CLL Biology and Initial Management. Gordon D. Ginder, MD Director, Massey Cancer Center Lipman Chair in Oncology

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1 CLL Biology and Initial Management Gordon D. Ginder, MD Director, Massey Cancer Center Lipman Chair in Oncology

2 CLL- Epidemiology Most common adult leukemia 25-30% in western world Incidence in US 4.5 cases/100,000 Average age of onset 70 years 5 year survival: % % Etiology agents implicated: Pesticides, herbicides, agent orange Genetic 2 to 8- fold increased risk with +FH

3 CLL- Diagnosis 5000 absolute lymphocytosis for >6 months Flow cytometry showing monoclonal population of lymphocytes CD19+, CD20 low, CD5+, CD23+ Kappa or Lambda monoclonal surface Ig Note: Up to 6% of adults > 60 years of age may have benign monoclonal B- lymphocytosis

4 C. Nabhan, S. Rosen. Clinical Review and Education 2014

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8 Micro- environment

9 CLL Biology Genomic Aberrations ~ 80% of patients have at least one genetic abnormality detected by FISH The Good, the Bad, the Ugly and the In Between

10 CLL - Genomic Aberrations The Good IGHV Mutations portend early stage and favorable prognosis. Lack of mutation More aggressive disease, shorter OS (Often use surrogate markers Zap 70, CD38) Del 13q 14 Prevalence 40 60% If sole aberration favorable prognosis In between Trisomy 12 Prevalence 10 20% Generally longer OS but shorter PFS

11 CLL - Genomic Aberrations The Bad Del 11q22 q23 (Often affecting ATM gene) Prevalence ~20%: Shorter OS and PFS The Ugly Del 17p13 or TP53 mutation Prevalence 4-9% Aggressive course, shorter OS, poor response to therapy and lower PFS (If 20% of CLL cells are TP53 del) * All patients should have FISH for 17p

12 CLL Genomic Aberrations Other Mutations G - MYD88 mutations Prevalence 3-5% Often younger patients (Median age 47 years) Favorable OS B - ATM mutations (outside of 11q23 del) More aggressive Shorter OS and PFS B - NOTCH I mutations (Qq43.3) Prevalence 4-10% More advanced stage and shorter time to treatment I - SF3BI mutations Prevalence ~ 10% No clear effect on OS but shorter PFS and refractoriness to Fludara

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14 Standard Diagnostic Workup at MCC H & P CBC (WBC with diff) Lymphocyte panel flow cytometry CD20, CD19, CD5, CD38/CD19 Β- 2 Microglobulin If splenomegaly and bulky peripheral nodes CT scans BM bx only under certain conditions Peripheral Blood or Bone Marrow FISH/Cytogenetics

15 CLL Staging Rai classification (Ca 1975) Binet classification Modified prognostic classification Incorporating biomarkers

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18 CLL Biomarkers Zap 70 - Positivity associated with later stage and more aggressive disease * CD38 - >30% positive correlates with more aggressive disease * Β- 2 Microglobulin > 3.5 mg /L * = Routinely available at MCC/VCUHS

19 Low Risk, 0-2pt, Intermediate risk 3-5, High risk 6-10 C.I. Amaya- Chanaga, L.Z. Rassenti. Best Practice and Research Clinical Haematology 29 (2016) 79-89

20 CLL Therapy When to Treat Rai stage III or IV Bulky, symptomatic adenopathy or splenomegaly Systemic symptoms (Auto- immune anemia or thrombocytopenia) Absolute lymphocytosis level rarely is an indication Even del17p is not an absolute indication outside of a clinical trial

21 CLL Therapy Risk Adapted Approach Age Performance status Co- morbidities Genetic and biological markers

22 Immuno Chemotherapy T. Robak et al. Cancer Treatment Reviews 53 (2017) 70-78

23 D. Jeyakumar, S. O Brien/ Best Practice and Research Clinical Haematology 29 (2016) 2-14

24 First Line Treatment Options in CLL < Age 65 and highly fit FCR (Fludarabine, Cytoxan, Rituxan) BR (Bendamustine, Rituxan) Ibrutinib (del17p) > Age 65 and highly fit BR Ibrutinib (del17p) >Age 70 Low to moderate fitness Obinutuzumab + Chlorambucil Ibrutinib Very low Fitness Anti- CD20 (Rituxan, Obinutuzumab)

25 CLL FCR vs. Ibrutinib + Rituxan Balancing Efficacy and Toxicity FCR High response rate and CR rate Potential for 10 years PFS Toxicity - Marrow toxicity can be long term Ibrutinib High response rate - including del17p/tp53mut Durable response over 4 years Toxicity - Marrow toxicity - modest Rare events Refractory A- fib, Hemorrhage Resistant disease is highly refractory Financial toxicity

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27 CLL Minimal Residual Disease Standardized methods: IGHV Q- PCR Quantitative 4 color FLC Extrapolated from results of MRD after Allo- SCT Eg. Logan et al % vs. 38% PFS if MRD- Insufficient data reported yet on 1 st line CLL Rx and OS Caveats: PFS OS Multiple salvage regimens available

28 Obinutuzumab Rituxan- Type I, Obinutuzumab=Type II K. Tobinai et al. Adv. Ther 2016

29 V. Ortiz- Maldonado, P. Mozas et al. Ther. Adv. Hematol., Vol. 7(6)

30 G.D. te Raa, A.P. Kater. Best Practice and Research Clinical Haematology 29 (2016) 90-99

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32 D. Jeyakumar, S. O Brien/ Best Practice and Research Clinical Haematology 29 (2016) 2-14

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34 CLL Variants Prolymphocytic Leukemia - Morphologically distinct Immature appearing nuclei - More aggressive behavior - Poor response to standard CLL regimens - Treatment Cladribine Alemtuzumab

35 Questions?