Chronic Lymphocytic Leukemia: Testing, Targets and Treatments

Versha Banerji MDUniversity of Manitoba

Consultant: Lunbeck, Abbvie, Janssen, Gilead, Roche, Astra Zeneca

Grant funding: Canadian Institutes of Health Research, Leukemia Lymphoma Society, CancerCare Manitoba Foundation, University of Manitoba, Research Manitoba, Lundbeck, Roche, Janssen, Abbvie

Licensing fees: Biogen

No off label use of therapeutics will be discussed

Disclosures

Outline

Who it affects

When to treat

What to treat with

and what it depends on

The definition of CLL and its

counterparts

CLL Blood Smear

CD19+, CD5+,CD23+

Smudge cell

CD19

CD20

CD23 CD5

CLL cellMonoclonalB Cell

MBL CLL SLL

<5 X109 cell/LUniformed cells

circulating

>5 X109 cell/LUniformed cells

circulating

<5 X109 cell/LUniformed cells

circulatingPositive lymph node/ Bone marrow biopsy

Monoclonal B cell Lymphocytosis

Chronic Lymphocytic Leukemia Small LymphocyticLymphoma

NOT Cancer but may progress

CLL: Who Does it Affect and disease course

• ~2600 new patients diagnosed in Canada each year (population based)

• Average age at diagnosis is 72 years

• More common in men (1.3 to 1)

• No known cause

• Incurable cancer

• Observed for period of time

• Treated at time of disease progression or symptoms

Prognostic markers can help predict progression

• Leukemia Research 33 (2009) 1463–1468

Prognostic Feature Superior prognosis Inferior Prognosis

Rai Stage Stages 0, I and II Stages III and IVAge ≤75 years >75 yearsSex Female MaleLDT >12 months ≤12 months

Cytogenetic Abnormalities Deletion 13qNormal Karyotype

Deletion 17pDeletion 11q

IGHV gene Status Mutated UnmutatedCD38 Expression <20% B cells ≥20% B cellsZap70 Expression <20% B cells ≥20% B cells

β2-Microglobulin Level Normal and Low HighCreatinine Normal and Low High

Creatinine Clearance ≥60 <60Vitamin D Normal Low

Prognostic Markers

Adapted from Wintrobe’s text book of Hematology, Chapter on CLL; Courtesy of James Johnston

Florescence In Situ Hybridization (FISH) Panel

• Molecular abnormalities can be detected by various techniques

• This techniques allows for detection in losses or gains in spefic regions

of a chromosome

• There are 4 common abnormalities: 13q, 17p, 11q deletions and

trisomy 12

• 80% of patients will harbour at least 1

FISH• del13q14

– Most common 50-60%– Micro RNA 15a and 16-1 are lost leads to increased BCL-2 expression

• del11q22-23 – Always includes ATM– Less than 10% at diagnosis, 20% at treatment and 30% at relapse

• del17p12– Leads to loss of p53– And frequently pairs with loss of the second allele with a mutation in p53

• Trisomy 12– Amplification of Notch-1 – ?Richter’s Transformation

• Changes with time and should be performed pre treatment

Clinically Relevant Somatic Mutations

• TP53 mutations– 4-8% of new patients but rises to 10% at time of 1st treatment– 30-40% at relapse– Median overall survival of 3-5 years (with traditional therapy)– 70% less than expected for the general population

• Can Change with time

IGVH Mutation• IGVH mutation status affects the kinetics of relapse and the PFS in those

receiving chemotherapy

• 50-60% of patients with IGVH mutated status may have durable remission, MRD negativity, no relapse beyond 10 years and an OS similar to normal healthy subjects

• Almost all patients with unmutated IGVH are projected to relapse with chemotherapy

• Novel agents have demonstrated response despite IGVH status

• Does not change over time

CLL-IPI

del17p/TP53 status (4), IGHV status (2), ß2M (2), Stage (1), Age (1)

Risk Category CLL-IPI Risk Score 5 yr OS 10 yr OS Hazard Ratio

(95% CI)

Low 0-1 93.2% 79% -

Intermediate 2-3 79.3 39.2 3.5 (2.5-4.8)

High 4-6 63.3 21.9 1.9 (1.5-2.3)

Very High 7-10 23.3 3.5 3.6 (2.6-4.8)

Lancet Oncology 2016

Outcomes based on response to chemi-immunotherapy

Minimal Residual Disease or MRD

• MRD PCR-based ligase assay for patient-specific clonal IGHV

• MRD using standard European Research Initiative in CLL multicolor flow cytometry assay

• MRD negative is the if by either means that the assay cannot detect 1/10000 tumour cells

The CLL Treatment Revolution

Chemi-immunotherapyFCR, FR, BR

Alkylating Agents:Chlorambucil

Cyclophosphamide (C)

1960-70 1980s 1990 2000 2010

Nucleoside analogues:

Fludarabine (F)PentostatinCladrabine

Combination:FC Monoclonal

Antibodies:Rituximab

(CD 20)Alemtuzumab

(CD52)

Targeted agentsIbrutinib

FostamatinibIdelalisib

Venetoclax

2006

Novel anti-CD 20 agentsObinotuzumab

2013 2018

Combinations of targeted agents with antibodies

Chemotherapy

Advantages• Time limited treatment• Cost effective as drugs

Disadvantages• Need to come into a

clinic/hospital• Intravenous• Resource intensive• Side effects

Standard Chemotherapy

Bendamustine

G1 phaseSynthesis of components

of DNA

S phaseDNA synthesis

G2 phaseSynthesis of

components for cell division

Resting cells

M phaseCell division

7 hours 3 hours

5 hours

1 hour

Cyclophosphamide;Chlorambucil

Fludarabine

CD38

CD19

CD20

CD23

CD52

CD5

CLL cellCLL CellZAP 70

RituximabOfatumumabObinutuzumab

Alemtuzumab

Monoclonal Antibodies

Targeting B-cell Receptor (BCR) Signaling

BTK PLCy2

BLNKPI3K

CD19

PIP2 PIP3

Cell survival, proliferation, activation

DAG IP3AKT

NFkB

Idelalisib Ibrutinib

SYKLYN

BTK, Bruton’s tyrosine kinase; PI3K, phosphatidylinositide 3-kinase.

Targeting BCL-2

Venetoclax Binds to and Inhibits Overexpressed BCL-2

Venetoclax

BH3-only

BAX BCL-2 BCL-2

Mitochondria

An Increase in BCL-2 Expression Allows the Cancer Cell to Survive

Mitochondria

Pro-apoptotic Proteins

(BAX, BAK)

Anti-apoptotic Proteins(BCL-2)

21Apoptosis is Initiated

Apoptosome

APAF-1

Cytochrome C

Active Caspase

Procaspase

Mitochondria

3

BAK

What factors influence treatment decisions?• Molecular Testing

– P53/del17p– IGVH unmutated– ?MRD

• Age: less than 65 versus greater than 65– Transplant eligibility– Type of chemotherapy

• Fitness: Comorbidity Index Rating Scale (CIRS)– Do you have heart disease?, diabetes? Etc.– Less than 6 =Fit – Greater than 6 = Medical issues– (or any evaluation of fitness that is standard by your institution)

• Kidney function: Drugs are cleared by the kidneys – If kidneys don’t work well this can lead to side effects

Upfront Standard Regimens

• Fludarabine, Cyclophosphamide, and Rituximab- 6 cycles– Age <65 – FIT (CIRS <6)

• Bendamustine, Rituximab- 6 cycles– Age >65 – FIT (CIRS<6)

• Chlorambucil, Obinutuzumab/Rituximab- 6 cycles– Multiple Medical issues (CIRS>6)

• Ibrutinib- indefinite– 17pdel/TP53 mutation

The Trade Off Between Efficacy and Tolerability

AE = Adverse Event; BR = Bendamustine With Rituximab; FC = Fludarabine and Cyclophosphamide; FCR = Fludarabine and Cyclophosphamide With Rituximab; FR = Fludarabine With Rituximab; Ob-Clb = Chlorambucil With Obinutuzumab; PFS = Progression-free Survival; R-Clb = Chlorambucil With Rituximab; TFS = Treatment-free Survival.

Updated From Eichhorst et al 44,45; † Updated From Hillmen et al52; § Updated From Goede et al.50

Owen C et al Clin Lymphoma Myeloma Leuk. 2015

1Phase 3 data2Phase 2data

Efficacy PFS/TFSChlorambucil112 months

§R-Clb1

16 months

Fludarabine1

Bendamustine1

Alemtuzumab1

+Ofatumumab-Clb1

20-23 months§Ob-Clb1

27 months

FC1

34 months

FR2

42 months

*BR1

42 months

FCR1

55-58 months

Toxicity % Grade 3 + AEsRituximab2

11%Alemtuzumab1

27%Bendamustine1

Chlorambucil1Fludarabine1

40%

§R-Clb1

+Ofatumumab-Clb1

50-56%FC1

64%-65%§Ob-Clb1

73%FR2

76%*BR1

79%*FCR1

76%-91%

Advantages• Easy to take• Self administer

Disadvantages• Taken until progression• Unpredictable side effects• COSTLY ~$9000/month

indefinitely

2014-2017 CIRS<6 CIRS>6 17p delUnfit for chemo

Age <65FCR 6 months

Age >65BR 6 months

CO/CR6 months

IbrutinibLifelong

Frail

ChlorambucilBMT

CIRS<6 FrailCIRS>6

Age <65FCR 6 months

FR 6 months Chlorambucil

2010-2013

BMT Chemo + mABs

CLL Treatment Schema Over Time

Manitoba CLL CLINIC

Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia

Philip A. Thompson,Constantine S. Tam, Susan M. O’Brien, William G. Wierda, Francesco Stingo, William Plunkett, Susan C. Smith,Hagop M. Kantarjian, Emil J. Freireich, Michael J. Keating, Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia, Blood, 2016, Figure 1

Copyright © 2019 American Society of Hematology

IGVH- M

IGVH- UM

IGVH-m, MRD negative

IGVH- M, MRD Positive

ASH 2018 Update Frontline Studies

Chronic lymphocytic leukemia (CLL) in older patients in A041202, an Alliance-led National Clinical Trials Network study phase III trial comparing

• bendamustine plus rituximab (arm 1)

• ibrutinib (arm 2)

• ibrutinib plus rituximab (arm 3)

N Engl J Med 2018;379:2517-28

Patient Characteristics

• The study randomly assigned 547 patients aged ≥ 65 years (median age, 71 years) with previously untreated, symptomatic CLL to treatment.

• High-risk Rai stage (stage III/IV) was seen in 54% of patients.

• 53% IGVH mutated and del(17p) or del(11q) in 28%.

• The primary analysis included 525 patients (96%).

Results

No. of Events/No. of

Patients

Median (95% CI) mo

Bendamustine + Rituximab 68/176 43 (38—NR)

Ibrutinib 34/178 NR

Ibrutinib+Rituximab 32/170 NRPatie

nts W

hoW

ere

Aliv

e an

d Fr

ee fr

omDi

seas

ePr

ogre

ssio

n (%

)

Ibrutinib+rituximab

Ibrutinib

Bendamustine+rituximab

Months

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 5252

A Trial of the ECOG-ACRIN Cancer Research Group (E1912)

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): • CLL patients who were age ≤70 and required treatment• Patients with deletion 17p- were excluded from participating

given the poor response of these patients to FCR therapy• Participants were randomly assigned in a 2:1. The planned

accrual was 519 patients

Endpoints

• The primary endpoint was PFS • The secondary endpoint was overall survival (OS)

Results• 529 patients were accrued between January 31, 2014 and June 9, 2016 • 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to

FCR

ResultsPr

obab

ility

Years

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4

Ibrutinib

FCR

Progression-Free Survival (all randomized)

P=1.62 x 10-5

Arm A: Ibruninib (37 events/354 cases)Arm B: FCR (40 events/175 cases)

Prob

abili

ty

Years

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4

Ibrutinib

FCR

Overall Survival (all randomized)

P=3.22 x 10-4

Arm A: Ibruninib (4 deaths/354 cases)Arm B: FCR (10 deaths/175 cases)

Lancet Oncology 2019

Results

Ibrutinib plus obinutuzumab

113(0)

109(1)

106(3)

105(3)

99(5)

94(6)

90(8)

85(9)

82(9)

81(9)

28(62)

6(84)

0(89)

Chlorambucil plus obinutuzumab

116(0)

111(4)

109 (4)

102(6)

81(7)

67(7)

56(8)

47(8)

35(10)

33(10)

6(36)

5(37)

0(42)

Prog

ress

ion-

free

su

rviv

al(%

)0

102030405060708090

100

0 3 6 9 12 15 18 21 24 27 30 33 36

PFS by IRC

Number at risk (number censored)

HR 0.23 (95% CI 0.15-0.37)Ibruninib plus obinutuzumabChlorambucil plus obinutuzumab

Prog

ress

ion-

free

su

rviv

al(%

)

0102030405060708090

100

0 3 6 9 12 15 18 21 24 27 30 33 36

PFS for High risk patientsHR 0.15 (95% CI 0.09-0.27)

P<0.0001

What Does This Mean For Canada?

• Many institutions are testing for Mutational status (IGVH), TP53 and FISH for 11q and 17p but not all.

• It is clear that for patients that are high risk (del 17p, p53, del 11q and IGVH unmutated) ibrutinib frontline is better than chemotherapy by PFS in the older patients, but even by OS in the younger patients.

• Neither studies provides evidence that Ibrutinib was superior to chemotherapy in mutated patients.

Non 17p del/TP53 & IGVH mutated

17p del/TP53 or IGVH unmutated

IbrutinibLifelong

IbrutinibLifelong

Idelalisib + Rituximab

Lifelong

CIRS<6 CIRS>6

Age <65FCR 6 months

Age >65BR 6 months

CO/CR6 months

Chemo EligibleChemo Ineligible, Not extremely frail

Extremely Frail

Chlorambucil

Front Line

Manitoba CLL CLINIC

Relapsed Setting

NEJM 2018

What is next ?

• Combinations of therapy are being tested– BTKi with BCL2i- front line– BCL2i with Anti CD20- front line– Chemi-immunotherapy +/- novel agent– Second Generation novel agents

• Questions being asked– Duration of therapy – Depth of response by MRD– Reduced toxicity– Reduced costs?

Thank you