Session: 906. Outcomes Research – Myeloid Malignancies: Poster I
Hematology Disease Topics & Pathways:
Research, Sickle Cell Disease, Acute Myeloid Malignancies, epidemiology, Sickle Cell Trait, APL, Clinical Research, health outcomes research, Genetic Disorders, Thalassemia, Hemoglobinopathies, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Study Population, Human
Methods: Patients with HHAs were identified from the Mass General Brigham Research Patient Data Repository using ICD-10 codes. Evaluated HHAs included sickle cell disease (SCD), sickle cell trait (SCT), thalassemia major, thalassemia trait, other hemoglobinopathy traits, and hereditary spherocytosis or elliptocytosis. A final HHA-MN cohort included patients with laboratory confirmed HHA diagnoses as well as incident myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), Ph+ chronic myelogenous leukemia (Ph+ CML), Ph negative myeloproliferative neoplasms (Ph- MPNs) or acute myeloid leukemia (AML). A control cohort of non-HHA MN patients was obtained from the Dana-Farber Hematologic Malignancies Data Repository. Clinical, molecular, and survival data were summarized and compared between HHA-MN and controls.
Results: The HHA-MN cohort included 62 patients with HHAs and incident MN (Table 1). HHAs included SCD (n = 6, 9.7%), SCT (n = 9, 14.5%), thalassemia trait (n = 36, 58.1%), thalassemia major (n = 2, 3.2%), hereditary spherocytosis or elliptocytosis (n = 4, 6.5%), and other hemoglobinopathy traits (n = 5, 8.1%). MN was diagnosed at a median age of 61 years [IQR: 48, 70] in the HHA-MN cohort and incident MNs included AML (n = 12, 19.4%), MDS/CMML (n = 22, 35.4%), Ph+ CML (n = 6, 9.7%), and Ph- MPNs (n = 22, 35.4%). A control population of 3388 MN patients without HHA included cases of AML (n = 754, 22.2%), MDS/CMML (n= 1272, 37.5%), Ph+ CML (n = 354, 10.4%), and Ph- MPNs (n = 1008, 29.7%). Compared to HHA patients, control patients were older at MN diagnosis (median age 65 years [IQR: 56, 73], p = 0.0071), driven by significantly younger ages at AML diagnosis for HHA-MN patients (median age 50 years [IQR: 33, 63] vs 65 years [IQR: 57, 73], p =0.0044).
AML was the most common MN in SCD (n = 4, 66.7%) whereas incident MDS/CMML was the predominant MN among individuals with thalassemia trait (n = 12, 33.3%) or hereditary spherocytosis and elliptocytosis (n = 2, 50%). Diagnostic cytogenetic data were available for 45 patients in the HHA-MN cohort (72.6% of cohort). Complex karyotype, defined as 3 or more chromosomal aberrations, was observed in 3 of 11 (27.3%) AML, 3 of 19 (15.8%) MDS/CMML and 1 of 17 (5.9%) Ph- MPN cases. Of the 33 HHA-MN patients with available diagnostic next generation sequencing, 60.6% had 2 or more pathogenic mutations at MN diagnosis. Including 2 cases of TP53-mutant AML in patients with SCD, the majority (90%) of AML and 38.9% of MDS/CMML diagnosed in HHA-MN patients were intermediate to adverse risk by ELN criteria or intermediate to very high risk by IPSS-R, respectively. High risk disease was also common in our control MN cohort, where 88.3% of AML cases were intermediate or adverse risk by ELN criteria and 55.9% of MDS/CMML cases were intermediate to very high risk by IPSS-R.
Survival varied by subtype of HHA and MN (Figure 1). Survival was lowest for SCD (33.3% at 60-months) and highest for thalassemia traits (67.1% at 60 months). In HHA patients compared to controls, 60-month survival was 65.0% overall (vs 56.4%), 14.3% for AML (vs 23.8%), 51.0% for MDS/CMML (vs 43.9%), 90.5% in Ph- MPN (vs 80.6%), and 100% in Ph+ CML (vs 89.4%). Within the limitations of our sample size, survival differences were not statistically significant.
Conclusion: In this retrospective analysis, we observe younger age of diagnosis of myeloid malignancy for patients with HHAs compared to non-HHA controls. Inferior survival in SCD and thalassemia major is largely explained by a higher proportion of AML diagnoses in patients with SCD. AML and MDS/CMML diagnosed in HHA patients tended to be intermediate or high-risk disease, with survival similar to the non-HHA control population that was also enriched for higher risk patients. Validation of our findings in an expanded cohort of HHA patients is currently underway.
Disclosures: Merz: Alexion Pharmaceuticals: Consultancy, Research Funding; X4 Pharmaceuticals: Honoraria. Chien: Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Lindsley: Verve Therapuetics: Consultancy; Sarepta Therapuetics: Consultancy; Jazz Pharmaceuticals: Consultancy; Qiagen: Consultancy; Bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy; Vertex Pharmaceuticals: Consultancy. Luskin: Novartis: Honoraria; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Pfizer: Honoraria. Stahl: GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Clinical care options: Other: GME activity ; Kymera: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Dedham group: Consultancy; Haymarket Media: Other: GME activity ; Curis Oncology: Other: GME activity . Mullally: Aclaris, Cellarity, Morphic, Biomarin: Consultancy; AOP Health: Speakers Bureau; Relay, Morphic: Research Funding; PharmaEssentia, Incyte: Other: Steering Committee ; Constellation, Protagonist: Other: Advisory Board . DeAngelo: Novartis: Honoraria; Takeda: Honoraria; Servier: Honoraria; GlycoMimetics: Research Funding; Autolus: Honoraria; AbbVie: Research Funding; Kite: Honoraria; Gilead: Honoraria; Blueprint: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Blueprint: Honoraria; Pfizer: Honoraria. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Achebe: Forma Therapeutics, Pharmacosmos, Fulcrum, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics: Consultancy; Fulcrum Therapeutics: Consultancy; Shield Therapeutics: Consultancy. Ebert: TenSixteen Bio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Calico: Research Funding; Abbvie: Consultancy; Neomorph Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Skyhawk Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Exo Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Weeks: Abbvie: Consultancy; Sobi: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy.
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