized to analyze real-world evidence (RWE) and identify clinical and/or laboratory variables that may be predictive of developing resistance to HU (HU-RES) tx. Methods: PV-AIM (PV advanced integrated models for prevention of TEs) is an analytical, retrospective cohort study of pts with PV that utilizes data from the US Optum database. Pts were eligible for the current analysis if they had a diagnosis of PV, were ≥18 years old, had received only HU tx for 9 months (mo), had 6 mo pre-index (first HU tx) history (laboratory data and observations) and 12 mo post-index follow-up. An ensemble machine learning classification model, Random Forest (RF), was developed to predict HU-RES in the 6-9 mo window post-index, based on the 2010 European LeukemiaNet (ELN) consensus definition for HU-RES (criteria 1, 2 and 4), and evaluated by ROC-AUC (Receiver Operating Characteristic-Area Under the Curve). The 10 variables having the greatest impact on HU-RES prediction were identified using RF variable importance; those pairs of variables that showed greatest synergy (more significant association with HU-RES than expected) in predicting HU-RES were examined and a novel heatmap-based method was developed to visualize the risk landscape of each pairwise combination. Results: Of 82,960 pts with PV identified in the Optum database (median record length 8.4 years), 2,453 pts were eligible for inclusion and 1,304 of these were assigned as HU-RES (n=733) or HU non-resistant (n=571) and were used to develop the model. The composite ROC-AUC was 0.71, illustrating the model's accuracy for predicting HU-RES at 6-9 mo post-index. Of the variables analyzed, the 10 most predictive for HU-RES (in rank order of importance) were: red blood cell count (RBC), hematocrit (HCT), red cell distribution width (RDW), age at index, hemoglobin (HGB), annualized phlebotomy count (APC), absolute neutrophil count (ANC), white blood cell count (WBC), weight, and time between diagnosis and treatment. These variables had higher values in the HU-RES pts except for 'age at index', which was lower in HU-RES pts. For these 10 variables, 45 pairwise combinations were generated to examine variable interaction. The HCT-APC pairwise combination had the strongest association with HU-RES (p=1.74E-22) at thresholds HCT 44% and APC 0.7; notably, APC was a key variable for the next 5 out of 10 most significant pairwise associations (in combination with RBC, ANC, WBC, RDW, and weight, respectively; p=7.16E-17 to 4.26E-22). Some combinations were synergistic; the most significant was RDW-HGB (synergy score: 4001) [Table] with optimal thresholds for this combination of RDW 17% and HGB 15.5 g/dL (p=4.67E-15) [Figure]. Comparisons of pts in the 'high RDW’ (≥17%; n=559) and 'low RDW’ (<17%; n=745) groups saw significant differences between these groups in WBC, ANC, RBC, lymphocytes, neutrophils, and HGB (p≤2.72E-09 for all), and neutrophil lymphocyte ratio (p=2.75E-37). Notably, a 1.36-fold greater proportion of HU-RES pts were in the 'high RDW’ than the 'low RDW’ group (p=2.74E-09). Conclusions: Failure of HU tx may put pts at risk of TEs; however, this analysis has shown that common clinical and laboratory variables can be utilized to predict the likelihood of pts developing resistance to HU before starting tx. Pre-index HCT and APC were strongly associated with HU-RES and a synergistic association between RDW and HGB provided thresholds indicative of HU-RES, which potentially could be applied in the clinic. This analysis highlights the clinical value of pt history to help identify pts at risk of HU-RES and potentially empowers physicians to proactively schedule laboratory analyses pre-HU tx to identify pts at risk, and then closer, focused monitoring of at-risk pts to take timely clinical decisions for a switch to appropriate second-line therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1, First-in-Human, Dose-Escalation Study of MGD024, a CD123 x CD3 Bispecific Dart® Molecule, in Patients with Relapsed or Refractory CD123-Positive (+) Hematologic Malignancies

Background The interleukin-3 receptor alpha chain CD123 is overexpressed in a number of hematologic malignancies and is particularly upregulated in leukemia stem cells, which are believed to serve as a reservoir for relapse (El Achi Cancers 2020). Several investigational agents targeting CD123 with diverse mechanisms of action including bispecific T-cell engagers, antibody-drug conjugates, and Chimeric Antigen Receptor (CAR) T-cell therapies, are being investigated in these malignancies, with many showing preliminary clinical anticancer activity (El Achi Cancers 2020). Of note, the CD123-directed therapy tagraxofusp has now become the standard of care (SoC) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) (Pemmaraju NEJM 2019). MGD024 is an investigational, second-generation CD123 × CD3 DART molecule that can simultaneously bind CD123 on malignant cells and CD3 on T cells, targeting CD123+ leukemic cells for recognition and elimination by CD3+ T lymphocytes as effector cells. MGD024 was engineered to minimize cytokine release syndrome (CRS), while maintaining antitumor activity. This new construct permits intermittent intravenous (IV) dosing due to a longer half-life (Alderson ASH 2021) compared with the first-generation DART molecule flotetuzumab, a continuous-infusion molecule that showed preliminary single-agent activity in refractory acute myeloid leukemia (AML) (Uy Blood 2021). Moreover, preliminary in vitro and in vivo data supported MGD024 clinical investigation as a single agent or in combination with SoC in patients with CD123+ hematologic malignancies (Alderson ASH 2021). Study Design and Method This is a Phase 1, first-in-human, dose-escalation study (CP-MGD024-01; NCT05362773) of MGD024 in patients with the following relapsed or refractory hematologic malignancies: AML, myelodysplastic syndrome (MDS), classical Hodgkin's lymphoma (cHL), chronic myeloid leukemia (CML), B-cell acute lymphoid leukemia (B-ALL), hairy cell leukemia (HCL), advanced systemic mastocytosis (ASM), and BPDCN. Eligible patients must have CD123+ malignant cells by flow cytometry or immunohistochemistry, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and no history or current evidence of any condition, therapy, or laboratory abnormality that may confound trial results. Primary objectives are to assess the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined) and identify a recommended Phase 2 dose and schedule of MGD024. Secondary objectives include pharmacokinetics, immunogenicity, preliminary assessment of MGD024 clinical activity, and preliminary evaluation of safety/efficacy of tocilizumab in the management of MGD024-induced CRS. Patients receive MGD024 via intermittent intravenous infusion for approximately one year or until discontinuation for unacceptable toxicity or disease progression, whichever occurs first. The dose escalation begins with an accelerated titration phase (1+3 design) and converts to a conventional 3+3 design after the first patient experiences a DLT or a Grade ≥2 nonhematologic adverse event (AE) considered at least possibly related to MGD024 during Cycle 1, whichever occurs first. Safety assessments are based on AEs occurring from the first dose until 30 days after the last dose or until starting another anticancer therapy. Response assessments are performed after Cycle 1, then after every even numbered cycle starting with Cycle 2 until progression or discontinuation, whichever occurs first, and at the end of treatment visit. Response evaluation is determined using modified European LeukemiaNet (ELN) 2017 criteria for ALM and ALL; International Working Group (IWG) 2006 criteria for MDS; Lugano 2014 criteria for cHL; ELN 2020 criteria for CML; 2017 consensus criteria for HCL; IWG-Myeloproliferative Neoplasms Research and Treatment (MRT) & European Competence Network on Mastocytosis (ECNM) 2013 criteria for ASM; and modified criteria from Pemmaraju NEJM 2019 for BPDCN. Patients benefitting from MGD024 may continue to receive MGD024 after completion of the study treatment period, at physician discretion.

Venetoclax in Combination with Hypomethylating Agents Compared to Standard Chemotherapy in Relapsed/Refractory Acute Myeloid Leukemia

Introduction: The safety and efficacy of venetoclax (VEN) in combination with hypomethylating agents (HMA) in older adults with newly diagnosed acute myeloid leukemia (AML) or those ineligible for intensive chemotherapy is well established. Recently, VEN/HMA has emerged as a potential option in relapsed or refractory (r/r) AML. Although encouraging, data on whether this combination compares favorably to standard chemotherapy (SC) in r/r AML are limited. Methods: This was a single-center, retrospective analysis from November 2012 to March 2022 that compared VEN/HMA to SC in r/r AML patients at a 923-bed tertiary care hospital with an outpatient cancer facility. The primary endpoint was overall response rate (ORR) defined as rate of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphological leukemia-free state (MLFS), and partial remission (PR). Key secondary outcomes included overall survival (OS), relapse-free survival (RFS), and toxicity. Continuous variables were compared using the Mann-Whitney U test or the two-sample t-test and categorical variables were compared using the Chi-squared or Fisher's exact test. Time to event data were assessed using the Kaplan-Meier method. Log-rank test was used to compare the survival endpoints between groups. A p-value < 0.05 was considered statistically significant. Results: A total of 281 patients underwent screening, of those, 63 adult patients were included in the analysis (VEN/HMA, n = 25 and SC, n = 38). The primary reason for exclusion was previously untreated AML or myelodysplastic syndrome. Baseline characteristics were balanced between the groups. Overall, 53 patients had de novo AML, 25 patients had received 3 or more prior lines of chemotherapy, 20 patients were ≥ 60 years, and 8 patients had undergone previous stem cell transplantation. In the VEN/HMA cohort, 32% had prior exposure to a hypomethylating agent and 36% received concomitant azole antifungals. The majority of patients in both groups were stratified as intermediate or poor risk according to the European LeukemiaNet (ELN) 2017 criteria. Common chemotherapy regimens included MEC (74%), ME (12%), and FLAG ± IDA (11%). Most patients in the VEN/HMA group received decitabine and of those, 60% initiated therapy in the outpatient setting. Treatment outcomes are shown in Table 1 and OS results are presented in Figure 1. Both therapies resulted in similar ORRs (VEN/HMA 52% vs SC 42%, p=0.44). Combined CR/CRi was achieved in 36% of patients in the VEN/HMA group and 37% of patients in the SC arm (p=0.95). Median time to response was 73 days for VEN/HMA and 45 days for SC (p=0.38). The OS between VEN/HMA and SC groups was not statistically different (p=0.99, log-rank test) with median OS of 287 days and 285 days, respectively. No difference in RFS was observed between the two groups (0.38, long-rank test) with median RFS of 304 days in the VEN/HMA arm and 325 days in SC group. Prior HMA exposure in VEN-treated patients was associated with a lower CR/CRi rate (13% vs 41%, p=0.09). Induction mortality rates at 30 and 60 days were similar between the groups. Duration of hospitalization was significantly shorter in patients who received VEN/HMA as compared to those who received SC (p=0.04). In terms of safety, patients treated with VEN/HMA had lower rates of any grade diarrhea (40% vs 71%, p=0.01), any grade mucositis (20% vs 61%, p=0.001), and grade ≥ 3 anemia (80% vs 97%, p=0.02). The rate of febrile neutropenia was significantly higher in the SC group than in the VEN/HMA group (97% vs 40%, p<0.00001), as was the rate of bacterial infections (50% vs 24%, p=0.03). Fungal pneumonias were also reported more frequently in patients receiving SC (37% vs 12%, p=0.04). Lastly, a trend toward a longer median time to platelet recovery was noted in VEN/HMA patients receiving concomitant azole antifungals (38 days vs 26 days, p=0.52). Conclusion: Treatment with VEN/HMA yielded similar outcomes compared with SC and was associated with lower infection rates, a potential advantage in a patient population at high risk for infectious complications. Additionally, safe initiation of this regimen in the outpatient setting and shorter duration of hospitalization when compared to SC could lead to a reduction in use of healthcare resources and improvement in quality of life. These findings add to a growing body of evidence that suggest VEN/HMA is non-inferior to SC with a favorable toxicity profile. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Features of Complex Karyotype in Newly Diagnosed Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) with complex karyotype (CK), which is defined as ≧3 chromosome abnormalities, has a poor prognosis. In a few reports, CK-AML was classified into typical CK-AML and atypical CK-AML (Mrózek, et al. Leukemia 2019; Leung, et al. Am J Hematol 2019; Schoch, et al. Genes Chromosomes Cancer 2005). The former was defined as CK including monosomy of chromosome 5, 7 and 17 or deletion of 5q, 7q and/or 17p and the latter was defined as CK without those abnormalities. Although it has been reported that patients with typical CK-AML had lower complete remission (CR) rates and shorter overall survival (OS) than those for patients with atypical CK-AML, the clinical features of CK-AML in Japanese patients have remained unclear. Patients and methods: Hokkaido Leukemia Net (HLN) is a regional prospective cohort study registering cases of newly diagnosed AML from affiliated hospitals covering Hokkaido, the northern most island of Japan. We retrospectively analyzed CK-AML cases registered in HLN between April 2010 and December 2021. Survival of patients with CK-AML was compared to that of patients with normal karyotype (NK) AML. We excluded acute promyelocytic leukemia (APL) patients. The definition of CK was based on the 2017 European LeukemiaNet (ELN) criteria. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional review boards. Results: CK-AML patients accounted for 13.8% (N=115) and NK-AML patients accounted for 41.5% (N=346) of the 834 AML patients. The characteristics of patients with CK-AML were as follows: age 17 to 91 (median 67); male 69 (60.0%), female 46 (40.0%); typical CK-AML 77 (67%), atypical CK-AML 38 (33.0%). In typical CK-AML patients, 49, 39, and 28 patients had monosomy or deletion of chromosomes 5, 7 and 17, respectively (Figure A). There were no significant differences between patients with typical CK-AML and those with atypical CK-AML in median age (68 years vs 66.5 years, P=0.338), white blood cell count at diagnosis (3600/μL vs 4700/μL, P=0.217), percentage of bone marrow blast cells at diagnosis (43.8% vs 58.4%, P=0.106), percentage of patients who received intensive chemotherapy (46.8% vs 63.2%, P=0.155), percentage of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (22.0% vs 26.3%, P=0.813), CR rate (47.8% vs 59.5%, P=0.310), relapse rate (42.9% vs 57.1%, P=0.589) and primary induction failure (PIF) rate (64.7% vs 56.8%, P=0.529). Regarding the degree of karyotype complexity, patients with typical CK-AML had larger numbers of chromosome abnormalities than did patients with atypical CK-AML (median, 9 vs 4 abnormalities; P<0.001). In AML subtypes, patients with typical CK-AML included a significantly larger percentage of AML patients with myelodysplasia-related changes (AML-MRC) than did patients with atypical CK-AML (48.1% vs 21.1%, P=0.008). Two-year OS rates in patients with typical CK-AML, patients with atypical CK-AML and patients with NK-AML were 7.1%, 34.6% and 50.8% respectively. Median OS of patients with typical CK-AML was 143 days (95% CI: 106-183), which was significantly inferior to that of patients with atypical CK-AML (median OS of 369 days, 95% CI: 63-751, P=0.009). In patients with typical CK-AML, patients with monosomy 17 or deletion of 17p had significantly shorter OS than that for patients without such abnormalities (105 days vs 165 days, P=0.033) (Figure B). Additionally, typical CK-AML patients without monosomy 17 or deletion of 17p had shorter OS than that of patients with atypical CK-AML, though the difference was not statistically significant (165 days vs 369 days, P=0.078). Conclusion: This retrospective analysis showed that a poor prognosis group of CK-AML could be further stratified into typical CK-AML and atypical CK-AML. Patients with typical CK-AML had a worse prognosis than that for patients with atypical CK-AML in a Japanese cohort. Patients with monosomy 17 or deletion of 17p had significantly shorter OS than that for other typical CK -AML patients. This extremely poor prognostic group of CK-AML patients with monosomy 17 or deletion of 17p can be identified without genetic testing and long survival has not been achieved by the current treatment strategy including allo-HSCT. A large percentage of AML cases with TP53 mutation located on chromosome 17 contributes to the refractory and/or relapse nature of the disease in this category. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of the 2022 European Leukemianet Genetic Risk Stratification of Acute Myeloid Leukemia

Background In 2022, an update of the widely adopted European LeukemiaNet (ELN) risk stratification system for AML has been published (Döhner et al. Blood 2022). So far, this new classification has not been validated in large and homogeneously treated patient cohorts. We set out to test the prognostic relevance of the ELN-2022 classification in intensively treated AML patients, and to compare it to ELN-2017. Methods We studied 1,138 newly diagnosed AML patients (median age 57 years; range, 18-86 years) who received cytarabine-based induction chemotherapy in two subsequent multicenter phase III trials of the German AML Cooperative Group (AMLCG-1999, clinicaltrials.gov identifier NCT00266136, n = 857; and AMLCG-2008, NCT01382147, n = 259) between 1999 and 2012. Twenty subjects were excluded due to missing cytogenetics or FLT3-ITD ratio. None of the patients received FLT3 inhibitors or gemtuzumab ozogamicin during first-line treatment. Median follow-up for of survivors was 98 months (m). Findings were validated in a cohort of 1109 mostly younger AML patients treated on trials of the AML-SG study group. Results Out of 1,118 patients classified according to ELN-2022, 363 (32%) were classified as favorable, 301 (27%) as intermediate, and 454 (41%) as adverse. For those ≥ 60a of age (n=518) the distribution was 20%, 23% and 57%. Compared to ELN-2017 15% of patients (n=171) were classified into a different risk category (3% into a more favorable and 12% into a less favorable category; Fig. 1). According to ELN-2022, median OS was 9.5y (95% CI, 4.8-12.3y), 1.6y (95% CI, 1.8-2.0y) and 0.8y (95% CI, 0.7-1.0y) for favorable, intermediate and adverse risk groups. For the ELN-2017 categories, corresponding mean OS was 8.2 y (95% CI, 4.6-11.9y), 1.7y (95% CI, 1.2-2.0y) and 0.8y (95% CI: 0.7-0.9y). 5y OS by risk group was 55%, 34% and 15% for ELN-2022 and 54%, 31% and 12% for ELN 2017. Complete response rates by risk group were 73%, 65% and 45% for ELN-2022 and 72%, 66% and 41% for ELN-2017 As in ELN-2017, ELN-2022 adverse risk significantly associated with age, male sex, sAML and WBC count at diagnosis (p<0.0001 for all). These associations also held in patients aged <60 years (n = 518) or ≥60 years (n = 600). We did not find a significant association between the ELN-2022 adverse risk group and tAML (p=0.21) Overall, time-dependent ROC-curves (Heagerty, Lumley and Pepe, 2000) show slightly better prognostic discrimination for ELN-2017 compared to ELN-2022 for OS at one year (AUC 0.66 vs. 0.65) and five years (AUC 0.72 vs. 0.71). Harrel's C-index confirms this finding, with values of 0.65 for ELN-2022 and 0.66 for ELN-2017 when controlling for age, sex and sAML. Several aspects may contribute to the slight reduction of prognostic accuracy we observed: The 61 patients reclassified from favorable to intermediate-risk had significantly higher 5y OS rates than other intermediate patients (30% v. 48%). In contrast, patients reclassified from adverse to intermediate-risk (n = 21) had a worse 5y OS rate than other intermediate patients (36% v. 10%). Interestingly, their outcome was fairly similar to those reclassified from intermediate to adverse-risk (n=70), whose 5y OS appeared better than that of other adverse-risk patients (median OS 1.4 v 0.8y). Sixty-five patients reclassified from intermediate to adverse-risk were reassigned based on the inclusion of additional myelodysplasia-related mutations (BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse-risk markers. Therefore, we analyzed patients re-classified from favorable (n=10) or intermediate (n=65) to adverse-risk due to presence of one or more of these mutations. This cohort (n =75) had significantly better 5y OS (28 % v 13%) than patients with mutations in ASXL1, RUNX1 or TP53, or other adverse-risk genotypes, and seems to behave more like the intermediate cohort (Fig. 2). Median OS was significantly better as well (1.7 v 0.7y). This finding was confirmed in a validation cohort of 1109 patients. Here, we found a median OS of 1.6 v 1.1y). Conclusions We conclude that the ELN-2022 risk classification identifies a larger group of adverse-risk patients, at the cost of slightly reduced prognostic accuracy compared to ELN-2017. This may in part be driven by the outcomes of patients re-assigned to the adverse-risk cohort based on the presence of myelodysplasia-associated gene mutations, which in our cohort had better outcomes than previously recognized adverse-risk subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Disruption of Intracellular Metal Homeostasis As a Vulnerability in SF3B1 Mutated AML

Acute Myeloid Leukemia (AML) is a heterogeneous disease in which outcome is highly dependent on cytogenetics and mutational profile. Adverse risk AML, recently defined and updated in the 2022 European LeukemiaNet (ELN) genetic risk classification, is associated with a poor overall survival. To identify novel therapeutic approaches for AML, we screened a library of 10,000 compounds across 56 genetically diverse primary AML specimens. We then looked for active compounds with increased activity towards adverse risk AML samples and with low cytotoxicity to normal hematopoietic cells. Among the hits identified, we were able to validate that S767 molecule is preferentially active on adverse risk AML samples. Additionally, we found a strong association between SF3B1 mutations and sensitivity to S767. To gain insights into S767 mechanism of action, we performed a CRISPR/Cas9 genome-wide functional screen, and identified multiples genes involved in mitochondrial processes both in synthetic rescue and synthetic lethal genes. In particular, knock-down of enzymes involved in heme biogenesis and iron-sulfur cluster biosynthesis appear to interfere with S767 cytotoxic activity. Given the central role of iron in these two synthetic pathways, and the structure of S767, we hypothesized that our molecule binds and disrupts intracellular iron homeostasis. Using UV-spectrometry analysis, we determined that S767 has metal affinity and binds to Fe2+, but also Cu2+ and Zn2+. We then quantified intracellular metal concentrations by ICP-MS (inductively coupled plasma mass spectrometry) and found that S767 exposure significantly decreases intracellular iron concentrations while increasing that of copper. Since metals are critical cellular cofactors involved in multiple enzymatic reactions, disruption of intracellular metal homeostasis can affect many processes. Mitochondrial respiratory chain is particularly sensitive to these perturbations as copper and iron-sulfur clusters are present in complexes I-IV of the electron transport chain and are essential for mitochondrial complexes function. By measuring oxygen consumption rate in leukemic cells exposed to S767, we found that the molecule indeed disrupts mitochondrial respiration. SF3B1 is a splicing factor recurrently mutated in myeloid malignancies including myelodysplastic syndromes (MDS) and AML. Heterozygous mutations typically affect SF3B1 splicing functions and induces consequently mis-splicing of target mRNAs, including the ABCB7 iron-sulfur cluster transporter. Analysis of the Leucegene transcriptomic data of primary AML specimens revealed mis-splicing and downregulation of ABCB7 in SF3B1 mutated patients. Strikingly, ABCB7 was one of the top synthetic lethal gene identified by chemogenomic CRISPR/Cas9 screen following exposure to S767 molecule. Given that ABCB7 exports iron-sulfur clusters out of the mitochondria to be assembled by cytosolic proteins and plays a role in iron homeostasis, we hypothesized that its aberrant expression in SF3B1 mutated AML participates to the high sensitivity of these leukemias to S767. We thus identified a novel molecule with selective activity in AML. Our data suggest that S767 is not a protein-targeting molecule but rather acts through the disruption of intracellular metal homeostasis, and ultimately affects mitochondrial respiration. Its mechanism of action highlighted a vulnerability in SF3B1 mutated AML which present a defect in ABCB7 expression. Importantly, SF3B1 mutations are now recognized in the 2022 ELN risk classification as an adverse prognostic marker if they are associated with intermediate or adverse risk AML, giving a unique opportunity to develop novel therapeutic approaches for this subgroup of patients with poor clinical outcome. In addition, SF3B1 mutations are found in 25% of MDS cases, which are associated with ring sideroblasts and accumulation of mitochondrial iron, and that could also benefit from such therapeutic approach.