Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia

Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML

Emergence of Natural Killer Cell Large Granular Lymphocytes during Gilteritinib Treatment in Acute Myeloid Leukemia with FLT3-ITD Mutation

As the potent, selective Fms-Like Tyrosine Kinase 3 (FLT3) inhibitor gilteritinib has only been approved for use for a few years, its efficacy and complications remain incompletely understood. We herein report an elderly patient with FLT3 internal tandem duplications (FLT3-ITD) mutated acute myeloid leukemia (AML) who developed natural killer cell large granular lymphocytes (NK-LGL) in the bone marrow and peripheral blood during gilteritinib treatment. Case: A 79-year-old Japanese female had been diagnosed with FLT3-ITD-mutated AML. The patient received hydroxycarbamide 2000 mg daily for induction chemotherapy but did not achieve remission at day 28 postinduction. The treatment was then changed to gilteritinib 120 mg daily. Although the reduction of blasts in peripheral blood occurred immediately, it was revealed abnormal lymphocytes with large granules developed in bone marrow and peripheral blood. These lymphocytes were analyzed by flow cytometry, which revealed that these cells were NK-LGL because they expressed CD2, CD7, CD16, and CD56 and did not express CD3, CD19, and CD20. The patient achieved partial remission (PR) in a month with gilteritinib treatment. Leukemia eventually could not be controlled, but PR persisted for about 4 months and leukemia was controlled for 4 months after progression disease (PD) with gilteritinib treatment alone. Conclusion: Gilteritinib may induce the NK-LGL. The exact mechanism and effect of LGL in patients with FLT3 mutated AML treated with gilteritinib warrants further investigation

Prognostic factors for the development of lower respiratory tract infection after influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients: A Kanto Study Group for Cell Therapy multicenter analysis

Objectives: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. Methods: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. Results: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. Conclusion: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease