Survival and Clinical Aspects for Patients with Chronic Lymphocytic Leukemia in Kermanshah, Iran Mehrdad Payandeh Department of Hematology and Oncology, Kermanshah University of Medical Sciences, Kermanshah, Iran August 18-19, 2016 London, UK

Faculty Medical Researcher Masoud Sadeghi, MSc Edris Sadeghi, MSc Department of Hematologic Malignancies, Medical Oncology Kermanshah University of Medical Sciences Kermanshah, Iran Masoud Sadeghi, MSc This slide lists the faculty who were involved in the production of these slides.

Background Chronic lymphocytic leukemia (CLL), most common leukemia in adults in Western countries but is relatively rare in Asia

Chronic Lymphocytic Leukemia ~ 15,000 new cases per yr Most common adult leukemia Chronic, incurable, mature B-cell neoplasm Most pts present with asymptomatic increase in lymphocyte count Many asymptomatic pts do not initially require therapy Therapy required once symptoms, cytopenias, or large lymphadenopathy occur Slide credit: clinicaloptions.com

CLL: Incidence of Genetic Lesions Treatment naïve CLL[1] (n = 452) CLL8[2] Frontline FC vs FCR (n = 635) CLL3X[3,4] High-Risk AlloSCT (n = 80) CLL2H[5,6] F-Refractory Alemtuzumab (n = 97) TP53mut 5.3 11.5 30.0 39.0 NOTCH1mut 12.6 10.0 14.0 13.4 SF3B1mut 8.6 18.4 26.0 17.5 IGHV UM 32.8 63.0 96.0 79.0 del(17p) 8.4 18.1 30.1 del(11q) 16.0 24.6 36.1 19.4 F, fludarabine. 1. Puente XS, et al. Nature. 2015;526:519-524. 2. Stilgenbauer S, et al. Blood. 2014;123:3247-3254. 3. Dreger P, et al. ASH 2012. Abstract 966. 4. Dreger P, et al. Blood. 2013;121:3284-3288. 5. Schnaiter A, et al. Blood. 2013;122:1266-1270. 6. Schneiter A, et al. ASH 2012. Abstract 710. Slide credit: clinicaloptions.com

Estimate of OS According to Cytogenetics Median OS, yrs NR 13.4 8.5 5.0 Events, n 27 53 41 57 Total, n 155 228 99 101 95% CI -- 12.1-14.7 5.6-11.5 3.4-6.5 Del(13q14) Normal/+12 NOTCH1 M/SF3B1 M/del(11q22-q23) TP53 DIS/BIRC3 DIS 100 80 60 Del(13q14) vs normal/+12 Normal/+12 vs NOTCH1 M/SF3B1 M/del(11q22-q23) NOTCH1 M/SF3B1 M/del(11q22-q23) vs TP53 DIS/BIRC3 DIS P = .0406 P = .0082 P = .0196 Cumulative Probability of OS (%) 40 20 P < .0001 5 10 15 Yrs From Diagnosis Slide credit: clinicaloptions.com Rossi D, et al. Blood. 2013;121:1403-1412.

Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies BCR signaling is required for tumor expansion and proliferation BCR signaling up-regulated in CLL New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk BCR LYN SYK Idelalisib Duvelisib Pilaralisib ┬ BCR, B-cell antigen receptor; BTK, Bruton’s tyrosine kinase; GSK-3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; NF-kβ, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; PLC, phospholipase C; Syk, spleen tyrosine kinase. ┬ PI3K delta Ibrutinib BTK PLCγ2 AKT GSK-3 NF-kβ pathway ┬ PKC mTOR Everolimus p70s6k elf4E Slide credit: clinicaloptions.com

Frontline CLL Therapy in 2016 Clinical trial should be considered for all pts with CLL Population Initial Therapy Younger, fit pts FCR (especially mutated IGHV) Older pts with comorbidities Bendamustine/Rituximab Chlorambucil/Obinutuzumab Chlorambucil/Ofatumumab Ibrutinib Pts with del(17p) or TP53 mutation AlloSCT? Slide credit: clinicaloptions.com

CLL Therapy in the Future Clinical trial should be considered for all pts with CLL Population Initial Therapy Relapsed Therapy Younger, fit pts with low risk FCR (especially mutated IGHV) Ibrutinib Idelalisib + R Ibrutinib + BR* Idelalisib + BR* Venetoclax* Older pts with comorbidities Bendamustine/rituximab Chlorambucil/obinutuzumab Chlorambucil/ofatumumab Pts with del(17p) or TP53 mutation AlloSCT? Venetoclax *Not currently approved by the FDA. Slide credit: clinicaloptions.com

Materials and Methods In this study, we did a retrospective analysis from 109 CLL patients that referred to Clinic of Hematology- Oncology, Kermanshah, Iran, between January 2006 and March 2014.

Materials and Methods For all of patients were calculated sex, age, survival, AIHA, Evan’s syndrome, lymphadenopathy, organomegaly, B symptoms, white blood cell, hemoglobin and platelet by patient or pathology reports or laboratory tests.

Materials and Methods Overall survival (OS) was calculated as the time from diagnosis to death or last contact. Curve of OS was plotted by Kaplan- Meier plot in Graph Pad prism 5 Software in a five-year period (March 2009 - March 2014) with completing a two-year period and curves of OS for male and female were compared by log-rank test.

Table 1. The baseline characteristics in the patients at time of diagnosis of chronic lymphocytic leukemia (n=109)

Patients Results Of all patients, 22 patients (20.8%) were treated with IVIG and 46 patients (43.3%) were treated with vaccine of the Flu.

Patients Results Of 109 patients with CLL, 29 patients died and 23 patients were lost to follow-up before completing a two-year period and should therefore be excluded from the analysis.

Table 2. The Primary Clinical Variables in CLL Patients

Table 3. Mean age and Percentage of Male for Chronic Lymphocytic Leukemia in Asian Countries

Table 4. Mean overall survival and survival rate (5- year period) for chronic lymphocytic leukemia in Asian countries

Treatment Results Survival rate for patients was 64% and mean of overall survival for 5-year period was 38.5 months.

Treatment Results There is a significant difference between sex and OS rate (P=0.018, 95% CI of ratio 1.14-4.65, Hazard Ratio (HR) 2.31).The survival rate for females is 78% and for males is 53.5%.

Figure 1. The 5-year overall survival for chronic lymphocytic leukemia for all of patients

Figure 2. The 5-year overall survival rate for chronic lymphocytic leukemia by sex

Therefore, it is probably that life conditions (smoking, ,hard work, etc) in males comparing with females have more affect on the appearance and mortality of CLL. In Western Iran (Kermanshah) majority of males work more than females in hard condition and smoking in males is more.

In previous studies were reported that smoking (Muirhead et al In previous studies were reported that smoking (Muirhead et al., 2009) and quality of life (Shanafelt et al., 2009) influence on development of CLL.

Conclusion First of all, CLL is a rare case of malignancy in Asian countries and lymphadenopathy and organomegaly, immunodeficiencies and the Flu virus are the main complaints in CLL. Second, in these countries, CLL is more in males and in ages of above 60 years. Third, here is not relationship between sex and age in patients. At last, OS rate in females is higher than males.

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