1. POST-ASH 2011 TALK Anna Schuh Consultant

3. 2865 Obatoclax in Combination with Fludarabine and Rituximab (FR) Is Well-Tolerated and Shows Promising Clinical Activity in Relapsed CLL/SLL J Brown, Dana Farber 3 hour infusions on day 1 and 3 Well tolerated ORR 54% Phase III with FCR backbone planned TARGETING THE CELL DEATH MACHINERY 1. Small molecule mimetic of the BH3 domain of Bcl-2 family proteins

4. Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL), T Kipps, La Jolla orally bioavailable, small molecule, binds with high affinity to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis FCR or BR as per standard protocols Navitoclax was administered on D3-5 cycle 1 and D1-3 subsequent cycles for 1 year or until PD Main AEs/ SAEs: cytopenias, in particular thrombocytopenia ORR:81%,responses also in TP53 deleted patients Phase III on-going 1. Small molecule mimetic of the BH3 domain of Bcl-2 family proteins, cont.

5. 2858 A Pilot Phase II Study of the Lyn Kinase Inhibitor Bafetinib in Patients with Relapsed or Refractory B Cell Chronic Lymphocytic Leukemia T Kadia, MD Anderson limited Src family kinase inhibitor targeting BCR/ABL, Lyn, and Fyn kinases oral, bd administration, continuously until PD 16 patients Median age : 71; 9 had del17p; Median 3 prior treatments (1-6) Well tolerated, reversible LFT rise 7/11 evaluable patients had PR; 2xSD; 2xPD Blocking the proximal B-cell receptor activated protein tyrosine kinases The three proximal PTKs mediating BCR signaling: Lyn, Syk and Btk all found to be over-expressed and constitutively activated in CLL cells compared to normal B lymphocytes Inhibitors to these kinases induce apoptosis of CLL cells in vitro

6. 983 The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II S O’Brian Oral, dose finding study, administered daily for 28-day cycles until progression of disease. 38% SAEs, 10% related to IMP lymphocytosis in first 2 months, resolving afterwards ORR: 70% with 10.2 months median follow-up 8% have progressive disease Blocking the proximal B-cell receptor activated protein tyrosine kinases, cont.

7. Blocking the PI-3K/Akt/mTOR pathway PI-3K activity is increased in CLL cells compared to normal B cells Inhibition of PI-3K induces apoptosis in CLL cells Unselective PI-3K inhibitors cause hyperglycemia CAL-101 is an orally available selective inhibitor of PI-3K delta isoform which is exclusively expressed in haemopoietic cells Original Phase I data presented at ASH 2010: CAL- 101 was given monthly over 1 year, lymphocyte re-distribution phenomenon

8. GS1101 bd cont. R 375mg/m2 D1 Weekly X8 GS1101 bd cont. B 90mgs/m2 D1-2 6 months GS1101 bd cont. R 375mg/m2 D1 B 90mgs/m2 D1-2 6 months 1787 A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Jeff Sharman, MD Anderson Less lymphocyte mobilization (due to chemo-comb)

10. PHASE III in Oxford: Randomized, double blind placebo-controlled study evaluating efficacy and Safety of GS-1101 in combination with BR as therapy for patients with previously treated CLL Prior treatment with >/=1 chemotherapy Documentation of CLL progression <24 months since completion of the last prior CLL 1:1 randomization oral bd administration, continously until unacceptable toxicity or progressive disease or other reasons

11. A Randomized, Multicenter, Phase 3 Study of the Bruton’s Tyrosine Kinase (Btk) inhibitor PCI-32765 versus Ofatumumab in subjects with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with Relapsed or Refractory Disease Inclusions: 1:1 randomization Disease progression following, or failure to respond during, a nucleoside analog- based chemo-immunotherapy regimen (at least two cycles). Must not be appropriate candidates for retreatment with nucleoside analog-based therapy, as defined as meeting at least one of the following criteria: A progression-free interval of less than 3 years from response to nucleoside analog-based chemoimmunotherapy Age ≥70 years or the presence of co-morbidities that would place the subject at an unacceptable risk of treatment-related toxicity with nucleoside analog-based therapy. History of nucleoside analog-associated autoimmune anemia or thrombocytopenia Pretreatment FISH with ≥20% cells with del 17p 12 infusions of Ofa vs 420mgs of PCI-32765 daily for 3 years or until PD

12. Targeting the microenvironment: Lenalidomide exact mechanism of action is unclear thought to inhibit angiogenesis changes the cytokine micro milieu modulates the immune system by enhancing cytotoxic T cells and natural killer (NK) cell activity severe toxicity (tumor lysis, septic shock) when using a starting dose of lenalidomide 10 mg/day Tumor flare Phase I study of lenalidomide with fludarabine and rituximab combination was terminated early due to excessive toxicity even at the lowest dose of fludarabine and lenalidomide, with idiosyncratic febrile syndrome and persistent myelosuppression

13. 291 Lenalidomide and Rituximab for the Initial Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) ­ A Multicenter Study of the CLL T Kipps et al Targeting the microenvironment

14. 291 Lenalidomide and Rituximab for the Initial Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) ­ A Multicenter Study of the CLL T Kipps et al; cont.

15. 1788 Combination Therapy with Ofatumumab and Lenalidomide in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): Results of a Phase II Trial, A Ferrajoli, MD Anderson Ofa for 24 months, Lena 10mgs for 24 months, no DVT prophylaxis 34 evaluable patients, median age: 62 (34-82), no of prior treatments: 2, ORR: 65% 22 responders Of the 22 responders, 13 are continuing on therapy with ongoing response (median time on therapy 14 months, range 8–20 months) Despite ongoing response, 7 pts discontinued therapy due to: transition to HSCT (3 pts; pulmonary embolism (1 pt), recurrent zoster infection (1 pt) and physician choice (2 pts). Two pts discontinued therapy because of loss of response after 12 and 18 months of treatment, respectively.

16. 776 International Phase III Study of Chlorambucil Versus Fludarabine As Initial Therapy for Waldenstrom’s Macroglobulinemia and Related Disorders: Results in 414 Patients on Behalf of FCG CLL/ WM, GOELAMS, GELA, NCRI, ALLG, Veronique Leblond et al F by oral route is a safe and effective ambulatory treatment in WM and close related disorders patients, even in the elderly and more effective than CBL with a duration of response over 3 years. An unexpected finding was a statistically higher number of second malignancies in the C arm and we cannot rule out an oncogenic role of CBL in this setting. Of note, we stress that it is the first time that a front- line treatment has a significant impact on overall survival in WM patients.