CLL Updated March 2017 by Doreen Ezeife Reviewed by Dr. Michelle Geddes (Staff Hematologist, University of Calgary) and Dr. Matt Cheung (Staff Hematologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: Most common adult leukemia in Western Countries and accounts for 25% of all leukemias. Incidence rates in United States 6.75 (males) and 3.65 (females) per 100,000 population per year. In 2010, 2195 Canadians were diagnosed with CLL. - Mortality: 5 year survival approximately 75-80%. In 2011, 600 Canadians died from CLL. RISK FACTORS - Age: Median age of diagnosis ~ 72 years - Environmental/Chemical/Infections: N/A - Genetic: First degree relatives, Gender (male > female), Ethnicity (Caucasian > Asian) PREVENTION & SCREENING - Prevention: N/A - Screening: Routine annual history and physical examination B) PRESENTATION & DIAGNIS SYMPTOMS & SIGNS - Common Symptoms: Asymptomatic, constitutional B symptoms (fevers >38 C, drenching sweats, weight loss ³10% in 6 months), lymphadenopathy, fatigue. - Common Signs: Lymphadenopathy, splenomegaly - Common Presentations: Asymptomatic and diagnosed with lymphocytosis on routine bloodwork. Immune thrombocytopenia, autoimmune hemolytic anemia, infections. INVESTIGATIONS - Laboratory: CBC, differential, peripheral blood smear, peripheral blood flow cytometry of lymphocytes, liver and renal function, LDH, SPEP, serum immunoglobulin levels, DAT, B2 microglobulin, FISH for del17p, del11q, or del13q - Diagnostic Imaging: Abdominal US (if difficult abdominal examination), CXR (if symptoms of infection) - Diagnostic Procedures: Neither lymph node biopsy nor bone marrow biopsy required for establishing diagnosis. Consider if initial investigations inconclusive or suggestive of Richter s transformation i.e. rapidly increasing lymph node size, B symptoms. DIAGNTIC CRITERIA - Common Histology: Monoclonal B lymphocytosis 5 X10 9 /L in peripheral blood for at least 3 months. - Immunophenotype profile: CD5/CD19/CD20/CD43/CD23/CD200 positivity and cyclin D1/FMC7 negative, dim surface immunoglobulin expression with restricted light chain expression. - Cytogenetics: FISH del17p should be done at the time when patients require treatment
- Small lymphocytic lymphoma is diagnosed when a lymph node or other tissue biopsy demonstrates a malignant lymphocytic infiltration with cells showing the same immunophenotype as CLL, but circulating B-lymphocyte count does not exceed 5 X10 9 /L. STAGING - Rai Staging System: Stage Description Risk Status Median Survival (years) 0 Lymphocytosis alone Low 11.7 I Lymphocytosis with lymphadenopathy Intermediate 8.3 II Lymphocytosis with hepatomegaly or splenomegaly Intermediate 5.8 with or without lymphadenopathy III Lymphocytosis and anemia (Hb<110) High 2-4 IV Lymphocytosis and thrombocytopenia (Plt <100) High 2-4 - Binet Staging System: Stage Description Median Survival (years) A Lymphocytosis and Hb 100 and plts 100 and <3 involved nodal areas* >10 B Lymphocytosis and Hb 100 and plts 100 and 3 involved nodal areas 5 C Lymphocytosis and Hb <100 and/or plts <100 and any # involved nodal areas 2-4 *Nodal areas = cervical, axillary, inguinofemoral, spleen, liver C) TREATMENT INITIATING TREATMENT - Assess patient fitness: Determine fitness score based on ECOG Performance Status and Cumulative Illness Rating Score (CIRS). o Fit Group ECOG 0-2 or CIRS 6 and CrCl 70mL/min o Frail Group ECOG 3-4 or CIRS > 6 or CrCl <70mL/min - Initiating Treatment: Treatment of indolent, early stage disease does not prolong survival therefore a watch and wait approach with clinical observation recommended. Treatment initiated when patient develops one of the following: o Progressive marrow failure (anemia and/or thrombocytopenia) o Massive (>6cm below left costal margin) or progressive or symptomatic splenomegaly o Lymphocyte doubling time <6 months o Progressive lymphocytosis with an increase of >50% over 2 months o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to steroids/standard therapy o Disease related constitutional symptoms (fever, night sweats, weight loss, fatigue) FIRST LINE TREATMENT OPTIONS - Bottom Line: Treatment goals are to achieve symptomatic control of the disease and prevent complications. No single standard treatment and treatment depends on age and cytogenetics ie presence of 11q or 17p deletion. Treatment options include: o Purine analogs (Fludarabine, Pentostatin) o Alkylating agents (Chlorambucil, Bendamustine, Cyclophosphamide) o Monoclonal antibodies against CD20 (Rituximab, Ofatumumab, Obinutuzumab) o Novel Agents (Inhibitors of Bruton s tyrosine kinase, PI3-kinase, and BCL2)
o Combination of above agents o Future or on clinical trials - Chimeric antigen receptor T cells (experimental) - General Approach: o Fit Population: Age <65:Fludarabine, cyclophosphamide, and rituximab (FCR) or Fludarabine and rituximab (FR) Age >65: Bendamustine and rituximab (BR) o Frail population: Chlorambucil and rituximab or Chlorambucil and obinutuzumab o Del17p Positive Patients: Ibrutinib with consideration for allogeneic stem cell transplantation Campath at relapse, or venetoclax on clinical trial if available in non-transplant patients - Prognosis: Median survival 3-8 years (poor prognosis if 17p deletion) - Important Phase III Clinical Trials: Physically Fit Population Trials Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomized, open-label, phase 3 trial (CLL8 Trial) Hallek M, et al. Lancet 2010; 376:1164. Primary Endpoint Inclusion/Exclusion Size (N) Phase III comparing 6 cycles of IV Fludarabine (25mg/m 2 /day) and cyclophosphamide (250mg/m 2 /day) for first 3 days of 28 day cycle with or without rituximab (375mg/m 2 on day 0 of first cycle, and 500mg/m 2 on day 1 of 2-6 cycle). FC vs FCR Rituximab: monoclonal antibody against CD20 Treatment naïve, physically fit, with CD20-positive CLL 817 patients At 3 yrs for FCR 65% vs FC 45% (p<0.0001) At 3 yrs for FCR 87% vs FC 83% (p=0.01) Toxicity Grade 3 / 4 neutropenia: FCR 34% vs FC 21% Grade 3 / 4 leukocytopenia: FCR 24% vs FC 12% Treatment related deaths: FCR 10 (3%) vs FC 8 (2%) Chemoimmunotherapy with FCR improves and Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab versus bendamustine and rituximab in previously untreated and physically fit patients with CLL. (CLL10 Trial) Eichhorst B, Fink A, Bahlo J, Busch R, Kovacs G, Maurer C, et al. Final results with data. Lancet Oncol 2016 Jul; 17(7):928-42. Phase III comparing 6 cycles Fludarabine, cyclophosphamide, and rituximab (FCR) vs Bendamustine and rituximab (BR). Designed as noninferiority trial Primary Endpoint Inclusion/Exclusion Treatment naïve, physically fit (CIRS score 6, CrCl 70mL/min), without del17p Size (N) 564 patients
Toxicity Median FCR 55.2mo vs BR 41.7mo (p<0.001, NOT non-inferior) benefit of FCR vs BR persisted in pts <65yo (53.6mo vs 38.5mo, p<0.01) benefit no longer statistically significant in pts >65yo (not reached vs 48.5mo, p=0.170) No difference in CR FCR 39.7% vs BR 30.8% No difference in. FCR 95% vs BR 96% (ns) Toxicity profiles favor BR especially in older patients Neutropenia: FCR 84.2% vs BR 59% Thrombocytopenia: FCR 21.5% vs BR 14.4% Infection: FCR 39.1% vs BR 26.8% Infection >65yo: FCR 47.7% vs BR 20.6% TRM: FCR 4.6% vs BR 2.1% Prolonged and higher CR rates in FCR compared to BR, therefore FCR remains standard frontline therapy for physically fit patients with advanced CLL. However, given milder toxicity profile of BR, BR may be appropriate alternative to FCR in older (>65yo) fit patients Frail Population Trials Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions Goede, et al. NEJM 2014; 370(12): 1101-1110. Primary Endpoint Inclusion/Exclusion Phase III trial comparing Chlorambucil (Clb), Chlorambucil and Obinutuzumab (Clb-Ob), or Chlorambucil and Rituximab (Clb-R) Obinutuzumab: type 2 glycoengineered antibody against CD20 (also known as GA101) Treatment naïve CIRS score >6 or CrCl <70mL/min Size (N) 781 patients Toxicity Clb-Ob vs Clb (26.7mo vs 11.1mo, p<0.001) Clb-R vs Clb (16.3mo vs 11.1mo, p <0.001) Clb-Ob vs Clb-R (26.7mo vs 15.2mo, p<0.001) Clb-Ob vs Clb. Chl-Ob prolonged (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%) Infusion related reaction: seen with Clb-Ob and Clb-R, increased in Clb-Ob arm occurring only with Cycle 1 Combining an anti-cd20 antibody with chemotherapy improves outcomes in pts with coexisting conditions. Obinutuzumab was superior to Rituximab when each was combined with Chlorambucil.
Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia Burger, et al. NEJM 2015; 373: 2425-2437. Phase III trial comparing Ibrutinib versus Chlorambucil for upfront treatment Ibrutinib: Inhibitor of Bruton s Tyrosine Kinase Primary Endpoint Inclusion/Exclusion Treatment naïve Age >65, not fit for Fludarabine based regimen Del17p excluded Size (N) 269 patients 18mo : Ibr vs Clb (90% vs 52%) 24mo : Ibr vs Clb (98% vs 85%) 24mo : Ibr vs Clb (98% vs 85%) Ibr vs Clb (86% vs 35%, p<0.001) Toxicity Ibrutinib: 4 pts Grade 3 hemorrhade, 1 pt Grade 4 hemorrhage Ibrutinib superior to chlorambucil in previously untreated pts with CLL as assessed by,, Response Rate, and improvement in hematologic variables Patients with del17p Efficacy and Safety of Ibrutinib in Patients with R/R CLL with 17p Deletion: from the Phase II RESONATE-17 Trial O Brien, et al. ASH Oral presentation Dec 2014 Phase II Single arm Ibrutinib 420mg daily until progression Primary Endpoint Overall Response Rate () Inclusion/Exclusion Patients with del17p CLL who failed at least one therapy Size (N) 114 patients 82.6% 12month 79.3% Richter Transformation 11 patients (7.6%) Toxicity Diarrhea, fatigue, cough, arthralgia, Afib (7.6%), hemorrhage (4.9%) Grade 3-4: neutropenia, anemia, pneumona, HTN Ibrutinib demonstrates efficacy in del17p patients in terms of, DOR, and with a favorable risk-benefit profile. All other therapies are proven ineffective in pts with del17p. Ibrutinib favored for use in frontline therapy with del17p CLL patients
SECOND LINE TREATMENT OPTIONS FOR RELAPSED/REFRACTORY PATIENTS - Bottom Line General Approach: o Second line treatment options should consider individual factors including comorbidities, length of disease free interval, previous treatments o No standard or optimal R/R regimen. Consider for clinical trial when available. o In fit patients, FCR effective regimen for rituximab naïve. Re-treatment with FCR also effective option for >3yrs after initial FCR o Other options include Ibrutinib, Idelalisib + Rituximab, Bendamustine + Rituximab, BCL2 inhibitors + Rituximab (trial ongoing), Venetoclax for patients with del(17p), Allogeneic Stem Cell Transplant if < 65 yo - Important Phase III Clinical Trials: Ibrutinib Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia Byrd, et al. NEJM 2014; 371:213-223 Phase III trial comparing daily Ibrutinib versus Ofatumumab Ibrutinib: Inhibitor of Bruton s tyrosine kinase Ofatumumab: anti-cd20 Antibody Primary Endpoint Inclusion/Exclusion Relapsed or refractory CLL/SLL Not candidates for purine analogue treatment Included del17p Size (N) 391 patients Ibr (significantly improved, median duration not reached, 88% at 6mo) Ofa (Median 8.1mo) 12mo Ibr 90% vs Ofa 91% Ibr 42.6% vs Ofa 4.1%, p<0.001 Ibrutinib compared with Ofatumumab had significantly improved,, and among patients with previously treated CLL/SLL Idelalisib Idelalisib and Rituximab in relapsed chronic lymphocytic leukemia Furman, et al. NEJM 2014. Mar 13;370(11): 997-1007. Primary Endpoint Inclusion/Exclusion Size (N) 220 patients Phase III trial, randomized, double blind comparing Idelalisib (150mg BID) plus Rituximab to Placebo plus Rituximab in relapsed CLL Idelalisib: oral inhibitor of phosphatidylinositol 3-kinase (PI3 kinase inhibitor) Relapsed or refractory CLL/SLL Not candidates for purine analogue treatment Idel-R (median not reached), Placebo (median 5.5mo)
Idel-R vs Placebo (81% vs 13%, p<0.001) 12mo Idel-R vs Placebo (92% vs 80%, p=0.02) Idelalisib and Ritux showed significant improved,, among pts with relapsed CLL who were unable to undergo standard chemotherapy Venetoclax Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 2016 Jun;17(6):768-778. Pivotal, single arm, phase II trial published 2016 in Lancet Oncology studied 107 patients with del(17p) relapsed or refractory CLL with daily oral Venetoclax (with weekly ramp-up dosing up to 400mg daily) until progression. : 74% Toxicity: Grade 3-4 neutropenia, infection, anemia and thrombocytopenia in 40%, 20%, 18% and 15% of patients, respectively. Also, pyrexia, AIHA, pneumonia and FNP. The impressive response rate led to approval of venetoclax for refractory/relapsed del(17p) CLL. COMPLICATIONS AND SUPPORTIVE CARE Infection o Avoid live vaccines. Recommend annual influenza vaccine and pneumococcal vaccine every 5 years o Antibiotic prophylaxis during chemotherapy (ie) Septra for PJP with Fludarabine, idelalisib or Bendamustine based treatment o Secondary immunodeficiency: recurrent infections and serum IgG <5g/L consider monthly IVIG o CMV monitoring and HSV, PJP prophylaxis for campath Autoimmune cytopenias o Can develop autoimmune hemolytic anemia, Idiopathic thrombocytopenia purpura, and pure red cell aplasia. o Treat with glucocorticoids Richter s Transformation o Transformation of CLL to Diffuse large B cell lymphoma o Requires histologic confirmation Tumor Lysis Syndrome o Higher risk includes high tumor burden, high rate of proliferation, disease highly responsive to therapy. o Prophylactic allopurinol (300mg/day) if renal dysfunction, chronic hyperuricemia, or WBC >200. Rasburicase if intolerant to allopurinol o Hydration and monitor electrolytes/uric acid Blood Product Support o Recipients of Fludarabine, Bendamustine or Alemtuzumab should receive irradiated products to prevent transfusion-related graft versus host disease and CMV negative products. D) REFERENCES - Alberta Health Services Guidelines - UptoDate - Canadian Cancer Society - Odette Cancer Centre Guidelines