Institutional Research Funding Research Articles

A Phase 1/2 Study to Evaluate the Safety and Efficacy of Ponatinib with Chemotherapy in Pediatric Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Introduction: Ph+ ALL accounts for 3-5% of pediatric ALL and is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) of 58-60% and 70-86%, respectively. Ponatinib is a potent third-generation TKI pan-BCR-ABL1 inhibitor that is active against BCR-ABL1 and all identified single resistance mutations, including the gatekeeper alteration, T315I, which confers resistance to other TKIs. Ponatinib has marketing approval in more than 50 countries, which includes the United States and European Union, for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. Ponatinib may also overcome drug resistance in pediatric patients with relapsed or resistant Ph+ ALL. This study will assess the pharmacokinetics, safety, and efficacy of ponatinib in pediatric patients. Methods: This Phase 1/2, single-arm, open-label, multicenter study (NCT04501614) will enroll approximately 18 patients in Phase 1 and 68 patients in Phase 2, including those enrolled in Phase 1 at the recommended Phase 2 dose (RP2D). Patients (aged ≥1 year to ≤21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with ABL class lesions will be enrolled. Enrolled patients must have either relapsed or are resistant or intolerant to ≥1 prior therapy with a BCR-ABL1-targeted TKI or have a BCR-ABL1 T315I mutation. Patients >16 years must have a Karnofsky performance status ≥50%; patients ≤16 years must have a Lansky Play Scale ≥50%. During Phase 1, prior to availability of an age-appropriate formulation (AAF), patients must weigh ≥30 kg and be able to swallow tablets. The Phase 1 study will establish the RP2D of ponatinib in combination with the chemotherapy backbone using the adult tablet formulation in patients able to swallow tablets. Patients will receive fixed doses of ponatinib based on body weight ranges. The initially selected doses are expected to achieve systemic exposures that approximately match adult exposures after a 30-mg dose. Dose selection for the AAF will be in a separate cohort and informed by the results of a relative bioavailability study in healthy adult volunteers. A rolling 6 design will be used for both cohorts; additional cohorts may be enrolled at lower or higher doses based on the emerging data. In both Phase 1 and Phase 2, patients will receive two 35-day blocks of therapy (reinduction and consolidation). Each block includes 29 days of study treatment consisting of daily ponatinib and a modified United Kingdom ALL R3 chemotherapy backbone regimen, followed by a rest period of at least 6 days with daily ponatinib only. Disease assessment will occur at the end of each block. Patients will undergo an end-of-treatment visit 25 to 30 days after the last dose of study treatment in the consolidation block, or earlier if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. For the Phase 1 study, the primary endpoint is the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR-ABL1 domain mutations prior to and following ponatinib treatment. For the Phase 2 study, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints will be summarized descriptively, and include the proportion of patients in continued CR or who achieve CR at the end of consolidation, the proportion with minimal residual disease-negative status <0.01% at the end of each block, and the proportion who relapsed or progressed, and time-to-event estimates including EFS, progression-free survival, and OS. The study will include approximately 70 study sites in approximately 16 countries. Disclosures Matloub: Takeda: Current Employment. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Pui:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Hanley:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Leonard:Takeda: Current Employment. Granier:Incyte: Current Employment. Silverman:Servier: Other: advisory board; Syndax: Other: advisory board; Takeda: Other: advisory board. OffLabel Disclosure: Ponatinib has marketing approval in the United States and European Union for adult patients with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. This trials-in-progress abstract describes a study in pediatric patients.

Enhanced Risk Stratification of 21,178 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia (ALL) Incorporating White Blood Count (WBC), Age, and Minimal Residual Disease (MRD) at Day 8 and 29 As Continuous Variables: A Children's Oncology Group (COG) Report

Current risk stratification for COG ALL patients (pts) relies on National Cancer Institute (NCI) risk group (RG) at diagnosis, somatic genetics, and early response to therapy as measured by specific thresholds of minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). NCI RG is defined as age 1-10 years (yrs) and white blood cell count (WBC) <50,000/uL (Standard Risk, SR); all other non-infant patients are high risk (HR). Using COG risk stratification, current therapies for SR and HR patients are based on 5-year projected event-free survival (EFS) of 92-97%, and 65-86%. Currently, two subsets, Ph-like and very high risk (VHR) ALL are identified with additional assays-genomic sequencing for Ph-like, and persistent BM MRD on D29 and at end of consolidation for VHR, and are eligible for different treatments. However, as UK investigators recently published (O'Connor, JCO 2018; Enshaei, Blood 2020), using multiple continuous variables as threshold-defined categorical data may diminish the power of accurately predicting relapse, and thus prescribe inappropriate post induction therapy. We tested the UK approach of transforming categorical variables into continuous data on 13,870 NCI SR and 7308 NCI HR B-ALL pts treated on two generations of COG trials: AALL0331 (SR; n=5094), AALL0932 (SR; n=8776), AALL0232 (HR; n=2883), and AALL1131 (HR; n=4425). Down syndrome and Ph+ pts were excluded from analysis. Clinical characteristics are listed in Table 1. ETV6-RUNX1 (25.24%) and double trisomies of chromosome 4, 10 (DT) (23.77%) comprised the favorable risk genetic RG (FRG) group (48.15% of risk classified) while KTM2A rearranged (1.71%), hypodiploidy (1.67%), and iAMP21 (2.56%) comprised the unfavorable risk genetic RG (URG) (6.26%). All others with genetic information were classified as intermediate risk genetic RG (IRG) (45.59% of risk classified). Among 4873 pts tested, 20.46% had Ph-like ALL. D8 PB and D29 BM MRD data were available for 76.42% and 96.69% pts, respectively. We first log transformed WBC, D8 and D29 MRD and displayed these by treatment protocol, NCI RG, and FRG/URG (separating out Ph-like independently). Age and WBC followed the normal expected distribution with the median age of SR pts 4.0 yrs (range 1-9) and HR 12 yrs (range 1-30). Transformed MRD was displayed as a variable t(MRD), corresponding to the negative log; max t(D29 MRD) was 13.82, corresponding to MRD <1.0 x 10-5.The great majority of pts were MRD-positive at D8 (mean t(D8 MRD) 7.42); but there was broad distribution of values, with NCI SR and FRG pts having lower t(D8 MRD) (mean 7.52 and 8.08) than NCI HR and URG pts (mean 7.20 and 6.56) (p < 0.001) . The great majority of pts were D29 MRD-negative (mean t(D29 MRD) 12.08), with NCI SR and FRG pts achieving lower D29 MRD (mean t(D29 MRD) 12.43 and 12.73) than NCI HR and URG pts (mean 11.40 and 10.95) (p< 0.0001). Ph-like ALL pts had a mean t(D8 MRD) and t(D29 MRD) of 6.22 and 9.37. We next conducted a univariate analysis for risk factors for relapse, including sex, age, WBClog, CNS status, protocol-defined rapid early response status, FRG, URG, t(D8 MRD), and t(D29 MRD); all variables except CNS status were significant p < 0.0001). Multivariable modeling showed that WBClog, FRG, URG, t(D8 MRD), t(D29 MRD) retained significance (p < 0.0001). Finally, we applied the UK Prognostic Index (PIUKALL) equation [t(d29 MRD) x -0.218 + CYTO-GR x -0.440 + CYTO-HR x 1.066 + WBClog x 0.138] to the COG data using protocol, NCI RG, FRG, URG, IRG, or Ph-like RG in the model and validated the trends for relapse-free survival (RFS), which were similar in our groups with an overall median PIUKALL of -2.63 (mean -2.32, SD -.90, min -3.54, max 1.79). We next added in t(D8 MRD) to define a PICOG and determined that D8 PB MRD added significantly to the model, mostly through discriminating between the hazard ratios of the FRG and the URG RGs. Importantly, the D8 PB MRD led to a qualitatively more distinctive group with a potentially lower predicted RFS in NCI SR pts, a group that has been more difficult to predict in the past, and yet comprises nearly half of all relapse events. Our analyses of 21,178 COG B-ALL pts confirm and extend the utility of integrating WBC and MRD as continuous rather than categorical values to refine risk stratification for patient treatment and trial design. Disclosures Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Hunger:Amgen: Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; AbbVie, Inc.: Research Funding.

Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p<0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p<0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p<0.0001), which appeared largely driven by the Ph-like HR cohort as expected (57.9% MRD+ vs 42.1% MRD- in HR CRLF2+ and 44.6% MRD+ vs 55.4% MRD- in SR CRLF2+ patients, p<0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p<0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p<0.0001) compared to CRLF2- patients (Figure 1A-B) and a greater 5-year cumulative incidence of relapse (CIR; 30.4% ±2.7 vs 13.2% ±0.6, p<0.001). While 5-year EFS and OS were particularly poor in Ph-like CRLF2+ HR patients (56.3% ±4.6 and 75.4% ± 3.9, respectively) and non-Ph-like CRLF2+ HR patients (EFS 63.7% ±10.2 and OS 74.4% ±8.9), outcomes for Ph-like CRLF2+ SR (EFS 87.2% ±4.5 and OS 94.5% ±3.1) and non-Ph-like CRLF2+ SR patients (EFS 86.2% ±9.3 and OS 100%) were quite good (p<0.0001 for both EFS and OS; Figure 1C-D). Discussion: Patients with newly-diagnosed CRLF2+ B-ALL treated on frontline COG trials have higher rates of EOI MRD positivity, inferior survival, and increased CIR compared to their CRLF2- counterparts. EFS is especially poor in children and AYAs with NCI HR CRLF2+ ALL, particularly those with the Ph-like expression profile. Conversely, outcomes for children with NCI SR CRLF2+ ALL are reasonably favourable, irrespective of Ph-like status. Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321). Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Safety and Efficacy of Idasanutlin in Patients (pts) with Hydroxyurea (HU)-Resistant/Intolerant Polycythemia Vera (PV): Results of an International Phase II Study

Safety and Efficacy of Idasanutlin in Patients (pts) with Hydroxyurea (HU)-Resistant/Intolerant Polycythemia Vera (PV): Results of an International Phase II Study

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

The Effect of Fedratinib, a Selective Inhibitor of Janus Kinase 2 (JAK2), on Weight and Metabolic Parameters in Patients with Intermediate (INT)- or High-risk Myelofibrosis (MF)

The Effect of Fedratinib, a Selective Inhibitor of Janus Kinase 2 (JAK2), on Weight and Metabolic Parameters in Patients with Intermediate (INT)- or High-risk Myelofibrosis (MF)

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Clinical Trial Design Features of Myelofibrosis Trials during the Last Decade: Comprehensive Review of Clinicaltrials.Gov Data 2010-2019

Introduction: FDA approval of JAK2-inhibitors for myelofibrosis (MF) has changed the landscape for treatment introducing possible increased complexity of clinical trial designs in MF. Many patients with MF will have insufficient response or intolerance to ruxolitinib, opening an opportunity for testing of novel agents alone or in combination. Novel trial designs exist for early stage (phase 1 and 2) studies. The Myeloproliferative Neoplasms Research Consortium (MPN-RC) is an NCI-funded academic group of laboratory and clinical scientists working to develop and evaluate treatments that will improve the survival of patients with MPNs focused on early stage trials in MF. This review was undertaken to understand the landscape of MF clinical trials and improve our approach to trial design. Methods: Studies with "myelofibrosis" as a condition were abstracted from clinicaltrials.gov using an application programming interface from 2010-2019 and reviewed for phase, trial design features, and endpoints. Trial design review captured such features as presence of dose escalation and approach (rule-based versus model-based/assisted) in the phase 1 setting. Observational and behavioral based studies were excluded. A total of 165 treatment interventional studies including MF patients (either MF as the primary cohort, or MF along with other MPN, myelodysplastic syndrome, or hematologic malignancies related cohorts) were reviewed. Primary and secondary endpoints were reviewed for quality of life, symptoms, or other patient-reported outcomes (PRO). Results: A median of 16.5 (range 13-20) trials were initiated per year; 92 (56%) phase 2, 54 (33%) phase 1; 17 (10%) phase 3 and 2 (1%) phase 4, with 77 (47%) industry sponsored (Figure 1). Among phase 1 trials, 41/54 (76%) included dose escalation, the majority employing a standard 3+3 design (or other rule-based design) or not specifically detailing the dose escalation schema. Less than 5 dose escalation trials were explicitly described as model-based or model-assisted. Almost half of the phase 1 trials (23/54; 43%) included combination treatment, with 17/23 (74%) using ruxolitinib or fedratinib. Among phase 2 trials, 82 (89%) were non-randomized and 10 (11%) randomized trials; 35/92 (38%) involved combination treatment and 57 (62%) single agent. Median actual/target enrollment for the phase 3 trials (n=16) was 192 patients (range 49-2233 patients); only 2 phase 3 trials were > 500 patients. Median number of total outcomes was 6.0 (range 1-28) across all studies with a median of 5.5 (range 1-28) for 2010-2014 versus 7.0 (range 1-22) for 2015-2019 (p=0.09). Overall 63/165 (38%) studies included at least one PRO endpoint; 15 (28%) phase 1, 33 (36%) phase 2 and 14 (82%) phase 3. Inclusion of PRO endpoints for years 2010-2014 was similar to studies started in years 2015-2019 [31/82 (38%) and 32/83 (39%)]. Industry sponsored studies included PRO endpoints more frequently [46/77 (60%) versus 17/88 (19%); p<0.001] than non-industry sponsored trials but this is primarily due to a higher proportion of phase 3/4 trials (n=17) being conducted by industry versus non-industry (n=2) (Figure 2). Conclusions: For phase 1 trials in MF, few dose-escalation trials included model-based or model-assisted methods. These designs are encouraged in order to maximize therapeutic benefits in MF, a rare cancer. Clinical trial designs in myelofibrosis have shifted in recent years as evidenced by an increase in number of endpoints, likely to accommodate new challenges in the post JAK2-inhibitors approval era. Use of patient-reported outcomes including quality of life and symptom assessment was high in the phase 3 setting, and continued use should be encouraged as endpoint assessments in MF clinical trial designs. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Mesa:LaJolla Pharma: Consultancy; Novartis: Consultancy; Sierra Onc: Consultancy; Abbvie: Research Funding; Celgene: Research Funding; CTI: Research Funding; Genetech: Research Funding; Incyte: Research Funding; Promedior: Research Funding; Samus: Research Funding. Hoffman:Dompe: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy.

Results of a Phase II Study of PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

Background: Myelofibrosis (MF) is a hematopoietic stem cell neoplasm characterized by abnormal JAK-STAT signaling, increased inflammation, and evolution to acute myeloid leukemia. Most patients harbor a phenotypic driver mutation- JAK2, CALR or MPL. In the last decade, two JAK2 inhibitors have been approved, however, outside of hematopoietic stem cell transplantation (HSCT), there are no medications that meaningfully modify MF disease biology. Thus, additional treatments are needed. We previously demonstrated the presence of multiple immunosuppressive mechanisms in MPN patients, including expanded myeloid derived suppressor cell (MDSC) populations and elevated expression of immune checkpoint receptors, particularly PD1, on T cells from MPN patients compared to healthy donors (Cimen Bozkus, Cancer Discovery 2019). Therefore, we conducted a multi-center, open-label, phase 2, single-arm study of pembrolizumab in patients with primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) (NCT03065400). Methods: Patients with intermediate-2/high DIPSS MF, ineligible for or previously failed ruxolitinib were eligible. Pembrolizumab was administered at the FDA-approved dose of 200 mg every 3 weeks for 6 cycles. The study was a Simon two-stage design, 9 patients enrolled in the first arm. The study was terminated after completion of this arm due to the lack of responses. Response assessment was conducted after 6 cycles utilizing the International Working Group (IWG-MRT) criteria. In addition, patients with accelerated or blast phase (MPN-AP/BP) could enroll as a separate, ten patient, exploratory cohort. Results: 9 patients enrolled in the MF cohort and 1 in the BP cohort between 6/2017 and 3/2020. Baseline characteristics are summarized in Table 1. Median weeks on treatment were 14.7 (range 4-20). All 9 MF patients were evaluable for response as they received at least 1 dose of pembrolizumab. Of the 9 patients who were evaluable for response, all had SD, 4 (44%) patients discontinued therapy prior to the end of cycle 6. Reasons for discontinuation were adverse events (n=1), patient decision (n=1), physician decision (n=2). Grade 3/4 AEs included anemia (n=3), thrombocytopenia (n=2), leukopenia (n=1), hyperglycemia (n=2), hyperuricemia (n=1), dyspnea (n=1), headache (n=1). No grade 3/4 immune related AEs occurred (Table 2). The effects of pembrolizumab on the immune suppressive milieu observed in MPN were analyzed. PD-1 was detected on peripheral blood T cells by flow cytometry at baseline, but not post-treatment, likely due to receptor occupancy by pembrolizumab. In all patients analyzed, the levels of soluble PD1 in the plasma by Olink assay were significantly higher post-treatment. Other soluble factors associated with T cell activation such as class I-restricted T cell-associated molecule (CRTAM) and CD27 were also elevated after pembrolizumab administration. Furthermore, ARG1, a molecule that mediates T-cell suppression by MDSC, was significantly reduced in the plasma of treated patients. An increase in peripheral blood T cell frequencies was observed in a subset of patients after two cycles. Discussion: Pembrolizumab did not demonstrate clinical activity in this phase 2 trial. The relevance of the preliminary correlative findings will be further confirmed by in situ gene profiling of immune cells and their microenvironment. The complete results will be available at the meeting. These results suggest that pembrolizumab may promote a phenotypical and soluble signature suggestive of a restored immune response. The fact that these molecular changes were not associated with clinical responses indicate that pembrolizumab alone may not be sufficient to reverse the multifactorial causes of immune tolerance in MPN. Disclosures Hobbs: Constellation: Honoraria, Research Funding; Bayer: Research Funding; Jazz: Honoraria; Incyte: Research Funding; Novartis: Honoraria; Merck: Research Funding; Celgene/BMS: Honoraria. Stone:Syndax: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Takeda: Other: DSMB; Syntrix: Other: DSMB; Arog: Consultancy, Research Funding; Jazz: Consultancy; Trovagene: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Biolinerx: Consultancy; Argenix: Other; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Other; Agios: Consultancy, Research Funding; Gemoab: Consultancy; Janssen: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Aztra-Zeneca: Consultancy; Macrogenics: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees. 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.

Analysis of the Global Methylation Profile of Accelerated and Blast Phase Myeloproliferative Neoplasms and Its Association with Response to Decitabine-Based Therapy

Analysis of the Global Methylation Profile of Accelerated and Blast Phase Myeloproliferative Neoplasms and Its Association with Response to Decitabine-Based Therapy

Two Phase 1b Studies Evaluating the Safety and Tolerability of BET Inhibitors, ABBV-744 and Mivebresib, as Monotherapies and in Combination with Ruxolitinib or Navitoclax in Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by uncontrolled inflammation and fibrotic deposition in the extracellular bone marrow space, resulting in cytopenias, constitutional symptoms, and splenomegaly. A minority of patients are eligible for allogeneic hematopoietic stem cell transplant (allo-HSCT), which can be curative but is associated with substantial risks. Janus-associated kinase inhibitors (JAKi), including ruxolitinib (Rux), are approved for treatment of MF but do not reliably alter the disease course or generate durable responses. The limited treatment options for MF after Rux failure highlight a clear unmet need. In murine models of MPN, bromodomain and extra-terminal family protein inhibitors (BETi) reduced inflammatory cytokine levels and, combined with JAKi, reduced MF disease burden (Kleppe et al, 2018). BETi also modulated key nodes in the intrinsic apoptosis pathway and synergized with the B-cell lymphoma-2 (BCL-2) family inhibitor navitoclax (Nav) in solid tumor models (data on file). Pan-BETi have shown activity in patients with MF, including reduction in spleen volume and improvements in symptom burden, anemia, and bone marrow fibrosis as monotherapy and in combination with Rux (Mascarenhas et al, 2019). Selective BETi may reduce off-target toxicity relative to pan-BETi. The studies described here aim to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of ≥2 dosing regimens of 2 novel BETi: mivebresib, an oral pan-BETi that demonstrated antitumor activity in preclinical models of malignancy, and ABBV-744, a novel, potent small molecule that selectively inhibits bromodomain II of the BET family. Both BETi will be investigated as monotherapy and in combination with Nav or Rux in patients with MF. Methods: The 2 Phase 1b, multicenter, open-label studies will recruit patients with MF to receive ABBV-744 (NCT04454658) or mivebresib (NCT04480086), respectively, as monotherapy or in combination with Nav or Rux. Patients ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly (intermediate-1 with palpable splenomegaly ≥5 cm below costal margin eligible for Segment A) and Eastern Cooperative Oncology Group Performance Status <2 who are not candidates for allo-HSCT will be enrolled into 4 segments (Figure). Segment A: JAKi-experienced and BETi-naïve patients will receive 1 of 2 dosing regimens of ABBV-744 or 1 of 2 dosing regimens of mivebresib. Segment B: BETi-naïve patients currently receiving Rux will receive ABBV-744 or mivebresib plus Rux; Segment C: JAKi-experienced, and BETi-naïve, and/or BCL-XL/BCL-2 inhibitor-naïve patients will receive ABBV-744 or mivebresib plus Nav; Segment D: JAKi-naïve and BETi-naïve patients will receive ABBV-744 or mivebresib plus Rux. A dose regimen will be stopped if ≥3 of the first 9 dose-limiting toxicity (DLT)-evaluable patients given that dose in Segment A experience a DLT, or if the DLT rate is ≥33% at any point thereafter. Segments B and C will begin only once a dose regimen is deemed safe in Segment A. Segment D will commence after safety is established in Segment B. Treatment may continue until ≥1 discontinuation criterion has been met. The primary endpoint in both studies is adverse events (AEs) defined by the Common Terminology Criteria for AEs v5, including DLTs at a dose considered tolerable in patients with MF. Key secondary endpoints include the proportion of patients with spleen volume reduction of ≥35% at Weeks 12 and 24, PK parameters, proportion of patients with ≥50% reduction in Total Symptom Score at Week 24, and objective response rate (complete remission + partial remission). Key exploratory endpoints include change from baseline in allelic frequency, improvement in bone marrow fibrosis grade, and cytokine modulation. The planned sample size is approximately 130 patients per study. Analyses will include all patients who received ≥1 dose of study drug. Safety will be assessed by study drug exposure, AEs (including DLTs), serious AEs, deaths, and changes from baseline in laboratory determinations and vital sign parameters. AEs will include treatment-emergent events with an onset after first dose and ≤30 days after the last dose of study drug. Efficacy analyses will include summary statistics for categoric and continuous variables. Confidence intervals will be derived from the Clopper Pearson method. First dosing is planned for Q4 2020. 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. Saab:AbbVie: Current Employment, Other: may own stock or stock options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Modi:AbbVie: Current Employment, Other: may own stock or stock options. Abraham:AbbVie: Current Employment, Other: may own stock or stock options. Ward:AbbVie: Current Employment, Other: may own stock or stock options. Verstovsek:Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; ItalPharma: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding.

Direct Oral Anticoagulants for Myeloproliferative Neoplasms (MPN-DOACs): Results from an International Study on 442 Patients

Direct Oral Anticoagulants for Myeloproliferative Neoplasms (MPN-DOACs): Results from an International Study on 442 Patients

A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor

A Randomized Open-Label, Phase 3 Study to Evaluate Imetelstat Versus Best Available Therapy (BAT) in Patients with Intermediate-2 or High-Risk Myelofibrosis (MF) Refractory to Janus Kinase (JAK) Inhibitor

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.

An Open-Label, Global, Multicenter, Phase 1b/2 Study of KRT-232, a First-in-Class, Oral Small-Molecule Inhibitor of Murine Double Minute 2 (MDM2), Combined with Ruxolitinib in Patients Who Have Myelofibrosis and a Suboptimal Response to Ruxolitinib

An Open-Label, Global, Multicenter, Phase 1b/2 Study of KRT-232, a First-in-Class, Oral Small-Molecule Inhibitor of Murine Double Minute 2 (MDM2), Combined with Ruxolitinib in Patients Who Have Myelofibrosis and a Suboptimal Response to Ruxolitinib

Prevalence of Unexplained Erythrocytosis and Thrombocytosis - an Nhanes Analysis

Introduction Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms characterized by erythrocytosis and thrombocytosis, with an estimated prevalence of 22 and 24 per 100,000, respectively in the United States (Ma X et al AJH 2008). However, the prevalence of undiagnosed disease is unknown. We examined the National Health and Nutritional Examination Survey (NHANES) database for unexplained erythrocytosis (UE) and thrombocytosis (UT). Methods NHANES is a cross-sectional, nationally representative, population-based survey administered by the Centers for Disease Control and Prevention that utilizes a combination of interviews, physical examinations, and laboratory testing. In the UE group, participants were included if they had a hemoglobin >18.5 g/dL in men or >16.5 g/dL in women or a hematocrit >55.5% in men and >49.5% in women. Participants were excluded if they required oxygen supplementation, had a reported history or pulmonary function test evidence of obstructive lung disease, were receiving exogenous steroids or smoked cigarettes, or had a history of blood, kidney, liver, or uterine cancer. The UT group included participants with a platelet count greater than 450 x 10^9/L, and excluded those with laboratory evidence of iron deficiency, an elevated LDH suggesting inflammation, or reported a current infection, history of cancer, or rheumatologic conditions. Given the availability of necessary eligibility data, NHANES was queried from 2007-2008 for the UE group and 1999-2002 for the UT group. Weighted statistics are presented. Results Of the 3348 participants evaluable for UE, 16 (0.38%; 383.0 per 100,000 population) had erythrocytosis of which 4 were unexplained (0.04% of the overall population; 40.8 per 100,000 population). Reasons for erythrocytosis are noted in Table 1. UE participants had a mean hemoglobin of 18.1g/dL (standard error [SE] 0.6) and hematocrit of 50.7% (SE 1.5). Table 2 shows the estimated prevalence of UE by age, gender, and race. The average age was 58.8 years (SE 2.8), which was significantly older than the general population without erythrocytosis (42.8 years [SE 0.5], p<0.0001). All UE participants in the sample were United States (US) born and had an educational level below a college degree. The mean family poverty income ratio was 2.4 (SE 0.6), which was lower, although not significantly different than the NHANES population without erythrocytosis (mean 3.2 [SE 0.1], p=0.2113). Of the 7403 participants evaluable for thrombocytosis, 108 participants (1.47%; 1,474.6 per 100,000 population) had thrombocytosis of which 33 (0.49% of the overall population; 494.2 per 100,000) were UT. Reasons for thrombocytosis are shown in Table 1. The mean platelet count of the UT group was 494.5 x 10^9/L (SE 9.1). The average age was 42.6 years (SE 3.5) which was not significantly different than the general population without thrombocytosis (45.1 years [SE 0.3], p=0.4582), but those with UT were significantly more likely to be female (76.4% vs. 50.5%, p=0.0117). Table 2 shows the estimated prevalence of UT by age, gender, and race group. The weighted percentage of US born was 86.7% in the UT group, with 63.1% having an educational level below a college degree. The mean family poverty income ratio was 3.1 (SE 0.4), which was not significantly different than the NHANES population without thrombocytosis (mean 3.0 [SE 0.1], p=0.8974). Conclusions Although this study is limited by inability to determine World Health Organization (WHO) diagnosis of ET and PV, this NHANES analysis suggests that the prevalence of UE and UT may be higher than commonly appreciated, with an estimated prevalence of 40.8 and 494.2 per 100,000, respectively. This is almost certainly an overestimate as a result of methodologic limitations of an NHANES analysis, including the fact that estimates are based on a small number of participants with UE or UT obtained at a static time point. It is also important to note that not all patients UE and UT fulfill WHO criteria for PV and ET. However, our data do suggest that PV and ET may be under-evaluated in the general population. While it is possible that certain factors may predispose some patients to having undiagnosed disease, the number of participants with unexplained conditions were too small to analyze this in more detail. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Molecular Response Patterns in Hydroxyurea (HU)-Resistant or Intolerant Polycythemia Vera (PV) during Treatment with Idasanutlin: Results of an Open-Label, Single-Arm Phase 2 Study

Molecular Response Patterns in Hydroxyurea (HU)-Resistant or Intolerant Polycythemia Vera (PV) during Treatment with Idasanutlin: Results of an Open-Label, Single-Arm Phase 2 Study

Outcomes of COVID-19 Infection in Patients Receiving Ruxolitinib and Hypomethylating Agent Therapy

IntroductionThe ongoing novel coronavirus disease 2019 (COVID-19) pandemic has provoked questions about treatment decisions in patients with hematologic malignancies. Of note, several anti-cancer agents have been shown to have preclinical activity against the SARS-CoV-2 virus, including ruxolitinib (Jakafi), as well as the hypomethylating agents (HMA) decitabine (Dacogen) and azacitidine (Vidaza). In addition, ruxolitinib has previously been shown to have potent activity against the cytokine response, similar to that seen in COVID-19 infections. The optimal management of patients on these agents who become infected with COVID-19 is unknown and it is not clear if the use of these agents modifies the clinical course of infection. We describe a case series of patients with hematologic malignancies receiving therapy with these agents while infected with COVID-19.MethodsWe conducted a retrospective chart review of consecutive patients between March 1 and May 21, 2020 who were receiving therapy with ruxolitinib, azacitidine, or decitabine when diagnosed with COVID-19 by SARS-CoV-2 PCR assay within the Mount Sinai Health System. The indications for these agents included acute lymphocytic leukemia, acute myeloid leukemia, myelofibrosis, polycythemia vera, and myelodysplastic syndromes. Patients who last received the agent more than thirty days prior to COVID-19 diagnosis were excluded from our series.ResultsSixteen patients on HMA or ruxolitinib were diagnosed with COVID-19 within our health system during this span. Full patient characteristics and clinical data are described in Tables 1a and 1b. Seven patients were receiving ruxolitinib and nine patients were on HMA: eight on azacitidine and one on decitabine. Of the patients on HMA, eight had therapy held after confirmed COVID-19 infection, and one was continued on therapy. Overall mortality in the HMA cohort was 88.9% (8/9), including 7/8 in the therapy-held group and the one patient for whom therapy was continued. Of the patients on ruxolitinib, three had therapy held and four were continued after confirmed infection. Overall mortality in the ruxolitinib cohort was 57.1% (4/7), with 75% (3/4) in the therapy-held and 33% (1/3) mortality in the therapy-continued groups. All patients who died (n = 12) required either non-invasive positive pressure ventilation or mechanical ventilation. Across all agents, patients who survived (n = 4) required no higher level of supplemental oxygen than non-rebreather mask, and one did not require hospitalization. Cytokine levels were on average higher on admission for the ruxolitinib-held group but were not associated with mortality or increased oxygen requirement.DiscussionHigh mortality rates were observed for both ruxolitinib and HMA in this high-risk group of patients with hematologic malignancy regardless of whether therapy was held. HMA was commonly held at time of infection: further investigation will be needed to elucidate any potential in-vivo anti-SARS-CoV-2 activity for these reagents. Mortality was numerically less in patients in receiving ruxolitinib who continued therapy, however this should be interpreted with caution given our small cohort. Further clinical trials to address the use of ruxolitinib are necessary and are ongoing. These data can help guide further investigation regarding use of anti-cancer therapy in patients with hematologic malignancy diagnosed with COVID-19.DisclosuresMascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).