Which is the optimal approach: BR or FCR/FR? Mitchell R. Smith, M.D., Ph.D. Director of Lymphoid Malignancy Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH

HAS BENDAMUSTINE-RITUXIMAB REPLACED FLUDARABINE-CYCLOPHOSPHAMIDE-RITUXIMAB AS FRONTLINE THERAPY FOR CLL? ABSOLUTELY!

HAS BENDAMUSTINE-RITUXIMAB REPLACED FLUDARABINE-CYCLOPHOSPHAMIDE-RITUXIMAB AS FRONTLINE THERAPY FOR CLL? Can Smith Win This Debate? Not so clear

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR 

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor Cool Accent

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor Cool Accent

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor Cool Accent

Can Smith Win This Debate? KEATING SMITH Instrumental in developing FC/FCR  Not so much Gets to use 3 drugs Only 2 Professorial demeanor Cool Accent LET’S ROOT FOR THE UNDERDOG!

WHAT DO WE KNOW ABOUT CHEMOTHERAPY FOR CLL? For PFS Endpoint: Fludarabine > Chlorambucil Alemtuzumab > Chlorambucil Bendamustine > Chlorambucil FLU/Cy > Fludarabine

WHAT DO WE KNOW ABOUT CHEMOTHERAPY FOR CLL? For PFS Endpoint: Fludarabine > Chlorambucil Alemtuzumab > Chlorambucil Bendamustine > Chlorambucil FLU/Cy > Fludarabine For OS: LITTLE OR NO DIFFERENCE Fludarabine = Chlorambucil (Flu a bit better?) Alemtuzumab = Chlorambucil Bendamustine = Chlorambucil FLU/Cy = Fludarabine

HOW DOES BR STACK UP AGAINST FCR? Balance of Efficacy and Toxicity? Applicable to what % of CLL patients? QoL: number of visits, supportive care, cost? What therapy can be given at relapse? Which is best platform for combining novel agents?

SELECTION OF INITIAL CHEMO-IMMUNO-THERAPY: EFFICACY RX Trial N = Med. age RR% CR % PFS FCR MDACC 300 57 94 72 80 mos CLL8 408 61 90 44 52 FR CALGB9712 104 63 84 38 42 BR Fisher 117 64 88 23 34 Adapted from Wierda JCO 2012

SELECTION OF INITIAL CHEMO-IMMUNO-THERAPY: EFFICACY RX Trial N = Med. age RR% CR % PFS FCR MDACC 300 57 94 72 80 mos CLL8 408 61 90 44 52 FR CALGB9712 104 63 84 38 42 BR Fisher 117 64 88 23 34 Adapted from Wierda JCO 2012

MINIMAL RESIDUAL DISEASE IN CLL BR? CHLORAMBUCIL ~1012 FLUDARABINE FCR/FR NCI-CR ~1010 Number of CLL cells (log scale) MRD negativity ~108 Time from therapy

CORRELATION OF MRD WITH PFS: GCLLSG CLL8 TRIAL Lower MRD associated with improved PFS (regardless of Tx) Lower MRD levels achieved with FCR at 2 months post-treatment MRD Median PFS < 10-4 Not reached ≥ 10-4 – < 10-3 35 months ≥ 10-3 – < 10-2 33 months ≥ 10-2 – < 10-1 16 months ≥ 10-1 12 months MRD Level Achieved FCR FC < 10-4 67% 34% ≥ 10-4 – < 10-2 23% 50% ≥ 10-2 10% 16% Boettcher A. Blood 2008, 112; abs 326

SELECTION OF INITIAL CHEMO-IMMUNO-THERAPY: DOES TOXICITY OUTWEIGH BENEFIT? For TOXICITY: ANYTHING + Rituximab = ANYTHING alone BR vs. FR ? FC(R) MORE TOXIC THAN F(R) FCR MORE TOXIC THAN BR

TOXICITY ISSUES: Benda vs. FLU COMMON CONCERNS FOR BOTH: Who can get safely treated with the regimen? Prolonged myelo-suppression Therapy related myeloid neoplasia (t-MN) FLUDARABINE: F(C)R difficult in older patients Immuno-suppression Fludarabine renal excretion Exacerbation of AIHA BENDAMUSTINE: Rash/Hypersensitivity ? Possible interaction with allopurinol

SELECTION OF INITIAL CHEMO-IMMUNO-THERAPY: Who got treated? Br German CLL sg phase 2 Fcr German CLL8 Age median 61 (30-80) 11% ≥ 70 31% ≥ 65 ECOG PS 0-1 CIRS  6 (median 1) CrCL > 70 No autoimmune cytopenia Median # cycles 4.8 26% < 6 cycles Age any, median 64 (34-78) 26% ≥ 70 49% ≥ 65 WHO PS 0-2 CIRS any CrCL > 30 No restriction Median # cycles 6.0 26% < 6 cycles

SELECTION OF INITIAL CHEMO-IMMUNO-THERAPY: TOXICITY Grade 3 or 4 Fcr German CLL8 Br German CLL sg phase 2 Neutropenia 34% Thrombocytopenia 7% Infection 25% AIHA 1% Neutropenia 20% Thrombocytopenia 22% Infection 8% AIHA (onset prior to Rx) 2%

FCR DOES NOT OVERCOME DEL17P: GERMAN CLL8 DATA ~11% Boettcher S et al. ASH 2009

PROLONGED CYTOPENIAS Strati P, et al MDACC Cancer 2013 207 CLL patients who achieved CR, CRi, nPR with FCR Months post-FCR Grade 2-4 cytopenia Late Infection incidence 3 35% 6 24% 9 12% 38% (2/3 bacterial)

RISK OF T-MN WITH F ± C AS INITIAL CLL THERAPY Regimen N Median F/U Median age (yrs) # MDS cases RISK MDACC Tam FCR 300 72 57 8 2.8% @ 6 yr Zhou 426 44 19 4.5% (1.9-8.3) CALGB Morrison F-chlor F chlor 142 188 141 50 5 1 3.5% 0.5% Australia Carney 61 41 59 3 6.4% @ 5 yr E2997 Smith FC 137 76 60 9 4 8.2% @ 7 yr 4.6% @ 7 yr

CALGB 10404: Genetic Risk Stratified Randomized Phase II Study of 4 fludarabine + antibody combinations for previously untreated CLL Cycle #1 N = 135/arm; 32/arm to Arm D FR FCR No del(11q) or 17(p) del(11q)+ or del(17p)+ FR x 5 FR x 5 FCR x 5 FCR x 5 Lenalidomide x 6 m Lenalidomide x 6 m

How does BR stack up against FCR How does BR stack up against FCR? Which is best platform for combining novel agents? As neither regimen is curative, we want to use these as a platform to add additional agents in induction and/or consolidation/maintenance Given that BR can be given to most CLL patients and is less myelosuppressive, easier to add new agents to BR

How does BR stack up against FCR? GOALS OF THERAPY IN CLL IS THIS A GOAL? FCR BR CURE YES NO PROLONG OS SURROGATE ENDPOINTS: PROLONG PFS MINIMAL RESIDUAL DISEASE ?

HOW DOES BR STACK UP AGAINST FCR? AWAIT CLL10 Phase 3 Trial: BR vs. FCR BUT, limited to CrCl > 70 and CIRS score ≤ 6 MEANWHILE, BR: equivalent RR, maybe lower CR rate, but in a higher risk population of patients applicable to more CLL patients, wider age and PS, less concern about renal function, AIHA less toxic, fewer doctor visits, requires less supportive care Less myelopsuppressive, so maybe less t-MN Less immunosuppressive, fewer late infections Easier to administer later lines of therapy Easier to combine with novel agents

HOW DOES BR STACK UP AGAINST FCR? Balance of Efficacy and Toxicity? Applicable to what % of CLL patients? QoL: number of visits, supportive care, cost? What therapy can be given at relapse? Which is best platform for combining novel agents? BR WINS ON ALL QUESTIONS!

HOW DOES BR STACK UP AGAINST FCR? So, for your CLL patient who is a 55 year-old marathon runner with 11q- by FISH, I will concede that patient might receive FCR For the rest of your patients, use BR!