Key Points A novel PCM1-FGFR1 gene rearrangement was identified in a patient with a myeloid neoplasm with eosinophilia. Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, resulted in a durable complete hematologic and cytogenetic remission.

Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by abnormal JAK-STAT signaling, chronic inflammation, cytopenias and risk of transformation to acute leukemia. Despite improvements in the therapeutic options for MF patients, allogeneic hematopoietic stem cell transplantation remains the only curative treatment. We previously demonstrated multiple immunosuppressive mechanisms in MF patients, including elevated PD1 expression on T cells compared to healthy controls. Therefore, we conducted a multicenter, open-label, phase 2, single-arm study of pembrolizumab in patients with DIPSS intermediate 2 or greater primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib (NCT03065400). The study followed a Simon two-stage design, and enrolled a total of 10 patients, 5 of which had JAK2V617 mutation, 2 had CALR mutation and 6 patients had additional mutations. Most patients were previously treated with ruxolitinib. Pembrolizumab treatment was well tolerated but there were no objective clinical responses and thus, the study closed after completion of the first stage. However, immune profiling by flow cytometry, TCR sequencing and plasma proteomics demonstrated changes in the immune milieu of patients suggesting improved T cell responses, which can potentially favor antitumor immunity. The fact that these changes were not reflected in a clinical response strongly suggest that combination immunotherapeutic approaches rather than monotherapy may be necessary to reverse the multifactorial mechanisms of immune suppression in MPN. The study is registered at http://www.clinicaltrials.gov as NCT03065400.

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Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody‐drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re‐induction chemotherapy for patients with CD30‐expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose‐limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease‐free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30‐expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age <60 and 2g/m2 daily D1-5 for age ≥60) with alisertib PO at 30mg BID, D6-12, and alisertib maintenance at 30mg BID PO (D1-7 of 3 week cycles) thereafter for 12 months. Patients who pursued stem cell transplant (SCT) were followed for EFS and OS. Results: 39 eligible patients were enrolled. The median age was 67 (range 33-83); 25 (64%) were male, and 33 (85%) were Caucasian. 22 patients (56%) had secondary AML (16 with antecedent MDS, 2 with antecedent CMML, 1 with antecedent MPN, and 3 with therapy-related AML). 13 (33%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (18%), NPM1 in 7 (18%), IDH1 in 5 (13%), IDH2 in 5 (13%), CEBPA in 3 (8%), and TP53 mutations in 4 (10%) patients. 33 patients (85%) demonstrated an ablated marrow at mid-treatment, and six (15%) received re-induction at mid-treatment. 8 patients (21%) were refractory to induction, and five (13%) died prior to response assessment due to infection or bleeding. The 30-day and 60-day mortality rates were 8% and 13%, respectively. Patients experienced expected grade 4 toxicities of leukopenia, anemia, thrombocytopenia, and febrile neutropenia; no new attributable safety signals were detected. The CR+CRi rate was 64% (2-stage 95% CI 48-79%) with 20 patients (51%) achieving CR and 5 (13%) achieving Cri. The CR+CRi rate was 59% (13 of 22) in those with secondary AML, 67% (18 of 27) in those aged ≥ 65, 77% (10 of 13) in those with adverse risk karyotype, and 75% (3 of 4 patients) in patients with TP53 mutations. One (3%) patient achieved a partial remission. Based on the composite remission rate of 64%, the combination was deemed effective per study design. 5 patients have relapsed to date. 10 have received at least 1 cycle of consolidation, 16 patients (41%) have gone on to SCT. With a median follow-up of 14 months (Figure), the 12-month overall survival (OS) is 51% (37-65%). Although the data continues to mature, median OS is 12.2 months (90% CI 8.8-NA). In the subset of patients achieving a CR+CRi, the 12-month relapse-free survival was 52% (90% CI 34-67%). Conclusions: Alisertib, a novel aurora A kinase inhibitor, combined with conventional induction, is efficacious and demonstrates a promising rate of remission and survival among patients with previously untreated high-risk AML. Larger randomized studies are under consideration to better assess the promise of this novel combination. Figure. Figure. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. DeAngelo:Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding. Amrein:Takeda: Research Funding. Steensma:Acceleron: Consultancy; Amphivena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; H3 Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kura: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Syros: Research Funding; Takeda: Consultancy. Garcia:Celgene: Consultancy. Rosenblatt:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria.