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

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

Masked DNA chain termination. GEMCITABINE Masked DNA chain termination. 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

All cycles can be delivered on an outpatient basis GEMCITABINE Schedule: 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 All cycles can be delivered on an outpatient basis Institute Seràgnoli

All pretreated with polychemotherapy (CHOP and others) GEMCITABINE 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 1200mg/m², day 1, 8, 15 cycles for 3 courses 1 CR, 8 PR, 4 NR ZINZANI et al (Ann Oncol 1998) Institute Seràgnoli

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

MF (n=30) PTCLU (n=14) Total (n=44) CR (%) 3* (10) 2** (14) 5 (11,5) GEMCITABINE MF (n=30) PTCLU (n=14) Total (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

RESPONSE ACCORDING TO PREVIOUS TREATMENTS AND TO DISEASE STATUS 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 3 (16) 2 (13) 12 (63) 9 (60) 5 (50) 15 (79) 11 (73) ZINZANI et al (JCO 2000) Institute Seràgnoli

Hematological toxicities: GEMCITABINE Hematological toxicities: 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 Non-hematological toxicity: 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

SALLAH et al (Br J Haematol 2001) GEMCITABINE SALLAH et al (Br J Haematol 2001) 10 patients with relapsed or refractory T-cell malignancies (2 CTCL, 2 PLL, 2 nodal PTCL, 2 SLL, 1 ALC, 1 angiocentric LNH) Gemcitabine at a dose of 1200mg/m² on day 1, 8, and 15 of each 28-day cycle 2 CR (1 PLL, 1 anaplastic) 4 PR (2 CTCL, 1 PTCL, 1 angiocentric) Median DR: 13.5 months for CR 16.2 months for PR ORR 60% Institute Seràgnoli

DUVIC et al (Clinical Lymphoma & Myeloma 2006) GEMCITABINE DUVIC et al (Clinical Lymphoma & Myeloma 2006) 33 patients with relapsed or refractory advanced heavily pretreated CTCL Gemcitabine at a dose of 1000mg/m² on day 1, 8, and 15 of each 28-day cycle for six or more cycles 2 ALC CD30+ 31 MF (11 SS) 3 CR 14 PR Median DR: < 1 year ORR 68% Institute Seràgnoli

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

PATIENTS’ CHARACTERISTICS OF THE STUDY GROUP GEMCITABINE PATIENTS’ CHARACTERISTICS OF THE STUDY GROUP Institute Seràgnoli

GEMCITABINE TREATMENT OUTCOME Institute Seràgnoli

GEMCITABINE TREATMENT TOXICITY Institute Seràgnoli

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

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

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

PHASE II STUDY IN PRETREATED CTCL GEMCITABINE PHASE II STUDY IN PRETREATED CTCL GEMCAM: Gemcitabine 1200 mg/m2 day 1-8-15 Campath-1H 10 mg (total dose) day 1-8-15 every 28 days for a total of 6 cycles Institute Seràgnoli