Treatment of Advanced Systemic Mastocytosis with Midostaurin: Practical Guidance for Optimal Therapy and Management.

Systemic mastocytosis (SM) is a rare disease with a range of clinical presentations, and the vast majority of patients have a KIT D816V mutation that results in a gain of function. The multikinase/KIT inhibitor midostaurin inhibits the D816V mutant and has a well-established role in treating advanced SM. Even if considered the standard of therapy, some open questions remain on optimizing midostaurin management in daily practice. The current review presents the opinions of a group of experts who met to discuss routine practice using midostaurin in patients with advanced SM. The efficacy and safety of midostaurin in Phase 2 trials are overviewed, followed by practical guidance for optimal therapy management and adverse events during therapy with midostaurin. Specific guidance is given for initiating therapy and evaluating response with midostaurin as general assessment and laboratory, instrumental, pathological, and molecular exams. Special consideration is given to dose interruption, reduction, and discontinuation of therapy, as well as adverse event management and supportive therapy. Patients should be informed about possible side effects and receive practical advice to avoid or limit them and antiemetic prophylaxis so that therapy with midostaurin can continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Lastly, considerations on the use of midostaurin during the ongoing Covid-19 pandemic are made. The overall scope is to provide guidance that can be useful in daily practice for clinicians using midostaurin to treat patients with advanced SM.

Responses to Sars-Cov-2 Vaccines in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Introduction: Patients with myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are at a high risk of severe SARS-CoV-2 infection. It is uncertain whether patients with AML and MDS, who frequently have quantitative or qualitative deficiencies of neutrophils and/or lymphocytes, will develop protective immunity from SARS-CoV-2 vaccines. The primary aim of this analysis was to describe the immune response and safety profile to the mRNA-1273 vaccine amongst a cohort of patients with AML and MDS. Methods: We enrolled AML and MDS patients to a large, single-site observational study of mRNA-1273 vaccination in cancer patients during the period January 12 to January 25, 2021. Blood specimens were collected from patients prior to the first and second vaccine doses (Days 1 and 29) and ~28 days after the second vaccine dose (Day 57) for antibody analyses. Retrospective chart review was done to collect information on baseline characteristics, cancer diagnoses, treatments received, and disease status. To evaluate serostatus, a two-step ELISA was performed, measuring IgG responses. SARS-CoV-2 antibody positivity rates were compared using the Fisher exact test or Chi-square test. The association of SARS-CoV-2 antibody titer and patient characteristics was examined by using Kruskal-Wallis test. Paired t-test was used to analyze the difference of SARS-CoV-2 antibody titers among day 1, after dose 1 and dose 2. Results: A total of 46 patients, 30 patients with AML and 16 patients with MDS, were included in this study. The median age at vaccination for the entire cohort was 68 yrs (range 37-85 yrs). The majority of patients were males (58.7%) and Caucasians (95.7%). Table 1 describes the baseline characteristics of the patients. The median time from diagnosis to the start of vaccination series was 24.3 months (range 4.5-105). One third of the patients (32.6%, n=15) were on active treatment for their disease during the course of vaccination with hypomethylating agents (n=6;13%), erythroid maturation agent i.e. luspatercept (n=2, 4.3%), immunomodulatory drugs i.e. lenalidomide (n=1;2.2%) and targeted therapy (6;13%). Targeted therapy included patients on enasidenib (n=4), midostaurin (n=1) and gilteritinib (n=1). A total of 32 patients (69.6%) were post allogeneic stem cell transplantation for their disease. The median time since allo-SCT for the entire cohort was 17 months (4.9-75.8 mos). The majority of the patients (n=40, 87%) were in remission at the time of vaccination. We found that two patients with AML relapsed post vaccination. Overall, 69.6% patients were seropositive at day 29 (after first vaccine dose) and 95.7% patients were seropositive on day 57 (after 2 vaccine doses). Table 2 describes response to the vaccine in our cohort and the differences in seropositivity rate after one and two doses of vaccine, based upon disease characteristics. Age, gender, race, disease status, time to vaccination from disease diagnosis, number of prior lines of therapy, whether on active treatment, laboratory parameters (including ALC and ANC), whether the patient had undergone allo-SCT, and therapy at time of vaccination did not significantly affect the seropositivity rate. Antibody titer levels were significantly higher after the 2 nd vaccine dose than after 1 st dose (mean 3806.5 vs 315, p<0.0001), a difference that was observed across the different variables and patient subsets (Figure 1). Mild injection site pain, fatigue, headache and arm swelling were the most common adverse events post vaccination. Conclusion: In this observational study, the largest reported to date amongst AML and MDS patients with serial serologic data following 2 vaccine doses, we found that the vast majority of patients with AML and MDS converted to seropositivity after two doses of the vaccine. Although the overall sample size was relatively small, most clinical and laboratory variables (including neutropenia and lymphopenia) did not affect the seropositivity rate. Antibody titer levels increased dramatically follo ing the 2 nd vaccine dose, indicating the potential utility for serial vaccination (i.e. additional dosing) in poorly-responsive patients. While these findings should be substantiated in a larger cohort, mRNA-273 SARS-CoV-2 vaccine appears to induce a strong humoral response in this population of patients with AML and MDS. [Formula presented] Disclosures: Komrokji: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees;Geron: Consultancy;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Acceleron: Consultancy;Jazz: Consultancy, Speakers Bureau;Taiho Oncology: Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy;BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;AROG: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Incyte: Speakers Bureau;AbbVie: Membership on an entity's Board of Directors or advisory committees;Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Agios: Membership on an entity's Board of Directors or advisory committees;Intellia: Membership on an entity's Board of Directors or advisory committees;Kite: Membership on an entity's Board of Directors or advisory committees;Magenta: Consultancy;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy. Padron: Taiho: Honoraria;Kura: Research Funding;BMS: Research Funding;Blueprint: Honoraria;Incyte: Research Funding;Stemline: Honoraria. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau;Abbvie: Honoraria;Celgene/BMS: Honoraria, Speakers Bureau;CTI Biopharma: Honoraria;Incyte: Consultancy;Novartis: Honoraria, Speakers Bureau;Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Prelude: Research Funding;PharmaEssentia: Honoraria. Giuliano: Merck & CO: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Daiichi Sankyo: Consultancy;BerGenBio: Consultancy;Celgene/BMS: Consultancy;Millenium Pharma/Takeda: Consultancy;Agios: Consultancy;ElevateBio Management: Consultancy;AbbVie: Consultancy;Astellas: Consultancy;Jazz: Consultancy.