Constellation Pharmaceuticals Research Articles

Safety and Efficacy of Polatuzumab Vedotin + Obinutuzumab for Relapsed/Refractory NHL: A Phase 1b/2 Study

Background: Single-agent polatuzumab vedotin (pola) and obinutuzumab (G) demonstrated safety/clinical activity in separate B-cell non-Hodgkin lymphoma (B-NHL) trials. Methods: Open-label, non-randomised, phase 1b/2 study (ROMULUS) of patients with relapsed/refractory (R/R) B-NHL evaluating safety/efficacy of pola 1·8 mg/kg + G 1000 mg in 21-day cycles, up to eight cycles. Primary objectives were safety/tolerability and anti-tumour response. Findings: Eighty-eight patients were enrolled and received ≥1 dose of any study drug; 43 patients with R/R follicular lymphoma (FL) and 45 with R/R diffuse large B-cell lymphoma (DLBCL). Grade 3–4 AEs occurred in 48·5% (n=48/88) of patients, most commonly, neutropenia (18·6%; n=18). In R/R FL, the most frequent any-grade adverse event (AE) was fatigue (n=23/43; 53·5%) and in R/R DLBCL diarrhoea (n=16/45; 35·6%). In R/R FL, the complete response (CR) rate (by independent review committee) was 36·1% (n=13/36; 90% confidence interval [CI]: 22·9–51·2) with an objective response rate (ORR) of 66·7% (n=24/36; 90% CI: 51·7–79·5). The ORR in R/R DLBCL was 19·4% (n=6/31; 90% CI: 8·8–34·7; no CRs). In R/R FL, investigator-assessed median duration of response was 8·5 months (interquartile range [IQR]: 6×3–9×7) and in R/R DLBCL was 3·7 months (IQR: 3×3–not estimable [NE]); median progression-free survival was 11·5 months (IQR: 7×8-12×4) and 2·8 months (IQR: 1×5-6×3); and median overall survival was not reached and 10·7 months, respectively. Interpretation: While the anti-tumour activity of pola (1.8 mg/kg)-G in R/R DLBCL was modest, pola-G warrants further investigation as a treatment for R/R FL. Trial Registration: www.clinicaltrials.gov (NCT01691898). Funding Statement: F. Hoffmann-La Roche. Declaration of Interests: T.P. has received research support from AbbVie and Pharmacyclics, and reports advisory board participation for Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. M.B. has no disclosures; the clinical and intellectual work on this paper was performed prior to employment with the Cigna Corporation and does not reflect the opinions or support of the Cigna Corporation. A.I.C. has acted as a consultant and has received research funding from Genentech, Inc. J.E. has nothing to disclose. A.C. reports advisory board participation for Celgene, Janssen, and iQone, and has received lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Servier. C.D. has served as a consultant/advisory board participant for Bristol-Myers Squibb, Celgene, Merck, Genentech, Inc./F. Hoffman-La Roche Ltd, and Seattle Genetics, and has received research support from Seattle Genetics, Bristol-Myers Squibb, Merck, Genentech, Inc., Incyte, LAM Therapeutics, Millennium/Takeda, MEI Pharma, and Trillium. J.C. is an employee of F. Hoffmann-La Roche Ltd. D.R. was a consultant to Genentech, Inc. at the time the study was carried out. J.H. is an employee of Genentech, Inc. F.M. has participated in advisory boards for Celgene, F. Hoffman-La Roche Ltd, Gilead, Bristol-Myers Squibb, Epizyme, and Bayer, and reports receiving lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Novartis, and research support from AbbVie, Pharmacyclics, and advisory board fees from Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. I.W.F. has acted as a consultant for AbbVie, Seattle Genetics, TG Therapeutics, and Verastem Oncology, and has received research funding from Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Inc., Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karo Pharma, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, F. Hoffman-La Roche Ltd, TG Therapeutics, Trillium Therapeutics, AbbVie, ArQule, BeiGene, Curis Inc., FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem Oncology, Gilead Sciences, Astra Zeneca, Juno Therapeutics, Unum Therapeutics, and MorphoSys AG. Ethics Approval Statement: Institutional review boards/ethics committees approved the protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice, and country-specific laws and regulations. All patients provided written informed consent.

The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells

The BET Inhibitor, CPI-0610, Promotes Myeloid Differentiation in Myelofibrosis Patient Bone Marrow and Peripheral CD34+ Hematopoietic Stem Cells

MANIFEST-2, a Global, Phase 3, Randomized, Double-Blind, Active-Control Study of CPI-0610 and Ruxolitinib Vs. Placebo and Ruxolitinib in JAK-Inhibitor-Naive Myelofibrosis Patients

The bromodomain and extraterminal domain (BET) family of proteins bind to chromatin to regulate the transcription of target genes involved in multiple pro-fibrotic pathways and is a novel therapeutic target for reducing fibrosis in myelofibrosis (MF). CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. Products with only one mechanism of action are approved currently for treatment of MF, Janus kinase 1/2 inhibitors (JAKi), with ruxolitinib (rux) being the standard of care for treatment-naïve MF patients. A minority of MF patients treated with rux (35%; 106 of 301) or fedratinib (37%; 35 of 96) achieved a spleen volume reduction ≥ 35% (SVR35) at 6-12 months. Disease-modifying therapeutic agents with a novel mechanism of action are needed to improve the outcomes in MF pts. Blocking BET activity with CPI-0610 inhibited aberrant maturation of megakaryocytes and decreased cytokine production in preclinical studies. In addition, synergistic antitumor activity of BETi and JAKi combination was observed in preclinical MF models. Clinical activity of CPI-0610 in combination with rux in JAKi-naïve MF patients observed in the phase 2 MANIFEST study was higher (SVR35 at wk 24: 63%) than that observed with rux alone in historical Phase 3 trials (Mascarenhas, EHA 2020). MANIFEST-2 is a global, phase 3, 1:1 randomized, double-blind, active-control study of CPI-0610 + rux vs. placebo + rux in JAKi treatment-naïve patients with primary MF, post-polycythemia-vera MF, or post-essential-thrombocythemia MF. Key eligibility criteria: DIPSS score ≥Int-1; platelet ≥100 x 109/L; spleen volume ≥ 450 cc by CT/MRI; ≥2 symptoms measurable (score ≥3) or a total symptom score (TSS) of ≥10 using the MFSAF v4.0; peripheral blast count <5%, ECOG ≤2. Approximately 310 patients (155 in each arm) will be enrolled in the study. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs. Intermediate-2 vs. High), platelet count (> 200 × 109/L vs. 100 - 200 × 109/L), and spleen volume (≥ 1800 cm3 vs. < 1800 cm3). Double-blind treatment (CPI-0610 or matching placebo) will be administered once daily (QD) for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment (1 cycle = 21 days). Rux will be administered twice daily (BID) for all 21 days within each cycle. Primary endpoint: SVR35 response (≥35% reduction in spleen volume) at wk 24; key secondary endpoint: TSS50 response (≥50% reduction in TSS) at wk 24; other secondary endpoints: safety, PK, PD, bone marrow morphology/fibrosis, duration of SVR35 response, duration of TSS50 response, PFS, OS, conversion from transfusion dependence to independence, rate of RBC transfusion for the first 24 wks, hemoglobin response, peripheral proinflammatory cytokines. Figure Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Harrison:Roche: Honoraria; Sierra Oncology: Honoraria; Promedior: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau. Luptakova:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Christo:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mertz:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Colak:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Shao:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bobba:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Trojer:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Senderowicz:Constellation Pharmaceuticals: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees. Humphrey:Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Gilead: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; CTI Biopharma Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding.

LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

LSD1 Inhibitor CPI-482 Shows Efficacy and Prolongs Survival in Mouse Models of AML and Post-MPN AML in the Context of Constitutive JAK-STAT Pathway Activation

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Cladribine, Idarubicin, Cytarabine (ara-C), and Venetoclax in Treating Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Cladribine, Idarubicin, Cytarabine (ara-C), and Venetoclax in Treating Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

PTG-300 Eliminates the Need for Therapeutic Phlebotomy in Both Low and High-Risk Polycythemia Vera Patients

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Since, they are seen periodically, PV patients likely spend significant time with hematocrit levels >45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit <45%. Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently >45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Hepcidin Mimetic (PTG-300) Reverses Iron Deficiency While Controlling Hematocrit in Polycythemia Vera Patients

Background. The majority of PV patients are iron deficient at diagnosis [Ginzburg Leukemia 2018]. PV patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels <45% in an effort to reduce the incidence of thrombotic events [Marchioli NEJM 2013]. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis and TP worsens iron deficiency and PV patients can be severely symptomatic from their iron deficiency [Krayenbuehl Blood 2011]. Iron deficiency is defined as insufficient iron stores to meet the needs of cellular homeostasis. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and iron availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in pre-clinical studies. In healthy volunteers PTG-300 decreases serum iron and transferrin saturation (TSAT) by >70% within 12 hours and the effect persists for 3-7 days. In a phase 2 trial in β-thalassemia, PTG-300 also decreased serum iron and TSAT but did not demonstrate off-target effects. The current study aims to compare the iron status in frequent TP-requiring PV patients before, during, and after treatment with PTG-300. Methods. Polycythemia patients who met 2016 WHO criteria for diagnosis were enrolled in the 28-week dose finding part of a Phase 2 trial. All patients required ≥3 phlebotomies with or without concurrent cytoreductive therapy over 6 months prior to enrollment. Patients were given PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly in individualized adjustment to maintain hematocrit <45%. Body iron status was quantified by monitoring serum ferritin, serum iron, transferrin saturation (TSAT), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 on concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. All subjects-maintained hematocrit <45% after appropriate dose adjustment. Mean baseline values were serum ferritin = 14.2 ng/mL (5, 37); serum iron = 33.0 ug/dL (16.8, 107.8); and TSAT = 7.6% (4, 30). During treatment with PTG-300, serum ferritin levels increased progressively toward normal (Figure 1a) reflecting increase in iron stores. TSAT (Figure 1b) and serum iron values increased modestly but remained below normal ranges, reflecting PTG-300's pharmacodynamic effect of inhibiting iron release from intracellular stores. This was associated with increased MCV (Figure 1c) and MCH (Figure 1d) and decreased hematocrit and erythrocyte counts, together suggesting a normalization of iron distribution. Conclusions. The current results indicate that PTG-300 is an effective agent for the controlling hematocrit and reversing iron deficiency. The effect of PTG-300 on PV-related symptoms and those of iron deficiency, are also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Kuykendall:Novartis: Research Funding; Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding. Yacoub:Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Hoffman:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Forbius: Consultancy; Protagonist: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding.

Outcomes of Patients with Myelofibrosis and Favorable Karyotype

Introduction Myelofibrosis (MF) is an aggressive myeloproliferative neoplasm negatively affecting patient's (pts) overall survival (OS). Several clinical and molecular factors, such as anemia, leukocytosis, thrombocytopenia, increased blasts, presence of unfavorable karyotype, or adverse molecular abnormalities (e.g., ASXL1, IDH1/2, SRSF2, EZH2), further worsen outcomes. Pts with favorable karyotype (e.g., diploid, single deletion 13q, or single deletion 20q), are assumed to have comparable and superior outcome, only affected by their clinical features and molecular background. We decided to evaluate how adverse clinical and molecular factors impact OS within this subset of patients. Methods We conducted a retrospective analysis on patients with favorable karyotype and newly diagnosed MF who presented to our institution within the last 20 years. Favorable karyotype was considered according to classification in DIPSS-Plus and MIPSS70v2.0 models. Prognostic models, IPSS, DIPSS, DIPSS-Plus and MIPSS70v.20 were calculated for patients as published. Molecular analysis was performed in some patients using at least 28-gene panel by next generation sequencing (NGS). Categorical variables were compared by Chi-squared test. Univariate analysis for association between variables and outcome was performed with Cox-regression analysis. Overall survival (OS) was estimated using Kaplan-Meier method and calculated from the time of presentation to our institution until the last follow-up or death. Results Among 1002 patients, 741 pts (74%) had diploid karyotype (DP); the remaining patients had single deletion 13q (del13q, n 33), single deletion 20q (n 97), single abnormality of chromosome 1, 9 or minus Y (n 131). Only pts with del13q had inferior OS to all other groups (42 vs ~ 62 months, p 0.001), and therefore we decided to further focus on pts with del13q and DP karyotype. Patients and disease characteristics are detailed in Tables 1 and 2. We did not observe any significant clinical differences between groups. Distribution by prognostic systems; IPSS, DIPSS, DIPSS-Plus and MIPSS10v2.0 is shown in Table 1. IPSS and DIPSS classified more patients with del13q into higher (combined intermediate 2 and high) risks. DIPSS-Plus and MIPSS70v2.0 showed similar distribution of patients into risks in both groups. Forty - two percent (n 87) and 36% (n 4) of patients with DP karyotype and del13q carried at least one high risk molecular mutation (HMR; such as ASXL1, IDH1/2, EZH2, U2AF1/SRSF2/SF3B1), respectively (Table 2). Whilst all applied clinical risk models (IPSS, DIPSS, DIPSS-Plus) appropriately discriminated distinct OS in pts with DP karyotype, only DIPSS-Plus was able to accurately predict distinct OS in those with del13q (Table 3). MIPSS70v2.0 (only patients with NGS panel) did not predict for distinct OS in DP or del13q pts (Table 3). Pts with DP karyotype had superior OS to those with del13q with median OS of 62 and 42 months, respectively (Figure 1), p < 0.001, HR 0.49, 95% CI 0.32-0.78. Although presence of HMR had negative impact on OS in both groups (Figure 2), pts with del13q with HRM had OS of only 15 months (vs 55 months in DP pts with HMR, p < 0.001). Conclusion Patients with MF and del13q appear to have inferior OS than those with diploid karyotype, despite similar clinical features. Impact of molecular abnormalities, especially presence of high-risk mutations, might be underestimated in this group and deserves further investigation. Ongoing research in our center is aimed to provide new evidence on the role of mutations for this karyotypically "favorable" subgroup. Disclosures Verstovsek: CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pemmaraju:Blueprint Medicines: Honoraria; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria; DAVA Oncology: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding.

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study

Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Long-Term Follow up of a Phase II Study of Guadecitabine (SGI-110) in Patients with Higher-Risk Myelodysplastic Syndrome (MDS)

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results

Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results

Breakthrough Invasive Fungal Infections (bIFI) Are Uncommon in Patients with Newly Diagnosed Acute Leukemia Receiving Primary Antifungal Prophylaxis

Introduction: Mold-active primary antifungal prophylaxis (PAP) is widely recommended in neutropenic patients (pts) with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who undergo remission-induction chemotherapy (RIC). Posaconazole (PCZ) prophylaxis resulted in fewer invasive fungal infections (IFIs) when compared to fluconazole and was associated with a survival advantage in this population (Cornely et al, 2007). Similarly, pts with acute lymphoblastic leukemia (ALL) undergoing RIC are also at risk of IFI due to prolonged neutropenia. Although PCZ is the preferred agent for PAP, the incorporation of targeted agents into acute leukemia therapy calls for more individualized choices in PAP. Other mold-active agents including voriconazole (VCZ) and isavuconazole (ISA) or the echinocandins are alternatives which may be preferred in individual settings due to variations in toxicity, patient co-morbidities, drug interactions, and cost. Little contemporary data exists to compare the incidence of breakthrough IFI (bIFIs) in pts with AML or ALL receiving PCZ, VCZ, or ISA as prophylaxis during RIC. Methods: We reviewed the medical records of all consecutive pts with newly diagnosed AML/MDS or ALL treated at our institution from 3/2016-7/2019. Included pts received high-intensity chemotherapy, or a lower-intensity venetoclax (VEN)-containing regimen, for RIC. Therapy with high-dose (> 1g/m2/day) cytarabine (HiDAC), continuous cytarabine plus an anthracycline (3+7), or HyperCVAD was considered high-intensity therapy. Patients receiving PCZ, VCZ, or ISA for > 5 days beginning during induction therapy were included. Baseline evidence of prior mold infection and treatment with a concomitant echinocandin were not allowed. Echinocandin use preceding mold-active PAP was allowed, however prior use of an amphotericin B product was not. bIFI were defined according to ECMM criteria (Cornely et al, 2019). Results: We identified 232 pts with AML/MDS (n=186), ALL (n=43), and biphenotypic leukemia (n=3). Among the AML/MDS pts, 31% (n=57) received a lower-intensity VEN-containing regimen, while 69% (n=129) received a high-intensity regimen with or without VEN. Nearly all pts with ALL and biphenotypic leukemia received high-intensity RIC with HyperCVAD or a HiDAC containing regimen. Of the 232 pts, PCZ (n=111), VCZ (n=84), or ISA (n=37) were used as PAP, respectively (Table 1). Most pts (n=157; 68%) received an echinocandin for a median of 6 days (range, 0-38), prior to transitioning to a mold-active triazole. Ten (4.3%) pts had a bIFI (6 proven, 1 probable, 3 possible) during induction therapy while receiving PAP (Table 2) including 9 (4.8%) pts with AML/MDS and 1 (2.3%) patient with ALL. An equal number of pts with bIFI were receiving lower-intensity, VEN-based therapy, or high-intensity therapy. Among the 84 pts receiving VCZ, 4 (4.8%) had a bIFI (4 proven); 3 pts (2.7%) receiving PCZ had a bIFI (2 proven, 1 possible); 3 pts (8.1%) receiving ISA had a bIFI (1 probable, 2 possible). C. glabrata (n=3), and C. krusei, Cryptococcus spp. and Fusarium spp. (one each) accounted for the 6 proven bIFIs. One patient had both C. glabrata and C. krusei fungemia. The probable bIFI was pneumonia with a positive Aspergillus GM from BAL. The 3 possible bIFI were pneumonia (n=2) and sinusitis (n=1). Eight pts (80%) were neutropenic (ANC < 500 cells/mm3) for >14 days at the time of bIFI, 1 pt was neutropenic for >7 days, and 1 pt had ANC > 500 cells/mm3. Seven pts with bIFI received a prior echinocandin for a median of 3 days (range, 0-15) prior to initiation of triazole PAP. Seven pts were neutropenic for < 7 days (n=2), 7-14 days (n=3), or > 14 days (n=2) at the time of azole initiation. bIFI occurred after a median of 20 days (range, 5-72) of azole PAP and a median of 24 days (range, 12-71) from the initiation of RIC. One patient with bIFI deceased within 42 days of starting RIC and did not achieve a response after RIC (bIFI-related mortality: 0.44%). Conclusion: The incidence (<5%) and mortality (< 0.5%) due to bIFI in a contemporary cohort of pts with newly diagnosed acute leukemia receiving PAP is low. bIFI occurred late in induction therapy and most often in pts with > 14 days of neutropenia. Prophylaxis with VCZ, PCZ, or ISA, with or without a prior echinocandin, appear to be comparable options for PAP in pts with newly diagnosed AML or ALL undergoing RIC. Disclosures Bose: CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Kontoyiannis:Gilead Sciences: Honoraria; United Medical: Honoraria; Astellas Pharma: Consultancy; Cidara Therapeutics: Consultancy; Amplyx Pharmaceuticals: Consultancy; Mayne Pharma: Consultancy; Pharma Pharmaceutical Industries: Consultancy; Merck & Co.: Consultancy, Honoraria. OffLabel Disclosure: Voriconazole and isavuconazole are approved for the treatment of invasive fungal infections rather than the prevention, as discussed in this abstract.

Role of Aneuploidy in Transcriptional Regulation and Clinical Prognosis in Relapsed and/or Refractory Multiple Myeloma (RRMM)

BACKGROUND Aneuploidy, defined by abnormal copy number changes of chromosomes, contributes to genome instability in multiple myeloma and has potential prognostic impact. Previous research has explored transcriptional pathways affected by aneuploidy. We aim to evaluate aneuploidy, clinical prognosis, and gene expression in RRMM patients (pts) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. We further used gene set analysis to identify enrichment and variation of genetic pathways associated with aneuploidy and overall survival (OS). This was a pilot study in view of applying similar methods to larger populations. METHODS DNA and RNA materials were obtained from 51 RRMM pts at the time of disease relapse. Targeted sequencing was performed with the Onco1700 panel and RNA sequencing was performed with a capture protocol using Agilent SureSelect All Exon V4, followed by paired end sequencing. Copy number variation (CNV) was estimated using an in-house pipeline using matched normal samples. Arm-level aneuploidy was defined as copy number status (gain, loss or neutral) with maximal proportion for each chromosomal arm. Aneuploidy score was determined by total number of arm-level CNV aberrations, with the median score defining high and low aneuploidy groups. Survival analysis was performed using Kaplan-Meier (KM) and Cox regression. RNA-seq libraries were aligned with STAR aligner to the hg38 reference and read quantification were performed with featureCounts. We used gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to obtain genetic pathway-level summaries for 50 hallmark pathways representative of cancer from the GSEA Molecular Signatures Database (https://www.gsea-msigdb.org/). Supervised GSEA was performed, based on differential analyses comparing gene expression profiles between high versus low aneuploidy groups to identify the differences in genetic pathways in RRMM pts. Unsupervised GSVA was applied to RNAseq count data of RRMM and newly-diagnosed multiple myeloma (NDMM) pts from the MMRF CoMMpass study (797 pts). Univariate Cox proportional hazard model was used to identify pathways having significant association with OS. RESULTS Arm scale aneuploidy analysis revealed high frequency of gains and losses in multiple chromosomes (Figure 1). RRMM pts with high aneuploidy scores had worse OS (median 15.9 months since study enrollment) compared to those with low scores (median not reached, p=0.027). Multivariate analysis demonstrated that high aneuploidy score is persistently associated with poor OS (hazard ratio (HR): 3.9, p=0.006), adjusting for t(4;14) and t(11;14). Hyperdiploidy (any whole chromosome carrying >2 copies) was identified in chromosomes 3, 5, 7, 9, 11, 19, 21, with frequency >20%. Pts with hyperdiploidy had better OS via KM (p=0.04). Using RNAseq gene expression data and GSEA analysis, we found enrichment of gene markers involving the pathways for targets of E2F transcription factors (Normalized Enrichment Score (NES) = 2.07), G2-M checkpoint in the cell division cycle (NES = 1.87), MYC proto-oncogene (NES = 1.93 and 1.85), and DNA repair (NES = 1.68) in RRMM pts with high aneuploidy compared against those with low scores (Benjamini-Hochberg adjusted p-value <0.001 for all pathways, Figure 2). GSVA analysis revealed 21 genetic pathways associated with survival in NDMM and RRMM pts, with 8, 2, and 11 pathways associated with OS in NDMM only, RRMM only, and both, respectively (Figure 3). Enrichment of several biological pathways involved with cellular growth, cell cycle regulation, and stress response (E2F, G2-M, MYC, DNA repair, mTORC1 signaling, UV radiation, mitotic spindle assembly, unfolded protein response, and peroxisome) are associated with poor survival (HR>1) in both NDMM and RRMM pts. Downregulation of KRAS signaling pathway is associated with better survival (HR<1) in both groups. CONCLUSION Aneuploidy, adjusted for chromosomal translocations, is an independent adverse prognostic factor for RRMM. Aneuploidy is correlated with dysregulation of major biological pathways involving cell cycle regulation, cellular division, oncogenes, and DNA damage repair. The majority of common pathways shared between RRMM and NDMM are linked to or reflective of genomic instability, and may explain association with poor survival. Disclosures Talpaz: IMAGO: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ye:Janssen: Research Funding; Portola: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Nektar: Research Funding; AbbVie: Research Funding.

Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series

Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series

Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)

Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia

Final Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome after Failure of Hypomethylating Agent Therapy

Final Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome after Failure of Hypomethylating Agent Therapy