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Hairy Cell Leukemia Foundation and The Royal Marsden NHS Foundation Trust THE GENETIC CAUSE OF HAIRY CELL LEUKAEMIA (HCL) AND ITS THERAPEUTIC TARGETING ENRICO TIACCI, M.D. Institute of Hematology, University of Perugia – Italy (Director: Prof. B. Falini) PATIENT SEMINAR London - September 20, 2014 Perugia: Etruscan Arch Perugia: Town Hall and Fountain Perugia: University Medical Center MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* HAIRY CELL *Tiacci et al., BRAF mutations in Hairy Cell Leukiemia New England Journal of Medicine 2011 MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* HAIRY CELL Signal from the environment Receptor Cell V600E surface RAS BRAF VEMURAFENIB pMEK pERK survival proliferation transformation *Tiacci et al., BRAF mutations in Hairy Cell Leukiemia New England Journal of Medicine 2011 VEMURAFENIB - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months Effect of Vemurafenib on HCL cells Hairy cell Vemurafenib Effect of Vemurafenib on HCL cells Hairy cell Trimming of hairy cells Vemurafenib Cell death MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* HAIRY CELL VEMURAFENIB survival proliferation transformation “hairiness” *Tiacci et al., BRAF mutations in Hairy Cell Leukemia New England Journal of Medicine 2011 VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - About 40% of HCL patients treated with purine analogues (cladribine or pentostatin) will relapse within 5-10 years, a problem especially for younger patients - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - About 40% of HCL patients treated with purine analogues (cladribine or pentostatin) will relapse within 5-10 years, a problem especially for younger patients - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months - Progressive decrease of response rate and duration after each successive course of purine analogue VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - About 40% of HCL patients treated with purine analogues (cladribine or pentostatin) will relapse within 5-10 years, a problem especially for younger patients - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months - Progressive decrease of response rate and duration after each successive course of purine analogue - Bone marrow toxicity and immune suppression after multiple courses of chemotherapy VEMURAFENIB VEMURAFENIB IN HCL - Highly active against patients’ hairy cells in the laboratory - About 40% of HCL patients treated with purine analogues (cladribine or pentostatin) will relapse within 5-10 years, a problem especially for younger patients - First drug inhibitor of BRAF - Orally available - Already approved for BRAF-mutated melanoma - Progressive decrease of response rate and duration after each successive course of purine analogue - Bone marrow toxicity and immune suppression after multiple courses of chemotherapy - Not toxic to the bone marrow - Overall responses in about 50% of cases (<5% complete responses) Median duration: ~7 months - Rationale for using Vemurafenib in HCL patients with multiple relapses after, or refractory to, standard chemotherapy HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: Vemurafenib 960 mg twice/day for 8 weeks 2 weeks off-drug no CR CR Vemurafenib 960 mg twice/day for 4 weeks Stop drug CR Stop drug CR = Complete Remission no CR Vemurafenib 960 mg twice/day 4 weeks Stop drug HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated - Drug very active: 25/26 (96%) patients responded HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated - Drug very active: 25/26 (96%) patients responded - 9/26 (34.6%) complete responses HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated - Drug very active: 25/26 (96%) patients responded - 9/26 (34.6%) complete responses - 16/26 (61.4%) partial responses HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated - Drug very active: 25/26 (96%) patients responded after 12 months - 9/26 (34.6%) complete responses - 16/26 (61.4%) partial responses normal blood counts in 6/9 pts. HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated - Drug very active: 25/26 (96%) patients responded after 12 months - 9/26 (34.6%) complete responses after 12 months - 16/26 (61.4%) partial responses normal blood counts in 6/9 pts. normal blood counts in 5/16 pts. HCL-PG02 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia Cell surface “hairiness” HCL-PG03 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia Cell YRITUXIMAB surface HCL cell “hairiness”