Transcript Presentation Slides - Hairy Cell Leukemia Foundation

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”