Chronic lymphocytic leukemia Tanya Siddiqi, MD Assistant Professor City of Hope National Medical Center Duarte, CA How the Experts Treat Hematologic Malignancies Las Vegas, NV 3/2017
Disclosures Speaker for Pharmacyclics/Janssen (ibrutinib) Speaker for Seattle Genetics (brentuximab vedotin) I will be mentioning off label use for some novel treatments currently being investigated
Objectives Epidemiology Diagnosis and workup Monoclonal B-lymphocytosis Prognostic markers Staging Treatment initiation guidelines Therapeutic options
Overview Chronic lymphocytic leukemia (CLL) is a low grade leukemic lymphocytic lymphoma; small lymphocytic lymphoma (SLL) is a nodal form of the same disease CLL/SLL is the most common hematological malignancy in the Western world; incidence is ~5/100,000 persons per year in the US; median age at diagnosis ~72 years Male predominance; higher in Caucasians Exact etiology is unknown; ~10% patients with a family history of some lymphoma Muller-Hermlink HK, et al. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours in Haematopoietic and Lymphoid Tissues. Lyon, France. IARC press, 2001: 195-6.
Initial Presentation Clinical course is variable Many are asymptomatic at diagnosis Referred when white blood cell and/or lymphocyte counts are elevated on routine tests 10% have B symptoms Nabhan C et al. JAMA. 2014;312:2265-2276. Furman RR. Hematology Am Soc Hematol Educ Program. 2010:77-81.
Initial Workup H&P, performance status: note any B-symptoms CBC, differential, CMP, LDH, direct Coombs test Flow cytometry for diagnosis and to rule out masquerading lymphomas Peripheral blood monoclonal B lymphocytes 5 x 10 9 /L Immunophenotyping: k/l dim, CD5+, CD19+, CD20 dim, CD23+, CD10-, cyclin D1- FISH t(11;14) Imaging studies and bone marrow/ln biopsies are not routinely required NCCN Guidelines for Non-Hodgkin s Lymphomas Version 1.2016.
Monoclonal B-lymphocytosis (MBL) Presence of monoclonal lymphocytosis but with <5000 B-cells/uL in the peripheral blood and no accompanying lymphadenopathy or organomegaly by physical examination or radiographical imaging, cytopenias or disease-related symptoms is defined as MBL Incidence in the US is 3% Progression to CLL/SLL can occur @ 1-2% per year
Prognostic markers in CLL/SLL Cytogenetics/FISH: Del13q Trisomy 12 Del11q Del17p Del6q Mutations: TP53 mutations Notch1 mutations SF3B1 mutations IgVH mutation status ZAP70 CD38 Lymphocyte doubling time β2 microglobulin Rai/Binet stage
CLL Staging Rai stage Risk category Clinical features 0 Low Lymphocytosis alone 1 Intermediate Lymphadenopathy 2 Intermediate Hepato/splenomegaly 3 High Anemia (<11g/dl) 4 High Thrombocytopenia (<100,000/L) Binet stage A B C Clinical features HGB 10 g/dl, platelets 100/L, <3 areas of lymphadenopathy/ organomegaly* HGB 10 g/dl, platelets 100/L, 3 areas of lymphadenopathy/ organomegaly* Anemia (<10g/dl), thrombocytopenia (<100,000/L), or both *nodal areas: cervical [head and neck], axillary, inguinal (including femoral lymph nodes), spleen, liver
CLL Disease Progression Curve Adapted from: www.vaccinogeninc.com/sites/default/files/images/figure_4.jpg
MRD in CLL Retrospective study N = 255 CR after 1 st line chemoimmunotherapy Median followup = 73 months from disease evaluation Median treatment free durations: MRD neg CR 76 months MRD pos CR 40 months PR 11 months No response 11 months MRD negativity also affected OS significantly Pts from CLL8 and CLL10 trials N = 542 CR after 1 st line chemoimmunotherapy Median followup = 45.9 months PFS difference [p<0.001]: MRD neg CR 69.2 months MRD pos CR 40.4 months Also, PFS difference [p<0.008]: MRD neg PR 61.7 months MRD pos CR 40.4 months No PFS difference between MRD neg CR and MRD neg PR Santacruz R, et al. Haematologica 2014; 99 Kovacs G, et al. Blood 2014; ASH abstract
Course of CLL/SLL Remains incurable with current available therapies Therapies are associated with morbidity and mortality Current recommendation: watch and wait until patients develop active disease
Who needs treatment? International workshop on CLL (iwcll) guidelines for treatment initiation Hallek M, et al. Blood 2008. 111: 5446-56
iwcll guidelines for treatment initiation progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia massive ( 6cm below left subcostal margin), progressive, or symptomatic splenomegaly massive ( 10cm in longest diameter), progressive, or symptomatic lymphadenopathy progressive lymphocytosis with an increase of >50% over a 2 month period or LDT of <6 months autoimmune hemolytic anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy constitutional symptoms defined as 1 of the following: (i) unintentional weight loss of 10% within the previous 6months (ii) significant fatigue (ECOG PS 2;inability to work or perform usual activities) (iii) fevers >100.5F or 38C for 2 weeks without other evidence of infection (iv) night sweats for >1 month without evidence of infection
Who needs treatment and how to pick the right first line regimen? iwcll guidelines for treatment initiation Stage of disease Symptoms Fitness of patient Cytogenetic risk
Therapeutic options for CLL Watch and wait Radiation Immunotherapy Chemotherapy Combination chemoimmunotherapy Novel targeted therapies Cellular therapy Clinical trials
GCLLSG: frontline treatment (cont.) CLL11 study: Chlorambucil + obinutuzumab vs. Chlorambucil + Rituximab vs. chlorambucil alone Randomized, previously untreated, CLL patients with comorbidities N = 781 Median age = 73 years 3 arms of the study = G+Clb vs. R+Clb vs. Clb alone for 6 cycles Goede V, et al. NEJM 2014; 370: 1101-10
Obinutuzumab + Clb: NEJM 2014 370;12:1101(cont.) 3 months after treatment, CRs were seen exclusively after antibody combinations compared with Clb alone Median PFS was 26.7 months (G-Clb) vs 11.1 months (Clb) [p<0.001] and 16.3 months (R-Clb) vs 11.1 months (Clb) [p<0.001] G-Clb improved OS compared to Clb (p=0.002) G-Clb improved PFS (p<0.001), CRs (20.7% vs 7%) and molecular responses compared to R-Clb
German CLL study group (GCLLSG): frontline treatment CLL4 study: FC vs. fludarabine alone CLL8 study: FCR vs. FC Subgroup with exceptionally good outcome has right age/fitness, mutated IGHV genes and no del17p/del11q (plateau after 4 yrs; MRD neg 6 yrs later) CLL10 study: FCR vs. BR Eichhorst BF, et al. Hematol J 2006; 107: 885-91 Hallek M, et al. Lancet 2010; 376: 1164-74 Eichhorst B, et al. Blood 2014; 124: abs.19 Lancet Oncol 2016 Jul; epub 2016 May 20
FCR vs. BR: ASH 2014 abstract Phase 3 randomized trial, fit CLL patients with advanced stage disease, previously untreated, no 17p deletion Planned interim analysis N = 564; 6 cycles of either regimen FCR BR P-value ORR 97.8% 97.8% 1.0 CR 40.4% 31.5% 0.026 [higher MRD negative CRs in FCR arm] Median PFS 53.7 months 43.2 months 0.001 [better in <65 years old] OS at 3 years 90.6% 92.2% 0.910 Severe neutropenia 87.7% 67.8% <0.001 Severe infections 39.8% 25.4% 0.001 [especially in older pts]
ASH2016 MDACC experience with FCR N=289 [median age 59 yrs] Prospective analysis of pts getting frontline FCR Bone marrow biopsy after cycle 3 (n=239) and at end of treatment (n=231) ORR=96% 19% had MRD neg after cycle 3 and 51% at end of treatment patients with IGHV-M who achieved MRD-negativity after 3 courses had a particularly favorable outcome The best pre-treatment predictor of achieving MRD-negativity and subsequent longer PFS was IGHV-M Despite achieving MRD-negativity, many patients subsequently relapse; serial MRD monitoring in peripheral blood can herald relapse with a lead-time of approximately 2 years and potentially direct monitoring and/or early intervention strategies. Thompson et al. ASH 2016
Targeted therapies (small molecule inhibitors)
Monoclonal antibodies: update Anti-CD20 (dim expression on CLL/SLL cells typically) Obinutuzumab Ublituximab Anti-CD37 (expressed strongly on the surface of B-cells and transformed mature B-cell leukemia and lymphoma cells)
BTK inhibitors Ibrutinib ACP-196 (Acalabrutinib) CC-292 ONO-4059
Ibrutinib Ph1b/2 study of 85 CLL pts, mostly high risk ORR of 71% (2 CR, 34 PR) + 15-20% PR-L At 26 months, estimated PFS was 75% and OS 83% Well tolerated Byrd JC, et al. N Engl J Med 2013; 369: 32-42
Ibrutinib: RESONATE trial Phase 3 trial of ibrutinib (420mg po daily) vs. ofatumumab in r/r CLL N = 391 ORR 42.6% (+20% PR-L) vs. 4.1% (p<0.001) Median PFS not reached (88% PFS at 6 months) vs. 8.1 months (p<0.001) At 12 months, OS 90% (ibru) vs. 81% (ofa) (p=0.005) Byrd JC, et al. N Engl J Med 2014; 371: 213-23
PCYC-1102/1103 Phase 2: 5 year update ASH2016 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/Refracto ry * (R/R) n=101 SD Long-Term Follow-Up 5-year update, O Brien et al. ASH 2016 * 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
Ibrutinib Treatment Continued in 65% of TN and 30% of R/R Patients 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 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%) After ~5 years of follow-up, 65% of TN and 30% of R/R patients continue treatment on study 5-year update, O Brien et al. ASH 2016
Cumulative Frequency of Grade 3 Adverse Events Over 5-Year Follow-Up Non-hematologic 5% Hematologic Infectious R/R TN R/R TN R/R TN Grade 3 Grade 4 Grade 5 5-year update, O Brien et al. ASH 2016
Best Response 100% 80% 60% 40% 20% TN (n=31) R/R (n=101) Total (N=132) 87% 89% 89% 10% 14% 29% 76% 71% 55% CR PR PR-L 0% Median DOR, months (range) Median followup, months (range) 3% 3% 3% NR (0.0+ to 65.5+) 56.8 (0.0+ to 65.5+) NR (0.0+ to 65.5+) 62 (1 67) 49 (1+ 67) 56 (1+ 67) NR, not reached. 5-year update, O Brien et al. ASH 2016
Best Response in Patients With High-Risk Abnormalities 100% 80% 60% R/R del11q (n=35) 97% 9% R/R Unmutated IGHV (n=79) 90% R/R Complex Karyotype (n=41) 90% 9% 7% R/R del17p (n=34) 79% 6% CR PR PR-L 40% 86% 77% 76% 65% 20% 3% 4% 7% 9% 0% Median DOR, 38.7 (0.0+ to 65.3+) 53.2 (0.0+ to 65.5+) 38.7 (0.0+ to 65.5+) 30.6 (0.0+ to 65.3+) months (range) Median followup, months 55 (1+ 67) 49 (1+ 67) 55 (1 67) 47 (1 67) (range) NR, not reached. 5-year update, O Brien et al. ASH 2016
Survival Outcomes: Overall Population Progression-Free Survival Overall Survival Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57% NR, not reached. 5-year update, O Brien et al. ASH 2016
Ibrutinib: RESONATE-2 trial Ph3, international, open label, randomized trial of ibrutinib vs. Clb in previously untreated older CLL/SLL patients N = 269 Median age = 73 years ORR 86% vs. 35% (p<0.001) Significant improvement in EFS, PFS and OS with single agent ibrutinib compared to Clb Burger JA, et al. N Engl J Med 2015 Dec 17;373(25):2425-37
RESONATE-2 update PFS was significantly improved for ibrutinib across high-risk subgroups, including del11q and unmutated IGHV gene OS analysis resulted in 2-yr survival rate estimates of 95% (ibr) vs. 84% (clb) ORR was 92% with ibr vs 36% with clb (P<0.0001); CR/CRi within the ibr arm improved from 11% at 18.4 mo to 18% with longer follow-up of 28.6-mo RESONATE-2 update, Barr et al.ash2016
RESONATE-2 update 1 patient on each arm developed Richter s transformation 4 patients had disease progression and discontinued ibr 41% switched from clb to ibr Major hemorrhage in 7% (ibr) within the first 2 yrs Atrial fibrillation in 10% (ibr) 79% pts remain on ibr with median treatment duration of 28.5 months RESONATE-2 update, Barr et al.ash2016
Ibrutinib: RESONATE-17 trial Ph2 trial of r/r CLL/SLL with del17p Ibrutinib 420mg po qd until PD or unacceptable toxicity N = 144 Median prior regimens = 2 (range 1-7) Median age = 64 yrs At median followup of 11.5 months, investigator-assessed ORR was 82.6% (including 17.4% PR-L); CR/CRi in 3 patients Median PFS and median DOR not reached; at 12 months, 79% alive and progression free (88% responders were progression free) At primary analysis, 101 patients continue ibrutinib (70%) PD in 20 (including Richter s transformation in 11) Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%); 7 had major bleed (5%) mostly grade 3 O Brien S, et al. Blood 2014; ASH abstract
Ibrutinib: HELIOS trial Ph3 multicenter, randomized (1:1), double blind study Ibrutinib+BR vs. placebo+br (crossover to ibrutinib permitted) Del 17p pts excluded N=578 (289 each) Median f/u=17 months mpfs not reached vs. 13.3 months in placebo arm IRC assessed PFS at 18 mo was 79% vs. 24% Most common AEs were nausea and neutropenia Chanan-Khan A, et al. Lancet Oncol 2016 Feb; epub 2015 Dec5
ACP-196 (acalabrutinib) Ph1/2 multicenter study N = 61, r/r disease 100mg po BID dose in ph2 portion Median f/u = 14.3 months ORR 95% (PR=85%, PR+L=10%, SD=5%) For the 18 patients with del17p, the response rate was 100% (PR=72%, PR+L=28%) In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%) No dose-limiting toxic effects in ph1 portion; most common adverse events were headache (43%), diarrhea (39%), and increased weight (26%); most AEs were Grade 2 ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile; it is being studied in Ph3 trials Byrd J, et al. New Engl J Med 2016; 374: 323
PI3K delta inhibitors Idelalisib IPI-145 (Duvelisib) TGR1202
Idelalisib Ph 3 multicenter, double blind, RCT of R + idela (150mg po BID)/placebo in 220 CLL pts with significant comorbities ORR (all PRs) 81% vs. 13% (p<0.001) Median PFS not reached (idela arm) vs. 5.5 months (p<0.001) OS at 12 months 92% vs. 80% (p=0.02) SAEs in 40% (idela arm) vs. 35% (placebo arm) mainly pneumonia, fever, F+N in both; 4 idela pts with gr3-4 diarrhea, 2 with rash, 6 with transaminitis - manageable Furman RR, et al. N Engl J Med 2014; 370: 997
Idelalisib Idelalisib+ofa Ph2 frontline study; significantly higher toxicities compared to r/r setting; n=21 grade 3 toxicities 76% (transaminitis 57%, enterocolitis (14%), pneumonitis (10%); toxicities appear immunemediated 76% patients required steroids 5% required mycophenolate mofetil Lampson BL, et al. ASH 2015 abs
Duvelisib FCR+duvelisib Ph1b, frontline N=12 ORR=100% CR=33% MRD neg=89% Davids M, et al. ASH 2015 abs
TGR-1202 Oral agent Unique structure different from other PI3Kδ inhibitors Promising single agent activity and in combination with ublituximab Ph1b combination study in CLL/NHL No liver or colitis type toxicities Ph3 studies now starting TGR-1202 Idelalisib IPI-145 Type Pts (n) ORR (%) Median Prior Rx CLL/SLL 16 5/7 evaluable at high dose (71%) 3 (1 9) Lunning M, et al. ASH2015
BCL2 inhibitors ABT199 (venetoclax)
ABT199 ABT-199 alone ABT-199+R 1 st generation oral Bcl2 inhibitor ABT-263 had 35% RR in heavily pretreated CLL pts, but caused significant thrombocytopenia 2 nd generation oral inhibitor ABT-199 is highly selective for Bcl2 and TLS is primary toxicity better with gradual weekly dose increments Seymour JF et al. EHA abs. S702, Haematologica 2014; 99 (s1) Roberts AW, et al. EHA abs. S703, Haematologica 2014; 99 (s1)
ABT-199+R Ph1b trial r/r CLL/SLL N = 49, 20% with del17p Median age = 68 years Median prior regimens = 2 (1-5 range) Median followup 17.4 months ORR = 86% (53% MRD neg) - 20 (41%) CR/CRi (75% MRD neg), 1 (2%) npr and 21 (43%) PR, 4 SD, 2 PD; 1 died before assessment (fatal TLS) Median PFS and OS not reached (87% and 94% respectively at 12 months) Most common gr3 AEs were heme, F+N Ma S, et al. Blood 2015; ASH abstract
ABT-199 (venetoclax) ASH 2015: LBA of ABT199 in r/r CLL with del17p (Ph2) N = 107 Primary endpoint of IRC-assessed ORR was 79.4% including 7.5% CR/CRi and 2.8% npr, by IRC 18 pts (17% of whole cohort, 21% of responders) had no detectable MRD in the PB; 10 of these also tested in BM, 6 were MRD-negative Overall median DoR, PFS, and OS were not reached. The actuarial 12-month PFS and OS rates were 72.0% and 86.7%, respectively 37 pts discontinued treatment: 22 PD (9 Richter's transformation), 9 AE, 2 withdrew consent, and 1 with non-compliance; 3 proceeded to allo-sct (2 PR, 1 CR by IRC at time of transplant) 11 deaths ( 30 days from last dose): 7 PD, 4 AE (stroke, liver derangement, septic shock, and cardio-respiratory insufficiency) Stilgenbauer S, et al. Blood 2015, ASH abs.
Cellular therapy Allogeneic hematopoietic cell transplantation N=694 (retrospective) High risk disease 2 yr-nrm 28% 5 yr EFS 37% CAR-T cells Schetelig J, et al. ASH 2015 abs
CD19 specific CAR-T cells N = 14; median cell dose = 7.5x10^8 cells 4 CRs (29%), 4 (29%) PRs, ORR 57% CAR-T cells detectable 3 yrs later in some Ph2 randomized study ongoing to determine best cell dose Expected toxicities: B cell aplasia, delayed TLS and cytokine release syndrome Porter D, et al. Blood 2013; ASH abs. 4162 Porter D, et al. Blood 2013; ASH abs. 873
CD19 specific CAR-T cells (cont.) CAR-T cell therapy may potentially be a good alternative to RIC allohct for very high risk patients Other targets being evaluated include CD20, CD23, ROR1 Mato A and Porter D. Blood 2015; 126: 478
ASH 2016 update (frontline therapies) Ibrutinib+FCR in young fit patients (Davids, et al) Ph2 N=35 Median age=55 yrs ORR 100% in 28 evaluable pts including 39% CR/Cri and 61% PR (all PR pts had residual nodes <2.5cm and 76% had MRD neg bone marrows) 11/26 (39%) evaluable pts (with bone marrow biopsies) in MRD neg CR CLL2-Bag Trial Evaluating a Sequential Treatment of Bendamustine, Obinutuzumab and Venetoclax in TN or RR CLL: Interim Safety Results of a Ph2 Trial of the GCLLSG (Cramer et al) Debulking, induction and maintenance steps N=66 (35TN, 31RR) Median age 59 yrs
ASH 2016 update (frontline therapies) Phase Ib Study (GO28440) of Venetoclax with BR or Bendamustine/Obinutuzumab in TN/RR CLL (Stilgenbauer et al) Interim analysis N=55 (47 venbr, 8 venbg)
ASH 2016 update (frontline therapies) Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs PFS in High Risk CLL: Interim Results of Phase 3 CLL M1 study of GCLLSG (Fink et al) N=89 (60 len, 29 placebo) Median age=64 yrs Median of 10 prior lines of therapy Median f/u=17.7 months, median PFS was 14.6 months (placebo) vs. NR (len) More neutropenia with len (30.4% vs 3.4%) but not infections (50% vs 62.1%)
Conclusions Explosion of novel therapies for CLL in recent years, including monoclonal antibodies (like obinutuzumab), small molecule inhibitors of various kinases (like BTK and PI3K) and the antiapoptotic pathway (especially Bcl2), and CD19-specific CAR-T cells These novel, non-chemotherapeutic agents may do away with the need for standard chemoimmunotherapy in CLL, especially in older/unfit patients Combination studies underway
Standard of care algorithm (frontline): clinical trials if possible
Frontline CLL trials at City of Hope Phase 3 TGR1202+ublituximab vs. TGR1202 vs. ublituximab vs. Gazyva+chlorambucil [crossover allowed] Phase 2 ibrutinib+venetoclax
Relapsed/refractory CLL trials at COH Ph3 randomized trial of ACP-196 vs ibrutinib in del17p/del11q patients Ph1b/2 trial of TGR1202+ublituximab+ibrutinib Ph1 ibrutinib+cd37 monoclonal antibody Ph1 pembrolizumab+dinaciclib Coming soon: Ritonavir+metformin trial [COH], ibrutinib+venetoclax [with Stanford], CAR-T cell trial in B- cell lymphomas [COH]
Acknowledgements Dr. Stephen Rosen Dr. Stephen Forman Patients and their families/friends, nurses, colleagues at City of Hope National Medical Center
?s tsiddiqi@coh.org