Perugia: Etruscan Arch
Perugia: Town Hall and Fountain
Perugia: University Medical Center
Visit of Dr. James Smith and his wife to our medical center.
HAIRY CELL LEUKEMIA AS A PARADIGM FOR
DEVELOPMENT OF NEW THERAPIES
Splenectomy
Interferon
Pentostatin
Cladribin
Mutated BRAF
(targeted therapy ?)
Recognition as clinicopathological entity
1958
(Blood)
1984
(NEJM)
1990
(NEJM)
2011
(NEJM)
Any place for molecular targeted therapy of HCL
with BRAF-V600E inhibitors ?
- About 40% of HCL patients treated with purine analogs (cladribin
or pentostatin) will relapse within 5-10 years. Major problem
especially for younger patients.
- Myelotoxicity after multiple course of chemotherapy
- Severe immune depression after purine analogues (increased
risk of opportunistic infections
BRAF mutation causes constitutive activation of MAPK pathway
sustaining survival of hairy cells: is it druggable ?
RTK
RAS
V600E
BRAF
VEMURAFENIB
DABRAFENIB
MEK
Increased
phosphorylation
ERK
Survival
Proliferation
Transformation
Vemurafenib (PLX4032)
Clinical activity of the Vemurafenib in metastatic
melanoma with BRAF V600E
- First BRAF-V600E inhibitor
- Orally available compound
- Dosage (960 mg, twice daily)
- Clinical activity in metastatic melanoma
- FDA approved for this indication
(2011)
(Flaherty et al., NEJM 2010)
Effect of Vemurafenib on HCL cells
Hairy cell
Trimming of
hairy cells
Drug
Cell death
HCL-PG01 CLINICAL TRIAL
Sponsor: Institute of Hematology, Perugia (PI: B. Falini)
Vemurafenib (Zelboraf – Roche):
N= 28 patients with refractory or
relapsed HCL have been recruited
Vemurafenib
960 mg twice/day
(8 weeks)
Stop therapy X 2 weeks
no CR
CR
Vemurafenib
960 mg twice/day
(4 weeks)
Stop drug
CR
CR= Defined according to
standard criteria
Stop drug
no CR
Vemurafenib
960 mg twice/day
(4 weeks)
Stop drug