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

1958(Blood)

Recognition as clinico-pathological entity

Splenectomy

1984 (NEJM)

Interferon

1990(NEJM)

Pentostatin Cladribin

2011(NEJM)

Mutated BRAF (targeted therapy ?)

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

RAS

RTK

V600E

MEK

ERK

BRAF

SurvivalProliferation

Transformation

VEMURAFENIB DABRAFENIB

BRAF mutation causes constitutive activation of MAPK pathwaysustaining survival of hairy cells: is it druggable ?

Increased phosphorylation

(Flaherty et al., NEJM 2010)

Clinical activity of the Vemurafenib in metastatic melanoma with BRAF V600E

Vemurafenib (PLX4032)

- First BRAF-V600E inhibitor

- Orally available compound

- Dosage (960 mg, twice daily)

- Clinical activity in metastatic melanoma

- FDA approved for this indication (2011)

Effect of Vemurafenib on HCL cells

Cell death

Hairy cell

Drug

Trimming ofhairy cells

HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia (PI: B. Falini)

Vemurafenib (Zelboraf – Roche):

N= 28 patients with refractory orrelapsed HCL have been recruited

Vemurafenib 960 mg twice/day

(8 weeks)

CR

Stop therapy X 2 weeks

Stop drug

Vemurafenib 960 mg twice/day

(4 weeks)

no CRCR

no CR

Vemurafenib 960 mg twice/day

(4 weeks)

Stop drug

Stop drug

CR= Defined according to standard criteria