CLL Updated February 2016 by Dr. Manna (PGY 5 Hematology Resident, University of Calgary)

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1 CLL Updated February 2016 by Dr. Manna (PGY 5 Hematlgy Resident, University f Calgary) Reviewed by Dr. Michelle Geddes (Staff Hematlgist, University f Calgary) and Dr. Matt Cheung (Staff Hematlgist, University f Trnt) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY 5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) PUBLIC HEALTH EPIDEMIOLOGY Incidence: Mst cmmn adult leukemia in Western Cuntries and accunts fr 25% f all leukemias. Incidence rates in United States 6.75 (males) and 3.65 (females) per 100,000 ppulatin per year. In 2010, 2195 Canadians were diagnsed with CLL. Mrtality: 5 year survival apprximately 75 80%. In 2011, 600 Canadians died frm CLL. RISK FACTORS Age: Median age f diagnsis ~ 72 years Envirnmental/Chemical/Infectins: N/A Genetic: First degree relatives, Gender (male > female), Ethnicity (Caucasian > Asian) PREVENTION & SCREENING Preventin: N/A Screening: Rutine annual histry and physical examinatin B) PRESENTATION & DIAGNIS SYMPTOMS & SIGNS Cmmn Symptms: Asymptmatic, cnstitutinal B symptms (fevers >38 C, drenching sweats, weight lss 10% in 6 mnths), lymphadenpathy, fatigue. Cmmn Signs: Lymphadenpathy, splenmegaly Cmmn Presentatins: Asymptmatic and diagnsed with lymphcytsis n rutine bldwrk. Immune thrmbcytpenia, autimmune hemlytic anemia, infectins. INVESTIGATIONS Labratry: CBC, differential, peripheral bld smear, peripheral bld flw cytmetry f lymphcytes, liver and renal functin, LDH, SPEP, serum immunglbulin levels, DAT, B2 micrglbulin, FISH fr del17p, del11q, r del13q Diagnstic Imaging: Abdminal US (if difficult abdminal examinatin), CXR (if symptms f infectin) Diagnstic Prcedures: Neither lymph nde bipsy nr bne marrw bipsy required fr establishing diagnsis. Cnsider if initial investigatins incnclusive r suggestive f Richter s transfrmatin i.e. rapidly increasing lymph nde size, B symptms. PATHOLOGY & MOLECULAR BIOLOGY Cmmn Histlgy: Mnclnal B lymphcytsis 5 X10 9 /L in peripheral bld fr at least 3 mnths. Immunphentype prfile: CD5/CD19/CD20/CD43/CD20 psitivity, dim surface immunglbulin expressin with restricted light chain expressin, cyclin D1/FMC7 negative.

2 Cytgenetics: FISH fr prgnstic and predictive bimarkers. Include del17p, del11q STAGING Rai Staging System: Stag e Descriptin Risk Status Median Survival (years) 0 Lymphcytsis alne Lw 11.7 I Lymphcytsis with lymphadenpathy Intermediate 8.3 II Lymphcytsis with hepatmegaly r splenmegaly with Intermediate 5.8 r withut lymphadenpathy III Lymphcytsis and anemia (Hb<110) High 2 4 IV Lymphcytsis and thrmbcytpenia (Plt <100) High 2 4 Binet Staging System: Stage Descriptin Median Survival (years) A Lymphcytsis and Hb 100 and plts 100 and <3 invlved ndal areas* >10 B Lymphcytsis and Hb 100 and plts 100 and 3 invlved ndal areas 5 C Lymphcytsis and Hb <100 and/r plts <100 and any # invlved ndal areas 2 4 * Ndal areas = cervical, axillary, inguinfemral, spleen, liver C) TREATMENT INITIATING TREATMENT Assess patient fitness: Determine fitness scre based n ECOG Perfrmance Status and Cumulative Illness Rating Scre (CIRS). Fit Grup ECOG 0 2 r CIRS 6 and CrCl 70mL/min Frail Grup ECOG 3 4 r CIRS > 6 r CrCl <70mL/min Initiating Treatment: Treatment f indlent, early stage disease des nt prlng survival therefre a watch and wait apprach with clinical bservatin recmmended. Treatment initiated when patient develps ne f the fllwing: Prgressive marrw failure (anemia and/r thrmbcytpenia) Massive (>6cm belw left cstal margin) r prgressive r symptmatic splenmegaly Lymphcyte dubling time <6 mnths Prgressive lymphcytsis with an increase f >50% ver 2 mnths Autimmune anemia and/r thrmbcytpenia that is prly respnsive t sterids/standard therapy Disease related cnstitutinal symptms (fever, night sweats, weight lss, fatigue) FIRST LINE TREATMENT OPTIONS Bttm Line: Treatment gals are t achieve symptmatic cntrl f the disease and prevent cmplicatins. N single standard treatment and treatment depends n age and cytgenetics ie presence f 11q r 17p deletin. Treatment ptins include: Purine analgs (Fludarabine, Pentstatin)

3 Alkylating agents (Chlrambucil, Bendamustine, Cyclphsphamide) Mnclnal antibdies (Rituximab, Ofatumumab, Obinutuzumab) Nvel Agents (Inhibitrs f Brutn s tyrsine kinase, PI3 kinase, and BCL2) Cmbinatin f abve agents Future r n clinical trials Chimeric antigen receptr T cells (experimental) General Apprach: Fit Ppulatin : Age <65:Fludarabine, cyclphsphamide, and rituximab (FCR) r Fludarabine and rituximab (FR) Age >65: Bendamustine and rituximab (BR) Frail ppulatin: Chlrambucil and rituximab r Chlrambucil and binutuzumab Del17p Psitive Patients: Ibrutinib with cnsideratin fr allgeneic stem cell transplantatin Campath at relapse, r venetclax n clinical trial if available in nn transplant patients Prgnsis: Median survival 3 8 years (pr prgnsis if 17p deletin) Imprtant Phase III Clinical Trials: Physically Fit Ppulatin Trials Additin f rituximab t fludarabine and cyclphsphamide in patients with chrnic lymphcytic leukemia: a randmized, pen label, phase 3 trial (CLL8 Trial) Hallek M, et al. Lancet 2010; 376:1164. Mechanism f Actin f Primary Endpint Inclusin/Exclusin Size (N) Phase III cmparing 6 cycles f IV Fludarabine (25mg/m 2 /day) and cyclphsphamide (250mg/m 2 /day) fr first 3 days f 28 day cycle with r withut rituximab (375mg/m 2 n day 0 f first cycle, and 500mg/m 2 n day 1 f 2 6 cycle). FC vs FCR Rituximab: mnclnal antibdy against CD20 Treatment naïve, physically fit, with CD20 psitive CLL 817 patients At 3 yrs fr FCR 65% vs FC 45% (p<0.0001) At 3 yrs fr FCR 87% vs FC 83% (p=0.01) Txicity Grade 3 / 4 neutrpenia: FCR 34% vs FC 21% Grade 3 / 4 leukcytpenia: FCR 24% vs FC 12% Treatment related deaths: FCR 10 (3%) vs FC 8 (2%) Cnclusin Chemimmuntherapy with FCR imprves and

4 Chemimmuntherapy with fludarabine, cyclphsphamide, and rituximab versus bendamustine and rituximab in previusly untreated and physically fit patients with CLL. (CLL10 Trial) Eichhrst, et al. Final results frm ASH 2014 Primary Endpint Inclusin/Exclusin Size (N) Txicity Cnclusin Phase III cmparing 6 cycles Fludarabine, cyclphsphamide, and rituximab (FCR) vs Bendamustine and rituximab (BR). Designed as nn inferirity trial Treatment naïve, physically fit (CIRS scre 6, CrCl 70mL/min), withut del17p 564 patients Median FCR 55.2m vs BR 41.7m (p<0.001) benefit f FCR vs BR persisted in pts <65y (53.6m vs 38.5m, p<0.01) benefit n lnger statistically significant in pts >65y (nt reached vs 48.5m, p=0.170) CR FCR 39.7% vs BR 30.8% N difference in. FCR 90.6% vs 92.2% Txicity prfiles favr BR especially in lder patients Neutrpenia: FCR 84.2% vs BR 59% Thrmbcytpenia: FCR 21.5% vs BR 14.4% Infectin: FCR 39.1% vs BR 26.8% Infectin >65y: FCR 47.7% vs BR 20.6% TRM: FCR 4.6% vs BR 2.1% Prlnged and higher CR rates in FCR cmpared t BR, therefre FCR remains standard frntline therapy fr physically fit patients with advanced CLL. Hwever, given milder txicity prfile f BR, BR may be apprpriate alternative t FCR in lder (>65y) fit patients

5 Frail Ppulatin Trials Obinutuzumab plus chlrambucil in patients with CLL and cexisting cnditins Gede, et al. NEJM 2014; 370(12): Mechanism f Actin f Primary Endpint Inclusin/Exclusin Phase III trial cmparing Chlrambucil (Clb), Chlrambucil and Obinutuzumab (Clb Ob), r Chlrambucil and Rituximab (Clb R) Obinutuzumab: type 2 glycengineered antibdy against CD20 (als knwn as GA101) Treatment naïve CIRS scre >6 r CrCl <70mL/min Size (N) 781 patients Txicity Cnclusin Clb Ob vs Clb (26.7m vs 11.1m, p<0.001) Clb R vs Clb (16.3m vs 11.1m, p <0.001) Clb Ob vs Clb R (26.7m vs 15.2m, p<0.001) Clb Ob vs Clb. Chl Ob prlnged (HR 0.41, p=0.002) Clb Ob vs Clb R (78.4% vs 65.1%, p<0.01) CR Clb Ob vs Clb R (20.7% vs 7%) Infusin related reactin: seen with Clb Ob and Clb R, increased in Clb Ob arm ccurring nly with Cycle 1 Cmbining an anti CD20 antibdy with chemtherapy imprves utcmes in pts with cexisting cnditins. Obinutuzumab was superir t Rituximab when each was cmbined with Chlrambucil.

6 Ibrutinib as Initial Therapy fr Patients with Chrnic Lymphcytic Leukemia Burger, et al. NEJM 2015; 373: Mechanism f Actin f Primary Endpint Inclusin/Exclusin Phase III trial cmparing Ibrutinib versus Chlrambucil fr upfrnt treatment Ibrutinib: Inhibitr f Brutn s Tyrsine Kinase Treatment naïve Age >65, nt fit fr Fludarabine based regimen Del17p excluded Size (N) 269 patients 18m : Ibr vs Clb (90% vs 52%) 24m : Ibr vs Clb (98% vs 85%) 24m : Ibr vs Clb (98% vs 85%) Ibr vs Clb (86% vs 35%, p<0.001) Txicity Cnclusin Ibrutinib: 4 pts Grade 3 hemrrhade, 1 pt Grade 4 hemrrhage Ibrutinib superir t chlrambucil in previusly untreated pts with CLL as assessed by,, Respnse Rate, and imprvement in hematlgic variables Patients with del17p Efficacy and Safety f Ibrutinib in Patients with R/R CLL with 17p Deletin: frm the Phase II RESONATE 17 Trial O Brien, et al. ASH Oral presentatin Dec 2014 Phase II Single arm Ibrutinib 420mg daily until prgressin Primary Endpint Overall Respnse Rate () Inclusin/Exclusin Patients with del17p CLL wh failed at least ne therapy Size (N) 114 patients 82.6% 12mnth 79.3% Richter Transfrmatin 11 patients (7.6%) Txicity Diarrhea, fatigue, cugh, arthralgia, Afib (7.6%), hemrrhage (4.9%) Grade 3 4: neutrpenia, anemia, pneumna, HTN Cnclusin Ibrutinib demnstrates efficacy in del17p patients in terms f, DOR, and with a favrable risk benefit prfile. All ther therapies are prven ineffective in pts with del17p. Ibrutinib favred fr use in frntline therapy with del17p CLL patients

7 SECOND LINE TREATMENT OPTIONS FOR RELAPSED/REFRACTORY PATIENTS Bttm Line General Apprach: Secnd line treatment ptins shuld cnsider individual factrs including cmrbidities, length f disease free interval, previus treatments N standard r ptimal R/R regimen. Cnsider fr clinical trial when available. In fit patients, FCR effective regimen fr rituximab naïve. Re treatment with FCR als effective ptin fr >3yrs after initial FCR Other ptins include Ibrutinib, Idelalisib + Rituximab, Bendamustine + Rituximab, BCL2 inhibitrs + Rituximab (trial nging), Allgeneic Stem Cell Transplant Imprtant Phase III Clinical Trials: Ibrutinib Ibrutinib versus Ofatumumab in Previusly Treated Chrnic Lymphid Leukemia Byrd, et al. NEJM 2014; 371: Phase III trial cmparing daily Ibrutinib versus Ofatumumab Mechanism f Ibrutinib: Inhibitr f Brutn s tyrsine kinase Actin f Ofatumumab: anti CD20 Antibdy Primary Endpint Inclusin/Exclusin Relapsed r refractry CLL/SLL Nt candidates fr purine analgue treatment Included del17p Size (N) 391 patients Ibr (significantly imprved, median duratin nt reached, 88% at 6m) Ofa (Median 8.1m) 12m Ibr 90% vs Ofa 91% Ibr 42.6% vs Ofa 4.1%, p<0.001 Cnclusin Ibrutinib cmpared with Ofatumumab had significantly imprved,, and amng patients with previusly treated CLL/SLL

8 Idelalisib Idelalisib and Rituximab in relapsed chrnic lymphcytic leukemia Furman, et al. NEJM Mar 13;370(11): Mechanism f Actin f Phase III trial, randmized, duble blind cmparing Idelalisib (150mg BID) plus Rituximab t Placeb plus Rituximab in relapsed CLL Idelalisib: ral inhibitr f phsphatidylinsitl 3 kinase (PI3 kinase inhibitr) Primary Endpint Inclusin/Exclusin Relapsed r refractry CLL/SLL Nt candidates fr purine analgue treatment Size (N) 220 patients Idel R (median nt reached), Placeb (median 5.5m) Idel R vs Placeb (81% vs 13%, p<0.001) 12m Idel R vs Placeb (92% vs 80%, p=0.02) Cnclusin Idelalisib and Ritux shwed significant imprved,, amng pts with relapsed CLL wh were unable t underg standard chemtherapy COMPLICATIONS AND SUPPORTIVE CARE Infectin Avid live vaccines. Recmmend annual influenza vaccine and pneumcccal vaccine every 5 years Antibitic prphylaxis during chemtherapy (ie) Septra fr PJP with Fludarabine, idelalisib r Bendamustine based treatment Secndary immundeficiency: recurrent infectins and serum IgG <5g/L cnsider mnthly IVIG CMV mnitring and HSV, PJP prphylaxis fr campath Autimmune cytpenias Can develp autimmune hemlytic anemia, Idipathic thrmbcytpenia purpura, and pure red cell aplasia. Treat with gluccrticids Richter s Transfrmatin Transfrmatin f CLL t Diffuse large B cell lymphma Requires histlgic cnfirmatin Tumr Lysis Syndrme Higher risk includes high tumr burden, high rate f prliferatin, disease highly respnsive t therapy. Prphylactic allpurinl (300mg/day) if renal dysfunctin, chrnic hyperuricemia, r WBC >200. Rasburicase if intlerant t allpurinl Hydratin and mnitr electrlytes/uric acid Bld Prduct Supprt Recipients f Fludarabine, Bendamustine r Alemtuzumab shuld receive irradiated prducts t prevent transfusin related graft versus hst disease and CMV negative prducts.

9 D) REFERENCES Alberta Health Services Guidelines UptDate Canadian Cancer Sciety Odette Cancer Centre Guidelines