1. Agne Paner, MD Assistant professor of Medicine RUSH University Medical Center

2. Blood Smear in CLL

3. Chronic Lymphocytic Leukemia Most prevalent type of adult leukemia 30% of all leukemias, ~15,000 cases / year Identical to SLL –small lymphocytic lymphoma Median age at diagnosis is 72 years Ries LAG et al. http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission. Accessed September 17, 2007; Stilgenbauer S. Hematology. 2004;1:164-170.

4. Chronic Lymphocytic Leukemia Often asymptomatic at diagnosis Median survival Low risk (Rai 0): > 10 years Intermediate risk (Rai I / II): 5 - 7 years High risk (Rai III / IV): 1 - 3 years Ries LAG et al. http://seer.cancer.gov/csr/1975_2004/, based on November 2006 SEER data submission. Accessed September 17, 2007; Stilgenbauer S. Hematology. 2004;1:164-170.

5. NCI-WG Indications to Treat Constitutional symptoms referable to CLL Progressive marrow failure Autoimmune anemia +/- thrombocytopenia poorly responsive to corticosteroids Massive or progressive splenomegaly Massive or progressive lymphadenopathy Progressive lymphocytosis Cheson BD et al. Blood. 1996;87:4990-4997.

6. Traditional Prognostic Factors Advanced stage at diagnosis Short lymphocyte doubling time Diffuse bone marrow infiltration Older age, males CLL / PLL Early relapse Rozman C, Montserrat E. N Engl J Med. 1995;333:1052-1057; Cheson BD et al. Blood. 1996;87:4990-4997.

7. Newer Prognostic Factors ParameterPoor prognostic marker  2M Increased FISHdel11q, del17p VH mutation status CD38 ZAP-70 Unmutated Positive Abdominal CTAbnormal

8. 8 1960s1970s1980s1990s2000s Chemo-immunotherapy Alemtuzumab Bendamustine Alkylating agents: Chlorambucil Cyclophosphamide Purine nucleosides: Fludarabine Pentostatin Cladribine Purine nucleosides and alkylators Frontline treatment for CLL Treatment Options

9. Commonly used regimens in frontline treatment of CLL: Fludarabine + cyclophosphomide + Rituximab, FCR Bendamustin + Rituximab, BR Fludarabine + Rituximab, FR Chlorambucil + anti-CD20

10. Treatment of relapsed CLL: Majority of patients relapse Same indications for retreatment as for initial therapy Refractory CLL - relapse within 6 months of initial therapy Retreatment with initial regimen reasonable if remission longer than anticipated PFS and well tolerated Subsequent remission usually get shorter

11. Defining early relapse RegimenRemission suboptimal if less than: Chlorambucil + anti-CD20 antibody 1 year Fludarabine + Rituximab2 years Bendamustin + Rituximab2 years Fludarabine + cyclophosphomide + Rituximab 3 years

12. Novel agents, clinical trials and/or bone marrow transplant should be considered for patients with early relapsed or refractory CLL

13. 2013-2014 FDA approved 3 new agents: Inhibitors targeting B-cell signaling pathways: Ibrutinib Idelalesib with Rituximab Novel anti-CD20 monoclonal antibody: Obinutuzumab with Chlorambucil

14. Ibrutinib Bruton tyrosine kinase inhibitor For patients with CLL who have received at least one prior therapy For upfront treatment of patients with CLL with 17p deletion.

15. Resonate trial for relapsed CLL Outcomes IbrutinibOfatumumab PFSNot reached at 9.4mo f/u 8.1 months OS at 12months 90%81% RR42%4% Similar effects in refractory CLL and del17p Byrd JC et al. N Engl J Med 2014;371:213-223.

16. Idelalesib P13Kdelta inhibitor FDA approved in combination with Rituximab for relapsed CLL When rituximab alone would be considered appropriate therapy due to co-morbidities.

17. Idelalesib and Rituximab in relapsed CLL Outcomes Idelalesib+RPlacebo+R PFSNot reached5.5 months OS at 12months 92%80% RR81%13% Furman RR et al. N Engl J Med 2014;370:997-1007.

18. Obinutuzumab CD20-directed cytolytic antibody In combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia

19. Obinutuzumab plus Chlorambucil in CLL with comobidities OutcomeObinutuzumab+ Chlorambucil Rituximab+ Chlorambucil PFS26.7months16.3months11 months RR77%65%31% Goede V et al. N Engl J Med 2014;370:1101-1110.

20. CLL with del17p Ibrutinib Allotransplantation Responses comparable to standard risk patients 1-year PFS of 79% Should be considered in a first remission or at first relapse: 2y OS 25% for non-transplant approach and 64% for transplanted patients with CLL del17p at first relapsed Dreger, P CLL3X trial Blood 2010; 116:2438-47

21. Future directions/Clinical trials AgentClinical trial IbrutinibIbrutinib plus Rituximab compared to FCR in frontline CLL BR +/- Ibrutinib in relapsed CLL Ibrutinib plus Lenalidomide in relapsed CLL Ibrutinib alone, Ibrutinib and Rituximab, Rituximab and bendamustin for older patients with CLL Ibrutinib plus FCR for younger patients IdelalisibBR +/- idelalisib Idelalesib + Ofatumumab ObinutuzumabLenalidomide + Obinutuzumab Idelalesib + obinutuzumab versus chlorambucil + obinuzutumab