Bosutinib, a <scp>L</scp>yn/<scp>B</scp>tk inhibiting tyrosine kinase inhibitor, is ineffective in advanced systemic mastocytosis
Authors: Nicole Randall, Elizabeth L. Courville, Linda Baughn, Lawrence Afrin, Celalettin Ustun
Journal: American Journal of Hematology (2015)

We read Tantravahi et al. 1 and Gambacorti-Passerini et al. 2 manuscripts with great interest. We described here the first experience of bosutinib in advanced systemic mastocytosis (ASM). Cytoreductive therapy is indicated in ASM because of shortened survival 3. A 50-year-old male presented with urticaria pigmentosa (UP) in 2000 had his first bone marrow (BM) biopsy showing 30% atypical mast cells in 2009 (Fig. 1A). He had hepatosplenomegaly and elevated serum tryptase (1187 ng/mL, normal <12 ng/mL) (Supporting Information Fig.). While he was treated antihistaminics with symptomatically, his platelet count decreased (from 250 × 109/L to 140 × 109/L). This and high serum tryptase level (2,479 ng/mL) prompted on December 2013 a BM biopsy showing osteosclerosis and increased (80–90% of the BM) spindle-shaped mast cells (Fig. 1B), expressing CD117, CD25, and CD2. Bosutinib 500 mg/day PO was initiated. Bosutinib dose was adjusted between 500 mg/day and 300 mg/day during therapy because of mild elevation of ALT and mild anemia. After four months of treatment, there was no change in mast cell involvement, with worsening myelofibrosis (Grade 2–3) and osteosclerosis (Fig. 1C). DNA sequencing for CALR, IDH1, IDH2, KRAS, NRAS, HRAS, JAK2, and TP53 mutations were negative, but was positive for the KITD816V mutation in the mast cells. Serum tryptase increased (2,976 ng/mL), hepatosplenomegaly worsened (2 cm larger), and UP remained the same (Supporting Information Fig.). Because of bosutinib failure, cladribine (0.12 mg/kg/day IV × 5 days) was administered. Partial response was reached after 4th cycle (serum tryptase of 1,600 ng/mL, atypical mast cells of 50–60% of the BM (Fig. 1D), with moderate improvement in UP (Supporting Information Fig.). Bone marrow biopsies show progression of neoplastic spindle-shaped mast cells and osteosclerosis between 2009 and 2013 with no therapy (A–B), stable disease before and after bosutinib (B–C), and response to cladribine regarding mast cells (C–D). (hematoxylin and eosin (H&E), 10× objective). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Tyrosine kinase inhibitors (TKI) with anti-KIT activity have been used in ASM with some success, indicating that other mechanisms/pathways contribute to neoplastic mast cell growth 1, 4, 5. Lyn, a member of the Src family, and Btk are activated in a KIT-independent manner in neoplastic mast cells in ASM and may contribute to malignant transformation 6. Bosutinib, a dual src/abl kinase inhibitor with a minimal anti-KIT activity, disrupted Lyn/Btk oncogenic signaling in neoplastic mast cells in vitro 6. Despite no significant activity on KIT, bosutinib inhibited—synergistically with dasatinib—growth of the mast cells 6. In our ASM patient, bosutinib alone was safe but ineffective; however, its impact in a combination with an anti-KIT TKI in ASM needs to be addressed. Nicole Randall,1 Elizabeth L. Courville,2 Linda Baughn,2 Lawrence Afrin,1 and Celalettin Ustun,1,* 1Division of Hematology-Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 2Department of Pathology and Laboratory Medicine, University of Minnesota, Minneapolis, Minnesota Additional Supporting Information may be found in the online version of this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.