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Successful treatment with gilteritinib for initially FMS‐like tyrosine kinase 3 gene internal tandem duplications‐positive elderly refractory acute myeloid leukemia that changed into FMS‐like tyrosine kinase 3 gene tyrosine kinase domain‐positive after cord blood transplantation

D. Akahane,Mitsuru Moriyama,S. Yoshizawa,S. Katagiri,Hiroaki Fujimoto,A. Gotoh

Published 2019 in Geriatrics & Gerontology International

ABSTRACT

Dear Editor, FMS-like tyrosine kinase 3 gene (FLT3) mutations are present in approximately one-third of patients with acute myeloid leukemia (AML). Mutations of FLT3 internal tandem duplications (FLT3-ITD) and FLT3 tyrosine kinase domain (FLT3-TKD) impact approximately 20% and 7% of AML, respectively, and these mutations are reported to be associated with treatment resistance. Patients who carry these mutations have a high risk of relapse without allogeneic stem cell transplantation. Gilteritinib is a specific potent FLT3 inhibitor with demonstrated activity against both the FLT3-ITD and FLT3-TKD. We report here an elderly AML patient who had an FLT3-ITD at onset and FLT3-TKD at second relapse after cord blood transplantation (CBT). Furthermore, gilteritinib was highly effective and the patient had a third remission. A 65-year-old man with pancytopenia during antiandrogenic therapy for his stage IV prostate cancer was referred to Tokyo Medical University Hospital (Tokyo, Japan) in January 2016. Blood tests showed white blood cell count of 1.0 × 10/L (with 4% blasts), hemoglobin level of 7.4 g/dL and platelet count of 65 × 10/L. Bone marrow (BM) examination showed 21.5% myeloblasts with normal karyotype, but FLT3-ITD mutation, and WT1 mRNA was 81 × 10 copies. NPM1 and DNMT3A, and other mutations were not assessed. Final diagnosis of FLT3/ITD-positive AML with myelodysplasiarelated changes was established according to World Health Organization criteria. We recommended low-dose chemotherapy of CAG (low-dose Ara-C, aclarubicin and G-CSF) for AML, as we were concerned about severe adverse events associated with intensive chemotherapy. Complete remission (CR) was obtained by one course of CAG, and an additional two courses were administered for consolidation. Treatment of prostate cancer undertaken in parallel also achieved CR. Thus, we made a recommendation of allogeneic hematopoietic stem cell transplantation for his leukemia at first CR, but the patient refused this because of the higher risk of treatment-related mortality. Even in CR, morphology of his BM continued showing dysplasia, so we started treatment with a regular dose of 5-azacitidine. After six courses of azacitidine, BM showed increasing myeloblasts at 7.5%. The karyotype was 46,XY,-9,+mar, which changed from the initial diagnosis. We did not evaluate the FLT3 mutation at this point. Reinduction therapy with CAG resulted in failure. After careful reassessment for frailty and comorbidity, the patient was considered eligible for reduced-intensity stem cell transplantation (RIST). As neither human leukocyte antigenmatched siblings nor unrelated donors were available, umbilical cord blood was selected as an alternative donor source. The cord blood unit had a sex match and two serological human leukocyte antigen loci mismatches in human leukocyte antigen-B and C. The cryopreserved number of CB nucleated cells was 2.2 × 10/kg and that of CD34+ cells was 0.63 × 10/kg. Hematopoietic stem cell transplantation was undertaken after a RIST regimen with fludarabine (125 mg/m), melphalan (80 mg/m) and total body irradiation 4 Gy in March 2018. Graft-versus-host disease prophylaxis was tacrolimus alone. Neutrophils were engrafted at day 19 after umbilical CBT without acute graft-versus-host disease. The patients successfully achieved second CR, while whole BM chimerism analysis showed complete donor and molecular remission of undetected levels of WT1 mRNA. Unfortunately, the patient suffered from a second relapse 6 months after umbilical CBT, with 14% myeloblasts in BM in September 2018. Whole BM chimerism analysis showed 51% recipient type. BM analyses showed the same karyotype of 46,XY,-9,+mar, as at the first relapse; however, FLT3-ITD was absent, but FLT3-TKD was discovered. Gilteritinib was commercially available in December 2018, and known to be active for FLT3-TKD. We treated the patient with 120 mg of gilteritinib. Before initiation of gilteritinib, the FLT3-TKD allelic burden was 57%. Three months later, BM blasts disappeared, normal hematopoietic cell recovered gradually and the patient eventually achieved third CR. Five months later, whole BM chimerism analysis showed complete donor type (Fig. 1). Gilteritinib treatment was mostly well tolerated, but the patient was complicated with pneumonia, pleural effusion, elevation of creatine phosphokinase and hypophosphatemia. Thus, the daily dosage of gilteritinib was reduced to 80 mg. He currently remains in CR with good performance status. A second transplantation is not planned because of his age and organ damage from the first transplant. Acquired TKD mutations in FLT3, including D835Y, have recently been identified in FLT3-ITD-positive patients relapsing after treatment with FLT3 inhibitors. However, reports of changes in such FLT3 gene mutations, from FLT3-ITD to FLT3-TKD, after conventional chemotherapy including hematopoietic stem cell transplantation are limited. Although the karyotype had changed from the initial diagnosis, we speculate that a very small amount of leukemic clone carrying both FLT3TKD and/or an abnormal karyotype already existed at the time of onset, and that the clone was selected during chemotherapy and/or CBT. The changes of karyotype might be related to the changes in FLT3 mutations; it is possible, but not clear. The target sequence of leukemia cells at the onset and relapse is desirable to determine if there is a clone of common origin. We also reported the effectiveness of gilteritinib for relapsed AML with FLT3-TKD after CBT. Gilteritinib treatment was generally

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