management of untreated cll for web (2015)

Management of Untreated CLL2015

Jeff Sharman M.D.Medical Director Hematology Research

US Oncology

Long Term Follow UpFCR at MD Anderson

Selecting Therapy

Genomics

Fitness

Genomics 2015

Genomic Sequencing

Untreated CLL

High RiskIntermediate(Very) Low Risk

Maximal Tolerated Therapy

Do No Harm Novel Agents

IgHV MutatedNo Int/High

Risk

SF3B1 / NOTCH1 / 11Q

IgHV Unmutated

17P / TP53BIRC3

TP53 Gene Mutation 17P Deletion

Idelalisib in Untreated CLL

High Risk CLL Summary

High risk CLL includes abnormal TP53 (del17P/mut) or BIRC3 mutation

These patients die quickly with traditional therapy

Novel agents most appropriate initial therapy in high risk CLL

Untreated CLL

High RiskIntermediate(Very) Low Risk

Maximal Tolerated Therapy

Do No Harm Novel Agents

IgHV MutatedNo Int/High

Risk

SF3B1 / NOTCH1 / 11Q

IgHV Unmutated

17P / TP53BIRC3

Untreated CLL

(Very) Low Risk

IgHV MutatedNo Int/High

Risk

Super Fit

Fit

Unfit

FCR

BR / BG

Gazyva

Can CLL be Cured?

MD Anderson CLL8 FCR vs FC

FCR vs BR in IgHV Mutated

Improved FCR outcomes only age < 65

Greater neutropenia and infection

More durable immune dysfunction

Greater secondary malignancy

What is Fitness?

• Median age MDA = 57• Median age CLL8 = 61• Median age SEER = 71

• Age associated with:– Higher comorbidity– Lower renal function– More advanced disease

at treatment initiation

• Approximately 20% CLL patients meet enrollment criteria for CLL 8/10 at first line rx

Mortality Following First Line Therapy

Setting Median Age Regimen 12 Month Mortality

MD Anderson 57 FCR 1%

German CLL8 61 FCR vs FC 4%

Community 74 Any 10%

German CLL11 Study

German CLL11 Study

German CLL11 Study

Single Agent Gazyva

Overall Approach in Low Risk CLL

Low Risk Summary• (Very) Low risk CLL lacks 17P/11Q deletions or NOTCH1, SF3B1,

BIRC3, TP53 mutations

• When treated aggressively, high fraction with durable response, many possibly cured

• Benefit of FCR primarily in patients with most favorable genomics and ideal fitness with age less than 65

• Obinutuzumab is more effective than rituximab and is appropriate therapy in patients not suitable for chemoimmunotherapy – or in combination with bendamustine on this trial

Untreated CLL

High RiskIntermediate(Very) Low Risk

Maximal Tolerated Therapy

Do No Harm Novel Agents

IgHV MutatedNo Int/High

Risk

SF3B1 / NOTCH1 / 11Q

IgHV Unmutated

17P / TP53BIRC3

FCR vs BR – When Better isn’t Best

Untreated CLL

High RiskIntermediate(Very) Low Risk

Maximal Tolerated Therapy

Do No Harm Novel Agents

IgHV MutatedNo Int/High

Risk

SF3B1 / NOTCH1 / 11Q

IgHV Unmutated

17P / TP53BIRC3

How I Manage Untreated CLL

High risk patients (17P/TP53/BIRC3) are treated with novel agents preferably on trial

Low risk patients (No high/int risk markers) are treated with maximal tolerated therapy. In community setting FCR use is uncommon

Intermediate risk patients (no high risk, but have an intermediate marker such as 11Q/SF3B1/NOTCH1/IgHV unmutated) do not receive FCR but get either BR (BG) or Gazyva

Using Gazyva

Infusion reactions / management

First cycle cytopenias

Lymphocyte clearance kinetics

Growth factor support

Questions?