selecting therapy in cll

CLL: Past, Present, and Future

Jeff Sharman M.D.Medical Director Hematology Research

US Oncologyhttp://cll-nhl.com

• Historical perspectives• FCR – The rise and fall• Choosing first line therapy in 2014• Management of relapsed disease• Ibrutinib considerations

CLL: Management in a TKI World

• Historical perspectives• FCR – The rise and fall• Choosing first line therapy in 2014• Management of relapsed disease• Ibrutinib considerations

CLL: Management in a TKI World

Chlorambucil

Fludarabine

Fludarabine / Cyclophosphamide

FCR

1999-2003 at MDA

Improved Outcomes with FCR (2008)

German CLL8 – FC vs FCR (2003)

MDA Long Term Follow Up

So what is the problem?

FCR not so popular….

Patterns of Care (FCR in Front Line)

•Age < 65 = 45% FCR•Age 65-75 = 32% FCR•Age > 75 = 20% FCR

Clinical trials versus real life

• MDA FCR Median Age– 57 years old

• German CLL8 (FC vs FCR)– 61 years old

• Real life– Age 71 at diagnosis– Age 74 at first treatment

Age Matters

• Decreased Renal Function – Clears fludarabine

• Decreased Marrow Reserves– Prolonged cytopenias– MDS / AML

• Infectious Complications– Really nasty gross stuff

MDA Long Term follow up

Death within 12 months of first line therapy

• MDA = 1%• German CLL8/10 study = 3-4%

• Registry Studies = 10%

Case Study• 72 year old retired lumber yard worker

– Lymphocytosis c/w CLL stage I, but over 2 years progressive adenopathy and hemoglobin down to 10

– Deletion 13q but unmutated IgVH

• Entered onto FCR vs PCR study– Stopped FCR after cycle 3 due to myelotoxicity– Has maintained remission for six years

• Multiple treatment complications– Pulmonary aspergillosis– Received > 50 units PRBC’s over next two years– Now has MDS

Where will FCR fit in the next five years?

”We’re going to get rid of FCR”

German CLL10 StudyFCR versus BR

CIRS < 7, Creatinine Clearance > 70, no 17P deletion

FCR BR

ORR 97.8% 97.8%

CR 47% 38%

MRD Negative 71% 66%

2 Year PFS 85% 78%

German CLL10 StudyFCR versus BR

CIRS < 7, Creatinine Clearance > 70, no 17P deletion

FCR BR

G3/4 Neutropenia 82% 56%

G3/4 Infection 47% 26%

Induction Death 4% 2%

Complete 6 cycles 70% 80%

CLL10 Summary

• FCR works a little better, but considerably more toxic than BR

• No clear winner as gains in response offset by increased toxicity

What about the elderly?

Complement 1Chlorambucil +/- Ofatumumab

Chlorambucil Clb-Ofatumumab

PFS (mo) 13 22

ORR 69% 82%

CR 1% 12%

MRD 4% 12%

• Historical perspectives• FCR – The rise and fall• Choosing first line therapy in 2014• Management of relapsed disease• Ibrutinib considerations

CLL: Management in a TKI World

Choosing first line therapy in 2014

Age & Comorbidity

FCR BR Obi

• Historical perspectives• FCR – The rise and fall• Choosing first line therapy in 2014• Management of relapsed disease• Ibrutinib considerations

CLL: Management in a TKI World

What is “one prior therapy?”

MRD in CLL8 Study

Post 3 cycles End of Treatment

MRD: Depth = Duration

New Mutation Markers

CLL: Beyond FISH

CLL – Evolution in Real Time

A: Pre-ChlorambucilB: Pre FCRC: Post FCRD: Pre OfatumumabE: Post Ofatumumab

• Historical perspectives• FCR – The rise and fall• Choosing first line therapy in 2014• Management of relapsed disease• Ibrutinib considerations

CLL: Management in a TKI World

Clinical Challenges

• Initial lymphocytosis• Interruptions (surgery / other)

• Adherence• Copayments

• Adventures in medical decision making• Progressions

Clinical Challenges

• Initial lymphocytosis• Interruptions (surgery / other)

• Adherence• Copayments

• Adventures in medical decision making• Progressions

Compartment Effect: Decreased Nodes with Lymphocytosis

Lymphocytosis

FR

BR

Ibrutinib

Clinical Challenges

• Initial lymphocytosis• Interruptions (surgery / other)

• Adherence• Copayments

• Adventures in medical decision making• Progressions

Long Term Drug Problems?

Clinical Challenges

• Initial lymphocytosis• Interruptions (surgery / other)

• Adherence• Copayments

• Adventures in medical decision making• Progressions

Clinical Challenges

• Initial lymphocytosis• Interruptions (surgery / other)

• Adherence• Copayments

• Adventures in medical decision making• Progressions

Thank Youhttp://cll-nhl.com