Khan, Irum

Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p<0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p < 0.0004 for Whites) but only predicted DFS for White AML patients (p < 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p <0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

PURPOSEStandard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.PATIENTS AND METHODSOne hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.RESULTSMean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.CONCLUSIONSubjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Abstract Abstract 3862 Somatic mutations in JAK2 and MPL are associated with the BCR-ABL negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). While oral JAK2 inhibitors improve peripheral blood counts and splenomegaly, these drugs show varying effects on JAK2 mutant allele burden and do not eliminate the malignant clone in humans or in animal models of MPN. Although much of the research to date has focused on JAK/STAT signaling, other pathways downstream of the class I cytokine receptors, including PI3K/AKT and ERK are also activated in MPNs. Our hypothesis is that persistent activation of these signaling pathways contributes to the progression of myeloproliferative neoplasms (MPNs). Multiple studies have shown that overexpression of activated JAK2 and MPL mutants (e.g. JAK2 V617F or MPL W515L) in primary murine bone marrow cells causes robust AKT, STAT3, and STAT5, JNK, ERK phosphorylation. To determine the extent to which these signaling pathways are involved in the disease, we cultured JAK2 V617F and MPL W515L expressing clones of the G1ME and 6133 megakaryocytic cell lines with a panel of small molecule kinase inhibitors. We discovered that inhibition of the PI3K/AKT and MAPK/JNK signaling pathways with triciribine and SP600125 respectively, potently suppressed growth of these cells by inducing G1 arrest and apoptosis. In contrast, inhibitors of Ras, ERK, Src family tyrosine kinase, and PKC failed to significantly inhibit proliferation of the JAK2 or MPL mutant expressing cells. Murine bone marrow cells transduced with MPL W515L show a dramatic expansion of megakaryocytes (CFU-MKs) and this expansion was abrogated in the presence of PI3K/AKT inhibitors suggesting a requirement for this pathway in aberrant megakaryocyte expansion. Since AKT inhibition showed the strongest effect, we assayed the activity of MK-2206, a potent and selective allosteric AKT inhibitor, on multiple models of MPNs. We discovered that MK-2206 induced proliferative arrest and apoptosis accompanied by suppression of PI3K/AKT signaling in G1ME and 6133 cells expressing MPLW515L. MK-2206 also potently inhibited liquid culture growth and colony formation of PMF patient CD34+ cells in vitro. Finally, in preliminary murine transplants experiments with MPLW515L expressing bone marrow progenitors, treatment with MK-2206 led to significant reductions in peripheral blood leukocytosis and extramedullary hematopoiesis. Together, these findings demonstrate that the PI3K/AKT axis represents a rational target for therapy in human myeloproliferative neoplasms. Disclosures: No relevant conflicts of interest to declare.