Clinical Characteristics and Outcomes of Leukemia in Patients with Germline IKZF1 Mutations

Background Germline mutations in IKZF1 are associated with immunodeficiency and predisposition to hematologic malignancies, including acute lymphoblastic leukemia (ALL). The penetrance of leukemia and associated clinical spectrum in affected individuals remain incompletely defined due to the rarity of these mutations. Objective To describe the clinical features, leukemia subtypes, therapeutic responses, and outcomes of four individuals with germline IKZF1 mutations. Methods Four unrelated patients with germline IKZF1 mutations were identified through clinical genetic testing. Clinical data, including leukemia diagnosis, treatment regimens, remission status, and long-term outcomes, were retrospectively reviewed. Genetic findings, including somatic alterations, were also evaluated to identify cooperative events driving leukemogenesis. Results The cohort included four patients (age 3–25 years) diagnosed with B-ALL (n = 3) or T-ALL (n = 1). All patients harbored pathogenic or likely pathogenic germline IKZF1 variants, missense variants (n = 3) in DNA-binding domain, and an entire gene deletion (n = 1), causing haploinsufficiency. Two patients were diagnosed with germline IKZF1 mutation during therapy due to identification of IKZF1 alterations from tumor profiling (confirmed with skin biopsy), while the other two were diagnosed after therapy was completed. Three patients were classified as NCI high risk at diagnosis, with one patient harboring very high-risk molecular features, including Philadelphia chromosome, additional somatic IKZF1 mutation, and CDKN2A deletion. Treatment protocols varied, with three patients receiving standard ALL chemotherapy and one undergoing hematopoietic stem cell transplantation (HSCT) due to very high-risk disease. At follow-up, three patients were alive and remained in complete remission, while one relapsed during therapy and succumbed to his leukemia. Those who survived developed prolonged hypogammaglobulinemia, requiring immunoglobulin replacement therapy due to recurrent infections. One patient who received HSCT developed chronic lung GVHD. None of these patients had history of recurrent infections or autoimmunity prior to leukemia diagnosis. Conclusion Germline IKZF1 mutations confer a predisposition to leukemia, with a spectrum of phenotypes and variable outcomes. The presence of somatic IKZF1 alterations is uncommon but if present may accelerate acquisition of high-risk molecular features which warrant more intensive therapy. Early identification of germline IKZF1 mutations (through routine tumor profiling) and tailored management strategies, including consideration of HSCT, may improve outcomes in this high-risk population.