Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Molecular response patterns in relapsed/refractory AML patients treated with selinexor and chemotherapy.

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.

Long-Term Efficacy and Safety of Luspatercept for Anemia Treatment in Patients With Lower-Risk Myelodysplastic Syndromes: The Phase II PACE-MDS Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Luspatercept has high clinical activity in patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and ring sideroblasts (RS) relapsed or refractory to erythropoietin. We report long-term luspatercept safety and efficacy in 108 patients with LR-MDS in the PACE-MDS study, including 44 non-RS and 34 non-transfusion-dependent or previously untreated patients. The primary end point was safety. Secondary end points included rates of hematologic improvement (HI) erythroid (HI-E), HI neutrophil, and HI platelet. Exploratory end points included erythropoiesis biomarker quantitation and mutation data. Median duration of luspatercept exposure was 315 days (range, 21-1,934 days). No new safety signals emerged. HI-E was observed in 53.7% of patients, including 36.4% of non-RS and 70.6% of non-transfusion-dependent patients. HI neutrophil and HI platelet were observed in 33.3% and 9.5% of patients, respectively. An almost three-fold increase in bone marrow late to early progenitor cell ratio accompanied HI-E response, irrespective of RS status. Lower baseline erythropoietin levels in non-RS patients (69.6 v 623.3 IU/L; P = .0077) and higher late to early erythroid progenitor cell ratio (10.44 v 4.48; P = .0106) in RS patients were associated with HI-E. This study highlights luspatercept's effects across LR-MDS subtypes, including untreated MDS-RS, serving as a platform for future trials.

Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies.

BACKGROUND: This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia. METHODS: Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250-350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m2; B, D7: 170 mg/m2; C, D1 and D7: 110 mg/m2]. In 1230.35 (Study 2; NCT02201329), patients received 200-300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m2 on D1-7. RESULTS: Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%). CONCLUSIONS: The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases.

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1-200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

Low-dose melphalan in elderly patients with relapsed or refractory acute myeloid leukemia: A well-tolerated and effective treatment after hypomethylating-agent failure.

Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.

Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis.

The prognosis for patients with acute myeloid leukaemia (AML) is still poor, thus calling for novel treatment strategies. Here, we report that the small-molecule Smac mimetic BV6, which antagonizes Inhibitor of Apoptosis (IAP) proteins, acts in concert with cytarabine (AraC) to trigger cell death in AML cells in a highly synergistic manner (combination index 0.02-0.27). Similarly, BV6 cooperates with AraC to trigger cell death in primary AML samples, underscoring the clinical relevance of our findings. Molecular studies reveal that the TNFα-blocking antibody Enbrel significantly reduces BV6/AraC-induced cell death, demonstrating that an autocrine/paracrine TNFα loop mediates cell death. Furthermore, BV6 and AraC synergize to induce loss of mitochondrial membrane potential, caspase activation and DNA fragmentation, consistent with apoptotic cell death. Nevertheless, the caspase inhibitor zVAD.fmk fails to protect against BV6/AraC-induced cell death. Intriguingly, this cell death upon caspase inhibition is significantly reduced by pharmacological inhibition of two key components of necroptosis signaling, i.e. by RIP1 kinase inhibitor Necrostatin-1 or MLKL inhibitor NSA. Thus, BV6 sensitizes AML cells to AraC-induced cell death and overcomes apoptosis resistance by triggering necroptosis as alternative form of cell death. These findings have important implications for Smac mimetic-based strategies to bypass apoptosis resistance of AML.