Decisions in CLL: Can Prognostic and Biological Markers ...€¦ · Research Institute CLL8 Study Design 817 Patients with untreated, active CLL and good physical fitness (CIRS ≤

1

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)

2


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

3 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Big Question at Diagnosis in Asymptomatic Patient

How will this “bad” leukemia influence my quality of life and

life expectancy?


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


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.


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


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


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

80

70

60

50

40

30

20

10

0 0 2 4 6 8 10 12 14 16

100

90

80

70

60

50

40

30

20

10

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

ty o

f Pro

gres

sion

(%)

Prob

abili

ty o

f Sur

viva

l (%

) Crespo M, et al. N Engl J Med. 2003;348(18):1764-1775 Problem: Not Reproducible

9


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

10


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


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)

11


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

12


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.


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

14


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 *

15

Hallek M, et al. Blood 15:5446-56, 2008 *NCCN Guidelines for NHL 2014


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)


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


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)

18

Hallek M, et al: Lancet. 376:1164, 2010


Kirsten Fischer et al. Blood 2016;127:208-215

PFS and OS of German CLL8 Study


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


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


CLL10 Study: FCR VS BR in FrontLine

22

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


PFS Based Upon IGHV mutation status: MDA

Thompson PA and Keating MR: Blood (on line) 2015

Median F/U 12.8 years


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


25

del(17)/p53 mutated Pt Outcome on Ibrutinib

Farooqui MZH, et al: Lancet Oncol 16: 169, 2015


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.


Burger JA et al. N Engl J Med 2015;373:2425-2437.


Overall Survival

Burger JA et al. N Engl J Med 2015;373:2425-2437.


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


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


§  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)


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.


§  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


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.


G-Clb vs Clb: Progression-free survival


Clb vs R-Clb: Overall survival

Total number of deaths: Clb, 24 (20%); G-Clb, 22 (9%)


R-Clb vs G-Clb: Progression-free survival


G-Clb vs R-Clb: Overall survival

Total number of deaths: R-Clb, 41 (12%); G-Clb, 28 (8%)


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


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

Documents

Decisions in CLL: Can Prognostic and Biological Markers ...€¦ · Research Institute CLL8 Study Design 817 Patients with untreated, active CLL and good physical fitness (CIRS ≤