Decisions in CLL: Can Prognostic and Biological Markers ...€¦ · Research Institute CLL8 Study...
Transcript of Decisions in CLL: Can Prognostic and Biological Markers ...€¦ · Research Institute CLL8 Study...
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
John C. Byrd M.D. D Warren Brown Chair of Leukemia Research Professor of Internal Medicine and Medicinal Chemistry Director, Division of Hematology The Ohio State University
Decisions in CLL: Can Prognostic and Biological Markers Help Manage Patients (2016)
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Chronic Lymphocytic Leukemia
§ The most prevalent type of adult leukemia § Defined by CD5, CD19, CD20, CD23, sIg (dim)+ cells in blood;
< 5 x 109/L cells is monoclonal B-cell lymphocytosis (MBL) which still has many CLL-type complications
§ Median age of diagnosis of CLL is approximately 72, with only 10% of patients under age 50.
§ More common in men than women (2:1 ratio) § Environmental predisposition uncertain, although Vietnam
Veterans with Agent Orange exposure warrant “service-connected status”
§ Genetic predisposition present, with approximately 10% of patients having a first-generation relative with CLL
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The Big Question at Diagnosis in Asymptomatic Patient
How will this “bad” leukemia influence my quality of life and
life expectancy?
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Clinical Stage and Outcome of CLL
Rai Stage Clinical Features Percent of Cases
Survival
Low Risk Lymphocyte Count > 5 x 109/L
30 >10 years
Intermediate Risk
Enlarged LN or Organomegaly
60 6 years
High Risk Hbg < 11 g/dl Plts < 100 x 109/L
10 2 years
Rai KR et al: Blood 46: 219, 1975
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CLL Outcome From Diagnosis by Interphase Chromosomal (FISH) Abnormalities
Abnormality % Pts Median Time to Treatment (mo)
Median Overall Survival (mo)
del(17)(p13.1) 7 9 32
del (11)(q22.3) 18 13 79
Trisomy 12 16 33 114
del(13)(q14) 55 49 133
None Detected 18 92 111
Döhner H, et al. N Engl J Med. 2000;343(26):1910-1916.
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Overall Survival is Influenced by IGHV Gene Mutation Status
M-24.5 yrs
UM-9.75 yrs
Hamblin T & Stevenson F Blood 94:1848, 1999
All Patients Binet Stage A Patients
UM-7.75 yrs
M-24.5 yrs
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ZAP-70, A Tyrosine Kinase Involved in T-Cell Activation Associates IGHV Mutational Status
Rosenwald A, et al. J Exp Med. 194:1639, 2001. Wiestner A, et al. Blood. 101:4944, 2003
Ig-mutated CLL Ig-unmutated CLL ZAP-70
Relative expression
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ZAP-70 Expression Predicts Early Progression and Short Survival in CLL
Years After Diagnosis Years After Diagnosis
Risk of Disease Progression Likelihood of Survival 100
90
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0 0 2 4 6 8 10 12 14 16
100
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0 0 4 8 12 16 20 24 28 32 36
≥ 20% ZAP-70–positive cells
< 20% ZAP-70–positive cells ≥ 20% ZAP-70–positive cells
< 20% ZAP-70–positive cells
P = 0.009 P = 0.01
Prob
abili
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Prob
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f Sur
viva
l (%
) Crespo M, et al. N Engl J Med. 2003;348(18):1764-1775 Problem: Not Reproducible
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Other New Prognostic Factors 9
• Stimulated Karyotype (not regular type) « Complexity (> 3 abnormalities) associated with short TFS and
poor response to therapy (including transplant and BTKi)
• Additional Interphase abnormalities « add 2p—increased risk of Richter’s transformation « +8 or amplication of myc—short TFS and OS
• ZAP-70 methylation (more reproducible than ZAP-70 protein expression and correlates with favorable outcome)
• Select mutations associated with rapid progression to treatment « p53 « NOTCH-1 « SF3B1 « BIRC3
All associated with IGHV un-mutated disease
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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Initial Work-up of CLL Patients § All patients at diagnosis:
« Flow cytometry to confirm CLL diagnosis § Informative for prognostic and/or therapy determination
« Interphase cytogenetics looking for +12, del(13q), del(17)(p13.1) and del(11)(q22.3); del 17p, 2p and del 11q portend for more aggressive disease
« Unmutated VH gene status assessment (good lab) « ZAP-70 expression by flow cytometry is not recommended
outside clinical trial; Zap-70 methylation may be more reproducible
§ Beta-2-microglobulin § No CT scan unless symptoms are present; PET scan can be helpful
if Richter’s suspected § Bone marrow biopsy and aspirate not necessary in absence of
cytopenias
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Autoimmune Cytopenias of CLL
§ Autoimmune hemolytic anemia and thrombocytopenia common in CLL (10-25%) and often presents when disease is active
§ Autoimmune cytopenias do not influence staging § Approach of AIHA and ITP requires assessment of
secondary causes and relationship to disease or therapy § If disease related, treat as primary autoimmune process until
controlled and then treat CLL after this only if symptomatic § If therapy related (i.e. fludarabine-associated AIHA), do not re-
challenge with offending agent
§ Therapy includes prednisone, rituximab, IVIG, cyclosporin, splenectomy and romiplostim (ITP)
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Infections in CLL § Most common cause of morbidity and mortality in CLL with
bacterial, viral and later opportunistic infections; often difficult to ascertain relationship to disease or therapy
§ Preventative strategies should include § Pneumococal vaccine (Prevnar 13) at diagnosis and Q5 yrs § Influenza vaccine yearly (poor response) and prophylaxis if
exposed; also consider IVIG if low IgG § No live vaccine (Including varicella zoster vaccine) § Viral and PCP prophylaxis for fludarabine based-Rx
§ IVIG use § Although expensive, this is very effective to augment
treatment of recurrent infections § Post influenza
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HSV infection in SLL lymph node
Richter’s transformation ?
ISH for EBER
HSV 1&2 IHC stain
AFB stain GMS stain Courtesy of Gerard Lozanski M.D.
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Other CLL Related Complications § Secondary cancers
§ More common in CLL and likely related to immune suppression-regular screening should be considered
§ MDS more commonly observed after introduction of FCR; bone marrow should always be done in setting of cytopenias; treatment for this is stem cell transplant
§ Richter’s Transformation (5-10%) § Pathology can be large cell lymphoma or Hodgkin’s Disease § Presents most commonly in previously treated patients with
high risk genomic features § PET scans can be useful in deciding nodal region to biopsy § Outcome of these patients poor and transplant should be
considered; de novo, non-del(17p) pts have better outcome § Common way CLL patients break through ibrutinib
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When to Treat CLL Patients § No advantage to treating CLL until symptoms develop
irrespective of genomic features § IWCLL 2008 criteria for treatment (primary and in relapse
include § Enlarging, symptomatic lymph nodes (> 10 cm) § Enlarging, symptomatic spleen (> 6 cm) § Cytopenias due to CLL (hemoglobin < 11, platelets < 100) § Constitutional symptoms due to disease (fatigue, B-symptoms) § Poorly controlled AIHA or ITP
§ Lymphocyte count < 300 x 109/L or doubling time not an indication for Rx *
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Hallek M, et al. Blood 15:5446-56, 2008 *NCCN Guidelines for NHL 2014
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How to Differentiate Patients for Treatment
§ Age or Functional Status § Age 65-70 often used in US § CIRS score or creatinine clearance < 60 ml/min often used in Europe
§ Genomic Features § Del(17p13.1) or not § Favorable markers (IgHV mutated with del(13q14) or +12)
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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
Follow- up
C1 C2 C3 C4 C5 C6
Updated results of the 3rd analysis Median observation time 5.9 years
Demographics similar between 2 treatment arms
Hallek M, et al: Lancet. 376:1164, 2010, Updated Blood 2016
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Summary of German CLL8 Study
§ Toxicity of FCR similar to FC except for more neutropenia
§ FCR versus FC a better therapy for young CLL § significantly improves ORR and CR § significantly improves PFS (57 versus 33 months, at 5.9 years) § significantly improves OS (69.2% vs 62.3% at 5.9 yrs)
§ MRD- status at end of therapy most predictive factor for long term PFS and OS
§ Majority of genetic groups benefit from FCR therapy except for § Del(17p13.1) § Normal karyotype (using FISH probes only)
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Hallek M, et al: Lancet. 376:1164, 2010
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Kirsten Fischer et al. Blood 2016;127:208-215
PFS and OS of German CLL8 Study
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Recent Data To Consider Decisions
§ What is the Best Therapy for CLL Treatment? § CLL10 Data from German CLL Group
§ Long-term Follow Up FCR data from MDA FCR300 series and German CLL VIII data (not shown) relative to “curability”
§ What is coming down the road with respect to targeted therapies
§ Ibrutinib data with del(17)(p13.1) and approval by FDA for initial use in symptomatic CLL
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CLL10 Study: FCR VS BR in FrontLine 21
1:1 Randomisation
Patients with untreated, active CLL without del(17p) and good physical fitness
(CIRS ≤ 6, creatinine clearance ≥ 70 ml/min
FCR
BR
Eichhorst B, et al: ASH 2014
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CLL10 Study: FCR VS BR in FrontLine
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Median PFS
FCR not reached
BR 44.9 months
(p=0.041)
Cytopenias and infections increased with FCR; Rx related mortality similar
Conclusion: FCR appears to be better than BR if chemoimmunotherapy is choice of therapy
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PFS Based Upon IGHV mutation status: MDA
Thompson PA and Keating MR: Blood (on line) 2015
Median F/U 12.8 years
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Ibrutinib: A Potent Irreversible BTK Inhibitor
§ Potent and irreversible BTK inhibition with IC50 = 0.5 nM
§ Orally bioavailable
§ Response noted in 45 (88%) of pts, with 5 (10%) attaining a CR (4 untreated)
§ PFS at 24 months is 82% for all pts; 8 (16%) of pts have died-5 with PD, 2 infection, and 1 sudden death
N
N
N N
N H 2
O
N O
Honigberg et al: PNAS 2010; 107:13075-80 Farooqui MZH, et al: Lancet Oncol 16: 169, 2015
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del(17)/p53 mutated Pt Outcome on Ibrutinib
Farooqui MZH, et al: Lancet Oncol 16: 169, 2015
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Ibrutinib versus Chlorambucil (Resonate 2)
§ Phase 3 study in symptomatic, untreated CLL/SLL patients comparing ibrutinib versus chlorambucil (cross-over allowed)
§ Eligibility criteria including 65 years of age, ANC 1 x 109/L, platelets 50 x 1012/L and no del(17)(p13.1)
§ Patient Demographics: median age of 73 years (70% > 70 y/o), 45% Advanced Rai stage, 20% del(11)(q22;q23)
§ Response: Ibrutinib 86% (4% CR) versus chlorambucil 36% (2% CR)
§ Significant PFS and OS with ibrutinib (despite cross-over) § Toxicity similar between except diarrhea and atrial fibrillation
(ibrutinib) Burger JA et al. N Engl J Med 2015;373:2425-2437.
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Burger JA et al. N Engl J Med 2015;373:2425-2437.
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Overall Survival
Burger JA et al. N Engl J Med 2015;373:2425-2437.
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My Approach for Patients < 70 § Repeat interphase cytogenetics, bone marrow
§ Clinical trial with strong consideration of non-chemotherapy regimen unless young and with favorable prognostic factors
§ Off trial « Del(17p13.1): ibrutinib (tissue typing for real young) « IGHV mutated: FCR « IGHV un-mutated: FCR or non-chemotherapy bridge (ibrutinib)
§ Do not use PCR, rituximab, alemtuzumab, CLB or rituximab maintenance
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Approaches to Consider in Elderly Population
§ Not Fludarabine-based regimens (Eichhorst Blood 2009, Woyach J Clin Oncol 2012)
§ Bendamustine + Rituximab « Slightly higher toxicity rate but feasible in this population
§ Chlorambucil + Rituximab « ORR 82% (9% CR,15% nPR) with median PFS of 23.5 months
§ High dose methylprednisolone + rituximab « Lower steroid dose typically utilized; favored regimen for
del(17p)
§ GA101 (Obinutuzumab + chlorambucil: A standard of care change
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§ Humanised monoclonal antibody targeting CD20 with novel properties as compared to rituximab § Recognizes unique epitope of CD20 different from rituximab § Type II antibody mediating direct CLL cell killing without
cross-linking superior to rituximab and ofatumumab § Diminished complement mediated lysis as compared to
ofatumumab § Glycoengineered to mediate enhanced antibody dependent
cell-mediated cytotoxicity superior to rituximab and ofatumumab
§ Phase I/II study in relapsed disease shows acceptable safety and ORR 20% (similar to rituximab with IWCLL 2008 criteria)
Mössner E, et al. Blood 2010;115:4393- 4402. Niederfellner G et al. Blood 2010;118:358-367.
Obinutuzumab (GA101)
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GA101 + chlorambucil x 6 cycles Previously untreated
CLL with comorbidities Total CIRS score > 6 and/or creatinine clearance < 70 mL/min Age ≥ 18 years N = 781
CLL11: Study design
R A N D O M I Z E
2:1:2
Chlorambucil x 6 cycles (control arm)
Rituximab + chlorambucil x 6 cycles
• GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2–6, every 28 days • Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 2–6, every 28 days • Chlorambucil: 0.5 mg/kg day 1 and day 15 cycle 1–6, every 28 days
• Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb
Stage 1, n = 590
Stage 1a G-Clb vs Clb
Stage 1b R-Clb vs Clb
Additional 190 patients in stage 2
Stage 2 G-Clb vs R-Clb
Goede V et al. N Engl J Med 2014: Jan 8. [Epub ahead of publication]. Goede V, 2013 ASCO Annual Meeting. Abstract :7004.
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§ Response § CLB 31% ORR, 0% CR § CLB + Rituximab 65% ORR, 7% CR § CLB + Obinutuzumab 77% ORR, 22% CR
§ Toxicity § Grade 3 and 4 infusion related events
§ 20% with Obinutuzumab versus 4% with Rituximab § Infusion events with Obinutuzumab early (day 1, within minutes of starting
infusion sometime) § Grade 3 and 4 neutropenia
§ 33% Obinutuzumab versus 28% with Rituximab § No increased risk in serious infections was noted in any arm
CLL11: Response and Toxicity
p<0.001
p<0.001
34 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
MRD Comparison and Impact on Outcome
GA101 Rituximab
Goede V et al. N Engl J Med 2014: Jan 8. [Epub ahead of publication]. Goede V, 2013 ASCO Annual Meeting. Abstract :7004.
35 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
G-Clb vs Clb: Progression-free survival
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Clb vs R-Clb: Overall survival
Total number of deaths: Clb, 24 (20%); G-Clb, 22 (9%)
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R-Clb vs G-Clb: Progression-free survival
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G-Clb vs R-Clb: Overall survival
Total number of deaths: R-Clb, 41 (12%); G-Clb, 28 (8%)
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My Approach for Patients > 70 § Repeat interphase cytogenetics, bone marrow
§ Clinical trial with strong consideration of non-chemotherapy regimen with 2nd generation BTKi (ACP-196) comparing to standard therapy
§ Off trial « Del(17p13.1): Ibrutinib monotherapy « Other genetic features: Obinutuzumab + CLB or
Bendamustine + rituximab « On the horizon: Ibrutinib (Resonate 2)
§ Do not use rituximab, alemtuzumab, CLB or rituximab maintenance
40 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CLL Important Conclusions § Select genomic studies can assist in risk stratification
of newly diagnosed patients.
§ CD20-antibody chemoimmunotherapy offers a survival advantage for symptomatic CLL.
§ Patients with del(17p13.1) who require therapy have very poor outcomes and require a different modality of therapy.
§ Kinase inhibitors such as ibrutinib will completely change the therapeutic landscape of CLL moving forward