Poor Risk Cytogenetics Research Articles

Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.

Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.

AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality. We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 109/L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS. The median age was 65 years (range, 23-86); the median WBC was 146 × 109/L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3, NPM1, and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109/L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS. Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.

Mutation profiles and outcomes of patients with acute myeloid leukemia with autoimmune disease.

6536 Background: Therapy-related acute myeloid leukemia (t-AML) defines a group of patients who develop AML after being treated with chemotherapy or radiation therapy. Most of these patients have a history of malignancy, but some have exposure to cytotoxic therapy for non-cancerous conditions such as autoimmune diseases (AD). This study looked at the characteristics, genetics, and outcomes of patients with AD and AML. Methods: This study included patients diagnosed with AML from 1999 - 2019. AML was divided into 4 groups: de novo AML, AD- AML (AML after AD diagnosis), t-AML (excluding AD-AML), secondary AML (s-AML) (AML arising out of myelodysplastic syndrome or myeloproliferative neoplasm). All molecular data were obtained via next generation sequencing (NGS) of genes frequently observed to be mutated in AML and analyzed using Chi-square test. BUM method was used to control false-discovery rate (FDR) at 8%. Overall survival (OS) and progression free survival (PFS) were estimated by Kaplan-Meier method and compared using log rank test. Results: A total of 1587 pts were included: 10.1% (n=160) with AD-AML, 71.3% (n=1131) de novo AML, 13.1% sAML (n=208) and 5.6% t-AML (n=88). The median age at diagnosis was 54.5 years; 54% were male; 67.3% received intensive induction therapy (Intensive defined as a 7+3 regimen). Cytogenetic (CG) data were available for 97.3% pts. According to MRC 2010 classification, CG were favorable in 14%, intermediate in 57%, and poor in 28% of the pts. The most prevalent AD were Crohn's/ulcerative colitis (n=30, 17%) and rheumatoid arthritis (n=23, 13%); 10.6% of pts had 2 disorders. In AD-AML group, the median age at diagnosis of first AD was 53 years; the median interval from AD diagnosis to AML was 82.5 months (mo); the majority of pts (56.25%) did not receive treatment (not including steroids) for their AD; 23.8% of pts were treated with immunomodulating agents, 23.1% with cytotoxic agents and 15% with anti-inflammatory agents; 20.1% received ≥ 2 drug classes. Poor risk CG were more common in AD-AML than in de novo AML (30% vs. 12.2%, p&lt;.0001). Mutations in NF1 were more common in AD-AML (9.7%) than in de novo (2.7%), sAML (1.0%), and t-AML (2.7%, p=0.024). FLT3 mutations were less common in AD-AML (9.5%) than in de novo (36.1%) and t-AML (33.3%, p=0.004). Mutations in SRSF2 were more common in AD-AML (20.3%) than in de novo (12.3%) and sAML (8.8%, p=0.119). Median PFS varied among de novo (8 mo), AD-AML (6 mo) and t-AML (5 mo) groups. For the AD-AML grp, the median OS was 9 months; less than the de novo AML (11 mo), and greater than t-AML (6 mo) and sAML (6 mo, p&lt;0.0001). Conclusions: Patients with AML and a prior history of AD have CG profile and outcomes similar to those with t-AML but with distinct molecular features (i.e. NF1 and SRSF2). These findings need to be validated in large series; however, they suggest that the MAPK signaling pathway as well as spliceosome inhibitors might be a future focus of investigation in pts with AD-AML.

A post-hoc analysis of outcomes of patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) who received oral azacitidine (Oral-AZA) maintenance therapy in the QUAZAR AML-001 study.

6522 Background: AML-MRC represents 25%–34% of all AML cases, and patients with this AML subtype generally have poor outcomes. In this subanalysis of the QUAZAR AML-001study, we report outcomes of patients with AML-MRC who received Oral-AZA vs placebo (PBO). Methods: QUAZAR AML-001 was a phase 3 study of Oral-AZA maintenance therapy in patients with AML in first remission after intensive chemotherapy who were not eligible for hematopoietic stem cell transplantation (HSCT). Patients ≥ 55 years of age with AML and intermediate- or poor-risk cytogenetics received Oral-AZA 300 mg or PBO QD for 14 d per 28-d cycles. In this analysis, WHO 2008 criteria were used to identify patients with secondary AML and/or patients with AML-MRC (both groups are referred to as AML-MRC in this analysis). Data on mutational profiles at diagnosis were not available. Overall survival (OS) from time of randomization to time of death from any cause after censoring for HSCT, and relapse-free survival (RFS) from time of randomization, were calculated using the Kaplan–Meier method. Duration of measurable residual disease (MRD) negativity achieved on treatment was calculated from the first MRD-negative assessment. Results: Overall, 101/472 patients had AML-MRC; 56/238 (23.5%) patients in the Oral-AZA arm and 45/234 (19.2%) patients in the PBO arm. Karyotype/cytogenetics data at diagnosis were available for 87/101 (86.1%) patients with AML-MRC and 331/371 (89.2%) patients with non-AML-MRC. A greater proportion of AML-MRC than non-AML-MRC patients had poor-risk cytogenetics (20/101 [19.8%] vs 46/371 [12.4%]), del(5q) (10/87 [11.5%] vs 9/331 [2.7%]), and monosomy 7/del(7q) (9/87 [10.3%] vs 14/331 [4.2%]). Median OS did not significantly differ in patients with AML-MRC vs non-AML-MRC in either treatment arm (Oral-AZA: 19.9 mo vs 25.1 mo, P = 0.2694; PBO: 14.8 mo vs 14.9 mo, P = 0.2099). In both treatment arms, the median RFS was inferior for patients with AML-MRC vs non-AML-MRC (Oral-AZA 7.5 mo vs 10.5 mo, P = 0.0430; PBO: 3.7 mo vs 4.9 mo, P = 0.0109). Oral-AZA significantly prolonged median OS and RFS, and the duration of MRD negativity for patients with AML-MRC compared with PBO (Table). Conclusions: Oral-AZA significantly improved OS and RFS compared with PBO for patients with AML-MRC indicating that Oral-AZA maintenance is an effective treatment option for these patients with particularly poor prognosis. Clinical trial information: NCT01757535 . [Table: see text]

Improved long-term survival rate in the responders to bortezomib, cyclophosphamide, dexamethasone induction therapy in a transplant-eligible cohort of predominantly middle-age multiple myeloma patients.

Multiple myeloma (MM) represents the second most common hematologic malignancy (15%). Induction with bortezomib, cyclophosphamide, and dexamthasone VCd (d: low dose dexamthasone) regimen is widely used due to its high effectiveness, low toxicity and good tolerability, particularly with renal impairment. Real-world data on the use of VCD in clinical practice is lacking. Evaluate the real-world experience of the VCD regimen. Retrospective. Tumor registry database of tertiary cancer care center. newly diagnosed MM patients who received VCD induction and underwent autologous stem cell transplant (ASCT) from July 2007 to July 2020. response evaluation, progression-free survival (PFS) and overall survival (OS). 87 patients. Of 102 patients who started induction with VCd, 87 patients experienced a partial response or more overall response rate of 85%). The median age of these 87 patients at diagnosis was 52 years, of which 29.9% presented with renal impairment and 60.3% of patients had stage 2 by the Revised International Staging System (R-ISS). Patients with a standard cytogenetic risk achieved a better response compared to those with a poor cytogenetic risk (P=.044). The post-induction response rates were 6.9% stringent complete remission (sCR), 35% complete remission (CR); 41.4% very good partial response (VGPR), and 16.1% partial response (PR), respectively; the response rates became greater for sCR and CR post-transplantation at day 100 with 16.1% sCR, 35.6% CR, 32.2% VGPR and 16.1% PR, respectively. The median PFS was 49 months and 5 years OS was 84%. PFS was better in patients who achieved sCR vs PR (83 vs 35 months, P=.037). High LDH, high-risk cytogenetic and stage 3 R-ISS showed a worse median PFS and OS. VCD induction in newly diagnosed MM is highly effective, convenient, tolerable and affordable regimen, especially in low and middle-income countries with limited resources, also with favorable outcomes and survival. while those who did not respond successfully shifted to VRD or VTD. The usual limitations of a retrospective analysis using registry-level data, no data on quality of life.

Prognostic factors in haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia

Background aimsHaploidentical hematopoietic stem cell transplantation (haplo‐HCT) is an appropriate option when an HLA-matched related or unrelated donor is not available. Haplo-HCT using post-transplant cyclophosphamide (PTCy) is being increasingly performed worldwide due to its effective suppression of GVHD and its safety. MethodsWe conducted a large nationwide cohort study to retrospectively analyze 366 patients with acute myeloid leukemia undergoing haplo‐HCT with PTCy between 2010 and 2019 and to identify prognostic factors. ResultsA multivariate Cox analysis revealed that an older recipient age (≥60 years), a male donor to a male recipient, a cytomegalovirus IgG-negative donor to a cytomegalovirus IgG-positive recipient, a poor cytogenetic risk, a noncomplete remission status at the time of transplantation, and a history of HCT were independently associated with worse overall survival (OS). Based on each hazard ratio, these factors were scored (1–2 points) and stratified by their total score into three groups: favorable (0–1 points), intermediate (2–3 points), and poor (4 points or more) groups, and 2-year OS rates were 79.9%, 49.2%, and 25.1%, respectively (P < 0.001). ConclusionsThe present study revealed significant prognostic factors in haplo‐HCT with PTCy, and a scoring system based on these factors may be used to predict outcomes.

Real-world Effectiveness of Azacitidine in Treatment-Naive Patients With Higher-risk Myelodysplastic Syndromes

IntroductionAzacitidine (AZA) is an approved frontline therapy for higher-risk myelodysplastic syndromes (HR-MDS); however, poor survival denotes unmet needs to increase depth/duration of response (DOR). MethodsThis retrospective study with patient chart review evaluated AZA effectiveness in 382 treatment-naive patients with HR-MDS from a US electronic health record (EHR)–derived database. Responses were assessed using International Working Group (IWG) 2006 criteria; real-world equivalents were derived from EHRs. Primary endpoint was IWG 2006-based complete remission rate (CRR). Secondary endpoints were EHR-based CRR, IWG 2006- and EHR-based objective response rates (ORRs), duration of CR, DOR, progression-free survival, time-to-next-treatment, and overall survival (OS). ResultsUsing IWG 2006 criteria, the CRR was 7.9% (n = 30); median duration of CR was 12.0 months (95% CI, 7.7-15.6). In poor cytogenetic risk (n = 101) and TP53 mutation (n = 46) subgroups, CRRs were 7.9% (n = 8) and 8.7% (n = 4), respectively. ORR was 62.8% (n = 240), including a hematologic improvement rate (HIR) of 46.9% (n = 179). Using EHR-based data, CRR was 3.7% (n = 14); median duration of CR was 13.5 months (95% CI, 4.5-21.5). ORR was 67.8% (n = 259), including an HIR of 29.3% (n = 112). Median follow-up was 12.9 months; median OS was 17.9 months (95% CI, 15.5-21.7). ConclusionsConsistent with other studies, CRRs and median OS with AZA in treatment-naive patients with HR-MDS were low in this large, real-world cohort. Novel agents/combinations are urgently needed to improve these outcomes in HR-MDS.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory tointensive chemotherapy.

The Impact of DNMT3A Mutation on Survival of AML Patients Receiving Allogeneic Hematopoietic Cell Transplantation in First Remission Depends on the Karyotype and Co-Occurring Mutations: On Behalf of the EBMT Acute Leukemia Working Party

DNMT3A gene mutations are more frequent in cytogenetically normal acute myeloid leukemia (AML) and frequently associated with NPM1 mutation and internal tandem duplication (ITD) of the FLT3 gene. However, DNMT3A mutation is not included as a distinct prognostic group in the recent European Leukemia Net (ELN) 2022 genetic risk classification of AML. In the context of allogeneic hematopoietic cell transplantation (allo-HCT), the prognostic value of DNMT3A is still not well studied. We evaluated, through the European Society for Blood and Marrow Transplantation (EBMT) registry, the impact of DNMT3A mutation, according to the karyotype, and NPM1 and FLT3-ITD mutation status, on post-transplant outcomes in AML patients receiving allo-HCT in first complete remission (CR1). We identified a total of 1374 adult AML patients (51% female, median age 57 years; range 18-78 years) with ELN-2022 intermediate- or poor-risk cytogenetics and available DNMT3A, FLT3ITD and NPM1 mutation status, who underwent their first allo-HCT in CR1 between 2013 and 2021. Of these, 631 (46%) patients had DNMT3A mutation. Patients with mutant DNMT3A were more likely to be female (57% versus 46%, p&amp;lt;0.001), to have normal cytogenetics (75% versus 54%, p&amp;lt;0.001), FLT3-ITD co-mutation (50% vs 23%, p&amp;lt;0.001), NPM1 co-mutation (60% vs 21%, p&amp;lt;0.001), and to receive a myeloablative conditioning and in vivo T cell depletion. After a median follow-up of 2.3 years, the 2-year leukemia free survival (LFS) and overall survival (OS) were 62% and 69%, respectively. The subsequent analysis was split according to baseline karyotype (normal or abnormal). Among 870 patients with normal cytogenetics, 472 (54%) patients had DNMT3A mutation. The 2-year relapse incidence (RI), LFS and OS were 24%, 63% and 70% respectively, in patients with DNMT3A mutation compared to 18%, 69% and 74% in patients with wild type DNMT3A. Among these patients with normal karyotype, multivariable analyses (MVA) were done within the 4 groups of FLT3-ITD and NPM1 mutations. Within the group of 324 patients with both FLT3-ITD and NPM1 positives, 244 were triple-positive (75%), LFS and OS were not significantly different with and without DNMT3A mutation (2y LFS: 62% vs 63%, HR: 0.98, p=0.95; 2y OS: 70% vs 73%, HR: 1.17, p=0.58). Conversely, among 146 patients with NPM1 mutation without FLT3-ITD, LFS was significantly lower for 91 patients with DNMT3A mutation (2y LFS: 68% vs 87%, HR: 2.70, p=0.02) but OS was not significantly different (2y OS: 79% vs 87%, HR: 2, p=0.13). On the other hand, among 318 with wild type NPM1 and without FLT3-ITD, LFS and OS were not significantly different for 108 patients with DNMT3A mutation compared to 210 patients with wild type DNMT3A (2y LFS: 62% vs 67%, HR: 1, p=0.98; 2y OS: 65% vs 71%, HR: 1.02, p=0.94). Conversely, among 82 patients with FLT3-ITD and wild type NPM1, 2-year LFS and OS were 53% and 58% respectively, for 29 patients with DNMT3A mutation compared to 71% and 76% respectively, for 53 patients with wild type DNMT3A. The number of patients didn't allow to perform MVA in this group. Finally, among 504 patients with abnormal cytogenetics, 159 (31%) patients had DNMT3A mutation. On MVA, DNMT3A mutation did not significantly affect LFS or OS. Poor-risk cytogenetics was associated with worse LFS, OS and increased RI. Older age negatively affected LFS and OS. In conclusion, in AML patients allografted in CR1, the impact of DNMT3A mutation depends on the karyotype and co-occurring mutations. Our data suggest that DNMT3A mutation negatively affects post-transplant survival selectively in patients with normal karyotype and either NPM1 mutation without FLT3-ITD, or patients with normal karyotype, FLT3-ITD and wild type NPM1. DNMT3A mutation shows no impact on post-transplant outcomes in other settings.

CLAG-Based Chemotherapy in Previously Untreated AML Patients: 12 Year Follow-up

Introduction: The 7+3 combination of cytarabine plus an anthracycline is the most commonly used induction regimen for AML in the US. There is evidence FLAG-IDA may be superior to 7+3 (Solh et al Leuk Res 2020), and that cladribine is superior to fludarabine (Holowiecki et al JCO 2012). Currently we report the results of CLAG-based chemotherapy in newly-diagnosed AML patients. Methods: This single-center retrospective cohort studied all patients with newly-diagnosed AML who received CLAG-based induction therapy (with or without an anthracycline, depending on cardiac function) between February 2011 and June 2023. Chemotherapy consisted of cladribine 5 mg/m 2 daily times 5 days, cytarabine 2 gm/m 2 over 4 hrs daily times 5 days (given 2 hours after the completion of each cladribine dose), plus G-CSF 300 ug daily during chemotherapy and then based on weight after that. Patients with adequate cardiac function also received 3 days of mitoxantrone 12 mg/m 2 (CLAG-M) or idarubicin 12 mg/m 2 (CLAG-IDA) on days 1-3 or 2-4. Many of these patients were treated prior to the current era of targeted therapies and thus most received chemotherapy without targeted agents. Post-remission therapy was given at the physician's discretion based on the patient's tolerance of induction chemotherapy. Complete response (CR) was defined as less than 5% blasts in the marrow with recovery of ANC &amp;gt;1000/mm 3 and platelets &amp;gt;100,000/mm 3. Lesser responses included CRi, CRp and PR. All others were considered failures or early deaths (within 30 days). This study was approved by the IRB of New York Medical College. Results: We analyzed all 87 newly-diagnosed AML patients that were treated with CLAG-based induction therapy (CLAG alone: 10%, CLAG-IDA: 87%, CLAG-M: 3%). 4 patients with a FLT-3 mutation received a FLT-3 inhibitor concurrently. Post-remission therapy included allo transplant (13%), further CLAG+/- IDA, reduced to 4+2 days (84%), HiDAC (27%), and hypomethylators (36%), in that order of priority. The intensity of the post-remission therapy was matched with the perceived ability of the patient to tolerate it. Many patients received more than one post-remission therapy in sequence. The median age of the cohort was 65 (33-85) years. 59% were male, 47% were smokers, 6% had prior MDS and 13% had therapy-related AML. The median baseline WBC was 9.7 (0.4-392) k/mm 3. 10% of patients were stratified as favorable ELN cytogenetic risk, 45% as intermediate, and 45% as adverse. TP53 mutation was present in 22% patients and FLT3 mutation in 14% patients. CR was obtained in 67% of patients overall and did not differ significantly by age (&amp;lt;60: 65%, 60-70: 70%, &amp;gt;70: 64%). Early deaths (within 30 days) were more common in older patients (&amp;lt;60: 3%, 60-70: 3%, &amp;gt;70: 8%). The CR rate was similar across all cytogenetic risk groups (good risk: 67%, intermediate risk: 68%, poor risk: 62%) and was favorable in patients with a TP53 mutation (68%), as well as those with therapy-related AML (69%). The median overall survival (OS) was 13 months. By cytogenetic risk the median OS was good: not reached, intermediate: 25.6 months and poor: 6.8 months (Figure 1). It should be noted that two patients with good risk cytogenetics who expired included an 80-year-old woman with therapy-related AML after treatment for breast cancer who declined further therapy after cycle 1 and survived 20 months with no further therapy, as well as a second unvaccinated patient who expired due to complications of COVID. Median OS by age was &amp;lt;60: 18 months, 60-70: 25.6 months and &amp;gt;70: 8 months (Figure 2). Median overall survival for patients with TP53 mutation was 5.6 months. Conclusion: CLAG provides an alternative induction regimen to 7+3. Interestingly, in contrast to 7+3, CR rates did not differ significantly by age or cytogenetic risk group. The older patients treated on this trial were a select group that were considered eligible for intensive chemotherapy. Many of the patients on this trial would be treated differently today, with the availability of more targeted therapies. However the relatively high response rates in patient with poor risk cytogenetics and/or TP53 mutation gives fit patients the opportunity of pursuing stem cell transplantation.

Differences within the Immune Microenvironment May Account for Poorer Outcomes in African American AML Patients Compared to European American Patients with AML

Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from an immature myeloid progenitor with notoriously poor outcomes. A critical factor responsible for the difficulty in treating this disease evasion of the host immune system by AML. Both the innate and adaptive immune systems have been shown to be dysfunctional in AML with poor type I interferon responses, decreased STING signaling and increased populations of granulocytic and monocytic myeloid derived suppressor cells ultimately leading to poor adaptive response. Studies in solid tumors have demonstrated that variation in immunity contributes to racial disparities in cancer and outcomes. This is felt to be due to variation in geographic ancestry leading to differences in the innate immune genome required due to the need for protection against environmental pathogens. However, no data exists comparing innate and adaptive immunity by race in patients (pts) with AML. Here we sought to characterize the immune microenvironment with treatment outcomes in racially diverse AML pts. Methods: Adults with newly diagnosed AML were identified who had corresponding cryopreserved bone marrow mononuclear cells available within Roswell Park Hematologic Procurement bank. Pts were matched as closely as possible for age, gender, cytogenetic risk per ELN 2017 and molecular profile. Transcriptional differences between African American (AA, n=26) and European American (EA, n=26) AML pts and healthy controls (n=10) were analyzed using transcriptomics data from NanoString Pan Cancer Immune Profile panels. AA and EA AML samples were compared to each other, as well as their race-matched healthy controls. The ‘Limma’ package in R was utilized for differential gene expression analysis. Research was conducted according to the Declaration of Helsinki in accordance with the Institutional Review Board regulated protocol. Results: The median age of the entire cohort (n=52) was 65 years (range: 28-92), with 28 female patients (53.8%) ( Table 1). Within the AA cohort, the majority of pts had intermediate risk cytogenetics per ELN 2017 (n=19; 73.1%, and 6 pts had FLT3 mut (26.1%). Three pts (11.5%) underwent allogeneic stem cell transplant, with a median overall survival (OS) censoring for transplant of 5 months (range; 0.5-68 months) ( Figure 1). Within the EA cohort, most pts had poor risk cytogenetics (n=15; 57.7%). Six pts had FLT3 mut (26.1%), and three pts had TP53 mut (12%). Five pts underwent allogeneic stem cell transplant (19.2%), with a median OS of 16.4 months (range; 0.8-67 months). Sixty-nine significantly (p&amp;lt;0.05, |logFC|&amp;gt;1.5) differentially expressed genes in AA vs. EA pts were identified. Gene set enrichment analysis (GSEA) revealed alterations to Interferon, Jun kinase and STAT signaling pathways in AA pts. In contrast, EA pt samples were enriched for pathways related to amyloid metabolism and other T and B cell immune pathways. Master regulator analysis using LISA highlighted transcriptional dysregulation attributed to PDGB5, CTCF, AR, and NOTCH in AA pts and to GLIS2, SMAD1 and NFE2 in EA pts. Conclusions: As previously reported, we found that a clinically matched cohort of AA AML patients experienced significantly worse OS as compared to EA counterparts. We have identified several significant alterations within the immune microenvironment between cohorts, which may potentially explain this discrepancy in survival in AA patients. These differences could potentially serve as targetable alterations for therapeutic purposes. This work represents the first of its kind evaluating the immune microenvironment by race in AML patients and are awaiting confirmation in a larger cohort.

A Retrospective Comparative Analysis of Intensive Vs. Non-Intensive Chemotherapy in Treatment Naïve Acute Myeloid Leukemia (AML) Patients in India

Background &amp; Significance: Acute Myeloid Leukemia (AML) is a hematological malignancy characterized by the rapid proliferation of abnormal myeloid cells. Intensive chemotherapy has been the main stay of therapy in young adults whereas Azacytidine and Venetoclax based therapy is preferred in older and unfit patients of AML. As per Indian Acute Leukemia Research Database of (INwARD) of the Hematology Cancer Consortium, 3+7 is the most commonly used intensive chemotherapy in India induction mortality (n=392) is 16.9% (range 6.1 - 43%). (1) Another Indian Study of acute leukemia (n=268), highlighted that 54% had baseline infections. Only 40% of infected patients received induction therapy as compared to 93% of non-infected patients. Venetoclax has improved outcomes in AML. There is an unmet need for protocols for younger patients who are unfit for 3+7 due to multi drug resistant baseline infections or ECOG ≥2 or organ dysfunction. Poor risk cytogenetics and mutations are associated poor response to intensive therapies. We did retrospective comparative analysis of overall outcomes in patients receiving intensive chemotherapy versus non-intensive chemotherapy in a tertiary care centre of North India Material &amp; Methods: We did a retrospective comparison of intensive chemotherapy 3+7/ FLAG based therapy versus Azacytidine and Venetoclax based therapy since 2019. Institutional electronic medical record software (PARAS) was utilized to identify patients. Type of therapy was decided as per physician discretion. Patients who were elderly (age &amp;gt;60 years), ECOG PS 2 or more, or clinic-radiological evidence of infection. Intensive therapy included received Inj. Daunorubicin 60 mg/m2 IV once daily for 3 days and Inj. Cytarabine 100 mg/m2 IV as a continuous infusion for 7 days. Or FLAG/VEN based therapy Inj. Fludarabine 30 mg/m2 IV once daily for 4 days, Cytarabine 1500 mg/m2 IV once daily for 4 days. Inj. Filgrastim (biosimilar)5 mcg/kg s/c once daily from day 1 to ANC &amp;gt; 500 cells/ μL. Non-Intensive therapy arm received Inj. Azacytidine @75mg/m2 for 7 days with Tab Venetoclax 100mg once a day for 7-14 days as per patient tolerance. Posaconazole was used as a anti-fungal prophylaxis. We recorded baseline characteristics, type of therapy, compared the tolerability and efficacy of both the regimens. We did survival analysis using Kaplan Meier Curves and statistical analysis using SPSS version 25. Results: Baseline Data is presented in Table 1, 69 patients received intensive chemotherapy and 58 patients received non-intensive therapy. Patient in the intensive therapy arm were younger and fit whereas patients were older in the non-intensive therapy arm. Post Induction bone marrow evaluation was done between day 28 to day 35 post therapy. CR rate was 78.2 per cent in Intensive therapy arm v/s 51.7 per cent in non-intensive therapy arm. Patients were stratified as per ELN risk category. Patients in the standard risk and intermediate risk groups did better in the intensive therapy arm but outcome did not differ in patients of poor risk ELN category patients. Fig:1 Non- intensive therapy was better tolerated with fewer grade 3 or more febrile neutropenia and fewer 3 rd line antibiotics lesser duration of stay. The decision between intensive and non-intensive chemotherapy should be carefully individualized, considering patient age, performance status, cytogenetic risk, and comorbidities. Conclusion: Our study re-affirms the role of intensive chemotherapy in younger and fitter patients, however in adverse risk ELN patients non-intensive therapy appears non inferior to intensive therapy

Real-World Study in Acute Leukemia: Epidemiology, Treatment Patterns and Outcomes for Newly Diagnosed AML in Adult Patients from Latin America - Loyal Study

Introduction. Acute myeloid leukemia (AML) is the most frequent leukemia among adults and representing 90% of all cases of acute leukemia in adults. Differences in incidence and burden of AML among regions of the world have been reported. When compared with registries from the US, UK and Sweden, Latin-America (LA) AML has a younger age at diagnosis (median age of 40-47 versus 64 -67 years old). Furthermore, single center studies have suggested poor treatment outcomes in LA. For example, Silveira et al reported a median age at diagnosis of 46 y, frequency of favorable cytogenetics of 26% and median overall survival (mOS) of 12 months in the Brazilian cohort of patients with newly diagnosed AML (nAML) whereas the respective values at Oxford University were 51.5y, 11% and 48 months in British patients. However, wider studies across the region are scarce and there is a need to further explore AML patient characteristics and treatment outcomes in LA. Methods. This is a non-interventional, retrospective multicenter study that aims to describe the epidemiology, clinical and demographic characteristics, treatment patterns, survival outcomes and healthcare resource use of adult patients with nAML in Argentina, Brazil, Chile, and Colombia. Data from medical records of eligible patients that met the inclusion criteria (≥ 18 years old at diagnosis, confirmed diagnosis of nAML between 01 January 2015 and 31 December 2019, and receiving at least one line of treatment) in these LA countries were considered for the analysis, which was descriptive in nature as no hypothesis has been tested. Results: A total of 518 nAML patients were included in the study, 166 from Argentina, 205 from Brazil, 63 from Chile, and 84 from Colombia. Table 1 shows the demographics and clinical characteristics. At treatment initiation, an evaluation of fitness (eligibility) for intensive chemotherapy was available for 94% of the patients (n=489). The majority were considered fit (75.5%; n=391) and received standard 7+3 therapy. About 11% of patients (n=9) were refractory to induction therapy. Median OS for fit patients was 11.9 months, whereas for unfit patients was 5.8 months. Mutational status of genes listed by the European LeukemiaNet (ELN) Classification of 2017 was not available for the majority of cases; risk categories were assigned based on cytogenetics. Patients in the favorable-risk category had a mOS of 30.5 months, whereas those in the intermediate- and unfavorable-risk had 11.1 and 9.1 months, respectively (Figure 1). The probability of 5year OS rates for favorable, intermediate- and unfavorable-risk groups were of 38.8%, 16.6% and 20.9%, respectively. Eighty-six patients (17%) discontinued treatment with reasons being adverse event/toxicity (33%; n=28), death (32%; n=27), and disease progression (17%; n=14). Only 24% of patients (n=125) underwent a subsequent stem cell transplantation (SCT), mainly allogenic (98%; n=121). For SCTs, identical (matched) related (50%; n= 59) and haploidentical donor (35%; n=41) were the most common. Patients not eligible to intensive chemotherapy were treated with HMA (9%; n=47) and LDAC (5%; n=25), with 10% of the patients receiving palliative/supportive care. The most common treatment protocols used in relapsed or refractory (R/R) patients were high-dose cytarabine (HDAC) (31%; n=85), followed by FLAG-IDA (24%; n=66). Conclusions: This study of newly diagnosed acute leukemia characterizes real-world treatment patterns and outcomes in LA clinical practices. Prior to this study, there has been limited published data on the epidemiology and treatment patterns across LA. This study highlights that for nAML patients, the most common treatment in LA is 7+3 and most patients are classified as fit. The vast majority of patients had their risk accessed by cytogenetics analysis only, reflecting the limited access to molecular tests. Fewer patients underwent stem cell transplantation as part of the treatment compared to that reported in US and Europe, probably due to restricted availability of hospital beds dedicated to bone marrow transplantation. When evaluating the overall survival, the study shows higher mOS for favorable risk. In addition, mOS for intermediate and poor cytogenetic risk were similar. A broader access in the region to molecular tests, transplant and new therapies are needed in order to reduce the gap in outcome, especially for patients with intermediate-risk.

Efficacy and Safety of AALL0232 Protocol in Adults with Acute Lymphoblastic Leukemia: Single Institution Experience

Background Over the past few decades, the outcomes for children with ALL have significantly improved with current regimens that yield a 5-year complete remission (CR) and event-free survival (EFS) rates of 98% and 70-80%, respectively. In contrast, the adult population has a CR of 85-90%, with a less satisfactory disease-free survival (DFS) rate of only 30-40% at 5-years. The feasibility of Children's Oncology Group (COG) AALL0232 protocol in older patients has not been established, especially adults older than 40 years and whether they will tolerate such unmodified pediatric based regimen. Therefore, we planned to assess our practice's outcomes in terms of the efficacy and safety of the COG AALL0232 protocol in adult ALL patients. Method This was a retrospective observational study that included patients ≥ 14 years with newly diagnosed ALL. Patients were excluded if they have secondary ALL. Our institute has adopted the AALL0232 protocol for both B-cell and T-cell ALL due to the similarities between the AALL0232 and CALGB 10403 protocols. MRD data was not included in our study since the cut-off for detection has been changed over the study period. Patient demographics and treatment-related outcomes will be reported using descriptive statistics. OS and RFS probabilities will be calculated using the Kaplan-Meier product-limit method from the date of pre-phase initiation. All P-values will be two-sided with P &amp;lt;0.05 indicating significance. Results Between 2014 and 2022, a total of 96 patients were included in our study. 74% had B-cell and 26% had T-cell ALL. The majority of the patients had standard risk ALL (23%). 65% of the patients were receiving AALL0232 protocol. Early death with AALL0232 protocol occurred in 11.1% of our population. The 2-year OS rate was 72.6% (95% CI 61.4-81.1) (Figure 1). The OS rate for B-cell ALL was 78.5% compared to 53.8% for T-cell ALL at 2-years (P =0.0912). The use of AALL0232 protocol was comparable to other protocols in terms of survival with a 2-year OS rate of 77% and 62.3%, respectively (P=0.0761). Adults with favorable cytogenetic risk had an OS rate of 100% compared to 67.6% for standard and 49.2% for poor risk (P =0.047). Adults younger than 40 years had a higher OS rate compared to those older than 40 (76.4% vs. 54.7%, P= 0.0187). RFS rate at 2-years was durable in 68.2% of the patients (95% CI 56.8-77.2) (Figure 2). RFS rates were 72.3% for B-cell and 54.8% for T-cell ALL. The AALL0232 Protocol had a significant impact on RFS compared to other protocols (73.6% vs. 56.5%, P= 0.0277) (Figure 3). Those who were younger than 40 had an RFS rate of 73.9%. The 2-year NRM occurred in 21.7% of the population. The AALL0232 protocol did not result in a higher NRM compared to other protocols (P= 0.492). Conclusion Although the use of AALL0232 protocol in the adult population has a remarkable impact on the rate of relapse, its effect on survival remains questionable especially for patients with T-cell ALL and poor cytogenetic risk. Another point of concern is the early death rate that was observed in our study. Further studies are needed to assess the overall impact of COG protocol in the adult population.

Combination of Venetoclax and Azacitidine in Patients with Treatment-Naive, High-Risk Myelodysplastic Syndromes with Responses Leading to Stem Cell Transplantation

Introduction: The standard of care for patients with high-risk myelodysplastic syndrome (HR-MDS) who are eligible for intensive therapy includes allogeneic stem cell transplantation (SCT), which is potentially curative. Venetoclax (Ven) is a potent, selective, orally bioavailable BCL-2 inhibitor, which has a synergistic effect when combined with hypomethylating agents in preclinical and clinical investigations of myeloid malignancies. Previous results showed that the combination of Ven and azacitidine (Aza) is associated with an acceptable safety profile and leads to rapid and durable responses in patients with treatment-naive HR-MDS. Here, we report the clinical outcomes of patients with HR-MDS who proceeded to SCT following combination Ven+Aza treatment on the M15-531 clinical trial. Methods: M15-531 is a global, open-label, phase 1b clinical trial (NCT02942290) to identify the recommended phase 2 dose and to study the safety and efficacy of Ven+Aza. Eligible patients were aged ≥18 years with the following criteria: de novo treatment-naïve HR-MDS; International Prognostic Scoring System (IPSS) risk categories of Int-2 or High, or Revised IPSS (IPSS-R) categories of Intermediate, High, or Very High; &amp;lt;20% blasts in bone marrow aspirate/biopsy; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2. Aza was administered at 75 mg/m 2 subcutaneously or intravenously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle. Ven was first evaluated at 100 once daily for 14 days of a 28-day cycle, then escalated to 200 and 400 mg in separate cohorts. Clinical outcomes with Ven+Aza treatment for patients who discontinued study treatment to undergo SCT and who did not experience disease progression are reported. Results: At the data cutoff of May 31, 2023, 124 patients were treated with all doses of Ven-based therapy, and 51 (41.1%) proceeded to allogeneic SCT. Key demographics and baseline characteristics for those who received SCT are shown in the Table. Median age was 64 years (range, 26-78), 58% had an ECOG PS of 0, and 25% had poor or very poor cytogenetic risk by IPSS-R. The median number of cycles of Ven+Aza was 3 (range, 1-22). Median time on study drug was 124 days (range, 28-763), and the median time from first dose of study treatment to SCT was 5.6 months (range, 1.4-29.7). Before SCT, 21 of 51 (41.2%) patients achieved complete remission (CR). Marrow CR (mCR) was achieved by 23 of 51 (45.1%) patients, and the composite response rate (mCR with Hematologic Improvement) was 30.4% (7 of 23; 95% CI, 13.2-52.9). The median time to best overall response (time from first dose of study drug to best response of CR, mCR, partial response, or stable disease) for Ven+Aza was 2.0 months (range, 1.0-10.4). The median overall survival was not reached for patients who achieved CR or mCR and proceeded to transplant. Among patients who underwent transplant, 64.7% (33/51) remained alive at the data cut-off date Conclusion: Early responses after Ven+Aza in patients with HR-MDS enabled them to receive allogeneic SCT. After escalating doses of the combination of Ven+Aza, 41% of patients went on to SCT. These results suggest that Ven-based regimens before SCT may provide a path to curative therapy.

Precise Single-Cell Transcriptomic Mapping of Leukemia Cell States Reveals Unconventional Lineage Priming in Acute Myeloid Leukemia

Initial disease classification within acute leukemia relies on identifying morphological and immunophenotypic features of hematopoietic differentiation retained by leukemic blasts. While existing approaches can classify leukemic cells into broad lineages, they lack precision in discerning between specific cell states, particularly at the level of immature blasts. Single-cell (sc) RNA-sequencing (RNA-seq) provides thousands of new markers to enable precise determination of leukemia cell state and provides an opportunity to refine our classification of acute leukemia. To extend our ability to identify leukemia cell states by scRNA-seq, we developed a comprehensive reference map of human bone marrow hematopoiesis. Specifically, we integrated three unsorted bone marrow datasets and three CD34+ hematopoietic stem and progenitor (HSPC) purified datasets to ensure balanced representation of early HSPCs and terminally differentiated immune cells. This culminated in a curated atlas of 263,159 high-quality sc transcriptomes, representing 55 cellular states spanning 45 healthy donors (Fig 1A). We validated our cell state annotations to ensure concordance between transcriptional states and functional populations through reference mapping of bulk and sc transcriptomes from purified HSPC subsets. For example, mapping of scRNA-seq profiles from Lin-CD34+38-45RA-90+49f+ long-term (LT) HSCs revealed 91% concordance between transcriptional HSC and functional LT-HSC. We next performed scRNA-seq profiling on 12 AML patient samples harbouring either myelodysplasia-related genetic features or classical alterations involving NPM1 or KMT2A. By mapping leukemia cells onto our reference atlas, we identified pronounced involvement of early erythroid-like blasts in a subset of AML samples. To further investigate unconventional lineage priming in AML, we processed and mapped scRNA-seq profiles from eleven studies comprising 166 additional AML samples and 9 mixed phenotype acute leukemia (MPAL) samples (Fig 1B). After quality control and exclusion of mature lymphoid cells, we performed composition analysis utilizing 600,570 leukemia cells mapped to 38 cell states to identify patterns of variation among leukemia cell states. Immature leukemia cells map to a range of cellular states spanning HSC/MPP-like, LMPP-like, MLP-like, GMP-like, MEP-like, and EarlyEry-like, among others. Notably, we identified a subset of AMLs with high MLP-like enrichment that co-cluster with MPALs as well as a subset with high EarlyEry-like involvement that co-cluster with acute erythroid leukemias (AEL), thus highlighting the biological continuum between these diseases. We next identified marker genes from each leukemia cell state and trained sparse regression models to estimate their relative abundance within bulk RNA-seq cohorts. Through bulk analysis, we confirmed that MPAL is highly enriched for MLP-like cells compared to AML (p=2.5e-12) and that M6 AELs are highly enriched for EarlyEry-like cells compared to M0-M5 AMLs (p=0.00067). Among 864 AML patients, we found that high MLP-like abundance was associated with NUP98-NSD1 fusions (p=0.0011) and RUNX1 mutations (p=8.0e-10) while high EarlyEry-like abundance was associated with Complex Cytogenetics (p=8e-15) and TP53 mutations (p=2.3e-25). Cellular states of immature leukemic cells captured inter-patient heterogeneity within 136 AEL samples, wherein high EarlyEry-like abundance was associated with TP53 mutations (p=3.6e-9) and Poor cytogenetic risk (p=1.1e-9) while high GMP-like abundance was associated with KMT2A alterations (p=0.00046) and Good/Intermediate risk (p=0.00032). Finally, through integration of sc transcriptomics and targeted DNA profiling, we found examples of genetic subclones impacting the cellular hierarchies of individual patients through induction of early differentiation blocks, skewing of lineage output from myeloid to erythroid, or potentiation of transcriptional self-renewal programs within mature myeloid cells. Together, our high-resolution mapping approach highlights the cellular state continuum between acute leukemias and enumerates the impact of genetic drivers on leukemia cell hierarchies. Precise definitions of cellular states, coupled with the presence or absence of genetic alterations, may help to refine future disease classification, prognostication, and therapy development.

Clonal Dynamics of Gene Mutations during Oral Azacitidine Maintenance Therapy in Patients with Acute Myeloid Leukemia (AML): Outcomes from the QUAZAR AML-001 Trial

Background: Acute myeloid leukemia (AML) is a genetically heterogeneous disease and despite some patients (pts) achieving remission with frontline intensive chemotherapy (IC), most eventually relapse. In the QUAZAR trial (NCT01757535), oral azacitidine (Oral-AZA) prolonged overall survival and relapse-free survival (RFS) vs placebo (PBO) in older pts with AML in remission post IC (Wei et al, N Engl J Med 2020). Here, we studied the molecular landscape and clonal dynamics of pts treated with Oral-AZA/PBO in the QUAZAR study. The mutational landscape for older patients with AML in remission after IC may be confounded by persistence of pre-leukemic (PL) or age-related clonal hematopoietic (CH) variants. The implications of these residual mutations on disease relapse and treatment (Tx) outcome are largely unknown. Aims: 1) characterize the mutational landscape from remission bone marrow at baseline (BL) prior to Oral-AZA maintenance (i.e., in remission post-IC); 2) determine the fate of variants over time and at relapse in the Oral-AZA vs PBO arms; 3) examine associations between mutational landscape and relapse risk between Tx arms. Methods: In QUAZAR, 472 pts (≥55 years) with AML with intermediate- or poor-risk cytogenetics in remission after IC (BL) were randomized 1:1 to Oral-AZA or PBO. Among pts who consented to biomarker analyses (n=310), targeted NGS (37 myeloid genes) was performed on bone marrow DNA at BL (Oral-AZA/PBO: n=165/145), cycle 6 (n=107/79) and relapse (n=83/77). Mean NGS coverage was 13K reads and median minimal detectable variant allele frequency (VAF) was 0.12% (range: 0.02-2.79). Clonal variants were categorized by the longitudinal association between VAF and blast percentage (slope of leukemic variants &amp;gt;0.1; PL/CHIP &amp;lt;0.1). RFS was computed from time of randomization to relapse (≥5% BM blasts) or death, estimated by Kaplan-Meier methods. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression models. Nominal P values were derived from log-rank tests. Results: In the NGS cohort (n=310), median RFS (mRFS) for Oral-AZA vs PBO was 10.2 vs 4.7 months (mo), respectively. At BL, prior to maintenance Tx, 221 (71.3%) had detectable mutations, the most frequently occurring mutations (&amp;gt;5% of pts) were in DNMT3A (28.4%), TP53 (15.5%), IDH2 (12.3%), TET2 (11.9%), SRSF2 (11.0%), IDH1 (6.1%) and ASXL1 (5.5%). At BL, 110/310 (35.5%) pts had VAF &amp;gt;5%, potentially representing persistence of PL/CH variants in remission. Comparative analysis of all gene variants at BL and relapse revealed that some VAFs increased with blast frequency, while other variants remained largely static. Applying a variant classification algorithm, 97/258 pts had potential leukemic variants detected at BL. These involved DNMT3A (16.1%), SRSF2 (7.1%), TP53 (7.1%) and IDH2 (5.7%). PL/CH variants included DNMT3A (17.5%), TP53 (8%), IDH2 (5.7%) or TET2 (5.7%). TP53 was detected in 19.4% PL/CH variants (mean VAF 1.7%; range 0.2-13.4). Notably, when analyses were limited to potential leukemic variants at BL (&amp;lt;5% VAF), their presence was correlated with worse RFS (PBO: mRFS for 0, 1 or 2+ mutations was 6.1, 4.7 or 1.9 mo, respectively). The presence of ≥2 leukemic mutations was associated with shorter RFS only in PBO arm (mRFS vs &amp;lt;2 mutations: 1.9 vs 5.7 mo, P=0.02; Oral-AZA: 10.2 vs 10.2 mo). RFS favored Oral-AZA in pts with low mutational burden at BL (&amp;lt;2 mutations: mRFS 10.2 vs 5.7 mo [ P=0.003]; n=145 vs 122 [PBO]), and in a small subset of pts with higher mutational burden (≥2 mutations: mRFS 10.2 vs 1.9 mo [ P=0.008]; n=14 vs 13 [PBO]). Oral-AZA prolonged RFS vs PBO in pts across most mutational subtypes, when assessed for mutations that were deemed potentially leukemic (Figure). At relapse, the frequency of mutations, hotspots variants and co-mutations were comparable between Tx arms. Mutation-based pathway analysis indicated Ras pathway genes were enriched at relapse in PBO (28.6%) vs Oral-AZA arm (14.5%, P=0.03). Summary: In pts with AML in remission post IC, post-hoc analyses showed that Oral-AZA improved RFS vs PBO regardless of the mutational landscape at baseline. The spectrum of mutations at relapse was similar between Tx arms, suggesting that Oral-AZA maintenance prolongs remission without altering mutational heterogeneity.

Selinexor in Combination with Azacitidine (AZA) in Patients with Myelodysplastic Syndrome (MDS): A Real-World Retrospective Study

Background: Patients with higher-risk MDS face limited treatment options and poor outcomes. While HMAs are approved as frontline therapy for higher-risk MDS, primary failure occurs in 50% of HMA-treated patients, and most responders progress within 2 years. There is an unmet need to improve the efficacy of AZA frontline therapy while maintaining a tolerable safety profile. Preclinical studies have demonstrated that the combination of selinexor and azacitidine synergistically inhibits MDS cell proliferation and arrests the cell cycle at the G2/M phase (Yixuan Guo, 2022). The combination of selinexor and azacitidine may be a promising approach for treating MDS. Here, we present this single-center, real-world evidence supporting the use of selinexor in combination with AZA in MDS patients. Methods: Medical records of 19 patients with MDS receiving selinexor in combination with AZA at the First Affiliated Hospital of Soochow University between Jan 2022 and March 2023 were reviewed. Inclusion criteria were a pathologically confirmed diagnosis of MDS, and receipt of ≥1 cycle of azacitidine in combination with selinexor. HMA-naïve patients and those previously treated with HMAs were included. Patients with a diagnosis other than MDS or progression to AML before treatment with selinexor + AZA were excluded. Patients received selinexor 40-60 mg QW orally and AZA 75 mg/m 2 intravenously or subcutaneously on days 1-5 or 7 of each 28-day cycle. Responses were evaluated per the International Working Group criteria. Results: A total of 19 pts (median age, 54 y [range, 13-68 y]) were treated (Table 1). IPSS-R risk was high or very high in 15.8% and 68.4% of pts, respectively. IPSS-M risk was high or very high in 10.5% and 78.9% of pts, respectively. 57.9% of pts were previously treated with HMA. 63.2% had myelofibrosis, 42.1% had hepatosplenomegaly, 31.6% had a TP53 mutation, and 63.2% had poor or very poor-risk cytogenetics. As of Jun 10, 2023 at a median follow-up of 5.9 months (range 1.5-17.4 months), eight pts died (42.1%) due to disease progression. For the total cohort, the overall response rate (ORR) was 73%. In pts with worse survival prognosis, such as relapse and refractory, high and very high in IPSS-R, high and very high in IPSS-M, myelofibrosis and TP53 mut, the ORR was 64%, 81%, 76%, 75% and 83%, respectively (Figure 1). In seven pts with splenomegaly, six pts had reduced spleen volume, and one pt had no significant change by abdominal palpation or imaging examination. The 6-month overall survival (OS) was 74.7% in total pts, and 70.0% in pts previously exposed to HMA (Figure 2a, 2b). Selinexor + AZA therapy improved survival of patients with poor prognosis, such as TP53 mut (0.099), MF (+) (0.613), ≥high in IPSS-R (0.938) (Figure 2c, 2d, 2e). The survival of six pts who received transplantation after combination therapy was significantly prolonged, with 6-month OS was 83.3% (Figure 2f). Conclusion: Selinexor + AZA combination therapy was well tolerated with promising efficacy in patients with untreated or relapse/refractory MDS, including those with TP53 mutation, myelofibrosis, and higher risk in IPSS-R.

Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia

Background Blinatumomab improves overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and is also FDA-approved for eradication of persistent or recurrent measurable residual disease (MRD). Blinatumomab also improves OS when added to standard chemotherapy, irrespective of MRD status, in newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Inotuzumab ozogamicin (INO) improves OS in the relapsed/refractory setting, and we hypothesized that the addition of INO to hyper-CVAD plus blinatumomab would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods In this phase II study, pts age 14-59 with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts had to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (except for CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C (which was also dose reduced to 500 mg/m2 of MTX and 1 g/m2 of Ara-C with this amendment) and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results As of June 2023, 75 pts have been treated (38 without INO and 37 with INO). Pt characteristics are shown in Table 1. The median age across both cohorts was 33 (range, 18-59). 36 pts (48%) had ≥1 high-risk pretreatment characteristic at enrollment (e.g. poor-risk cytogenetics, CRLF2 overexpression by flow and/or TP53 mutation). Sixteen pts were in complete remission (CR) at enrollment after 1-2 cycles of off-protocol therapy, 10 of whom were MRD-negative by 6-color flow cytometry. All 59 pts (100%) with active disease upon study entry achieved CR, with 50 pts (84%) achieving CR after the first cycle. MRD negativity by flow (sensitivity 10 -4) was achieved in 60 of 65 evaluable pts (92%), with 43 pts (66%) achieving flow MRD negativity after the first cycle. Two of the 5 patients who did not achieve flow MRD negativity had NUP214::ABL1 fusion, 1 had KMT2A rearrangement, and 2 are still early in treatment and have not yet received blinatumomab. Overall, 25 of 36 tested pts (69%) achieved next-generation sequencing-based MRD negativity at a sensitivity of 10 -6. The median duration of follow-up is 26 months (range, 1-77 months). Overall, 8 pts (11%) relapsed in the absence of SCT, 23 pts (31%) underwent stem cell transplantation (SCT) in first remission (2 of whom relapsed post-SCT), 3 pts (4%) died in CR, and 41 pts (55%) remain in continuous remission without SCT. Among the 10 relapses, 3 were in the CNS, 2 of which were CNS-only. All but one relapse occurred in pts with ≥1 poor-risk feature(s). Across both cohorts, the estimated 3-year OS was 88% and the 3-year relapse-free survival (RFS) was 79% . The 3-year OS rate for pts without a high-risk baseline feature was 93% vs 83% in pts with ≥1 high-risk feature. In a landmark analysis, there was no difference in outcomes between pts who underwent SCT in first remission versus those who did not (3-year OS: 90% versus 87%). With a median follow-up of 18 months in the INO group, 3 pts (8%) have relapsed, 2 with CNS-only relapses, and none have died. The 18-month RFS in the cohorts with and without INO were 92% vs 76% (p=0.18), and the OS was 100% vs 84% (p=0.04) ( Figure 1). One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.