Management of 17p Deleted CLL Patients in the Era of Targeted Therapy

Management of 17p Deleted CLL Patients in the Era of Targeted Therapy Jennifer R Brown, MD PhD Director, CLL Center Dana-Farber Cancer Institute Associate Professor Harvard Medical School November 11, 2016

Conflict of Interest Disclosure I hereby declare the following potential conflicts of interest concerning my presentation: Consultancy: Janssen, Pharmacyclics, Celgene, Roche/Genentech, Gilead, Infinity, Abbvie, Sun Biopharma Research Funding: Acetylon Discussion of off-label drug use: venetoclax, idelalisib for upfront therapy

Overall Survival by FISH Patients surviving (%) 100 80 60 40 20 Del 17p: 32 m Del 11q: 79 m 17p- 11q- 12q trisomy Normal 13q deletion as sole abnormality 0 0 12 24 36 48 60 72 84 96 120 144 168 Months NEJM 2000;343:1910

CLL8: Survival after FCR by FISH 17p deletion +12q 13q-single 11q- Not 17p-/11q-/+12q/13q- 17p- Lancet 2010: 376: 1164

CLL8: Impact of TP53 Mutation on OS TP53: wild type mutated Therapy: FCR FC

CLL8 Multivariable Analysis: Predictive Factors Cox regression including: FC, FCR, TP53, NOTCH1, SF3B1, and treatment interaction PFS: HR p-value FCR 0.544 <.001 TP53 mut 3.607 <.001 SF3B1 mut 1.355 0.012 NOTCH1 mut 1.652 0.022 Interaction OS: HR p-value FCR 0.654 0.002 TP53 mut 4.470 <.001 NOTCH1 mut 1.331 0.344 Interaction

MVA Analysis: Impact of MRD and Clinical Response in CLL8 & COX regression PFS MRD status Univariate comparison 10 HR Lower 95 % CI Upper p value Positive vs. negative 3.487 2.678 4.541 < 0.001 Clinical response PR vs. CR 1.420 1.075 1.876 = 0.014 Deletion 17p Yes vs. no 9.082 4.325 19.072 < 0.001 IgHV analysis Unmutated vs. mutated 2.582 1.930 3.455 < 0.001

Incidence of Genetic Lesions CLL8: CLL3X:* CLL2H: # 1st Line High-Risk F-refractory (FC vs. FCR) (Allo-SCT) (Alemtuzumab) n=635 n=80 n=97 TP53 mut 11.5 30.0 37.4 NOTCH1 mut 10.0 13.8 13.4 SF3B1 mut 18.4 26.3 17.5 IGHV UM 63.0 95.6 76.3 17p- 8.2 18.1 30.1 11q- 24.6 36.1 19.4 *Dreger et al. abstract 966, Tue 8:45, # Schnaiter et al. abstract 710, Mo 4:45

Ibrutinib (PCI-32765): BTK Inhibitor O Forms a specific and irreversible bond with cysteine-481 in Btk NH 2 Potent Btk inhibition N N N N IC 50 = 0.5 nm Orally available N O Once daily dosing results in 24-hr sustained target inhibition

Phase II in CLL/SLL PCYC-1102-CA 116 patients treated with ibrutinib monotherapy Endpoints: ORR, PFS, OS, Safety, PK/PD Enrolled May 2010 July 2011 Treatment Naïve (TN) 65 yrs 420 mg/d or 840 mg/d ibrutinib (n=31) Median follow-up 20.3 months Relapsed/Refractory (R/R) 420 mg/d or 840 mg/d ibrutinib (n=61) Median follow-up 22.1 months High-risk* Relapsed/Refractory (HR) 420 mg/d ibrutinib (n=24) Median follow-up 14.7 months *High risk defined as progression of disease < 24 months after initiation of a chemoimmunotherapy regimen or failure to respond

100% 80% 60% 40% 1102 Best Response (Investigator-Assessed) 90% 84% 89% 7% 11% 23% 1% 3% 80% 74% 55% CR npr PR PR+L SD PD 20% 0% Median DOR in months (range)3 Month 30 (95% CI) 6% 10% 0% 3% 4% 2% 4% 5% 2% TN (n = 31) R/R (n = 101) Total (N = 132) NR (0 to 35.0+) NR (0 to 35.2+) NR (0 to 35.2+) 100.0% (NE) 79.1% (64.2 to 88.4) 85.3 (74.4 to 91.8) 5/6 patients who received prior idelalisib responded to ibrutinib (4PR, 1 PR+L) 2/5 responders continue treatment with one additional patient moving on to SCT O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

1102 PFS by Cytogenetics (FISH) in 1.0 Relapsed/Refractory CLL Progression-Free Survival (Proportion) 0.8 0.6 0.4 0.2 0 30- month PFS Del17p Del11q No del17p/ 11q 45.9% 74.2% 87.0% (95% CI) (25.0 64.6) (53.3 86.8) (69.0 96.4) Median PFS 28.1 mos NR NR del17p del11q No del17p or del11q + Censored 0 6 12 18 24 30 36 42 Months From Initiation of Study Treatment O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

Overall Survival by Cytogenetics (FISH) in Relapsed/Refractory Population 1.0 Overall Survival (Proportion) 0.8 0.6 0.4 0.2 0 del17p del11q No del17p or del11q + Censored Del17p Del11q No del17p/11q 30-month OS 65.9% 84.9% 93.9% (95% CI) (45.5 80.2) (64.5 94.0) (77.8 98.4) Median OS NR NR NR 0 6 12 18 24 30 36 42 Months From Initiation of Study Treatment O Brien et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7014).

MDACC: EFS on Ibrutinib Del 17p only No complex karyo Thompson et al. Cancer 2015 1

Byrd et al. N Engl J Med. 2014 Jul 17;371(3):213-23. RESONATE Phase 3 Study Design Patients with previously treated CLL/SLL R A N D O M I Z E 1:1 Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity n=195 IV ofatumumab initial dose 300 mg followed by 2000 mg 11 doses over 24 weeks n=196 Crossover to ibrutinib 420 mg once daily after IRC-confirmed PD (n=57) Stratification according to: Disease refractory to purine analog chemoimmunotherapy (no response or relapsed within 12 months) Presence or absence of 17p13.1 (17p del) At time of interim analysis, median time on study was 9.4 months

PCYC 1112 RESONATE: PFS by Del17p Brown et al. ASH 2014.

PCYC 1112 RESONATE: PFS by Del17p Brown et al. ASH 2014.

RESONATE: Characteristics of Patients With Progressive Disease

Outcomes of Del(17p) CLL Patients Treated with Ibrutinib (n=243) Del17p by FISH* S T U D Y PCYC-1102 Central laboratory PCYC-1112 Local assessment PCYC-1117 Central laboratory Once-daily ibrutinib 420 mg (n=232) or 840 mg (n=11) until PD or unacceptable toxicity R/R (n=241) TN (n=2) Endpoints ORR*, PFS, and OS Sustained hematologic improvement over baseline Grade 3 adverse events (AEs) of clinical interest PCYC-1102/1103 Complex karyotype outcomes *% of del17p reflected the assay specific definition of positive and negative. ORR includes CR, CRi, PR, npr, and PR-L. Complex karyotype: 3 unrelated chromosomal abnormalities by stimulated cytogenetics as assessed by a reference laboratory. J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

Overall Response Rate Median time on study, mo (range) 42 (0.9-61) 31 (0.3-37) 28 (0.5-31) 28 (0.3-61) Median duration of response (DOR) not reached at 30 months For patients who achieved CR/CRi (n=23), an estimated 81% maintained response at 30 months J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

PFS for Patients with Del17p CLL on Ibrutinib 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: 0.3-61) J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

Cumulative Incidence of Richter s Transformation and Other Progression Cumulative incidences similar for RT and other PD in the first year All but 2 RT events occurred in the first 2 years Median time to PD for patients who have progressed RT (n=28): 239 days Non-RT (n=53): 582 days PD, progressive disease; RT, Richter s transformation. J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

PFS and OS by Lactate Dehydrogenase Levels, Prior Therapies, and Bulky Disease J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

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): 72»10 9 /L (20-151) vs 110»10 9 /L (17-310) Rai stage III-IV: 64% vs 40% CK, complex karyotype; NR, not reached. J. Jones et al. EHA Annual Meeting 2016. Abstract S429.

OSU, Survival: Progressive CLL v. Richter s Median = 17 months Median = 3.5 months

Characteristics of Patients with Identified Mutations at CLL Relapse Patient Age No. Prior Therapies Cytogenetics Study Treatment Duration on Ibrutinib Best Response Identified Mutation 1 59 5 del(17p13.1), +12 560 mg qd 621 days PR C481S BTK 2 75 2 del(17p13.1), complex karyotype 420 mg qd 673 days PR R665W PLCγ2 3 59 3 del(11q22.3) 4 51 2 complex karyotype BR x 6 cycles, 420 mg qd Ofatumumab x 24 weeks, 420 mg qd 388 days CR C481S BTK 674 days CR C481S BTK 5 69 9 del(17p13.1), complex karyotype 840 mg qd 868 days PR C481S BTK 6 61 4 del(17p13.1), complex karyotype Ofatumumab x 24 weeks, 420 mg qd 505 days PR * No mutations identified in kinases with homology at C481 L845F, R665W, S707Y PLCγ2, C481S BTK Woyach et al, NEJM 2014

Frontline Ibrutinib in del(17p) 100 Overall Survival Overall Survival (%) 80 60 40 20 0 Relapsed/Refractory Previously Untreated P = 0.42 0 6 12 18 24 30 Months Previously Untreated Relapsed Refractory N 35 16 Median Follow-up 15 months 26 months 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):169-176.

Venetoclax (ABT-199) Response in Response Overall response Relapsed/Refractory CLL/SLL All (n = 116) del(17p) (n = 31) F- Refractory (n = 70) IGHV Unmutated (n = 46) 79% 71% 79% 76% 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 48 38 (24, 53) 83 (70, 93) Roberts AW, et al. N Engl J Med. 2015. Online ahead of print.

Venetoclax (ABT-199) in Relapsed/Refractory CLL/SLL Roberts AW, et al. N Engl J Med. 2015. Online ahead of print.

Detailed Risk Stratification of Patients for Tumor Lysis 2014 EHA Annual Meeting, Poster 868 30

Venetoclax in High-Risk R/R CLL with del17p: Baseline Characteristics Characteristic, n (%) N=107 a (%) Age, years Median, range 67, 37 85 Sex Male 70 (65) Prior therapies Median, range 2, 1 10 Prior bendamustine / refractory 54 (50) / 38 (70) Prior fludarabine / refractory 78 (73) / 34 (44) Bulky nodes One or more nodes 5 cm 57 (53) Absolute lymphocyte count 25 x 10 9 /L 54 (51) Low 19 (18) TLS risk category Medium 43 (40) High 45 (42) Rai stage III or IV 51(48) IGHV Unmutated 30 (81) Stilgenbauer et al., ASH 2015 (abstract LBA-6, oral presentation)

Venetoclax in R/R CLL with 17p del iwcll Response (74%) MRD-negativity Median time-to-first response: 0.8 months (0.1 8.1) Median time to CR/Cri (16%): 8.2 months (3.0 16.3) Of 45 patients tested, 18 achieved MRD-negativity in peripheral blood Stilgenbauer S et al, Blood 2015; 126(23): LBA-6.

Del 17p CLL: Durability of Venetoclax Activity Duration of Response (N=85) PFS and OS (N=107) 12-month estimates: All responders: 84.7% CR/CRi/nPR: 100% 12-month estimates (95% CI): PFS: 72.0% (61.8, 79.8) OS: 86.7% (78.6, 91.9) MRD-negative: 94.4% Stilgenbauer et al, ASH 2015

Venetoclax after Failure of Ibrutinib Characteristic Ibrutinib Arm n=41 Idelalisib Arm n=13 Median age, years (range) 67 (48 80) 69 (56 75) Male, n (%) 31 (76) 9 (69) Prior therapies Median (range) 5 (1 12) a 3 (1 9) b Prior ibrutinib, n (%) 41 (100) 3 (23) Median months (range) on ibrutinib 16 (1 56) 5 (2 10) Prior idelalisib, n (%) 3 (7) 13 (100) Median months (range) on idelalisib 10 (2 31) 10 (1 27) Intolerant to prior ibrutinib/idelalisib 11 (27) 6 (38) As of August 25, 2015 Jones JA et al. Blood 2015; 126(23): 715.

Disease Burden and Biologic Disease Burden at Study Entry, n (%) ALC Characteristics Ibrutinib Arm n=41 Idelalisib Arm n=13 25 x 10 9 /L 16 (39) 5 (39) Bulky disease 1 or more nodes >5 cm 14 (34) 7 (54) 1 or more nodes >10 cm 8 (20) 5 (39) Prognostic Factors, n/n (%) IGHV unmutated 24/28 (86) 6/8 (75) del(17)(p13.1) 19/39 (46) 0/13 (0) del(11)(q22.3) 12/41 (29) 3/13 (23) TP53 mutation 14/39 (36) 0/12 (0) As of August 25, 2015 Jones JA et al. Blood 2015; 126(23): 715.

Best Percent Change from Baseline in Nodal Mass by CT Scan Ibrutinib Arm n=41 Idelalisib Arm n=13 Assessed, post baseline CT or MRI scans, n (%) 31 (76) 9 (69) Achieved 50% reduction in nodal masses, n/n (%) 23/31 (74) 5/9 (56) Median time to 50% reduction in nodal masses, days (range) 50 (44 162) 50 (49 52) As of August 25, 2015 Jones JA et al. Blood 2015; 126(23): 715.

Best Objective Responses To Date Ibrutinib Arm (Up to Week 36) Idelalisib Arm 61% ORR a 3 CR 1 npr 19 PR b 50% ORR a 5 PR a Patients who have not reached assessment were not included in best objective response rate calculation b 2 subsequently progressed after achieving a PR at Week 24: 1 Richter s Transformation at Week 30 and 1 CLL progression at Week 32 As of August 25, 2015 Jones JA et al. Blood 2015; 126(23): 715.

Venetoclax after Failure of Ibrutinib: Response at Weeks 8 & 24 Median 19 wks on venetoclax in the ibrutinib arm N=41 Week 8 Week 24 Assessed, n 38 23 Not yet assessed 3 18 Overall Response, n (%) Complete response 0 3 (13) Partial response 20 (53) 11 (48) Stable disease 13 (34) 3 (13) Disease progression 1 (3) 2 (9) D/C prior to assessment 4 (10) 4 (17) As of August 25, 2015 Jones JA et al. Blood 2015; 126(23): 715.

Survival after Failure of Venetoclax 70 patients enrolled in Australia (2011-15) M12-175 : Venetoclax Monotherapy (Phase I) M13-365 : Venetoclax + Rituximab (Phase I) M13-982 : Venetoclax Monotherapy (Phase II, del(17p) CLL) 28 patients discontinued venetoclax: 16 (57%) Richter Transformation 7 (25%) CLL progression 5 (18%) other reasons Median 7.5 mos on venetoclax and 12 months (0 34) follow-up after discontinuation Median 4 prior regimens, 59% del 17p

Survival After Discontinuation of Venetoclax CLL (n=7), 1y OS 69% RS (n=16), 1y OS 48% Median OS 1 year CLL vs RS, p=0.88 Others (n=5) Months

PI3K Signaling Pathway as a Target in B Cells

GILEAD 116: PFS, Including Extension Study* Idelalisib + R vs Placebo + R All Patients Progression-free Survival (% ) 100 80 60 40 20 Idelalisib + R (N=110) Placebo + R (N=110) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 N at risk Time (months) IDELA + R 110 102 95 92 83 64 43 26 19 12 7 1 1 0 PBO + R 110 86 66 58 51 33 15 5 1 0 - - - - Median PFS (95% CI) HR (95% CI) p-value IDELA + R 19.4 mo (16.6, ) PBO + R 7.3 mo (5.5, 8.5) 0.25 (0.16, 0.39) <0.0001 *Placebo + R includes those patients who received open-label idelalisib after unblinding without prior progression (n=42). Blood 2014; 124: 330

PFS Subgroup Analysis* Idelalisib + R (N=110) IGHV: Unmutated vs Mutated Del17p/TP53mut: Present vs Not Present 100 100 Progression-free Survival (% ) 80 60 40 20 0 Mutated (n=19) Unmutated (n=91) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 80 60 40 20 0 No del17p/tp53mut (n=64) Del17p/TP53mut (n=46) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) N at risk Mutated 19 18 18 18 17 12 9 5 3 2 1 0 Unmut 91 84 77 75 68 54 34 21 16 10 6 1 1 0 Time (months) No del 64 61 59 59 52 37 21 14 11 8 4 1 1 1 Del 46 41 36 36 33 30 22 12 8 4 3 0 Median PFS (95% CI) p-value Median PFS (95% CI) p-value Mut NR (10.7, ) Unmut 19.4 mo (16.6, ) 0.75 No del 20.3 mo (19.4, ) Del 16.6 mo (13.9, ) 0.94 *Including extension study Blood 2014; 124: 330

GILEAD 115: BR-Idela vs BR IRC-Assessed PFS Study 115: Primary Endpoint Probability of PFS (%) Probability of PFS 100 80 60 40 20 IDELA + BR BR + Placebo IDELA + BR BR + Placebo Median PFS (mo) 23.1 11.1 HR (95% CI) 0.33 (0.24, 0.45) p-value <0.0001 Median follow-up time = 12 mont No. at risk (events) 0 0 6 12 18 24 30 Time (months) IDELA + BR 207 (0) 154 (25) 74 (51) 27 (61) 6 (63) 1 (64) BR + Placebo 209 (0) 145 (46) 36 (111) 11 (126) 1 (131) 0 (132) HR, hazard ratio; IRC, independent review committee. Zelenetz et al., ASH 2015 Abstract LBA-5

Results: Overall Survival Study 115: Secondary Endpoint 100 Probability of Survival (%) Probability of PFS 80 60 40 20 IDELA + BR BR + Placebo No. of deaths (%) 34 (16.4) 51 (24.4) Median OS (mo) NR NR HR (95% CI) 0.55 (0.36, 0.86) p-values = 0.008 (stratified) and 0.023 (unstratified) IDELA + BR BR + Placebo No. at risk (events) 0 0 6 12 18 24 30 Time (months) IDELA + BR 207 (0) 181 (14) 104 (27) 52 (30) 13 (33) 1 (34) BR + Placebo 209 (0) 180 (20) 93 (35) 33 (47) 8 (51) 0 (51) Zelenetz et al., ASH 2015 Abstract LBA-5

(New) Safety Information (March 2016) + Idela Control *Idela +/- BR Untreated CLL *Idela +/- R Prev treated NHL *Idela +/- BR Prev treated NHL N=664 7.4% death N=402 3.5% death Idela +/- R 2-3 prior therapies CLL Idela +/- Ofa 2-3 prior therapies CLL N=491 23.2% death N=406 31.5% death Idela +/- BR 2-3 prior therapies CLL

Infection Risk Already Known Median Prior Therapies DFCI Initial Therapy Initial Therapy Overall Relapsed Phase I 0 0 1 (2-3) 5 Gr 3-4 ANC 29% 28% / 22% 43% Febrile neutropenia Grade 3-4 Infection Opportunistic Infns 3% / 5% 11.1% 13% 17% / 17% 31.6% 5.6% PsA bacteremia 2 PJP 1 fungal 1 CMV 1 brain abscess Most PJP / CMV on combo studies with BR No PJP or CMV on 116 or 119 studies; a few on 115 2 PJP 2 fungal 1 CMV

Idelalisib + Rituximab in 65 Years Median time on therapy 22.4 months 97% ORR, 19% CR PFS 83% at 36 months 9 patients with del(17p)/tp53 mutation 100% ORR, 33% CR O Brien S, et al. Blood. 2015; 126(25):2686-94.

Idelalisib + R in Untreated CLL Over 65: All Cause AEs 25% Adverse Event n (%) with any Grade n (%) with Grade 3 Diarrhea** 35 (64) 15 (42) Pyrexia 27 (42) 2 (3) Nausea 24 (38) 1 (2) Rash 37 (58) 8 (13) Chills 23 (36) 0 (0) Cough 21 (33) 1 (2) Fatigue 20 (31) 0 (0) Pneumonia 18 (28) 12 (19) **10 patients reported as Gr 3 colitis, including 6 lacking any AE report of Gr 3 diarrhea Med time to Gr 3 diarrhea/colitis = 9 mos Lab Abnormality* n (%) with Increase to Grade 3 Transaminase elevations 15 (23) Neutropenia 18 (28) Anemia 2 (3) Thrombocytopenia 1 (2) O Brien S, et al. Blood. 2015; 126(25):2686-94.

Grade 3 4 Immune Tox More Common in Median Prior Therapies Less Pretreated Patients Phase I 3 Overall Relapsed 2 Initial Therapy 1 Upfront idela + ofa 5 1 (2-3) 0 0 Diarrhoea/Colitis 5.6% 14% 42% 13% Transaminitis 2% 14% 23% 52% Pneumonitis 5.6% 3% (6% pneumonitis/ fibrosis) 13% Rash 0 5% 13% 13% 1. O Brien SM et al. Poster 1994 presented at ASH 2014; 2. Coutré SE et al. Oral presentation at EHA 2015: S433.OI:10.3109/10428194.; 3. Brown JR et al. Blood 2014;123:3390 7.

Summary: Idelalisib Highly active in R/R (and untreated) CLL Extends PFS and OS in high risk relapsed patients No difference based on IGHV or 17p status Several categories of toxicity: Autoimmune: transaminitis, diarrhea /colitis, and pneumonitis Neutropenia and sepsis (primary cause of infectious deaths on recently halted upfront trials): not as common without BR, monitor closely and use growth factor Opportunistic infections previously described: PJP, CMV Prophylaxis mandatory for PJP, VZV, neutropenia CMV monitoring when febrile Idelalisib should not be used in the upfront setting (unless absolutely necessary) Limited data on response after ibrutinib

PFS by Ibrutinib vs Idelalisib (first KI)

PFS for Alternate KI by Discontinuation Reason RT excluded from analysis

Where Are We with 17p Deleted CLL? Three very active classes of drugs Start with ibrutinib, follow with venetoclax or PI3K Duration of ibrutinib response is still shorter than without del 17p : as little as 28 mos Efficacy of sequencing single agents is unknown To achieve durable responses, combinations are certainly needed, but no data yet

Allogeneic SCT for CLL in the Era of Novel Agents 2014 by American Society of Hematology Peter Dreger et al. Blood 2014;124:3841-3849

Outcomes RIC SCT in CLL GCLLSG MDACC Seattle DFCI CLL3X N 90 86 136 84 Conditioning FC-based +/- FCR mostly 2 GyTBI + F FB ATG PFS 42% EFS @ 36% @ 5 32% @ 5 42% @ 5 yrs 4 yrs yrs yrs OS 65% 51% 41% 62% NRM 23% 17% 32% 18% Relapse 40% 39% 36% 40% Key Poor Prognostic Factors -CD4 < 100 -Low serum IgG Uncontrolled disease at SCT -Alem TCD -LNs >= 5 cm -Alem w/in 12 mos Uncontrolled disease -SCT pre- 2004 DFCI 2004+ 42 64% at 5 yrs 83% 9.5% 26%

DFCI CLL SCT: PFS pre and post 2004 Probability RIC, >=2004 _ RIC, <2004 - - - MAC, >=2004.... MAC, <2004 RIC 2004-2008 Years from Transplantation Leukemia epub

TP53, SF3B1, and NOTCH1 Mutations and Outcome of Allotransplantation Dreger et al. Blood 2013: 121 (16); 3284-3286

Who Should Have SCT in the Era of BCR Inhibitors? del 17p patients, potentially in first remission (if post ibrutinib) but definitely in any later remission (especially if you are running out of known active agents or cannot access them) Progressors on ibrutinib?? Progressors on idelalisib vs venetoclax: Less clear, may have prolonged remission with ibrutinib

Issues with Considering SCT after Novel Agents Remissions are not deep, often insufficient to be optimal for SCT Time to recurrence after stopping the drug can be short Waiting for relapse may be too late due to fulminant relapse With current single agents, venetoclax is by far best for prepping a patient for transplant How to avoid resistance and/or better prepare for SCT? Combination therapy : potential for deeper remissions (ideally MRD negative) that may allow breaks, which will reduce selective pressure for resistance, or allow for SCT for consolidation