Genetic Profiling and Survival Analysis of Patients with Acute Myeloid Leukemia and a History of Autoimmune Disease

Introduction: Most patients (pts) diagnosed with therapy-related acute myeloid leukemia (t-AML) develop AML following chemotherapy or radiation therapy for a non-hematologic malignancy. However, some patients develop AML after exposure to cytotoxic and/or immunosuppressive therapy for autoimmune diseases (AD). Here, we characterize the genetic profiles and outcomes of pts with AML and a prior history of AD. In addition, a subset of these pts was screened for the UBA1 hotspot mutation to rule out VEXAS syndrome, a known acquired syndrome that predisposes patients to autoimmune and hematologic disorders.

Methods: Patients diagnosed with AML at the Cleveland Clinic between 1999 and 2022 were grouped into de novo AML, AD-AML (AML following an AD diagnosis), t-AML (excluding AD-AML), s-AML (secondary AML preceded by myelodysplastic syndrome or myeloproliferative neoplasm), and AD-t-AML (AD-AML & t-AML overlap). Molecular genetics features were assessed via chromosome analysis and next-generation sequencing (NGS) of genes observed to be frequently mutated in AML and analyzed using the Fisher's Exact test. Screening for UBA1 mutations in AD-AML pts was performed using Sanger sequencing for pts with available samples (n = 50). The BUM method was used to control the false-discovery rate (FDR) at 20%. Survival analysis was limited to pts who received intensive induction chemotherapy only. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and compared with the log-rank test.

Results: 1230 pts were included in this study. 11% (n=136) had AD-AML, 64% (n = 787) de novo AML, 14% (n=177) s-AML, 9% (n=116) t-AML, and 1% (n=14) AD-t-AML. The median age at AML diagnosis was 55.5 years; 54% were male. 66% received intensive induction chemotherapy (including 7+3 or CPX-351) and 28.6% (n = 352) received an allogeneic hematopoietic stem cell transplant, of which 40 were AD-AML pts. Using the MRC 2010 classification, 12% of pts had favorable cytogenetics (CG), 56% intermediate, and 27% poor risk. The most common autoimmune diseases were Crohn's disease/Ulcerative colitis (n = 26; 17%), rheumatoid arthritis (n = 21; 14%), psoriasis (n=13; 8.6%), hypothyroidism (n=12; 8%), and lupus (n=11; 7.3%). The median age at first AD diagnosis was 54 years and the interval from AD to AML diagnosis was 77.5 months. Half of the patients did not receive treatment (excluding steroids) for their AD. The remainder of the pts were treated with immunomodulating (30%), cytotoxic (28%), or anti-inflammatory agents (18%); 24% were treated with more than 2 agents. CG analysis revealed that poor risk CGs were higher among AD-AML and AD-t-AML pts compared to de novo AML (34% vs. 36% vs 21%; p <0.0001). When compared to de novo AML, t-AML and s-AML, pts with AD-AML had a higher frequency of mutations in NF1 (12.8% vs. 6.4% vs. 5.4% vs. 1.7%, p = 0.141) and SRSF2 (20.9% vs. 12.7% vs. 10.6% vs. 9.7%, p = 0.221); however, this was not statistically significant. When compared with t-AML, pts with AD-AML had a higher frequency of mutations in NPM1 (27.4% vs. 9.3%, p <0.001) and NRAS (11.9% vs 0%, p = 0.007). Conversely, mutations in FLT3 were less commonly seen in AD-AML compared to de novo (18.2% vs 31.2%, p = 0.022). Of note, none of the 50 AD-AML pts screened had UBA1 hotspot mutations. Among the AD-AML group, the median OS was 20 months, similar to the de novo group (23 months) but significantly higher than t-AML (10 months) and s-AML (11 months) (p = 0.0001). Median PFS for the AD-AML group was 12 months, lower than that of de novo AML (14 months), but greater than t-AML (7 months) and s-AML (8 months) (p = 0.0079).

Conclusion: Patients with AD-AML have a higher frequency of poor-risk CGs but comparable outcomes when compared to pts who develop AML de novo and are treated with intensive chemotherapy. Furthermore, this group of patients demonstrates distinct molecular features implicating signal transduction pathways (NF1) and spliceosome regulation (SRSF2) as potential areas of focus for research. While the analysis was not statistically significant, this may be related to a small sample size, and validation of these findings in a larger series is recommended. Finally, although VEXAS syndrome is commonly associated with rheumatologic disorders, neither of our AD-AML cohorts had mutations in UBA1, potentially implicating different mechanisms of action.

Sawalha:ADC: Consultancy; Beigene: Research Funding; Genmab: Honoraria, Research Funding; AbbVie: Research Funding. Madanat:Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences, and Novartis: Other: Advisory Board; Blueprint Medicines, MD Education and Morphosys: Other: Supporting or attending meetings and/or travel; BMS, Kura Oncology, Blueprint Medicines, Geron: Consultancy. Kuzmanovic:Pfizer: Consultancy. Sobecks:CareDx, Inc: Membership on an entity's Board of Directors or advisory committees. Hamilton:Orca Bio: Research Funding; CSL Behring: Other: Adjudication committee; Rigel: Other: ad hoc advisory board; Angiocrine: Other: DSMB; Maat Pharma: Other: ad hoc advisory board; Incyte: Consultancy; ACI group: Consultancy; Nkarta: Other: Ad hoc advisory board; Sanofi: Other: ad hoc advisory board. Gerds:Agios: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; Rain Oncology: Consultancy; GSK: Consultancy; AbbVie: Consultancy; BMS: Consultancy. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees. Sekeres:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kurome: Membership on an entity's Board of Directors or advisory committees; Schroedinger: Membership on an entity's Board of Directors or advisory committees. Molina:Autolus: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mustafa Ali:Daiichi Sankyo: Consultancy. Jain:Rigel: Other: Teaching and Speaking. Advani:Wiley: Honoraria; MD Education: Honoraria; Amgen: Research Funding; Springer: Honoraria; Pfizer: Other: Manuscript help, Research Funding; American Society of Hematology: Honoraria; Glycomimetics: Research Funding; BEAM: Other: Research support, Research Funding; OBI: Research Funding; Incyte: Research Funding; Immunogen: Research Funding; Seattle Genetics: Research Funding; Macrogenics: Research Funding; Servier: Research Funding; Kura: Research Funding; Novartis: Consultancy; Emmes: Honoraria; PER: Honoraria; Web MD: Honoraria; Wolters Kluwer: Honoraria; Kite: Consultancy, Research Funding; MJH Life: Honoraria.