Impact of Therapy on the Anamnestic Response to Seasonal Influenza Vaccination in Patients with Myeloid Malignancies

Myelodysplastic syndromes (MDS) are diseases of bone marrow failure that result in dysplasia of multiple hematopoietic lineages producing anemia, thrombocytopenia, and increased risk of infections. While progression to acute myeloid leukemia (AML) is a phenomenon that receives most of the focus in managing this disease, prior studies have shown that infection is the leading cause of mortality. This is true across all MDS risk groups and highlights the critical importance of research into the clinical management and prevention of infection in patients with MDS, especially in the age of emergent pandemics such as COVID-19. We have previously observed that patients with MDS exhibit decreased responses to vaccination against SARS-CoV-2 (Bellusci, et al., Blood, 2022). There remains a gap in our knowledge regarding the success of vaccination against common seasonal pathogens in patients with MDS, such as influenza. Although patients with MDS and AML are routinely offered yearly influenza vaccination during the flu season, the efficacy of vaccination in producing immunity in the context of the underlying disease biology and the impact of therapies used for treatment of the disease (azacitidine & decitabine (HMAs), venetoclax + HMA and cytarabine based intensive chemotherapy) remains understudied. We hypothesized that MDS/AML patients would exhibit a decreased response to vaccination against seasonal influenza compared to healthy age-matched controls. To test this hypothesis, we enrolled patients in an IRB-approved non-randomized study (I-54017) that spanned the 2017-2018 to 2020-2021 influenza seasons. This study examined 5 patient groups: Cohort 1: Patients with MDS on best supportive care (ESAs, growth factors, transfusions, antibiotics; no disease modifying therapy; n = 28); Cohort 2: Patients with MDS or AML early in HMA therapy (≤5 cycles; n = 26); Cohort 3: Patients with MDS or AML on longer term HMA (> 6 cycles; n = 28); Cohort 4: Patients with AML receiving cytarabine based intensive chemotherapy ("7+3", HIDAC, CLAG+/-M, FLAG+/-Ida, etc.). Patients in this arm should not have received an HMA in the 6 months prior to enrollment (n = 10); Cohort 5: Healthy volunteers of similar age profile without antecedent or concurrent hematologic disorders (n = 12). All subjects received the yearly Fluzone High-Dose vaccine (Sanofi). Serum samples were collected at 1) baseline; 2) days 25-95 after vaccination; and 3) days 115-185 after vaccination. Viral titers were measured using the viral microneutralization assay against seasonal influenza vaccine strains based upon the yearly vaccine product. Positive responses to vaccination were defined as a 4-fold increase in titer compared to baseline. For each subject, we calculated a strain score (range 0-1) based on the fraction of 4-fold changes across either 3 to 4 influenza strains depending upon the yearly vaccination product; a score of 1 indicates a 4-fold increase in titers against all tested strains. Strain score was modeled as a function of study year, disease cohort, and age; blood-type, gender, race, and IPSS-M were analyzed but were not statistically significant. The primary analysis was a generalized linear model (GLM). In concert with prior reports, we found that compared to healthy donors, AML patients receiving intensive chemotherapy showed decreased vaccine response (Fig.1). In contrast, those with MDS responded equivalently to vaccination compared with healthy donors. Overall, these results demonstrate that in contrast with vaccination against newly emergent diseases (COVID-19) against which MDS patients appear to have inferior immune response, anamnestic responses to vaccination against previously encountered pathogens (influenza) are normal. As reported previously, patients with AML receiving intensive chemotherapy exhibit reduced protection from vaccination against both emergent pathogens (COVID-19) and amnestic vaccines (influenza). These results indicate that vaccination boosters, such as those given yearly against influenza, against previously encountered pathogens are likely to provide protection in MDS patients irrespective of standard therapy, but the efficacy of vaccination against novel pathogens may be less effective. These data highlight the complex immune milieu in patients with MDS and emphasize the importance of careful individualized vaccination strategies in those with hematological malignancy.

Vachhani:Incyte: Speakers Bureau; Blueprint Medicines, Incyte, AbbVie, CTI BioPharma Corp, Novartis, Amgen, Pfizer, Genentech, Stemline: Consultancy. Przespolewski:Jazz Pharmaceuticals: Research Funding. Thompson:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Wang:Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory Board; Genentech: Consultancy; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data Safety Monitoring Committee; Novartis: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: member of data monitoring committee ; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Dava Oncology: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory Board, Steering Committee, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory Board; Gilead: Consultancy, Honoraria, Other: Advisory Board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory Board; Macrogenics: Consultancy. Griffiths:Physician Educational Resource: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celldex Therapeutics: Research Funding; Blueprint Medicines: Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AAMDSIF: Honoraria; Picnic Health: Honoraria; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees.