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 andThe Royal Marsden NHS Foundation Trust

PATIENT SEMINAR

London - September 20, 2014

Perugia: Etruscan Arch

Perugia: Town Hall and Fountain

Perugia: University Medical Center

MUTATION OF THE BRAF GENE INALMOST ALL PATIENTS WITH HCL*

*Tiacci et al., BRAF mutations in Hairy Cell LeukiemiaNew England Journal of Medicine 2011

HAIRY CELL

MUTATION OF THE BRAF GENE INALMOST ALL PATIENTS WITH HCL*

RAS

pMEK

pERK

BRAF

Receptor

survivalproliferation

transformation

V600E

Signal from the environment

VEMURAFENIB

Cell surface

HAIRY CELL

*Tiacci et al., BRAF mutations in Hairy Cell LeukiemiaNew 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

- 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

Effect of Vemurafenib on HCL cells

Hairy cell

Vemurafenib

Effect of Vemurafenib on HCL cells

Cell death

Hairy cell

Vemurafenib

Trimming ofhairy cells

MUTATION OF THE BRAF GENE INALMOST ALL PATIENTS WITH HCL*

*Tiacci et al., BRAF mutations in Hairy Cell LeukemiaNew England Journal of Medicine 2011

HAIRY CELL

survivalproliferation

transformation“hairiness”

VEMURAFENIB

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

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

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

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

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

HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia

26 patients with refractory or pluri-relapsed HCL recruited and evaluable:

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

Stop drugCR = Complete Remission

HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia

26 patients with refractory or pluri-relapsed HCL recruited and evaluable:

HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia

26 patients with refractory or pluri-relapsed HCL recruited and evaluable:

- Drug generally well tolerated

HCL-PG01 CLINICAL TRIALSponsor: 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 TRIALSponsor: 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 TRIALSponsor: 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 TRIALSponsor: 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

HCL-PG01 CLINICAL TRIALSponsor: 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

after 12 months

Cell surface

HCL-PG02 CLINICAL TRIALSponsor: Institute of Hematology, Perugia

“hairiness”

HCL-PG03 CLINICAL TRIALSponsor: Institute of Hematology, Perugia

YRITUXIMAB +

Cell surface

HCL cell

“hairiness”