ALBERT

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: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: Introduction: Cytopenias are a leading cause of ruxolitinib (RUX) discontinuation for patients (pts) with myelofibrosis (MF). Though RUX 5 mg BID is recommended for pts with platelet (PLT) counts of 50 to

Description: Human pentraxins are a family of proteins with a unique pentameric structure. Unlike C-reactive protein (CRP), serum amyloid P (SAP) and pentraxin-3 (PTX3) play an opposite role in tissue remodeling. PTX3 induces whereas SAP inhibits the differentiation of CD14+ monocytes into fiborcytes. While in patients with CLL CRP levels are high and were found to be associated with poor overall survival (OS) (Herishanu et al. Ann Med 2017), little is known about the plasma levels or clinical significance of other pentraxins in CLL. Therefore, we obtained plasma sample from 36 randomly chosen treatment-naïve CLL patients and 12 age-matched healthy individuals and, using an enzyme linked immuno-sorbent assay, found that PTX3, CRP and SAP plasma levels were significantly higher in CLL patients than in healthy individuals (P

Description: Hematopoietic progenitor cells of myeloproliferative neoplasms with myelofibrosis (MPN-MF) exhibit constitutive activation of JAK-STAT5/3 and NFkB signaling. Transformation of MPN-MF to AML (post-MPN sAML) occurs in up to 15% of patients with MPN-MF. Standard induction anti-AML chemotherapy and the JAK1 & 2 inhibitor (JAKi) ruxolitinib are ineffective in post-MPN sAML. BET protein BRD4 is a non-oncogene addiction target in AML, and treatment with acetyl-lysine mimetic BET protein inhibitor (BETi) disrupts binding of BRD4 to acetylated chromatin and transcription factors (TFs). This attenuates transcription of super-enhancer regulated oncogenes, including MYC, Bcl-xL, PIM1 and CDK4/6, inhibiting growth and survival of post-MPN sAML blasts. BETi treatment also inhibits binding of BRD4 to acetylated RELA (NFkB-p65), inhibiting its transcriptional activity and attenuating levels of its target cytokines. However, BETi treatment induces BRD4, potentially reducing BETi activity in repressing oncogenes. Preclinical and clinical studies have demonstrated that innate or adaptive BETi-resistance is common in sAML cells. To model BETi-resistance, we repeatedly exposed (10 times) secondary (s) AML SET2 and HEL92.1.7 (HEL) cells to 1.0 µM of the BETi OTX015 for 48 hours followed by full recovery, thus generating BETi persister-resistant (BETi-P/R) SET2-P/R and HEL-P/R cells. These cells showed 〉 10-fold resistance to OTX015 and cross-resistance to other BETis. Compared to the parental controls, BETi-P/R cells lacked additional genetic alterations or altered levels of TRIM33, SPOP, DUB3 or phosphorylated BRD4 (previously described mechanisms of BETi-resistance). However, ATAC-Seq and ChIP-Seq (H3K27Ac mark) analyses demonstrated that, as compared to their parental controls, BETi-P/R cells showed gain of peaks and active enhancers with enrichment of STAT5, MYC, PU.1 and GATA2 binding sites. Newly gained peaks were in the enhancers of JAK1/2, RUNX1, PU.1, MYC and BCL2L1. RNA-Seq determined mRNA level alterations, included induction of gene-sets involving MYC/MAX, STAT5, NFkB and TCF7L2 targets. QPCR and Western analyses confirmed increase in the mRNA and protein levels of TCF7L2, JMJD6, c-Myc, Survivin and PIM1 in HEL-P/R over HEL92.1.7 cells. Expression of the arginine demethylase JMJD6, recruited by BRD4 to regulate enhancer-mediated transcriptional pause-release, was also increased. This was associated with increased expression of the nuclear β-catenin-TCF7L2 targets, including Cyclin D1, TERT, survivin, c-Myc and PU.1. Patient-derived human AML blasts that exhibited innate resistance ex vivo to BETi, also demonstrated increased expression of TCF7L2, JMJD6 and c-Myc. We next probed the mechanistic role of the β-catenin-JMJD6-TCF7L2-MYC axis in conferring BETi-resistance. CRISPR-Cas9-mediated knockout of TCF7L2 or JMJD6 significantly reversed BETi-resistance in BETi-P/R sAML cells (p 〈 0.001). Conversely, ectopic overexpression of TCF7L2 or JMJD6 significantly conferred BETi-persister-resistance in HEL and SET2 cells (p 〈 0.001). Notably, confocal microscopy demonstrated increased binding of β-catenin with TBL1 and TCF7L2 in the nucleus of BETi-P/R sAML cells. BC2059, which disrupts binding of nuclear β-catenin with TBL1 and TCF7L2, depleted β-catenin levels and exerted similar lethality in BETi-P/R sAML and control sAML cells. shRNA-mediated knockdown of BRD4 and treatment with BRD4-PROTAC (proteolysis-targeting chimera) ARV-771 (Arvinas, Inc.) that degrades BRD4/3/2, also induced similar levels of apoptosis in BETi-P/R and control sAML cells. Co-treatment with ARV-771 and BC2059 synergistically induced lethality in BETi-P/R sAML cells as well as in patient-derived, CD34+ sAML BPCs (combination indices 〈 1.0). This was associated with marked attenuation of c-Myc, TCF4, Survivin, CDK6, PIM1 and Bcl-xL levels. Also, compared to each agent alone, in vivo treatment with ARV-771 (30 mg/kg SQ daily x 5, per week) and BC2059 (30 mg/kg IP BIW per week) for 3 weeks, significantly reduced sAML burden and improved survival of NSG mice engrafted with HEL-P/R cells (p 〈 0.01). Collectively, these findings underscore that increased levels and activity of β-catenin-TCF7L2-JMJD6-MYC axis is mechanistically responsible for BETi-P/R, and co-targeting with BRD4 degrader and β-catenin-TCF7L2 inhibitor is a promising therapeutic strategy against BETi-P/R sAML BPCs. Disclosures Bhalla: Beta Cat Pharmaceuticals: Consultancy. Verstovsek:Pharma Essentia: Research Funding; 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.

Description: INTRODUCTION: Most clinical trials exclude patients with poor performance, organ dysfunction, and presence of other active malignancies or comorbidities. Although some of these criteria are based on clinical reasoning, patients with such clinical features have dismal expected outcomes and limited therapeutic options and could therefore have a more favorable risk/benefit ratio if treated with a low intensity investigational intervention. The current study was designed to test whether it is feasible to treat patients not eligible for conventional studies in a clinical trial. METHODS: We conducted an initial Bayesian designed single-arm study and a subsequent randomized study for patients with AML or higher-risk MDS (intermediate-2 or high risk by IPSS) with either ECOG performance status (PS) ≥3, creatinine or bilirubin ≥2mg/dL, presence of other malignancy or other comorbidities. Primary endpoint was survival at day 60. The study included stopping rules for survival, response and toxicity. All patients received azacitidine 75mg/m2 sc daily for 5 days. Patients in the single-arm study and in the combination arm of the randomized study also received vorinostat 200mg tid for 5 days. Cycles could be repeated every 3-8 weeks. Responses were evaluated following the revised 2006 IWG criteria for patients with MDS and the IWG 2003 recommendations for patients with AML. Comorbidities were evaluated using the Adult Comorbidity Evaluation-27 (ACE-27) index. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 30 patients (16 with MDS, 14 with AML) were enrolled in the initial single-arm study. Patient characteristics and inclusion criteria are detailed in Table 1. Median age was 73 years (44-83). Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. Median number of cycles administered was 3.5 (1-12). The overall response rate (ORR) was 40% with 8 (27%) patients achieving CR, 4 with AML and 4 with MDS. Median OS was 7.8 months (0.3-29, CI 7.54-8.03) (Figure 1A) and median EFS was 5.1 months (0.3-15.9, CI 4.87-5.37) (Figure 1B). Stopping rules for survival and response were not met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. Mortality at 4 and 8 weeks was 10 and 20% respectively. A total of 79 patients were enrolled in the subsequent randomized study: 27 to azacitidine (A) and 52 to azacitidine and vorinostat (A+V). Patient characteristics and inclusion criteria are also shown in Table 1. Median age was 70 years (30-90). Forty-seven (59%) patients had MDS and 32 (41%) had AML. Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rates were 67% (A) and 85% (A+V), respectively (p=0.07). No differences in ORR (48% vs 46%, p=0.87), OS (6.1 vs 7.6 months, p=0.49) (Figure 1C) or EFS (3 vs 5.5 months, p=0.05) (Figure 1D) were observed between groups. Main AEs included grade 1-2 gastrointestinal toxicities with a higher proportion of AEs with A+V (81 vs 56%). Mortality at 4 and 8 weeks was 10% (A: 4, A+V: 4) and 19% (A: 9, A+V: 6) respectively. By univariate analysis neither PS ≥3, creatinine or bilirubin ≥2mg/dL nor presence of other malignancy were predictive for 60-day survival, OS or EFS. There were no significant differences in survival between patients with ACE-27 scores of 0-1 compared to 2-3 both in the single-arm (6.3 vs 7 months, HR=0.88, 95% CI 0.41-1.91, p=0.75) and the randomized phase of the study (A: 13.5m vs 6.1m, HR 0.93, 95% CI 0.27-3.17, p=0.9 and A+V: 12.1m vs 7.4m, HR 1.38, 95% CI 0.61-3.14, p=0.4). CONCLUSION: Most enrolled patients met the study's primary endpoint of survival at 60 days without major toxicity. Patients obtained clinical benefit with acceptable responses and survival despite their high comorbidity burden. Our results support the feasibility of treating patients with MDS or AML not eligible to other clinical trials due to poor performance status, comorbidities or organ dysfunction, with low intensity therapies within a clinical trial. These findings suggest relaxation of such criteria may likely increase the pool of clinical trial patient candidates and allow access to potential beneficial therapies for patients with otherwise dismal prognosis. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria.

Description: Introduction - Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with myelofibrosis (MF). MF is stratified into various risk groups based on Dynamic International Prognostic scoring system (DIPSS plus), which determines the eventual prognosis of the disease at any time. Previous studies and expert opinion indicate that for patients with Intermediate-2 risk (INT-2) and High risk (HR) disease, HCT is a reasonable option. How applicable is this to all patients with MF and what are the barriers to doing a transplant are not known. We therefore reviewed medical records of all patients who were referred for HCT. The main purpose of this study was to determine the proportion of patients who underwent transplantation as well as to ascertain the major reasons why patients referred for transplantation did not receive it despite its reported benefit. Methods- This was a retrospective, single institution, observational study. We analyzed patients referred for HCT with a diagnosis of MF. One hundred and ninety-eight consecutive patients with a preliminary diagnosis of MF were seen at the stem cell transplantation and cellular therapy (SCTCT) clinic of MD Anderson cancer center (MDACC) from 1/1/2004 to 12/31/2012. Out of the 198 patients, 26 had a diagnosis other than MF and hence were excluded. We stratified the remaining patients according to their DIPSS plus score at the initial consult and also traced their progression. For the non-transplanted patient with HR and INT-2 DIPSS plus scores, the major reason for deferring transplant was retrieved from the chart. Results & Discussion- Out of 172 patients seen in the stem cell transplant clinic with MF, 70(41%) underwent transplantation and 102(59%) did not receive HCT. Of the 102 patients who did not undergo SCT, 72(70%) had INT-2 or HR disease at the initial consultation (transplant eligible). Of the remaining 30 patients with low risk or intermediate-1 risk disease, 7(23%) patients eventually progressed to INT-2 or HR disease and became transplant eligible. The median time from MF diagnosis to consultation for non-transplanted patients was 331days (11 months) (Range-0-8675). For patients with INT-2 and HR disease (79/102), the major reasons for not receiving a transplant (Figure) are patient choice (36/79; 46%), financial issues (23/79; 29%), comorbidities (9/79; 11%), lack of donor (7/79; 9%) and poor performance status (4/79; 5%). Patient choice of not pursuing transplant is understandable because there was limited data on efficacy of HCT for MF in early years. The most common insurance provider not covering transplantation was Medicare (20/23; 87%). The co-morbidities that precluded HCT were cardiopulmonary disease (4/9; 44%), liver dysfunction due to advanced disease (3/9; 33%) and other comorbidities (2/9; 22%). Of note 5/7 (72%) patients who were not transplanted due to lack of appropriate donor were non-Caucasian patients. Conclusion- Only 41% of patients referred for transplant with MF receive HCT. The major barriers to wider application and usage of HCT for MF were patient choice and lack of coverage by Medicare. Patient education, coverage by Medicare, use of alternative donors, and earlier transplant referrals can further increase the accessibility of transplantation and improve outcomes of patients with MF. Figure 1. Figure 1. Disclosures Alousi: Therakos, Inc: Research Funding.

Description: Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). OBJECTIVE: The purpose of this study is to determine the safety, tolerability and efficacy of orally administered NS-018 in patients with PMF, post-PV MF, or post-ET MF. METHODS: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. The study drug, NS-018, was given orally either daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses were assessed according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis (BMF) was evaluated by biopsy, according to WHO criteria. Changes in grade of BM fibrosis from baseline were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study has been completed and data are presented here. RESULTS: In this Phase 1 study, 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID). Characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF with a median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. At 400 mg QD/BID, NS-018 dosing was associated with drug-related neurologic adverse events (AEs) including dizziness, peripheral neuropathy, headache, disturbance in attention, vertigo, dysesthesia, paresthesia, aphasia, and nervous system disorder (not otherwise specified). The 300 mg QD dose was better tolerated than 250 mg BID or 300 mg BID, with fewer neurologic AEs, and was selected as the recommended phase 2 dose (RP2D). For the 48 phase 1 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including for patients with prior JAK2 inhibitor treatment. In all dose cohorts, ≥ 50% patients achieved ≥ 50% score reduction from baseline in night sweats, pruritus and bone pain after 1 cycle. Moreover, ≥ 50% patients achieved ≥ 50% score reduction from baseline in abdominal pain and inactivity after 3 cycles. In patients who had received prior JAK2 inhibitor, ≥ 50% patients achieved ≥ 50% score reduction from baseline in filling up quickly, inactivity, night sweats and quality of life after 3 cycles. Among 36 patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 20 (56%) showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement (CI) for ≥ 8 weeks, 4 had hemoglobin CI, and 1 had platelet CI. After 3 cycles of NS-018 treatment, 11/31 (37%) evaluable patients had a reduction in bone marrow fibrosis(BMF) by ≥ 1 grade. At any time during NS-018 treatment, 17/31 (55%) evaluable patients had a reduction in BMF by ≥ 1 grade. Overall, 23% (7/31) patients maintained improvement in BMF for ≥ 12 weeks. Reduction in BMF after 3 cycles was correlated with reduction in splenomegaly and hemoglobin responses. To date, 8 patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Updated Phase 2 data will presented at the meeting. CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided an acceptable safety and tolerability profile, and reduction in symptomatic splenomegaly. Phase 2 is ongoing and includes patients previously treated with other JAK2 inhibitors. Disclosures Talpaz: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Sanofi Aventis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Odenike:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. Jamieson:GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; CTI Biopharma: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Genentech: Research Funding.

Description: Background: Among the most frequent and challenging hematologic manifestations of myelofibrosis (MF) are anemia and thrombocytopenia, the presence of which portends an adverse outcome. Few effective modalities to address these cytopenias exist, particularly thrombocytopenia. Further, although the FDA-approved JAK1/2 inhibitor Ruxolitinib (RUX) has demonstrated significant clinical efficacy in MF patients, RUX frequently results in anemia and thrombocytopenia. Thrombocytopenia in particular often results in dose attenuation of RUX. Thalidomide (THAL) is a first-in-class immunomodulatory agent. Studies of THAL in MF patients, alone and with prednisone, have demonstrated improvements in anemia and thrombocytopenia. We therefore sought to examine whether combination of RUX and THAL could result in improvement in both disease-related and therapy-related cytopenias, as well as improve overall disease response in patients with MF. Here we report initial analysis of this study (NCT03069326). Methods: We conducted a multicenter two stage phase II trial designed to assess the effect of RUX and THAL combination in subjects with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Patients taking RUX at the time of enrollment must have had less than PR per IWG-MRT/ELN 2013 criteria, or be refractory, to RUX single-agent therapy. Patients must have been taking RUX for a minimum of 3 months, and must have been on a stable dose of RUX for a minimum of 4 weeks immediately prior to enrollment. Treatment-naïve patients received single-agent RUX for 3 months (run-in phase) per label, and went on to combination therapy if they achieved less then a PR per IWG-MRT/ELN criteria. Each cycle of therapy was 28 days. Response assessment was evaluated according to the IWG-MRT/ELN 2013 criteria. Platelet response criteria in patients with baseline thrombocytopenia (less than lower limit of normal) included: Major response (≥75% increase in platelet count), Intermediate Response (≥50% increase) and Minor Response (≥25% increase). Adverse events were assessed using the NCI CTCAE v. 4.0. The primary endpoint was the proportion of treated subjects that achieved a response by IWG-MRT criteria and by platelet response criteria. Results: A total of 25 patients are planned to be accrued. At the time of this writing, a total of 18 patients have been accrued. The median age was 70.5 years (47-85). 8 patients had received prior therapies other than RUX, including imetelstat, momelotinib, danazol, pomalidomide, darbepoetin alpha and sotatercept. 7 patients enrolled to the run-in phase. 14 patients received red blood cell transfusions prior to study enrollment. Evaluation of platelet count in patients with baseline thrombocytopenia demonstrated a significant increase in platelet count at cycle 3 of therapy compared to baseline (Figure 1A and B; P

Description: Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.