Hypomethylating Agents Exposure Research Articles

Selinexor in Combination with Hypomethylating Agent (HMA) in Patients with Refractory/Relapsed Acute Myeloid Leukemia (AML) Previously Exposed to Venetoclax: A Retrospective Study

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic tumor with varied clinical manifestations. Venetoclax combination regimens have shown promising results as a first-line treatment for AML. However, for patients who fail venetoclax treatment, the prognosis remains poor, necessitating the exploration of new therapeutic approaches. Selinexor, a selective inhibitor of XPO1, has shown potential as a therapeutic strategy to overcome resistance to conventional chemotherapy for AML. Here, we report the safety and efficacy data from a real-world study of selinexor + HMA in patients with refractory/relapsed (R/R) AML previously exposed to venetoclax. Methods We conducted a monocentric retrospective analysis on adult patients with unfit R/R AML or those with comorbidities preventing the use of intensive induction chemotherapy. The patients received selinexor-based combinations between May 2021 and December 2022. AML genetic risk stratification and response criteria were assessed according to the 2022 European Leukemia Net (ELN) consensus. The selinexor + HMA regimen consisted of selinexor 40 mg twice weekly for 3 weeks orally, and either decitabine (DAC, 10 mg/dfor 7-10 days intravenously) or azacytidine (AZA, 75 mg/m 2/d for 7 days subcutaneously, halved for patients over 60 years). Supportive treatments and dose adjustments were administered based on individual clinical indications. Some patients underwent allogeneic hematopoietic stem-cell transplantation. Results A total of 12 patients with R/R AML treated with selinexor-based combinations were considered in this study, including 7 patients with refractory AML and 5 patients with relapsed AML (one with post-transplant recurrence). The median age of the patients was 36 years (range 18-68 years). All patients had intermediate or adverse ELN genetic risk. All patients had previously received venetoclax-based combinations, and 58% (7/12) had been treated with HMAs. The overall response rate (ORR) was 66.7% (8/12) with a combined CR rate (CRc) of 50% (6/12). Among the 6 patients with CRc, 3 (50%) achieved negative minimal residual disease (MRD,≤1*10 -3). CRc was 42.9% (3/7) in patients previously exposed to HMA-based therapy and 100% in patients without exposure history. The most common grade 3 or 4 adverse events were neutropenia (83.3%) and thrombocytopenia (58%), with the median recovery time of 14 (8-21) and 16 (8-24) days, respectively. Common non-hematologic toxicities included infection (66.7%) and gastrointestinal reactions (66.7%). As of Jun 20, 2023, with a median follow-up of 11.3 months (range 0.7-19.5 months), 50% (6/12) of the patients died due to disease progression or severe infections. 66.7% (8/12) of the patients received transplants after achieving remission. The median overall survival (OS) was significantly longer in the transplantation group compared to the non-transplantation group (p=0.009) (Figure.1a). Patients without previous HMA exposure seemed to have a better efficacy benefit from the X+HMA combination regimen, although the difference was not statistically significant due to the llimited sample size (Figure.1b). Conclusion The real-life study demonstrated that the combination of selinexor and HMAs is a viable and safe option for patients with unfit R/R AML who were previously exposed to venetoclax. X+HMA salvage therapy followed by transplantation showed durable survival benefits in R/R AML patients, especially those without prior HMA exposure, suggesting a potential efficacy advantage.

Outcomes and Hospital Resource Utilization Associated with Decreased Ven Exposure in Acute Myeloid Leukemia Patients: A Real-World Retrospective Review

Patients (pts) with acute myeloid leukemia who are ineligible for intensive chemotherapy are treated with hypomethylating agent (HMA) and Venetoclax (Ven). We previously reported outcomes on a cohort of our pts hospitalized for induction therapy demonstrating that the majority of pts required Ven exposure de-escalation. Despite its widely accepted clinical practice, no prospective study has evaluated the efficacy in retaining remission or the tolerability of less Ven exposure per cycle (cyc). Additionally, there is no study evaluating the effect of delaying treatment secondary to its myelosuppressive toxicities. We aim to present outcome data on a large cohort of all AML pts treated with HMA + Ven within our healthcare system. We queried Northwell Cancer Institute's electronic health records to identify all pts with AML who received at least one cyc of Ven and HMA between January 2019 and December 2022. Groups for analysis were created for pts who received at least 3 cyc of HMA and Ven based on the median Ven exposure days per cyc (≤ 14 days or ≥ 15 days) and the median days between cyc (≤ 34 or ≥ 35 days) excluding cyc 1 and 2. Median relapse-free survival (mRFS) and median event-free survival (mEFS) in months (m) were defined by ELN 2022 criteria. Pts who received allogeneic transplants (n=4) were excluded from survival evaluations. Kaplan-Meier (KM) method and log rank testing was used to compare time to event data. We identified 142 AML pts who received at least 1 cyc of Ven + HMA. Pts had an ORR of 42%, mEFS of 4m and mOS of 9.6m. The median age was 77. Only 76 pts received 3 or more cyc of HMA + Ven with mRFS 11.6m of and mOS of 20.6m. Of these pts, 39 had AML with myelodysplastic changes, 29 had De Novo AML and 8 had secondary AML. 75% of pts received HMA + Ven as first line treatment. Utilizing the 2022 ELN risk categories (Dohner et al, Blood 2022), 12 had favorable risk, 12 had intermediate risk and 52 had adverse risk. 93% had treatment regimen modifications by either reduced Ven/cyc or increased cyc intervals. All prognostic indicators appeared evenly dispersed among the groups. Pts with ≤14 days of Ven/cyc (n=35) had a median of 7 cyc (range 3-24) and remained on treatment for a median of 11.3 m. Meanwhile, pts with ≥15 days/cyc (n=41) had a median of 5 cyc (range 3-24) with a median of 10.1m on treatment. The ≤14 days of Ven/cyc group had significantly improved RFS (15.8m vs 8.7m) and OS (24.7m vs 11.3m) compared to the group of pts receiving ≥15 days/cyc (p <0.01). Additionally, there was a decrease in number of hospital days, RBC and platelet transfusions in this group compared to the ≥15 days/cyc group (figure 2). 66% of pts (n=50) required increased time interval between cycles. Both ≤ 34 and ≥ 35 days cyc interval groups completed median of 6 cyc. No significant difference was found in mRFS (11.6m vs 11.8m) or mOS (15.1m vs 21.8m). However, there was a reduction in hospital days, pRBC and platelet transfusions in the ≥ 35 day interval group (figure 2). The overall response rate, mRFS and mOS of all 144 patients seem to be decreased compared to reported prospective trials. This may be due to differences in frailty in our pt population. Although limited by the bias of retrospective analyses, our evaluation of pts outcomes demonstrates a statistically and clinically significant improvement in mRFS and mOS in pts with decreased Ven days/cycle. The majority of pts had Ven/cycle decreased by cycle 3 and most were intermediate or high risk. Our results also highlight the decrease in hospital resource utilization and transfusion needs in this group which may lead to improved quality of life and decreased costs. The ≤14days Ven/cycle group had improved survival compared to the VIALE-A and DEC10-VEN trial despite a larger proportion of our pts having adverse risk. We hypothesize that this improvement is likely multifactorial secondary to decreased mortality from higher Ven exposure, improved tolerance causing increased HMA exposure from timely dosage and from a theoretically possible decreased intracellular adaptive mechanisms generating resistance from continuous Bcl-2 inhibition. This emphasizes the need for continued reporting of outcomes of therapy with HMA/Ven. Additionally, due to the clinically significant improvement in mRFS and mOS, a prospective trial evaluating the efficacy, tolerability, and impact on quality of life of reduced Ven exposure/cyc should be considered.

Real-World Outcomes with CPX-351 Induction in Adults with Newly Diagnosed Acute Myeloid Leukemia

Introduction: CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine with a fixed molar ratio of 1:5. CPX-351 is approved for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia related changes (AML-MRC) in the U.S. and Europe for adult patients (pts) eligible for intensive chemotherapy. In a randomized phase 3 study of older pts ages 60-75, CPX-351 induction showed improved CR rates and OS compared to conventional 7+3 induction, with the greatest benefit seen in pts with t-AML and those without prior hypomethylating agent (HMA) use. There is limited data on the use of CPX-351 in younger pts, although the U.S. FDA approval was not age-restricted. This study examined real-world CPX-351 usage, including patient selection, clinical outcomes, and complications during induction hospitalizations. Methods: We identified previously untreated AML pts who received CPX-351 induction chemotherapy at the University of Kansas Medical Center via retrospective chart review from August 2017 - May 2023. Determination of t-AML and AML-MRC was made by patient history, bone marrow morphology, and available cytogenetic and molecular information at the time of therapy selection. We excluded pts who received CPX-351 as part of a clinical trial. Data was collected for baseline demographics, disease characteristics, outcomes, and safety profile. The composite complete remission rate (CRc) was defined as CR+CRi+CRh at recovery marrow after induction. Primary refractory disease included pts who failed to achieve CR, CRi, or CRh after 2 courses of intensive induction and excluded those who died in aplasia or due to an indeterminate cause. Results: 74 pts with previously untreated AML who received CPX-351 were identified. Median age was 64 years (21-78): 29% of pts were <60 years old, 50% were males, 84% were Non-Hispanic White, 32% had t-AML, 68% had AML-MRC, 20% had prior HMA treatment, and 22% had prior anthracycline exposure. ELN 2022 risk categories were 13% favorable, 20% intermediate, and 68% adverse. 21 pts had complex karyotype (28%), and 16% were TP53 mutant (Table 1). Indications for induction with CPX-351 versus 7+3 included history of prior chemotherapy (n=24), prior MDS (n=32), or MDS-related changes in bone marrow morphology (n=50). The CRc for the total study population was 61% (45/74). Of these, 29% (13/45) achieved MRD negativity by multiparameter flow cytometry <10 -4. CRc in the ELN adverse risk group was 54% (27/50), 73% (11/15) in the intermediate-risk group, and 78% (7/9) in the favorable risk group. Among TP53 mutant pts, CRc was 42% (5/12). CRc in the t-AML group was 71% (17/24), 56% (28/50) in the AML-MRC group, and 53% (8/15) in the prior HMA treatment group. The CRc in pts ≥60 was 63%, 15% were primary refractory, and 37% underwent alloSCT in CR1. In pts <60, the CRc was 54%, 32% were primary refractory, and 27% underwent an alloSCT in CR1 (Table 2). A second course of induction therapy was given for persistent disease at day 14 or similar time point in 36% (n=27) of pts. Among those, 55% (15/27) had primary refractory disease, 20% of the cohort. At a median follow-up of 11 mos, the mOS was 10.8 mos (0.4-54). The mOS for t-AML was 13 mos, whereas the mOS for the group with prior HMA treatment was 10.4 mos. For pts that achieved CR, mOS was 13.6 mos; for pts that achieved MRD negativity, mOS was 13.8 mos. The mOS for pts <60 was 16 mos, and for pts ≥60 was 10 mos (p=0.39). The mOS for pts that achieved CRc in the group <60 was 20.3mos, and for ≥60 was 11.2 mos (p=0.27). Pts that underwent alloSCT in CR1 <60 had mOS of 25 mos; for ≥60, it was 14.2 mos (p=0.37). During induction hospitalization, febrile neutropenia was the most common adverse event in 84% (n=62). ICU treatment was required in 14% (N=5). There were 2 deaths during induction: one due to respiratory failure and one attributed to sepsis. Conclusion: The use of CPX-351 demonstrated efficacy across subgroups, especially in t-AML and pts without prior HMA exposure, as shown in larger studies. In pts <60 years, even though CRc rates were lower, CPX-351 led to longer mOS in those who achieved CRc and in those who underwent alloSCT compared to pts ≥60 years, although it didn't reach statistical significance in this small cohort. Induction therapy outcomes and treatment-related complications in our study corroborate the data for prior CPX-351 studies.

A Phase I/II Study of Combination of Azacitidine, Venetoclax and Pevonedistat in Patients with Newly-Diagnosed Secondary Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Hypomethylating Agent (HMA) Failure

Background: Pevonedistat (PEV) is an inhibitor of NEDD8-activating enzyme (NAE) which is critical for degradation of several cellular proteins essential for tumor growth and survival. The combination of azacitidine (AZA) and venetoclax (VEN) is approved for patients (pts) with newly diagnosed (ND) AML who are unsuitable for intensive chemotherapy, and clinical studies show preliminary efficacy with AZA+VEN in higher risk MDS pts. We evaluate the efficacy and safety of the combination of AZA, VEN, and PEV in ND secondary AML (s-AML) and in MDS after HMA failure. Methods: This phase 1/2 trial enrolled pts with ND s-AML, including therapy-related AML (t-AML), AML from prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN), or AML with dysplasia in ≥50% cells in ≥2 myeloid lineages (MRC). A second arm enrolled pts with MDS or CMML that had progressed on prior HMA therapy. Pts had to have a performance status ≤2, total bilirubin ≤1.5 x upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. Pts in AML arm may have received prior HMA for preceding hematologic malignancy. In both AML and MDS/CMML cohorts, pts received AZA 75 mg/m2 SC/IV on days 1-7 and PEV 20 mg/m2 IV on days 1, 3 and 5 on every 28 day-cycle. In AML cohort, VEN was given on days 1-28 in cycle 1 and days 1-21 on cycle 2+. In MDS/CMML cohort, VEN was given on days 3-14 in cycle 1 and days 1-14 on cycle 2+. In initial phase 1 portion of the study (AML cohort only), VEN at max dose 200 mg and 400 mg were explored. Results: Between 3/2019 and 8/2021, 32 pts with AML (10 t-AML, 22 AML from MDS/CMML/MPN, 4 MRC) and 8 pts with MDS/CMML post-HMA failure (6 with MDS, 2 with CMML) were treated (Table). In the AML cohort, the median age was 74 years, with 14 pts (44%) ≥75 years of age. Cytogenetics was adverse in 21 pts (66%), and adverse risk mutations, including TP53, RUNX1, and ASXL1 were present in 34%, 31%, and 22%, respectively. 17 pts (53%) had treated secondary AML (ts-AML; i.e. prior exposure to HMA or chemotherapy for preceding myeloid neoplasm). The overall response rate (ORR, defined as CR+CRi+MLFS) was 75%, with CR in 15 pts (47%), CRi in 6 pts (19%), and MLFS in 3 pts (9%). One pt achieved PR (3%). 78% of pts achieved best response after 1 cycle of therapy (range, 1-4 cycles to best response). Among 21 pts with CR/CRi, 10 pts (48%) achieved MRD negativity by flow cytometry. 14/21 pts (67%) with poor-risk cytogenetics responded, compared to 10/11 pts (91%) with non-poor cytogenetics. 9/11 pts (82%) with TP53-mutated AML responded. 11/17 pts (65%) with ts-AML responded, compared with 13/15 pts (87%) who did not have ts-AML. With median follow up of 20 months (mos) for the AML cohort, the median OS was 8.2 mos and median relapse-free survival (RFS) was 7.4 mos. 5 pts proceeded to transplant in first remission. The median OS for pts with adverse cytogenetics was 6.8 mos and was not reached in pts without adverse cytogenetics (1-year OS of 70%). The median OS for pts with TP53-mutated AML (n=11) was 8.1 mos, pts with inv(3) (n=4) was 3.8 mos, and pts without TP53 mutation or inv(3) (n=17) was 18 mos (Figure). In MDS/CMML HMA failure cohort, the median age was 73 years. Most pts had adverse cytogenetics (50%) and were high to very high-risk by IPSS-R (87%). Overall response rate (CR+marrow CR [mCR]+HI) was 75%, with CR in 3 pts (37%), mCR in 2 pts (25%), and HI in 1 pts (13%). With a median follow up of 11 mos, the median OS was 9.9 mos. Transformation to AML occurred in 1 pt (after 11 mos). No DLTs were observed in the phase 1 portion, and VEN 400 mg daily was the recommended phase 2 dose. Myelosuppression was similar to expectations with AZA+VEN alone. Grade 3/4 non-hematologic adverse events occurring in ≥10% pts were febrile neutropenia or other infection in 75%, hypophosphatemia in 22%, and hyperbilirubinemia in 10%. The 4-week and 8-week mortality rates were 9% and 25% in AML cohort and 0% and 13% in MDS/CMML cohort, respectively. Conclusion: AZA, VEN, and PEV combination is active and well-tolerated in both ND s-AML and MDS/CMML after HMA failure. This population was enriched with very poor risk features, including a majority of pts in the AML cohort with prior HMA or chemotherapy exposure for an antecedent myeloid malignancy and 1/3 of pts with a TP53 mutation. Response rates were high across disease subgroups, although duration of responses and survival were modest in pts with historically poor risk features, including those with adverse risk cytogenetics and TP53 mutations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Real‐world experience with venetoclax and hypomethylating agents in myelodysplastic syndromes with excess blasts

Real‐world experience with venetoclax and hypomethylating agents in myelodysplastic syndromes with excess blasts

Impact of Frontline Treatment Approach in Patients with Secondary AML and Prior Hypomethylating Agent Exposure: A Retrospective Analysis of 562 Patients with Treated Secondary AML

Impact of Frontline Treatment Approach in Patients with Secondary AML and Prior Hypomethylating Agent Exposure: A Retrospective Analysis of 562 Patients with Treated Secondary AML

Outcomes of Patients Treated with CPX-351 As First Line Therapy for AML Based on Their Antecedent History of Myeloid Malignancy

Outcomes of Patients Treated with CPX-351 As First Line Therapy for AML Based on Their Antecedent History of Myeloid Malignancy

Evaluating Venetoclax Treatment Duration When Combined with Hypomethylating Agents in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes

Evaluating Venetoclax Treatment Duration When Combined with Hypomethylating Agents in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes

An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

Hypomethylating Agent Leads to Enhanced Immunogenicity of a Dendritic Cell/Acute Myeloid Leukemia Fusion Vaccine and Prolonged Survival in an Immunocompetent Mouse Model

Immunotherapy for acute myeloid leukemia (AML) holds great promise as a modality to overcome tolerance and elicit memory responses needed for durable remissions. Our group pioneered a novel personalized vaccine that targets a broad array of leukemic antigens (Ags) by fusing whole patient-derived AML cells to autologous dendritic cells (DCs). In a clinical trial of AML patients in chemotherapy-induced remission, vaccination induced an expansion of tumor-specific T cells and resulted in prolonged remissions in a subset of patients. Enhancing response to vaccination relies on increasing Ag presentation and overcoming factors in the microenvironment that contribute to tolerance.While the mechanism of action of hypomethylating agents (HMAs) is multifactorial, HMAs are increasingly recognized as exhibiting immunomodulatory functions thought to contribute to therapeutic efficacy. We have previously shown that the HMA SGI-110 augments AML Ag processing and increases AML susceptibility to T cell-mediated killing. In the present study, we aimed to elucidate the effect of HMAs on enhancing Ag presentation and modulating the AML microenvironment as well as to investigate the impact of HMA on the immunogenicity of a DC/AML vaccine.We first investigated the ability of SGI-110 to reverse critical aspects of the AML immunosuppressive milieu and enhance vaccine efficacy. C57BL/6J mice were retro-orbitally inoculated with 1x105 syngeneic TIB-49 AML cells and treated with low-dose SGI-110 (1mg/kg) to assess immunologic effects without preventing engraftment. AML engraftment in the spleen and bone marrow (BM) was similarly observed in treated and control animals. However, SGI-110-treated animals showed decreased PD-1 expression on CD4 T cell splenocytes (mean 3.1% vs. 6.3%; n=4; p=0.01). SGI-110 therapy was also associated with decreased myeloid-derived suppressor cell (MDSC) burden in the BM (n=5; p=0.01) and spleen (n=4; p=0.03) compared to control.Consistent with these findings, treated mice demonstrated increased AML-specific immunity via increased T cells isolated from the BM or spleen that expressed intracellular IFNϒ following ex-vivo exposure to TIB-49 lysate (mean 3% vs. 0.5%; n=5; p=0.02).We then examined the potential synergy of SGI-110 + vaccine in this model. Mice treated with SGI-110 + vaccine showed a significant increase in BM and spleen CD4 (n=5; p=0.05) and CD8 (n=5; p=0.02) T cell IFNϒ in response to tumor lysate as compared to vaccine or SGI-110 alone.To further elucidate the mechanism behind the immune activating effects of HMAs, we investigated the effect of HMA on the endogenous retroviral (ERV) pathway. Activation of this pathway results in increased IFN ß expression leading to increased MHC HLA Class I expression and subsequently, immune stimulation in a solid tumor model (Chiappinelli et al. Cell . 2015). MOLM-14 cells were exposed to low-dose HMA daily X 3 days and analyzed for ERV-3 expression using western blotting (WB). The results showed significant upregulation of ERV-3 expression after treatment. Due to activation of the ERV pathway, increased IFN ß expression was observed with WB analysis. Indeed, analysis of an HLA-A2 positive human AML cell line, THP1, showed significant HLA-A2 upregulation after HMA exposure. Most importantly, HLA-A2 upregulation led to a significant rise in tumor Ag presentation, detected by measuring the binding capacity of a unique T-cell receptor-like antibody using flow cytometric analysis in THP-1 cells.Given these effects, we sought to examine whether treatment with vaccine + SGI-110 would enhance survival in this model. Mice were treated with: vehicle, SGI-110 X 5 days, vaccine, or both agents. Monotherapy with either agent led to a survival advantage compared to untreated mice (p<0.05). Notably, the combination arm further prolonged survival as compared to untreated mice (p<0.05).In conclusion, SGI-110 modulates critical factors contributing to the immunosuppressive milieu in AML by decreasing T cell PD-1 expression and promoting MDSC expansion, resulting in enhanced anti-AML immunity. Moreover, SGI-110 augments the immune response to an autologous DC/AML vaccine in a murine model resulting in a survival benefit. In addition, HMA enhances Ag presentation, in part due to activation of the ERV pathway. The combination of a novel personalized DC/AML fusion vaccine and HMA holds great potential and a clinical trial is being initiated. DisclosuresAvigan:Genus Oncology: Research Funding.

Prognostic Factors and Survival Outcomes in Blast Transformed Chronic Myelomonocytic Leukemia: A Mayo Clinic-MD Anderson Cancer Center Study of 171 Cases

Background:Blast transformed (BT) chronic myelomonocytic leukemia (CMML); defined by ≥20% blood or bone marrow (BM) blasts, occurs in 15-30% of patients and is a major cause of mortality. Reported risk factors include high risk karyotype, circulating blast count, circulating immature myeloid cells (IMC), CMML morphological subtype, and the presence of ASXL1 mutations. In the current study, we reviewed consecutive cases of BT CMML from the Mayo Clinic, MN, and the MD Anderson Cancer Center, Texas, USA, with the intent to examine i) prognostic factors, ii) survival trends, and iii) treatment outcomes.Methods:Diagnoses of CMML and BT-CMML were according to the 2016 WHO criteria. Treatment response in BT-CMML patients was assessed according to standard AML response criteria. Statistical analyses considered clinical and laboratory data collected at the time of BT. Survival was calculated from the date of BT to the date of death or last contact.Results:171 cases of BT CMML were identified from the Mayo Clinic (n=84) and MDACC (n=87). The median age at BT was 69 years and 64% were male. Eight one (49%) had received prior hypomethylating agent (HMA) therapy (Decitabine 50, 5-azacitidine 31), with 30% having achieved a complete remission (CR) prior to BT. CMML patients that received prior HMA therapy were more likely to have thrombocytopenia (p=0.03), higher LDH levels (p=0.007), lower frequency of TET2 mutations (p=0.04) and higher risk stratification by the Mayo prognostic model (p=0.009). The two institutional cohorts were comparable with regards to variables, both at CMML diagnosis and BT.Patient characteristics at time of BT: The median time from CMML diagnosis to BT was 12 months (range, 1-36). At BT, 16 (10%) presented with extramedullary disease, 81 (63%) with an abnormal karyotype, 41 (34%) with cytogenetic clonal evolution, with the following mutational distribution; TET2 50%, ASXL1 39%, NRAS 39%, FLT3 ITD 20%, NPM1 6%, RUNX1 6%, and 5% each for IDH1/2, EZH2 and JAK2 . Molecular clonal evolution was seen in 4 (22%) of 18 evaluable cases.Survival trends: After a median follow-up of 4.4 months (range 0-122), 141 (82%) deaths were recorded. Median overall survival (OS) was 6 months with 1- and 3-year survival rates of 25% and 9%, respectively; survival trends were similar (p=0.4) for patients diagnosed prior to and after the year 2006 (figure 1A).Treatment and response rates: Specific treatment for BT-CMML was documented in 157 cases and included induction chemotherapy (n=61), induction chemotherapy followed by stem cell transplant (HCT, n=18), HCT alone (n=3), HMA (n=18), novel therapeutic agents (n=18), and best supportive care (BSC, n=39). Treatment response was assessable in 113, including 76 treated with induction chemotherapy, 18 with HMA and 16 with novel therapeutics; with respective CR rates of 24%, 0% and 41%; with an additional 24%, 16% and 16% of patients achieving CR with incomplete blood count recovery (CRi), with a survival similar to those with CR (figure 1B). HCT was reported in 25 patients, 17 myeloablative and 8 reduced intensity, with a median OS of 7 months.Predictors of survival in BT-CMML: In univariate analysis of variables recorded at time of BT, risk factors adversely impacting survival included older age, lower hemoglobin, PB blast %, adverse cytogenetics at BT, prior exposure to HMA, not receiving induction chemotherapy, not achieving CR or CRi and not receiving HCT; all of these risk factors remained significant when analysis was adjusted for age. In multivariable analysis, lack of prior HMA exposure (p=0.001, HR 5.1; 95% CI 1.9-14.1) and the achievement of CR/CRi (p=0.02, HR 1.4; 95% CI 1.2-3.4) remained significant while HCT lost its significance (p=0.09). Gene mutations, including FLT3 ITD, cytogenetic and molecular clonal evolution at the time of BT did not impact survival. The 3-year survival rates for BT patients receiving induction chemotherapy, induction chemotherapy followed by HCT, HMA, novel agents and BSC were 8%, 20%, 12%, 3% and 0% respectively (figure 1C).Conclusions: Survival in patients with BT- CMML is dismal (≈6 months) and is adversely impacted by prior exposure to HMA and by the failure to achieve CR/CRi. After BT, the use of HMA therapy is largely ineffective (0% CR), with intensive therapies such as induction chemotherapy with or without HCT, failing to achieve durable remissions. [Display omitted] DisclosuresJabbour:Amgen: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda Oncology: Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding.

A Phase 1 Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes: University of California Hematologic Malignancies Consortium (UCHMC) Study 1503

Introduction: Higher risk myelodysplastic syndromes (HR-MDS) have poor outcomes, particularly after hypomethylating agent (HMA) failure. The HMA azacitidine (AZA) is a standard of care for HR-MDS and works through several mechanisms, including inhibition of NF-kB signaling. Ibrutinib (IBR) inhibits Bruton9s Tyrosine Kinase (BTK) and has an antiproliferative effect on myeloblasts in preclinical models through BTK binding and inhibition of NF-kB signaling. IBR also has immunomodulatory activity mediated through binding interleukin-2-inducible kinase (ITK) and promoting Th1-polarized immunity, which is decreased in HR-MDS. These features suggest that the combination of IBR and AZA may improve outcomes in HR-MDS. Methods: This is an ongoing multicenter prospective Phase 1 dose-escalation trial of IBR in combination with AZA in patients with HR-MDS (NCT02553941). Results of the dose escalation phase are reported. Eligibility included World Health Organization or French-American-British classification-defined MDS and Revised International Prognostic Scoring System (IPPS-R) intermediate or higher risk. Any prior therapy was allowed or patients could be untreated if unfit for, or had refused, high intensity chemotherapy. Transfusion-dependent patients were eligible. Patients received AZA 75 mg/m2 IV/SC daily for 7 days and IBR orally daily for 28 days. Cycles repeated every 28 days. Dose-escalation used a 3+3 design with IBR dose levels of 420 mg (Cohort 1) and 560 mg (Cohort 2). The primary objective was to determine the safety and tolerability of IBR in combination with AZA. Adverse events (AEs) were monitored throughout treatment, and dose-limiting toxicities (DLT) were assessed during cycle 1. The secondary objective was to assess preliminary efficacy using modified International Working Group Response Criteria. Exploratory objectives evaluated pharmacodynamic and biological effects of the combination, including BTK occupancy in CD34+ bone marrow mononuclear cells (BMMC). Results: As of June 1, 2017, 9 patients [89% male, median age 80 years (range 64-81)] were enrolled into Cohort 1 (n=3) and Cohort 2 (n=6). MDS subtypes included single lineage dysplasia (n=1), multilineage dysplasia (n=1), excess blasts (EB)-1 (n=2), EB-2 (n=3), refractory anemia with EB in transformation (n=1) and unclassifiable (n=1). IPSS-R scores were intermediate (n=2), high (n=2) and very high (n=5). Three patients were HMA-naive and six had prior HMA therapy [AZA (n=3), decitabine (n=2), both (n=1)]. All patients completed cycle 1. No DLTs were observed. All patients experienced at least one treatment-emergent adverse event (TEAE). Seven patients experienced a grade 3-4 TEAE with neutropenia (n=6), thrombocytopenia (n=3) and febrile neutropenia (n=3) most common. Four patients (three in Cohort 1 and one in Cohort 2) experienced a serious adverse event including febrile neutropenia (n=3) and gastric hemorrhage (n=1). No patients experienced atrial fibrillation. Median time on study was 160 days (range 42-283) with a median of five cycles (range 1-10) received. Six patients remain on IBR plus AZA, and three patients have discontinued study therapy (two disease progression and one withdrawal of consent and subsequent death on hospice). Four patients have reduced AZA to 5 days per cycle per investigator discretion, and four patients have had interruptions of IBR dosing due to febrile neutropenia (n=3) and concurrent azole use (n=1). Three patients (33%) achieved complete remission (CR), one (11%) had a partial remission (PR), and five (55%) had stable disease (SD). All three CRs occurred in patients without prior HMA exposure and included one complete and two partial cytogenetic responses. CR was achieved after 1, 4 and 6 cycles in these patients. One patient (11%) with SD had a hematologic improvement-erythroid response (HI-E). The overall hematologic normalization rate (CR+PR+HI) was 55%. BTK occupancy in CD34+ BMMC after cycle 1 was 42.0% and 51.7% in two patients at IBR 420 mg and 41.5% in one patient at IBR 560 mg. Conclusions: The combination of IBR and AZA demonstrates a tolerable safety profile in patients with HR-MDS. No DLTs were observed at either IBR dose level. The combination shows promising preliminary efficacy, including responses in patients with prior HMA exposure. CD34+ BMMC BTK occupancy was seen. An expansion cohort at the IBR 560 mg dose level in AZA-naive patients is ongoing. Disclosures Jonas: AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees; Rigel: Consultancy. Logan: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Astellas: Research Funding; Shire: Consultancy; Kite: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Jazz: Consultancy. Abedi: Takeda: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding. Bejar: Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Genoptix: Consultancy, Honoraria, Patents & Royalties; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria. Wieduwilt: Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding. Curtin: Amgen, Celgene, Onconova, Pharmacyclics: Research Funding.

Outcomes in AML patients receiving HMA + venetoclax combination with prior HMA exposure.

e19011 Background: Venetoclax (Ven) is a BCL-2 inhibitor approved in combination with hypomethylating agents (HMAs) in newly diagnosed AML patients who are not candidates for intensive induction based on impressive response rates (CR+CRi of 66.4%) and median overall survival (14.7 months) compared to HMA therapy alone (DiNardo CD, NEJM, 2020). Ven was also used in combination with 10 days of a HMA (Decitabine) in a phase II study. In the subgroup of patients with relapsed AML, some of which previously received HMA, the ORR, CR+CRi, and median OS were 62%, 42%, and 7.8 months respectively. (DiNardo CD, Lancet, 2020). To our knowledge there are no studies specifically looking at patients with AML receiving HMA + Ven with previous exposure to a HMA agent. Methods: We conducted a single center retrospective study of AML patients who received HMA + Ven therapy after previously receiving a HMA agent. Baseline demographic, clinical, laboratory, pathology, and outcomes data were collected by retrospective chart review. Response criteria was determined by 2017 ELN recommendations. Kaplan Meier was constructed to summarize time to event data. Results: A total of 17 patients were identified that met these criteria. 7 patients (41%) had progressed on prior HMA treatment, 11 patients (65%) received prior intensive chemotherapy, and 5 patients (29%) received previous Allogenic SCT prior to HMA+Ven therapy. 10 patients (59%) had either a TP53 mutation or 17p deletion and 11 patients (65%) had complex cytogenetics (≥ 3 cytogenetic abnormalities). Other patient characteristics are included in table below. For the entire cohort, the ORR (CR, CRi, PR) was 41% and the CR/CRi rate was 6%; The ORR in the following subgroups for previous HMA failure, TP53 mutation/17p deletion, and complex cytogenetics were 14%, 30%, and 36% respectively. The median Progression free survival and overall survival for the entire cohort was 2 months (1-4 months 95% CI) and 3 months (1-5 months, 95% CI) respectively. 15 patients (88%) were deceased and all deaths were attributed to AML (12/15) or infection (3/15). None of the patients went on to receive an Allogenic SCT. Conclusions: Although a limited sample size which includes many patients with a TP53/17p aberration, complex cytogenetics, Allogenic SCT relapse, and/or heavily pre-treated AML, this data describes poor outcomes in patients receiving HMA+Ven after previous HMA exposure. Patients with previous HMA failure in particular had a poor response rate. None of the patients received 10 day decitabine and it is unclear if this had any effect on the results. It would be beneficial to supplement this data with experience from multiple centers. Patient Characteristics (N = 17).[Table: see text]

Secondary AML Emerging After Therapy with Hypomethylating Agents: Outcomes, Prognostic Factors, and Treatment Options.

Secondary AML (s-AML) encompasses a distinct subgroup of AML with either therapy-related AML or AML arising from preexisting myeloid neoplasms. Despite recent advances in the treatment armamentarium of AML, outcomes remain poor in s-AML. The purpose of this review is to highlight distinct characteristics, prognostic factors, and treatment options for patients with s-AML. Further, we focus on a distinctly poor-risk subgroup of s-AML with previous exposure to hypomethylating agents (HMAs) and describe ongoing clinical trials in this patient population. CPX-351 (liposomal daunorubicin and cytarabine) is the first drug approved for s-AML and represents an advancement in the management of fit patients with this subtype of AML. Despite incremental improvement in remission rates and survival, long-term survival remains poor. Patients who have received prior HMAs for antecedent MDS rarely benefit from CPX-351 or other cytotoxic chemotherapy regimens. The approval of venetoclax in combination with azacitidine has led to a paradigm shift in the management of newly diagnosed older unfit AML patients; however, patients with s-AML and prior HMA therapy were excluded from the landmark randomized phase 3 study. Several early phase clinical trials with both low- and high-intensity therapies are ongoing for s-AML patients, though prior HMA exposure limits inclusion in many of these studies that include HMAs. Patients with s-AML previously treated with an HMA have dismal outcomes with standard therapeutic options and are under-represented in clinical trials. Trials investigating novel therapeutic options in this population are critically needed.

Combination of Homoharringtonine with Venetoclax and Azacitidine Excerts Better Treatment Response in Relapsed /Refractory Acute Myeloid Leukemia

Overexpression of Bcl-2 is known to be an important factor for drug resistance in relapsed /refractory acute myeloid leukemia (R/R-AML). Combination of Bcl-2 inhibitor venetoclax with hypomethylating agents (HMA) has shown promising killing effect in elder patients with newly diagnosed AML, also worked in R/R-AML but with low rate of complete response (CR). High expression of Bcl-XL and/or Mcl-1 is the main reason for resistance to venetoclax. As an inhibitor of both Bcl-XL and Mcl-1, homoharringtonine (HHT) has presented a synegetic effect with venetoclax in inhibition of Mcl-1 and killing of lymphama. In this study, we analyzed the treatment response and safety of combination of HHT (1mg/m2 d1-7) with venetoclax (400mg d1-14) and azacitidine (75mg/m2 d1-7) (HVA) in R/R-AML. From 6, 2019 to 5, 2020, in Nanfang Hopsital, 22 patients with RR-AML were treated with HVA (HVA group), with a median age of 39(16-62) years, previous chemotherapy of 3(1-7) cycles. 15 (68.2%) relapsed within one year after allogenetic hematopoietic stem cell transplantation (allo-HSCT) and 12 (54.5%) previously exposed to HMA treatment. Meanwhile, 7 patients with RR-AML were treated with venetoclax combined with HMA (control group), with a median of 42(31-74) years, previous chemotherapy of 3(1-6) cycles. 2 (28.6%) relapsed after allo-HSCT and 5 (71.4%) had HMA exposure. In HVA group, totally 11/17(64.7%) patients acquired treatment response, and 7/15(46.7%) obtained CR/CRi, of whom 6 presented minimal residual disease (MRD) negative. While in control group, only 2/7(28.6%) acquired treatment response and 1 obtained CR. Subgroup analysis in HVA group showed allover response rate (ORR) was 9/13(69.2%) and CR rate was 6/11(54.5%) (all with MRD negative) in the patients with allo-HSCT. And in the patients without allo-HSCT ORR was 2/4(50.0%) and CR rate was 1/4. With a median follow-up of 6(1-7) months, one patient was bridged to allo-HSCT, 2 out of 7 patients with CR relapsed. All patients were well tolorated to both treatment regimens, showing as a median neutropenia of 9.5(5-14) days, 5 patients with Febrile neutropenia and 4 with pulmonary infection. In conclusion, combination of HHT with venetoclax and azacitidine (HVA) excerts better treatment response in R/R-AML, especially in those with allo-HSCT, and shows well tolorated. A multi-center prospective clinical trial (NCT04424147) has been initiated. Key words: HVA regimen, relapsed /refractory acute myeloid leukemia, treatment response, safety Disclosures No relevant conflicts of interest to declare.

Correlating Clinical and Genomic Features with Ex Vivo Drug Sensitivity in Patients with Myelodysplastic Syndromes and Related Myeloid Neoplasms

Background Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms characterized by ineffective hematopoiesis, dysplasia, cytopenias, and a variable risk of progression to acute myeloid leukemia (AML). The biologic heterogeneity of MDS and related myeloid neoplasms relates to the genomic complexity of these disorders with different combinations of cytogenetic abnormalities and mutations associated with distinct clinical phenotypes. Ex vivo drug sensitivity screening (DSS) is a promising tool that may inform personalized therapy in MDS, particularly in patients refractory to standard therapies such as hypomethylating agents (HMAs). We report our updated experience using a fully automated ex vivo DSS platform in 64 patients with MDS and related myeloid neoplasms and identify correlations between clinical and genomic features and ex vivo drug sensitivity. Methods Patients: Patients were evaluated at the Stanford MDS Center between September 2016 and May 2020 and had a diagnosis of MDS, MDS/MPN, or secondary AML. Bone marrow (BM) aspirate and peripheral blood (PB) samples were procured for mutation testing (164-gene panel) and ex vivo DSS (Notable Labs, Foster City, CA). Ex vivo DSS: Fresh BM aspirate and PB specimens were RBC-lysed and resuspended in serum-free media with cytokines as previously described (Spinner et al, Blood Adv 2020;4(12):2768-78). Samples were plated in 384-well microtiter plates and screened against a collection of up to 74 drugs and 36 drug combinations in triplicate. Specimens were treated for 72 hours and assayed using high-throughput, multi-parametic flow cytometry, gating on the blast population (expressing CD34, CD33, and/or HLA-DR) to assess for blast viability. Patient clustering &amp; statistical analysis: The Euclidean distance metric and Ward minimum variance method were used to identify patient clusters with distinct ex vivo drug sensitivity patterns. A 1-way repeated measures ANOVA was used to identify drug classes with variable sensitivity across clusters and to identify associations between clusters and clinical variables, including blast count, mutations and cytogenetic groups, IPSS-R risk group, and prior HMA exposure. A generalized estimation equation model was used to identify associations between mutations and ex vivo drug sensitivity. Results Ex vivo DSS was performed in 64 patients with myeloid neoplasms including 43 with MDS (67%), 11 with MDS/MPNs (17%), and 10 with secondary AML (16%). The median age was 75 years (range 23-90) and 78% were male. The majority of patients had higher risk disease with IPSS-R &amp;gt;3.5 (66%), excess blasts (58%), and adverse cytogenetics or mutations (53%) by IPSS-R or the ELN classification. Patients had a median of 2 pathogenic mutations (range 0-7), with the most frequent including TET2, ASXL1, DNMT3A, SF3B1, RUNX1, STAG2, SRSF2, NRAS, KRAS, BCOR, TP53, and EZH2. The majority of patients (64%) had prior HMA exposure. Ex vivo DSS defined three distinct patient clusters with differential sensitivity to numerous drug classes (Figure 1). Cluster 1 (N=13) demonstrated the greatest ex vivo sensitivity to HMAs, HMA/venetoclax combinations, cytotoxic agents, kinase inhibitors, mTOR inhibitors, HDAC inhibitors, and PARP inhibitors, while cluster 3 (N=19) demonstrated the greatest ex vivo resistance (p&amp;lt;0.0001 for all comparisons). Correlating clinical variables with drug sensitivity clusters, only IPSS-R score differed significantly among clusters, with fewer higher risk patients in cluster 3 (p=0.02). Correlating specific mutations with ex vivo drug sensitivity, STAG2 mutations were associated with greater ex vivo sensitivity to HMAs (p=0.002), HMA/venetoclax combinations (p=0.003), kinase inhibitors (p=0.002), and PARP inhibitors (p=0.003). TP53 mutations were associated with greater ex vivo sensitivity to proteasome inhibitors (p=0.0002). Conclusions Ex vivo DSS defined distinct patient clusters with differential sensitivity to numerous drug classes. Specific mutations, such as STAG2 and TP53, were associated with greater ex vivo sensitivity to specific drug classes. A larger sample size is needed to evaluate combinations of mutations and better define associations between genotype and drug sensitivity phenotype. Ultimately, combining both genomics and functional screening may further refine personalized therapy selection for patients with MDS and related myeloid neoplasms. Figure Disclosures Spinner: Notable Labs: Honoraria. Schaffert:Notable Labs: Current Employment. Aleshin:Notable Labs: Consultancy. Santaguida:Notable Labs: Current Employment. Tada:Notable Labs: Current Employment, Current equity holder in private company. Greenberg:BMS: Research Funding; Aprea: Research Funding; H3 Biotech: Research Funding; Notable Labs: Research Funding.

Outcomes of Therapy with Venetoclax Combined with Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)

Outcomes of Therapy with Venetoclax Combined with Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)

AZA + Glutaminase Inhibition with Telaglenastat (CB-839) for Advanced MDS: An Updated Interim Analysis

AZA + Glutaminase Inhibition with Telaglenastat (CB-839) for Advanced MDS: An Updated Interim Analysis

AML-062: Long-Term Follow-Up of a Phase 1/2 Study of Venetoclax (VEN) Plus Low-Dose Cytarabine (LDAC) in Previously Untreated Older Adults with Acute Myeloid Leukemia (AML)

Aims To report long-term safety/efficacy of VEN+LDAC. Methods Patients ≥ 60 yrs with previously untreated AML ineligible for standard induction chemotherapy (ECOG performance status: 0–2 [≥75 yrs]; 0–3 [60–74 yrs]) were enrolled. Before dose ramp-up of VEN in cycle 1, patients received prophylaxis to mitigate risk of tumor lysis syndrome (TLS). Patients were treated at recommended phase 2 dose (RP2D): VEN 600 mg per day (QD) orally in 28-day (d) cycles, with subcutaneous LDAC 20 mg/m2 QD on d1–10. Key objectives at RP2D were to assess response rates, duration of response (DOR), overall survival (OS), and safety/tolerability. Results Eighty-two patients received RP2D and ≥1 dose of VEN. Median age was 74 yrs; secondary AML: 49%, prior treatment with a hypomethylating agent (HMA): 29%, poor-risk cytogenetics: 32%. In patients evaluable for molecular analyses, baseline mutations in TP53, FLT3, IDH1/2, and NPM1 were detected in 14%, 21%, 26%, and 13%, respectively. Median treatment duration was 4.2 mo (range 0.2–41.8); 26% received >12.0 mo of treatment. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 54% (CR: 26%; CRi: 28%); median time to first response, 1.4 mo (range 0.8–14.9). Median with 95% confidence interval (CI) DOR (CR/CRi) was 9.8 mo (5.3, 14.9), and median OS was 9.7 mo (5.7, 14.0). Among patients with de novo AML (n=42), CR/CRi rate was 71% (CR: 45%; CRi: 26%); median DOR: 10.8 mo (5.5, 32.8), median OS: 15.7 mo (9.7, 22.4). Patients with prior HMA exposure (n=24), CR/CRi was achieved in 33% (CR: 4%; CRi: 29%); median DOR: 5.3 mo (2.3, 10.2), median OS: 4.1 mo (2.9, 10.1). Longer median OS showed in patients with mutations in NPM1 or IDH1/2 (not reached and 15.9 mo, respectively), intermediate-risk cytogenetic features (14.2 mo), or no prior treatment with HMA (11.7 mo). Common grade 3 or 4 treatment-emergent adverse events (≥30%) were febrile neutropenia (43%), thrombocytopenia (39%), and decreased white blood cell count (34%); 2 patients reported grade ≥3 laboratory TLS event. Conclusion At median 3.5-yr follow-up, VEN+LDAC resulted in median OS of 10 mo. At 2 yrs, 22% of study population remained alive; 32%, 36%, and 64% were alive with IDH1/2, de novo, or NPM1 mutant AML, respectively. Further analyses identifying baseline features predictive of response with prolonged duration are ongoing. Abstract was previously published at EHA25.