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Perugia: Etruscan Arch. Perugia: Town Hall and Fountain. Perugia: University Medical Center. Visit of Dr. James Smith and his wife to our medical center. HAIRY CELL LEUKEMIA AS A PARADIGM FOR DEVELOPMENT OF NEW THERAPIES. Mutated BRAF (targeted therapy ?). Pentostatin Cladribin. - PowerPoint PPT Presentation

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  • Perugia: Etruscan Arch

  • Perugia: Town Hall and Fountain

  • Perugia: University Medical Center

  • Visit of Dr. James Smith and his wife to our medical center.

  • HAIRY CELL LEUKEMIA AS A PARADIGM FOR DEVELOPMENT OF NEW THERAPIES 1958(Blood)Recognition as clinico-pathological entity

    Splenectomy 1984 (NEJM)Interferon1990(NEJM)Pentostatin Cladribin 2011(NEJM)Mutated BRAF (targeted therapy ?)

  • Any place for molecular targeted therapy of HCL with BRAF-V600E inhibitors ? - About 40% of HCL patients treated with purine analogs (cladribin or pentostatin) will relapse within 5-10 years. Major problem especially for younger patients.

    - Myelotoxicity after multiple course of chemotherapy

    - Severe immune depression after purine analogues (increased risk of opportunistic infections

  • RASRTKV600EMEKERKBRAFSurvivalProliferationTransformationBRAF mutation causes constitutive activation of MAPK pathwaysustaining survival of hairy cells: is it druggable ? Increased phosphorylation

  • (Flaherty et al., NEJM 2010)Clinical activity of the Vemurafenib in metastatic melanoma with BRAF V600EVemurafenib (PLX4032)- First BRAF-V600E inhibitor

    - Orally available compound

    - Dosage (960 mg, twice daily)

    - Clinical activity in metastatic melanoma

    - FDA approved for this indication (2011)

  • Effect of Vemurafenib on HCL cells Cell death Hairy cell DrugTrimming ofhairy cells

  • HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia (PI: B. Falini) Vemurafenib (Zelboraf Roche):N= 28 patients with refractory orrelapsed HCL have been recruited

  • Vemurafenib 960 mg twice/day (8 weeks) CRStop therapy X 2 weeks Stop drug Vemurafenib 960 mg twice/day (4 weeks) no CRCRno CRVemurafenib 960 mg twice/day (4 weeks) Stop drugStop drugCR= Defined according to standard criteria

  • Vemurafenib, this oral ATP-competitive inhibitor of active BRAF