Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax

Introduction: The Phase 3 VIALE-A study established the combination of venetoclax and a hypomethylating agent (VEN/HMA) as a new standard of care option for acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy due to age (≥ 75 years) or comorbidities. The NCCN recommends antifungal prophylaxis (AFP) for relapsed/refractory AML patients receiving VEN/HMA, but its role in newly diagnosed AML patients treated with VEN/HMA remains controversial. Additionally, the impact of VEN dose-reduction due to concomitant azole use on AML outcomes and rates of fungal infection remains unclear. We evaluated the pattern of AFP use and its association with infectious and AML outcomes in patients receiving VEN/HMA at our institution. Methods: Consecutive patients aged ≥18 who received frontline VEN/HMA for newly diagnosed AML at the Dana-Farber Cancer Institute between 2016-2021 were identified in the Hematologic Malignancy Data Repository for retrospective chart review. Antibacterial and antifungal prophylaxis use at any time during VEN/HMA therapy and reasons for hospitalizations were recorded. Invasive fungal infections (IFIs) were adjudicated as "possible," "probable," or "proven" according to consensus guidelines (Donnelly, Clin Infect Dis 2020). Rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi) per European LeukemiaNet (ELN) criteria were determined. Descriptive statistics on patient characteristics were compared between groups via nonparametric testing including Wilcoxon rank-sum, chi-squared, and the Fisher's Exact tests. Overall survival (OS) was estimated using the method of Kaplan and Meier, and log-rank tests were used to compare survival between groups. Multivariable Cox proportional-hazards models were used to obtain hazard ratios between groups. Results: 131 patients met inclusion criteria, of which 22 patients (16%) received AFP at any time. For the entire cohort, the median age at AML diagnosis was 72 (range 22-89), and the majority of patients were <75 years old (66%), had ELN adverse risk (70%), and had secondary AML (sAML)/sAML-like disease (73%; "sAML-like" defined per Lindsley, Blood 2015). Frequently mutated genes include TP53 (37%), ASXL1 (22%), and RUNX1 (19%). These baseline characteristics did not differ between patients who did and did not receive AFP. However, compared to patients who never received AFP, patients receiving AFP at any time were more likely to have received HMA therapy for an antecedent hematologic malignancy (41% vs. 13%, p=0.004) and concomitant antibacterial prophylaxis at any time (82% vs. 54%, p=0.016). Among the 171 hospitalizations that occurred in 90/131 patients, bacterial infection was suspected or identified in 139 admissions, and possible/probable/proven IFIs were identified in 21. Receiving AFP prior to admission was not associated with fewer hospitalizations in which an IFI was suspected or identified (Table, p=0.36). 3/21 IFIs were deemed "probable" or "proven." All 21 IFIs prompted antifungal therapy. No patient experienced more than one hospitalization involving an IFI. After a median of two cycles (range 1-15), best response (CR/CRi) for the entire cohort was 49%. Receiving AFP at any time was associated with lower CR/CRi than never receiving AFP (57% vs. 32%, p=0.014). The median OS for the entire cohort was 11.0 months (95% CI 8.8-14.6) and did not differ based on AFP use (11.9 months for patients without AFP, 8.1 months for those receiving AFP; p=0.23). In a multivariable model that included patient age, ELN risk, and AML ontogeny, AFP use was not significantly associated with OS (HR 1.40, p=0.22). Conclusion: AFP use and incidence of invasive fungal infection were overall low at our institution. Receiving AFP was not associated with improved OS nor with decreased number of hospitalizations for a suspected or confirmed IFI. At an institution where the incidence of fungal infections is low, there is presently no clear role for antifungal prophylaxis in newly-diagnosed AML patients receiving HMA with venetoclax. Figure 1 Figure 1. Disclosures Winer: Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Lane: AbbVie: Research Funding; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. DeAngelo: Blueprint Medicines Corporation: Consultancy; Takeda: Consultancy; GlycoMimetics: Research Funding; Autolus: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Stone: Syros: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Boston Pharmaceuticals: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Garcia: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

Efficacy of HMA +/- Venetoclax or Intensive Chemotherapy in Blast-Phase Myeloproliferative Neoplasms

Introduction Blast-phase (BP), or leukemic transformation is a rare and devastating complication of myeloproliferative neoplasms (MPNs) (primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), and post-PV/ET myelofibrosis). Patients with BP-MPNs have a poor prognosis with a median overall survival of less than 6 months, and there is no standard treatment regimen for these aggressive diseases (Dunbar et al, Blood. 2020). The development of hypomethylating agent (HMA)/venetoclax (Ven) combination offers new hope for some with AML, but has been relatively disappointing in BP-MPN, though data are limited and retrospective (Masarova et al, Blood Adv. 2021; Gangat et al, Am J Hematol. 2021). Here, we add our experience with several common treatment regimens for BP-MPN. Methods We retrospectively analyzed data from 39 consecutive patients with BP-MPNs diagnosed from December 2008 to February 2021 who received treatment at the University of Michigan. We included all patients with a previous diagnosis of MPNs who had ≥ 20% blasts in the peripheral blood or bone marrow, and subsequently received systemic therapy. One patient with a myeloid sarcoma was included as well. Disease characteristics at time of BP-transformation were noted. Patients were divided into the following groups based on 1 st-line induction therapy: 7+3 (daunorubicin and cytarabine), FLAG (fludarabine, high-dose cytarabine and G-CSF), hypomethylating agent only (decitabine or azacitidine), and HMA/Ven. Patients were followed for 2 years post-diagnosis. Differences in induction response were assessed using the Chi-square test. Differences in overall survival were calculated using the Kaplan-Meier regression with the log-rank test. Two patients who received alternate induction therapy outside of the four groups were not included in these analyses. Results The composite BP-MPN population had a median advanced age of 69 years old and a median ECOG performance status (PS) of 1. Most (97.4%) had received systemic treatment prior to their transformation for their MPN, with 71.8% receiving hydroxyurea and 41.0% receiving ruxolitinib. The rate of response (CR, CRi, MLFS) was highest in the HMA/Ven group at 42.9%, followed by FLAG (29.4%), HMA only (11.1%), and 7+3 (0%), p = 0.033 (Table 3). Despite the higher response rate, differences in 2-year OS were not significantly different among the 4 groups: 7+3 (25.0%), FLAG (7.7%), HMA (0%), HMA/Ven (20.0%) (p=0.92, Figure 1). Median time to relapse after achieving remission ranged from 2-10 months, and did not vary significantly based on induction regimen. Patients in the HMA and HMA/Ven groups had higher incidences of death with induction at 77.8% and 28.6%, respectively (Table 3). Conclusions The highest rates of response, including complete remission, were achieved with the combination of HMA and venetoclax compared to intensive induction chemotherapy or HMA alone. However, this did not translate into significant differences in OS, which is consistent with other retrospective reports. No responses were seen with 7+3 induction, though several patients were able to go on salvaged with other therapies and subsequent allogeneic stem cell transplantation thereafter. Finally, the baseline poor ECOG PS of the HMA group and borderline ECOG PS of the HMA/Ven group also contribute to their low survival rates.Larger, prospective studies comparing currently available treatment regimens in BP-MPN would be helpful, but ultimately new therapies are desperately needed for this high-risk disease. Figure 1 Figure 1. Disclosures Bixby: Takeda: Consultancy. Talpaz: Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Imago: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup

Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003–2005 trial. Our results indicated that T-ALL is epigenetically heterogeneous consisting of five subtypes (C1-C5), which were either associated with co-occurring DNA methyltransferase 3 alpha (DNMT3A)/isocitrate dehydrogenase [NADP(+)] 2 (IDH2) mutations (C1), TAL bHLH transcription factor 1, erythroid differentiation factor (TAL1) deregulation (C2), T cell leukemia homeobox 3 (TLX3) (C3), TLX1/in cis-homeobox A9 (HOXA9) (C4), or in trans-HOXA9 overexpression (C5). Integrative analysis of DNA methylation and gene expression identified potential cluster-specific oncogenes and tumor suppressor genes. In addition to an aggressive hypomethylated subgroup (C1), our data identified an unexpected subset of hypermethylated T-ALL (C5) associated with poor outcome and primary therapeutic response. Using mouse xenografts, we demonstrated that hypermethylated T-ALL samples exhibited therapeutic responses to the DNA hypomethylating agent 5-azacytidine, which significantly (survival probability; P = 0.001 for C3, 0.01 for C4, and 0.0253 for C5) delayed tumor progression. These findings suggest that epigenetic-based therapies may provide an alternative treatment option in hypermethylated T-ALL.