UPDATES IN CHRONIC LYMPHOCYTIC LEUKEMIA TANYA SIDDIQI, MD

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1 UPDATES IN CHRONIC LYMPHOCYTIC LEUKEMIA TANYA SIDDIQI, MD

2 DISCLOSURE Speaker s bureau: Pharmacyclics, Janssen, Seattle Genetics, Astra Zeneca Consultant: Juno therapeutics, Astra Zeneca, BeiGene, Pharmacyclics

3 Epidemiology Chronic lymphocytic leukemia (CLL) is a low grade leukemic lymphocytic lymphoma; small lymphocytic lymphoma (SLL) is a nodal form of the same disease CLL/SLL is the most common hematological malignancy in the Western world; incidence is ~5/100,000 persons per year in the US Median age at diagnosis ~72 years Male predominance; higher in Caucasians ~10% patients with a family history of some lymphoma Exact etiology is unknown Muller-Hermlink HK, et al. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours in Haematopoietic and Lymphoid Tissues. Lyon, France. IARC press, 2001:

4 Diagnosis and workup Rule out masquerading other lymphoma Incidental diagnosis History and physical examination; trend of CBCs; B symptoms (fever, night sweats, unexplained weight loss); severe fatigue Review CBC/differential, peripheral blood smear, flow cytometry/immunophenotyping: peripheral blood lymphocytosis with the presence of 5000 monoclonal B- cells/ul is required Bone marrow biopsy typically not needed for diagnosis

5 Monoclonal B-lymphocytosis (MBL) Presence of monoclonal lymphocytosis but with <5000 B- cells/ul in the peripheral blood and no accompanying lymphadenopathy or organomegaly by physical examination or radiographical imaging, cytopenias or disease-related symptoms is defined as MBL Incidence in the US is 3% Progression to CLL/SLL can 1-2% per year

6 Prognostic markers in CLL/SLL Cytogenetics: Del13q Trisomy 12 Normal Del11q Del17p Del6q TP53 mutations Notch1 mutations SF3B1 mutations IGHV mutation status ZAP70 CD38 Lymphocyte doubling time (LDT) β2 microglobulin Stage of disease by Rai or Binet staging

7 CLL Staging Rai stage Risk category Clinical features 0 Low Lymphocytosis alone 1 Intermediate Lymphadenopathy 2 Intermediate Hepato/splenomegaly 3 High Anemia (<11g/dl) 4 High Thrombocytopenia (<100,000/L) Binet stage A B C Clinical features HGB 10 g/dl, platelets 100/L, <3 areas of lymphadenopathy/ organomegaly* HGB 10 g/dl, platelets 100/L, 3 areas of lymphadenopathy/ organomegaly* Anemia (<10g/dl), thrombocytopenia (<100,000/L), or both *nodal areas: cervical [head and neck], axillary, inguinal (including femoral lymph nodes), spleen, liver

8 Who needs treatment? International workshop on CLL (iwcll) guidelines for treatment initiation Hallek M, et al. Blood :

9 iwcll guidelines for treatment initiation progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia massive ( 6cm below left subcostal margin), progressive, or symptomatic splenomegaly massive ( 10cm in longest diameter), progressive, or symptomatic lymphadenopathy progressive lymphocytosis with an increase of >50% over a 2 month period or LDT of <6 months autoimmune hemolytic anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy constitutional symptoms defined as 1 of the following: (i) unintentional weight loss of 10% within the previous 6months (ii) significant fatigue (ECOG PS 2;inability to work or perform usual activities) (iii) fevers >100.5F or 38C for 2 weeks without other evidence of infection (iv) night sweats for >1 month without evidence of infection

10 Frontline therapeutic options

11 German CLL study group (GCLLSG): frontline treatment CLL4 study: FC vs. fludarabine alone CLL8 study: FCR vs. FC Subgroup with exceptionally good outcome has right age/fitness, mutated IGHV genes and no del17p/del11q (plateau after 4 yrs; MRD neg 6 yrs later) Eichhorst BF, et al. Hematol J 2006; 107: Hallek M, et al. Lancet 2010; 376: Eichhorst B, et al. Blood 2014; 124: abs.19

12 CLL8 study: FCR vs. FC

13 ASH2016 MDACC experience with FCR Thompson et al., Blood, 2016

14 German CLL study group (GCLLSG): frontline treatment CLL4 study: FC vs. fludarabine alone CLL8 study: FCR vs. FC Subgroup with exceptionally good outcome has right age/fitness, mutated IGHV genes and no del17p/del11q (plateau after 4 yrs; MRD neg 6 yrs later) CLL10 study: FCR vs. BR Eichhorst BF, et al. Hematol J 2006; 107: Hallek M, et al. Lancet 2010; 376: Eichhorst B, et al. Blood 2014; 124: abs.19

15 CLL10: FCR vs. BR Phase 3 randomized trial, fit CLL patients (ages yrs) with advanced stage disease, previously untreated, no 17p deletion N = 564; 6 cycles of either regimen; median followup 37.1 months FCR BR P-value ORR 95% 96% 1.0 CR 40% 31% [higher MRD negative CRs in FCR arm] Median PFS 55.2 months 41.7 months [better in <65 years old] OS at 3 years 91% 92% Severe neutropenia Severe infections 84% 59% < % 25% [especially in older pts] Eichhorst B, et al. Lancet Oncol 2016; 17:

16 CLL Disease Progression Curve Minimal residual disease (MRD) defined cutoff Adapted from:

17 Targeted therapies

18 Ibrutinib FDA approved Ph1b/2 study of 85 CLL pts, mostly high risk ORR of 71% (2 CR, 34 PR) % PR-L At 26 months, estimated PFS was 75% and OS 83% Well tolerated Byrd JC, et al. N Engl J Med 2013; 369: 32-42

19 Ibrutinib: RESONATE trial Phase 3 trial of ibrutinib (420mg po daily) vs. ofatumumab in r/r CLL N = 391 ORR 42.6% (+20% PR-L) vs. 4.1% (p<0.001) Median PFS not reached (88% PFS at 6 months) vs. 8.1 months (p<0.001) At 12 months, OS 90% (ibru) vs. 81% (ofa) (p=0.005) Byrd JC, et al. N Engl J Med 2014; 371:

20 RESONATE trial: 5 year update Progression-Free Survival Overall Survival Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57% NR, not reached. 5-year update, O Brien et al. ASH 2016

21 Best Response in Patients With High-Risk Abnormalities 100% 80% 60% R/R del11q (n=35) 97% 9% R/R Unmutated IGHV (n=79) 90% R/R Complex Karyotype (n=41) 90% 9% 7% R/R del17p (n=34) 79% 6% CR PR PR-L 40% 86% 77% 76% 65% 20% 3% 4% 7% 9% 0% Median DOR, 38.7 (0.0+ to 65.3+) 53.2 (0.0+ to 65.5+) 38.7 (0.0+ to 65.5+) 30.6 (0.0+ to 65.3+) months (range) Median followup, months 55 (1+ 67) 49 (1+ 67) 55 (1 67) 47 (1 67) (range) NR, not reached. 5-year update, O Brien et al. ASH 2016

22 Ibrutinib: RESONATE-2 trial Ph3, international, open label, randomized trial of ibrutinib vs. chlorambucil in previously untreated older CLL/SLL patients N = 269 Median age = 73 years ORR 86% vs. 35% (p<0.001) Significant improvement in EFS, PFS and OS with single agent ibrutinib compared to Clb Burger JA, et al. N Engl J Med 2015 Dec 17;373(25):

23 RESONATE-2 update PFS was significantly improved for ibrutinib across high-risk subgroups, including del11q and unmutated IGHV gene OS analysis resulted in 2-yr survival rate estimates of 95% (ibr) vs. 84% (clb) ORR was 92% with ibr vs 36% with clb (P<0.0001); CR/CRi within the ibr arm improved from 11% at 18.4 mo to 18% with longer follow-up of 28.6-mo RESONATE-2 update, Barr et al.ash2016

24 Other targeted therapies Idelalisib - FDA approved but further trials halted due to toxicities Copanlisib FDA approved for rel/ref CLL; IV Duvelisib - FDA approved for rel/ref CLL Umbralisib Phase 3 trials ongoing in CLL; much better safety profile Venetoclax FDA approved in del17p CLL and rel/ref CLL Acalabrutinib in phase 3 trials ongoing in CLL; FDA approved for mantle cell lymphoma Zanubrutinib studies ongoing in MCL, MZL, CLL, WM

25 ASH 2018 update (frontline therapies)

26 Abstract 6 Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) age 65 years with previously untreated, symptomatic CLL Between 12/9/2013 and 5/16/2016, 547 pts were registered and randomized (Arms 1: 183, 2: 182, and 3: 182) Median age=71 years; 67% were men High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28% median follow-up of 32 months Woyach J, et al. ASH 2018

27 Abstract 6 ( cont.): median PFS was 41 mo in Arm 1 and has not been reached in Arms 2 or 3 (Arm 2 to 1 p<0.0001; Arm 3 to 1 p<0.0001; Arm 3 to 2 p=0.48) ibrutinib produces superior PFS to standard CIT in older pts with CLL and justifies it as a standard of care treatment for pts age 65 and older. The addition of rituximab does not prolong PFS with ibrutinib. Woyach J, et al. ASH 2018

28 Abstract 6 (cont.): no significant differences in OS among arms (p=0.87), median OS has not been reached for any arm, and 2-year OS estimates were 95%, 90%, and 94% in Arms 1, 2, and 3, respectively Grade 3+ treatment-emergent AEs were seen in 428 of 537 evaluable pts with 61%, 41%, and 38% of pts experiencing Grade 3+ heme AEs (p<0.0001) and 60%, 72%, and 71% of pts experiencing Grade 3+ non-heme AEs (p=0.03) in Arms 1, 2, and 3 respectively Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) pts (p=0.07); unexplained or unwitnessed death was seen in 2 (1.1%), 7 (3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively Woyach J, et al. ASH 2018

29 Abstract 691 Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 illuminate international, open-label, randomized phase 3 study previously untreated CLL/SLL requiring treatment 65 years of age or were <65 years old with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 ml/min, and/or del(17p) or TP53 mutation) 229 pts randomized 1:1 to receive ibr (420 mg once daily continuously) with G for a total of 6 cycles (n=113), or clb with G for 6 cycles (n=116) Median age = 71 years (range, 40-87) 65% of pts had high-risk genomic features median follow-up = 31.3 mo Moreno C, et al. ASH 2018

30 Abstract 691 (cont.): Ibr-G resulted in superior PFS compared with clb-g (median not reached [NR] vs 19.0 mo (P<0.0001) PFS benefit with ibr-g was consistent across subgroups examined Response rates and depth of remission (CR and undetectable MRD) were also higher with ibr-g Combination therapy with ibr-g was tolerable With ~3 yrs of follow-up, 70% of pts in the ibr-g arm remain on single-agent ibr Moreno C, et al. ASH 2018

31 Late Breaker Abstract-4 A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912) treatment-naive individuals with CLL who were age 70 and required therapy Patients with deletion 17p- were excluded 529 pts were randomized in a 2:1 ratio to receive ibrutinib (420 mg/day until disease progression) and rituximab for 6 cycles starting in cycle 2 (n = 354) OR 6 courses of intravenous FCR (n = 175) 19 patients did not start protocol therapy median follow-up of 33.4 months Shanafelt T, et al. ASH 2018

32 LBA-4 (cont.): The combination of ibrutinib and rituximab provides superior PFS (p<0.0001) and OS (p<0.0003) relative to FCR for patients with previously untreated CLL age 70 Shanafelt T, et al. ASH 2018

33 LBA-4 (cont.): Superior PFS for IR was independent of age, sex, performance status, disease stage or the presence/absence of del11q23 IR was also superior to FCR for IGHV unmutated patients (p<0.0001) but not IGHV mutated patients (p=0.07) FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 44% vs. IR: [23%]; p<0 0001) and infectious complications (FCR: 17.7% vs. IR: 7.1%; p<0.0001) Shanafelt T, et al. ASH 2018

34 Ibrutinib+FCG (MDACC) Dr. Nitin Jain Ph2 study in younger, previously untreated patients with IGHV-M N=43 (1 was later found to have IGHV-U); med age 60 yrs; no del(17p)/ TP53 mutation ifcg x 3 cycles and time limited ibrutinib; median followup 18.6 mo ORR 100% at 3 months (17 CR/Cri, all MRD-U; 25 PR); 38/42 (90%) achieved U-MRD in BM at 3 months Responses continue to improve over time (6 months (n=35): CR/CRi 74%, U-MRD 94%; 12 months (n=28): CR/CRi 86%, U-MRD 100%) All 28 pts who reached the 12 month time-point were U-MRD and stopped ibr; all 28 maintain U-MRD status at a median follow-up of 10.1 months (range, ) after stopping ibr without progression ifcg achieves high rate of U-MRD in previously-untreated patients with CLL with IGHV-M CLL. No patient has progressed and all patients who have stopped ibrutinib maintain U-MRD status. Manageable toxicities

35 Ibrutinib + venetoclax (MDACC) Dr. Nitin Jain Phase 2 trial in previously unteated and rel/ref CLL Previously untreated cohort = 80; median age was 65 yrs (26-83) All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age 65 years (yrs) Ibrutinib x3 cycles then venetoclax ramp up started Ibrutinib continues indefinitely if MRD positive BM at 2 yrs but venetoclax stops at 2 yrs median follow-up = 9.6 months After 3 months of IBR monotherapy, the majority pts were in PR; after addition of VEN, increasing proportions of pts achieved CR/CRi and BM U-MRD remission; no pt has had CLL progression Responses were noted in older adults and across all high-risk subgroups Adverse event profile was similar to what has been reported individually with IBR and VEN.

36 Relapsed/refractory therapeutic options

37 Murano trial update: ASH Dr. John Seymour Venetoclax + rituximab (VR) vs. BR x6 cycles [V continued for 2 yrs] Randomized ph3 trial for rel/ref CLL 389 pts were enrolled in VenR (n=194) or BR (n=195) arms superior PFS of VenR over BR shown in ASH 2017 Med followup now 36 months With all pts off treatment, continued substantial benefit was observed with VenR, with PFS and OS superior to BR no new safety signals; most pts were able to complete treatment. rate of CLL progression in the first 12 mo after Ven completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration

38 Ibrutinib + venetoclax (CLARITY trial) Dr. Peter Hillmen Ph2 trial N = 54 10/51 (20%) of patients had 17p del, 13/54 (25%) 11q del (but not 17p), and 40/53 (75%) had unmutated IGVH genes Ibrutinib for 8 weeks then venetoclax ramp up Stopping options built in if MRD neg After 6 months of combined ibrutinib plus venetoclax, undetectable MRD was achieved in 19/49 (39%) patients in peripheral blood (PB) and 12/49 (24%) in bone marrow (BM) After 12 months of combined therapy all patients had responded by IWCLL criteria and 23/40 (58%) had achieved a complete remission (CR or CRi) undetectable MRD (MRD4) was achieved in 23/40 (58%) patients in PB and 17/41 (41%) in BM

39 Cellular therapy Allogeneic hematopoietic cell transplantation N=694 (retrospective) High risk disease 2 yr-nrm 28% 5 yr EFS 37% CAR-T cells Schetelig J, et al. ASH 2015 abs

40 CD19 specific CAR-T cells in CLL N = 14; median cell dose = 7.5x10^8 cells 4 CRs (29%), 4 (29%) PRs, ORR 57% CAR-T cells detectable 3 yrs later in some Ph2 randomized study ongoing to determine best cell dose (n=18, ORR 39%, CR 17%) Expected toxicities: B cell aplasia, delayed TLS and CRS Porter D, et al. Blood 2013; ASH abs Porter D, et al. Blood 2013; ASH abs. 873

41 CD19 CAR-T cells (JCAR014) in ibrutinib-refractory CLL N = 24, median age 60 yrs MTD 2x10^6 CAR-T cells/kg; CD8+:CD4+ CAR-T cells 1:1 19 ibrutinib ref, 3 ibrutinib intolerant, 2 had not progressed on ibrutinib; 6 were ref to venetoclax; 23 had complex karyotype and/or del17p 20 pts (83%) had CRS and 8 pts (33%) had neurotoxicity ORR at 1 month in 19 of 20 restaged pts who had received Flu/Cy and CAR-T cells was 74% (4/19 CR, 10/19 PR) 15/17 patients (88%) with marrow disease before CAR-T cells had no disease by flow cytometry after CAR-T cells; 12 underwent deep IGH sequencing and 7 had no malignant IGH sequences detected in marrow Absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% progressionfree survival and overall survival (median 6.6 months follow-up) after CAR-T cell immunotherapy Turtle C, et al. J Clin Oncol 2017; 35 (26):

42 ASH ABSTRACT #300 Rapid MRD-negative Responses in Patients With Relapsed/Refractory CLL Treated With Liso-cel, a CD19-Directed CAR T-cell Product: Preliminary Results From TRANSCEND CLL 004, A Phase 1/2 Study Including Patients With High-risk Disease Previously Treated With Ibrutinib Tanya Siddiqi, 1 Jacob D. Soumerai, 2 William G. Wierda, 3 Jason A. Dubovsky, 4 Heidi H. Gillenwater, 4 Lucy Gong, 4 Alan Mitchell, 4 Jerill Thorpe, 4 Lin Yang, 4 Kathleen A. Dorritie 5 1 City of Hope National Medical Center, Duarte, CA, USA; 2 Center for Lymphoma, Massachusetts General Hospital, Boston, MA, USA; 3 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4 Juno Therapeutics, a Celgene Company, Seattle, WA, USA; 5 University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

43 Transcend CLL 004 Phase 1 study design (NCT ) Key Eligibility Relapsed/refractory CLL/SLL Failed or ineligible for BTKi a High-risk disease b : failed 2 prior therapies Standard-risk disease: failed 3 prior therapies ECOG PS 0 1 Dose-escalation: mtpi-2 Design c 28-day DLT period Primary Objective Determine recommended dose Safety Exploratory Objectives Antitumor activity Pharmacokinetic profile Dose Level Dose Treated (N=16) CAR+ T cells CAR+ T cells CAR+ T cells 10 a Failure defined as SD or PD as best response, or PD after previous response, or discontinuation due to intolerance (unmanageable toxicity). Ineligibility defined as requirement for full-dose anticoagulation or history of arrhythmia. b Complex cytogenetics abnormalities, del(17p), TP53 mutation, or unmutated IGHV. c Guo W, Wang SJ, Yang S, et al. Contemp Clin Trials. 2017;58: BTKi, Bruton's tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; DLT, doselimiting toxicity; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IGHV, immunoglobulin heavy chain variable region; mtpi, modified toxicity probability interval; PD, progressive disease; SD, stable disease; SLL, small lymphocytic lymphoma. Data on file 21 September Siddiqi T et al. ASH Abstract 300.

44 Baseline characteristics Characteristic All Patients (N=16) Age, median (range) y 64.5 (51 76) Male, n (%) 8 (50.0) Stage, n (%) Rai Stage III/IV 10 (62.5) Binet Stage C 10 (62.5) High-risk features (any), n (%) 12 (75.0) TP53 mutation 10 (62.5) Complex karyotype a 8 (50.0) Del (17p) 7 (43.8) Prior lines of therapy, median (range) 4.5 (2 11) Prior ibrutinib, n (%) 16 (100.0) Ibrutinib relapse/refractory, n (%) 13 (81.3) Ibrutinib progression and prior venetoclax, b n (%) 8 (50.0) a At least 3 chromosomal aberrations. b 7 patients progressed on venetoclax; 1 patient had best response of SD after 3 months of treatment. Siddiqi T et al. ASH Abstract 300.

45 Serious AEs All Patients (N=16) Any serious AEs of any grade, n (%) 7 (43.8) Lung infection 3 (18.8) Aphasia 1 (6.3) Blood fibrinogen decreased 1 (6.3) Encephalopathy 1 (6.3) Febrile neutropenia 1 (6.3) Hypertension a 1 (6.3) Hyponatremia 1 (6.3) a 1 DLT of grade 4 hypertension was reported in DL2. All serious AEs were of grade 3 and all were reversible Siddiqi T et al. ASH Abstract 300.

46 AEs of Special Interest (none were Grade 4/5) Total DL1 DL2 (N=16) (n=6) (n=10) CRS any grade, n (%) 12 (75.0) 6 (100.0) 6 (60.0) Median time to first onset, d (range) 6.5 (1 10) 6.5 (1 9) 5.0 (2 10) Median duration, d (range) 5.5 (2 30) 5.5 (3 30) 5.5 (2 13) Grade 3, n (%) 1 (6.3) 0 1 (10.0) Neurologic events (NE) a any grade, n (%) 6 (37.5) 2 (33.3) 4 (40.0) Median time to first onset, d (range) 10.0 (4 21) 16.0 (11 21) 8.0 (4 11) Median duration, d (range) 6.5 (2 20) 4.0 (2 6) 8.0 (3 20) Grade 3 b, n (%) 3 (18.8) 2 (33.3) 1 (10.0) Any, n (%) CRS or NE a 13 (81.3) 6 (100.0) 7 (70.0) CRS and NE a 5 (31.3) 2 (33.3) 3 (30.0) Tocilizumab and/or dexamethasone use 11 (68.8) 4 (66.7) 7 (70.0) Tumor lysis syndrome any grade, n (%) 2 (12.5) 1 (16.7) 1 (10.0) Grade 3, n (%) 2 (12.5) 1 (16.7) 1 (10.0) a Neurologic events are treatment-related events defined by the Investigator. b Encephalopathy n=1; aphasia n=1; confusional state and encephalopathy n=1. Siddiqi T et al. ASH Abstract 300.

47 Response Rates Total DL1 DL2 Best Overall Response, n (%) (N=16) (n=6) (n=10) ORR 13 (81.3) 6 (100.0) 7 (70.0) CR/CRi 7 (43.8) 5 (83.3) 2 (20.0) PR/nPR 6 (37.5) 1 (16.7) 5 (50.0) SD 2 (12.5) 0 2 (20.0) PD 1 (6.3) 0 1 (10.0) Total DL1 DL2 Response at 30 Days Post liso-cel, n (%) (N=16) (n=6) (n=10) ORR 12 (75.0) 6 (100.0) 6 (60.0) CR/CRi 5 (31.3) 3 (50.0) 2 (20.0) PR/nPR 7 (43.8) 3 (50.0) 4 (40.0) Response at 3 Months Post lisocel, n (%) (N=10) (n=6) (n=4) ORR 8 (80.0) 5 (83.3) 3 (75.0) CR/CRi 5 (50.0) 3 (50.0) 2 (50.0) PR/nPR 3 (30.0) 2 (33.3) 1 (25.0) Siddiqi T et al. ASH Abstract 300.

48 Phase 1 TRANSCEND CLL 004: Minimal Residual Disease 11 of 15 (73.3%) patients had umrd4 in blood by flow at day 30 All continue to remain undetectable at latest follow-up 5 patients have post-dose follow-up at month 6 Total DL1 DL2 Blood, flow (N = 15) (n = 6) (n = 9) umrd4 at any time point, n (%) 11 (73.3) 6 (100.0) 5 (55.6) Bone marrow, NGS (N = 8) (n = 5) (n = 3) umrd4 at any time point, n (%) 7 (87.5) 4 (80.0) 3 (100.0) All continue to maintain umrd4 response (CR, n = 4 and PR, n = 1 by iwcll criteria) Siddiqi T et al. ASH Abstract 300.

49 Conclusions Explosion of novel therapies for CLL in recent years, including monoclonal antibodies (like obinutuzumab), small molecule inhibitors of various kinases (like BTK and PI3K) and the antiapoptotic pathway (especially Bcl2), and CD19-specific CAR-T cells These novel, non-chemotherapeutic agents may do away with the need for standard chemoimmunotherapy in CLL, especially in older/unfit patients If chemo being considered for a patient, must check IGVH mutation status and FISH/cytogenetics first Combination studies are underway to improve outcomes further

50 COH CLL trials Ibrutinib + cirmtuzumab (frontline and rel/ref) Umbralisib + ublituximab + venetoclax (coming soon for rel/ref pts) Ibrutinib+obinutuzumab vs. ibrutinib+venetoclax+ obinutuzumab in pts >/= 70 yrs, previously untreated (coming soon) JCAR017 CAR-T cells (rel/ref, failed BTKi) COH CAR-T cells (any rel/ref)