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AbstractBackgroundMyeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice.MethodsSonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML).ResultsSixty‐two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose‐finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1–28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia‐free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia‐free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment.ConclusionsOur study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.

Abstract Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

AbstractBackgroundMyelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy.MethodsLongitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data.ResultsMomelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm.ConclusionsThese findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings.

AbstractAcute myeloid leukemia (AML) is a challenging cancer in terms of achieving and maintaining long‐duration remissions. Many novel therapies have been added to the standard regimen (combining cytarabine and anthracycline “7 + 3”) to achieve such goals. Nilotinib is an oral multikinase inhibitor that is active against KIT tyrosine kinase, an important stem cell target. In this trial, we combined nilotinib with 7 + 3 induction (daunorubicin 60 mg/m2), high‐dose cytarabine consolidation, and subsequently, if the patient was a candidate, for 2 years' maintenance therapy in patients with AML and KIT (CD117) expression. Patients were allowed to proceed to allogeneic hematopoietic cell transplantation (HCT) if deemed necessary. Our primary goal was increased complete remission rate with this combination. Thirty‐four patients (with a median age 58.5 years) were enrolled on a single‐arm phase II bi‐institutional study; 21 (62%) patients achieved remission. The complete remission rate was 78% in evaluable patients. Thirteen of 34 (38%) patients had allogeneic HCT, all thirteen of which are still alive (100%). Common (>20%) grade 3 non‐hematological toxicities included febrile neutropenia, hypophosphatemia, elevated liver enzymes, and hypertension. Only one patient (3%) died in induction due to liver failure, which was thought secondary to daunorubicin. Our current study reveals good outcomes in patients who received HCT and may warrant a larger study to confirm our findings in that specific population.