ALBERT

Description: Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations.

Description: Background: The Hyper-CVAD regimen is safe and effective in the frontline treatment of B-ALL. The addition of rituximab to the Hyper-CVAD regimen (HCVAD-R) improved the 3-year overall survival (OS) to 60% in pts with B-ALL. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of the CD20 molecule and has greater in vitro potency and increased complement-mediated cell lysis compared to rituximab. We hypothesized that ofatumumab plus Hyper-CVAD may increase the rates of complete remission (CR) and measurable residual disease negativity (MRD-) and improve survival by decreasing relapse rates. Methods: Pts were eligible if they had newly diagnosed untreated or minimally treated (≤ 1 cycle) Philadelphia chromosome (Ph)-negative CD20+ B-ALL. CD20 positivity was defined as ≥ 1% positive B-ALL cells. Pts received 8 alternating cycles of Hyper-CVAD and high-dose methotrexate/cytarabine (MTX/AraC). Ofatumumab was administered on days 1 and 11 of cycles 1 and 3; and days 1 and 8 of cycles 2 and 4. Pts then received POMP maintenance on cycles 1-5, 8-17 and 20-30 and late intensifications on cycles 6-7 and 18-19 (Hyper-CVAD + ofatumumab followed by MTX + peg-asparaginase). Pts received a total of 8 intrathecal injections of MTX and AraC for CNS prophylaxis. The primary endpoint was relapse-free survival (RFS) and secondary endpoints include CR rates, MRD negativity rates and OS. On a subset of 27 patient samples, transcriptome sequencing (RNA-seq) was performed to identify translocations and RNA expression signature for Ph-like ALL. We also performed a comprehensive detection of fusions and mutations reported in Ph-like ALL on RNA from these 27 samples using a multiplex fusion and mutation detection assay (Archer® FusionPlex® ALL). Results: Between August 2011 and May 2017, 69 pts were enrolled, including 4 already in CR at baseline after receiving 1 cycle of chemotherapy. Pts characteristics are summarized in Table 1. The median age was 41 years (18-71) and 48% pts were in the adolescent and young adult (AYA) age category (18-39 year-old). 7 of the 27 pts (26%) who had RNA-seq had Ph-like ALL gene expression signature. Among the 7 pts; 5 had Ph-like ALL fusions identified by Archer and/or RNA-seq-based fusion detection, including 2 P2RY8-CRLF2, 1 IGH-CRLF2, 1 BCR-FGFR1, and 1 ATF71P-PDGFRB. One patient had high CRLF2 expression with an unknown fusion partner. The remaining case lacked a fusion by either platform. Pts with Ph-like ALL had a higher median WBC of 41 x 109/L (range, 2 - 184). 43 pts (62%) had CD20 expression on ≥20% of the leukemic cells. 10/44 tested pts (23%) had TP53 mutation and 10/37 (27%) had CRLF2 overexpression by flow cytometry (4/5 CRLF2 rearrangement confirmed by Archer). 4 pts (6%) had low-hypodiploidy / near triploidy (Ho-Tr) and 2 (3%) pts had complex karyotype (CK). All but 1 pt (98%) achieved CR (2 after 2 cycles); only 1 pt (2%) died during induction. The MRD- rate was 65% after cycle 1 and 93% overall. These rates were 14% and 71%, respectively for pts with Ph-like ALL. The median time to MRD- was 0.7 month (range, 0.4-8 months) overall and 3 months (range, 0.7-6.5 months) for pts with Ph-like ALL. A total of 13 pts (19%) underwent allogeneic stem cell transplantation for adverse-risk cytogenetics (CK or Ho-Tr), Ph-like ALL (n=1/7), or persistent MRD+. The most common non-hematologic grade 3-4 toxicity was infection which occurred in 56% and 81% of pts, during induction and consolidation, respectively. With a median follow-up of 44 months, 46 pts (64%) are alive, including 37 pts (54%) in CR1. The median RFS and OS were 52 months (95% CI, 43 - NR) and not reached (95% CI, 65 - NR), respectively. The estimated 4-yr RFS and OS rates were 60% (95% CI, 49 - 73%) and 68% (95% CI, 58 - 81%), respectively (Figure 1A-1B). For AYA pts, the 4-yr OS rate was 74% (95% CI, 60 - 91%) (Figure 2A). The 4-yr OS rates were 54% (95%, 26 - 100%) for pts with Ph-like ALL compared to 74% (95% CI, 57 - 97%) for pts without Ph-like ALL (Figure 2B). There was no difference in OS according to the CD20 expression level (20% cut-off; p = 0.31). Using historical control pts, there was a trend towards improved OS with HCVAD-O versus HCVAD-R for pts with CD20 ≥ 20% (4-yr OS rate 63% vs 49%, p = 0.16) and HCVAD-O versus HCVAD alone for pts with CD20 1-19% (4-yr OS rate 73% vs 62%, p = 0.46). Conclusion: HCVAD-O is a safe and highly effective regimen in pts with CD20+ Ph-negative B-ALL. This regimen achieves excellent outcomes in the AYA population. Disclosures Kantarjian: BMS: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Kisoji: Consultancy, Honoraria; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding. Jain:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding. Mullighan:Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel. O'Brien:AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Celgene: Consultancy; Kite: Research Funding; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. OffLabel Disclosure: Ofatumumab is not approved by the FDA for treatment of B-cell acute lymphoblastic leukemia.

Description: Introduction: Venetoclax (VEN) is approved for the treatment of acute myeloid leukemia (AML) in combination with hypomethylating agents (HMAs) or low-dose cytarabine and commonly used for patients (pts) unfit for intensive chemotherapy. Prophylaxis with triazole antifungals (azoles) during induction treatment in pts with AML has decreased mortality and is the standard of care for pts receiving treatment regimens associated with prolonged myelosuppression (Cornely et al, 2007). Azoles inhibit CYP3A4 (CYP3A4i), the enzyme responsible for the metabolism of VEN, and p-glycoprotein to varying degrees, which VEN is a substrate. Based on this interaction and the results of a small pharmacokinetic study, significant VEN dosage reductions are recommended (Agarwal et al, 2017). Little real-world data exists to demonstrate the tolerability of VEN in combination with azoles during induction treatment with VEN and HMAs. Methods: All pts with newly diagnosed AML treated at our institution with VEN and HMAs from 11/2014-1/2019 were retrospectively reviewed. Pts were treated as standard of care or as part of clinical trial in combination with azacitidine (NCT02203773) or decitabine (NCT03404193; NCT02203773). Pts who received concomitant antifungal for 〉5 days while also receiving VEN for 〉7 days were included. VEN 100mg daily with posaconazole or voriconazole (strong CYP3A4i) and VEN 200mg daily with isavuconazole or fluconazole (moderate CYP3A4i) were considered 400mg equivalent dosages. Higher doses of VEN in these combinations were considered 〉VEN 400mg equivalent. To determine the clinical impact of concomitant azoles, time to absolute neutrophil count (ANC) and platelet (PLT) recovery after induction was analyzed, in addition to response rates, episodes of febrile neutropenia (FN) and documented infections. Results:One-hundred twenty-one pts treated with HMA and VEN were identified (Table 1). The median age was 72 years (48-86) and 35% were 〉 75 years. Forty pts (33%) had secondary AML, and 10% had therapy-related AML. Most were treated with decitabine 20mg/m2 administered for 10 days (67%) or 5 (22%). VEN was administered for a median of 23 days (7-30) at a 400mg daily dose equivalent in 74 pts (62%) and 〉400mg dose equivalent in 40 pts (33%). Eighty-nine (74%) received a concomitant azole with VEN including posaconazole (38%), isavuconazole (21%), voriconazole (13%), or fluconazole (2%). Following induction therapy with VEN and HMA, 37% achieved a complete response (CR) and 22% achieved a CR with incomplete blood count recovery (CRi). An additional 10% achieved a morphologic leukemia free state (MLFS) (Table 2). Prior to cycle 2, 55% of pts achieved ANC〉500 cells/mm3 and 64% achieved PLT〉50,000 cells/mm3 after a median of 34 days and 24 days, respectively. No difference in response was observed based on VEN dosage or duration (Table 3). Pts achieving CR/CRi received VEN for a median of 22 days (7-29), and 38% at the 400mg equivalent VEN dosage with an azole. When analyzing VEN dosage by the use of an azole, duration of neutropenia (ANC0.05) (Table 4). Number of pts achieving PLT〉50,000 cells/mm3 was not affected by concomitant antifungal or VEN dosage, but duration of thrombocytopenia was. Time to PLT〉50,000 cells/mm3 was significantly longer for pts receiving VEN 400mg equivalent with an azole (25 vs 20 days, p=0.01) as well as time to PLT〉100,000 cells/mm3 (27 vs 22 days, p=0.03). Despite prolonged cytopenias, all pts receiving the VEN 400mg equivalent dosage had similar rates of FN, documented infections, and hospital duration regardless of the use of an azole (Table 4). Those receiving 〉400mg VEN equivalent had numerically higher rates of FN, infections, and duration of hospitalization. Conclusion: The combination of VEN with HMA is an effective treatment option in pts with newly diagnosed AML. VEN is associated with significant myelosuppression which can be enhanced by concomitant CYP3A4i, such as the azoles. The combination of VEN and azoles resulted in prolonged cytopenias, namely thrombocytopenia, compared to the use of VEN without an azole. This did not result in higher rates of FN, infections, or duration of hospitalization, therefore the concomitant use of VEN and azole appear to provide a clinically safe and effective therapeutic regimen. Higher doses of VEN do not appear to be advantageous in this setting. Disclosures DiNardo: daiichi sankyo: Honoraria; jazz: Honoraria; syros: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria. Maiti:Celgene: Other: research funding. Kadia:Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; Arvinas: Research Funding; Oncoceutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Agensys: Research Funding. Pemmaraju:affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; incyte: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding. Kantarjian:Astex: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding. Konopleva:Astra Zeneca: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Agios: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Description: Background: Recent advance in massively parallel sequencing technology has enabled identification of a number of novel somatic driver mutations in myelodysplastic syndromes (MDS). While these efforts have clearly advanced our understanding of MDS pathogenesis, clinical implication of driver mutations in MDS is less studied. Methods: We performed whole exome sequencing on bone marrow aspiration samples obtained from 114 consecutive patients with untreated MDS. Exome capture was performed using Agilent's SureSelect V4 and sequencing was conducted using Illumina's HighSeq 2000 platform. Sequencing achieved median 124x coverage for the targeted exons. Mutect and Pindel algorithm were used to call single nucleotide variants (SNV) and small indels against virtual common normal reference. Annotation of high-confidence driver mutations followed the previous publication by Pappaemmanuil et al. (Blood 2013). Clonal heterogeneity of driver mutations was assessed in patients who have 2 or more driver mutations by Pearson's goodness of fit test. Results: Among the 114 patients with MDS, total 221 high-confidence driver mutations were detected in 39 genes by sequencing. Eighty eight percent (100/114) of the patients were found to have at least one driver mutation. The number of driver mutation ranged from 1 to 5 per case. Commonly detected driver mutations include TET2 (25%), SRSF2 (22%), ASXL1 (20%), RUNX1 (19%), TP53 (12%), SF3B1 (9%), and U2AF1 (9%). As a rare driver mutation, we confirmed ETNK1 p. N244S mutation in 2 MDS patients (2%). This mutation was recently described as a recurrent somatic mutation in atypical CML (Gambacorti-Passerini et al. Blood 2015). Clonal heterogeneity of driver mutations was evaluable in 65 patients (57%). Nineteen patients were found to have clonal heterogeneity in driver mutations (29%). Among the 114 patients, 61 patients (54%) were treated with HMA therapy. Complete response (CR), partial response (PR), and hematological improvement (HI) was observed in 22 (36%) patients, 4 (7%) patients, and 5 (8%) patients, respectively. Presence of TET2 mutation did not predict response to HMA therapy in this series (P = 0.57) even when we restricted to TET2 mutations with variant allele frequency (VAF) 〉10%. There was a trend toward poor response to HMA therapy in ASXL1 mutated patients (P = 0.074). None of the other driver mutations were predictive of response to HMA therapy as a sole. However, patients who were found to carry 4 or more driver mutations had significantly poor response to HMA therapy (CR rate 0%) compared to patients with less than 4 driver mutations (P = 0.035). Presence of clonal heterogeneity in driver mutations was not predictive of response to HMA therapy (P = 0.43) In regards to survival outcome, presence of SF3B1 mutation predicted favorable overall survival (OS, P = 0.02) while TP53, and DNMT3A mutations were associated with worse OS (P 〈 0.001 and P = 0.02, respectively). Presence of clonal heterogeneity in driver mutations was not prognostic for OS (P = 0.71). Patients who were found to have 4 or more driver mutations were associated with significantly worse OS (P = 0.014). None of the patients with 4 or more driver mutations had SF3B1 mutation. Multivariate Cox proportional hazard regression analysis considering dichotomized variables relevant to IPSS-R classification (absolute neutrophil count 〈 0.8 x 103 / µ l, hemoglobin 〈 8 g/dL, platelet count 〈 50 x 103 / µ l, and bone marrow blast 〉 10%, and poor or very poor risk cytogenetics), SF3B1 mutation, DNMT3A mutation, TP53 mutation, and the number of driver mutations (≥ 4) revealed that the presence of 4 or more driver mutations (HR = 2.72 95% CI: 1.34-5.53, P = 0.06), platelet count 〈 50 x 103 / µ l (HR = 4.73, 95% CI: 2.53-8.85, P 〈 0.001), and TP53 mutation (HR = 3.34, 95% CI: 1.65-6.75, P = 0.001) significantly predicted worse OS. Conclusion: With the modern sequencing technology, approximately 90% of MDS patients were found to have at least one known myeloid driver mutation. Presence of 4 or more driver mutations in MDS patients predicted poor response to HMA therapy. Multivariate model incorporating mutation profile showed that the presence of 4 or more driver mutations and TP53 mutation status were significantly prognostic in MDS independent of IPSS-R variables. Screening for driver mutations in MDS has clinical impact and mutation profiles should be incorporated into the existing prognostic model. Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. DiNardo:Novartis: Research Funding.

Description: Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Description: Abstract 471 Multiple myeloma (MM) is characterized by widespread dissemination of the MM cells at diagnosis associated with multiple focal bone lesions, implying (re)circulation of MM cells into the peripheral blood and (re)entrance or homing into new sites of the BM. However, the driving force for MM cells to leave the BM, egress, and home to new BM niches is still not well understood. Hypoxia (low oxygen) in solid tumors was shown to promote metastasis in solid tumors through activation of proteins involved in the endothelial to mesenchymal Transition (EMT). In this study, we hypothesized that MM tumor progression induces hypoxic conditions, which in turn activates EMT related proteins and promotes metastasis of MM cells. To test this hypothesis, we examined levels of hypoxia in MM cells at different stages of tumor progression in vivo in two animal models: the first by injecting MM1s cell to SCID mice, and the second by injecting 5T33MM cells to C57BL/KaLwRijHsd mice. Hypoxic markers were examined using flow cytometry and immunohistochemistry. We found that tumor progression induced hypoxia in both the MM cells and the tumor microenvironment. Similarly, hypoxia induced genes (HIF1a, HIF1b, HIF2b, CREBBP, HYOU1, VEGF1, HIF1a-inhibitory protein) were increased in MM patients (n=68) compared to plasma cells from healthy donors (n=14). Using flow cytometry we found that the number of circulating MM cells increased with the progression; however, the correlation was observed in late stages of the progression but not in the early stages. A better direct correlation was achieved with the hypoxic state of the MM cells in the BM. Circulating MM cells were more hypoxic that MM cells in the BM (especially at low tumor burden). Moreover, we found that the level of hypoxia in MM cells in the PB did not correlate with the hypoxia in the BM. Next, we tested the mechanism in which hypoxia induces cell egress. We found that MM cells isolated from MM patients have higher gene expression of EMT inducing proteins (E-cadherin, SNAIL, FOXC2, TGFb1) in parallel to a decrease of expression in E-cadherin, and we confirmed the downregulation of E-cadherin expression in correlation with the increase of hypoxia in MM cell and cells in the BM microenvironment in vivo. Culturing MM cells under hypoxic conditions increased the expression of HIF1a and HIF2a. In parallel, hypoxia induced acquisition of EMT related features including downregulation of E-cadherin, upregulation of SNAIL, and inhibition of GSK3b. In addition, hypoxia decreased the adhesion of MM cells to stromal cells. To complete the metastatic process after egress, MM cells need to home to new sites in the BM. Therefore we investigated the effect of hypoxia on expression of CXCR4, chemotaxis and homing of MM cells to the BM. Using flow cytometry we found a direct correlation between hypoxia and the expression of CXCR4 in MM cells in vivo using the SCID-MM1s model. These results were confirmed in vitro, where hypoxia increased the expression of CXCR4 at protein and mRNA levels in MM cells. Moreover, the expression of CXCR4 in MM cells isolated from the PB was higher than cells isolated from the BM especially at low tumor burden, correlating with higher hypoxic state of the circulating tumor cells. Functionally, hypoxia increased the chemotaxis of MM cells towards SDF1a in vitro and, using in vivo confocal microscopy, it was shown to accelerate the homing of MM cells to the BM in vivo. To demonstrate that the chemotaxis and homing were CXCR4 dependent, we treated the hypoxic MM cells with AMD3100 (a CXCR4 inhibitor) and showed that it inhibited chemotaxis in vitro and homing of MM to the BM in vivo. In conclusion, we demonstrate that tumor progression induces hypoxia in the MM cells and in the BM microenvironment. Hypoxia activates EMT-related machinery in MM cells, decreases expression of E-cadherin and consequently decreased the adhesion of MM cells to the BM, and enhance egress of MM cells to the circulation. In parallel, hypoxia increases the expression of CXCR4, and consequently increased the migration and homing of MM cells in from the peripheral blood to the BM. Further studies to manipulate hypoxia in order to regulate tumor dissemination as a therapeutic strategy are warranted. Disclosures: Roccaro: Roche: . Kung:Novartis Pharmaceuticals: Consultancy, Research Funding. Ghobrial:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL) is an aggressive malignant disease with poor long-term outcomes. Blinatumomab, a bispecific T-cell engager (BiTe) CD3-CD19 antibody, showed improved overall survival compared to standard chemotherapy. This is a long-term follow-up analysis evaluating outcomes of adult patients with R/R B-ALL treated in a phase 2 trial of blinatumomab at a single institution. Methods: Adult patients with R/R Philadelphia negative B-ALL were enrolled in this open-label single arm phase 2 trial from January 2012 until January 2015. During screening period, patients who had high tumor burden were given 10 mg/m2/day of dexamethasone for up to 5 days until 3 days prior to treatment initiation in order to prevent cytokine release syndrome. Patients received continuous IV infusion of blinatumomab 28 µg/day over 4 weeks (wk) followed by 2 wk treatment-free interval. For the first cycle, blinatumomab was initiated at 9 µg/day for 1 wk and then escalated to 28 µg/day, if tolerated. Patients who achieved response within 2 cycles received up to 3 additional cycles of consolidation treatment (total of 5 cycles). Allogeneic stem cell transplantation (ASCT) was offered to responding patients at the discretion of the investigators. The primary objective of the trial was to evaluate efficacy as well as safety of blinatumomab in patients with R/R B-ALL. During long-term follow-up, hematological relapse, treatment received after blinatumomab failure and survival data were collected. Overall survival was defined as the time elapsed from the date of start of treatment until death or date of last follow-up. Results: A total of 35 patients received blinatumomab, with baseline characteristics summarized in Table 1. The median number of cycles received was 2 (range, 1-5 cycles). The overall response rate was 54% (19/35), with only 2 achieving response after 2 cycles. The median time to response was 28 days (range, 14-69 days). Complete remission (CR), CR with partial hematologic recovery (CRp), CR with incomplete hematologic recovery (CRi) were achieved in 13 (37%), 4 (11%), and 2 (5%) patients, respectively. Sixteen out of 19 (84%) responding patients achieved negative minimal residual disease (MRD) by flow cytometry. Treatment was well tolerated with most adverse events being transient. Cytokine release syndrome was observed in 17 (49%) patients, all were of grade 2 toxicity. Neurotoxicity of grade 1 and 2 were observed in 9 (26%) patients; 5 patients had tremors, 3 had confusion, and 1 had seizure. Of all patients, 17 (49%) underwent subsequent ASCT: 6 (32%) had ASCT as consolidation after blinatumomab; of them 3 remained in continuous MRD negativity post ASCT for a median of 53.6 months (range, 2.4-57). Of the 19 responding patients, 16 relapsed after a median of 3 months (range, 0.5 to 26.1); 4 of them (25%) with CD19-negative disease. Eleven patients received subsequent ASCT after other salvage strategies. Anti-CD19 therapies were given to 8 (23%) patients after failure. Two patients received an anti-CD19 drug conjugate, and 6 other patients received anti-CD19 CAR T cells (2 patients for relapsed disease after ASCT and 4 patients as consolidation post-ASCT). None of the patients was re-challenged with blinatumomab after relapse. After a median follow-up of 11 months, 5 patients (14%) remained alive. The median OS was 10.6 months (range, 0.2-68). The 2-year and 3-year OS were 23% and 14% respectively. Outcomes of long-term survivors (i.e. 〉2 years) are summarized in Table 2. Conclusion: Blinatumomab followed by ASCT confers good long-term survival among patients with heavily pretreated R/R ALL. Long-term survival of more than 2 years was only observed in those who received subsequent ASCT. Disclosures Short: Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Jazz: Honoraria; Jazz: Honoraria. Sasaki:Otsuka Pharmaceutical: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. O'Brien:Pfizer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Alexion: Consultancy; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; Aptose Biosciences Inc.: Consultancy; Janssen: Consultancy; Kite Pharma: Research Funding; GlaxoSmithKline: Consultancy; Sunesis: Consultancy, Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Acerta: Research Funding; Amgen: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

Description: Background: The combination of inotuzumab ozogamicin with low-intensity therapy was shown to be safe and highly effective in elderly patients with newly diagnosed Philadelphia-negative ALL. There is no standard of care for these patients, and the optimal frontline therapy remains unknown. The aim of this study is to compare outcome of elderly patients with newly diagnosed Philadelphia-negative ALL treated with the combination of inotuzumab ozogamicin with low-intensity chemotherapy (mini-HCVD) (Kantarjian et al. Lancet Oncol. 2018; 19 (2): 240-248.) to those who received standard hyper-CVAD (HCVAD). Methods: We analyzed 135 elderly patients, 60 years and older at diagnosis with newly diagnosed Philadelphia-negative ALL who were treated with frontline HCVAD (N=77) or the combination of inotuzumab ozogamicin with mini-HCVD (N=58). Mini-HCVD comprised 50% dose reduction of cyclophosphamide and dexamethasone, 75% dose reduction of methotrexate, and 83% dose reduction of cytarabine without anthracyclines compared to the dose of standard HCVAD. Multiple imputations were performed to minimize bias due to missing variables. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Propensity scores were calculated with logistic regression from baseline covariates including age, performance status, white blood cell count, percentage of blasts in peripheral blood and bone marrow, cytogenetics, percentage of CD20 and CD22 positive blasts at diagnosis, and presence of central nervous system disease. Event-free survival (EFS) was calculated from the time of treatment initiation until date of no response (after 2 cycles), relapse, or death. Overall survival (OS) was calculated from the time of treatment initiation until death. Using pre-matched cohorts, univariate and multivariate Cox proportional hazards regression was performed to identify prognostic factors for OS with a p-value cutoff of 0.100. Time from therapy to allogeneic stem cell transplant was handled as a time-dependent variable. Results: Overall, 58 patients (43%) and 77 patients (57%) were treated with mini-HCVD + inotuzumab ozogamicin and HCVAD, respectively (Table 1). The median follow-up was 66 months (range, 0.4-191). Median age at the start of therapy was 68 years (range, 60-81) and 69 years (range, 60-83), respectively (p= 0.483). In the pre-matched cohort, CR/CRi/CRp rate was 98% and 88%, respectively (p= 0.037); early death rate was 0% and 8%, respectively (p= 0.030). The 3-year EFS rates for mini-HCVD + inotuzumab ozogamicin and HCVAD were 47% and 29%, respectively (p=〈 0.001); the 3-year OS rates were 54% and 32%, respectively (p=0.001). The median EFS was 34 months and 8 months in the mini-HCVD + inotuzumab ozogamicin and HCVAD, respectively (p=0.002) (Figure 1A); the median OS was not reached and 15.8 months, respectively (p= 0.002) (Figure 2A). Propensity score matching identified 38 patients in each cohort. Baseline differences were minimized without statistical significance between cohorts. With propensity score matching, CR/CRi/CRp rate was 97% and 90%, respectively (p= 0.361); early death rate was 0% and 5%, respectively (p= 0.493). The 3-year EFS rates for mini-HCVD + inotuzumab ozogamicin and HCVAD were 64% and 34%, respectively (p= 0.001) (Figure 1B); the 3-year OS rates were 63% and 34%, respectively (p= 0.001) (Figure 2B). Using the pre-matched cohorts, multivariate Cox proportional regression confirmed therapy with mini-HCVD + inotuzumab ozogamicin (p= 0.020; hazard ratio [HR], 0.550; 95% confidence interval [95% CI], 0.332-0.911), and age at the start of therapy (p= 0.019; HR, 1.045; 95% CI, 1.007-1.085) as prognostic factors for OS (Table 2). Conclusion: The combination of inotuzumab ozogamicin with low-intensity therapy is safe and effective in elderly patients with newly diagnosed Philadelphia-negative ALL, and confers better outcome when compared with standard HCVAD chemotherapy. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Jazz: Honoraria; Orsenix: Honoraria. Daver:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Sunesis: Consultancy; Kiromic: Research Funding; ImmunoGen: Consultancy; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Novartis: Consultancy. Kadia:Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Jain:Seattle Genetics: Research Funding; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; Cellectis: Research Funding; BMS: Research Funding; Verastem: Research Funding; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; BMS: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Pemmaraju:plexxikon: Research Funding; samus: Research Funding; novartis: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. O'Brien:Kite Pharma: Research Funding; Acerta: Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Vaniam Group LLC: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Alexion: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Regeneron: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding.

Description: Background: Cigarette smoking impairs response and outcome in pts with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell-lung cancer are treated with EGFR-TKI. Prior history of cigarette smoking might contribute to adverse outcome in pts with other types of cancer and may increase the risk of vascular events, particularly in pts treated with TKIs. The aim of this study is to evaluate the impact of cigarette smoking on outcome in pts with newly diagnosed Ph+ALL treated with the combination of intensive chemotherapy with a TKI. Methods: Pts with newly diagnosed Ph+ALL who received the combination of intensive therapy (hyper-CVAD) with imatinib, dasatinib, or ponatinib were analyzed. The whole population was divided into non-smoker and smoker cohorts. Smoker was defined as prior history of smoking equal to or more than 1 pack-year history of smoking before the diagnosis of Ph+ALL. Univariate and multivariate Cox proportional hazard model was used to identify prognostic factor for OS. Cumulative incidence of relapse in patients who achieve CR was assessed with death in CR as a competing risk. Gray's test was used for the comparison of cumulative incidence between cohorts. Results: From 4/2001 to 4/2018, 202 pts with newly diagnosed Ph+ALL were analyzed including 54 pts (27%) who were treated with HCVAD + imatinib; 72 pts (36%) with HCVAD + dasatinib; and 76 pts (38%) with HCVAD + ponatinib. The median follow-up was 77 months (range, 0.2-148.9). Eighty-two pts (41%) were identified as smokers (Table 1). The median pack years of smoking was 20 pack years (range, 1-160). Smoker cohort included older pts, more males, and worse performance status than the non-smoker cohort. TKI received was similar between cohorts (p=0.667). The rates of CR, negativity of flow cytometry, and complete molecular response (CMR) were similar between cohorts. There was a tendency of higher rates of allogeneic stem cell transplant (ASCT) in the non-smoker cohort (p=0.056). Five-year CR duration was 53% and 78% in the smoker and non-smoker cohort, respectively (p=0.006) (Figure 1A); 5-year OS rate was 31% and 67%, respectively (p

Description: Introduction: Outcomes of adverse risk acute myeloid leukemia (AML) remain dismal. Despite some morphologic remission following therapy, the majority of patients relapse and succumb to their disease. Induction chemotherapy leads to a significant reduction in tumor burden, however, resistant leukemia cells persist as minimal residual disease (MRD), the reservoir for relapse. This is likely due to the capacity of these persistent cells to hijack properties from normal hematopoietic stem cells such as self-renewal, quiescence, and recapitulation of the malignant progeny. Thus leukemia cells are functionally heterogeneous, with the majority of cells at diagnosis susceptible to chemotherapy, and a minority of resistant cells that persist despite treatment. Deeper understanding of all leukemia sub-populations is necessary in order to understand mechanisms of resistance. We hypothesized that sub-populations such as leukemia-stem cells (LSCs), and post-therapy residual cells possess identifiable, targetable characteristics that drive resistance. We performed RNA-sequencing and compared differences in gene expression between these sub-populations. Methods: We collected 47 bone marrow samples from 27 patients who met criteria for adverse risk AML by ELN 2017 risk stratification. We performed RNA-sequencing on paired pre- and post-treatment sorted samples. Mononuclear cells were flow-sorted for bulk (CD45dim) and LSCs (Lin-CD34+CD38-CD123+) from diagnostic samples. Post-treatment samples were sorted for bulk mononuclear cells and MRD, determined based on patient-specific aberrant phenotype using multi-color flow cytometry analysis (Xu J et al., Clinics in laboratory medicine 2017). Sixteen patients (59%) had mutations in TP53, 9 (33%) had mutations in FLT3, and 3 (11%) had no mutations in these genes but had other adverse risk features. RNA was isolated using low-input methodology, and RNA-sequencing was performed using Illumina HiSeq 2000. Samples with low-expression of housekeeping genes were excluded from the analysis. Differential expression was analyzed using DESeq2 and Gene Set Enrichment Analysis (GSEA) was performed using the HALLMARK gene set. Results: The median age of patients included in this cohort was 67 years (range: 35-81). Baseline characteristics, including adverse risk features, commonly mutated genes, treatments and responses are described in Figure 1A. Differentially expressed genes were compared between sub-populations. Figure 1B includes pathways with statistically significant changes (changes with q