Hypomethylating Agent Monotherapy Research Articles

Hypomethylating agent monotherapy in core binding factor acute myeloid leukemia: a French multicentric retrospective study

Very few data are available about hypomethylating agent (HMA) efficiency in core binding factor acute myeloid leukemias (CBF-AML). Our main objective was to evaluate the efficacy and safety of HMA in the specific subset of CBF-AML. Here, we report the results of a multicenter retrospective French study about efficacy of HMA monotherapy, used frontline or for R/R CBF-AML. Forty-nine patients were included, and received a median of 5 courses of azacitidine (n = 46) or decitabine (n = 3). ORR was 49% for the whole cohort with a median time to response of 112 days. After a median follow-up of 72.3 months, median OS for the total cohort was 10.6 months. In multivariate analysis, hematological relapse of CBF-AML at HMA initiation was significantly associated with a poorer OS (HR: 2.13; 95%CI: 1.04–4.36; p = 0.038). Responders had a significantly improved OS (1-year OS: 75%) compared to non-responders (1-year OS: 15.3%; p < 0.0001). Hematological improvement occurred for respectively 28%, 33% and 48% for patients who were red blood cell or platelet transfusion-dependent, or who experienced grade 3/4 neutropenia at HMA initiation. Adverse events were consistent with the known safety profile of HMA. Our study highlights that HMA is a well-tolerated therapeutic option with moderate clinical activity for R/R CBF-AML and for patients who cannot handle intensive chemotherapy.

Outcomes of intermediate or high-risk CMML patients treated with hypomethylating agents combined with venetoclax: A single center experience.

Chronic myelomonocytic leukemia (CMML) treatment remains a pressing clinical challenge. We conducted a retrospective analysis on 52 CMML cases, exploring the effectiveness of combining venetoclax (Vene) with hypomethylating agents (HMAs). The study's findings show promise: the HMAs plus Vene group (n = 13, 53.8%) demonstrated superior overall response rates compared to the HMA monotherapy (mono) group (n = 19, 31.6%) and HMA plus arsenic trioxide group (n = 9, 22.2%) by the second cycle, and notably higher response rates (53.8% vs. 15.7%, p = 0.04) compared to the HMA mono group after four cycles. Over a median follow-up of 14.7 months, the HMAs plus Vene group exhibited significantly lower cumulative mortality (23.1%) compared to the other two groups (p = 0.003 and p = 0.008, respectively). Furthermore, this group displayed extended overall survival compared to the others. The study also delved into the molecular mechanisms, revealing significant BCL2 mRNA overexpression in patients with CMML. These findings suggest the potential for HMAs combined with Vene therapy in CMML but emphasize the necessity for further prospective studies to determine its precise role in managing CMML.

Clinical Implications of TP53 Mutations/Allelic State in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Treated with Hypomethylating Agents (HMA)- a Multicenter, Retrospective Analysis from the Validate Database

TK and JPB Co-first; RK, DS, and AMZ are Co-senior authors. Introduction MDS with TP53 mutations ( TP53 MT) are associated with high-risk disease features and rapid progression to AML. Effective treatment for this aggressive subtype is still not available. As compared to monoallelic TP53 MT, biallelic MT have been associated with adverse outcomes and worse overall survival (OS), but the impact of allelic status on treatment response and OS after HMA therapy are not well established. In this study, we analyzed TP53 allelic state for a large well annotated cohort of pts with MDS who were treated with HMAs. Methods The VALIDATE database includes pts with MDS treated with frontline HMA from 14 specialized centers. Pts were considered to have biallelic TP53 MT according to the ICC definition (Arber et al. 2022, Blood) if they meet any of the following: a. two TP53 MT (variant allelic frequency [VAF]&amp;gt;10% for each) b. single TP53 MT with copy neutral loss of heterozygosity (CN-LOH, available for 308 pts) c. TP53 MT with del17p and d. Single TP53 MT with VAF &amp;gt;50%. Time to event analyses were estimated using Kaplan-Meier estimator and groups were compared by the log-rank test from the time of HMA initiation. Only higher risk (HR)-MDS pts (IPSS&amp;gt;1 or IPSS-R&amp;gt;3.5) with BM biopsy within 180 days after HMA initiation were assessed for complete response (CR) and overall response rate (ORR) according to the IWG 2023 criteria (Zeidan et al, Blood 2023) (n=480). OS was calculated from time of HMA therapy initiation. This study was supported by an independent research grant from AbbVie. Results A total of 816 pts met eligibility and were included in this analysis. Median age was 68 years (IQR: 61-74) and 64% were men. MDS excess blast (EB) 1/2 was the most common MDS subtype (62%). Overall, 78% of the pts were treated with HMA monotherapy (26% decitabine [DEC] and 74% azacitidine [AZA]) and 22% received HMA as part of combination therapy. In total, 40% of the pts underwent allogenic HSCT. Median HMA treatment time was 5 months (mo), IQR:3-11. Median follow up time was 17 mo (IQR:9-31). TP53 MT were detected in 253 pts (31%) at time of MDS diagnosis, of whom 153 (60%) pts had biallelic TP53 MT and 100 (40%) pts had monoallelic TP53 MT. Missense MTs were identified in 80% of pts with monoallelic TP53 MT. TP53 MT/del17p (33%), TP53 MT/CN-LOH (28%), and multiple TP53 MT (25%) were the most common combinations in pts with biallelic TP53 MT. Pts with TP53 MT had higher rates of MDS-EB (74% vs. 61%, p&amp;lt;0.001). Complex karyotype was observed in 112 (73%) pts with biallelic TP53 MT and 81 (81%) pts with monoallelic TP53 MT (p=0.154). Median number of HMA cycles among pts with TP53 MT was 8 (IQR:5-12) and higher compared to pts without TP53 MT (5 cycles, IQR:3-9), p=0.032 ( Panel-A). In a logistic regression model for CR, TP53 MT was not associated with probability of achieving CR (1.4, 0.89-2.29). CR rates for pts with biallelic TP53 MT (18%) and monoallelic TP53 MT (14%) were not significantly different, p=0.37. There were also no significant differences in ORR observed between biallelic TP53 MT (59%) and monoallelic TP53 MT (54%) pts, p=0.39. Among TP53 MTpts treated with HMA monotherapy, pts treated with AZA compared to DEC had similar odds for ORR (OR:1.1, 95%CI: 0.7-1.6)/CR (OR: 0.8, 95%CI: 0.4-1.3) and hazard for OS (HR: 1.1, 0.9-1.4). As expected, the median OS (mo, 95%CI) for pts with TP53 MT (12, 10-13) was significantly lower than pts without TP53 MT (28, 25-31), p&amp;lt;0.001. Importantly, pts with biallelic TP53 MT (11, 9-14) had no significant difference in median OS compared to monoallelic TP53 MT (13, 11-17), p=0.268 (Panel-B). In a multivariable cox proportional hazard regression model for OS (hazards ratio, 95%CI) adjusted for age (1.0, 0.9-1.0), HSCT (0.4, 0.3-0.4), IPSS-M score (1.2, 1.1-1.3), and complex karyotype (1.4, 1.1-1.8), TP53 MT status (1.8, 1.4-2.3) was still associated with OS. However, biallelic TP53 MT had comparable risk to monoallelic TP53 MT (1.2, 0.9-1.7). Conclusions To our knowledge, VALIDATE is the largest database of MDS pts with TP53 MT who were treated with HMA. We confirm that TP53 MT have significant negative impact on survival, but not on response to HMA therapy. Importantly, we did not observe OS differences between monoallelic and biallelic TP53 MT. We also show that the type of HMA monotherapy used does not impact outcome of these pts. Overall, pts with TP53 MT have very poor outcomes and are in desperate need of new, effective therapies.

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 &amp; untreated pts with lower &amp; 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 &amp;gt;1 or IPSS-R score &amp;gt; 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 &amp;gt;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: &amp;lt;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.

Acute Myeloid Leukemia in Elderly, Unfit Patients: Analysis of Turkish AML Prospective Registry Database, on Behalf of Acute Leukemia Working Group of Turkish Society of Hematology

Objective: Low dose Ara-C and hypomethylating agents (HMAs) - decitabine (DEC) and azacitidine (AZA) - have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs demonstrated efficacy in monotherapy and in combination with targeted therapies. We analyzed the outcomes of elderly and unfit patients with newly diagnosed AML in our population. Methods: Analyses of our database revealed 222 eligible AML patients from diagnosed between January 2013 to December 2020. All patients were received low intensity treatments including AZA +/- venetoclax, DEC and low dose Ara-C. The effects of cytogenetic risk group, response rate, treatment type on overall survival (OS) and PFS (progression-free survival) were evaluated. Survival analyses were performed with the Kaplan-Meier method and log-rank test. A p-value of &amp;lt;0.05 was considered statistically significant. Results: Median age was 73 years (51-89). Eastern Cooperative Oncology Group (ECOG) performance score was &amp;lt;2 and ≥2 for 75 patients (36.8%) and 147 patients (63.2%), respectively. Of the patients 8.2% had favorable, 76.9% intermediate and 15.0% adverse risk according to European Leukemia Network (ELN) risk classification. Extramedullary involvement was present in 4.5%. Low dose treatment regimens included AZA in 119 patients (53.6%), DEC in 38 (17.6%), low dose ARA-C in 26 (11.7%) and AZA + venetoclax in 39 (17.1%). Complete remission was achieved in 61 patients (27.5%), whereas 39 patients (17.6%) had partial remission (PR) and 64 (28.8%) had stable/progressive disease (SD/PD). Overall response rate was 48.1%. CR rate was higher with AZA + venetoclax (44.7%, p=0,005) and other regimens had similar outcomes. Median OS was 10.3 months. No significant difference difference in PFS was observed between the regimens. However, the lowest PFS was observed with low-dose Ara-C (p=0.33). ELN risk groups revealed no significant effect on PFS and OS (p=0.77 and p=0.82, respectively). Infections were the most common cause of death (42.7%). Conclusions: The prognosis of AML in the elderly remains poor. HMA monotherapy is effective among elderly and unfit patients. However, combination therapies may be more effective and safe. The incorporation of targeted therapies may provide additional benefit in this patient group. However, the accessibility of several novel targeted drugs is still very limited in many countries.

Outcomes of Patients with Accelerated/Blast-Phase MPNs That Received Allogeneic Stem-Cell Transplant in the Current Era of Myeloid Therapies

Background Patients (pts) with Philadelphia chromosome-negative (Ph-neg) myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have a median overall survival (mOS) of less than 1 year (Odenike, Blood 2018; Tam et al, JCO 2009). Allogeneic hematopoietic stem cell transplant (allo-HCT) is the only curative approach for MPN-AP/BP, but mOS remains about a year for pts with MPN-BP that undergo allo-HCT (2005-2019) (Orti et al, AJH 2023). We previously reported on outcomes of pts with MPN-AP/BP treated in the current era of myeloid therapies (2017 onward) and found a mOS of 0.73 years in a multi-center cohort of 80 pts (Patel et al, ASH 2022). We aim to characterize treatment patterns and outcomes of pts with MPN-AP/BP that underwent allo-HCT via a multi-center retrospective analysis. Methods Retrospective chart review was performed at 8 institutions to identify pts with pathology-confirmed Ph-neg MPN-AP/BP diagnosed in 2017 or later. All patients that met inclusion criteria were included. Response was assessed using 2017 European Leukemia Net AML (2017 ELN) criteria (Dohner et al, Blood 2017). OS from diagnosis of MPN-AP/BP and from time of allo-HCT was calculated utilizing Kaplan-Meier analysis. Results The full MPN-AP/BP cohort consists of 180 pts. This analysis includes 58 pts that underwent allo-HCT for MPN-AP/BP across 8 institutions. Median age at MPN-AP/BP diagnosiswas 64 years. The most common therapies for chronic-phase MPN included hydroxyurea (55%), JAK inhibitor (JAKi) (26%), interferon (9%), and hypomethylating agent (HMA, 4%). No patient previously received allo-HCT for chronic-phase MPN. Driver mutations included JAK2 (60%), CALR (22%), MPL (10%), but some pts had triple-negative disease (7%). Sixty-two percent of pts had high-risk disease by 2017 ELN criteria. Forty-four pts had next-generation sequencing performed at time of MPN-AP/BP diagnosis. The most frequently co-occurring mutations detected at time of MPN-AP/BP diagnosis were ASXL1 (30%), SRSF2 (23%), RUNX1 (23%), TP53 (18%), TET2 (16%), IDH2 (11%), U2AF1 (7%), EZH2 (7%), and IDH1 (9%). Additional characteristics are in Table 1. One pt proceeded directly to allo-HCT at time of MPN-AP/BP diagnosis. Frontline therapies (1L) for MPN-AP included intensive chemotherapy (IC) (n=26), hypomethylating agent (HMA) + venetoclax (VEN) (n=16), HMA monotherapy (n=14), and low-dose cytarabine (LDAC) + VEN + JAKi (n=1). Responses are summarized in Table 2A. Thirty-seven pts proceeded to allo-HCT after 1L therapy (17 after IC, 10 after HMA+VEN, 9 after HMA, 1 after LDAC+VEN+JAKi). Twenty pts proceeded to allo-HCT after 2 nd-line and beyond (2L+) therapies. Therapies utilized and responses are summarized in Table 2B. Transplant-specific characteristics include 15 pts receiving myeloablative conditioning while 43 received reduced-intensity conditioning. Donor source was matched unrelated donor for 33 pts, haploidentical donor for 10 pts, matched related donor for 9 patients, mismatched unrelated donor for 5 patients, and cord blood for 1 patient. Twenty-two pts developed acute GVHD while 15 developed chronic GVHD. Amongst the 58 pts that underwent allo-HCT, 19 had relapse of disease and 8 patients received treatment after relapse. Amongst the full cohort of 180 patients, mOS was 0.72 years from time of MPN-AP/BP diagnosis. The mOS for the 58 pts that underwent allo-HCT was 1.82 years from time of MPN-AP/BP diagnosis and 1.30 years from time of allo-HCT. Survival analysis by initial MPN-AP/BP therapy demonstrated a mOS from time of MPN-AP/BP diagnosis of 1.9 years for HMA-based therapy, 1.9 years for HMA + VEN, and 1.5 years for IC ( p=0.006). We also analyzed mOS by disease status prior to transplant. Thirty-four pts had a complete response (CR) or CR with incomplete count recovery (CRi) with mOS of 1.7 years from time of allo-HCT, 12 pts with a partial response (PR) or morphologic leukemia-free state (MLFS) had mOS of 1.8 years, and 11 pts with treatment failure (TF) had mOS of 0.47 years (p=0.82). Conclusions Our cohort of 180 pts with MPN-AP/BP treated in the current era of myeloid therapies had limited survival with a mOS of 0.72 years from MPN-AP/BP diagnosis. Amongst the 58 pts that underwent allo-HCT the mOS was 1.82 years with longer mOS seen in pts that received HMA or HMA + VEN as their 1L therapy when compared to IC. This underscores the need for novel management strategies even in pts eligible for allo-HCT.

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 &amp;gt;3.5 (n=213 pts excluded). Pts were excluded from the survival analysis if age at diagnosis was &amp;lt;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&amp;lt;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.

Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database

JPB and TK are co-first authors; RK and AMZ are co-senior authors Introduction: Efficacy of therapies used in HR-MDS pts has long been assessed using IWG 2006 MDS criteria, but important limitations in clinical utility and practical application of these criteria have become apparent. The revised IWG response criteria for HR-MDS were proposed in 2023 (Zeidan et al., Blood 2023) were proposed to address these gaps. IWG 2023 re-defined CR by lowering hemoglobin (Hb) threshold from 11 to 10 g/dL and bone marrow [BM] blasts from ≤5% to &amp;lt;5%. Further, CR with partial hematologic recovery (CRh; &amp;lt;5% BM blasts, no Hb threshold, platelets ≥50 × 10 9/L; neutrophils ≥0.5 × 10 9/L; peripheral blood [PB] blasts 0%), CR with limited count recovery (CR-L; &amp;lt;5% BM and 0% PB blasts + PB parameters for CR met in 1 [CRuni] or 2 lineages [CRbi]), and CR equivalent (CRequ; defined for pts with baseline BM of &amp;lt;5%.) were all proposed as provisional endpoints. Per IWG 2023 hierarchical response assessment, if a pt met criteria for both CR-L and CRh, they would be recorded as CR-L. We sought to validate the IWG 2023 definitions of cCR (CR+CR-L+CRh+CRequ) in a large, multi-center dataset of HR-MDS pts who received HMAs. Methods: The VALIDATE database includes HR-MDS pts treated with HMA-based therapies in frontline setting from 14 specialized centers. HR-MDS was defined as IPSS ≥1.5 or IPSS-R &amp;gt;3.5 (n=213 pts excluded). Pts were excluded (N=90) if age at diagnosis was &amp;lt;18 years, BM blasts ≥20% or unknown at HMA initiation, or if survival status, follow-up time, HMA type or initiation date were unknown. To preserve validity of response assessments, pts also were excluded (N=290) if no BM evaluation was performed or if first BM assessment was &amp;gt;180 days after HMA initiation, except in cases of overt disease progression. Best responses were assessed based on IWG 2006 and 2023 criteria. Kaplan-Meier analysis estimated OS from HMA initiation, and the log-rank test was used to compare subgroups. Cox multivariable regression models identified predictors of OS. This study was supported by an independent research grant from AbbVie. Results: Of 1,223 pts in VALIDATE database, 629 were met eligibility. Median age was 68 years, 27.7% and 27.4% were red blood cell and platelet transfusion-dependent, respectively, 38.1% had TP53 mutations, and 45.3% underwent allogeneic transplantation (allo-HCT). Most pts (71.6%) received HMA monotherapy (51.7% azacitidine, 19.9% decitabine), while 28.4% received HMA-based combinations. Median duration of therapy was 4 cycles (Range: 1-94). Median OS of different subgroups pts are shown in Figure 1. Median OS for pts with IWG 2023-defined cCR (CR+CR-L+CRh+CRequ; N = 230) was 26.5 months (mo; 95% CI: 20.7 - 32.2 mo) vs 14.3 mo (95% CI: 12.5 - 16.9 mo) for pts who did not achieve cCR (p=0.002). Median OS for pts who achieved IWG 2023-defined CR (N = 90) was 29.8 (95% CI: 23.1 - 41.8) vs. 26.4 mo (95% CI: 22.0 - 41.3) for IWG 2006-defined CR (p=0.71). The 124 pts (19.7%) who achieved CR-L had a median OS of 26.4 mo (95% CI: 17.6 - 36.2 mo); of those 67 pts achieved CRbi and had a median OS of 29.1 mo (95% CI: 20.7 - not reached), while 57 pts achieved CRuni and had a median OS of 18.7 mo (95% CI: 15.5 - 54.4 mo), with no significant difference in OS between CRbi and CRuni (Hazard ratio: 1.24; 95% CI: 0.78-1.98, p=0.71). Given the hierarchical prioritization of CR-L designation over CRh in IWG 2023 if a pt meets both response definitions, only 6 pts achieved CRh which precluded a reliable estimate of their OS. Similarly, CRequ was achieved only in 10 pts limiting a reliable assessment of OS in these pts. In a multivariable Cox model that adjusted for sex, HMA type, age, allo-HCT, complex karyotype, TP53 mutation, and IPSS-M risk group, achieving a cCR per IWG 2023 criteria was statistically significantly associated with improved OS was associated with improved OS compared to those who did not achieve cCR (HR: 1.64; 95% CI: 1.30 - 2.08; p&amp;lt;0.001, Figure 2). Discussion: In this real-world analysis of HR-MDS pts treated with HMA-based therapy, cCR according to IWG 2023 were associated improved OS. In particular, CR and CRL (including CRbi and CR uni) were associated with improved OS, supporting their inclusion in the overall response rate in clinical trials. The number of pts who achieved CRh and CRequ was too small to reliably assess their specific association with OS. Additional pts are being added to the database and detailed analyses will be presented in the meeting.

Clinical Characteristics of Patients with TP53 Multihit MDS and AML. a Single-Center Experience

Introduction TP53 is a tumor suppressor protein encoded by the TP53 gene that plays a pivotal role in maintaining genomic stability in response to DNA damage, activates DNA repair programs and triggers cell-cycle arrest. Mutations in TP53 (TP53-mut) are present in approximately 5-10% of de novo myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), and confer an extremely poor prognosis, irrespectively of the treatment administered. The frequency of TP53 abnormalities increases up to 25-40% in therapy-related MDS and AML, up to 70%-80% in patients with complex karyotype and in patients with loss of chromosome 17/17p, 5/5q, or 7/7q. “Multihit” TP53-mut present with the loss of both wildtype TP53-alleles, either through point mutations or larger aberrations to chromosome 17, in complex monosomal karyotypes. Recent data strongly support the concept that TP53mut, particularly multi-hit TP53, results in similarly poor clinical outcomes, regardless of its classification as MDS or AML, arguing for a revised TP53 mutant myeloid entity that includes both MDS and AML. The aim of our analysis is to assess the impact of the multihit TP53-mut on clinical outcomes according to the type of treatment received. We will particularly focus on the presence of mono or biallelic mutation status of TP53 mutation. Methods We retrospectively evaluated 42 patients with TP53 mutated MDS or AML diagnosed from October 2016 to June 2023 in our department at the Catalan Institute of Oncology-L'Hospitalet in Spain. We analyze the prognosis of these two diseases, focusing on single-hit or multi-hit status of TP53 mutation and treatments received. Results Median age at diagnosis was 71 years (range, 44-87 years) with a male predominance (67%). Thirty-five (84%) patients were diagnosed of AML and 7 (16%) of MDS. Among AML patients, 17% had a prior diagnosis of dysplasia, 78% were diagnosed of AML with dysplasia-related changes, 13% with therapy-related neoplasms, and 9% were AML with maturation and/or AML with mutated NPM1. Regarding MDS patients, 57% had an excess of blast-2 (EB2) MDS, 43% MDS multilineage dysplasia (MLD) and MDS with excess of blast-1(EB1). Complex karyotype was present in 79% of the patients. The median variant allele frequency (VAF) of TP53mut was 36%. Multi-hit TP53 status was observed in 24 patients (57%). In this group of multi-hit TP53mut median age was 72 years (range,44-81 years) with a male predominance (67%), the median VAF of TP53mut was 40%. Twenty (83%) patients had MDS diagnosis and 4 (17%) had AML diagnosis; all of them presented complex karyotype. In the whole group the most concurrent mutations associated with TP53 were TET2 in 17%, ASXL1 in 14% and DNMT3A, NRAS y CREBBP in 12% of patients. Intensive chemotherapy (IC) was administrated as first-line treatment in 17% of patients, 45% received hypomethylating agents (HMA) monotherapy, 24% venetoclax-based combination with HMA, and 14% exclusively supportive treatment. 16 patients (38%) achieved a complete response (CR), 44%, 31% and 25% with HMA+venetoclax, IC and with HMA monotherapy, respectively. Eight patients (19%) achieved a partial response (PR), 88% with HMA and 12% with IC, 7 patients (17%) stable disease, 86% with HMA monotherapy and 14% with HMA+venetoclax and 2 patients (5%) were refractory to IC. In 2 patients (5%), disease was not evaluable. The treatment related mortality was 4.2%. Median overall survival (OS) was 12.5 months [IC 95 % (0.0, 23.54)] and median progression free survival (PFS) was 9, 2 months [IC 95% (3.2, 32.6)]. Median OS of patients with multihit TP53 was 9.8 months, vs 25.7 months in patients with single-hit TP53-mut (P=0.026) (Figure1). Median PFS of the patients with multi-hit and single-hit TP53 was 9.1 and 11.6 months (P=0.07), respectively. The impact of multi-hit TP53 on OS and PFS according to the treatment received (HMA monotherapy vs HMA + venetoclax vs IC) was not statistically significant, just like in the single-hit TP53 (Figure1). Conclusions The presence of multihit TP53 -mut is a prognostic variable for survival in our group of patients analyzed with TP53-Mut. Survival is poor, around one year, in this group of patients independently on the treatment strategy received; this fact would call into question the benefit of IC with the toxicity it entails, in this group of patients. Further development of new effective therapies for multihit TP53-mut AML and MDS is needed.

Performance of the Molecular International Prognostic Scoring System (IPSS-M) in Hypomethylating Agent-Treated Patients with Myelodysplastic Syndromes

Background: Patients with myelodysplastic syndromes (MDS) undergo risk stratification with various prognostication tools, such as the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). Recently, the Molecular IPSS (IPSS-M) was developed incorporating genomic data in addition to clinical and cytogenetic characteristics. Though IPSS-M has been shown to improve prognostication in all MDS patients at baseline, its utility in specifically patients undergoing hypomethylating agent (HMA) therapy remains unknown. Here, we assess the efficacy of IPSS-M in HMA-treated patients with MDS. Methods: We retrospectively evaluated all untreated patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who later received HMA therapy. Patient characteristics and bone marrow (BM) data, including morphology, cytogenetics, and mutations, were assessed at diagnosis. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in July 2023. Results: Out of 799 untreated MDS patients, 455 patients (57%) eventually underwent treatment with HMA. At diagnosis, the median age was 69 (range: 22-90) with 289 (64%) male patients. Patients were generally high risk, with therapy-related MDS in 160 (35%), complex cytogenetics in 167 (37%), and TP53 mutations in 168 (37%). By IPSS-R, 259 patients (58%) had high- or very high-risk disease, and 340 patients (75%) had higher-risk disease (moderate high-, high-, and very high-risk) by IPSS-M. A total of 291 patients (64%) were treated with HMA monotherapy, and lower-risk MDS patients received more cycles of HMA (p &amp;lt; 0.001). By IPSS-R, the median overall survival was 60.0 months (95% CI: 46.0, not estimable (NE)) in very low-, 87.4 months (95% CI: 59.9, NE) in low-, 36.2 months (95% CI: 30.0, 58.1) in intermediate-, 23.7 months (95% CI: 19.6, 34.8), in high-, and 12.8 months (95% CI: 11.0, 16.7) in very high-risk patients (p &amp;lt; 0.0001) with a concordance index of 0.669. Figure 1 depicts the reclassification of patients between IPSS-R and IPSS-M. Risk stratification by IPSS-M (Figure 2) provided similar results: not reached (95% CI: 56.8, NE) in very low-, 60.0 months (95% CI: 49.8, NE) in low-, 40.8 months (95% CI: 22.8, NE) in moderate low-, 44.2 months (95% CI: 27.8, NE) in moderate high-, 33.4 months (95% CI: 22.8, 44.5) in high-, and 16.6 months (95% CI: 13.8, 19.4) in very high-risk patients (p &amp;lt; 0.0001). The concordance index of IPSS-M in all HMA-treated MDS patients was 0.648. When analyzing patients with MDS who were more likely to undergo HMA as per standard-of-care treatment (those with IPSS-M moderate low-, moderate high-, high-, and very high-risk disease), the IPSS-M remained statistically significant (p &amp;lt; 0.0001) though less discerning in the patients with moderate-risk MDS, as seen by the concordance index of 0.620. Conclusions: In this group of MDS patients treated with HMA, the IPSS-M did not provide additional prognostic power over the IPSS-R though median overall survival remained inversely proportional to IPSS-M risk category. Concordance indices for survival remained below 0.7, likely due to the overlapping curves in moderate-risk patients by IPSS-M. Further development and validation of prognostic scoring systems in patients treated with HMA are warranted.

Molecular Ontogeny in AML Is Both Prognostic and Predictive in Patients Treated with Hypomethylating Agents Plus Venetoclax

Introduction The prognostic value of secondary ontogeny in newly diagnosed acute myeloid leukemia (AML) is based on data from patients (pts) treated with intensive chemotherapy. Secondary ontogeny-defining mutations have been integrated into recently revised diagnostic and prognostic criteria, irrespective of initial therapy. We conducted a retrospective cohort study of pts treated with hypomethylating agents (HMA) +/- venetoclax (VEN) in order to determine the prognostic value of molecular ontogeny in AML treated with low-intensity regimens and evaluate whether the observed benefit of VEN is distinct for each ontogeny. Methods We included all pts with newly diagnosed AML who were treated with either HMA (HMA monotherapy or HMA+non-VEN drug) or HMA+VEN at Dana Farber Cancer Institute between 2014 and 2022. We defined three ontogeny groups in hierarchical order (Lindsley, Blood 2015) based on the presence of a TP53 mutation (“ TP53 group”), the presence of ≥1 secondary ontogeny mutation without concurrent TP53 mutation (“secondary group”), and all others (“de novo” group). Overall 314 pts were included: 111 (35%) in the TP53 group (60 with HMA+VEN, 51 with HMA); 115 (37%) in the secondary group (68 with HMA+VEN, 47 with HMA); 88 (28%) in the de novo group (38 with HMA+VEN, 50 with HMA). No significant differences in baseline characteristics were observed between pts treated with HMA+VEN vs HMA. Composite complete response (cCR) was defined as Complete response (CR) plus CR with incomplete recovery (CRi) and was evaluable in 252/314 (80%). Overall survival (OS) was compared by a log-rank test. Univariate and multivariable Cox regression models were fitted to assess the effect of covariates on OS with allogeneic hematopoietic cell transplant (HCT) as a time-varying covariate. Results Overall, the cCR rate (49% vs 28%, p=0.001), HCT rate (17% vs 8%, p=0.018), and OS (median OS 9.9 [95% confidence interval (CI) 8-13] vs 7.4 [95% CI 6-10], p=0.018) were significantly better in pts treated with HMA+VEN compared with those treated with HMA. To determine whether the benefit of VEN was different based on molecular ontogeny, we assessed outcomes in each group separately. In patients with TP53 mutations, there was no difference in cCR rate between pts treated with HMA+VEN (30%) vs HMA (25%), p=0.82. Conversely, the cCR rates were significantly higher with HMA+VEN vs HMA in those in the secondary (50% vs13%, p&amp;lt;0.001) and de novo groups (50% vs 22%, p=0.034). The HCT rates between HMA+VEN vs HMA were higher in the secondary group (24% vs. 6%, p=0.02) and were similar in the TP53 and de novo groups (15% vs 8%, p=0.38 and 11% vs 10%, p&amp;gt; 0.99, respectively). In the TP53 group, OS was similar in those treated with HMA+VEN vs HMA (median OS 5.7 months [95% CI 4-8] vs 6.1 [95% CI 4-10], respectively, p=0.93). In contrast, pts in the secondary group treated with HMA+VEN vs HMA had significantly better OS (median OS 14.1 months [95% CI 10- 20] vs 6.9 [95% CI 5-11], p=0.0054, Figure). In the de novo group, OS was not significantly different between HMA+VEN ( median OS 13.2 months [95% CI 8-23]) vs HMA (median OS 10.3 [95% CI 6-14]), p=0.12. To verify the prognostic significance of VEN in each ontogeny and adjust for potential confounders, we performed regression models for each ontogeny separately. HMA+VEN vs HMA was associated with significantly improved survival only in the secondary group (secondary: hazard ratio [HR] 0.59, 95% CI 0.38-0.94, p=0.025; TP53: HR 1.19, 95% CI 0.78-1.81, p=0.42; de novo: HR 0.67, 95% CI 0.40-1.12, p=0.13). HCT was associated with improved OS across all groups ( TP53: HR 0.17, 95% CI 0.07-0.42, p&amp;lt;0.001; secondary: HR 0.40, 95% CI 0.18-0.89, p=0.026; de novo: HR 0.14, 95% CI 0.03-0.58, p=0.0067). Among all pts treated with HMA+VEN (n=166), the OS was similar between de novo and secondary groups (p=0.92); and both groups had better OS compared to the TP53 group (comparison vs de novo p=0.007; comparison vs secondary p&amp;lt;0.001). These results were verified in a regression analysis, adjusting for age, HCT, and disease characteristics. Conclusion In newly diagnosed AML patients, treatment with HMA+VEN had a particular benefit in those with secondary mutations, with better response and HCT rates, and prolonged OS compared with HMA. Consequently, outcomes were similar in pts with genetically defined secondary and de novo disease. In pts with TP53 mutations, treatment with HMA+VEN did not improve any clinical outcomes compared with HMA.

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction MDS are genetically heterogenous neoplasms with diverse prognoses. While hypomethylating agents (HMA) can improve outcomes, HSCT remains the only potentially curative therapy. The IPSS-M incorporates clinical and molecular features to improve outcome prediction beyond traditional risk stratification tools. The IPSS-M has been validated in studies that either variably included pts who underwent HSCT, were limited by sample size, or were single-institution analyses. We aimed to validate the performance of the IPSS-M in predicting outcomes among pts with MDS who were treated with HMAs and subsequently underwent HSCT. Methods The VALIDATE database includes MDS pts treated with frontline HMA from 14 specialized centers. Only pts with available molecular data pre-HMA therapy and subsequently underwent HSCT were included. Time-to-event analyses used Kaplan-Meier estimator and the log-rank test. Overall survival (OS) was measured from time of HSCT. Multivariate-adjusted survival analysis used Cox proportional hazards. We compared the different scoring scores by Harrell's c-index. This study was supported by an independent research grant from AbbVie. Results A total of 350 pts met eligibility ( Panel A). Median age was 63 years (IQR: 58-68). MDS with excess blasts 1/2 (66%) was the most common type. Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. The most prevalent mutations were TP53 (29%), ASXL1 (21%), RUNX1 (13%), STAG2 (12%), SRSF2 (12%), and DNMT3A (11%); 53% of pts had disease harboring &amp;gt;1 gene mutation. Only 44% had TP53 CN-LOH and 40% had MLL-PTD testing. The most common donor types were matched unrelated donors (MUD, 46%), haploidentical donors (21%), and matched related donors (MRD, 17%). Myeloablative, non-myeloablative, and reduced-intensity conditioning were used in 38%, 27%, and 27% of the pts, respectively. Only 14% of pts received post-HSCT maintenance therapy. Our cohort was enriched with very high risk (41%) and high risk (30%) IPSS-R groups at time of diagnosis, while very low (1%), low (9%), and intermediate (20%) IPSS-R risk groups accounted for remaining 29% of pts. According to the IPSS-M, pts were classified into very low (2%), low (10%), moderate low (13%), moderate high (14%), high (27%) and very high (34%) risk groups. The IPSS-M re-stratified 198 (57%) pts, of whom 77 (39%) pts were up-staged and 121 (61%) pts were down-staged. More specifically, 35% and 26% of pts with intermediate risk IPSS-R MDS, and 32% and 35% of pts with high risk IPSS-R MDS were up-staged and down-staged, respectively. Importantly, 45% of pts with very high risk IPSS-R MDS were down-staged. Median follow-up time was 20 (IQR:8-36) months (mo). The median OS for the entire cohort was 32 mo (IQR:10-Not reached [NR]). The IPSS-M groups showed significantly different OS (p-value= 0.001, Panel B)withmedian OS (mo, 95%CI) of: very low (NR, 11.5-NR), low (55, 22-NR), moderate low (48, 25-NR), moderate high (35, 22-NR), high (29, 23-NR), and very high (20, 13-28). The 5-year OS (%) were as following: very low (56%), low (47%), moderate low (37%), moderate high (40), high (43%), and very high (17%). IPSS-M risk (HR: 1.3, 95% CI:1.1-1.5) was significantly associated with OS in a multivariable model (HR, 95%CI) adjusted for age (1.01, 1.00-1.03), sex (1.2, 0.9-1.7), type of HMA used before HSCT (1.0, 0.9-1.1), number of HMA cycles (1.0, 0.9-1.05), donor type (1.0, 0.9-1.1), and conditioning regimen used (1.3, 1.1-1.5). For OS, the IPSS-M significantly stratified pts assigned to the very high risk IPSS-R subgroup (p=0.009). However, the IPSS-M showed comparable performance to IPSS-R with c-index (95%CI): 0.597 (0.555-0.640) vs. 0.599 (0.554-0.643), respectively, for OS. When IPSS-M/IPSS-R were analyzed as continuous scores, the c-index (95%CI) for OS were: 0.606 (0.561-0.651) vs. 0.611 (0.559-0.662). When focusing on the higher risk group defined as IPSS ≥.1.5, the IPSS-M (c-index: 0.584) still had performance comparable to the IPSS-R (c-index: 0.606). Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R.

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.

Efficacy of Hypomethylating Agents with Venetoclax in TP53mut AML

Background: Patients with TP53mut AML or with del(17p) experience refractoriness to conventional intensive chemotherapy and dismal outcomes. Treatment with 10-day decitabine may be beneficial in these patients. The utility of augmenting a hypomethylating agent (HMA) backbone with the BCL-2 inhibitor, venetoclax (VEN), in these patients is under debate, as recent studies suggest TP53mut may also confer resistance to VEN. The aim of this study was to report response, survival, and toxicity of HMA with and without addition of VEN in matched cohorts of del(17p) and TP53mut AML. Patients & Methods: We analyzed 47 patients with TP53mut or del(17p) AML treated with HMA +/- VEN from January 2016 to December 2021 at VCU Massey Cancer Center. Baseline patient and disease characteristics including molecular and cytogenetic profiling, treatment regimens, responses, and survival data were obtained via retrospective chart review. Patients were considered evaluable for response if there was a bone marrow biopsy following a minimum of 28 days of treatment. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Thirteen patients with TP53mut/del(17p) AML were treated with HMA + VEN in the first-line setting. The median age at diagnosis was 73 years, median ECOG score 2, and the median Charlson Comorbidity Index (CCI) score was 5. The composite response rate (CRR; CR + CRi) was 33.3% in those evaluable (1 CR, 3 CRi). The median OS was 9.4 months and no patients proceeded to allogeneic stem cell transplant (alloSCT). In the HMA monotherapy cohort, nine patients were treated with decitabine (33.3%) or azacitidine (66.6%) with TP53mut or del(17p). The median age was 73 years, median ECOG score 1, and median CCI score 7. No patients achieved a CR or CRi. The median OS was 8.2 months and no patients proceeded to alloSCT. There was no significant difference in survival with or without the addition of VEN in the first-line setting (p = 0.8735). There were 12 patients in the relapsed/refractory (R/R) cohort treated with HMA/VEN that did not previously receive this therapy upfront. The median age was 63 years, median ECOG score was 2, and the median CCI score was 4. The CRR was 40.0% in those evaluable (2 CRi, 2 CRi). The median OS was 4.6 months. In the relapsed/refractory HMA monotherapy cohort, 13 patients were identified. The median age was 59 years, the median ECOG score was 1, and the median CCI score was 4. The CRR was 20.0% (1 CR, 1 CRi) in those evaluable. The median OS was 5.9 months. Conclusions: While HMA + VEN in the first-line setting did translate to a higher CRR in TP53mut disease compared to HMA monotherapy, our data suggest no clear additional survival benefit with the addition of VEN. These patients continue to experience refractory disease, inability to proceed with alloHSCT, and poor survival even with augmentation of the HMA backbone by BCL-2 inhibition. These findings suggest cautious selection for VEN candidates and highlight the need for novel therapeutic interventions for TP53mut disease. Larger studies with propensity score-based techniques are needed to confirm these findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Transfusion Burden Among Newly Diagnosed Older Adults with Acute Myeloid Leukemia

Background: The approval of Venetoclax (VEN; a BCL-2 inhibitor) has changed the treatment paradigm for older/unfit newly-diagnosed AML patients (ND AML) and improved outcomes in the landmark randomized phase 3 clinical trial, VIALE-A. However, real world evidence of population-level clinical benefit is still limited, especially on the impact of transfusion burden and achievement of transfusion independence (TI). Repeated transfusions are associated with significant risks and costs and impair quality of life for patients. This study examined real-world treatment patterns and clinical outcomes focusing on transfusion independence in a contemporary cohort of Medicare beneficiaries with newly diagnosed AML. Methods: This cohort study examined newly diagnosed Medicare beneficiaries (age ≥65 years) with AML using claims from the Centers for Medicare & Medicaid Services, representing 100% of Medicare fee-for-service beneficiaries. The identification period was July 2016-June 2020, with an observational period from January 2016 to December 2020. The first active AML treatment identified in the data was categorized into four different treatment categories; 1) Venetoclax combination (VEN; Venetoclax in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC)), 2) low-intensity treatment (LOW; HMA monotherapy or LDAC), 3) high-intensity chemotherapy (HIGH; patients with an inpatient stay lasting ≥22 days or ≥7 days where a non-specific antineoplastic treatment or cytotoxic chemotherapy was documented), and 4) other targeted therapies (OTHER; ivosidenib, glasdegib, gilteritinib, enasidenib, midostaurin, gemtuzumab ozogamicin). Patients who received any AML therapy prior to the index date except for treatments for myelodysplastic syndromes (e.g., HMAs and lenalidomide) were excluded. Transfusion independence (TI) was defined as a rolling period of no red blood cell (RBC) or platelet (PLT) transfusions for a consecutive 56-days. Results: We identified 5,855 ND AML Medicare beneficiaries, with 734 patients who met eligibility criteria and were categorized as VEN, 2,562 patients as LOW, 1,318 patients as HIGH, and 146 patients as OTHER. The median follow-up duration was 8 months and the median age at diagnosis was 76 years old in all patients. Patients had a mean Charlson Comorbidity Index score of 3, including common comorbidities: 23.4% with congestive heart failure and 27.6% with chronic pulmonary disease. The VEN cohort initiated their first line (1L) treatment on an average of 30 days from their diagnosis. Median duration of 1L therapy was 4.8 months (IQR: 1.9-6.6) in the VEN cohort, 3.1 months (IQR: 1.1-8.1) for the LOW cohort, 1.7 months (IQR: 0.9-1.8) for the HIGH cohort, and 2.1 months (IQR: 1.0-6.1) in the OTHER cohort. The mean daily dose in the VEN cohort over the 1L treatment period was 287 mg (median: 332). 15.4% of VEN patients had overlapping hospitalizations, indicating that patients may initiate Venetoclax at inpatient setting. Within 56-days prior to treatment initiation, 86.4% of VEN cohort had PLT-TI and 54.5% had RBC-TI, and similar proportions of TI were observed in other treatment groups. When evaluating the transfusion status every 56-days on a rolling weekly basis (Figures 1 & 2): a trend of decreased proportion of TI were observed from 56-days prior to the treatment initiation across treatment groups. By weeks 0-7 post-treatment initiation, 49.5% in VEN cohort achieved TI in PLT and 18.0% in RBC, which was lower than the LOW cohort (58.2% were TI in PLT vs. 29.4% in RBC). However, there was an apparent increasing trend of TI rate in both RBC and PLT since the first week after the patients initiating VEN, while the TI rate only slightly increased over time since the treatment initiation in the other treatment group. At weeks 8-15, a higher proportion of patients achieved TI in PLT and RBC in the VEN cohort, compared with the other treatment groups (PLT-TI: 74.2% in VEN, 70.1% in LOW, 40.0% in HIGH, and 57.6% in OTHER; RBC-TI: 52.2% in VEN, 41.9% in LOW, 35.6% in HIGH, and 41.3% in OTHER). At week 12-19, 62.1% in VEN achieved RBC-TI, versus 47.7% in LOW, 44.2% in HIGH, and 48.1% in OTHER. Conclusions: In the Medicare elderly population, ND AML patients treated with VEN had a longer median duration of therapy compared with other treatment groups. A larger proportion of VEN patients were able to achieve transfusion independence over time compared to the other treatment groups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

International Working Group (IWG) Response Criteria and Association with Overall Survival in Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agents - a Systematic Review and Meta-Analysis

* A.M.Z. and M.S. contributed equally Introduction: Response assessments in clinical trials and routine practice for patients (pts) with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) are based on the International Working Group (IWG) criteria proposed in 2000 and revised in 2006. However, it is not clear whether response criteria correlate with overall survival (OS). Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with a systematic search using controlled vocabulary and free text terms for MDS and survival of Cochrane Library, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases to find relevant articles published from inception to January 2022. The search was peer-reviewed by a second medical librarian. A targeted search of recent conference proceedings was also performed. Titles, abstracts, and full texts were reviewed for inclusion in the meta-analysis by two reviewers independently and conflicts were resolved by consensus discussion. Clinical trials and cohort studies with >100 pts reporting on the association of IWG 2000 or 2006 response criteria with OS among pts treated with HMA monotherapy or combinations were eligible for inclusion. Studies were excluded if they were (i) review or basic research articles, (ii) studies with <50% higher-risk MDS pts (inclusion of a minority of pts with MDS/MPN, oligoblastic AML, and lower-risk MDS was permitted), (iii) not published in English, and (iv) had insufficient reporting of the primary endpoint. The primary endpoint was the hazard ratio (HR) for OS for patients achieving an IWG-defined response (complete remission [CR], marrow CR, partial remission, hematologic improvement [HI]) compared to patients not achieving a response. Random-effects models were used to pool the HRs for death. Cochran Q and I2 indices were used to assess heterogeneity across included studies. Study heterogeneity was graded based on I2 indices as low (I2 <30%), moderate (I2 =30-60%), or high (I2 >60%). Comprehensive Meta-Analysis (CMA version 2.2, Biostat) was used for all analyses. Results: Our search strategy identified 7023 studies after duplicate removal. Following abstract and title review to identify clinical trials and large cohort studies reporting IWG response and OS among MDS pts treated with HMA, 195 studies were assessed for eligibility as full texts. Among these 185 studies were excluded for the following reasons: insufficient reporting of the primary outcome of OS and IWG response (n=114), duplicate publications from the same pt cohort (n=42), <50% higher-risk MDS pts (n=13), cohort studies with <100 pts (n=6), not on HMA therapy (n=4), ongoing clinical trials without published results (n=3), transplant (n=2), and review article (n=1). The final set of studies included 3896 MDS pts treated with azacitidine, decitabine, guadecitabine, or HMA-combination in 9, 4, 1, and 2 studies, respectively. Among the 5 available studies with data on the impact of CR on OS, the HR for death was 0.365 (95% CI: 0.311-0.430) for pts who achieved a CR compared to pts without a CR. Study heterogeneity was low (Cochran's Q=0.5; I2=0%; Figure A). Six studies reported the impact of HI on OS. Pts who achieved HI had favorable outcomes compared to pts without HI (HR: 0.419; 95% CI: 0.299-0.585) but with high heterogeneity across studies (Cochran's Q=14.34; I2=65.13%; Figure B). The prognostic impact of other response categories (e.g., marrow CR, partial remission) was only reported by 1 study each, precluding a meta-analysis. Conclusion: Achieving CR as defined by the IWG MDS response criteria is associated with improved OS among higher-risk MDS pts treated with HMA-based regimens. HI was also associated with OS, but with high study heterogeneity. The strong and consistent association of CR with OS supports its use as an outcome in clinical trials in MDS. The prognostic implications of other response categories as such CR with partial hematologic recovery (CRh) especially with novel combination therapies require additional studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Central Nervous System Specific Characteristics and Outcomes in Acute Myeloid Leukemia Patients with Neurologic Involvement

Introduction: Rates of leukemic central nervous system (CNS) involvement in acute myeloid leukemia (AML) are lower than in acute lymphoblastic leukemia, with estimates ranging from about 1.1% - 32%, based largely on differences in lumbar puncture (LP) screening protocols. Although risk factors for CNS AML and the prognostic implications are widely documented, the CNS specific characteristics and outcomes with intrathecal (IT) therapy have not been previously reported. Methods: We retrospectively identified patients at The Mount Sinai Hospital with CNS AML, defined as having leukemic blasts in the cerebral spinal fluid (CSF), as identified by flow cytometry or cytology, or as having atypical immature myeloid cells in the CSF with either concerning imaging findings or neurologic symptoms. Patients with neurologic symptoms with imaging findings suggestive of CNS disease, but no CSF diagnosis, were excluded. Patient, disease, and treatment-related variables were summarized by the median and range; categorical variables were summarized by n (%). The Kaplan-Meier method was used to estimate the median times to event for outcomes including CSF blast clearance and overall survival (OS). Results: A total of 25 patients were identified with CNS AML, with a median age of 57 years and 52% male. Seventy-six percent of patients had de novo AML, 20% AML secondary to myeloproliferative neoplasm or myelodysplastic syndrome, and 4% (n=1) had acute promyelocytic leukemia. Baseline characteristics previously associated with CNS AML were frequently observed, including monocytic differentiation (28%), elevated LDH (84%), and WBC >100K (36%). The most common karyotype abnormality was trisomy 8 (32%) with 46% having a normal karyotype and 24% having a complex karyotype. The most common mutations were FLT3 (56%), TET2 (32%), NPM1 (32%), and SRSF2 (20%) (Table 1). Of the 25 patients, 56% had CD34+ blasts and 44% had atypical myeloid cells in the CSF accompanied by either imaging findings or neurologic symptoms; 40% of all patients had imaging findings concerning for leukemic infiltration. Fifty-six percent of patients were diagnosed with CNS disease before or during induction, whereas 44% were diagnosed at time of relapse. Neurologic symptoms were reported in 76% of patients, with headache being the most common (36%), followed by vision changes (24%), radicular pain (16%), and hearing loss/tinnitus (12%). Other neurologic symptoms recorded include vertigo, seizure, hemorrhage and altered mental status. Systemic AML therapy received during or immediately after CNS diagnosis was 7+3 (56%), 7+3+midostaurin (16%), hypomethylating agent (HMA) + venetoclax (12%), HMA monotherapy (12%), and all-trans retinoic acid + idarubicin (4%). Eighty-four percent of patients received at least one dose of IT methotrexate, 52% at least one dose of IT cytarabine, and 40% at least one dose of both. The median number of IT doses received was 4 with a range of 0-31. Twelve percent of patients received 1 dose, 38% received between 2-5 doses, 25% received 6-10 doses, 12% 11-15 doses, 12% 15+ doses, and 4% received no intrathecal therapy. Of the 23 patients that had repeat LPs, 96% achieved CSF clearance with a median number of IT doses before clearance of 1 (range 0-9) and a median time to CSF clearance of 3.79 weeks (95% CI 2.14 to 5.29) (Figure 1). Of those patients who had CSF clearance, 16% of patients (n=4) had CSF relapse with concurrent bone marrow relapse. All 4 of these patients were FLT3+. Of the 18 patients with baseline neurologic symptoms at time of CNS diagnosis, 56% had improvement in original symptoms, 33% had no improvement, and 11% had no clear documentation of clinical symptoms post-IT therapy. The median overall survival after CNS diagnosis was 6.53 months (4.1-Not Reached) for patients diagnosed before/during induction and 3.55 months (2.75-Not Reached) for patients diagnosed at relapse. Discussion: In the present study, IT therapy was shown to be rapidly effective in clearing blasts and atypical myeloid cells from the CSF. Furthermore, neurologic symptoms improved in a majority of patients that received IT therapy. Lastly, a minority of patients had CSF relapse which were all accompanied by BM relapse. Prospective clinical trials and multi-center retrospective cohort studies with greater sample size are needed to further fill the gaps in treatment and outcomes for AML patients with CNS disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-430 A Surveillance, Epidemiology, and End Results (SEER)-Medicare Analysis of the Economic Burden Among Elderly Patients With Acute Myeloid Leukemia (AML) Treated With Hypomethylating Agents (HMA)

The economic burden of relapse among Medicare patients with newly diagnosed AML is high, with >50% receiving ≥1 cycle of HMA therapy. To assess healthcare resource utilization (HCRU) and costs associated with AML phases among elderly patients who received HMA monotherapy only during induction, followed by remission. A retrospective analysis of Medicare claims (parts A, B, and D; 2007-2016) and cancer diagnoses (2007-2015) in the SEER-Medicare database was conducted. Eligible patients were diagnosed with AML at ≥65 years of age and had initiated HMA in the outpatient (OP) setting during the first post-diagnosis induction cycle, followed by remission. Induction period was from HMA initiation (index date) to the end of cycle when remission occurred. The baseline period was the 6 months preceding index date. The post-relapse phase was from date of first AML post-remission relapse to end of follow-up. HCRU and costs (adjusted to 2019 USD) associated with induction and post-remission therapy were assessed during the treatment cycle. Of 71 eligible patients, 50.7% were male and 85.9% were White, with AML diagnosis at a median age of 78.8 years. Mean number of total treatment days was 181.3 and 153.0 for induction and post-remission phases, respectively. Among all patients, 43.7% had relapsed and 85.9% had died by the end of follow-up. During induction, post-remission, and post-relapse phases, 91.5%, 77.8%, and 77.4% of patients received a blood transfusion, respectively. The proportion of patients with inpatient (IP) visits was highest in the post-relapse phase, with 77.4% having ≥1 visit. Mean perpatient monthly (PPM) healthcare costs were highest for the post-relapse phase, followed by the post-remission and induction phases. OP-setting costs were the greatest contributor to induction costs (48.6%), while IP-setting costs contributed most to post-remission (56.2%) and post-relapse (72.8%) phase costs. The economic burden of AML treated with HMA was highest in the post-relapse phase, approximately 1.7x and 1.6x the PPM costs during induction and post-remission phases, respectively. In addition, IP costs made up approximately two-thirds of total PPM costs in the post-relapse phase, up from approximately 44% and 56% of the induction and post-remission phases, respectively.

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.

P757: RESULTS OF A PHASE 1 STUDY OF AZACITIDINE COMBINED WITH VENETOCLAX FOR TREATMENT-NAIVE AND RELAPSED HIGH-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA

Background: Patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) who are ineligible for allogeneic stem cell transplant (SCT) have limited treatment options beyond the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC). Responses to HMA monotherapy are time-limited and prognosis after HMA-failure is dismal. Venetoclax (VEN) is an oral small molecule BCL-2 inhibitor with the potential to prolong/deepen responses when combined with an HMA. Aims: To evaluate the safety/tolerability, recommended phase 2 dose (RP2D), and preliminary efficacy of VEN in combination with AZA for the treatment of HR-MDS/CMML. Methods: This was a single-center dose-escalation phase 1 study with “3 + 3” design. Key inclusion criteria were a diagnosis of MDS or CMML by WHO 2016, age ≥ 18 yrs, int-2 or high risk by IPSS, and bone marrow (BM) blasts of 5-19%. Pts could be treatment-naïve or relapsed/refractory, defined as failure after 4+ cycles of HMA. Prior VEN exposure was not permitted. Treatment consisted of AZA 75 mg/m2 on D1-5 and escalating doses of VEN on D1-7 or 1-14 (Table 1) every 28D. VEN dosing was adjusted for pts on concomitant CYP3A inhibitors. The primary objective was safety/tolerability and determination of the RP2D. Secondary objectives were response rates, overall survival (OS), and progression-free survival (PFS). Adverse events (AEs) were graded as per the CTCAE v5.0 and responses assessed using the modified IWG 2006 criteria. All pts provided informed consent. The study was registered on ClinicalTrials.gov (NCT04160052). Results: Data cutoff was February 19th, 2022. 23 pts (13 HMA-naïve MDS, 4 HMA-naïve CMML, 4 HMA-failure MDS, 2 HMA-failure CMML) were enrolled. The median age was 68 years (range 58-84) and median BM blasts 11% (range 6-19%). IPSS was int-2 in 78% of pts and high in 22% of pts. 8/23 (35%) had complex cytogenetics, 6/23 (26%) had TP53 mutations, and 5/23 (22%) had therapy-related MDS/CMML. A single dose-limiting toxicity (DLT) occurred at dose level +2 (BM aplasia and delayed count recovery). The maximum tolerated dose (MTD) was not reached. The most common grade 3/4 AEs were neutropenia (39%), thrombocytopenia (39%), anemia (13%), and infections: pneumonia (30%), neutropenic fever (17%), diverticulitis (9%), sepsis (9%), cellulitis (4%), and splenic abscess (4%). The RP2D was established at AZA 75 mg/m2 on D1-5 plus VEN 400 mg on D1-14. 3 deaths occurred on study, all from sepsis. 30 and 60-day mortality were 4% and 9%, respectively. Other reasons for discontinuing therapy included progression of MDS/CMML (n=6), transformation to AML (n=4), SCT (n=4), and social reasons (n=1). The ORR by intention-to-treat (ITT) analysis was 82% (14/17; 3 CR, 5 mCR+HI, 6 mCR) in the HMA-naïve cohort and 100% (6/6; 6 mCR) in the HMA-failure cohort. A median of 3 cycles (range 1-11) were given. Responses occurred after a median of 1 cycle (range 1-2) and lasted a median of 4.5m (range 1.2m to 21.2m). At a median follow-up of 13.2m, median OS was not reached (1-year OS 68.6%) in the HMA-naïve cohort and 8.3m (1-year OS 22%) in the HMA-failure cohort. Median PFS was 13.1m (1-year PFS 51.5%) in the HMA-naïve cohort and 6.8m (1-year PFS 0%) in the HMA-failure cohort. Image:Summary/Conclusion: AZA combined with VEN is tolerable and yields a high ORR in HR-MDS/CMML, with or without prior HMA. Rates of myelosuppression and infection are high and careful monitoring is required. The RP2D is AZA 75 mg/m2 on D1-5 plus VEN 400 mg on D1-14, every 28D. The phase 2 dose expansion component of this study is ongoing.