International Working Group Response Criteria Research Articles

Efficacy and safety analysis of venetoclax combined with hypomethylating agents for the treatment of higher-risk myelodysplastic syndromes in the real world

Objective: To investigate the efficacy and safety of combining venetoclax (VEN) with hypomethylated drugs (HMA) in the treatment of higher-risk (IPSS-R score >3.5) myelodysplastic syndromes (MDS) . Methods: From March 2021 to December 2022, forty-five MDS patients with intermediate and high risk were treated with VEN in combination with HMAs. Clinical data were collected and analyzed retrospectively, including gender, age, MDS subtype, IPSS-R score, treatment regimen, and efficacy, etc. Kaplan-Meier method and Cox regression model were used to analyze univariate and multivariate of survival prognosis. Results: ①Forty-five patients with MDS, including ninety-one percent were classified as high or very high risk. According to the 2023 consensus proposal for revised International Working Group response criteria for higher-risk MDS, the overall response rate (ORR) was 62.2% (28/45), with the complete response rate (CR) was 33.3% (15/45). For twenty-five naïve MDS, the ORR was 68% (17/25) and the CR rate was 32% (8/25). In nonfirst-line patients, the ORR and CR were 55% (11/20) and 35% (7/20) respectively. The median cycle to best response was 1 (1-4). ②With a median followup of 189 days, the median overall survival (OS) time was 499 (95% confidence interval, 287-711) days, and most patients died from disease progression. Responders had a significantly better median OS time than nonresponders (499 days vs 228 days, P<0.001). Multifactor analysis revealed that IPSS-R score and response to treatment were independent prognostic factors for OS; the presence of SETBP1 gene mutations was associated with a longer hospital stay (51.5 days vs 27 days, P=0.017) . Conclusions: There is clinical benefit of venetoclax in combination with hypomethylated agents in patients with higher-risk MDS, but adverse events such as severe hypocytopenia during treatment should be avoided.

Phase 1/2 Study of Pacritinib in Combination with Azacitidine in Chronic Myelomonocytic Leukemia

Introduction and preclinical rationale Treatment options for chronic myelomonocytic leukemia (CMML) are limited. Hypomethylating agents (HMAs) are the only approved therapies but are associated with unsatisfactory response rates and do not impact disease evolution (Merlevede Nat Comm 2016). JAK inhibition can reduce GM-CSF signaling, which contributes to CMML pathobiology; ruxolitinib has been clinically evaluated in CMML demonstrating promising, but insufficient clinical activity. Pacritinib is a JAK inhibitor that has a unique profile which suggests it may be uniquely well suited for the treatment of CMML, including targeting of CSF1R and IRAK1, both of which are upregulated in CMML and related diseases (Obba Autophagy 2015, Rhyasen Cancer Cell 2013). Additionally, pacritinib was recently shown to be a potent inhibitor of ACVR1 (Oh AJH 2023), potentially allowing for increased iron availability and improvement in anemia. Pacritinib has been evaluated preclinically in CMML primary samples and mouse models where it demonstrated significant, albeit heterogenous activity (Yoshimi Blood 2017). To enhance the activity of pacritinib in CMML, it was also evaluated in combination with azacitidine in GM-CSF hypersensitive cell lines and primary CMML cells where profound synergy was noted (Ma ASH 2015). Based on encouraging preclinical data, we hypothesize that the combination of pacritinib with azacitidine will be an effective treatment strategy in CMML patients. Methods In this phase 1/2 trial, we will evaluate the safety and efficacy of pacritinib and azacitidine in newly diagnosed or previously treated CMML. Patients must be JAK inhibitor and HMA naïve (≤1 cycle of HMA allowed). Phase 1 will follow a ‘3+3‘ dose de-escalation design and will enroll 6-12 patients. The primary objective of this phase is to determine the recommended phase 2 dose (RP2D) of pacritinib in combination with a fixed dose of azacitidine. Pacritinib will be administered at 200mg twice daily (with a lower dose of 100mg twice daily being explored in the case of dose limiting toxicity) in combination with azacitidine 75mg/m 2 for 7 days. Phase 2 will utilize a Simon's two stage design to assess the preliminary efficacy of pacritinib in combination with azacitidine at the RP2D. In the first stage, after treating 6 patients at the RP2D, there will be an interim response assessment as part of the phase 2 portion. If at least 4 among these 6 patients show a response, the trial will proceed to a second stage and enroll an additional 12 patients. Patients will be treated for 6 cycles of 28 days each with an interim bone marrow biopsy after cycle 3. The primary endpoint of the phase 1 portion is the recommended RP2D through the assessment of dose limiting toxicities and of the phase 2 portion is the overall response rate (ORR) by the end of cycle 6 as defined by a clinical benefit or greater by myelodysplastic syndrome/myeloproliferative neoplasm International Working Group response criteria (Savona 2015). Secondary endpoints include duration of response, disease free survival, overall survival, changes in MPN-SAF total symptom scores, palpable splenomegaly, and adverse events. Several correlative studies are planned as part of this clinical trial. Modulation of biomarkers of disease activity with treatment including GM-CSF dependent STAT5 phosphorylation, MAPK, and PI3K signaling will be analyzed. We will also evaluate changes in mutational and cytogenetic burden with treatment as well as at baseline to identify predictive biomarkers of response.

Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk

Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low. Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT. Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

Preliminary Results from a Phase 1b Dose De-Escalation Stage of Abnl-Marro 001: An International MDS/MPN Working Group Study

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Decitabine in Combination with Aclacinomycin, Cytarabine and Granulocyte Colony-Simulating Factor (CAG) Had a High Response Rate in Children with Advanced Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia-Related Changes

Advanced myelodysplastic syndrome (MDS) is a rare disease in children with poor prognosis. Allogeneic transplantation is the only curative option. However, there has been no established treatment prior to transplant. We conducted a retrospective study exploring the response rates and safety of decitabine combined with aclacinomycin, cytarabine and granulocyte colony-stimulating factor (CAG) for induction treatment of advanced MDS and acute myeloid leukemia with myelodysplasia-related changes (MDR-AML) in children. Patients from 1 to 14 years administrated in Pediatric Blood Disease Center of CAMS Blood Disease Hospital between January 1the 2019 and December 31th 2022 were screening. All diagnosed with MDS-EB or MDR-AML according to WHO 2016 criteria and treated with decitabine combined with CAG were identified. The efficacy of one-cycle treatment of MDS-ED was evaluated based on The International Working Group Response Criteria 2006. The response for MDR-AML was evaluated according to the criteria for AML published by ELN. The response of MDR-AML was defined as complete remission (CR) or CR with incomplete count recovery (CRi). The response of MDS-EB was defined as CR or bone marrow CR with hematological improvement (HI). A total of 13 patients, including MDS-EB (n=7) and MDR-AML (n=6), were enrolled for analysis. 5-day decitabine was administrated, combined with modified CAG regimen for 7 days. Eventually 12 patients of those were available for evaluation. For patients with MDS-EB, four achieved CR and three reached marrow CR with HI. Four patients with MDR-AML, three achieved CR and two reached CRi. The overall response rate was 100%(12/12). The most frequent adverse events were myelosuppression and suppression-induced infections, but no infection-related mortality was recorded. There had been no cardiotoxic event happened, either. Only one patient experienced fatal bleeding in early stage after treatment. The median follow-up time was 16 months (range 1-48). At last follow-up, 10 patients who had underwent allo-HCT were alive without disease. The remaining 2 patients died of disease progression. The 2-year estimated overall survival was 62.9%. Decitabine combined with modified CAG had a high response rate for children with advanced MDS and MDR-AMl, and it can bridge patients to curative allogeneic transplantation.

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.

Venetoclax (VEN) Plus Intensive Chemotherapy (IC) with FLAG-IDA in Patients (Pts) with Newly Diagnosed (ND) and Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Background: Despite the high complete remission (CR) rates achieved with IC, relapse rates remain high underscoring the need for novel combination regimens capable of inducing deeper remissions via eradicating measurable residual disease (MRD). Recently, several studies have shown promising clinical activity of VEN when combined with different IC regimens in pts with ND AML with composite CR rates (CRc) above 90% and MRD-ve rates exceeding 80% (Wang 2022; Kadia 2021). FLAG-IDA + VEN has also shown significant clinical activity in pts with ND AML with a CRc rate of 89% and MRD-ve remission rate of 93% (DiNardo 2022). Methods: We conducted a single-center retrospective study to assess the clinical activity of FLAG-IDA + VEN in pts with AML. During induction, VEN was initially given for 14 days which was later on reduced to 7 days due to encouraging results by Kadia et al. Standard cytogenetic (CN) analysis was performed and molecular data was obtained using a 40-gene NGS platform. Responses were assessed using the modified International Working Group response criteria and included CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR). Time-to-event analyses were estimated using the Kaplan-Meier method and compared using the log rank test. Results: From March 2020 to May 2022, 24 pts with AML (17 ND and 7 R/R) were treated using FLAG-IDA + VEN (Table 1). Median age was 48 years (range, 21-68) with male predominance (67%). Among the 17 pts with ND AML (8 de novo, 5 AML-MRC, 2 treated-secondary, 2 therapy-related), 3 had extramedullary disease (EMD). The most common ELN CN risk groups were complex (N=5), KMT2A-rearranged (N=4), other adverse (N=3), and diploid (N=3). Eight pts (47%) harbored a RAS mutation. Median time to initiation of therapy was 5 days (range, 2-14). Twelve pts (71%) [KMT2A-rearranged, N=4; complex CN, N=3; diploid, N=3; other adverse, N=1; other intermediate, N=1] achieved CR/CRi including 1 pt with EMD. Median time to ANC (≥ 500) and platelet (≥ 50,000) recovery were 29 days (range, 19- 42) and 25 days (range, 17- 42), respectively. Median number of consolidation cycles given were 1.5 (range, 1- 5). MRD status was available in 6 out of 12 pts and all 6 pts achieved MRD negativity using flow cytometry (<10-3). Median follow-up among ND AML pts was 4.3 months (mths) (range, 0.7- 13.2). Among the 12 responders: (1) 3 pts received allo-SCT [KMT2A-rearranged, N=2; (-7), N=1] after 7, 4, and 3 mths, respectively, and remain alive in CR 10+, 7.5+, and 3+ mths, respectively, after initiation of therapy, (2) 6 pts with ELN favorable (N=3), intermediate (N=2), and adverse (N=1) risk AML remain in CR/CRi for 6+, 4+, 1+, 3+, 2+, and 2+ mths, respectively, (3) 3 pts with ELN adverse risk AML (including 1 pt with de novo MLLr AML and EMD) achieved CR and relapsed after 0.7, 1.7, and 7.6 mths, respectively. One pt died due to progressive disease (PD) 4.7 mths after relapse and the remaining 2 pts are receiving salvage therapy and alive 4.3+ and 5.2+ mths after relapse, respectively. All nonresponders (N=5) had ELN adverse risk AML including 2 pts with EMD and 2 pts with treated secondary AML. All 5 nonresponders died due to PD including 3 pts who had no response to HMA+VEN based salvage therapy. Among the 7 pts with R/R AML, 6 were in salvage 1 and 1 pt received prior allo-SCT. Responses were observed in all pts: 4 CR, 1 CRi, 1 MLFS, and 1 PR. Median time to count recovery in R/R AML pts was 33 days (range, 24-78). Median follow-up in R/R AML pts was 6.2 mths (range, 1.5- 15.6). Of the 5 pts who achieved CR/CRi, 4 were bridged to allo-SCT and 1 pt died in CR after 3 cycles of consolidation due to sepsis. Of the 4 SCT recipients: (1) 2 pts relapsed 2 mths after allo-SCT and died 4 and 6.5 mths, respectively, after allo-SCT; (2) 2 pts (KMT2A-rearranged and NPM1mut) remain alive in CR for 8+ and 14+ mths, respectively. Two pts with complex CN achieved MLFS and PR after 1 cycle of therapy and died due to PD and fungal pneumonia after 5.3 and 1.5 mths of starting therapy, respectively. Median overall survival (OS) for pts with ND AML and R/R AML were 13.2 mths (95% CI: Not reached) and 6.2 mths (95% CI: 5-7), respectively (p=0.62; Figure 1). Among pts with ND AML, median OS was not reached among responders and was 2.6 mths in non-responders (p=0.002). Conclusion: FLAG-IDA + VEN is a feasible and active regimen in AML. Longer follow-up and larger multicenter studies are needed to confirm the efficacy of this regimen. 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

Phase I Study of TQB3455, a Selective Inhibitor of IDH2 with Favorable Safety and More Potent Efficacy to IDH2-R172K Mutation, for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction: Approximately 15% of patients with acute myeloid leukemia (AML) and 5% of patients with myelodysplastic syndrome(MDS) harbor IDH2 mutations (mIDH2). Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455, a novel selective inhibitor of IDH2, different from ENA, showed stronger inhibitory activity against IDH2-R172K in vitro, and also demonstrated potent antileukemic activity in humans. The current analysis is the first to evaluate the safety and clinical efficacy of TQB3455 monotherapy in pts with mIDH2-positive AML or MDS. Methods: This multicenter, phase 1, open-label, dose-escalation/expansion study enrolled AML or MDS pts with mIDH2, who were RR or not candidate for standard treatment, estimated survival ≥12w and ECOG performance status＜2. Prior allogeneic hematopoietic stem cell transplantation is prohibited. TQB3455 is administered continuously as oral tablets QD in 28-day cycles. Dose levels are 25mg, 50mg, 75mg, 100mg, 150mg, and 300mg.Dose escalation followed a modified 3+3 design. Once the recommended phase 2 dose (RP2D) is determined, subjects will be enrolled into expansion cohort. Primary objectives include safety, tolerability, maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Safety was assessed by treatment-emergent adverse event (TEAE) reporting and TEAEs were graded per CTCAE version 5.0. DLT was defined as any Grade ≥4 hematologic toxicity or Grade ≥3 non-hematologic toxicity（alopecia excluded）occurring within the first 28 days after initiation of treatment. Secondary objectives include pharmacokinetics (PK), preliminary efficacy per International Working Group (IWG) response criteria for AML and MDS. Fisher's exact test was used to assess the association between categorical variables. Results: As of May 31, 38 pts were enrolled in the study and had received at least one dose of TQB3455, 35 with AML and 3 with MDS. Baseline characteristics are detailed in Table 1. Pts received daily TQB3455 doses of 25mg(n=1), 50mg(n=1), 75mg(n=3), 100mg(n=3), 150mg(n=7), 300mg(n=1). When the dose escalated to 300mg, the patient experienced a DLT of pneumonia, then the dose was switched back to 150mg. The 150mg cohort was expanded to 7 evaluable patients and 1 patient experienced a DLT of differentiation syndrome. Therefore, the RP2D of TQB3455 was identified as 100 mg daily. 22 additional pts were enrolled on this dose during the expansion phase. Safety analysis was performed in all patients. The most frequent Grade 3-4 TEAEs in all regimens were 25mg(n=1, 100%), 50mg(n=1, 100%), 75mg(n=2, 66.67%), 100mg(n=13, 68.42%), 150mg(n=7, 87.50%) and 300mg(n=1, 100%). The most frequent TEAEs were pancytopenia(Table 2). 24 pts discontinued treatment, primarily due to progressive disease or relapse (n=17, 44.74%), adverse events (n=1, 2.63%), withdrawal by patient (n=3, 7.89%) or death (n=2, 5.26%). Efficacy was analyzed only in patients with AML. Three pts was not evaluable for response due to withdrawal by patients before the first efficacy evaluation. Of the 32 evaluable pts, overall response rate (ORR) was 40.63 %, including 12 pts (37.5%) in complete remission(CR) or CR with incomplete hematologic recovery (CRi), 1 pts (3.13%) in partial remission (PR). TQB3455 shows more powerful inhibitory effects on IDH2-R172K rather than IDH2-R140Q/W mutation (ORR, 66.67% vs 25.00%, p=0.03; CR, 41.67% vs 15.00%, p=0.12). The presence of FLT3 and/or RAS co-mutations at study entry was significantly associated with lack of response (ORR, 10% vs 45.46%; CR, 10% vs 31.82%). Median duration of response was 9.17 months (95% CI 7.39-not reached). After a median follow up of 5.49 months, the median overall survival (mOS) was 7.43 months (95% CI 5.55- not reached). Conclusion: TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA. These encouraging findings have prompted further studies of TQB3455 combination therapy in patients with mIDH2 AML and MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: Results of a Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Background: In immune thrombocytopenia (ITP), immunoglobulin G (IgG) platelet autoantibodies accelerate platelet clearance and impair platelet production. IgG homeostasis is regulated by the neonatal Fc receptor (FcRn). Efgartigimod (EFG), a human IgG1 Fc-fragment, is a natural ligand of FcRn engineered to competitively bind to FcRn with high affinity and prevent recycling of endogenous IgG, but not albumin, thereby reducing IgG levels including IgG autoantibody levels. Methods: The efficacy and safety of intravenous (IV) EFG were evaluated in ADVANCE, a phase 3, multicenter, randomized, double-blinded, placebo (PBO)-controlled trial (NCT04188379) in adults with persistent or chronic ITP. Participants with an average of 2 platelet counts (PLTs) of <30×109/L during screening were randomized 2:1 to receive 10 mg/kg EFG or PBO for 24 weeks. Concurrent oral corticosteroids, oral immunosuppressants, dapsone, danazol, fostamatinib, and oral thrombopoietin receptor agonists (not romiplostim) were permitted but required to remain at the entry dosage and frequency. Participants received weekly dosing (weeks 1-4) followed by response-dependent weekly or every 2 weeks (q2w) dosing (weeks 5-16) and then maintained their dosing regimen from weeks 17-24. The primary and key secondary endpoints were tested in hierarchical order. The primary endpoint was the proportion of chronic ITP participants with a sustained PLT response (PLT of ≥50×109/L in ≥4 of 6 visits between weeks 19 and 24 without intercurrent events, e.g., rescue therapy at week 12 or later). Key secondary endpoints included extent of disease control (cumulative weeks with PLTs of ≥50×109/L) in the chronic population, proportion of participants in the overall population (chronic and persistent) with sustained PLT response, incidence of bleeding events, and a durable sustained platelet response (PLT of ≥50×109/L in ≥6 of 8 visits between weeks 17 and 24) in the overall population. Safety and pharmacodynamic measures were also evaluated. Results: 131 participants (118 chronic ITP, 13 persistent ITP; 86 EFG, 45 PBO) were randomized. Participants had long-standing, severe ITP (median time since diagnosis of 4.57 years; baseline median PLT of 17×109/L) and were heavily pretreated (67.2% had ≥3 prior ITP therapies). In chronic ITP participants, sustained PLT response was reached in more EFG-treated participants (21.8%; 17/78) than PBO (5.0%; 2/40; p=0.0316). EFG achieved all PLT-related secondary endpoints (Table1). Model-based mean changes from baseline in PLT levels over time showed a clear differentiation from PBO as of week 1, indicating an early onset of PLT response in the EFG group. A sustained PLT response was achieved in 90% (9/10) of participants who reached and maintained the q2w fixed dosing. EFG-treated participants responded better than PBO regardless of age, sex, severity of disease, time since diagnosis, prior ITP treatment, or background medication (Figure1). International working group (IWG) response (consecutive visits ≥7 days apart with PLTs of ≥30×109/L and 2-fold increase from baseline in the absence of bleeding events) was seen in 51.2% (44/86) of EFG treated participants compared to 20.0% (9/45) in the PBO group. Mean IgG levels in EFG-treated participants decreased steadily over the first 4 weeks of treatment, after which the mean maximum reductions from baseline remained greater than 60% throughout the trial. Mean IgG levels were similar in the group on q2w treatment. Adverse events (AEs) were reported in 93.0% (80/86) of participants in the EFG group and 95.6% (43/45) in the PBO group. Most frequent AEs included bruising, headache, hematuria, and petechiae. Serious AEs were reported in 8.1% (7/86) of participants in the EFG group and in 15.6% (7/45) in the PBO group, and none were treatment related. These included bleeding or events related to bleeding (n=5), infections (n=4), and worsening primary ITP (n=3). No deaths or increased risk of infection were observed. Conclusions: Compared to PBO, EFG showed an early PLT increase, higher sustained PLT response, and more weeks with PLT ≥50×109/L. EFG achieved the primary and all PLT-related secondary endpoints and also showed that 51.2% of participants on EFG achieved IWG response criteria versus 20% on PBO. EFG was well tolerated with no new safety signals. Long-term efficacy and safety data are being evaluated in the open-label extension trial (ADVANCE+; NCT04225156). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 5435: CCRL2 affects the sensitivity of MDS and secondary AML to azacitidine

Abstract INTRODUCTION: We recently found that the atypical chemokine receptor, CCRL2 promotes the growth of MDS and secondary AML (sAML) while CCRL2 knockdown inhibits their growth. The aim of the current study is to investigate if CCRL2 regulates pathways associated with the development of resistance to hypomethylating agents (HMA), commonly used drugs in MDS and occasionally sAML. MATERIALS AND METHODS: We used lentivirus-mediated transduction of MDS92, MDS-L and TF-1 MDS/sAML cells to suppress CCRL2 expression. Two different shRNA constructs were used. We performed RNA sequencing and gene-set enrichment analysis of CCRL2 knocked down (KD) and wild-type (WT) TF-1 cells. We measured DNA methyl-transferases’ expression by western blot, CD11b and CD71 expression was measured in MDS and sAML cells to assess cell differentiation. Apoptosis was measured by Annexin V/PI staining, and clonogenicity by methylcellulose assays. CD34+ cells were sorted from bone marrow aspirates of MDS patients before the initiation of treatment with HMA by using magnetic beads and measurement of CCRL2 was performed by flow cytometry. Response to HMA in MDS patients was assessed by 6 months of treatment based on the International Working Group response criteria. RESULTS: CCRL2 KD cells demonstrated suppression of pathways associated with PRC2 complex activity, histone modification, and DNA methylation. CCRL2 KD also lead to a more prominent degradation of DNMT1, DNMT3A and DNTM3B under azacitidine treatment. CCRL2 increased apoptosis in response to 0.5 and 1 μM azacitidine (P&amp;lt;0.010) and MDS-L cells (P&amp;lt;0.010 with both sh1 and sh2). Similarly, CCRL2 knockdown increased morphologic differentiation with both 0.5 and 1 μΜ azacitidine (P&amp;lt;0.010) as well as increased the clonogenic inhibition caused by azacitidine (P&amp;lt;0.05). In order to analyze the effect CCRL2 clinically, we analyzed CCRL2 expression in CD34+ cells from patients undergoing HMA treatment. Non-responders to HMA (progressive disease) express higher levels of CCRL2 compared to CD34+ cells from responders (complete remission, partial remission or stable disease) (P=0.020). DISCUSSION: Our analysis suggests that CCRL2 regulates the expression of genes associated with induction of PRC2-mediated histone modification and DNA methylation in sAML cells. CCRL2 suppression also increased the sensitivity of MDS and sAML cells to azacitidine. In addition, increased CCRL2 expression in MDS cells is associated with worse response to HMA. These data suggest that targeting CCRL2 has therapeutic potential in MDS and sAML. Citation Format: Theodoros Karantanos, Patric Teodorescu, Brandy Perkins, Marios Arvanitis, Ilias Christodolou, Christopher Esteb, W. Brian Dalton, Tania Jain, Amy E. DeZern, Lukasz P. Gondek, Mark J. Levis, Gabriel Ghiaur, Richard J. Jones. CCRL2 affects the sensitivity of MDS and secondary AML to azacitidine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5435.

Genomic landscape of myelodysplastic/myeloproliferative neoplasm can predict response to hypomethylating agent therapy

There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative overlap neoplasm (MPN) patients’ response to hypomethylating agents (HMA). Forty-three patients with MDS/MPN who were treated with HMA during chronic phase and had next-generation sequencing using the established 63-genes panel were identified. Complete and partial remission and marrow response were assessed based on the MDS/MPN International Working Group response criteria. On univariate analysis, younger age, higher number of mutations, and mutations in SETBP1, RUNX1, or EZH2 were associated with no response. Multivariable analysis for modeling response were conducted via least absolute shrinkage and selection operator logistic regression approach, and showed that mutations in SETBP1, RUNX1, or EZH2 predict lack of HMA response. While limited by sample size, our findings suggest that genomic landscape can potentially identify MDS/MPN patients with lower likelihood of response to HMA.

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

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

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients.

Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven)

Background:The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML.Methods:Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression.Results:82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS.There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10).Conclusions:Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. [Display omitted] DisclosuresMannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Frontline Venetoclax (ven) Based Combination Therapy in Older Adults with Acute Myeloid Leukemia Treated in the Real-World Setting; A Multi-Institutional Retrospective Study

Introduction: Acute myeloid leukemia (AML) is a disease of the older population, with a median age at diagnosis of 68 years. Outcomes remain poor for patients (pts) older than 60 years of age who are unfit to receive intensive chemotherapy. Ven based combination therapy has become the standard of care based on the results of the Viale-A and Viale-C in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), respectively. This combination therapy is myelosuppressive leading to multiple dose adjustments in the real-world setting, which may impact the validity of the trial responses and overall survival (OS) in a community-based practice. We therefore sought to investigate the outcomes of pts treated with ven based combination therapy in the real-world setting to better understand efficacy and patterns of adverse events.Methods: Pts 65 years of age or older, diagnosed with AML on or after January 1, 2019, and who received frontline ven based combination therapy with azacitidine (aza), decitabine (dac) or LDAC were identified in the COTA real-world database. The COTA database is a USA-based dataset comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of pts with cancer. Clinical outcomes, including real-world overall response rate (rwORR), OS and adverse events were calculated by treatment group. Responses were defined per treating physician as complete response (CR) or partial (PR) or progressive disease (PD). Categorical variables and rwORR were compared using Fisher's exact test. Survival outcomes were calculated using the Kaplan-Meier method and compared amongst groups using log-rank test.Results: A cohort of 112 pts were treated with ven based combination: ven/aza (n=54), ven/dac (n=52) and ven/LDAC (n=6). Across all treatment groups, the majority (91.1%) of pts were treated in the community setting. The median age at diagnosis was 77 yrs (IQR: 71-81 yrs). Per ELN risk, 6.2% had favorable, 19.6% had intermediate and 62.5% had high-risk AML. Five of the 6 pts receiving ven/LDAC had secondary AML (Table 1). The most common molecular abnormalities across the cohort were TP53 (38.4%), TET2 (26.8%), ASXL1 (27.7%), and DNMT3A (20.5%). The rwORR by treatment was 57.7% for ven/dac, 55.6% for ven/aza and 33.3% for ven/LDAC (ven/dac vs. ven/aza, p=0.85). Median OS (mOS) was similar for ven/dac with a longest mOS of 13.9 mo, followed by ven/aza with a mOS of 11.3 mo, and ven/LDAC mOS of 6.5 mo (ven/dac vs. ven/aza, p=0.77). The most common reasons for treatment discontinuation were toxicity (32.1%) followed by progression/inadequate response (10.7%). The most common toxicities were related to myelosuppression/cytopenias (Table 3). In this cohort, only 6 pts underwent an allogeneic stem cell transplant in first remission and no pts underwent an allogeneic transplant in second remission.Conclusions: To our knowledge, this dataset represents the largest cohort of pts treated with ven based combination therapy in the real world setting across multiple community practices. As less intense regimens are used to treat AML, more pts are receiving induction in the community setting, making these findings relevant in clinical practice. Although ven/dac combination had the longest OS, this was not significantly different from ven/aza. The ven/HMA response rates were lower and survival outcomes were shorter than those reported in the Viale-A trial, which raises concerns about early discontinuation of therapy in the real world setting due to myelosuppression. Ven/LDAC combination had the shortest OS, though most of these patients had sAML. Despite this enriched population for targeted therapies, the outcomes remained poor overall.There are drawbacks to interpreting retrospective outcomes data. First, there were no treatment related AML cases in this dataset, which would be highly unusual in an elderly population of 112 cases of AML. It is more plausible that the diagnosis of treatment related AML was not utilized in the patient's chart. Other data points that were not adequately captured were cause of death and International Working Group response criteria. Mutational panel testing remains underutilized for AML patients in a community-based practice setting. However, this dataset highlights the need for larger datasets to compare the outcomes of AML therapy by practice setting. [Display omitted] DisclosuresMadanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Hansen: COTA, Inc.: Current Employment. Foss: COTA, Inc.: Current Employment. Schulte: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

The Presence of SETBP1, RUNX1 or EZH2 Mutation in MDS/MPN Is Associated with Absence of Response to Hypo-Methylating Agents

INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN.PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and marrow response (MR) were assessed based on the MDS/MPN International Working Group response criteria. Univariate logistic regression analysis was used to associate the number of somatic mutations or high-risk (HR) mutations (NRAS, SETBP1, RUNX1, EZH2, TP53, ASXL1, STAG2), and other disease specific factors at the time of the initiation of HMA with response categories. Multivariable analysis for modeling response were conducted via Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression approach, where the predictors were selected based on 5-fold cross validation with turning parameter selected to minimize deviance of logistic regression model. Kaplan-Meier was used to assess the overall survival based on the CR/PR status at 6 months from the initiation of HMA in landmark analysis. Cox-regression analysis considering the occurrence of CR/PR as a time-varying covariate was used to assess the impact of CR/PR on overall survival.RESULTS: Fifteen women and 28 men with a median age 67 years (range: 45 - 85 years) and a median follow up of 1.5 years (range: 91 days - 5.2 years) were included. Twenty five (58.1%) had CMML, 15 (34.9%) had MDS/MPN-U and 3 (7%) had aCML. Thirty-four patients (79.1%) received azacitidine (median number of cycles: 4.5, range: 1 - 65) and 9 patients (20.9%) received decitabine (median number of cycles: 4, range: 3 - 21). Seventeen patients (39.5%) underwent BMT following HMA therapy. The incidence of AML transformation was 16%. No patients had CR while 56% achieved a PR and 42% had an MR. Univariate analysis showed that ≥2 HR mutations (OR 0.19, 95% CI 0.05-0.67), SETBP1 mutation (OR 0.16, 95% CI 0.02-0.76), RUNX1 mutation (OR 0.1, 95% CI 0.01-0.48) and a mutation in at least one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.05, 95% CI 0.01-0.21) were associated with absence of PR. ≥2 HR mutations (OR 0.23, 95% CI 0.05-0.9), and the presence of a mutation in one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.16, 95% CI 0.03-0.62) were associated with absence of MR on univariate analysis. Finally, older age as a continuous variable was associated with PR (OR 1.09, 95% CI 1.01-1.19) and MR (OR 1.12, 95% CI 1.03-1.24). Presence of a mutation in one of the SETBP1, RUNX1 and EZH2 genes with age adjusted was selected from LASSO approach and significantly predicted the absence of PR (OR 0.05, 95% CI 0.01-0.27), and MR (OR 0.19, 95% CI 0.04-0.91) (Table 1). Using the landmark of 6 months after the initiation of treatment, Kaplan-Meier analysis showed that PR at 6 months was associated with superior overall survival (P=0.010) compared to patients with no response (Figure 1). Similarly, Cox-regression analysis revealed that the occurrence of PR following the initiation of treatment was associated with better overall survival (HR 0.26, 95% CI 0.9-0.13, P=0.010).CONCLUSIONS: Mutations in SETBP1, RUNX1 or EZH2 genes predicted absence of response to HMA among patients with MDS/MPN independent of other factors including karyotype, blast percentage and R-IPSS. These findings suggest that the molecular profile of MDS/MPN patients can potentially identify patients with HMA-refractory phenotype. Multi-institutional studies of larger cohorts are required to verify these results and develop novel treatment strategies especially for patients with high-risk mutations in MDS/MPN.Figure 1. Kaplan-Meier estimates of OS by PR status at 6 months in landmark analysis. P-value was based on log-rank test. [Display omitted] DisclosuresLevis: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas and FujiFilm: Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Jain: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy.

A Phase 1 Dose Escalation Study of Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor PRT543 in Patients with Myeloid Malignancies

A Phase 1 Dose Escalation Study of Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor PRT543 in Patients with Myeloid Malignancies

Meaningful response criteria for myelodysplastic syndromes

Standardizing response criteria for myelodysplastic syndromes (MDS), a clinically and biologically heterogeneous group of disorders, has been historically challenging. The International Working Group (IWG) response criteria, first proposed in 2000 and modified in 2006 and 2018, represent the best effort by a group of international experts to define a set of clinically meaningful end-points in MDS. These criteria have been adopted in many MDS clinical trials, allowing for comparisons of response across trials. However, clinical experience has also revealed some limitations of these criteria, and most of the end-points proposed by the IWG require further validation. In this review, we present a critical analysis of the current MDS response criteria from both a practical standpoint and based on currently available clinical trial data. Potential areas for improvement in the criteria are highlighted, which may be considered in future iterations of the response criteria.