Combination Of Hypomethylating Agents Research Articles

Clinical efficacy and immune response of BCL-2 inhibitors combined with hypomethylating agents in the treatment of acute myeloid leukemia

ObjectiveAcute myeloid leukemia (AML) is a malignant clonal proliferative disease with a high mortality rate. The combination therapy of BCL-2 inhibitor Venetoclax (VEN) and hypomethylating agents (HMAs) has significant anti-leukemia activity.MethodsWe analyzed the efficacy, safety and immune response characteristics of AML patients who were unfit for high-dose chemotherapy and accepted the medication of VEN + HMAs.ResultsAfter VEN + HMAs treatment, 31 newly diagnosed AML patients had the morphologic leukemia-free state rate (MLFS%) of 80.6% (25/31), complete response rate (CR%) of 54.8% (17/31), the minimal residual disease negative rate (MRD-%) of 51.6% (16/31), and the median progression-free survival (PFS) of 14 months. After treatment, the proportion of bone marrow primitive cells, the MRD level, white blood cell (WBC) count, fibrinogen (FIB) level and the proportion of B cells were significantly decreased. The red blood cell (RBC) count, hemoglobin (HGB) level, platelet count (PLT) count, activated partial thromboplastin time (APTT), the proportion of total T cells, CD8 + T cells and the IFN-γ level were significantly increased. After VEN + HMAs treatment, 12 relapsed AML patients had a MLFS% of 50% (6/12), CR% of 33.3% (4/12), MRD-% of 25% (3/12), and a median PFS of 7 months. After treatment, the proportion of bone marrow primitive cells and MRD level were slightly decreased, the proportions of CD8 + T cells and NK cells were significantly increased, the proportion of B cells and IL-10 level were significantly decreased. 12 AML patients who receive microtransplantation (MST) treatment using VEN + HMAs as a pretreatment regimen had a PFS of 20.5 months, which was much greater than VEN + HMAs group alone. Hematological recovery was better in the MST group with significantly increased RBC count, HGB level and PLT count. The most common adverse events were myelosuppression, agranulocytosis, infection and cardiovascular toxicity. No fatal adverse events were reported.ConclusionThe combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Beyond HMAs: Novel Targets and Therapeutic Approaches

Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.

Pracinostat combined with azacitidine in newly diagnosed adult acute myeloid leukemia (AML) patients unfit for standard induction chemotherapy: PRIMULA phase III study

Non-intensive therapies such as the hypomethylating agent (HMA) azacitidine (AZA) have been used in patients with AML ineligible for intensive induction chemotherapy (IC) or stem cell transplant due to advanced age, comorbidities, and/or risk factors. However, response rates and survival remain dismal. Pre-clinical studies indicate the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes synergistically. The activity of pracinostat, an oral pan-HDAC inhibitor, has been shown in xenograft tumor models of AML and promising efficacy was seen in a Phase 2 study. This Phase 3 study (NCT03151408) evaluated the efficacy/safety of pracinostat administered with AZA in adult patients with newly diagnosed AML ineligible to receive IC. Patients were randomized to either pracinostat plus AZA or placebo/AZA and stratified by cytogenetic risk and ECOG status. As planned, an interim analysis was performed when 232/390 events (deaths) occurred. A total of 406 patients were randomized (203/group) at the time of the analysis. Median overall survival was 9.95 months for both treatment groups (p=0.8275). There was no significant difference between treatments in secondary efficacy endpoints, reflecting a lack of clinical response. This study did not show a benefit of adding pracinostat to AZA in elderly patients unfit for IC.

Treatment of Post-Allogeneic HCT Relapsed AML/MDS with a Combination of Hypomethylating Agent, Venetoclax (HMA/VEN) and Donor Lymphocyte Infusion (DLI)

Treatment of Post-Allogeneic HCT Relapsed AML/MDS with a Combination of Hypomethylating Agent, Venetoclax (HMA/VEN) and Donor Lymphocyte Infusion (DLI)

Venetoclax and hypomethylating agents in critically ill patients with newly diagnosed acute myeloid leukaemia.

Venetoclax (VEN) in combination with hypomethylating agents (HMAs) is considered the standard of treatment for individuals with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. We conducted a retrospective analysis that encompassed 16 critically ill patients newly diagnosed with AML who were admitted to the intensive care unit (ICU) and received the VEN and HMA regimen. Among them, 13 were primary AML, and three were MDS-transformed AML. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 18.9, and the mean sepsis-related organ failure assessment score (SOFA) was 6.2. The average length of the ICU stay was 27.3 days. The median duration of VEN administration was 16 days. After the first course of VEN + HMA, 12 cases (75%) achieved complete remission (CR) or CR with incomplete haematological recovery (CRi). Among the five patients harbouring TP53 mutations, the overall response rate (ORR) was 90%. All patients experienced grade 3-4 haematological adverse events (AEs). With a median follow-up of 9.5 months (range: 0.5-23), the overall survival (OS) rate was 43.75%. TP53-wild patients and CR state after the first course of VEN-HMA indicated better survival. The combination of VEN and HMA has demonstrated a significantly elevated therapeutic response rate in newly diagnosed AML patients with critical illness.

A Phase 1 Study of Avapritinib in Combination with Decitabine in Patients with Systemic Mastocytosis with an Associated Hematologic Neoplasm

Background and Rationale: Systemic mastocytosis (SM) is a clonal hematologic neoplasm characterized by abnormal accumulation of mast cells which can lead to symptoms related to mast cell degranulation and/or, in the case of advanced systemic mastocytosis (AdvSM), organ dysfunction due to mast cell infiltration. AdvSM is a category of SM comprised of aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). Among these, SM-AHN is the most common subtype, accounting for approximately 70% of AdvSM. A KIT D816V mutation found in up to 95% of SM cases is the primary oncogenic driver, making it a key therapeutic target. Avapritinib, a highly potent and selective inhibitor of D816V mutant KIT, has demonstrated high rates of rapid, deep, and durable responses in all AdvSM subtypes, including SM-AHN. However, a recent analysis of the EXPLORER study showed that avapritinib-treated patients were still at risk for progression of the AHN component, despite continued control of mast cell disease burden, indicating that combination therapy is likely to be required for optimal control of SM-AHN due to its inherent molecular complexity. Hypomethylating agents (HMA) form the backbone of therapy for advanced myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN), hematologic neoplasms most likely to co-occur with SM in patients (pts) with SM-AHN. To date, the combination of HMA and KIT inhibitors has not been clinically evaluated. In this study, we aim to assess the safety and tolerability of the combination of avapritinib and decitabine in patients with SM-AHN. Study design: The primary objective of the study is to establish the recommended dose (RP2D) of avapritinib in combination with decitabine based on dose-limiting toxicity, overall safety, and clinical activity data. A dose evaluation steering committee (DESC) comprised of participating investigators will review the totality of safety and efficacy data to determine RP2D. Secondary endpoints include SM overall response rate by the end of 6 cycles by the m-IWG consensus criteria and proposed ECNM-AIM criteria ( Gotlib et al., J Allergy Clin Immunol Pract, 2022), as well as incidence and frequency of adverse events. Exploratory endpoints will consist of patient reported outcomes, progression free survival, overall survival, and correlative biomarkers linked to mast cell disease or AHN. Adult pts with a diagnosis of SM-AHN by the WHO 2022 classification criteria will be eligible for inclusion. Eligible pts must have any of the following myeloid AHN per WHO 2022 criteria: MDS, chronic myelomonocytic leukemia, MDS/MPN with neutrophilia, MDS/MPN with SF3B1 mutation and thrombocytosis, or MDS/MPN- not otherwise specified. Patients with MDS must have intermediate, high- or very-high risk by IPSS-R. Patients with very-low or low-risk MDS by IPSS-R must be intolerant/refractory to ESA or have serum EPO > 200 U/L. A baseline platelet count of ≥ 75 x 10 9/L and ≥ 25 x 10 9/L will be required for inclusion in the dose-finding and the dose-expansion phases, respectively (Figure). Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. In the dose finding part of the study, a Bayesian adaptive design will be employed to assess different doses of avapritinib (50 to 200 mg PO daily) in combination with fixed doses of decitabine (oral decitabine/cedazuridine: 35/100 mg/day or intravenous decitabine: 20 mg/m 2/day on days 1-5) in a 28-day treatment cycle. Close attention will be paid to treatment-emergent thrombocytopenia with protocol-driven treatment holds and dose modification strategies employed when platelet count drops below 50 x 10 9/L. After RP2D is determined, an additional 10 patients will be enrolled in the dose expansion phase. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Impact of Type of Hypomethylating Agent (HMA) Used on Outcomes of Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) - a Large, Multicenter, Retrospective Analysis

JPB and TK Co-first; RK and AMZ are Co-senior authors Introduction HMAs remain the mainstay for frontline treatment of HR-MDS. Azacitidine (AZA) and decitabine (DEC; including oral cedazuridine/decitabine) are the only FDA-approved HMAs. However, AZA and DEC have not been compared directly in randomized trials. In this study, we aimed to assess the clinical outcomes of pts with HR-MDS treated with different HMA regimens, focusing on overall survival (OS) and treatment responses. Methods The VALIDATE database includes pts with HR-MDS treated with HMA-based therapies in the frontline setting from 14 specialized MDS centers. HR-MDS pts treated with HMA-based therapies in the frontline setting were included. HR-MDS was defined as having an IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded from the survival analysis if age at diagnosis was <18 years (n=1), bone marrow (BM) blasts ≥20% or unknown at HMA initiation (n=61), or if survival status, follow-up time, date of HMA initiation, or HMA type was unknown (n=28). To be included in the analysis of response based on IWG 2023 criteria (Zeidan A et al, Blood 2023), pts had to have a BM response assessment within 180 days after HMA initiation to allow determination of response (n=290 pts excluded). Time to event analyses were estimated using the Kaplan-Meier method and treatment groups (AZA vs DEC monotherapy) were compared by log-rank test and assessed from the time of HMA initiation. Multivariable Cox regression models were performed among pts treated with AZA and DEC monotherapy to identify predictors of response and OS. This study was supported by an independent research grant from AbbVie. Results 1,223 pts were screened of whom 919 were included in the survival analysis. Median age was 68 years (Range [R]: 19-95) with 66% males. Our cohort was enriched for pts with adverse genetic features including complex karyotype (38%) and TP53 mutations (36%). Overall, 76% of pts were treated with HMA monotherapy (56% AZA, 20% DEC) and 24% received HMA-based combination therapy (HMA/VEN: 15%, other HMA combinations: 9%). 38.2% underwent allogeneic hematopoietic cell transplant (allo-HCT). The median HMA duration was 5 cycles (R: 1 - 94). Due to the small number and the heterogeneity of pts receiving HMA combinations, as well the multiple partner drugs used in these pts ( Table), we compared OS and responses only between pts treated with AZA (n = 512 pts) or DEC monotherapy (n = 186 pts). In unadjusted analyses, median OS differed by treatment type (p = 0.002) and was 19.8 months (mo) with AZA (95% CI: 17.0 - 23.1 mo) and 14.3 mo with DEC (95% CI: 11.2 - 18.5 mo). Among 629 pts evaluable for response, rates of complete remission (CR) and overall response (ORR) were 14.8% and 48.6% for AZA monotherapy and 5.6% and 50.4% for DEC monotherapy, respectively. In a Cox multivariable regression model ( Figure) adjusted for age, sex, TP53 mutation status, complex karyotype, IPSS-M category (compared to very high risk), and receipt of allo-HCT, there was no difference in OS when comparing AZA and DEC monotherapy (Hazard ratio [HR]: 0.95, 95% CI: 0.72 - 1.26; p = 0.740). Variables associated with adverse OS were male sex (HR: 1.52; 95% CI: 1.16 - 2.00; p = 0.002) and presence of TP53 mutation (HR: 1.50, 95% CI: 1.05 - 2.14; p = 0.027). Conversely, receipt of allo-HCT (HR: 0.26, 95% CI: 0.19 - 0.37; p<0.001) and IPSS-M moderate-high (HR: 0.57, 95% CI: 0.37 - 0.87; p=0.009) and moderate-low (HR: 0.58, 95% CI: 0.36 - 0.95; p = 0.031; both compared to IPSS-M very high risk) were associated with improved OS. Similarly, there were no statistically significant differences in ORR between AZA and DEC (OR: 1.05, 95% CI: 0.66 - 1.68; p = 0.832) in a Cox multivariable regression model adjusted for age, sex, TP53 mutation, complex karyotype, IPSS-M category, and treatment type. Conclusions: Among pts included in the real-world VALIDATE database, there were no significant difference in OS or ORR (IWG 2023) between AZA- and DEC-treated pts in adjusted analyses. Other factors (e.g., TP53 mutations, complex karyotype) are substantially more relevant to outcomes than the specific HMA used. The small number of pts and heterogeneity of partner drugs in HMA-based combinations precluded robust analyses or conclusions regarding differences in efficacy. Additional analyses evaluating the impact of combinations and molecular subtypes on response and survival will be presented during the meeting as more pts are added to the database.

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.

Anti-PD-1 Antibody (Sintilimab) Plus Decitabine As First Line Treatment for Patients with Higher-Risk Myelodysplastic Syndrome (MDS): Primary Results from a Single-Arm,Open-Label,Phase II Study

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients with higher-risk Myelodysplastic Syndrome (MDS). However, the survival rate of patients after HMA treatment remains poor. Studies have shown that HMAs upregulate the expression of PD-1/PD-L1 in MDS patients, making the combination of HMAs with PD-1 antibodies a compelling approach for MDS treatment. Consequently, we conducted this single-arm, open-label clinical trial (ChiCTR2100044393) to assess the safety and efficacy of sintilimab in combination with decitabine for patients with higher-risk MDS. Methods: Adult patients with higher-risk MDS, according to the IPSS-R, were eligible for enrollment in this study. The treatment regimen consisted of daily intravenous administration of decitabine at a dose of 20mg/m 2 for 5 consecutive days, along with intravenous administration of sintilimab at 200mg on the first and 22nd day of a 42-day treatment cycle. Treatment continued until disease progression, death, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons, with a maximum of 8 cycles allowed. The primary endpoint of this study was the overall response rate (ORR). To determine the sample size, we utilized Simon's optimal two-stage design. Secondary endpoints included the assessment of safety and various survival outcomes. Additionally, we investigated the relationship between the expression levels of immune checkpoints and the efficacy of the combination therapy and other potential biomarkers through genomic profiling. Results: As of the data cut-off on June 16, 2023, 53 patients were enrolled, with a median follow-up time of 14 months, and 52 patients were eligible for response evaluation. The median age of patients was 65 years (range 19-83), other characteristics were summarized in Table 1.The ORR was 76.9%, and 15 patients achieved complete response (CR), 13 marrow complete response(mCR),7 mCR+ hematologic improvement(HI), and 5 HI. Among the 40 responders, six patients (4 with CR and 2 with mCR) underwent allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) has not reached, and the median event-free survival (EFS) was 16 months. The 24-month OS and EFS rates were 54.8% (95%CI: 39.5-76.2) and 46.2% (95%CI: 31.2-68.3), respectively. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) reported in 10% or more of the patients were febrile neutropenia (67.9%) and pulmonary infection (20.8%). A total of 17 patients (32.1%) experienced immune-related adverse events (irAEs), with the most common irAEs being rash (17.0%), thyroid dysfunction (9.4%), and pneumonia (7.5%), all resolved after glucocorticoid treatment. Regarding genetic mutations, the most frequently mutated genes were ASXL1 (34.0%), RUNX1 (30.2%), TET2 (17.0%), and U2AF1 (17.0%). Conclusion: To the best of our knowledge, this is the first study evaluating the efficacy and safety of the combination therapy with sintilimab and decitabine in previously untreated patients with higher-risk MDS. This regimen showed an encouraging anti-tumor activity with a manageable safety profile.

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Were Treated with Hypomethylating Agents (HMA)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction Recognition of the growing importance of genetic mutations in prognostication for pts with MDS prompted the development of IPSS-M to improve outcome prediction. Subsequent validation studies included a heterogenous groups of pts; treated & untreated pts with lower & higher risk (HR) disease, and thus the value of IPSS-M in predicting outcomes of pts with HR-MDS treated with HMA remains unclear. We aimed to evaluate the ability of IPSS-M to predict outcomes of pts with HR-MDS who were treated with HMA in a large multicenter cohort. Methods Using the multi-center VALIDATE database, we included pts with HR-MDS (Defined as IPSS score >1 or IPSS-R score > 3.5) who were treated with any HMA in the frontline setting and had available molecular data before HMA initiation. Time-to-event analysis used Kaplan-Meier estimator and the log-rank tests. Survival was measured from time of HMA initiation. We compared the different scoring systems by Harrell's c-index. Best response to HMA was assessed using the IWG 2023 response criteria in HR pts (n=480) who had a marrow evaluation within 180 days of HMA initiation. This study was supported by an independent research grant from AbbVie. Results A total of 925 pts were included in the analysis. Median age was 68 years (IQR: 62-75) and 66% of the pts were men. MDS excess blast 1/2 accounted for 65% of the diagnosis. Overall, 76% of pts were treated with HMA monotherapy (29% decitabine and 71% azacitidine), 24% received HMA combination therapy, and 39% of pts had HSCT. The most common mutations (MT) were TP53 (32%), ASXL1 (20%), TET2 (13%) and SRSF2 (12%); 36% of pts had MDS harboring >1 gene MT. As anticipated, the cohort was enriched with high risk (26%) and very high risk (46%) IPSS-R groups. According to pre-therapy IPSS-M, pts were classified into very low (2%), low (9%), moderate low (11%), moderate high (14%), high (29%) and very high (36%) risk groups. IPSS-M reclassified 54% of pts, of whom 184 (37%) were up-staged and 317 (63%) were down-staged. Specifically, 38%/21% of pts with intermediate risk IPSS-R MDS, and 30%/36% of pts with high risk IPSS-R MDS were up-staged/down-staged, respectively. In addition, 44% of pts with very high risk IPSS-R MDS were down-staged. The median follow-up time was 19 (IQR:10-35) months (mo). Median overall survival (OS) was 19 (95% CI: 17-22) mo. Overall, 35% of the pts progressed to AML during follow up. IPSS-M groups showed significant differences for both OS and LFS (p-value: <0.0001 for both). The median OS (mo, 95%CI) based on IPSS-M categories were: low (37, 25-62), moderate low (30, 23-47), moderate high (29, 22-35), high (17, 14-20), and very high (14, 12-15) (Panel A). The 3-year LFS (%) were: low (20%), moderate low (48%), moderate high (41), high (50%), and very high (59%). IPSS-M was significantly associated with OS in a multivariable model adjusted for age, sex, type of HMA, number of HMA cycles and receiving allogeneic HSCT (HR: 1.4, 95% CI:1.2-1.5). However, IPSS-M showed comparable performance when compared with the IPSS-R with c-index (95%CI): 0.599 (0.557-0.622) vs. 0.619 (0.560-0.641) for OS. In addition, IPSS-M showed similar performance for LFS: 0.583 (0.560-0.606) vs. 0.588 (0.565-0.610) (Panel B). When IPSS-M/IPSS-R were used as continuous scores, the c-indices (95%CI) for OS and LFS were: 0.617 (0.592-0.640) vs. 0.6400 (0.616-0.664) for OS and 0.598 (0.575-0.622) vs. 0.606 (0.581-0.632) for LFS. We then analyzed the performance of IPSS-R/IPSS-M in pts with HR MDS (IPSS ≥1.5). Both IPSS-R and IPSS-M had comparable performance for OS prediction (c-index:0.548 vs. 0.566) and LFS (0.551 vs. 0.538). Based on the proposed IWG 2023 response criteria, complete remission rate (CR)/ overall response rate (ORR) were 12/47%, 9/58%, 13/47%, and 17/57% of pts assigned to moderate low, moderate high, high, and very high IPSS-M risk groups. No significant association was observed between IPSS-M and ORR (OR: 1.1, p=0.475) or CR (1.1, p=0.286). Conclusions In our multi-center large cohort of pts with HR MDS treated with frontline HMA, IPSS-M significantly stratified pts for OS and LFS. However, when compared with IPSS-R, IPSS-M did not seem to substantially improve prediction of outcomes among HMA-treated pts. Our results emphasize the high predictive prognostic power of clinical features and cytogenetic alterations among HR-MDS pts treated with HMA.

Real-World Use of Hypomethylating Agents (HMA)/Venetoclax Combinations in Patients with Myelodysplastic Neoplasms (MDS) in the Arabian Gulf Region

Context: Retrospective data thus far has supported improved responses with HMA/venetoclax combinations in both the frontline and relapsed settings. A Phase Ib trial of azacitidine and venetoclax for high-risk MDS patients demonstrated an overall response rate (ORR) of 80%. Retrospective data from the Moffitt Centre comparing HMA/venetoclax to patients who received HMA showed an ORR of 77% compared to 40% for patients who only received HMA. Objectives: Our aim was to obtain real-world evidence for use of combination HMA/venetoclax to treat myelodysplastic patients in the Arabian Gulf region. Methods: This is a retrospective study of patients with myelodysplastic neoplasm treated with a HMA/venetoclax in 4 different countries from Jan 2020 - May 2023. Cases were included if they were over the age of 18, and had a diagnosis of MDS or MDS/AML. Both frontline and relapsed/refractory patients were included. Patients were excluded if they had more than 20% blasts or received an additional agent with their treatment. Results: Data on 16 patients was collected across 4 centres in the Arabian Gulf. The median age was 66 (range 51-84). All patients had high-risk MDS, MDS/AML including four patients with a TP53 mutation and/or complex cytogenetics. Median follow-up was 15 months (range 4-23). A median of 6 cycles were received (range 3-14). Azacitidine was the only HMA used at a starting dose of 75mg/m 2 for 7 days. Venetoclax starting dose was 400mg (or equivalent if given with an azole) and given for a median of 15 days (range 10-28). Thirteen patients received azole prophylaxis. Thirteen patients achieved a CR/CRi (81%), one patient who didn't had a TP53 mutation with complex cytogenetics, another had secondary MDS, and the third had stable disease and proceeded to transplant. Overall survival (OS) at 12 months was 86.2% (95% CI 55.0-96.4). For patients with poor risk disease (TP53 or complex cytogenetics) OS was 66.7% (95% CI 5.4-94.5) vs 90.9% (95% CI 50.8-98.7) for non-poor risk patients; p=0.006. Median OS was 22 months (22-NR) for non-poor risk patients compared to 14 months (10-NR) for poor risk patients. Event-free survival (failure, transformation or relapse) at 12 months was 84.6% (95% CI 51.2-95.9); it was 90.0% (95% CI 47.3-98.5) for those with no poor risk features and 66.7% (5.4-94.5) for those with poor-risk features; p=0.027. For those who stopped, 4/16 stopped due to failure and disease progression or transformation, 4/16 underwent stem cell transplantation, 3 stopped due to infectious complications, two from drug access issues, and one patient with secondary MDS had recurrence of their primary solid tumour. The most common toxicities were cytopenias and one patient died from cellulitis and COVID while on HMA/venetoclax. Conclusion: The combination of HMA/ venetoclax is a feasible treatment for patients with high-risk MDS with significantly worse outcomes in patients with complex cytogenetics and/or TP53 mutations. This regimen seems to be adapted by many hematologists in our region. However, the long-term efficacy in comparison to standard of care for various subgroups of MDS needs to be explored in larger prospective studies

A Phase Ib/II Study Evaluating Navitoclax after Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome

BACKGROUND AND SIGNIFICANCE Myelodysplastic syndrome (MDS) is a heterogeneous group of blood cancers of myeloid progenitor cells. They vary widely in genetic landscape, risk of progression to acute myeloid leukemia, and risk of death, as predicted by the revised international prognostic score (IPSS-R). The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) are the standard of care for treatment of high risk (HR)-MDS, however complete response rates are <15% and most patients (pts) eventually progress. Outcomes after HMA failure are dismal. Defective apoptosis is a major feature of MDS. Increased expression of anti-apoptotic members of the BCL-2 family (BCL-2, BCL-X L and BCL-W) correlates with disease progression and poor outcomes. The addition of venetoclax (VEN), a selective BCL-2 inhibitor, has shown benefit when added to AZA in pts with relapsed or refractory (R/R) MDS (Zeidan, et al., AJH, 2023). However, patterns of BCL-2 family proteins are heterogeneous and response to inhibition of BCL-2 family proteins depends on the balance of pro- and anti-apoptotic proteins. Navitoclax (NAV) is a broad oral inhibitor of BCL-2, BCL-X L, and BCL-W. Increased expression of BCL-X L has been shown to make MDS cells insensitive to VEN. Further, VEN-resistant myeloid cell lines derived by prolonged VEN exposure showed up-regulation of BCL-X L, driving acquired drug resistance in these cell lines. Thus, the addition of NAV to the combination of VEN and HMA is a logical strategy to induce response in pts with R/R after HMA with or without prior VEN exposure. STUDY DESIGN AND METHODS We will perform a phase Ib/II, dose escalation and expansion study to evaluate escalating doses of NAV in combination with standard dose VEN and DEC in pts with R/R HR-MDS after failure of HMA (NCT05564650). The primary objective of the phase Ib portion of the study will be to evaluate the safety profile and determine the recommended phase II dose (RP2D) of NAV in the combination. The primary objective of the phase II portion of the study will be to evaluate the efficacy of combination therapy NAV/VEN/DEC in pts with R/R HR-MDS after failure of HMA/VEN. During cycle 1, to limit the risk of tumor lysis, pts will be treated with a short dose ramp-up with VEN 200 mg daily on day 1 and 400 mg daily on days 2-16, DEC 20 mg/m2 on days 3-7 and NAV 25 mg, 50 mg or 100 mg daily on days 3-16 during cycle 1. During cycles 2 and beyond, dosing will be similar to cycle 1 without dose ramp-up ( Figure 1). We will employ the Bayesian optimal interval (BOIN) design to identify the maximum tolerated dose and RP2D of NAV. Subsequently, the study will proceed to phase II to further evaluate the safety and efficacy of the combination. The study will enroll pts with IPSS-R ≥3 who have been previously treated with HMA/VEN. Pts in the phase I portion of the trial may be enrolled if they have not received VEN. Pts must have adequate performance status and organ function. Pts with a WBC >25,000 cells/µL and those taking prohibited medications will be excluded. Correlative studies will be performed to determine the impact of treatment on molecular targets and will include profiling of BCL-2 family members and single cell gene expression patterns pre- and post-treatment and at relapse. Pts who achieve a complete response (CR) or modified CR (mCR) will continue on the study until disease progression, dose limiting toxicity, availability of an alternative therapy or withdrawal of consent. Pts who have hematologic improvement but who do not attain CR or mCR can continue the study at the discretion of their treating physician in conjunction with the primary investigator.

Long-Term Follow-up and T Cell Characteristics of Patients with ASXL1-Mutated Relapsed or Refractory MDS or CMML Treated with Guadecitabine and Atezolizumab

Background Treatment of patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) after failure of a hypomethylating agent (HMA) remains an unmet need. We and others demonstrated a modest overall response rate (ORR) to the combination of immune checkpoint inhibition (ICI) and an HMA in such patients; a promising overall survival (OS) compared to historical data (5-6 months) was seen in some, but not all, studies. Our study and that of Daver et al. suggested that patients with ASXL1 mutations, in particular, may benefit from the addition of ICI. We conducted a Phase I/II clinical trial evaluating the addition of a programmed death ligand 1 (PD-L1) inhibitor, atezolizumab, to a subcutaneous prodrug of the HMA decitabine, guadecitabine. We evaluated the presence of common driver mutations in CD3- bone marrow mononuclear cells (BMMC) and CD3+ T lymphocytes. Among 27 tested patients, 12 had the ASXL1 mutations in the myeloid compartment and, of those, 5 patients' T cells carried the exact same mutation at a variant allele frequency (VAF) of >10%. Both patients with complete remission in the study (n=2) carried the mutation in both compartments (co-mutated) and median OS was significantly better for co-mutated patients (not reached) than for those with CD3- BMMC (myeloid) mutations (9.5 months) or wild type ASXL1 (16.5 months). Herein we report long-term follow-up of this cohort of patients, along with T cell programmed death-1 (PD-1) expression analyzed based on mutational status. Methods Details of the trial design and correlative plan are published. In the published study we used a VAF cutoff of 2% (1% for TP53) for BMMC and 10% for CD3+ T lymphocytes for the panel of 40 commonly mutated genes. In the current study we also evaluated patients with a T cell ASXL1 VAF of 5-10%. Patients have been followed for progression and survival every 6 months. Demographic and disease characteristics and outcome data were compared based on ASXL1 mutation status. Previously obtained T lymphocyte PD-1 expression data from samples obtained pre-treatment (PRE), during cycle 2 (EARLY) and after cycle 3 or 4 (LATE) were analyzed based on ASXL1 mutation status. Results Among 27 patients from 4 centers with DNA available for genetic analysis, 15 had no ASXL1 mutation ( ASXL1 WT), 5 had ASXL1 mutations restricted to the myeloid lineage, and 7 had ASXL1 mutations in both the myeloid and T-cell populations ( ASXL1 co-mutated). Two co-mutated patients had T cell VAFs of 5-10% and 5 had VAFs>10% (Figure 1). No baseline characteristic by ASXL1 mutational status was significantly associated with response to study treatment, though 6 of 7 co-mutated patients (vs 3/5 myeloid-only patients) had not responded to first-line HMA (refractory). With a median follow-up time of 64.9 months, median survival times were 48.9 months (15.1, 64.9+) for co-mutated patients with T cell VAF >10%, 34.9 months (8.5, NR) for co-mutated patients including those with T cell VAF of >5%, 16.4 months (3.3, 27.3) for ASXL1 WT patients, and 9.5 months (2.1, 35) for myeloid-only patients (Figure 2). This was statistically significant after adjusting for age and ECOG performance status at study entry, diagnosis, baseline bone marrow blast percentage, and number of prior chemotherapy regimens using the likelihood ratio test from multivariate analysis for overall survival (P = 0.008). Early treatment-induced upregulation of CD8 + T cell PD1 was observed in the ASXL1 WT, before returning to baseline levels. This upregulation was more pronounced in the ASXL1 co-mutated group beginning at a lower baseline and peaking at a higher MFI and was statistically significant (P = 0.0098). No significant treatment-induced change in PD-1 expression was noted in the myeloid-only subset. Discussion In patients with relapsed or refractory MDS or CMML, the presence of an ASXL1 mutation in both myeloid and T lymphocyte compartments, as compared to WT or myeloid-only mutations, was associated with a significantly longer median OS when treated with the combination of ICI and HMA. Significant upregulation of PD-1 was noted in T lymphocytes from both wild-type and co-mutated patients. The effect of mutant ASXL1 on T cell responsiveness to ICI deserves further investigation; patients with ASXL1-mutated HMA-refractory myeloid malignancies may benefit from ICI.

Venetoclax (VEN) Improves Response Rates but Not Survival in Patients with Chronic Myelomonocytic Leukemia (CMML) Treated with Hypomethylating Agents (HMA): A Multicenter, Propensity Score Analysis

Introduction HMAs are the only approved therapy for CMML. In order to improve response rates and survival, the addition of VEN has been utilized in both CMML and after blast transformation (CMML-BT) with conflicting results in small single center studies. To clarify the role of upfront HMA+VEN in CMML and CMML-BT, we performed a large multicenter analysis. Methods We included patients with HMA-naïve CMML and CMML-BT treated with combination HMA and VEN from 4 academic centers. The primary outcome was overall survival (OS) with secondary outcomes including overall response rate (ORR) by 2015 MDS/MPN IWG criteria for CMML and 2022 ELN criteria for CMML-BT. To better appreciate the benefit of adding VEN to HMA treatment, we also performed 1:1 propensity score matched (PSM) analysis of patients treated with HMA alone as upfront therapy for CMML or CMML-BT. Matching was based on age, sex, ECOG performance status, CPSS-Mol, blood counts, peripheral and bone marrow blasts. Results Eighty-nine patients were treated with frontline HMA+VEN, 51 CMML and 38 CMML-BT (5 had received HMA alone for prior CMML). The median age was 71 years, 70% were male, and 83% had ECOG 0-1. Among CMML patients, 55% had MP-CMML subtype, 65% had CMML-2 and 12%, 30%, 58% were CPSS-mol intermediate-1, intermediate-2 and high risk, respectively. In the entire cohort, ASXL1 (63%), TET2 (47%), SRSF2 (39%) and RUNX1 (27%) were the most commonly mutated genes and 55% of patients harbored a RAS mutation ( KRAS [20%], NRAS [18%], CBL [13%], NF1 [11%], PTPN11 [9%]). For HMA combination partner, 46 (52%) were treated with azacitidine, 35 (39%) with decitabine, and 8 (9%) with both during their VEN course. During a median follow-up time of 15.8 months (mos) 52 patients (58%) died: 23 (45%) with CMML and 29 (76%) with CMML-BT. Among CMML patients, the ORR was 90%, including complete remission (CR) in 22%, complete cytogenic remission (CCR) in 4%, optimal marrow response (CMR) in 50%, and partial marrow response (PMR) in 6%. The OS of CMML patients was 25.1 mo (95% CI 15.7 - NR). A PSM population of HMA patients matched to HMA+VEN treated patients showing similar baseline characteristics. ORR was significantly higher with HMA+VEN (95%) as compared those treated with HMA alone (46%), p < 0.001. However, there was no significant OS difference between HMA+VEN vs HMA alone (19.1 mos vs 19.1 mos, p = 0.85, Figure 1). For CMML-BT patients, the ORR of HMA+VEN was 81% including CR in 17%, CR with partial hematologic recover (CRh) in 3%, CR with incomplete hematologic recovery (CRi) in 28%, morphologic leukemia-free state (MLFS) in 22% and partial response (PR) in 11%. The OS of CMML-BT patients was 8 mos (95% CI 4.6 - 26.2). A PSM population of CMML-BT patients treated with HMA alone showed a significantly increased ORR with HMA+VEN (82% vs 40%, p = 0.039). However, there was no difference in OS (7.49 mos vs 9.26 mos, p = 0.83, Figure 2). Among HMA-VEN treated patients, achievement of a CR was associated with an improved OS in the CMML (HR 0.31, 95% CI 0.13 - 0.75) and CMML-BT (HR 0.37, 95% CI 0.19 - 0.74). No predictors of response were identified, including the presence of a RAS mutation. In terms of safety, 7 patients (7.9%) had a grade 3/4 (G3/4) neutropenic infection and 2 patients (2.2%) had a G3/4 hemorrhagic event while being treated with HMA+VEN. A total of 29 patients went on to receive allogeneic transplant (alloSCT): 22 (43%) with CMML and 7 (18%) with CMML-BT. CMML patients who underwent alloSCT after HMA+VEN were younger as compared to non-transplanted patients (64 vs 74 years, p < 0.0001), but had otherwise similar baseline characteristics including stage, CPSS-mol category and prevalence of RAS mutations. Similarly, CMML-BT patients bridged to alloSCT were younger (66 vs 74 years, p < 0.002) and had a better ECOG performance status (p = 0.047). Of patients who received alloSCT, 10 patients (34%) died, 5 with CMML and 5 with CMML-BT. The median OS after alloSCT was 26.7 mo. Conclusions Although the use of VEN with HMA in the upfront treatment of CMML and AML secondary to CMML results in higher response rates compared to HMA alone, this combination does not improve survival based on this multi-center PSM analysis. The current sample size of CMML-BT may limit detection of OS differences between treatment groups. The role of VEN to reduce blasts and serve as a bridge to alloSCT, particularly after HMA failure, requires further investigation in larger studies in both the CMML and CMML-BT populations.

AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.

Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax+HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60days of therapy. Infections were confirmed as the most common nonhematologic adverse event. Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax+HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax+HMA effectiveness and toxicities in real life.

The Impact of Maintenance Therapy Post Allogeneic Hematopoietic Cell Transplantation on Survival Outcomes in Patients Diagnosed with Acute Myeloid Leukemia and Persistent Measurable Residual Disease: A Retrospective Cohort

Background: Despite achieving complete remission with standard chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), patients with acute myeloid leukemia (AML) are still at high risk of transplant failure due to disease relapse. Maintenance therapy post allo-HSCT including hypomethylating agents or FLT3 inhibitors is implemented in our institutional guidelines to mitigate this risk. Moreover, measurable residual disease (MRD) status of patients is considered an important independent marker of disease prognosis, in which a detectable MRD status pre-transplant is associated with poorer long-term outcomes. Objective: The aim of this research is to evaluate the impact of maintenance therapy post allo-HSCT on the survival outcomes of transplanted patients based on their pre-transplant MRD status. Methods: We performed a retrospective chart review for a total of 108 adult patients diagnosed with AML and who had undergone allo-HSCT at our center between 2015 and 2021. We estimated both overall survival (OS) and relapsed free survival (RFS) using Kaplan Meier curves from the time of transplant among patients who received maintenance treatment based on their MRD status pre-transplant. MRD status was determined using either multiparametric flow cytometry, next-generation sequencing, and/or RT-PCR. Results: The median age at transplant was 47 years, 60% (n=65) of the patients were males. 66.7% of the patients had an intermediate disease risk index score. 25.2%, 61.8% and 13% of the patients had favorable, intermediate and adverse ELN risk respectively. Among the 108 patients, 77 received maintenance therapy post-transplant, of which 36 patients had a detectable pre-transplant MRD and 41 patients did not. Maintenance therapy consisted mainly of low dose hypomethylating agent (HMA) azacitidine in 68.8% (n=53) of the patients, followed by tyrosine kinase inhibitors (TKI) in 18.2% (n=14) of the patients, and a combination of HMA with TKI, and/ or a BCL2 inhibitor in 13% (n=10). Median duration of maintenance was 20.7 months (range: 0.1-84.2 months). Among patients who received maintenance therapy (n=77), there were no statistically significant difference in both OS and RFS based on MRD status pre-transplant, (4-year OS: 76% versus 63%, p=0.6; 4-year RFS: 63% versus 57%, p=0.53). Conclusions: Our analysis showed no significant difference in survival outcomes of patients receiving maintenance therapy post allo-HSCT based on their pre-transplant MRD. Maintenance treatment could overcome the negative predictive value of detectable MRD to be confirmed by larger prospective studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes Following Hypomethylating Agent / Venetoclax Combination-Therapy for MDS or AML Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the consolidation therapy with the highest chance of sustained remission for most patients (pts) with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse occurs in up to 40% of pts and adversely affects prognosis. Currently, post-HSCT relapse strategies include intensive chemotherapy, hypomethylating agents (HMA), as well as targeted therapy, e.g. FLT3-inhibitors frequently combined with donor lymphocyte infusions (DLIs). Here we investigated combinations of HMA and venetoclax (VEN) as salvage options for relapse after alloHSCT. Methods: 2 MDS and 24 AML pts (median age 60 [range 38-73] years) relapsed after a median of 6.2 (range 1.6-55.5) months (mo) after 1st (n=22) or 2nd (n=4) HSCT. Conditioning regimens were myeloablative (n=5) or non-myeloablative (n=21). Remission status at HSCT was composite complete remission (CRc; including CR, CR with incomplete recovery [CRi] and morphologic leukemia free state [MLFS]; 50%), partial remission or stable disease (12%), and refractory (38%). While 22 pts had hematological relapse, 4 pts showed either combined (n=3) or sole (n=1) extramedullary disease. All pts subsequently received HMA/VEN-based therapies (azacitidine/venetoclax [n=22], azacitidne/venetoclax/gilteritinib [n=3] or decitabine/venetoclax [n=1]) with concomitant DLI in 13 pts. Prior to HMA/VEN, 13 pts received a different relapse therapy including azacitidine [n=7], gilteritinib [n=2], radiation [n=1], an investigational therapy with an IRAK4 inhibitor [n=1], or a combination therapy with azacitidine and pevonedistat [n=1] or tagraxofusp [n=1]. European LeukemiaNET 2022 risk at the timepoint of relapse was favorable (n=2), intermediate (n=4) or adverse (n=20). Median follow-up since HMA/VEN start was 6.4 mo. Results: HMA/VEN was well tolerated and administered in an outpatient setting in 20/26 pts (77%). The most common adverse effects were expected and included neutropenia CTCAE 3/4° in 25/26 pts (96%) and thrombocytopenia CTCAE 3/4° in 22/26 pts (85%). Eight pts (31%) developed at least one episode of febrile neutropenia. Four pts (15%) showed signs of afebrile infections and were hospitalized. Thirteen pts (50%) achieved a CRc (CR [n=3], CRi [n=8], MLFS [n=2]) under HMA/VEN therapy (Figure 1A), with a median time to 1st and best morphological response of 1.0 and 2.1 mo, respectively. Later relapse (>12 mo after HSCT) and a lower number of prior therapies before HMA/VEN (≤2 vs. >2 lines) associated with improved outcomes (cumulative incidence of achieving a CRc: P=.004 and P=.04, and OS: P=.02 and P=.02, respectively). Six of 13 pts (46%), who received a prior non-HMA/VEN therapy for the current relapse achieved a CRc after switching to HMA/VEN. Pts achieving a CRc had a significantly longer OS compared to pts with no CRc (P=.002; Figure 1B). Of the pts with CRc, 7 continued HMA/VEN with a median response duration of 7.2 mo (6/7 pts are still on treatment at last follow-up), 5 received a 2nd HSCT and 1 an experimental CART-therapy. For those that could be bridged to a 2nd HSCT outcomes were beneficial with 4/5 pts (80%) alive and disease-free (median follow-up since 2nd HSCT: 4.3 months). One patient with CART-therapy suffered from a 2nd relapse 1.7 months after treatment and is currently again salvaged with HMA/VEN. Two of 13 pts (15%) died after initial CRc, 1 due to non-relapse mortality of a 2nd HSCT and 1 by losing treatment response. Of the 13 pts who did not achieve a CRc, 1 patient could be bridged to 2nd HSCT with a post-HSCT relapse free survival of 12 mo. In the remaining 12 non-CRc pts median OS since start of HMA/VEN was 2.9 mo (range 0.7-6.5 mo) and 9/12 pts (75%) died due to progressive disease. Regarding the molecular risk profile, none of the TP53 mutated pts (n=3) responded, whereas pts with IDH1/2, NPM1, or myelodysplasia-related gene mutations, i.e.ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2, had mixed responses (2/5 pts [40%], 1/3 pts [33%], and 8/15 pts [53%], respectively). Conclusion: HMA/VEN is a promising and well tolerated treatment strategy for MDS and AML pts relapsing after HSCT with a CRc of 50% and potential long-term survival. Especially pts that could be bridged to a 2nd HSCT benefited from the treatment. However, in pts with a disease resistant to HMA/VEN, outcome was very poor with a median OS of only 2.9 mo. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MDS-407 Disease Characteristics and Outcomes of Hypomethylating Agent Failure in Patients With Myelodysplastic Syndromes

Hypomethylating agents (HMA) improve cytopenias and delay progression of myelodysplastic syndromes (MDS), but most patients eventually lose their response. Although patients with HMA failure (HMA-F) pose significant treatment challenges with dismal outcomes, the clinicopathologic characteristics of MDS patients at the time of HMA-F are still poorly understood. We retrospectively evaluated 135 untreated patients with MDS diagnosed between 2017-2021 who later developed HMA-F. Pt characteristics, laboratory values, and bone marrow (BM) data, including cytogenetics and next generation sequencing, were assessed at both diagnosis and the time of HMA-F. The median age was 70 at diagnosis, with therapy-related MDS (t-MDS) in 39%. Most patients had higher-risk MDS with IPSS-R high (30%) or very high (42%) disease, and complex karyotype was seen in 47%. The median number of mutations identified was 2 with TP53 (46%) and ASXL1 (21%) the most frequently discovered mutations. Regarding treatment, 67% received HMA monotherapy and 33% received HMA in combination with various agents. The median number of cycles of HMAs received was 7 (range: 1-37). At the time of HMA-F, patients presented with higher BM blasts (p<0.001), lower platelet counts (p<0.001), and more cytogenetic abnormalities (p=0.002) and mutations (p<0.001) than at diagnosis. The median time from diagnosis to HMA-F was 10.6 mo, and the median overall survival (mOS) from HMA-F was 6.5 mo. Survival was well-stratified by both IPSS-R at diagnosis (p=0.066) and at HMA-F (17.8 mo in lower-risk vs 3.8 mo in higher-risk MDS, p<0.001). There was no difference in mOS from HMA-F by number of HMA cycles, response to HMA, and treatment regimen at HMA-F; however, in patients with higher-risk MDS, stem cell transplantation (p<0.001) was associated with improved mOS and upfront HMA combination therapy (p=0.008) with inferior survival. Patients with HMA-F MDS have high-risk features which are often therapy-related. At the time of HMA-F, patients present with higher BM blasts, worsening thrombocytopenia, and more genomic aberrations. Unfortunately, after failure of HMA, patients have poor prognosis. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy.

The combination of the IAP antagonist, tolinapant and hypomethylating agents (HMA) is highly synergistic in in vitro models of T-cell lymphoma (TCL).

e15088 Background: Peripheral T-cell lymphoma (PTCL) are a highly aggressive and heterogeneous group of non-Hodgkin lymphomas that often carry a poor prognosis with standard chemotherapy. Tolinapant is a potent antagonist of inhibitors of apoptosis proteins (cIAP1/2 and XIAP). In a phase 2 trial (NCT02503423), tolinapant showed activity against heavily pre-treated patients with TCL. We explored the sensitivity of a range of TCL lines to tolinapant, established the synergy coefficient and interrogated the mechanism of synergy between tolinapant and drugs active against PTCL including romidepsin, pralatrexate, and the HMAs; azacytidine and decitabine. Methods: A panel of 10 human TCL lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10 ng/ml of TNFα. For combination studies, each drug was tested, in the presence or absence of TNFα. Synergy coefficient was calculated using Excess over Bliss. Additionally, the on-target effects of the drugs were measured by analyzing levels of the IAPs, acetylated histones, DNMTs and key apoptosis and necroptosis markers by Western blotting. Results: TCL Lines demonstrated varying sensitivities to tolinapant with the most sensitive cell line, ALK+ ALCL SUP-M2, having an IC50 as low as 20 nM ± 1 nM while a resistant CTCL cell line HH had an IC50 of over 20 µM. In combination experiments using both cell lines, tolinapant plus azacytidine or decitabine displayed the highest degree of synergism, compared to romidepsin or pralatrexate. Of note, a high degree of synergism was also seen with concentrations 10 folds lower of azacytidine or 100 folds lower of decitabine, added daily (Table). The combination of tolinapant and the HMAs led to a decrease in the levels of cIAP1 and DNMT3a in TCL lines, demonstrating on-target activity of tolinapant and the HMAs, respectively. In addition, both azacytidine and decitabine increased the levels of RIPK3 and MLKL by western blot analysis, indicating activation of the necroptosis pathway. Conclusions: Tolinapant has demonstrated varying cytotoxic effects against a range of TCL lines as a monotherapy and displays a very high degree of synergism in combination with the HMAs, azacytidine and decitabine, also at low concentration, in vitro. The HMAs were also able to activate the necroptosis pathway, providing a possible mechanism for the high degree of synergism displayed when combined with tolinapant in the TCL lines in vitro. These data provide the rationale to initiate phase I trials with the combination of tolinapant and HMAs. Average synergy scores at 48 hrs for drugs used in combination with tolinapant in a CTCL line HH and ALK+ ALCL line SUP-M2. Above 10 indicates synergy.[Table: see text]