CTCL INNOVATIVE TREATMENTS GEMCITABINE Monica Tani Institute of

CTCL: INNOVATIVE TREATMENTS GEMCITABINE Monica Tani Institute of Hematology and Medical Oncology “L. e A. Seràgnoli” University of Bologna, Italy

GEMCITABINE l Gemcitabine is a novel nucleoside analog that exerts its antitumor activity via multiple mechanisms of action. These include: 1 Incorporation of gemcitabine into replicating DNA, which inhibits DNA replication and cell growth. Institute Seràgnoli

GEMCITABINE 2 Masked DNA chain termination. 3 Several self-potentiation mechanisms that serve to increase intracellular levels of the active compound. Like the ara-C analogue, gemcitabine may be an active drug in lymphoproliferative disorders. Institute Seràgnoli

GEMCITABINE l Schedule: l Gemcitabine 1000 -1200 mg/m² (over 30 minutes) on day 1, 8 and 15 of a 28 -day schedule for a total of 3 -6 cycles l All cycles can be delivered on an outpatient basis Institute Seràgnoli

GEMCITABINE l l 13 pretreated patients with PTCL with isolated skin involvement (5 MF, stage IIb-III; 8 unspecified, stage IV) All pretreated with polychemotherapy (CHOP and others) Gemcitabine 1200 mg/m², day 1, 8, 15 cycles for 3 courses 1 CR, 8 PR, 4 NR ZINZANI et al (Ann Oncol 1998) Institute Seràgnoli

GEMCITABINE * TNM classification ** Ann Arbor Staging System ZINZANI et al (JCO 2000) Institute Seràgnoli

GEMCITABINE MF PTCLU Total (n=30) (n=14) (n=44) CR (%) 3* (10) 2** (14) 5 (11, 5) PR (%) 18 (60) 8 (57) 26 (59) CR+PR (%) 21 (70) 10 (71) 31 (70, 5) * 1 with histologic CR ** 1 with histologic CR ZINZANI et al (JCO 2000) Institute Seràgnoli

GEMCITABINE RESPONSE ACCORDING TO PREVIOUS TREATMENTS AND TO DISEASE STATUS No. of pts CR+PR CR (%) PR (%) Relapsed 34 4 (12) 20 (59) 24 (71) Refractory 10 1 (10) 6 (60) 7 (70) Prior regimens: 2 3 4 19 15 10 3 (16) 2 (13) 0 12 (63) 9 (60) 5 (50) 15 (79) 11 (73) 5 (50) ZINZANI et al (JCO 2000) Institute Seràgnoli

GEMCITABINE l Hematological toxicities: l anemia of WHO grade III was observed in 5 -10% of patients; neutropenia of WHO grades III and IV in 20% and 10% of patients, respectively; WHO grade III and IV thrombocytopenia in 20% and 10% of patients, respectively l Non-hematological toxicity: l transient elevations in liver transaminases were observed in 5 -10% of patients; renal and pulmonary toxicity was very rare, WHO grade III-IV less than 1%; flu -like symptoms with headache, fever, myalgias and fatigue occurred in up to 10% of patients; usually, no alopecia occurs during Gemcitabine therapy Institute Seràgnoli

GEMCITABINE SALLAH et al (Br J Haematol 2001) l 10 patients with relapsed or refractory Tcell malignancies (2 CTCL, 2 PLL, 2 nodal PTCL, 2 SLL, 1 ALC, 1 angiocentric LNH) l Gemcitabine at a dose of 1200 mg/m² on day 1, 8, and 15 of each 28 -day cycle l ORR 60% 2 CR (1 PLL, 1 anaplastic) 4 PR (2 CTCL, 1 PTCL, 1 angiocentric) l Median DR: 13. 5 months for CR 16. 2 months for PR Institute Seràgnoli

GEMCITABINE DUVIC et al l (Clinical Lymphoma & Myeloma 2006) 33 patients with relapsed or refractory advanced heavily pretreated CTCL l Gemcitabine at a dose of 1000 mg/m² on day 1, 8, and 15 of each 28 -day cycle for six or more cycles l 2 ALC CD 30+ 31 MF (11 SS) l 3 CR 14 PR l ORR 68% Median DR: < 1 year Institute Seràgnoli

GEMCITABINE ITALIAN CUTANEOUS LYMPHOMA STUDY GROUP l Phase II study of Gemcitabine as primary chemotherapy of patients with advanced CTCL (eventually pretreated only with PUVA or RT) l Population studied: MF and PTCLU with exclusive skin involvement l Conventional dose: 1200 mg/m² on days 1, 8, and 15 of a 28 -day schedule for 6 cycles Cancer 2005 Institute Seràgnoli

GEMCITABINE PATIENTS’ CHARACTERISTICS OF THE STUDY GROUP Institute Seràgnoli

GEMCITABINE TREATMENT OUTCOME Institute Seràgnoli

GEMCITABINE TREATMENT TOXICITY Institute Seràgnoli

GEMCITABINE PROGRESSION FREE SURVIVAL CURVE OF ALL RESPONDER PATIENTS 1, 0 , 9 , 8 , 7 , 6 , 5 , 4 , 3 , 2 , 1 0, 0 0 3 6 9 12 15 18 21 24 months Institute Seràgnoli

GEMCITABINE OVERALL SURVIVAL CURVE OF ALL STUDY POPULATION 1, 0 , 9 , 8 , 7 , 6 , 5 , 4 , 3 , 2 , 1 0, 0 0 6 12 18 24 30 36 42 months Institute Seràgnoli

GEMCITABINE CONCLUSIONS l l l Impressive single agent data Brief treatment Outpatient administration Excellent activity to toxicity ratio Future: l Larger trials to consolidate these data l First-line treatments l In combination with other drugs: l Fludarabine l Oxaliplatin l Campath-1 H Institute Seràgnoli

GEMCITABINE PHASE II STUDY IN PRETREATED CTCL GEMCAM: Gemcitabine 1200 mg/m 2 day 1 -8 -15 Campath-1 H 10 mg (total dose) day 1 -8 -15 every 28 days for a total of 6 cycles Institute Seràgnoli