1. 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

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*
HAIRY CELL
*Tiacci et al., BRAF mutations in Hairy Cell Leukiemia
New England Journal of Medicine 2011

7. MUTATION OF THE BRAF GENE IN ALMOST ALL PATIENTS WITH HCL*
Signal from the environment
HAIRY CELL
Receptor
Cell surface
RAS
V600E
BRAF
VEMURAFENIB
pMEK
pERK
survival
proliferation
transformation
*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
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

10. Effect of Vemurafenib on HCL cells
Hairy cell
Vemurafenib

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

12. 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

13. 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

14. 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

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

16. 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
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
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

17. 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
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
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

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

19. CR = Complete Remission Stop drug
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
no CR
Stop drug
Vemurafenib
960 mg twice/day
4 weeks
CR = Complete Remission
Stop drug

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

21. Sponsor: Institute of Hematology, Perugia
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. Sponsor: Institute of Hematology, Perugia
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. Sponsor: Institute of Hematology, Perugia
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. Sponsor: Institute of Hematology, Perugia
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. Sponsor: Institute of Hematology, Perugia
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. Sponsor: Institute of Hematology, Perugia
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
after 12 months

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

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