GATA2-Mutated AML: Clinical Outcomes and Spectrum of Infections in Patients Undergoing or Not Allogeneic Stem Cell Transplantation
Authors: Sanchez-Petitto Gabriela , El Boghdadly Zeinab , Nicolet Deedra , Cooper Julia , Eisfeld Ann-Kathrin , Klein Victoria , Walker Michael C , Mrózek Krzysztof , Bezerra Evandro , Brammer Jonathan E. , Denlinger Nathan , Shindiapina Polina , Penza Sam , Wall Sarah A. , Behbehani Gregory K , Blachly James S. , Blaser Bradley Wayne , Borate Uma , Grieselhuber Nicole R. , Koenig Kristin L , Larkin Karilyn T. , Long Meixiao , Mims Alice , Srisuwananukorn Andrew , Vasu Sumithira , de Lima Marcos 
Published: December 2024

Introduction: GATA2 mutations are acquired in acute myeloid leukemia (AML) and are associated with autosomal dominant forms of AML and myelodysplastic syndromes (MDS), as well as predisposition to human papillomavirus (HPV), nontuberculous mycobacterium (NTM), and Epstein-Barr virus (EBV) infections. It is currently unknown whether patients with GATA2 mutations are at generally higher risk for infectious complications during treatment for AML and subsequent transplant.
Methods: We retrospectively analyzed 35 patients with AML who harbored a GATA2 mutation detected by NGS testing between January 2, 2011 and April 25, 2023. We examined patients' clinical outcomes: overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier estimates and log-rank tests stratified by mutation location [zinc finger or (ZF-1), ZF-2 domains, and non-ZF: including L, M, and R] and transplant status. Categorical variables were compared using the Fisher's exact test. Continuous variables were compared using the Kruskal-Wallis test.
Results: The median patient age at diagnosis was 61 years (range, 18-87), 18 patients (51%) were male, and 34 (97%) were white. Thirty-eight GATA2 mutations were identified in 35 patients. Three patients harbored two GATA2 mutations. The most frequent variants were c.1168_1170delAAG (N = 4, 11%), c.481C&gt;G (N = 2, 5%), and c.953C&gt;T (N = 2, 5%). The median VAF of GATA2 mutations was 31.4% (range, 4.3-50.7%). Sixteen (42%) mutations were clustered in the ZF-2 domain, 14 (37%) in ZF-1, and 8 (21%) were outside the ZF domains (non-ZF). The most common GATA2 mutation types were missense (N = 25, 66%), in-frame deletion (N = 8, 21%), frameshift (N = 3, 8%), and nonsense mutations (N = 2, 5%). Normal cytogenetics was present in 12 patients (40%) while complex karyotype was present in 3 (10%). The most common co-mutations were in: TET2 (N=9, 31%), RUNX1 (N=7, 24%), SRSF2 (N=7, 28%), FLT3 (ITD; N=6, 18%), DNMT3A (N=6, 21%), and NRAS (N=6, 21%). Mutations were unknown in some patients.
With a median follow-up of 5.9 years, there was no difference in OS based on mutation location (p=0.16). However, a comparison of the outcome of 10 patients (29%) who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) with that of 8 (23%) patients who achieved CR or CRh but did not undergo alloHSCT, those who received alloHSCT had better 5-year OS (86% vs 40%, p=0.05), but DFS did not differ (5-year rates: 14% vs 13%, p=0.28). Of note, patients who did not undergo alloHSCT had a better ECOG performance status (0-1) than those who did (100% vs 63%, p=0.03), while the presence of normal cytogenetics or complex karyotype was similar across the groups.
Twenty-two of 25 patients (88%) who did not undergo alloHSCT experienced a median of 3.5 infectious events/patient (range, 0-10), compared to 4.5 events/patient (range 1-15) for those who underwent alloHSCT (including pre- and post-transplant infections) (p=0.11). Among patients who did not receive alloHSCT, the most frequent infections included: bacteremia (56%), pulmonary infections (52%), and skin and soft tissue infections (32%). All patients who underwent alloHSCT experienced post-alloHSCT infection events with a median of 2.5 events (range, 0-12), and these included bacteremia (80%), pulmonary (30%), and urogenital infections (30%). One patient who had alloHSCT experienced skin mucormycosis. Two patients who did not have transplant developed pulmonary cryptococcosis and blastomycosis. No NTM or HPV infections were reported in our cohort, however two patients experienced EBV reactivation after transplantation.
Conclusion: While our study was small and did not investigate germline mutations, it suggests that GATA2 AML patients who receive alloHSCT, have a better survival and similar infection risk to non-transplanted patients. Early referral to alloHSCT for this group of patients is essential.