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Perugia: Etruscan Arch

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.

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Perugia: Etruscan Arch

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  1. Perugia: Etruscan Arch

  2. Perugia: Town Hall and Fountain

  3. Perugia: University Medical Center

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

  5. HAIRY CELL LEUKEMIA AS A PARADIGM FOR DEVELOPMENT OF NEW THERAPIES Mutated BRAF (targeted therapy ?) Pentostatin Cladribin Splenectomy Interferon Recognition as clinico-pathological entity 1958 (Blood) 1984 (NEJM) 2011 (NEJM) 1990 (NEJM)

  6. 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

  7. BRAF mutation causes constitutive activation of MAPK pathway sustaining survival of hairy cells: is it druggable ? RTK RAS V600E BRAF VEMURAFENIB DABRAFENIB MEK Increased phosphorylation ERK Survival Proliferation Transformation

  8. Clinical activity of the Vemurafenib in metastatic melanoma with BRAF V600E Vemurafenib (PLX4032) - First BRAF-V600E inhibitor - Orally available compound - Dosage (960 mg, twice daily) - Clinical activity in metastatic melanoma - FDA approved for this indication (2011) (Flaherty et al., NEJM 2010)

  9. Effect of Vemurafenib on HCL cells Hairy cell Trimming of hairy cells Drug Cell death

  10. HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia (PI: B. Falini) Vemurafenib (Zelboraf – Roche): N= 28 patients with refractory or relapsed HCL have been recruited

  11. Vemurafenib 960 mg twice/day (8 weeks) Stop therapy X 2 weeks no CR CR Vemurafenib 960 mg twice/day (4 weeks) Stop drug CR no CR CR= Defined according to standard criteria Stop drug Vemurafenib 960 mg twice/day (4 weeks) Stop drug

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