Raising the Bar in CLL Michael E. Williams, MD, ScM Byrd S. Leavell Professor of Medicine Chief, Hematology/Oncology Division University of Virginia Cancer Center
The Clinical Continuum of CLL Early asymptomatic Later symptomatic Late active, resistant, limited disease control Progressive, refractory disease Healthy MBL Healthy at risk FISH: del(13q) > Normal > Tri(12) > del(11q) > del(17p) IGVH: mutated > unmutated Slide courtesy of William Wierda, MD
Molecular Function of Cellular Biomarkers in CLL Mertens D, et al. J Clin Oncol. 2014;32(9):869-872.
Approaching the Patient With CLL: Cumulative Index Rating Scale [CIRS] Unfit patients: Supportive therapy CIRS >12 Less fit: Reduced-intensity treatment CIRS 7-12 Fit patients: Standard treatment CIRS 0-6 Physically fit No significant comorbidities [CIRS 3/4] Excellent renal function Regardless of age Frailty Miller MD, et al. Psychiatry Res. 1992;41(3):237-248. Moffitt Cancer Center CIRS-G Score Calculator Online Tool. Available at: http://eforms.moffitt.org/cirsgscore.aspx. Accessed April 22, 2015.
CIRS 14 Organs and Systems Scored Scoring of severity rating: 0 No problem affecting that system 1 Current mild problem or past significant problem. 2 Moderate disability or morbidity and/or requires first line therapy 3 Severe problem and/or constant and significant disability and/or hard to control chronic problems 4 Extremely severe problem and/or immediate treatment required and/or organ failure and/or severe functional impairment Online calculator: http://farmacologiaclinica.info/scales/cirs-g/ Miller MD, et al. Psychiatry Res. 1992;41(3):237-248.
Renal Level 0: No problem CIRS Level 1: S/P kidney stone passage within the past 10 years or asymptomatic stone/pyelonephritis within 5 years Level 2: Serum creatinine >1.5 mg/dl but <3.0 mg/dl, without antihypertensive or diuretic use Level 3: Serum creatinine >3.0 mg/dl, or > 1.5 mg/dl in conjunction with diuretic, antihypertensive, or bicarbonate therapy/current pyelonephritis Level 4: Requires dialysis / Renal carcinoma S/P, status post Moffitt Cancer Center CIRS-G Score Calculator Online Tool. Available at: http://eforms.moffitt.org/cirsgscore.aspx. Accessed April 22, 2015.
Treatment of the Fit Patient With CLL Patient criteria Physically fit No significant comorbidities Excellent renal function Regardless of age CLL8 trial: Superiority FCR over FC (OS advantage) FCR v FR unknown Ongoing CALGB/Alliance Trial for non-del(11q) BR commonly used CLL 10 addressed FCR v BR Long-term data from MDACC suggest a survival plateau after 10 years with FCR front-line therapy MDACC, MD Anderson Cancer Center
CLL10 Study FCR vs BR in Front-Line: Schema Patients with untreated, active CLL without del(17p) and good physical fitness (CIRS 6, CrCl 70 ml/min) Randomization FCR Fludarabine 25 mg/m² IV, days 1-3 Cyclophosphamide 250 mg/m², days 1-3, Rituximab 375 mg/ m 2 IVday 0, cycle 1 Rituximab 500 mg/m² IV day 1, cycle 2-6 BR Bendamustine 90 mg/m² day 1-2 Rituximab 375 mg/m² day 0, cycle 1 Rituximab 500 mg/m² day 1, cycle 2-6 Noninferiority of BR in comparison to FCR for PFS:HR (λ BR/FCR) less than 1.388 CrCl, creatinine clearance Eichhorst B, et al. Blood. 2014;124: Abstract 642.
CLL10 Study FCR vs BR in Front-Line: Patient Prognostic Factors Baseline Prognostic Factors FCR n = 282 BR n = 279 Binet stage A 22.4% 22.2% P Value Binet stage B 37.4% 38.4%.970 Binet stage C 40.2% 39.4% IGHV unmutated 55% 68%.003 11q deletion 24.1% 22.6%.691 Trisomy 12 12.4% 12.2% 1.000 13q deletion 55.0% 52.7%.612 s-tk (U/L) 0.0 73.9% 74.3%.921 s-β2m (mg/l) 3.5 31.6% 39.5%.059 Median CIRS score = 2 More patients >70 years in BR arm (22% vs 14%; P =.02) Eichhorst B, et al. Blood. 2014;124: Abstract 642.
CLL10 Study FCR vs BR in Front-Line: Results Median Follow-Up 36 Months; ORR 98% in Each Arm FCR n = 282 BR n = 279 P Value CR 41% 32%.026 MRD neg PB 74% 63%.024 MRD neg BM 58% 32% <.001 MRD neg @18 months 54% (35/65) 25% (16/65.006 Med PFS 54 mo 43 mo.001 PFS same for IGVH mutated patients, but unmutated better with FCR: 44 months vs 34 months BM, bone marrow; CR, complete response; MRD, minimal residual disease; PFS, progression-free survival; PB, peripheral blood Eichhorst B, et al. Blood. 2014;124: Abstract 642.
CLL10 Study FCR vs BR in Front-Line: Adverse Events (AEs) Grade 3-5 Adverse Event FCR % BR % P Value All 90.8 78.5 <.001 Hematologic AEs 90.0 66.9 <.001 Neutropenia 88 68 <.001 Anemia 14 12 NS Thrombocytopenia 22 17 NS Infection 40 25.001 Treatment-related mortality 3.9 2.1 NS Eichhorst B, et al. Blood. 2014;124: Abstract 642.
CLL10 Study FCR vs BR in Front-Line: Conclusions Final analysis shows that FCR remains standard front-line therapy for very fit CLL patients BR remains an appropriate choice for many patients No difference in OS at 36 months: FCR 91 vs BR 92% Imbalance in IGHV status biases against BR arm FCR induces higher rates of serious AE (neutropenia, infections) Antimicrobial prophylaxis and growth factor use to be reevaluated (not recommended in this trial) Eichhorst B, et al. Blood. 2014;124: Abstract 642.
Treatment of the Medically Unfit Patient With CLL Patient criteria One or more significant comorbidities May have impaired renal function Increases treatment-related toxicities Chlorambucil typically used as control arm in clinical trials FR may reduce hematologic toxicity vs FCR Trials of newer anti-cd20 antibodies combined with chlorambucil Trials of targeted agents
Determining the Goals of Treatment for Older Patients With CLL Shanafelt T. Hematology Am Soc Hematol Educ Program. 2013;2013:158-167.
The Tight Link Between Efficacy and Toxicity With Historic CLL Therapy a b b b a a a a a a b a a a b a b b b a a. Phase III data. b. Phase II data Shanafelt T. Hematology Am Soc Hematol Educ Program. 2013;2013:158-167.
GCLLSG CLL11 Trial Untreated CLL Elderly/Comorbid Patients Chlorambucil Rituximab/ Chlorambucil Obinutuzumab/ Chlorambucil Obinutuzumab (GA101) Novel type II anti-cd20 antibody Increased direct cell killing and ADCC
Obinutuzumab (GA101)/Chlorambucil vs Rituximab/Chlorambucil in CLL: Patients Characteristic Age, median (range) 74 (39-88) Obinutuzumab-Clb (G-Clb) v Clb 72 (43-87) Rituximab-Clb (R-Clb) v Clb 73 (40-90) 73 (43-87) G-Clb v R-Clb 74 (39-89) 73 (40-90) CIRS Score 8 (1-20) 8 (0-18) 8 (0-18) 8 (0-18) 8 (0-22) 8 (0-18) Median CrCl, ml/min 61.4 63.8 61.8 63.8 62.5 62.6 Binet A B C 23% 41% 36% 20% 42% 37% 21% 43% 36% 20% 42% 37% 22% 43% 35% 22% 41% 37% Unmutated 61% 59% 62% 58% 62% 61% del(17p) 8% 10% 5% 10% 7% 7% Goede V, et al. N Engl J Med. 2014;370(12):1101-1110.
Obinutuzumab (GA101)/Chlorambucil vs Rituximab/Chlorambucil in CLL: Results Goede V, et al. N Engl J Med. 2014;370(12):1101-1110.
Obinutuzumab (GA101)/Chlorambucil vs Rituximab/Chlorambucil in CLL: Summary and Conclusions G-Clb demonstrated superiority to R-Clb ORR: 78% vs 65%; CR: 21% vs 7% (P<.0001) PFS: 26.7 months vs 15.2 months (P<.0001) MRD negativity: 20% vs 3% (BM) and 38% vs 3% (blood); (both P<.0001) G-Clb had an acceptable safety profile Most common AE was neutropenia (33% G-Clb vs 28% R-Clb) Higher infusion-related reactions occurred during cycle 1 (20% G-Clb vs 4% R-Clb) Goede V, et al. Blood. 2013;122: Abstract 6.
COMPLEMENT 1: Chlorambucil ± Ofatumumab in Elderly or Unfit Patients With CLL Key eligibility criteria Untreated CLL patients with active disease (N = 447) Inappropriate for F-based therapy ECOG 2 1:1 Ofatumumab + Chlorambucil (O + Clb; n = 221) Clb alone (n = 226) Primary: PFS by IRC Secondary: ORR*, OS, safety Chlorambucil: 10 mg/m 2 PO d1-7 q28d; maximum 12 cycles Ofatumumab: 300 mg IV d1 cycle 1, 1000 mg d8 cycle 1; 1000 mg d1 cycle 2-12; q28d Phase III comparison of front-line chlorambucil alone vs chlorambucil + ofatumumab *Response measured per IWCLL 2008 criteria. Hillmen P, et al. Lancet. 2015 April 13. [Epub ahead of print].
Chlorambucil ± Ofatumumab in Elderly or Unfit Patients With CLL: Efficacy Response Clb (n = 226) O + Clb (n = 221) P Value ORR 69% 82%.001 CR 1% 14% SD 23% 12% PD 4% 2% Median PFS, months (95% CI) 13.1 (10.6-13.8) 22.4 (19.0-25.2) Median TTNT, months (95% CI) 24.7 (22.6-29.1) 39.8 (34.7-48.8) 2-year OS 87% 89% NS More neutropenia in O+CHL arm; no difference in infection rates ORR, overall response rate; OS, overall survival; PD, progressive disease; SD, stable disease; TTNT, time to next treatment Hillmen P, et al. Lancet. 2015 April 13. [Epub ahead of print].
Chlorambucil ± Ofatumumab in Elderly or Unfit Patients With CLL: Summary and Conclusions O + Clb showed improved efficacy over Clb Elevated grade 3/4 AEs were shown with O + Clb, including mild infusion-related reactions and neutropenia First-line O + Clb demonstrated clinical improvement over Clb with a manageable side effect profile in patients with CLL unfit for fludarabine-based therapy Hillmen P, et al. Lancet. 2015 April 13. [Epub ahead of print].
PCYC-1102/1103: Phase II Study Design Patients with CLL/SLL treated with oral, once-daily ibrutinib (420 mg/day or 840 mg/day) Treatment Naïve (TN) 65 years n = 31 Relapsed/ Refractory a (R/R) n = 101 SD n = 95 Long-Term Follow- Up Study a 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 Phase II (PCYC-1102) and extension (PCYC-1103) study 132 patients with treatment-naïve (TN) or R/R CLL/SLL Efficacy and safety 3 years follow-up SLL, small lymphocytic leukemia Byrd JC, et al. N Engl J Med. 2013;369(1):32-42. O Brien SM, et al. J Clin Oncol. 2014;32 (5s): Abstract 7014.
Ibrutinib: Response Improves Over Time Median time to first response: 1.9 months (range, 1.4-23.2) Median time to best response: 7.3 months (range, 1.7-31.8) 92% of patients who achieved a PR-L converted to better response *Cumulative response as assessed by investigator Byrd JC, et al. N Engl J Med. 2013;369(1):32-42. O Brien SM, et al. J Clin Oncol. 2014;32 (5s): Abstract 7014.
Progression-Free Survival, % PFS 100 90 80 70 60 50 40 30 20 10 0 TN R/R + Censored TN R/R 30-month PFS 96.3% 68.4% (95% CI) (76.5 99.5) (56.1 77.9) Median PFS Not reached Not reached 0 6 12 18 24 30 36 42 Months Byrd JC, et al. N Engl J Med. 2013;369(1):32-42. O Brien SM, et al. J Clin Oncol. 2014;32 (5s): Abstract 7014.
PFS, Proportion 1.0 PFS by Cytogenetics (FISH) in Relapsed/Refractory Population 0.8 0.6 0.4 0.2 0 30-month PFS Del17p Del11q No del17p/ 11q 45.9% 74.2% 89.0% (95% CI) (25.0 64.6) (53.3 86.8) (69.0 96.4) Median PFS 28.1 months Not reached Not reached del17p del11q + Censored No del17p or del11q 0 6 12 18 24 30 36 42 Months From Initiation of Study Treatment Byrd JC, et al. N Engl J Med. 2013;369(1):32-42. O Brien SM, et al. J Clin Oncol. 2014;32 (5s): Abstract 7014.
RESONATE Phase III 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 of 300 mg followed by 2000 mg 11 doses over 24 weeks n = 196 Enrollment Dates: June 2012 April 2013 Crossover to ibrutinib 420 mg once daily after IRC-confirmed PD (n = 57) (August 2013) Stratification according to: Disease refractory to purine analogue 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 Protocol amended for crossover with support of Data Monitoring Committee and discussion with health authorities. Byrd JC, et al. N Engl J Med. 2014;371(3):213-223.
RESONATE: Outcomes PFS and OS Byrd JC, et al. N Engl J Med. 2014;371(3):213-223.
Life After Ibrutinib? A New Unmet Need in CLL Possible Outcomes After Ibrutinib Discontinuation Pinilla-Ibarz J, et al. Blood. 2015;125(3):2013-2014.
Idelalisib/Rituximab: Randomized, Double-Blind, Placebo-Controlled Trial in Relapsed CLL (Study 116) Primary Study 116 Extension Study 117 Randomized Combination Therapy Continuing Single-Agent Therapy Extension Single-Agent Therapy Arm A (N = 110) Screening Arm B (N = 110) Rituximab (6 months) Idelalisib (150 mg BID) Placebo (BID) Rituximab (6 months) Disease Progression Idelalisib (300 mg BID) Idelalisib (150 mg BID) Rituximab administration 375 mg/m 2, then 500 mg/m 2 Q2W x 4, then 500 mg/m 2 Q4W x 3 Clinical Endpoints Primary: PFS as assessed by IRC Events: Disease progression or death Secondary: ORR, LNR, OS IRC, independent review committee Planned interim analyses at 50% and 75% of events Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
Study 116: Key Eligibility Criteria Relapsed CLL Lymphadenopathy Prior therapies Appropriate for noncytotoxic therapy Bone marrow function Karnofsky score Requirement CLL progression <24 months since last therapy Treatment warranted according to IWCLL criteria Presence of 1 measurable nodal lesion 1 anti-cd20 antibody containing therapy or 2 prior cytotoxic therapies CIRS score >6 or CrCl<60 ml/min ( 30 ml/min) or grade 3/4 neutropenia or thrombocytopenia due to prior myelotoxicity Any grade anemia, neutropenia, or thrombocytopenia allowed 40 IWCLL, International Workshop on Chronic Lymphocytic Leukemia Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
Response Idelalisib + R Placebo + R ORR a %, (95% CI) (n = 88; 88)* 50% reduction in lymph nodes b %, (95% CI) (n = 85; 84)* Organomegaly response % a P<.0001 b 50% reduction in SPD, P<.0001 * Number of evaluable patients (idelalisib; placebo) 81 (71-88) 13 (6-21) 93 (85-97) 4 (1-10) Spleen (n = 68; 52)* 79 25 Liver (n = 46; 50)* 70 52 Hematologic response % Hemoglobin (n = 56; 57)* 73 37 Neutrophils (n = 25; 25)* 84 64 Platelets (n = 47; 49)* 77 59 Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
B e Best s t % % C Change h a n g e in SPD S P D Change in Lymph Node Size 1 2 5 1 0 0 7 5 Idelalisib ID E L A + R+ it Rituximab u x im a b n = 858 5 a P laplacebo c e b o + + RRituximab u x im a b n = 884 4 a 5 0 2 5 0-2 5-5 0-7 5-1 0 0 a Evaluable patients SPD, sum of the products of the perpendicular diameters of measured lymph nodes Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
P r o g r e s s io n -fr e e s u r v iv a l (% ) PFS, % Primary Endpoint: PFS 1001 0 0 75 7 5 ID Idelalisib E L A + R+ it Rituximab u x im a b MMedian e d n PFS: P F S Not : n oreached t r e a c h e d 500 2255 HR H R = = 0.15 0 5 95% 9 5 % CI C(0.08, I.00.28) 8, 0.2 8 ) P<.0001 p < 0.0 0 0 1 PPlacebo e b o + + Rituximab R u x im a b MMedian e d n PFS: P F S 5.5 = 5 months.5 m o n t h s S u b je c ts a t ris k, n Idelalisib + R ID E L A + R : 1 1 0 Placebo + R P la c e b o + R : 1 1 0 0 0 2 4 6 8 110 0 112 2 114 4 116 6 Time, months T im e (m o n th s ) 6 9 4 4 3 4 3 0 1 4 6 2 0 6 2 3 0 1 8 1 3 6 1 1 0 Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
OS, % O v e r a ll s u r v iv a l (% ) OS 1001 0 0 75 7 5 IDIdelalisib E L A + R+ itrituximab u x im a b 505 0 2255 HR H R = 0.280 8 95% 9 5 % CI C I (0.09, 90.86), 0.8 6 ) P =.018 p 0.0 1 8 PPlacebo c e b o + Rituximab R u x im a b S u b je c ts a t ris k, n Idelalisib + R ID E L A + R : 1 1 0 Placebo + R P la c e b o + R : 1 1 0 0 0 2 4 6 8 110 0 112 2 114 4 1166 Time, months T im e (m o n th s ) 8 8 5 5 4 0 3 1 1 6 7 4 0 7 6 4 3 2 5 1 8 8 2 1 0 Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
Laboratory Abnormalities n (%) Idelalisib + R (n = 110) Placebo + R (n = 107) Any Grade Grade 3/4 Any Grade Grade 3/4 Anemia 28 (25) 6 (5) 32 (30) 15 (14) Neutropenia 60 (55) 37 (34) 52 (49) 24 (22) Thrombocytopenia 19 (17) 11 (10) 28 (26) 17 (16) ALT/AST elevation 38 (35) 6 (5) * 20 (19) 1 (1) * 4 of the 6 patients were successfully re-challenged (2 at 150 mg BID, 2 at 100 mg BID) Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
Summary and Conclusions In patients with heavily pretreated relapsed CLL not suitable for chemotherapy, idelalisib added to R: Improved PFS (HR = 0.15, P<.0001) including patients with del(17p)/tp53 mutation Improved ORR (OR = 29.92; P<.0001) and LNR (OR = 264.46; P<.0001) Improved OS (HR = 0.28, P =.018) Idelalisib + R demonstrated an acceptable safety profile Furman RR, et al. N Engl J Med. 2014;370(11):997-1007.
ABT-199 Monotherapy in R/R CLL: Schema Daily ABT-199 doses increased weekly to the designated cohort dose (DCD) * 3 patients (1 each in cohorts 2, 3, & 5) received ABT-199 20 mg as initial dose ** Step-up doses range from 100 to 400 mg # DCD ranges from 150 mg to 1200 mg Initial Ramp-Up Schema: Dose Escalation Ramp-Up Schema: Expanded Safety Cohort Seymour J, et al. Haematologica. 2014;99(Suppl 1): Abstract S702.
PFS at 400 mg or Higher Time, months Median PFS for patients treated at or above 400 mg has not yet been reached, (median follow-up of 5.3 months, range [0.03-22]) As of April 9, 2014, the median PFS for all patients is approximately 18 months Seymour J, et al. Haematologica. 2014;99(Suppl 1): Abstract S702.
PFS at 400 mg or Higher in High-Risk Patients Time, months Median PFS for fludarabine-refractory and/or del(17p) patients treated at or above 400 mg has not yet been reached (median follow-up 5.3 months, range [0.03-22]) Seymour J, et al. Haematologica. 2014;99(Suppl 1): Abstract S702.
ABT-199: Adverse Events All Grades 20% of Patients 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% Patients 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) Seymour J, et al. Haematologica. 2014;99(Suppl 1): Abstract S702.
Venetoclax (ABT-199/ GDC-199) Oral Bcl-2 inhibitor with potent therapeutic activity Complete remissions in Rel/Ref CLL MRD-negative CRs observed Active in very high-risk CLL R/R del(17p) CLL Fludarabine-refractory CLL Combinations under study ABT-199 plus ibrutinib in trials for mantle-cell lymphoma (MCL) and CLL
Phase I/Ib Study of Ibrutinib Plus ABT-199 in R/R MCL UVA Hematologic Malignancies Program, Craig Portell, MD, PI Doses of ibrutinib and ABT-199 will be escalated; 6 sequential doses ABT-199 given at low dose initially due to tumor lysis risk Combination given for 6 months, then single agent ibrutinib Rationale based upon preclinical CLL and MCL studies at UVA ABT-199 (mg per day) Zone and Arm, Designation by Combination 400 (week 3+) 200 (week 2) Zone 2 / Arm C Zone 3 / Arm E Zone 4 / Arm F 100 (week 1) 200 (week 3+) 200 (week 2) Zone 1 / Arm A Zone 2 / Arm B Zone 3 / Arm D 100 (week 1) All subjects 100 ABT (week 0) 280 420 560 Ibrutinib begin week 1+ (mg per day) Dose Schedule Week 0 Week 1 Week 2 Week 3 + ABT-199 ABT-199 ABT-199 ABT-199 100 mg D 100 mg D 200 mg D 200 mg D OR 400 mg D Ibrutinib 0 Ibrutinib fixed dose D Ibrutinib fixed dose D Ibrutinib 280 mg D Axelrod M, et al. Leukemia. 2014;28(2):407-410. Portell C, et al. Blood. 2014;124: Abstract 509.
Evolving Approaches in CLL Shift toward front-line noncytotoxic regimens MRD negativity as a therapeutic goal in younger and fit patients Risk-adapted therapy based upon biomarkers: cytogenetics, IGVH status, etc Combinations of targeted agents aimed at deep remissions Prolonged TTNT Cure?