GDC-0199) in Acute Myeloid Leukemia Models

Abstracts median: 34) were screened for each of the previously identified LAIPs. A LAIP-positive cell population was considered significant based on a 0.01% of BM cellularity cut-off. Results: Overall we were able to identify 53 distinct LAIPs on the whole AML diagnostic bone marrow specimens series. Of these, 25 (47%) were detectable in at least one healthy donor BM specimen with frequencies ranging from 0.01% to 1.56% of total BM cellularity. Notably, 23 LAIPs (43.4%) were detectable in at least 50% of control specimens (Table). With a median 3 years follow up, none of the patients in the control group developed AML or related myeloid neoplasms. Conclusion: Taken together, our data point out a substantial lack of disease-specificity for almost half of these conventionally defined AML-specific aberrant immunophenotypic profiles. This observation could be of utmost importance in the context of MRD monitoring by flow-cytometry in AML and raises concern about the possibility of misinterpretation and the occurrence of falsely positive MRD evaluations; reactive post-chemotherapy bone marrow could possibly constitute a source of paraphysiological immunophenotypic aberrations and attribution of an apparently aberrant cell cluster to disease persistence should always be driven by careful and thoughtful analysis. Therefore we strongly believe that flow-cytometrical MRD evaluation in AML should only be performed by highly and specifically trained professionals.

AML-113 Targeting MAPK Signaling Pathway with Cobimetinib (GDC-0973) Enhances Anti-Leukemia Efficacy of Venetoclax (ABT-199/GDC-0199) in Acute Myeloid Leukemia Models Lina Han ,1 Qi Zhang,1 Ce Shi,2 Antonio Cavazos,1 Vivian R. Ruvolo,1 Joel D. Leverson,3 Monique Dail,4 Darren C. Phillips,3 Jun Chen,3 Sha S. Jin,3 Rodrigo Jacamo,1 Naval Daver,1 Elias Jabbour,1 Hagop M. Kantarjian,1 Michael Andreeff,1 Deepak Sampath,4 Marina Konopleva1

suppressed by the combination, while normal progenitor function was minimally affected. The CyTOF study revealed that BCL-2 protein was highly enriched in CD34+ leukemia stem/progenitor cells (LSPCs), especially in the venetoclax-sensitive sample. G-CSFinduced pERK in LSPCs was largely downregulated by cobimetinib irrespective of responses in proliferation assays, indicating suppression of pERK does not predict sensitivity to cobimetinib. However p-S6 was highly activated by SCF and effectively suppressed by cobimetinib in cobimetinib-sensitive AML. Functional proteomics RPPA data in AML cell lines indicated that p-ERK, p-S6 (S235/ 236) and p-RSK pathways were significantly down-regulated in response to the combination in cells showing synergy. Transcriptomics by RNA sequencing study revealed that increased sensitivity to the combination correlated with a previously identified “KRAS dependency” gene signature. To test the efficacy in vivo, we injected NSGS mice with genetically engineered MOLM3/Luc/GFP cells. Bioluminescent imaging demonstrated significantly reduced leukemia burden in treated groups compared to controls, more prominently in the venetoclax (100 mg/kg/d) group and in venetoclax plus cobimetinib (10 mg/kg/d) co-treated mice. In summary, combinatorial blockade of MAPK and BCL-2 pathways promotes cell death and suppresses proliferation in the majority of primary AML cells. The anti-leukemia efficacy of combined blockade of signaling and pro-survival pathways is associated with suppression of p-S6 and upregulation of KRAS dependency gene signature. Combined efficacy of these agents is under clinical investigation in a Phase I trial in elderly relapsed/refractory AML (NCT02670044).

AML-122 Age Does Not Adversely Influence Outcomes among Patients Older than 60 Years Who Undergo Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Inc., Chicago, United States; 4Genentech, South San Francisco,

Dipenkumar Modi , Abhinav Deol, Seongho Kim, Lois Ayash, Asif Alavi, Marie Ventimiglia, Divaya Bhutani, Voravit Ratanatharathorn, Joseph Uberti

United States

Karmanos Cancer Institute/Wayne State University, Detroit, United

1

Department of Leukemia, University of Texas MD Anderson Cancer 2

Center, Houston, United States; Department of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China; 3AbbVie

States

The anti-leukemia potency of selective BCL-2 inhibitor venetoclax (ABT-199/GDC-0199) has been demonstrated in acute myeloid leukemia (AML) models. However, the potential emergence of drug resistance requires rational combination strategies. In this study, we evaluated the anti-leukemia effects of concomitant BCL-2 and MAPK blockade by venetoclax in combination with MEK1/2 inhibitor GDC-0973 (cobimetinib). First, in 18 primary AML samples with diverse genetic alterations, the combination significantly enhanced cell death and suppressed cell growth, as compared to the single agent treatment. The clonogenic potential of AML progenitors was significantly

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Clinical Lymphoma, Myeloma & Leukemia September 2017

Introduction: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a successful treatment modality for AML and MDS. Information on transplant outcomes among older patients is limited because of concern of adverse transplant-related mortality (TRM) and poor overall survival (OS). Patients and Methods: We retrospectively evaluated consecutive patients 60 years or older with AML and MDS who underwent AHSCT between January 2005 and December 2014. The primary objectives of our study were to determine non-relapse mortality (NRM), relapse, relapse free survival (RFS) and OS at 1-year. The secondary objectives were to