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THE GENETIC CAUSE OF HAIRY CELL LEUKAEMIA (HCL) AND ITS THERAPEUTIC TARGETING ENRICO TIACCI, M.D. Institute of Hematology, University of Perugia – Italy.

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Presentation on theme: "THE GENETIC CAUSE OF HAIRY CELL LEUKAEMIA (HCL) AND ITS THERAPEUTIC TARGETING ENRICO TIACCI, M.D. Institute of Hematology, University of Perugia – Italy."— Presentation transcript:

1 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) Hairy Cell Leukemia Foundation and The Royal Marsden NHS Foundation Trust PATIENT SEMINAR London - September 20, 2014

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3 Perugia: Etruscan Arch

4 Perugia: Town Hall and Fountain

5 Perugia: University Medical Center

6 MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* *Tiacci et al., BRAF mutations in Hairy Cell Leukiemia New England Journal of Medicine 2011 HAIRY CELL

7 MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* RAS pMEK pERK BRAF Receptor survival proliferation transformation V600E Signal from the environment VEMURAFENIB Cell surface HAIRY CELL *Tiacci et al., BRAF mutations in Hairy Cell Leukiemia New England Journal of Medicine 2011

8 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

9 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 - Highly active against patients’ hairy cells in the laboratory VEMURAFENIB IN HCL

10 Effect of Vemurafenib on HCL cells Hairy cell Vemurafenib

11 Effect of Vemurafenib on HCL cells Cell death Hairy cell Vemurafenib Trimming of hairy cells

12 MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL* *Tiacci et al., BRAF mutations in Hairy Cell Leukemia New England Journal of Medicine 2011 HAIRY CELL survival proliferation transformation “hairiness” VEMURAFENIB

13 - 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 - Highly active against patients’ hairy cells in the laboratory VEMURAFENIB IN HCL

14 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 - 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 VEMURAFENIB IN HCL

15 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 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 - Progressive decrease of response rate and duration after each successive course of purine analogue

16 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 - 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 - 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 IN HCL

17 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 - 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 - 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 - Rationale for using Vemurafenib in HCL patients with multiple relapses after, or refractory to, standard chemotherapy VEMURAFENIB IN HCL

18 HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable:

19 Vemurafenib 960 mg twice/day for 8 weeks CR 2 weeks off-drug Stop drug Vemurafenib 960 mg twice/day for 4 weeks no CRCR no CR Vemurafenib 960 mg twice/day 4 weeks Stop drug CR = Complete Remission

20 HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable:

21 HCL-PG01 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia 26 patients with refractory or pluri-relapsed HCL recruited and evaluable: - Drug generally well tolerated

22 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

23 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

24 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

25 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 normal blood counts in 6/9 pts. - 16/26 (61.4%) partial responses after 12 months

26 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 normal blood counts in 6/9 pts. - 16/26 (61.4%) partial responses normal blood counts in 5/16 pts. after 12 months

27 Cell surface HCL-PG02 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia “hairiness”

28 HCL-PG03 CLINICAL TRIAL Sponsor: Institute of Hematology, Perugia Y RITUXIMAB + Cell surface HCL cell “hairiness”

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