Targeted Therapy in FLT3-ITD Positive Myeloid Sarcoma: Proof of Principle

Abstract

INTRODUCTIONAcute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutation is a poor prognosis disease, with a high rate of relapse and poor OS, even after allogeneic hematopoietic cell transplantation (alloHCT).In recent years FLT3 inhibitors have emerged in the treatment of FLT3-ITD AML both as monotherapy and in combination with standard chemotherapy; they were used both during induction therapy and in relapsed or refractory disease. They have also been used as maintenance therapy after transplantation.FLT3 inhibitors act by blocking the proliferative boost due to FLT3-ITD.Some of these drugs are approved for the treatment of solid cancers such as hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma.We report the case of a patient with FLT3-ITD-positive AML whose disease relapsed after alloHCT as a myeloid sarcoma and who was successfully treated with Sorafenib.CASE REPORTA 54-year old male was diagnosed with AML with a normal karyotype and FLT3-ITD and NPM1 mutations. A molecular complete response (CR) was observed after “3+7” induction therapy. A consolidation therapy with Citarabine was administered and then alloHCT was performed. Conditioning was tBu-Flu and donor was an HLA-identical sibling. Cyclosporine and short term Methotrexate were used as Graft Versus Host Disease (GVHD) prophylaxis.No sign of acute GVHD occurred, molecular CR was confirmed at bone marrow evaluation at day +100, thereafter CSPA was tapered.Nine months after alloHCT a left pectoral subcutaneous nodule appeared. The biopsy consisted with myeloid sarcoma; molecular analysis revealed that sarcoma was FLT3-ITD positive. Meanwhile many sarcomas quickly appeared in different areas of the body and patient referred tingle in his right leg. A CT-PET scan showed pathological uptake in cervical lymph nodes, in subcutaneous and muscular lesions at left upper limb, right hip, thighs, and at right tibia bone. At the same time bone marrow exam confirmed molecular CR and full donor chimerism.Immunosuppression was stopped and he was admistered Sorafenib 200 mg twice for day in off-label use 11 months after alloHCT. Superficial lesions and right leg tingle decreased within 7 days and no lesion was detected by physical examination after 10 weeks of therapy; CT-PET scan after 8 weeks showed partial remission.Sorafenib was increased to 400 mg twice for day and the expected side effects occurred, namely diarrhoea and palmar-plantar erythrodysesthesia.After four months of therapy with Sorafenib, he was treated with donor lymphocyte infusion (DLI), the drug was continued and no clinical manifestation of GVHD appeared. He received a second dose of DLI after seven weeks from the first dose.After 23 weeks of Sorafenib treatment and two dose of DLI, sarcomas localization continued to slowly decrease, bone marrow exam confirmed molecular CR and full donor chimerism, and patient was in good physical condition, with limited oral chronic GVHD.CONCLUSIONOur observation is the proof of Sorafenib activity even in FLT3-ITD myeloid sarcoma, and of his ability to reach extramedullary tissue and to be effective against sarcoma myeloblasts. This experience suggest to look for FLT3 mutation in myeloid sarcoma tissue and to consider therapy with FLT3-inhibitors, alone or in association with chemotherapy. DisclosuresNo relevant conflicts of interest to declare.