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Chronic lymphocytic leuekmia

Jennifer Woyach, MD

​

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

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Objectives

  • Discuss the biology and natural history of CLL/SLL
  • Discuss criteria for the initiation of therapy
  • Discuss specific therapies for CLL/SLL
  • Discuss what may be coming next

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CLL

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  • CLL is often considered a disease of disordered apoptosis—> cells do not die
  • Cells accumulate in lymph nodes, blood, spleen, and bone marrow, all of which cause symptoms
  • CLL cells also disrupt normal immune cells
  • SLL is the same disease, but with less blood involvement

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CLL Prognostic Factors

  • Heterogeneous disease with survival ranging from months to 25+ years from diagnosis
  • Prognostic factors commonly used
    • Stage
    • Lymphocyte doubling time
    • Beta 2 microglobulin
    • IGHV mutational status
    • FISH/Stimulated karyotype
    • TP53 mutation

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Can Prognosis Change Over Time?

  • IGHV mutational status does not change
  • Cytogenetic abnormalities and gene mutations can, a process called clonal evolution
    • TP53 abnormalities seen in 10% at baseline, but ~40% later

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Treatment

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Indications for Therapy

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Category

Reasons for Treatment

CLL-related symptoms

  • Significant B symptoms (eg, night sweats, weight loss, �fever without infection, severe fatigue)

Tumor burden

  • Progressive lymphadenopathy
  • Progressive splenomegaly�Lymphocyte doubling time <6 months (if ALC >30 x 109/L)
  • Threatened end-organ function (eg, enlarged lymph node

obstructing biliary tree)

Bone marrow failure

  • Progressive anemia (Hgb <11 mg/dL)
  • Progressive thrombocytopenia (platelets <100K)

Immune dysfunction

  • Autoimmune anemia and/or thrombocytopenia �poorly responsive to corticosteroids or other standard therapy

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Why Don’t We Treat at Diagnosis?

  • Multiple clinical trials have investigated this question—none yet have shown a survival advantage to early treatment.
  • This remains a question of interest, especially with advances in prognosis (so high risk patients can be targeted) and with newer better tolerated therapies.
  • SWOG 1925 is a new early intervention trial of venetoclax/obinutuzumab for high risk patients early vs standard timing of therapy

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Natural history of CLL has been changed by targeted therapy

  • Therapies used in the front line setting
    • Ibrutinib
    • Ibrutinib/rituximab
    • Ibrutinib/obinutuzumab
    • Acalabrutinib
    • Venetoclax/obinutuzumab
    • FCR
    • Other CIT (BR, Chlorambucil/obinutuzumab)

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Mechanism of Targeted Therapies

BLNK

Syk

Lyn

Btk

PLCγ2

BCR

IP3

DAG

PKC

Akt pathway

NFκB

Ibrutinib

Acalabrutinib

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How do we choose therapy? First consideration:

Targeted

therapy

VS

Chemo-

immunotherapy

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ECOG 1912

Arm A – Ibrutinib + Rituximab

Cycles 1:

Ibrutinib 420 mg PO daily, days 1-28

​

Cycle 2:

Ibrutinib 420 mg PO daily, days 1-28

Rituximab 50 mg/m2 IV, day 1

Rituximab 325 mg/m2 IV, day 2

Cycles 3-7:

Ibrutinib 420 mg PO daily, days 1-28

Rituximab 500 mg/m2 IV, day 1

Arm B - FCR

Cycles 1-6:

Fludarabine 25 mg/m2 IV, days 1-3

Cyclophosphamide 250 mg/m2 IV, days 1-3

​

Cycle 1:

Rituximab 50 mg/m2 IV, day 1, cycle 1

Rituximab 325 mg/m2 IV, day 2, cycle 1

​

Cycle 2-6:

Rituximab 500 mg/m2 IV, day 1, cycles 2-6

Cycle 8 until progression:

Ibrutinib 420 mg PO daily, days 1-28

Planned Accrual: 519

E1912

Eligibility:

-Previously untreated CLL

-Requires treatment (IWCLL 2008)

-Age < 70

-ECOG 0-2

-CrCL>40

-Able to tolerate FCR

-No deletion 17p by FISH

Randomization

Disease Progression

Shanafelt, et al., NEJM 2019

ASH 2019, abstract 33

Key Points

  • No del(17p)
  • Median age 58
  • 71% IGHV unmutated

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E1912 Progression Free Survival and Overall Survival

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PFS

Shanafelt, et al, ASH 2019, abstract 33

3 yr PFS 89% vs 71%

3 yr OS 99% vs 93%

OS

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A041202

Stratify*

​

R

A

N

D

O

M

I

Z

E

Bendamustine 90mg/m2 days 1&2 of each 28 day cycle +

Rituximab 375 mg/m2 day 0 cycle 1,

then 500 mg/m2 day 1 cycles 2-6

Ibrutinib 420mg daily until disease progression

Stratification

  • High risk vs intermediate risk Rai Stage
  • Presence vs absence of del(11q22.3) or del(17p13.1) on FISH performed locally
  • < 20% vs ≥ 20% Zap-70 methylation of CpG 3 performed centrally

PRE-REGISTER

Ibrutinib 420mg daily until disease progression +

Rituximab 375 mg/m2 weekly for 4 weeks starting cycle 2 day 1, then day 1 of cycles 3-6

Untreated patients age ≥ 65 who meet IWCLL criteria for CLL treatment

Documented Progression

Planned accrual: 498

Key Points

  • Median age 71
  • 6% del(17p), 10% TP53 mutated
  • 61% IGHV unmutated

Woyach et al, NEJM 2018

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A041202 Progression Free Survival and Overall Survival�

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Pairwise Comparisons

​

I vs BR:

Hazard Ratio 0.39

95% CI: 0.26-0.58

(1-sided P-value <0.001)

​

IR vs BR:

Hazard Ratio 0.38

95% CI: 0.25-0.59

(1-sided P-value <0.001)

​

IR vs I:

Hazard Ratio 1.00

95% CI: 0.62-1.62

(1-sided P-value 0.49)

​

​

Woyach et al, NEJM 2018

Median Follow-up: 38 months

​

Arm

N

24 Month Estimate

BR

176

74% (95% CI: 66-80%)

I

178

87% (95% CI: 81-92%)

IR

170

88% (95% CI: 81-92%)

Arm

N

24 Month Estimate

BR

183

95% (95% CI: 91-98%)

I

183

90% (95% CI: 85-94%)

IR

182

94% (95% CI: 89-97%)

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ELEVATE TN (ACE-CL-007)

Acala-G

100 mg PO BID

1000 mg IV on D1, 2, 8, and 15 of Cycle 2, + D1 of subsequent 28-day cycles for a total of 6 cycles

Treatment-naive CLL (N=535)

Age ≥65 or

<65 years with coexisting conditions:

  • CIRS score >6, or
  • creatinine clearance <70 mL/min

​

Stratification

  • del(17p), y vs n
  • ECOG PS 0-1 vs 2
  • Geographic region (N America, W Europe, or other)

Primary endpoint

  • PFS (assessed by IRC) Acala-G vs G-Clb

Key secondary endpoints

  • PFS acalabrutinib vs G-Clb
  • ORR (assessed by IRC and investigator)
  • Time to next treatment
  • OS
  • Safety

RANDOMIZE

Crossover from G-Clb to acalabrutinib monotherapy was allowed after IRC-confirmed progression

1:1:1

G-Clb

1000 mg IV on D1, 2, 8, and 15 of Cycle 1, + D1 of subsequent 28-day cycles for a total of 6 cycles

0.5 mg/kg PO on D1 + 15 of each 28-day cycle for 6 cycles

Acalabrutinib monotherapy

100 mg PO BID

Sharman et al, ASH 2019 Abstract 31

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ELEVATE-TN Progression-Free Survival�

Sharman et al, EHA 2021

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CLL14

Stratify

​

R

A

N

D

O

M

I

Z

E

Chlorambucil 0.5 mg/kg d1 and 15 of cycles 1-6

Obinutuzumab 100 mg c1d1, 900 mg c1d2, 1000 mg c1d8 and 15, then 1000 mg day 1 of cycles 2-6

​

Stratification

  • Binet stage
  • Geographic region

Venetoclax weekly ramp-up to 400 mg starting c1d22+

Obinutuzumab 100 mg c1d1, 900 mg c1d2, 1000 mg c1d8 and 15, then 1000 mg day 1 of cycles 2-6

Untreated patients with CIRS>6 or CrCl <70

Key Points

  • Median age 72
  • 7-9% del(17p), 8-11% TP53 mutated
  • 60% IGHV unmutated

Fischer et al, NEJM 2019

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CLL14 Progression Free and Overall Survival

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What do these trials tell us?

  • BTKi +/- anti-CD20 antibody is more effective than chemoimmunotherapy in the treatment of CLL
  • Venetoclax + obinutuzumab is more effective than chlorambucil + obinutuzumab
  • With current follow-ups PFS for VO is similar to what is reported for ibrutinib
  • Long term results will be critical to determine which regimen is more effective

​

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Second Consideration: How to Choose Between Targeted Therapies?

Ibrutinib

VS

Acalabrutinib

Venetoclax

VS

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Efficacy Considerations

  • At 4 years, ibrutinib, acalabrutinib, and venetoclax/obinutuzumab appear relatively equivalent
    • There might be a difference in TP53 altered patients and IGHV unmutated patients
  • There is more long-term data with ibrutinib than either venetoclax or acalabrutinib
  • Acalabrutinib and Ibrutinib are equally effective

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Safety Considerations

  • Ibrutinib toxicities: Atrial fibrillation (10-15%, more with older patients), Hypertension (7-30% significant), Bleeding (G3+ <5%), Ventricular arrhythmias (<1%, risk factors unclear)
    • There is much more long term data with ibrutinib
  • Acalabrutinib toxicities: Atrial fibrillation (5-10%), Bleeding (significant <5%)
  • Venetoclax toxicities: Neutropenia (significant 50%), Febrile neutropenia (5%), Diarrhea (significant <5%)

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Intangibles

  • Fixed duration venetoclax/obin vs indefinite BTKi
  • More intensive run-in venetoclax/obin vs BTKi
  • Once daily ibrutinib vs twice daily acalabrutinib
  • Cost

​

​

Conclusion: Choice of BTKi vs Venetoclax/obin is patient-specific and involves discussion of data and considerations of pros/cons with each therapy

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What is the future of CLL frontline therapy?

  • Combination vs single targeted therapy to allow BTKi discontinuation
    • Excellent data from single arm studies of IVO, IV, AVO

​

  • Combinations of CIT and novel therapies: I-FCG, others
  • New therapies or strategies

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NCTN Study: EA9161

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  • Age <70
  • No del(17p)
  • Primary Endpoint: PFS

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NCTN Study: A041702

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  • Age ≥ 70
  • Primary Endpoint: PFS
  • Planned Enrollment 494

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Exciting Treatments/Strategies Currently in Trials

  • New ways to target the B cell receptor signaling pathway

​

  • New antibody treatments

​

  • Harnessing the immune system to combat CLL

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New ways to target the B cell receptor signaling pathway

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BLNK

Syk

Lyn

Btk

PLCγ2

CD19

p110δ

p85

BCR

Lyn

IP3

DAG

PI(3,4,5)P3

PKC

MAPK pathway

Akt pathway

NFκB

NFκB

Ibrutinib

Acalabrutinib

Idelalisib

Duvelisib

Reversible BTKi: ARQ 531, Loxo 305, others

Umbralisib

MS 553

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New Antibody Targets

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CD20

ROR1

BAFFR

CD19

New Antibody Techniques:

  • Bispecific antibodies

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Harnessing the Immune System

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CAR-T cells (or CAR-NK cells)

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Take-away Points

  • CLL is a cancer of the blood, bone marrow, lymph nodes, and spleen
  • Currently, there is no advantage to treating CLL early
  • When it is time for therapy, there are many excellent non-chemotherapy options
  • As our CLL therapy gets better, other supportive care issues, like infection prevention and secondary cancer screening becomes even more important
  • Ask about clinical trials—this is how we will make the next big leap in CLL therapy!

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Thank You!

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