Advances in the treatment of Chronic Lymphocytic Leukemia Lab of B Cell Neoplasia - Division of Experimental Oncology Strategic Research Program on CLL Department of Onco-Hematology Università Vita-Salute San Raffaele - Milano Istituto Scientifico San Raffaele - Milano Paolo Ghia
Disclaimer: The event is supported by Janssen, Pharmaceutical Companies of Johnson & Johnson in EMEA The views expressed in these slides are those of the individual speaker(s) and do not necessarily reflect the views of Janssen, Pharmaceutical Companies of Johnson & Johnson in EMEA The presentations may include discussions on offlabel use of drugs
CLL treatment has evolved over multiple decades 1960s 1970s 1980s 1990s 2000s 2010s 2014-16 Single-agent alkylating agents (e.g. chlorambucil) Representative PFS/TFS (months) 1,a 12 Purine analogs (e.g. fludarabine) 20 Combination chemotherapy (e.g. FC) 34 Chemoimmunotherapy (e.g. FCR) 58 BR for patients not suitable for FCR 2 43 Novel targeted agents: idelalisib, ibrutinib and Venetoclax a PFS representative only; cannot be used to compare regimens directly because results are drawn from across trials with different patient characteristics B: bendamustine; C: cyclophosphamide; CIT: chemoimmunotherapy; CLL: chronic lymphocytic leukemia; F: fludarabine; PFS: progression-free survival; R: rituximab 1. Shanafelt T. Hematology Am Soc Hematol Educ Program 2013; 2013:158 167. 2. Eichhorst B, et al. ASH 2014 (Abstract 19; oral presentation).
ESMO 2016 guidelines update for first line CLL Confirmed diagnosis of CLL Early-stage (Binet A/B) with active disease or advanced stage (Binet C) Early-stage (Binet A/B) without active disease del(17p) or TP53 mutation No del(17p) or TP53 mutation Watch and wait until symptomatic Less fit Ibrutinib Or Idealisib + R*; Consider allosct in remission Fit Ibrutinib Or Idealisib + R*; Consider allosct in remission * only if not suitable for alternative treatment Less fit Clb + CD20 antibody Or Ibrutinib Fit FCR (BR considered in fit elderly patients with history of infections) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016
ESMO 2016 guidelines update for first line CLL Confirmed diagnosis of CLL Early-stage (Binet A/B) with active disease or advanced stage (Binet C) Early-stage (Binet A/B) without active disease del(17p) or TP53 mutation No del(17p) or TP53 mutation Watch and wait until symptomatic Less fit Ibrutinib Or Idealisib + R*; Consider allosct in remission Fit Ibrutinib Or Idealisib + R*; Consider allosct in remission * only if not suitable for alternative treatment Less fit Clb + CD20 antibody Or Ibrutinib Fit FCR (BR considered in fit elderly patients with history of infections) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016
Updated BHS guidelines for first line CLL Janssens et al,, Belg J Hematol 2015;6(5):195-202
Probability of PFS Percent Progression-Free Long term remissions with FCR CLL8 1 MDACC 2 N FCR IGHV M patients 113 FC IGHV M patients 117 FCR IGHV UM patients 197 FC IGHV UM patients 195 N IGHV-M, MRD neg 35 IGHV-M, MRD pos 34 IGHV-UM, MRD neg 35 IGHV-UM, MRD pos 66 1.0 100 0.8 75 0.6 50 0.4 0.2 25 0 p<0.001 by log-rank test 0 12 24 36 48 60 72 84 96 Time (Months) 0 p<0.0001 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (Years) IGHV, immunoglobulin heavy chain; M, mutated; MDACC, MD Anderson Cancer; UM, unmutated. 1. Fischer K, et al. Blood 2016; 127:208 215; 2. Thompson PA, et al. Blood 2016; 127:303 309.
ESMO 2016 guidelines update for first line CLL Confirmed diagnosis of CLL Early-stage (Binet A/B) with active disease or advanced stage (Binet C) Early-stage (Binet A/B) without active disease del(17p) or TP53 mutation No del(17p) or TP53 mutation Watch and wait until symptomatic Less fit Ibrutinib Or Idealisib + R*; Consider allosct in remission Fit Ibrutinib Or Idealisib + R*; Consider allosct in remission * only if not suitable for alternative treatment Less fit Clb + CD20 antibody Or Ibrutinib Fit FCR (BR considered in fit elderly patients with history of infections) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016
RESONATE-2 (PCYC-1115) Study Design Patients (N=269) Treatment-naïve CLL/SLL with active disease Age 65 years For patients 65-69 years, comorbidity that may preclude FCR del17p excluded Warfarin use 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 PD or unacceptable toxicity chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles IRCconfirmed progression PCYC-1116 Extension Study * In clb arm, n=43 crossed over to ibrutinib *Patients with IRC-confirmed PD enrolled into extension Study 1116 for follow-up and second-line treatment per investigator s choice (including ibrutinib for patients progressing on chlorambucil with iwcll indication for treatment). Phase 3, open-label, multicenter, international study Primary endpoint: PFS as evaluated by IRC (2008 iwcll criteria) 1,2 Secondary endpoints: OS, ORR, hematologic improvement, safety 1. Hallek et al. Blood. 2008;111:5446-5456; 2. Hallek et al, Blood. 2012; e-letter, June 04, 2012 Burger J et al, NEJM 2015
RESONATE-2 updated efficacy and safety data ORR in the ibrutinib arm 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 Barr et al., ASH 2016 (abstract 234, oral presentation)
Are We Harming Our Patients without MRD? RESONATE-2: Ibrutinib vs chlorambucil 1 No MRD-negative cases were reported 1.0 0.8 0.6 GCLLSG CLL11: Obinutuzumab + chlorambucil 2 Stratified HR: 0.39 95% CI: 0.31 0.49 p<0.0001 0.4 0.2 G-Clb R-Clb 88% reduction in the risk of progression or death for patients randomized to ibrutinib 41% of patients receiving chlorambucil have crossed over to receive ibrutinib 0.0 15.2 26.7 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) 1. Barr et al., ASH 2016; 2. Goede V, et al. N Engl J Med 2014
ESMO 2016 guidelines update for first line CLL Confirmed diagnosis of CLL Early-stage (Binet A/B) with active disease or advanced stage (Binet C) Early-stage (Binet A/B) without active disease del(17p) or TP53 mutation No del(17p) or TP53 mutation Watch and wait until symptomatic Less fit Ibrutinib Or Idealisib + R*; Consider allosct in remission Fit Ibrutinib Or Idealisib + R*; Consider allosct in remission * only if not suitable for alternative treatment Less fit Clb + CD20 antibody Or Ibrutinib Fit FCR (BR considered in fit elderly patients with history of infections) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016
1 Fraction Alive % Surviving TP53 disruption is associated with poor prognosis del13q14 +12 del11q22-q23 del17p13 Aberration Incidence Median OS (%) 1 (months) 1 17p del 7 32 11q del 18 79 +12 16 114 Normal 18 111 13q del 55 133 100 80 60 40 20 OS 1 Months 17p deletion 11q deletion Trisomy 12q Normal 13q deletion as sole abnormality 0 0 12 24 36 48 60 72 84 98 108 132 156 180 Missense Nonsense Frameshift 5 3 EX4 EX9 TP53 TP53 M 17p- TP53 M /17p- Wt t: wildtype; OS: overall survival DNA BINDING 393 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 OS 2 Wt (n=277; median not reached) TP53 M (n=14; 30.2 median months) 17p- (n=16; median 19.2 months) 0 12 24 36 48 60 72 84 96 108 Time (months) 1. Döhner H, et al. N Engl J Med 2000;343:1910 6; 2. Zenz T, et al. J Clin Oncol 2010;28:4473 9.
Overall survival FCR not effective in del17p/tp53 disrupted patients CLL8: FCR CLL8: FCR and FC in patients with TP53 mut 100 90 1.0 FC and TP53 WT FCR and TP53 WT FC and TP53 mut FCR and TP53 mut 80 70 60 50 40 30 20 10 0 +12q 13q-single 11q Not11p /11q /+12q/13q 17p Time since randomisation (months) 0 6 12 18 24 30 32 42 48 54 60 66 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Time (months) Hallek M, et al. Lancet 2010; Stilgenbauer S, et al. Blood 2014; Pettitt A, et al. J Clin Oncol 2012
Progression free survival (%) No Difference in PFS With or Without Del17p Del17p/TP53mut: Present vs Not Present 1 0 0 8 0 6 0 4 0 2 0 0 No del17p/tp53mut (n=64) Del17p/TP53mut (n=46) 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 T im e (m o n th s ) ibrutinib del17p, no ibrutinib del17p, yes ofatumumab del17p, no ofatumumab del17p, yes 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 (mo) NR NR 8.2 5.9 Hazard ratio 1.314 1.413 (95% CI) (0.698-2.473) (1.017-1.963) P value 0.396 0.039 Median PFS (95% CI) No del 20.3 mo (19.4, ) Del 16.6 mo (13.9, ) p-value 0.94 Thornton et al, EHA 2015 Vienna Sharman, ASH, 2014, Abstract 330
TP53 Network ERIC aims to advance assessment of TP53 aberrations through education about: Importance of testing all cases needing therapy, before first and later lines of treatment Quality of appropriate techniques in diagnostic laboratories to ensure reliable and comparable results between institutions Certification of laboratories Uppsala Copenhagen London Amsterdam Ulm Paris Bellinzona Brno Novara Madrid Thessaloniki Disease stage Clinical trial General practice Diagnosis Recommended Not indicated Update coming Comment Results of TP53 mutation testing will not influence soon initial watch and wait strategy 1L treatment Recommended Desirable Patients with TP53 mutation should be entered Patients should be treated with BCR >2L treatment Recommended Recommended Desirable onto a clinical trial exploring new therapeutic pathway agents inhibitor www.ericll.org. 1L: first-line; 2L: second-line Pospisilova S, et al. Leukemia 2012; 26:1458 1461.
ESMO 2016 guidelines update for first line CLL Confirmed diagnosis of CLL Early-stage (Binet A/B) with active disease or advanced stage (Binet C) Early-stage (Binet A/B) without active disease del(17p) or TP53 mutation No del(17p) or TP53 mutation Watch and wait until symptomatic Less fit Ibrutinib Or Idealisib + R*; Consider allosct in remission Fit Ibrutinib Or Idealisib + R*; Consider allosct in remission * only if not suitable for alternative treatment Less fit Clb + CD20 antibody Or Ibrutinib Fit FCR (BR considered in fit elderly patients with history of infections) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016
Idelalisib in first line: changes in 2016 2016 March April May June July August September 8 July PRAC concluded its review of idelalisib and recommended idelalisib-treated patients: receive PJP prophylaxis during treatment and for up to 6 months after treatment end are regularly monitored for CMV infection if CMV serology is positive at start of treatment or if there is a history of CMV infection Patients with evidence of CMV viraemia and clinical signs of infection should have their treatment interrupted until the infection is resolved are monitored for infection and have regular blood tests for white cell counts PRAC also concluded that idelalisib can again be initiated in first-line CLL treatment, in patients with del(17p)/tp53 mutation who are ineligible for other therapies 22 July The CHMP confirmed the PRAC recommendations 15 September. Final EC decision EC: European Commission; EMA: European Medicines Agency; CHMP: Committee for Medicinal Products for Human Use; PJP: Pneumocystis jirovecii pneumonia; PRAC: Pharmacovigilance Risk Assessment Committee EMA press release (8 July 2016; available at www.ema.europa.eu). EMA press release (22 July 2016; available at www.ema.europa.eu). Zydelig SmPC (Date TBC 2016; available at www.ema.europa.eu).
A cross-study analysis: ORR, del(17p) CR* 8% CR* 8% CR* 10% CR* 9% ORR 81% ORR 89% ORR 83% ORR 84% 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 not reached at 30 months *CR = CR + CRi Of patients with CR/CRi (n=23), 81% maintained response at 30 months CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete marrow recovery; IBR, ibrutinib; ORR, overall response rate; PR, partial response; PR-L, partial response with lymphocytosis; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma; TN, treatment-naïve Jones, EHA 2016, S429
Results: PFS and OS, del(17p) PFS OS 12-mo PFS, % (95% CI) 24-mo PFS, % (95% CI) 30-mo PFS, % (95% CI) 80% (74, 84) 63% (57, 69) 55% (48, 62) Median PFS not reached 12-mo OS, % (95% CI) 24-mo OS, % (95% CI) 30-mo OS, % (95% CI) 85% (80, 89) 75% (68, 80) 67% (59, 74) Median OS not reached With a median (range) study duration of 28 (0.3-61+) months, median PFS and OS were not reached CLL, chronic lymphocytic leukemia; IBR, ibrutinib; OS, overall survival; PFS, progression-free survival; R/R, relapsed/refractory; SLL, small lymphocytic lymphoma Jones, EHA 2016, S429
EMA approval for Venclyxto on 08DEC16 Venclyxto monotherapy is conditionally approved for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor Venclyxto monotherapy is conditionally approved for the treatment of CLL in without 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor Venetoclax WE&C Advisory Board I 2016 21
Ultra-high Risk R/R CLL patients with del17p Best Response with Venetoclax IRC, n (%) Investigator, n (%) Overall Response 85 (79.4) 79 (73.8) CR or CRi 8 (7.5) 17 (15.9) npr 3 (2.8) 4 (3.7) PR 74 (69.2) 58 (54.2) No response 22 (20.6) 28 (26.2) Stable disease NA 24 (22.4) Disease progression NA 2 (1.9) Incomplete data NA 2 (1.9) 25 of 48 patients with no CLL in the bone marrow 18 of 45 patients assessed were MRD-negative in PB Stilgenbauer et al, Lancet Oncology 2016
Cumulative Incidence of Response MRD-Negativity PFS and OS (N=107) Of 45 patients tested, 18 achieved MRD-negativity in peripheral blood 12-month estimates (95% CI): PFS: 72.0% (61.8, 79.8) OS: 86.7% (78.6, 91.9) Stilgenbauer et al, Lancet Oncology 2016
ESMO 2015 clinical practice guidelines for R/R CLL Relapsed CLL requiring treatment or refractory CLL Early relapse (within 24 36 months after chemoimmunotherapy) Late relapse ( 24 36 months after chemoimmunotherapy) Less fit Clinical study BCR inhibitor (± R) (BR or FCR- Lite may be considered if no del(17p) or TP53 mutation) Fit Clinical study BCR inhibitor (± R) Consider allo- SCT in remission del(17p) or TP53 mutation Treat as per early relapse Less fit Clinical study Repeat frontline or change to BR or BCR inhibitor (± R) No del(17p) or TP53 mutation Fit Clinical study Repeat frontline or change to BR/FCR or BCR inhibitor (± R) Eichhorst B, et al. Ann Oncol 2015; 26(Suppl 5):v78 v84
Updated BHS guidelines for Relapsed/Refractory CLL Janssens et al,, Belg J Hematol 2015;6(5):195-202
5-year experience with ibrutinib in TN and R/R CLL Median PFS 5-year PFS Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) 52 mo 43% TN (n=31) NR 92% R/R (n=101) NR 57% O Brien et al., ASH 2016 (abstract 233, oral presentation)
5-year experience with ibrutinib in TN and R/R Dose reductions and dose discontinuations due to AEs occurred more frequently in R/R patients than in TN patients, and during the first year after treatment compared with subsequent time periods. O Brien et al., ASH 2016 (abstract 233, oral presentation)
Patients (%) Searching for MRD HELIOS (BRI versus BR) ORR (investigator assessment) 2-yr update (October 2015) OR = 87.2% versus 66.1% (p<0.0001) 100 CR/CRi PR 80 53,3% 60 40 58.9% 20 0 33.9% Ibrutinib + BR 7.2% Placebo + BR BR, bendamustine + rituximab; CRi, CR with incomplete marrow recovery; OR, overall response. As of March 2016, 60/289 (20.7%) on IBR+BR demonstrated MRD-negativity Fraser G, et al. EHA 2016 Fraser G, et al. J Clin Oncol 2016; 34(suppl):Abstract 7525.
EMA approval for Venclyxto on 08DEC16 Venclyxto monotherapy is conditionally approved for the treatment of chronic lymphocytic leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor Venclyxto monotherapy is conditionally approved for the treatment of CLL in without 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor Venetoclax WE&C Advisory Board I 2016 29
Complete responses with BCL2 inhibitors: ABT-199 MRD-neg (% of CR) 80% 35% Roberts AW, et al. N Engl J Med 2016; 374(4): 311-22; EHA 2016 P209
M13-365: Venetoclax Combined with Rituximab in Patients with R/R CLL/SLL 55% of patients MRD-negative (27/49) Venetoclax + Rituximab in Patients with R/R CLL M13-365 (N=49) 11 patients stopped venetoclax after achieving an objective response (9 MRD-negative); 9 remain in follow-up* # None of the MRD-negative patients have progressed; 2 patients with MRD-positive CR/CRi had asymptomatic progression * * Time on venetoclax Time off venetoclax # MRD-negative PR * Discontinued from study Asymptomatic progression 0 5 10 15 20 25 30 35 40 * Two discontinued with no Brander, EHA 2016 P223 evidence of progression. Seymour JF et al, Lancet Oncol 2017
ORR to ABT-199 in CLL after Ibrutinib or Idelalisib 10 June 2016 Best response, n (%) Arm A n=43 Assessed by Arm B n=21 Assessed by IRC Investigator IRC Investigator ORR 30 (70) 29 (67) 13 (62) 12 (57) CR/CRi 0/1 (2) 2 (5)/1 (2) 0/0 2 (10)/1 (5) 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) *Non-responder category for IRC includes both SD or PD, which were not identified as separate categories per IRC. CLL progression and discontinued due to progression. D/C, patient discontinued the study prior to assessment. 9 (43) 8 (38) 1 (5) 0 Jones J et al, ASH 2016 Oral presentation
A r m B A rm A ORR to ABT-199 in CLL after Ibrutinib or Idelalisib 10 June 2016 Median time on study (range): Arm A, 13 months (0.1 18); Arm B, 9 months (1.3 16) # # P D # # # * # P D P D -R T # # # # # P D P D P D P D P D P D P D P D -R T P D # # P D A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) D is c o n tin u e d # P D P D C R i a s b e s t re s p o n s e * # M R D n e g a tiv e in b lo o d 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 T im e o n v e n e to c la x, m o n th s PD, progressive disease. PD-RT, progressive disease due to Richter's transformation. Early discontinuations were due to AEs (n=3) and withdrawn consent (n=1). Jones J et al, ASH 2016 Oral presentation
Anthony Mato. Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in CLL: Results from a Large Multi-Center Study of 683 US-Patients 683 patients treated with KI therapy (IBR=621; IDELA=62) were included Significantly better PFS for IBR vs IDELA in all settings; front-line, R/R, clinical trials, commercial use, del17p, or CKT Response to first kinase inhibitor ORR 81% ORR 69% Mato A et al, ASH 2016 Oral presentation
ESMO 2015 clinical practice guidelines for R/R CLL Relapsed CLL requiring treatment or refractory CLL Early relapse (within 24 36 months after chemoimmunotherapy) Late relapse ( 24 36 months after chemoimmunotherapy) Less fit Clinical study BCR inhibitor (± R) (BR or FCR-Lite may be considered if no del(17p) or TP53 mutation) Fit Clinical study BCR inhibitor (± R) Consider allo- SCT in remission Patients not responding nor progressing upon therapy with kinase inhibitors might be switched to a different kinase inhibitor or to BCL2 antagonists when available (according to clinical trials) del(17p) or TP53 mutation Treat as per early relapse Less fit Clinical study Repeat frontline or change to BR or BCR inhibitor (± R) No del(17p) or TP53 mutation Fit Clinical study Repeat frontline or change to BR/FCR or BCR inhibitor (± R) Eichhorst B, et al. Appendix 6: CLL: eupdate. Ann Oncol 2016 Eichhorst B, et al. Ann Oncol 2015; 26(Suppl 5):v78 v84
IS THIS THE END OF CHEMOTHERAPY? CLL13-TRIAL OF THE GCLLSG in cooperation with HOVON, Nordic CLL Study Group and SAKK (GAIA) Previously untreated Fit CLL patients (N=920) (CIRS 6 and normal creatinine clearance) Randomise FCR* or BR^ ABT-199 + Rituximab ABT-199 + Obinutuzumab ABT-199 Obinutuzumab Ibrutinib *<65 years of age ^>65 years of age Follow-up for progression and survival 2 primary endopints - Rate of MRD negativity - PFS Obinutuzumab: 6 cycles Venetoclax: 12 cycles Ibrutinib: 36 cycles or MRD neg
Università Vita-Salute San Raffaele Istituto Scientifico San Raffaele Department of Onco-Hematology Division of Experimental Oncology Laboratory of B Cell Neoplasia Lydia Scarfò, Andreas Agathangelidis, Maria Gounari, Alessandra Rovida, Tania Veliz-Rodriguez, Engin Bojnik, Pamela Ranghetti, Federica Barbaglio, Cristina Scielzo Laboratory of Lymphocyte Activation Eleonora Maria Fonte, Maria Giovanna Vilia, Marta Muzio CERTH, Thessaloniki Anna Vardi, Stavroula Ntoufa, Aliki Xochelli, Anastasia Hadzidimitrious, Kostas Stamatopoulos Uppsala University, Uppsala Lesley Ann Sutton, Panayotis Baliakas, Viktor Ljungstrom, Richard Roseqnuist Strategic Research Program on CLL Lydia Scarfò, Piera Angelillo, Maria Colia, Virginia Sgarlato, Stefania Cresta, Eloise Scarano Janssen-Cilag NV - vu/er Erik Present, Antwerpseweg 15-17, 2340 Beerse