Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia

References

• Everett JL, Roberts JJ, Ross WCJ. Aryl-2 halogenoalkylamines. Part XII. Some carboxylic derivatives of NN-Di-2-chloroethylaniline. J Chem Soc 1953;2386–2392.
   Web of Science ®Google Scholar
• Kyle RA, Greipp PR, Gertz MA, et al. Waldenstrom's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 2000;108:737–742.
   PubMed Web of Science ®Google Scholar
• Nicolle A, Proctor SJ, Summerfield GP. High dose chlorambucil in the treatment of lymphoid malignancies. Leuk Lymphoma 2004;45: 271–275.
   PubMed Web of Science ®Google Scholar
• Gellhorn A, Hyman GA, Ultmann JE. Chlorambucil in treatment of chronic lymphocytic leukemia and certain lymphomas. J Am Med Assoc 1956;162:178–183.
   PubMed Web of Science ®Google Scholar
• Galton DA, Wiltshaw E, Szur L, et al. The use of chlorambucil and steroids in the treatment of chronic lymphocytic leukaemia. Br J Haematol 1961;7:73–98.
   PubMed Web of Science ®Google Scholar
• Ezdinli EZ, Stutzman L. Chlorambucil therapy for lymphomas and chronic lymphocytic leukemia. JAMA 1965;191:444–450.
   PubMed Web of Science ®Google Scholar
• Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750–1757.
   PubMed Web of Science ®Google Scholar
• Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230–239.
   PubMed Web of Science ®Google Scholar
• 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;112:975–980.
   PubMed Web of Science ®Google Scholar
• 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;376:1164–1174.
   PubMed Web of Science ®Google Scholar
• Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010; 28:1756–1765.
   PubMed Web of Science ®Google Scholar
• Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623.
   PubMed Web of Science ®Google Scholar
• 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;27:4378–4384.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369: 32–42.
   PubMed Web of Science ®Google Scholar
• Seymour JF, Davids MS, Pagel JM, et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood 2013;122(Suppl. 1): Abstract 872.
   Web of Science ®Google Scholar
• Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014;370: 997–1007.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014;15:48–58.
   PubMed Web of Science ®Google Scholar
• Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study COMPLEMENT 1 (OMB110911). Blood 2013;122(Suppl. 1): Abstract 528.
   Web of Science ®Google Scholar
• Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101–1110.
   PubMed Web of Science ®Google Scholar
• Bank BB, Kanganis D, Liebes LF, et al. Chlorambucil pharmacokinetics and DNA binding in chronic lymphocytic leukemia lymphocytes. Cancer Res 1989;49:554–559.
   PubMed Web of Science ®Google Scholar
• Begleiter A, Mowat M, Israels LG, et al. Chlorambucil in chronic lymphocytic leukemia: mechanism of action. Leuk Lymphoma 1996;23:187–201.
   PubMed Web of Science ®Google Scholar
• Aydogdu I, Ozcan C, Harputluoglu M, et al. Severe adverse skin reaction to chlorambucil in a patient with chronic lymphocytic leukemia. Anticancer Drugs 1997;8:468–469.
   PubMed Web of Science ®Google Scholar
• Levin M, Libster D. Allergic reaction to chlorambucil in chronic lymphocytic leukemia presenting with fever and lymphadenopathy. Leuk Lymphoma 2005;46:1195–1197.
   PubMed Web of Science ®Google Scholar
• Kilickap S, Kurt M, Aksoy S, et al. Extensive exfoliative dermatitis induced by chlorambucil. Am J Hematol 2006;81:891–892.
   PubMed Web of Science ®Google Scholar
• Ozkan A, Baskan EB, Ali R, et al. Profuse erythema multiforme induced by chlorambucil. Ann Hematol 2007;86:539–540.
   PubMed Web of Science ®Google Scholar
• Vaida I, Roszkiewicz F, Gruson B, et al. Drug rash with eosinophilia and systemic symptoms after chlorambucil treatment in chronic lymphocytic leukaemia. Pharmacology 2009;83:148–149.
   PubMed Web of Science ®Google Scholar
• Giles FJ, Smith MP, Goldstone AH. Chlorambucil lung toxicity. Acta Haematol 1990;83:156–158.
   PubMed Web of Science ®Google Scholar
• Crestani B, Jaccard A, Israel-Biet D, et al. Chlorambucil-associated pneumonitis. Chest 1994;105:634–636.
   PubMed Web of Science ®Google Scholar
• Khong HT, McCarthy J. Chlorambucil-induced pulmonary disease: a case report and review of the literature. Ann Hematol 1998;77:85–87.
   PubMed Web of Science ®Google Scholar
• Hehn ST, Dorr RT, Miller TP. Mood alterations in patients treated with chlorambucil. Clin Lymphoma 2003;4:179–182.
   PubMedGoogle Scholar
• Salloum E, Khan KK, Cooper DL. Chlorambucil-induced seizures. Cancer 1997;79:1009–1013.
   PubMed Web of Science ®Google Scholar
• Morrison VA, Rai KR, Peterson BL, et al. Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol 2002;20:3878–3884.
   PubMed Web of Science ®Google Scholar
• Callea V, Brugiatelli M, Stelitano C, et al. Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leuk Lymphoma 2006;47:2314–2320.
   PubMed Web of Science ®Google Scholar
• Chlorambucil prescribing information. Available from: www.accessdata.fda.gov/drugsatfda_docs/lable/2011/010669s032lbl.pdf
   Google Scholar
• Silvennoinen R, Malminiemi K, Malminiemi O, et al. Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses. Pharmacol Toxicol 2000;87:223–228.
   PubMedGoogle Scholar
• Alberts DS, Chang SY, Chen HS, et al. Comparative pharmacokinetics of chlorambucil and melphalan in man. Recent Results Cancer Res 1980;74:124–131.
   PubMedGoogle Scholar
• Han T, Ezdinli EZ, Shimaoka K, et al. Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer 1973;31:502–508.
   PubMed Web of Science ®Google Scholar
• Knospe WH, Loeb V Jr, Huguley CM Jr. Proceedings: bi-weekly chlorambucil treatment of chronic lymphocytic leukemia. Cancer 1974;33:555–562.
   PubMed Web of Science ®Google Scholar
• Sawitsky A, Rai KR, Glidewell O, et al. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977; 50:1049–1059.
   PubMed Web of Science ®Google Scholar
• Shustik C, Mick R, Silver R, et al. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988;6:7–12.
   PubMed Web of Science ®Google Scholar
• The French Cooperative Group on Chronic Lymphocytic Leukemia. Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. The French Cooperative Group on Chronic Lymphocytic Leukemia. Blood 1990;75:1414–1421.
   PubMed Web of Science ®Google Scholar
• Catovsky D, Richards S, Fooks J, et al. CLL trials in the United Kingdom. The Medical Research Council CLL trials 1, 2 and 3. Leuk Lymphoma 1991;5:105–111.
   PubMed Web of Science ®Google Scholar
• Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 1998;338:1506–1514.
   PubMed Web of Science ®Google Scholar
• Montserrat E, Alcala A, Parody R, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer 1985;56:2369–2375.
   PubMed Web of Science ®Google Scholar
• Hansen MM, Andersen E, Christensen BE, et al. CHOP versus prednisolone + chlorambucil in chronic lymphocytic leukemia (CLL): preliminary results of a randomized multicenter study. Nouv Rev Fr Hematol 1988;30:433–436.
   PubMedGoogle Scholar
• Montserrat E, Alcala A, Alonso C, et al. A randomized trial comparing chlorambucil plus prednisone vs cyclophosphamide, melphalan, and prednisone in the treatment of chronic lymphocytic leukemia stages B and C. Nouv Rev Fr Hematol 1988;30:429–432.
   PubMed Web of Science ®Google Scholar
• The French Cooperative Group on Chronic Lymphocytic Leukemia. A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia. Blood 1990; 75:1422–1425.
   PubMed Web of Science ®Google Scholar
• Raphael B, Andersen JW, Silber R, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol 1991;9:770–776.
   PubMed Web of Science ®Google Scholar
• Jaksic B, Brugiatelli M, Krc I, et al. High dose chlorambucil versus Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia. Results of an international multicenter randomized trial. International Society for Chemo-Immunotherapy, Vienna. Cancer 1997;79:2107–2114.
   Google Scholar
• Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990–4997.
   PubMed Web of Science ®Google Scholar
• Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446–5456.
   PubMed Web of Science ®Google Scholar
• Robak T, Blonski JZ, Kasznicki M, et al. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 2000;96:2723–2729.
   PubMed Web of Science ®Google Scholar
• Mulligan SP, Karlsson K, Stromberg M, et al. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia. Leuk Lymphoma 2014 Apr 16. [Epub ahead of print]
   Web of Science ®Google Scholar
• Catovsky D, Else M, Richards S. Chlorambucil—still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk 2011;11(Suppl. 1): S2–S6.
   Google Scholar
• 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;114:3382–3391.
   PubMed Web of Science ®Google Scholar
• 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;159:67–77.
   PubMed Web of Science ®Google Scholar
• 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;31:440–447.
   PubMed Web of Science ®Google Scholar
• Tefferi A, Levitt R, Li CY, et al. Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously untreated B-cell chronic lymphocytic leukemia. Am J Clin Oncol 1999;22:509–516.
   PubMed Web of Science ®Google Scholar
• 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;45:79–84.
   PubMed Web of Science ®Google Scholar
• Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:49–56.
   PubMed Web of Science ®Google Scholar
• Reyes C, Satram-Hoang S, Hoang K, et al. What is the impact of comorbidity burden on treatment patterns and outcomes in elderly chronic lymphocytic leukemia patients. Blood 2012;120(Suppl. 1): Abstract 758.
   Web of Science ®Google Scholar
• Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: trial results of the German CLL Study Group. Haematologica 2014;99: 1095–1100.
   PubMed Web of Science ®Google Scholar
• 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;32:1236–1241.
   PubMed Web of Science ®Google Scholar
• Foa 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; 89:480–486.
   PubMed Web of Science ®Google Scholar
• Laurenti L, Vannata B, Innocenti I, et al. Chlorambucil plus rituximab as front-line therapy in elderly/unfit patients affected by B-cell chronic lymphocytic leukemia: results of a single-centre experience. Mediterr J Hematol Infect Dis 2013;5:e2013031.
   PubMedGoogle Scholar
• Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 2010;115:4393–4402.
   PubMed Web of Science ®Google Scholar
• Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol 2011;152: 295–306.
   PubMed Web of Science ®Google Scholar
• Leblond V, Laribi K, Ilhan O, et al. Rituximab in combination with bendamustine or chlorambucil for treating patients with chronic lymphocytic leukemia: interim results of a phase IIIb study (MaBLe). Blood 2012;120(Suppl. 1): Abstract 2744.
   Web of Science ®Google Scholar
• Nikitin E, Kisilichina D, Zakharov O, et al. Randomised comparison of FCR-lite and CLR (chlorambucil plus rituximab) regimens in elderly patients with chronic lymphocytic leukemia. Haematologica 2013;98(Suppl.): Abstract 1147.
   Google Scholar
• Hebb J, Assouline S, Rousseau C, et al. A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 2011;68:643–651.
   PubMed Web of Science ®Google Scholar
• O’Brien SM, Lamanna N, Kipps TJ, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab ® in treatment-naive patients (pts) ≥ 65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol 2013;31(Suppl.): Abstract 7005.
   Web of Science ®Google Scholar