Characterization of Myeloid Neoplasms in Inflammatory Bowel Disease

Introduction Patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD) are exposed to chronic systemic inflammation and are at risk for secondary malignancies. While risk is highest for solid tumors or lymphoproliferative disorders, secondary myeloid neoplasms (MN) including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are also observed. Clonal hematopoiesis (CH) is associated with systemic inflammatory disease, increased risk of MN, and is enriched in UC (Zhang et al, Exp Hematol 2019). It is not known how the inflammatory milieu of IBD may affect progression to, or severity of, MN. We sought to characterize the disease profiles of patients with IBD diagnosed with MN at our institution in order to identify associations between severity or duration of their inflammatory disease and subtype, molecular, or cytogenetic features of MN.

Methods We performed a database query for patients with a diagnosis of AML or MDS or chronic myelogenous leukemia (CML) and a diagnosis of UC or CD seen within the Mount Sinai Health System between 2007 and 2022. Treatment history for IBD, age at diagnosis of IBD and MN, molecular, cytogenetic, and morphologic diagnosis of MN, and pertinent laboratory values were collected for analysis.

Results Forty-three patients were found to have a dual diagnosis of IBD and MN. CD was the preceding diagnosis in 70% (30/43) of cases. MDS was diagnosed in 51% (22/43) of all cases. Most patients (71%) were male. Twenty-eight patients had extractable data for further analysis including 12 cases of AML (7 de novo, 3 secondary AML, and 2 acute promyelocytic leukemia), 12 cases of MDS, and 4 cases of CML. The average ages at diagnosis of IBD and MN were 49.0 years (yr) and 61.1 yr, respectively, with an average latency between diagnoses of 14.2 yr. Two patients were diagnosed with IBD after MN. The mean age at diagnosis of AML was younger than at diagnosis of MDS (55.9 vs 68.6 yr, p = 0.05), a difference that was driven by CD patients (52.1 vs 71.1 yr, p = 0.03) but not seen with UC patients (67.4 vs 65.2 yr, p = 0.83).

A plot of mutations and clinical characteristics for each analyzed record can be found in Figure 1. The most common therapies for IBD included steroids, 5-ASA, and anti-TNF monoclonal antibodies. There was no association (analysis not shown) of any type or number of IBD therapies with type of MN, disease severity at diagnosis, adverse cytogenetics, or enrichment for specific mutations.

Longitudinal complete blood counts were available for 9 patients. At least one cytopenia was found in 89% (8/9) of patients within 3 years of diagnosis of MN. Six patients had anemia (4 CD and 2 UC) with mean hemoglobin 10.5 g/dL (95% CI 9.6 - 11.5), 4 had leukopenia (3 CD and 1 UC), and 4 had thrombocytopenia (2 CD and 2 UC). In 100% (6/6) of patients with anemia there was either normocytosis or macrocytosis, with an average mean corpuscular volume of 93.0 fL (95% CI 89.9 - 96.1) preceding the diagnosis of MN.

Conclusion In our cohort, patients with IBD were diagnosed with AML at a younger age than is seen in the general population (55.9 vs 68 yr). Type of IBD, IBD directed therapy, or severity of disease was not associated with type of MN, adverse cytogenetics, or MN risk category. The mutational profile of our cohort mirrors that of the general population of patients diagnosed with MN. A larger longitudinal study is underway to further elucidate the relationship between chronic inflammation in IBD, CH, and risk for progression to MN.

Of interest are the types of cytopenias observed in IBD patients as early as three years prior to diagnosis of MN. A normocytic or macrocytic anemia, or thrombocytopenia, was evident prior to diagnosis of MN and is inconsistent with typical IBD-associated thrombocytosis and microcytic anemia. Given established risks of progression to MN, we therefore highlight that patients with IBD who develop atypical cytopenias should be referred for comprehensive hematologic assessment.

Mascarenhas:Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; PharmaEssentia: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Galecto: Consultancy; Forbius: Research Funding; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Merck: Research Funding; Janseen: Research Funding; Merus: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.