Emerging Treatments and Evolving Pathways for the Management of Chronic Lymphocytic Leukemia

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2 Emerging Treatments and Evolving Pathways for the Management of Chronic Lymphocytic Leukemia This educational activity is supported by an educational grant from AbbVie

3 Faculty Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor Harvard Medical School Boston, Massachusetts

4 Disclosures Dr Brown has served as a consultant for Janssen, Pharmacyclics, AstraZeneca, Sun, Redx, AbbVie, and Gilead. She has received grant/research support from Gilead.

5 Learning Objectives Discuss the importance of CLL biomarkers and staging in prognostic assessment and subsequent treatment decisions Evaluate the efficacy, safety, and indications of new and emerging CLL treatments with respect to patient age, comorbidities, and overall health Integrate the latest evidence-based guidelines, clinical trial results, and cost utility studies into the CLL clinical pathway development process Implement strategies to improve guideline adherence and patient outcomes through the inclusion and sequencing of novel therapies in CLL clinical pathways

6 Talk Outline and Key Topics Initial prognostic assessment Current first-line therapy options Selection of therapy Biologic criteria Fitness criteria Relapsed refractory CLL therapy Novel agents CLL = chronic lymphocytic leukemia.

7 CLL: Chronic Lymphocytic Leukemia Most common adult leukemia 17,000 new cases per year Better thought of as a chronic, incurable low-grade lymphoma Most patients present with asymptomatic increase in lymphocyte count These asymptomatic patients do not require therapy initially Therapy required once symptoms, low blood counts, or large lymph nodes intervene

8 IW-CLL Criteria for Initiating Therapy B symptoms, severe fatigue Progressive anemia/thrombocytopenia Massive or rapidly progressive splenomegaly or lymphadenopathy LDT <6 months Refractory AIHA or ITP Note that ALC is not specifically a criterion AIHA = autoimmune hemolytic anemia; ALC = absolute lymphocyte count; ITP = immune thrombocytopenia; IW-CLL = International Workshop on Chronic Lymphocytic Leukemia meeting; LDT = lymphocyte doubling time.

9 What Is High-risk CLL? Historically defined solely by clinical features: Stage, lymphocyte doubling time, b2m Therapy resistance Biologic prognostic factors are increasingly important: FISH, TP53 mutation IGHV? Novel somatic mutations: SF3B1, NOTCH1 FISH = fluorescence in situ hybridization; IGHV = unique immunoglobulin gene rearrangement.

10 Clonal Aberrations in CLL: Interphase FISH 83% Abnormal: No. patients (%) 13q deletion 178 (55) 11q deletion 58 (18) Trisomy (16) 17p deletion 23 (7) 6q deletion 21 (6) Normal 57 (18) Döhner H, et al. New Engl J Med. 2000;343:

11 Overall Survival by FISH Patients surviving (%) Del 17p: 32 m Del 11q: 79 m 17p- 11q- 12q trisomy Normal 13q deletion as sole abnormality Döhner H, et al. New Engl J Med. 2000;343:

12 Immunoglobulin V H Gene Mutation Med Surv >24 yrs Med Surv 9 yrs Years from Diagnosis Damle RN, et al. Blood. 1999;94(6):

13 IGHV Mutation and Cytogenetics: Independent Predictors Kröber A, et al. Blood. 2002;100(4):

14 TP53 Mutations in the DNA Binding Motifs Associate with Worse Survival Regardless of 17p Del With 17p Del Trbusek M, et al. J Clin Oncol. 2011;29(19):

15 TP53 Mutation Has a Dose-dependent Effect on OS OS = overall survival. Yu L, et al. Blood. 2015;126(23):2907.

16 CLL-IPI: Final Model of Multivariate Analysis Variable Adverse factor Coeff. HR TP53 (17p) deleted and/or mutated IGHV status Unmutated B2M, mg/l > Clinical stage Binet B/C or Rai I-IV Age >65 years Grading Prognostic Score 0 10 B2M = beta 2 microglobulin; CLL-IPI = international prognostic index for CLL; HR = hazard ratio. Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

17 Definition of Risk Groups Score Frequency Risk group Score Patients, N (%) Survival after 5 years, % HR (95% CI) P value Low (29) 93.2 Intermediate (39) ( ) <0.001 High (27) ( ) <0.001 Very High (5) ( ) <0.001 Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

18 CLL-IPI: Risk GroupsDa Training dataset [N = 1192] Internal validation dataset [N = 575] 1,0 1,0 0,8 0,8 Cum Survival 0,6 0,4 Cum Survival 0,6 0,4 0,2 0,2 0,0 0, Time to Event [OS] (months) Time to Event [OS] (months) C- statistic = [95% CI, ] C- statistic = [95% CI, ] Soumerai JD, et al. J Clin Oncol. 2016;34(suppl):abstr 7513.

19 What Is High-risk CLL? Comes down to: Patient factors: age, ECOG/comorbidities Biologic factors: 17p, UM, 11q, B2M ECOG = Eastern Cooperative Oncology Group scale

20 Recurrent Mutations Refine Prognosis Balakas et al. Leukemia. 2014:1-8.

21 Previously Untreated CLL 1960s 1970s 1980s 1990s 2000s 2010s Alkylating agents - Chlorambucil - Cyclophosphamide 5% CR Purine nucleosides - Fludarabine - Pentostatin - Cladribine 5% - 20% CR Better PFS in younger pts BCL-2 = B-cell lymphoma-2; BCR = beta-cell receptor; CR = complete remission; PFS = progression-free survival. Purine nucleosides and alkylators 30% CR Better PFS BCR/BCL-2 inhibitors??? Chemo-immunotherapy (CIT) 45% CR; better PFS & OS Alemtuzumab monotherapy 24% CR Bendamustine 30% CR

22 CLL8 Study Design 817 patients with untreated, active CLL and good physical fitness (CIRS 6, creatinine clearance 70 ml/min) R FCR FC 6 courses C1 C2 C3 C4 C5 C6 Follow up Demographics similar between two treatment arms Median observation time 5.9 years CIRS = cumulative illness rating scale. Hallek M, et al. Lancet. 2010;376:

23 CLL8: Addition of Rituximab to FC REFERENCES Fischer K, et al. Presented at: American Society of Hematology 54th Annual Meeting; December 8-11, 2012; Atlanta, GA..

24 CLL8: Addition of Rituximab to Fludarabine and Cyclophosphamide REFERENCES Fischer K, et al. Presented at: American Society of Hematology 54th Annual Meeting; December 8-11, 2012; Atlanta, GA..

25 CLL8: Survival After FCR by FISH 17p deletion Hallek M, et al. Lancet. 2010;376: Stilgenbauer et al. Blood May 22;123(21): q 13q-single 11q- Not 17p-/11q-/+12q/13q- 17p-

26 CLL8: Impact of TP53 Mutation on OS TP53: wild type mutated Therapy: FCR FC Eichhorst et al. Lancet Oncol Jul;17(7): Stilgenbauer et al. Blood May 22;123(21):

27 CLL8 Multivariable Analysis: Predictive Factors Cox regression including: FC, FCR, TP53, NOTCH1, SF3B1, and treatment interaction PFS: HR P value FCR <0.001 TP53 mut <0.001 SF3B1 mut NOTCH1 mut Interaction OS: HR P value FCR TP53 mut <0.001 NOTCH1 mut Interaction Eichhorst et al. Lancet Oncol Jul;17(7): Stilgenbauer et al. Blood May 22;123(21):

28 MDACC: TTF After FCR Based on FISH ( ) Pts. Failed FISH p q Trisomy q Negative Courtesy of M Keating Months

29 CLL10 Study: FCR vs BR in Frontline Consort Diagram 688 CLL patients screened centrally for: immunophenotype genomic aberrations (FISH) IGHV sequencing CIRS GFR 564 underwent 1:1 randomization FCR n = 284 BR n = treatment before randomization 1 patient decision 1 misdiagnosis (MCL) GFR = glomerular filtration rate; MCL = mantle cell lymphoma. REFERENCE Eichhorst et al. Lancet Oncol Jul;17(7): ITT: FCR n = 282 ITT: BR n = 279 Median observation time: 37.1 (0-59.9) months

30 CLL10 Study: FCR vs BR in Frontline (Cont d) = P = Primary Median PFS FCR 55.2 months BR 41.7 months P <0.001 HR = = >1.388 Eichhorst et al. Lancet Oncol Jul;17(7):

31 CLL10 Study: FCR vs BR in Frontline (Cont d) Response FCR n=274 BR n=273 P value CR (CR + CRi) 47.4% 38.1% CR 40.1% 36.3% CRi 7.3% 1.8% PR 50.4% 59.7% ORR 97.8% 97.8% 1.0 ORR = objective response rate; PR = partial remission. Eichhorst et al. Lancet Oncol Jul;17(7):

32 CLL10 Study: FCR vs BR in MRD Negativity MRD Minimal negativity residual disease (MRD) FCR %(N) in ITT n=282 BR %(N) n=279 BM at FR 26.6% (75/282) PB at FR PB 12 months after FR 48.6% (137/282) 19.7% (47/238) 11.1% (31/279) 38.4% (107/279) 9.0% (20/222) PB 18 months after FR 18.0% (37/206) 8.5% (16/187) BM=bone marrow; FR=final restaging; MRD = minimal residual disease; PB=peripheral blood. Eichhorst et al. Lancet Oncol Jul;17(7):

33 CLL10 Study: FCR vs BR in Frontline Adverse Events CTC 3-4 (1st cycle until end of study) Adverse event FCR (%) N= 279 BR (%) N=278 P value Neutropenia <0.001 Anemia Thrombocytopenia Infection <0.001 Sec Neoplasm* TRM Infections Sec Neoplasm Other 1.0 Eichhorst et al. Lancet Oncol Jul;17(7): *saml/mds: FCR=6, BR=1

34 CLL10 Study: FCR vs BR in Front-line Infections CTC 3-4 in detail Adverse event FCR (% of pt) BR (% of pt) P value All Infections <0.001 Infections during therapy only Infections during first 5 months after therapy All infections in patients 65years All infections in patients >65years < <0.001 Eichhorst et al. Lancet Oncol Jul;17(7):

35 Predictors of PFS in Multivariable Analysis COX regression PFS Treatment arm Univariate comparison Hazard ratio 95% Confidence Interval Lower Upper P value BR vs. FCR <0.001 S-TK (U/L) >10 vs Cytogenetic subgroup del (11q) vs no del(11q) <0.001 IGHV MS Unmutated vs mutated <0.001 Eichhorst et al. Lancet Oncol Jul;17(7):

36 Predictors of OS in Multivariable Analysis COX regression OS Univariate comparison Hazard ratio 95% Confidence Interval Lower Upper P value Age at study entry >65 years vs 65 years IGHV MS Unmutated vs mutated <0.001 Eichhorst et al. Lancet Oncol Jul;17(7):

37 CLL10: FCR vs BR FCR more effective in CR, MRD, PFS Most noticeable in patients <65 yo FCR toxicity higher especially in those >65 yo No growth factors or antibiotic prophylaxis Young fit FCR Older fit or intermediate fitness Role for BR

38 FCR300: PFS and OS Proportion Surviving PFS OS Median Follow-up Time All: 9.8 yrs Alive: 11.5 yrs Events Total Median yrs yrs Mos Wierda WG, et al. iwcll 2013 Abstracts.

39 FCR300: PFS by IGHV Mutation Status Proportion Progression Free Group Events Total IGHV-M IGHV-UM Unknown P < Mos Wierda WG, et al. iwcll 2013 Abstracts.

40 First-line FCR300: PFS and OS Outcomes by MRD Status Overall Survival MRD- MRD- Proportion Not Progressed n events MRD MRD MRD+ Proportion Alive n events MRD MRD MRD+ 0.0 p< p< Months Months Strati P, et al. Blood. 2014;123(24):

41 MRD-negative Status at EOT Strongly Associated with PFS but Modified by IGHV EOT = end of treatment. Thompson P, et al. MRD analysis after FCR.

42 First-line FCR: Rossi Data Overall Survival Mut IGHV, no 11 or 17 UM IGHV or 11q 17p Rossi D, et al. Blood. 2015;126:

43 Second Malignancy Risks MDACC Italian Data 50% p= % (4/21) Probability Prevalence of second tumors 40% 30% 20% 10% 3.9% (3/77) 12.1% (21/173) Time (years) 0% Low-risk Intermediate-risk High-risk Rossi D, et al. Blood. 2015;126: Thompson PA, et al. Blood Jan 21;127(3):303-9.

44 Kwok M, et al. Blood. 2016;128(24): MRD Negativity Predicts Best PFS and OS

45 MRD Negativity Does Not Overcome Poor Prognosis of Del(17p/11q) Kwok M, et al. Blood. 2016;128(24):

46 Better PFS and OS If MRD Negativity After First-line Therapy Kwok M, et al. Blood. 2016;128(24):

47 Summary: Fit Patients FCR remains most effective upfront therapy A subset of patients remain progression free more than 10 yrs: Mutated IGHV, low risk FISH Key predictors of outcome after therapy: 17p / TP53 mutn 11q deletion and IGHV mutation status Response (CR) and MRD status

48 First-line Treatment of CLL For physically fit patients, FCR prolongs survival Until recently, no standard treatment in elderly population Phase 3 CLL elderly trial: fludarabine vs chlorambucil PFS OS Fludarabine Fludarabine NOT superior to chlorambucil in PFS or OS Fludarabine Chlorambucil Chlor Chlorambucil Retrospective analysis of CALGB first-line CLL trials No benefit of fludarabine over chlorambucil in patients age 70 yrs Rituximab added benefit regardless of age CALGB = Cancer and Leukemia Group B Eichhorst BF, et al. Blood Feb 10;117(6):

49 Association of Age and Comorbidity in CLL: Meta-analysis of GCLLSG CLL4 and CLL5 Trials Incidence of comorbidities increases with age <20% of youngest patients had comorbidities >60% of oldest patients had comorbidities Number of comorbidities increases with age ~5% of youngest patients had 2 comorbidities >30% of oldest patients had 2 comorbidities Cramer P, et al. Blood. 2006;108:Abstract 2840.

50 CLL11: Study Design 590 patients Previously untreated CLL Total CIRS score >6 and/or creatinine clearance <70 ml/min N=780 (planned) R A N D O M I Z E 2:1:2 GA101 + chlorambucil x 6 cycles Chlorambucil x 6 cycles (control arm) Rituximab + chlorambucil x 6 cycles G-Clb vs. Clb Primary analysis data cut-off: 07/2012 R-Clb vs. Clb Primary analysis data cut-off: 08/2012 Goede V, et al. N Engl J Med Mar 20;370(12):

51 CLL11: Study Design (Cont d) 590 patients Additional 190 patients Previously untreated CLL Total CIRS score >6 and/or creatinine clearance <70 ml/min N=780 (planned) R A N D O M I Z E 2:1:2 GA101 + chlorambucil x 6 cycles Chlorambucil x 6 cycles (control arm) Rituximab + chlorambucil x 6 cycles G-Clb vs. R-Clb Primary analysis data cut-off: 05/2013 Goede V, et al. N Engl J Med Mar 20;370(12):

52 Lymphocyte Counts After Obinutuzumab and CLB Goede V, et al. N Engl J Med Mar 20;370(12): Goede V, et al., Leukemia. 2013;27:

53 Baseline Patient Characteristics G-Clb (n=333) % R-Clb (n=330) % Male Median age, years (range) 74 (39-89) 73 (40-90) Aged 65 years Aged 75 years Median ECOG PS (range) 1 (0-3) 1 (0-3) Median CIRS score CIRS score > Median CrCl CrCl <70 ml/min CrCl <50 ml/min Goede V, et al. N Engl J Med Mar 20;370(12):

54 Adverse Events of Interest G-Clb (n=336) a % R-Clb (n=321) a % Any AE grade 3 b Infusion-related reaction 20 4 Neutropenia Anemia 4 4 Thrombocytopenia 10 3 Infection Pneumonia 4 5 a Safety population for G-Clb includes 5 patients randomized to R-Clb who received 1 infusion of GA101 in error b Incidence rate of 3% in any treatment arm AE = adverse event. Goede V, et al. N Engl J Med Mar 20;370(12):

55 Minimal Residual Disease As measured by central laboratory assessment (ASO-RQ-PCR) at 3 months after end of treatment; bone marrow samples were usually only taken from patients thought to be in CR. Goede V, et al. N Engl J Med Mar 20;370(12):

56 Progression-free Survival (Head-to-Head) Progression-free survival No. at risk G-Clb: R-Clb: Time (months) Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. Type 1 error controlled through closed test procedure; P value of the global test was < Independent Review Committeeassessed progression-free survival (PFS) was consistent with investigator-assessed PFS. Goede V, et al. N Engl J Med Mar 20;370(12):

57 Overall Survival (GA101) Overall survival No. at risk G-Clb: Clb: Time (months) Total number of deaths: G-Clb, 22 (9%); Clb, 24 (20%) Median observation time: G-Clb, 23.2 months; Clb, 20.4 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med Mar 20;370(12):

58 Overall Survival (Head-to-Head) Overall survival No. at risk G-Clb: R-Clb: Time (months) Total number of deaths: G-Clb, 28 (8%); R-Clb, 41 (12%) Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months. No multiplicity adjustment was done for secondary endpoints. Goede V, et al. N Engl J Med Mar 20;370(12):

59 CLL11: TTNT G-Clb vs R-Clb Stratified HR % CI P < G Clb R Clb Time to new anti-leukemic treatment Time (months) No. at risk GClb RClb Goede V, et al. Leukemia Jul;29(7):

60 Summary: Unfit Patients Randomized phase 3 trials establish PFS benefit of adding anti-cd20 antibody to chlorambucil Only obinutuzumab has been compared head-to-head with rituximab, with improved MRD negativity and PFS but not improved OS Time to next therapy quite good for 6 months of welltolerated treatment VS Kinase inhibitors likely to move into this space where resources permit How should therapy be selected?

61 PCYC-1102/1103 Phase 2 Study Design Phase 2 (PCYC-1102) N=132 Extension Study (PCYC-1103) Patients with CLL/SLL treated with oral, once-daily ibrutinib (420 or 840 mg/day) Treatment Naïve (TN) 65 years n=31 Relapsed/Refractory * (R/R) n=101 SD Long-Term Follow-Up * R/R includes patients with high-risk CLL/SLL, defined as progression of disease <24 months after initiation of a chemoimmunotherapy regimen or failure to respond O Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, Abstract 233.

62 Ibrutinib Treatment Continued in 65% TN and 30% R/R Patients After ~5 years of followup Disposition Median time on study, months (range) Duration of study treatment, n (%) 1 year >1 2 years >2 3 years >3 4 years 4 years O Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, Abstract 233. TN (n=31) 62 (1 67) 5 (16%) 0 1 (3%) 1 (3%) 24 (77%) R/R (n=101) 49 (1 67) 24 (24%) 14 (14%) 9 (9%) 19 (19%) 35 (35%) Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%) Primary reason for discontinuation, n (%) Progressive disease Adverse event Consent withdrawal Investigator decision Lost to follow up 1 (3%) 6 (19%) 3 (10%) 0 1 (3%) 33 (33%) 21 (21%) 5 (5%) 11 (11%) 1 (1%)

63 Survival Outcomes by Chromosomal Abnormalities Detected by FISH in R/R Patients Progression-Free Survival Overall Survival Median PFS 5-year PFS Del17p (n=34) 26 mo 19% Del11q (n=28) 55 mo 33% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 66% O Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, Abstract 233. Median OS 5-year OS Del17p (n=34) 57 mo 32% Del11q (n=28) NR 61% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 83%

64 Survival by Complex Karyotype Progression-Free Survival Overall Survival Complex karyotype (n=41) No complex karyotype (n=71) Media n PFS 5-year PFS 33 mo 36% NR 69% Complex karyotype (n=41) No complex karyotype (n=71) The majority (90%) of patients with complex karyotype had R/R disease (median 4 prior therapies). NR = not reached. O Brien SM, et al. American Society of Hematology 59 th Annual Meeting and Exposition. Atlanta, GA; December 9-12, Abstract 233. Media n OS 5-year OS 57 mo 46% NR 84%

65 PFS for Patients with Del17p CLL on Ibrutinib (n=243) Estimated 12- mo PFS, % (95% CI) Estimated 24- mo PFS, % (95% CI) Estimated 30- mo PFS, % (95% CI) 80% (74, 84) 63% (57, 69) 55% (48, 62) Median time on study = 28 months (range: ) Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract S429.

66 PFS of Del17p Patients +/- Complex Karyotype in the PCYC-1102/1103 Study Median PFS, mo Del17p + CK (n=22) 25 Del17p no CK (n=10) 52 Median OS, mo Del17p + CK (n=22) 32 Del17p no CK (n=10) NR 69% of del17p patients had CK vs 31% of del17p patients without CK Median age (range): 65 y (49-79) vs 60 y (44-82) Median prior therapies (range): 4 (1-9) vs 2.5 (0-12) Median platelets (range): /L (20-151) vs /L (17-310) Rai stage III-IV: 64% vs 40% CK = complex karyotype; NR = not reached. Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract S429.

67 PCYC 1112 RESONATE: PFS by Del17p Progression-Free Survival (%) Ibrutinib with del17p (n=63) Ibrutinib without del17p (n=132) Ofatumumab with del17p (n=64) Ofatumumab without del17p (n=132) Months Brown, et al. Leukemia

68 Brown, et al. Leukemia PCYC 1112 RESONATE: PFS by TP53 / Del17p

69 Front-line Ibrutinib in del(17p) 100 Overall Survival Overall Survival (%) Relapsed/Refractory Previously Untreated P = Months Previously Untreated Relapsed Refractory N Median 15 months 26 months Follow-up Rai Stage III/IV 63% 75% Bulky adenopathy IGHV unmutated 23% 50% 63% 75% PFS 82%, OS 80% at 24 mos Farooqui MZ, et al. Lancet Oncol. 2015;16(2):

70 Ibrutinib for Upfront Therapy of 17p Deleted CLL: Clearly the drug of choice given current data But unsatisfying as a single agent given the continuous relapse and Richter s seen in any trial with reasonably long follow-up. BUT still no combination data in an upfront setting 17p remains an unmet need not yet adequately addressed SCT still needs to be considered

71 RESONATE-2 (PCYC-1115/1116) Study Design Patients (N=269) Treatment-naïve CLL/SLL with active disease Age 65 years For patients years, comorbidity that may preclude FCR del17p excluded Stratification factors ECOG status (0-1 vs. 2) Rai stage (III-IV vs. II) R A N D O M I Z E 1:1 ibrutinib 420 mg once daily until progression chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1, 15 of 28- day cycle up to 12 cycles CLL PD or 1115 study closure Efficacy (PFS, OS, ORR) determined by investigator-assessment. PCYC Extension Study* In clb arm, n=55 crossed over to ibrutinib following PD *Patients could enroll in separate extension study PCYC-1116 after independent review committeeconfirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up. Barr, et al. Blood

72 Patient Characteristics Barr et al, Blood Characteristic Median age, years (range) 70 years, % ECOG performance status, % 1 2 Ibrutinib (n=136) 73 (65 89) Chlorambucil (n=133) 72 (65 90) 70 Rai stage III or IV, % CIRS score >6, % Creatinine clearance <60 ml/min, % Bulky disease 5 cm, % β2-microglobulin >3.5 mg/l, % Hemoglobin 11 g/dl, % Platelet count 100 x 10 9 /L, % Del11q, % Unmutated IGHV, %

73 RESONATE 2: PFS and OS by Investigator Assessment 18-month PFS rate: 90% with ibrutinib vs. 52% with chlorambucil AEs: 14% hypertension, 6% atrial fibrillation, 4% major hemorrhage, 2 sudden deaths 24-month OS rate: 98% with ibrutinib and 85% with chlorambucil 3 deaths on ibrutinib arm vs 17 deaths on chlorambucil arm Burger JA, et al. N Engl J Med Dec 17;373(25):

74 Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status (n=40) (n=58) (n=42) (n=60) 79% of patients continue on ibrutinib treatment on study with 83% of patients receiving at least 2 years of treatment Barr, et al. Blood

75 ORR in the Ibrutinib Arm Best Response (%) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% PR-L PR npr CR/CRi 100% 92% 14% 90% 18% 20% 1% 1% 71% All Patients (N=136) 1% 86% With Del11q (n=29) 21% 67% 74% Without Del11q (n=101) 2% 95% Unmutated IGHV (n=58) 88% 20% 65% Mutated IGHV (n=40) Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to 15% at 24 months to 18% with median follow-up of 29 months 1 3% *Response rates with chlorambucil are the same as in the original report 2 1. Barr, et al. Blood. 2016; 2. Burger, et al. NEJM

76 Treatment-emergent AEs ( Grade 3) Over Time in First-line Ibrutinib Patients ( 4% Over 29 Months Median Follow-Up) Ibrutinib Arm 0-12 months (n=135), % >12-24 months (n=123), % >24-36 months (n=112), % Neutropenia Pneumonia* Anemia Hypertension Hyponatremia Atrial fibrillation Grade 3 AEs in 4% of patients over the 29 mo follow-up: neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%) Major hemorrhage occurred in 7% of ibrutinib-treated patients (1 Grade 2, 7 Grade 3, 1 Grade 4; 5 in first 12 months and 4 between 1-2 years) Atrial fibrillation occurred in 10% of ibrutinib-treated patients (1 Grade 1, 7 Grade 2, 6 Grade 3) Barr et al. Blood Barr et al, Blood 2016.

77 Ibrutinib for Upfront Therapy: What Are the Issues? Only data in a non-representative population of very healthy older patients with low disease burden and disease risk, short follow-up, and a very poor comparator arm Patients all 65 or over but low comorbidity Toxicity is not negligible even in this population (afib, hemorrhage, arthralgia)

78 OSU Experience: Long-term Ibrutinib Cumulative Incidence Estimates At 2 Years At 3 Years At 4 Years CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0% Woyach JA, et al. J Clin Oncol May 1;35(13):

79 Predictors of Ibrutinib Discontinuation: OSU Experience Transformation Progressive CLL Other Event Variable HR P HR P HR P Complex karyotype (yes v no) MYC abnormality (yes v no) Del17p (yes v no) Age ( v <65 years) Prior therapies > 3 (yes v no) Woyach JA, et al. J Clin Oncol May 1;35(13):

80 OSU: Discontinuation for Non-PD by Age Maddocks et al. JAMA Oncology. 2015

81 Real World KI Use: Reasons for Discontinuation Most Common Reasons for Ibrutinib Discontinuation Ibrutinib Toxicity 51% CLL progression 28% Richter s transformation 8% SCT / CAR-T 2% Unrelated death or other 11% 5 Most Common Toxicities as a Reason for Discontinuation Atrial fibrillation 20% Infection 12% Hematologic 9% Bleeding 9% Pneumonitis 8% Others: Arthralgia Edema Diarrhea/GI KI =. Mato et al, Blood

82 PFS for Alternate KI by Discontinuation Reason Mato et al, Blood RT excluded from analysis

83 Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients: Design and Patient Characteristics Retrospective analysis: 621 ibrutinib-treated patients at 9 US cancer centers or Connect R CLL Registry Characteristics, n Ibrutinib in Frontline (n=80) Ibrutinib in Relapse (n= 536) Median age at diagnosis, years (range) 62 (37-88) (N=78) 60 (22-95) (n=532) Prior therapies, median (range) 0 2 (1-10) del(17p), % 37% (n=76) 26% (n=368) del(11q), % 19% (n=75) 35% (n=367) TP53 mutation, % 12% (n=42) 13% (n=142) Complex karyotype ( 3 abnormalities), % 40% (n=60) 34% (n=214) Median time from diagnosis to Ibrutinib, months (range) 26 (1-232) 78 (1-660) Median ibrutinib starting dose, mg Ibrutinib as monotherapy, % 68% (n=80) 89% (n=536) Ibrutinib hold required, % 30% (n=79) 37% (n=310) Ibrutinib dose adjustment required, % 15% (n=79) 20% (n=309) Mato et al, Blood patients (88%) were treated with commercial drug; Clinical trial patients were younger (median age 57 vs 61 years), had longer time from diagnosis to ibrutinib (median 85 vs 72 months), and were more consistently initiated at 420 mg (100% vs 89%).

84 Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-Treated Patients: Discontinuations With a median follow-up of 14.5 months, estimated discontinuation rate was 42%; median time to discontinuation was 7 months Reasons for Discontinuation, % Ibrutinib in Front Line Commercial use (n=10) Clinical Trial (n=9) Ibrutinib in Relapse Commercial Use (n=200) Clinical Trial (n=31) Toxicity CLL progression Other/unrelated death Physician or patient preference RT DLBCL SCT/CAR-T cells Financial concerns Secondary malignancy RT Hodgkin lymphoma Mato et al, Blood

85 Retrospective Analysis of Toxicities and Outcomes for Ibrutinib-treated Patients Median PFS and OS for entire cohort were 36 months and NR, respectively (median follow-up 17 months) PFS was not significantly different based on use in front-line vs relapsed (P=0.27) or commercial use vs clinical trial (P=0.14) In multivariable model, complex karyotype validated as independent predictor of PFS (HR 1.6, CI , P=0.04) but not OS (HR 1.6, CI , P=0.1) Mato et al. American Society of Hematology 58 th Annual Meeting. San Diego, CA; December 3-6, Abstract #3222.

86 Bleeding Events by Time to New Event Onset in PCYC-1102 In PCYC-1102, major bleeding occurred in 5% of patients Most bleeding events occurred early, during the first 3-6 months of therapy Jones JA et al. Br J Haematol Jul;178(2):

87 AF Incidence Over Time on Ibrutinib 100 Patients with Event (%) Months from Study Initiation Ibrutinib (n=49) Comparator (n = 12) De novo Prior history De novo Prior history Patients with Event (%) Brown JR et al, Haematologica Prior History De Novo >36 Months from Study Initiation

88 Risk Factors for AF in Ibrutinib RCTs Brown JR et al, Haematologica 2017.

89 Conclusions: Ibrutinib in R/R CLL Ibrutinib in R/R CLL has excellent results, mostly PRs (not a cure) Median PFS 52 mos on clinical trial Worse for 17p, complex karyotype, 11q BUT: outside trials, 40% stop in 14 mos, mostly due to adverse events, and median PFS is 36 mos Real-world outcomes are not aligning with trials Better management strategies for toxicity, and/or less toxic BTK inhibitors, may be needed Those patients who progress on drug have been difficult to salvage RT about 30-50% of the time in the relapsed setting, although randomized trials are balanced so far Frequent BTK Cys481 mutations Next-generation drugs: more specific; target BTK Cys mutation

90 Ibrutinib for Upfront Therapy: What Are the Issues? NO data in young fit patients to whom RESONATE-2 data are being generalized Who often do not want indefinite therapy Who do not achieve CR much less MRD negativity Who if maintained on ibrutinib may be hard to salvage on relapse No data that CIT can be used later Cost and compliance are huge issues

91 PCYC 1112 RESONATE: PFS by Line of Therapy Brown et al. American Society of Hematology 56 th Annual Meeting. San Francisco, CA; December 6-9, 2014.

92 PFS by Prior Lines of Therapy: RESONATE and RESONATE-2 O Brien et al. American Society of Clinical Oncology Annual Meeting. Chicago, IL; June 3-7, 2016.

93 OSU Experience: Long-Term Ibrutinib Cumulative Incidence Estimates At 2 Years At 3 Years At 4 Years (95 % Cl) CLL progression 5.0% 10.8% 19.1% Transformation 7.3% 9.1% 9.6% Other event 18.7% 23.9% 25.0% Woyach JA, et al. J Clin Oncol May 1;35(13):

94 Venetoclax (ABT-199) Response in Relapsed/Refractory CLL/SLL Response All (n = 116) del(17p) (n = 31) F- Refractory (n = 70) IGHV Unmutated (n = 46) Overall 79% 71% 79% 76% response CR 20% 16% 16% 17% PR 59% 55% 63% 59% Bulky nodes (>5 cm) N CR/CRi % (95% CI) ORR % (95% CI) Yes 67 6 (2, 15) 78 (66, 87) No (24, 53) 83 (70, 93) Roberts AW, et al. N Engl J Med (4):

95 Venetoclax (ABT-199) in Relapsed/Refractory CLL/SLL Roberts AW, et al. N Engl J Med (4):

96 Adverse Events All Grades 20% of pts N=105 n (%) Diarrhea 42 (40) Neutropenia 38 (36) Nausea 37 (35) Upper respiratory tract infection 35 (33) Fatigue 27 (27) Cough 21 (20) Grades 3/4 5% pts n (%) Neutropenia 35 (33) Anemia 10 (10) Febrile neutropenia 7 (7) Thrombocytopenia 7 (7) Hyperglycemia 7 (7) Tumor lysis syndrome (TLS) 7 (7) Hypokalemia 5 (5) Roberts AW, et al. N Engl J Med (4):

97 Detailed Risk Stratification of Patients for Tumor Lysis 19 th Congress of the European Hematology Association. Milan, Italy; June 12-15, Poster 868.

98 Venetoclax Dosing Schedule To mitigate TLS risk, patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before first venetoclax dose Patients with high tumor burden were hospitalized for first dose at 20 and 50 mg and received IV hydration and rasburicase Laboratory values were monitored at first dose and each subsequent dose increase High tumor burden: any lymph node 10 cm; or both lymph node 5 cm and ALC 25x10 9 /L Stilgenbauer S et al, Lancet Oncol Jun;17(6):

99 Venetoclax in High-risk R/R CLL with del17p: Baseline Characteristics Characteristic, n (%) N=107 a (%) Age, years Median, range 67, Sex Male 70 (65) Prior therapies Median, range 2, 1 10 Prior bendamustine / 54 (50) / 38 (70) refractory Prior fludarabine / refractory 78 (73) / 34 (44) Bulky nodes One or more nodes 5 cm 57 (53) Low 19 (18) TLS risk category Medium 43 (40) High 45 (42) Rai stage III or IV 51(48) IGHV Unmutated 30 (81) Stilgenbauer S et al, Lancet Oncol Jun;17(6):

100 Venetoclax in High-risk R/R CLL with 17p del iwcll Response (74%) MRD-negativity Median time-to-first response: 0.8 months ( ) Median time to CR/Cri (16%): 8.2 months ( ) Stilgenbauer S, et al. Blood. 2015; 126(23):LBA-6. Stilgenbauer S et al, Lancet Oncol Jun;17(6): Of 45 patients tested, 18 achieved MRD-negativity in peripheral blood

101 Del 17p CLL: Durability of Venetoclax Activity 12-month estimates: All responders: 84.7% CR/CRi/nPR: 100% MRD-negative: 94.4% Stilgenbauer S, et al. 57 th American Society of Hematology Meeting and Exposition. Atlanta, GA; December 5-8, Abstract LBA-6, oral presentation. 12-month estimates (95% CI): PFS: 72.0% (61.8, 79.8) OS: 86.7% (78.6, 91.9)

102 Pooled Multi-Trial Analysis of Venetoclax Efficacy in R/R CLL Patient Disposition N=387 Venetoclax 400 mg/day*, n 305 Median duration of venetoclax, months (range) 16.3 ( ) Discontinuation, % Due to PD Due to AEs Due to stem cell transplant Withdrew consent ORR 76% for all patients and in patients receiving the 400 mg RP2D of venetoclax CR/CRi rate was 22%; median time to CR/CRi was 8.3 months MRD-negativity in the marrow achieved in 57/387 patients (15%) including 21/211 patients (10%) with del(17p) Estimated 12 month and 24 month PFS in all 387 patients was 76.8% (95% CI ) and 57.8 (95% CI ) respectively Stilgenbauer S et al, Lancet Oncol Jun;17(6): ; Roberts AW et al, Blood : DOR and PFS in All Patients

103 Pooled Analysis of Venetoclax Efficacy DOR DOR (24-month estimate) n % (95% CI) All patients ( ) Marrow MRD negative ( ) Marrow MRD non-negative* ( ) CR + CRi ( ) No CR/CRi ( ) Neither del(17p) nor TP53 mutation ( ) Either del(17p) or TP53 mutation ( ) PFS by Best Response PFS by Marrow MRD Status PFS by TP53 Status Roberts AW et al, Blood :3230

104 M14-032: Venetoclax After Failure of Ibrutinib Phase 2, open-label study evaluating venetoclax for patients with CLL who relapsed after or are refractory to ibrutinib (Arm A) or idelalisib (Arm B) Primary study objectives: ORR and safety Secondary and exploratory objectives: DoR, PFS, OS, MRD Inclusion criteria: Indication for treatment by iwcll criteria 1 ECOG 0, 1, or 2 Adequate bone marrow function ANC 1000/μL Hg 8 g/dl Platelets 30,000/mm 3 CrCl 50 ml/min Exclusion criteria: Richter s transformation confirmed by PET scan and biopsy Active and uncontrolled autoimmune cytopenias Allogeneic stem cell transplant within 1 year of study entry Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637.

105 Patient Characteristics Arm A n=43 Arm B n=21 Age, median (range), years 66 (48 80) 68 (56 85) Unmutated IGVH,* n/n (%) 25/29 (86) 11/13 (85) del(17)(p13.1),* n/n (%) 21/43 (49) 2/21 (10) Baseline laboratory values, median (range) Hemoglobin, g/dl Platelet count, x10 9 /L Lymphocyte count, x10 9 /L Bulky nodal disease, n (%) 5 cm 10 cm 11.2 ( ) 117 (20 446) 19 (.2 263) 12.2 ( ) 115 (30 439) 14 (.3 407) 15 (35) 7 (16) 11 (52) 5 (24) Prior therapies, median (range) 4 (1 12) 3 (1 11) Prior ibrutinib, n (%) Months on ibrutinib, median (range) Refractory, n (%) 43 (100) 17 (1 56) 39 (91) 5 (24) 6 (2 11) 2 (10) Prior idelalisib, n (%) Months on idelalisib, median (range) Refractory, n (%) 4 (9) 10 (2 31) 2(5) 21 (100) 8 (1 27) 14 (67) Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637.

106 Safety All Patients Event, n (%) N=64 Any grade AE 64 (100) Common all-grade AEs ( 20% patients) Neutropenia Thrombocytopenia Diarrhea Nausea Anemia Fatigue Decreased WBC Hyperphosphatemia 37 (58) 28 (44) 27 (42) 26 (41) 23 (36) 20 (31) 14 (22) 14 (22) All Patients Event, n (%) N=64 Grade 3/4 AEs 53 (83) Common grade 3/4 AEs ( 10% patients) Neutropenia Thrombocytopenia Anemia Decreased WBC Febrile neutropenia Pneumonia 29 (45) 18 (28) 14 (22) 8 (13) 7 (11) 7 (11) Serious AEs 34 (53) Febrile neutropenia Pneumonia Multi-organ failure Septic shock Increased potassium 6 (9) 5 (8) 2 (3) 2 (3) 2(3) No clinical TLS was observed; 1 patient with high tumor burden met Howard criteria for laboratory TLS Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637. Data as of June 10, 2016

107 Efficacy Arm A n=43 Arm B n=21 Best response, n (%) Assessed by Assessed by IRC Investigator IRC Investigator ORR 30 (70) 29 (67) 13 (62) 12 (57) CR/CRi 1 (2) 3 (7) 0/0 3 (15) npr 0 2 (5) 0 0 PR 29 (67) 24 (56) 13 (62) 9 (43) Non-responder* SD PD D/C 13 (30) 14 (23) 9 (21) 1 (2) 4 (9) 8 (38) 9 (43) 8 (38) 1 (5) 0 Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637. Data as of June 10, 2016

108 Current Status Median time on study (range): Arm A, 13 months (0.1 18); Arm B, 9 months (1.3 16) Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637. Data as of June 10, 2016

109 Efficacy Per Independent Review Median DoR, PFS, and OS had not been reached after 11.8 months of follow-up Estimated 12 month PFS for all patients: 80% (95% CI: 67%, 89%) Jones J, et al. EHA Annual Meeting Copenhagen, Denmark; June 9-16, Abstract 637. Data as of June 10, 2016

110 Venetoclax Venetoclax as a single agent has an ORR 76%, CR 22% and 15% BM MRD negativity in heavily pretreated relapsed refractory patients DOR is much higher if CR or MRD negativity Activity is preserved in del17p patients and those who have progressed on ibrutinib or idelalisib Clinical care required due to TLS No data yet in the upfront setting Resistance likely to emerge? Early signal of excess Richter s transformation

111 PI3K Signaling Pathway as a Target in B Cells

112 Where Does Idelalisib Stand? Highly active in R/R (and untreated) CLL Several categories of toxicity: Autoimmune: transaminitis, diarrhea/colitis, and pneumonitis Neutropenia and sepsis (primary cause of infectious deaths on halted upfront trials): less common without BR, monitor and use growth factor Opportunistic infections: PJP, CMV With current information, idelalisib use in CLL is limited to the relapsed refractory setting and after ibrutinib Yet very limited data on response after ibrutinib, where we clearly need it

113 Comparison of Safety Profiles of PI3K Inhibitors Diarrhea/ Colitis Idela + Ofa (ASCO 15) 1 (n=173) Idelalisib Label (CLL & NHL) 2 (n=256) Duvelisib (ASCO 15) 3 (n=18) TGR-1202 All Studies (ASCO 2015) 4 (n=137) Grade 3/4 Grade 3/4 Grade 3/4 Grade 3/4 20% 10% 22% 1%** Pneumonia 13% 16% N/A 4% ALT Elevations N/A 11% N/A 2% AST Elevations N/A 7% N/A 2% ALT/AST Elevations 13% N/A 17% 2% 1 Jones et al. 51st ASCO Annual Meeting. Chicago, IL; May 29- June 2, 2015; 2 Aggregated from Idelalisib Prescribing Information; 3 Patel et al. 51st ASCO Annual Meeting. Chicago, IL; May 29-June 2, 2015; 4 Aggregated from Burris et al, Lunning et al, Fowler et al, 51st ASCO Annual Meeting. Chicago, IL; May 29- June 2, Discontinuations due to AE 31% 12% 33% 4%

114 Where Are We? Highly effective risk stratification Highly effective chemoimmunotherapy 3 classes of oral targeted inhibitors, mostly approved as single agents given continuously Very limited data on whether sequential therapy will work and in what order Including whether CIT will work after novel agent therapy upfront Very limited data on combinations or time limited therapy, or outcomes after discontinuation for progression or adverse events Short follow-up

115 Relapsed Therapy for CLL If ibrutinib naïve: then ibrutinib Could change with expected expanded venetoclax label For patients with very long response to prior chemoimmunotherapy and no adverse prognostic markers, can consider repeat CIT If progressed on ibrutinib: then venetoclax If off ibrutinib for adverse event: idelalisib, venetoclax

116 Front-line Therapy for CLL Asymptomatic (incl. high risk pts) Observe (W&W) 17p /TP53mut 1 Symptomatic (active disease by IWCLL) No 17p /TP53mut Clinical Trial Ibrutinib Venetoclax R HDMP Idelalisib ±R 4 Alemtuzumab 5 <65 70, no 11q mutated IGHV FCR (Ibrutinib) <65 70, unmutated IGHV FCR Ibrutinib Fit 2 Less Fit 3 Unfit BR / PCR >65 70 Ibrutinib Obinutuzumab + Clb Ibrutinib BR / PCR Ofatumumab + Clb Rituximab + Clb Obinutuzumab + Clb Ofatumumab + Clb Rituximab + Clb Ibrutinib 1 17p and/or TP53 mutation 2 CIRS <= 6, CrCl >=70 ml/min 3 CIRS > 6 or CrCl < 70 ml/min 4 Approved frontline in EU but not recommended due to toxicity 5 Only available compassionate use from the manufacturer FIT UNFIT ECOG 1912 (FCR v IBR R) (NAIG) Alliance A (BR v IBR R v IBR) (NAIG) UK FLAIR trial (FCR vs IBR R) PCYC 1130 (Obin Clb v Obin IBR) GCLLSG CLL13 (CIT vs 3 VEN based arms) CLL14 (Obin Clb v Obin Ven)

117 Should Biologic Agents Replace Chemo? PROs: Oral Well tolerated (mostly!) Highly effective even in high-risk disease Efficacy difference from chemo is most marked in relapsed setting Randomized trials are assessing the upfront setting CONs: Given continuously indefinitely patients don t like it vs 6 mos chemo and done! Do not want to abandon CURE with FCR in IGHV mut CLL Many low-grade nagging side effects Unknown long-term effects Tolerability worsens with increasing age Unknown ability to salvage after relapse Cost

118 JCO 35: 166, 2017 Recent Cost Analysis for CLL Therapy

119 JCO 35: 166, 2017 Increase in Lifetime Costs to Payers and Patients

120 JCO 35: 166, 2017 Projected Costs of CLL Management

121 How Can We Address These Cons? Risk-adapted front-line therapy Find effective, well-tolerated combinations that induce deep remissions Stop therapy after a fixed, relatively short period of time (6-24 mos) Advantages: Patient preference Reduce long-term side effects Reduce cost Reasonable chance that subsequent relapse will still be sensitive to prior agents

122 What Is the Future? In fit or higher-risk patients: combination therapy to achieve deep, ideally MRD-negative remissions (?cure) and give treatment breaks: saves money and toxicity and avoids resistance Sequential single agents lead to resistance but may be adequate for older more frail pts or those with lower disease risk: can we stop? 17p - BTK / BCL2 / acd20 combination Older higher disease risk (11q, maybe IGHV unmutated) BTK- or BCL-2 or combo Older lower disease risk acd20-clb Younger IGHV mutated/low-risk FISH: FCR-based therapy may be curative Need better understanding of which patients achieve these outcomes Younger IGHV unmutated patients have continuous relapse with FCR but often achieve MRD negativity that leads to 5+ years remission Good candidates for combination trials, with goal of MRD negativity and therapy discontinuation

123 Ongoing Clinical Trials in CLL Agent Initial Therapy Relapsed Therapy Ibrutinib FCR vs IR two Ph 3 Ibrutinib FCR Ph 2 BR vs IR vs I Ph 3 I-Obin vs Clb-Obin Ph 3, >65/Co I in Del 17p CLL Ph 2 BR +/- I Ph 3 I vs IR ABT-199 Next slide ABT199-R vs BR Ph 3 ABT199 after BCRi Co = with comorbidities; I = ibrutinib.

124 Fourth-generation GCLLSG Trials Risk, Stage, and Fitness Adapted, Using Targeted Agents Active disease CLL13 CLL14 Go go Slow go FCR/ BR VenR VenG Ven IG CLB-G Ven-G Disease (MRD) eradication and longer survival Long-term disease-control with minimal side effects G = obinutuzumab; Ven = venetoclax.

125 DFCI Biostatistics Donna Neuberg Lillian Werner Haesook Kim Kristen Stevenson Wu Lab, DFCI Catherine Wu Lili Wang Youzhong Wan Acknowledgments Brown Lab, DFCI Ben Lampson Siddha Kasar Bethany Tesar Stacey Fernandes Lijian Yu Reina Improgo Josephine Klitgaard Weijie Poh Ritz Lab, DFCI Tiago Matos Research Nurses Karen Francoeur Victoria Patterson Kathleen McDermott Kim Coleman Lymphoma Program, DFCI Arnold S Freedman David C Fisher Ann S Lacasce Eric Jacobsen Philippe Armand Matthew Davids Caron Jacobson Broad Institute Eric Lander Gaddy Getz Carrie Sougnez Nir Hacohen Stacey Gabriel Mike Lawrence Petar Stojanov Andrey Sivachenko Kristian Cibulskis David Deluca Center for Cancer Genome Discovery Megan Hanna Laura Macconaill -NIH, NHGRI -CLL Research Consortium -ACS Clinical Research Staff Sara Schlegel John Hanna Krystle Benedict Karen Campbell Shannon Milillo Hazel Reynolds MO Pilot Grant Okonow-Lipton Fund Melton Fund Rosenbach Fund

126 Questions?