Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia
- Kanti R Rai, MD
Kanti R Rai, MD
- Professor of Medicine and Molecular Medicine
- Hofstra North Shore-LIJ School of Medicine at Hofstra University
- Stephan Stilgenbauer, MD
Stephan Stilgenbauer, MD
- Professor of Medicine
- Ulm University
Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent B lymphocytes, which are usually monoclonal in origin.
CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal. While there is some difference to the treatment of early stage CLL and SLL, the treatment of advanced stage disease is the same. (See "Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia".)
The selection of initial therapy for advanced stage or symptomatic disease will be reviewed here. General issues regarding the treatment of CLL/SLL, the treatment of relapsed/refractory CLL, the use of hematopoietic cell transplantation in CLL, and the management of complications of CLL and its treatment are discussed separately. (See "Overview of the treatment of chronic lymphocytic leukemia" and "Overview of the complications of chronic lymphocytic leukemia" and "Treatment of relapsed or refractory chronic lymphocytic leukemia" and "Hematopoietic cell transplantation in chronic lymphocytic leukemia".)
The pathophysiology, clinical manifestations, diagnosis, staging, and prognosis of CLL and SLL are also discussed separately. (See "Clinical presentation, pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia" and "Staging and prognosis of chronic lymphocytic leukemia" and "Pathophysiology and genetic features of chronic lymphocytic leukemia".)
Our general approach — There is no single agreed upon standard treatment regimen for symptomatic chronic lymphocytic leukemia (CLL) or advanced small lymphocytic lymphoma (SLL). Experts in the field use different treatment approaches. As such, there are several initial treatment options for patients with symptomatic CLL or advanced SLL. These include the following options, administered as single agents or as combinations:
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm369846.htm (Accessed on September 26, 2013).
- Gill S, Carney D, Ritchie D, et al. The frequency, manifestations, and duration of prolonged cytopenias after first-line fludarabine combination chemotherapy. Ann Oncol 2010; 21:331.
- Woyach JA, Ruppert AS, Rai K, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol 2013; 31:440.
- Bauer K, Rancea M, Roloff V, et al. Rituximab, ofatumumab and other monoclonal anti-CD20 antibodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2012; 11:CD008079.
- Wierda WG, Kipps TJ, Dürig J, et al. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 2011; 117:6450.
- Cazin B, Divine M, Leprêtre S, et al. High efficacy with five days schedule of oral fludarabine phosphate and cyclophosphamide in patients with previously untreated chronic lymphocytic leukaemia. Br J Haematol 2008; 143:54.
- Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376:1164.
- Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 2016; 127:208.
- Steurer M, Pall G, Richards S, et al. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2006; :CD004270.
- Rai KR, Peterson BL, Appelbaum FR, et al. Long-term survival analysis of the north american intergroup study C9011 comparing fludarabine (F) and chlorambucil (C) in previously untreated patients with chronic lymphocytic leukemia (abstract 536). Blood 2009; 114:224.
- Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4079.
- Tam CS, Wolf M, Prince HM, et al. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer 2006; 106:2412.
- Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27:498.
- Lamanna N, Jurcic JG, Noy A, et al. Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses. J Clin Oncol 2009; 27:491.
- Foon KA, Mehta D, Lentzsch S, et al. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood 2012; 119:3184.
- Ferrario A, Pulsoni A, Olivero B, et al. Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation. Cancer 2012; 118:3954.
- Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood 2014; 123:3247.
- Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112:975.
- Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia. Cancer 2013; 119:3805.
- Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 2016; 127:303.
- Bosch F, Abrisqueta P, Villamor N, et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol 2009; 27:4578.
- Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003; 101:6.
- Woyach JA, Ruppert AS, Heerema NA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 2011; 29:1349.
- Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005; 105:49.
- Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 2016; 17:928.
- Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27:4378.
- Knauf WU, Lissitchkov T, Aldaoud A, et al. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol 2012; 159:67.
- Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 2012; 30:3209.
- FDA warns against using Treanda Injection (solution) with closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene; provides list of compatible devices http://www.fda.gov/Drugs/DrugSafety/ucm437469.htm (Accessed on September 08, 2015).
- Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007; 109:405.
- Samaniego F, Fanale M, Pro B, et al. Pentostatin, cyclophosphamide, and rituximab achieve high response rates in indolent B-cell lymphoma without prolonged myelosuppression (abstract 835). Blood 2008; 112:309.
- Dillman RO, Mick R, McIntyre OR. Pentostatin in chronic lymphocytic leukemia: a phase II trial of Cancer and Leukemia group B. J Clin Oncol 1989; 7:433.
- Oken MM, Lee S, Kay NE, et al. Pentostatin, chlorambucil and prednisone therapy for B-chronic lymphocytic leukemia: a phase I/II study by the Eastern Cooperative Oncology Group study E1488. Leuk Lymphoma 2004; 45:79.
- Shanafelt TD, Lin T, Geyer SM, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 2007; 109:2291.
- Kay NE, Wu W, Kabat B, et al. Pentostatin and rituximab therapy for previously untreated patients with B-cell chronic lymphocytic leukemia. Cancer 2010; 116:2180.
- Reynolds C, Di Bella N, Lyons RM, et al. A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. Invest New Drugs 2012; 30:1232.
- Gribben JG. One step back but 2 steps forward. Blood 2009; 114:3359.
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 2015; 373:2425.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205552s007lbl.pdf (Accessed on March 11, 2016).
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf (Accessed on February 11, 2015).
- Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015; 125:2497.
- Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica 2015; 100:1571.
- Caron F, Leong DP, Hillis C, et al. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood advances 2017; 1:772.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014; 370:1101.
- Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol 2014; 32:1236.
- Foà R, Del Giudice I, Cuneo A, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol 2014; 89:480.
- Rai KR, Barrientos JC. Movement toward optimization of CLL therapy. N Engl J Med 2014; 370:1160.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.pdf (Accessed on November 01, 2013).
- Hillmen P, Tadeusz R, Janssens A, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 2015.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125326s060lbl.pdf (Accessed on April 18, 2014).
- Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009; 114:3382.
- Gribben JG. How I treat CLL up front. Blood 2010; 115:187.
- Polizzotto MN, Tam CS, Milner A, et al. The influence of increasing age on the deliverability and toxicity of fludarabine-based combination chemotherapy regimens in patients with indolent lymphoproliferative disorders. Cancer 2006; 107:773.
- Danese MD, Griffiths RI, Gleeson M, et al. An observational study of outcomes after initial infused therapy in Medicare patients diagnosed with chronic lymphocytic leukemia. Blood 2011; 117:3505.
- Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343:1910.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406916.htm (Accessed on July 29, 2014).
- Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2015; 16:169.
- Jones JA, Ruppert AS, Zhao W, et al. Patients with chronic lymphocytic leukemia with high-risk genomic features have inferior outcome on successive Cancer and Leukemia Group B trials with alemtuzumab consolidation: subgroup analysis from CALGB 19901 and CALGB 10101. Leuk Lymphoma 2013; 54:2654.
- Pettitt AR, Jackson R, Carruthers S, et al. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 2012; 30:1647.
- Geisler CH, van T' Veer MB, Jurlander J, et al. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood 2014; 123:3255.
- Dreger P, Schetelig J, Andersen N, et al. Managing high-risk CLL during transition to a new treatment era: stem cell transplantation or novel agents? Blood 2014; 124:3841.
- Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2014; 15:1090.
- Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103:3278.
- Ravandi F, O'brien S. Alemtuzumab in CLL and other lymphoid neoplasms. Cancer Invest 2006; 24:718.
- Osuji NC, Del Giudice I, Matutes E, et al. The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53. Haematologica 2005; 90:1435.
- Pettitt AR, Matutes E, Oscier D. Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 2006; 20:1441.
- INITIAL THERAPY
- Our general approach
- Infectious complications and prophylactic antimicrobials
- Fludarabine-based therapy
- - Choice of fludarabine regimen
- - Fludarabine, cyclophosphamide, and rituximab
- - Fludarabine plus rituximab
- Bendamustine-based therapy
- Pentostatin-based therapy
- SPECIAL PATIENT POPULATIONS
- Older patients
- - Defining "older adult"
- - Choice of therapy
- - Ibrutinib
- - Chlorambucil-based therapy
- Chlorambucil plus anti-CD20 monoclonal antibodies
- Single agent chlorambucil
- - Fludarabine-based regimens
- High-risk disease: del(17p) or TP53 mutations
- SUMMARY AND RECOMMENDATIONS