Difference between revisions of "Chronic lymphocytic leukemia - historical"
Warner-admin (talk | contribs) m (Text replacement - "https://ascopubs.org/doi/full/10.1200" to "https://doi.org/10.1200") |
m |
||
Line 72: | Line 72: | ||
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S0140-6736(86)91663-6 Binet et al. 1986 (FRE-CLL-80)] |
|style="background-color:#1a9851"|Phase III (E-esc) | |style="background-color:#1a9851"|Phase III (E-esc) | ||
|[[Chronic_lymphocytic_leukemia#Observation|Observation]] (*) | |[[Chronic_lymphocytic_leukemia#Observation|Observation]] (*) | ||
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS | | style="background-color:#ffffbf" |Did not meet primary endpoint of OS | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S0140-6736(86)91663-6 Binet et al. 1986 (FRE-CLL-80)] |
|style="background-color:#1a9851"|Phase III (C) | |style="background-color:#1a9851"|Phase III (C) | ||
|[[#CVP|CVP]] (*) | |[[#CVP|CVP]] (*) | ||
Line 242: | Line 242: | ||
===References=== | ===References=== | ||
− | # '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https:// | + | # '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https://doi.org/10.1016/S0140-6736(86)91663-6 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2872470 PubMed] |
# '''FRE-CLL-85:''' Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. [https://www.nejm.org/doi/full/10.1056/NEJM199805213382104 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9593789 PubMed] | # '''FRE-CLL-85:''' Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. [https://www.nejm.org/doi/full/10.1056/NEJM199805213382104 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9593789 PubMed] | ||
# '''CALGB 9011:''' Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. [https://www.nejm.org/doi/full/10.1056/NEJM200012143432402 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11114313 PubMed] | # '''CALGB 9011:''' Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. [https://www.nejm.org/doi/full/10.1056/NEJM200012143432402 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11114313 PubMed] | ||
Line 345: | Line 345: | ||
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | !style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S0140-6736(86)91663-6 Binet et al. 1986 (FRE-CLL-80)] |
|style="background-color:#1a9851"|Phase III (E-esc) | |style="background-color:#1a9851"|Phase III (E-esc) | ||
|[[#CVP|CVP]] | |[[#CVP|CVP]] | ||
Line 368: | Line 368: | ||
===References=== | ===References=== | ||
− | # '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https:// | + | # '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https://doi.org/10.1016/S0140-6736(86)91663-6 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2872470 PubMed] |
## '''Update:''' Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2141.1989.tb07749.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/2690923 PubMed] | ## '''Update:''' Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2141.1989.tb07749.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/2690923 PubMed] | ||
# '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed] | # '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed] | ||
Line 566: | Line 566: | ||
## '''Update:''' Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13824/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26457986 PubMed] | ## '''Update:''' Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13824/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26457986 PubMed] | ||
<!-- Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL; the 12th Congress of the European Hematology Association, June 7-10, 2007, Vienna, Austria; the XII International Workshop on Chronic Lymphocytic Leukemia, September 14-16, 2007, London, United Kingdom; the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA; the 13th Congress of the European Hematology Association, June 12-15, 2008, Copenhagen, Denmark; and the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. --> | <!-- Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL; the 12th Congress of the European Hematology Association, June 7-10, 2007, Vienna, Austria; the XII International Workshop on Chronic Lymphocytic Leukemia, September 14-16, 2007, London, United Kingdom; the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA; the 13th Congress of the European Hematology Association, June 12-15, 2008, Copenhagen, Denmark; and the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. --> | ||
− | # Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1863.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20212251 PubMed] | + | # '''PALG-CLL3:''' Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ; Polish Adult Leukemia Group. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. [http://jco.ascopubs.org/content/28/11/1863.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20212251 PubMed] |
# Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961381-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20888994 PubMed] | # Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961381-5/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20888994 PubMed] | ||
## '''Update:''' Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. [http://www.bloodjournal.org/content/127/2/208.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/26486789 PubMed] | ## '''Update:''' Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. [http://www.bloodjournal.org/content/127/2/208.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/26486789 PubMed] | ||
Line 698: | Line 698: | ||
## '''Update:''' Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13824/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26457986 PubMed] | ## '''Update:''' Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13824/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26457986 PubMed] | ||
<!-- Results from an interim analysis were presented, in part, at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003. Preliminary results from the final analysis were presented, in part, at the 14th International CLL Workshop, London, United Kingdom, September 14-16, 2007, as well as at the 49th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 8-11, 2007. --> | <!-- Results from an interim analysis were presented, in part, at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003. Preliminary results from the final analysis were presented, in part, at the 14th International CLL Workshop, London, United Kingdom, September 14-16, 2007, as well as at the 49th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 8-11, 2007. --> | ||
− | # '''GCLLSG CLL5:''' Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group | + | # '''GCLLSG CLL5:''' Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group. 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 Oct 15;114(16):3382-91. Epub 2009 Jul 15. [http://www.bloodjournal.org/content/114/16/3382.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/19605849 PubMed] |
# '''CAM 314:''' Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70242-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/21992852 PubMed] | # '''CAM 314:''' Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70242-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/21992852 PubMed] | ||
− | # '''Abstract:''' Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. [http://www.bloodjournal.org/content/122/21/4127 link to abstract] | + | # '''Abstract:''' Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD; German CLL Study Group. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. [http://www.bloodjournal.org/content/122/21/4127 link to abstract] |
==Fludarabine & Prednisone {{#subobject:d4f71b|Regimen=1}}== | ==Fludarabine & Prednisone {{#subobject:d4f71b|Regimen=1}}== | ||
Line 764: | Line 764: | ||
<!-- Byrd JC, Peterson B, Park K, Morrison V, Vardiman JW, Jacobson RJ, et al. Rituximab added to fludarabine improves response in previously untreated chronic lymphocytic leukemia: preliminary results from CALGB 9712. Journal of Clinical Oncology 2001;20 (Pt 1):280a. --> | <!-- Byrd JC, Peterson B, Park K, Morrison V, Vardiman JW, Jacobson RJ, et al. Rituximab added to fludarabine improves response in previously untreated chronic lymphocytic leukemia: preliminary results from CALGB 9712. Journal of Clinical Oncology 2001;20 (Pt 1):280a. --> | ||
<!-- Byrd JC, Peterson BL, Park K. Concurrent rituximab and fludarabine has a higher complete response rate than sequential treatment in untreated chronic lymphocytic leukemia (CLL) patients: results from CALGB 9712. Blood 2001;98(1):A-3212. --> | <!-- Byrd JC, Peterson BL, Park K. Concurrent rituximab and fludarabine has a higher complete response rate than sequential treatment in untreated chronic lymphocytic leukemia (CLL) patients: results from CALGB 9712. Blood 2001;98(1):A-3212. --> | ||
− | # Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. 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 Jan 1;101(1):6-14. Epub 2002 Jul 5. [http://www.bloodjournal.org/content/101/1/6.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12393429 PubMed] | + | # '''CALGB 9712:''' Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. 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 Jan 1;101(1):6-14. Epub 2002 Jul 5. [http://www.bloodjournal.org/content/101/1/6.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12393429 PubMed] |
## '''Update:''' Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. 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 Jan 1;105(1):49-53. Epub 2004 May 11. [http://www.bloodjournal.org/content/105/1/49.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15138165 PubMed] | ## '''Update:''' Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. 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 Jan 1;105(1):49-53. Epub 2004 May 11. [http://www.bloodjournal.org/content/105/1/49.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15138165 PubMed] | ||
## '''Update:''' Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. 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 Apr 1;29(10):1349-55. Epub 2011 Feb 14. [http://jco.ascopubs.org/content/29/10/1349.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21321292 PubMed] | ## '''Update:''' Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. 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 Apr 1;29(10):1349-55. Epub 2011 Feb 14. [http://jco.ascopubs.org/content/29/10/1349.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21321292 PubMed] |
Revision as of 03:42, 10 March 2020
The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? Please go to the main CLL/SLL regimen page to find other regimens.
22 regimens on this page
42 variants on this page
|
First-line therapy
CAP
back to top |
CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Keating et al. 1990 | Phase II | |||
Johnson et al. 1996 | 1990-1992 | Phase III (C) | Fludarabine | Inferior TTP (*) |
Leporrier et al. 2001 (FCGCLL 1996) | Phase III (C) | 1. CHOP | Did not meet primary endpoint of OS | |
2. Fludarabine | Did not meet primary endpoint of OS |
Note: the inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
1-month cycle for 6 cycles
References
- Keating MJ, Hester JP, McCredie KB, Burgess MA, Murphy WK, Freireich EJ. Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma. 1990;2(6):391-7. link to original article PubMed
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; The French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains protocol PubMed
- FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains protocol PubMed
Chlorambucil monotherapy
back to top |
Regimen variant #1, 0.1 mg/kg
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Binet et al. 1986 (FRE-CLL-80) | Phase III (E-esc) | Observation (*) | Did not meet primary endpoint of OS |
Binet et al. 1986 (FRE-CLL-80) | Phase III (C) | CVP (*) | Did not meet primary endpoint of OS |
Dighiero et al. 1998 (FRE-CLL-85) | Phase III (E-esc) | Observation | Seems to have superior PFS |
Note: In FRE-CLL-80, this was the experimental arm for Binet Stage A and the control arm for Binet Stage B. This is one of two trials reported in Dighiero et al. 1998; the other was comparing chlorambucil & prednisone vs. observation.
Chemotherapy
- Chlorambucil (Leukeran) 0.1 mg/kg PO once per day
Continued indefinitely
Regimen variant #2, 0.4 mg/kg
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Knauf et al. 2009 | Phase III (C) | Bendamustine | Inferior PFS |
This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.
Chemotherapy
- Chlorambucil (Leukeran) 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16
28-day cycle for up to 6 cycles
Regimen variant #3, 0.4 mg/kg, with dose escalation
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Eichhorst et al. 2009 (GCLLSG CLL5) | Phase III (C) | Fludarabine | Did not meet primary endpoints of PFS/OS |
This regimen was intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.
Chemotherapy
- Chlorambucil (Leukeran) as follows:
- Cycle 1: 0.4 mg/kg PO once on day 1
- To be increased as tolerated by 0.1 mg/kg each cycle, up to a maximum of 0.8 mg/kg PO once on day 1
14-day cycle for up to 24 cycles
Regimen variant #4, 0.5 mg/kg
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | Phase III (C) | 1. Chlorambucil & Obinutuzumab | Inferior OS |
2. Chlorambucil & Rituximab | Inferior PFS | ||
Burger et al. 2015 (RESONATE-2) | Phase III (C) | Ibrutinib | Inferior OS (*) |
Note: Patients enrolled on RESONATE-2 were allowed to increase the dose up to 0.8 mg/kg if "there was not an unacceptable level of toxic effects." Reported efficacy for RESONATE-2 is based on the 2019 update.
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
28-day cycle for 6 to 12 cycles
Regimen variant #5, 0.8 mg/kg
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Knauf et al. 2009 | Phase III (C) | Bendamustine | Inferior PFS |
Chanan-Khan et al. 2017 (ORIGIN) | Phase III (C) | Lenalidomide | Did not meet primary endpoint of PFS |
This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.
Chemotherapy
- Chlorambucil (Leukeran) 0.8 mg/kg PO once per day on days 1 & 15
28-day cycle for up to 6 cycles (Knauf et al. 2009) or indefinitely (ORIGIN)
Regimen variant #6, 10 mg/m2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III (C) | 1. FC | Did not meet primary endpoint of OS |
2. Fludarabine | Did not meet primary endpoint of OS | ||
Hillmen et al. 2015 (COMPLEMENT 1) | Phase III (C) | Chlorambucil & Ofatumumab | Inferior PFS |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
Supportive medications
- Per Catovsky et al. 2007: Patients with stage C disease (hemoglobin less than 10 g/dL or platelet count less than 100 x 109/L) received Prednisolone (Millipred) 30 mg/m2 PO once per day for 3 weeks, then 1 week taper before starting Chlorambucil (Leukeran) to reduce its myelotoxicity
28-day cycle for up to 12 cycles
Regimen variant #7, 40 mg/m2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Rai et al. 2000 (CALGB 9011) | Phase III (C) | 1. Chlorambucil & Fludarabine | Not reported |
2. Fludarabine | Inferior PFS | ||
Hillmen et al. 2007 (CAM 307) | Phase III (C) | Alemtuzumab | Inferior PFS |
In CALGB 9011, this regimen was intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months. In CAM 307, this regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the National Cancer Institute Working Group (NCI-WG) 1996 criteria, no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, WHO performance status of 0 to 2, and adequate renal and liver function.
Chemotherapy
- Chlorambucil (Leukeran) 40 mg/m2 PO once on day 1
28-day cycle for up to 12 cycles
References
- FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains verified protocol PubMed
- FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains verified protocol PubMed
- CALGB 9011: Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. link to original article contains protocol PubMed
- LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains verified protocol PubMed
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- CAM 307: Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. link to original article contains protocol PubMed
- Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. link to original article contains verified protocol PubMed
- Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article contains verified protocol PubMed
- GCLLSG CLL5: Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group (GCLLSG). 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 Oct 15;114(16):3382-91. Epub 2009 Jul 15. link to original article contains protocol PubMed
- GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article contains verified protocol PubMed
- Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
- COMPLEMENT 1: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. 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 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article contains protocol PubMed
- RESONATE-2: Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. link to original article contains verified protocol link to PMC article PubMed
- Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
- Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article PubMed
- ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains verified protocol PubMed
Chlorambucil & Prednisone
back to top |
Regimen variant #1, 0.3/40
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Dighiero et al. 1998 (FRE-CLL-85) | Phase III (E-esc) | Observation | Superior PFS |
Chemotherapy
- Chlorambucil (Leukeran) 0.3 mg/kg PO once per day on days 1 to 5
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
1-month cycle for up to 36 cycles (3 years)
Regimen variant #2, 12/30
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Robak et al. 2000 (PALG CLL1) | Phase III (C) | Cladribine & Prednisone | Inferior ORR |
Chemotherapy
- Chlorambucil (Leukeran) 12 mg/m2 PO once per day on days 1 to 7
- Prednisone (Sterapred) 30 mg/m2 PO once per day on days 1 to 7
28-day cycles, continued until CR
Regimen variant #3, 30/80
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Raphael et al. 1991 (ECOG E2480) | Phase III (C) | CVP | Did not meet efficacy endpoints |
Chemotherapy
- Chlorambucil (Leukeran) 30 mg/m2 PO once on day 1
- Prednisone (Sterapred) 80 mg PO once per day on days 1 to 5
14-day cycle for up to 39 cycles (18 months)
References
- ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. 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 May;9(5):770-6. link to original article contains verified protocol PubMed
- FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P. Chlorambucil in indolent chronic lymphocytic leukemia: French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains verified protocol PubMed
- PALG CLL1: Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. link to original article contains protocol PubMed
CHOP
back to top |
CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Binet et al. 1986 (FRE-CLL-80) | Phase III (E-esc) | CVP | Superior OS |
Leporrier et al. 2001 (FCGCLL 1996) | Phase III (C) | 1. CAP | Did not meet primary endpoint of OS |
2. Fludarabine | Did not meet primary endpoint of OS |
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1 to 5
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1 mg/m2 IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
28-day cycle for 6 cycles
References
- FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains verified protocol PubMed
- Update: Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. link to original article PubMed
- FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains protocol PubMed
CVP
back to top |
CVP: Cyclophosphamide, Vincristine, Prednisone
Regimen variant #1, PO cyclophosphamide; uncapped vincristine
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Raphael et al. 1991 (ECOG E2480) | Phase III (E-switch-ic) | Chlorambucil & Prednisone | Did not meet efficacy endpoints |
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1 to 5
- Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for up to 26 cycles (18 months)
Regimen variant #2, capped vincristine
Study | Evidence |
---|---|
Hochster et al. 2009 (ECOG E1496) | Non-randomized portion of RCT |
Chemotherapy
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
Subsequent treatment
- Rituximab maintenance versus observation
References
- ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. 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 May;9(5):770-6. link to original article contains protocol PubMed
- ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains verified protocol link to PMC article PubMed
FC
back to top |
FC: Fludarabine, Cyclophosphamide
Regimen variant #1, 75/750 (IV fludarabine)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III (E-esc) | 1. Chlorambucil | Did not meet primary endpoint of OS |
2. Fludarabine | Did not meet primary endpoint of OS | ||
Robak et al. 2010 (PALG-CLL3) | Phase III (E-switch-ic) | CC | Did not meet primary endpoint of CR rate |
Hallek et al. 2010 (GCLLSG CLL8) | Phase III (C) | FCR | Inferior OS (*) |
Note: efficacy for GCLLSG CLL8 is based on the updated 2016 results.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
Supportive medications
- Per Robak et al. 2010: "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
28-day cycle for up to 6 cycles
Regimen variant #2, 90/750
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Eichhorst et al. 2005 (GCLLSG CLL4) | Phase III (E-esc) | Fludarabine | Superior PFS | No statistical difference in HRQoL |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 3
Supportive medications
- No routine antibiotic, antiviral, or growth factor use
28-day cycle for up to 6 cycles
Regimen variant #3, 100/600
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Flinn et al. 2007 (ECOG E2997) | Phase III (E-esc) | Fludarabine | Superior PFS |
This regimen was intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.
Chemotherapy
- Fludarabine (Fludara) 20 mg/m2 IV once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles
Regimen variant #4, 120/750 (PO fludarabine)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Geisler et al. 2014 (HOVON-68) | Phase III (C) | FCA | Inferior PFS |
This regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the National Cancer Institute guidelines, 18 to 75 years of age, with WHO performance status less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, 17p deletion, 11q deletion, or trisomy 12 by FISH.
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Supportive medications
- Cotrimoxazole 400/80 mg PO once per day until 6 months after end of treatment
- Acyclovir (Zovirax) 400 mg PO three times per day until 3 months after end of treatment
OR
- Valacyclovir (Valtrex) 500 mg PO twice per day until 3 months after end of treatment
28-day cycle for 6 cycles
Regimen variant #5, 120/750 (all PO)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III (E-esc) | 1. Chlorambucil | Did not meet primary endpoint of OS |
2. Fludarabine | Did not meet primary endpoint of OS |
Chemotherapy
- Fludarabine (Fludara) 24 mg/m2 PO once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 150 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 cycles
References
- GCLLSG CLL4: Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. link to original article contains protocol PubMed
- HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
- ECOG E2997: Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007 Mar 1;25(7):793-8. Epub 2007 Feb 5. link to original article contains verified protocol PubMed
- Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
- LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains verified protocol PubMed
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- PALG-CLL3: Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ; Polish Adult Leukemia Group. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article contains verified protocol PubMed
- Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. link to original article contains protocol PubMed
- Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
- HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
- Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. link to original article contains verified protocol PubMed
Fludarabine monotherapy
back to top |
F: Fludarabine
Regimen variant #1, IV
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Johnson et al. 1996 | Phase III (E-de-esc) | CAP | Superior TTP (*) | |
Rai et al. 2000 (CALGB 9011) | Phase III (E-switch-ic) | 1. Chlorambucil | Superior PFS | |
2. Chlorambucil & Fludarabine | Did not meet primary endpoint of CR rate | |||
Leporrier et al. 2001 (FCGCLL 1996) | Phase III (E-de-esc) | 1. CAP | Did not meet primary endpoint of OS | |
2. CHOP | Did not meet primary endpoint of OS | |||
Eichorst et al. 2005 (GCLLSG CLL4) | Phase III (C) | FC | Inferior PFS | No statistical difference in HRQoL |
Flinn et al. 2007 (ECOG E2997) | Phase III (C) | FC | Inferior PFS | |
Catovsky et al. 2007 (LRF CLL4) | Phase III (C) | 1. Chlorambucil | Did not meet primary endpoint of OS | |
2. FC | Did not meet primary endpoint of OS | |||
Eichhorst et al. 2009 (GCLLSG CLL5) | Phase III (E-switch-ic) | Chlorambucil | Did not meet primary endpoints of PFS/OS | |
Elter et al. 2011 (CAM 314) | Phase III (C) | Fludarabine & Alemtuzumab | Seems to have inferior OS | |
Bergmann et al. 2013 (GCLLSG CLL1) | Phase III (E-esc) | Observation | Superior PFS |
Eligibility criteria:
- CALGB 9011: intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months.
- ECOG E2997: intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.
- GCLLSG CLL5: intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.
Note: the superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5
28-day cycle for up to 6 to 12 cycles
Regimen variant #2, PO
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III (C) | 1. Chlorambucil | Did not meet primary endpoint of OS |
2. FC | Did not meet primary endpoint of OS |
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 to 12 cycles
References
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; The French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains protocol PubMed
- CALGB 9011: Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. link to original article contains protocol PubMed
- FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains protocol PubMed
- GCLLSG CLL4: Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. link to original article contains protocol PubMed
- HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
- ECOG E2997: Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007 Mar 1;25(7):793-8. Epub 2007 Feb 5. link to original article contains verified protocol PubMed
- Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
- LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains protocol PubMed
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- GCLLSG CLL5: Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group. 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 Oct 15;114(16):3382-91. Epub 2009 Jul 15. link to original article contains protocol PubMed
- CAM 314: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. link to original article PubMed
- Abstract: Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD; German CLL Study Group. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. link to abstract
Fludarabine & Prednisone
back to top |
Regimen
Study | Evidence |
---|---|
O'Brien et al. 1993 | Phase II |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5
- Prednisone (Sterapred) 30 mg/m2 PO once per day on days 1 to 5
28-day cycles
References
- O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. link to original article contains protocol PubMed
- Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed
FR
back to top |
FR: Fludarabine, Rituximab
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Byrd et al. 2002 (CALGB 9712) | Randomized Phase II (E-switch-ic) | F, then R | Did not meet primary endpoint of CR rate |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1 & 4
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive medications
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
- Diphenhydramine (Benadryl) 50 mg IV once per infusion, 30 minutes prior to Rituximab (Rituxan)
- Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to Rituximab (Rituxan)
28-day cycle for 6 cycles
Subsequent treatment
- If restaging done 2 months after 6 cycles of therapy shows SD or better: Rituximab consolidation
References
- CALGB 9712: Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. 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 Jan 1;101(1):6-14. Epub 2002 Jul 5. link to original article contains protocol PubMed
- Update: Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. 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 Jan 1;105(1):49-53. Epub 2004 May 11. link to original article PubMed
- Update: Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. 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 Apr 1;29(10):1349-55. Epub 2011 Feb 14. link to original article link to PMC article PubMed
Lenalidomide monotherapy
back to top |
Regimen variant #1, target 10 mg/day
Study | Evidence | Efficacy |
---|---|---|
Chen et al. 2010 | Phase II | ORR: 56% |
Chemotherapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 2.5 mg PO once per day on days 1 to 21
- Cycle 2: Increased if tolerated to 5 mg PO once per day on days 1 to 21
- Subsequent cycles: Increased if tolerated to 10 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin 81 mg PO once per day
28-day cycles
Regimen variant #2, target 15 mg/day
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Chanan-Khan et al. 2017 (ORIGIN) | Phase III (E-switch-ooc) | Chlorambucil | Did not meet primary endpoint of PFS |
Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been previously published with encouraging non-randomized results.
Chemotherapy
- Lenalidomide (Revlimid) 5 mg PO once per day, increased to a target dose of 15 mg PO once per day
Continued indefinitely
Regimen variant #3, target 25 mg/day
Study | Evidence | Efficacy |
---|---|---|
Badoux et al. 2011 (MDACC 2006-0715) | Phase II | ORR: 65% |
Chemotherapy
- Lenalidomide (Revlimid) 5 mg PO once per day on days 1 to 56, then increased to a target dose of 25 mg PO once per day
Continued indefinitely
References
- Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, Kukreti V, Wei E, Leung-Hagesteijn C, Li ZH, Brandwein J, Pantoja M, Johnston J, Gibson S, Hernandez T, Spaner D, Trudel S. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol. 2011 Mar 20;29(9):1175-81. Epub 2010 Dec 28. link to original article contains verified protocol link to PMC article PubMed
- Update: Chen CI, Paul H, Wang T, Le LW, Dave N, Kukreti V, Nong Wei E, Lau A, Bergsagel PL, Trudel S. Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. Br J Haematol. 2014 Jun;165(5):731-3. Epub 2014 Feb 24. link to original article PubMed
- MDACC 2006-0715: Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O'Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3489-98. Epub 2011 Jul 1. link to original article contains protocol link to PMC article PubMed
- Update: Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, Ferrajoli A. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734-7. Epub 2013 Jun 25. link to original article link to PMC article PubMed
- ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains verified protocol PubMed
R-FCM
back to top |
R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
FCM-R: Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Hillmen et al. 2011 (NCRI CLL201) | Randomized Phase II (E-esc) | FCM | Did not meet primary endpoint of ORR at 2 mo |
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Fludarabine (Fludara) 24 mg/m2 PO once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 150 mg/m2 PO once per day on days 1 to 5
- Mitoxantrone (Novantrone) 6 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2
Study | Evidence |
---|---|
Bosch et al. 2009 | Phase II |
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 60 minutes once per day on days 1 to 3
- Mitoxantrone (Novantrone) 6 mg/m2 IV over 30 minutes once on day 1
Supportive medications
- Pegylated granulocyte colony-stimulating factor once on day 4
- Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 5
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose not specified) PO twice per week for up to 9 months after completion of therapy
28-day cycle for 6 cycles
Subsequent treatment
- Patients with a PR or CR at 3 months: Rituximab maintenance
Regimen variant #3
Study | Evidence |
---|---|
Faderl et al. 2009 | Phase II |
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2/day (route not specified) on days 2 to 4
- Cycles 2 to 6: 25 mg/m2/day (route not specified) on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2/day (route not specified) on days 2 to 4
- Cycles 2 to 6: 250 mg/m2/day (route not specified) on days 1 to 3
- Mitoxantrone (Novantrone) as follows:
- Cycle 1: 6 mg/m2 IV once on day 2
- Cycles 2 to 6: 6 mg/m2 IV once on day 2
Supportive medications
- Acetaminophen (Tylenol) 650 mg PO once on day 1, prior to Rituximab (Rituxan)
- Diphenhydramine (Benadryl) 25 to 50 mg PO once on day 1, prior to Rituximab (Rituxan)
- Ondansetron (Zofran) 24 mg IV once, prior to chemotherapy
- Pegfilgrastim (Neulasta) (dose not specified) following the last day of each treatment cycle
- Antiviral prophylaxis was at the physician's discretion
- PCP prophylaxis was at the physician's discretion
4- to 6-week cycle for up to 6 cycles
References
- Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
- Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article contains verified protocol PubMed
- Faderl S, Wierda W, O'Brien S, Ferrajoli A, Lerner S, Keating MJ. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years. Leuk Res. 2010 Mar;34(3):284-8. Epub 2009 Jul 30. link to original article contains protocol link to PMC article PubMed
- NCRI CLL201: Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. link to original article contains verified protocol PubMed
- ADMIRE: Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. link to original article PubMed
Uracil mustard monotherapy
back to top |
Regimen
Study | Evidence |
---|---|
Kennedy & Theologides 1961 | Non-randomized |
Chemotherapy
References
- Kennedy BJ, Theologides A. Uracil mustard, a new alkylating agent for oral administration in the management of patients with leukemia and lymphoma. N Engl J Med. 1961 Apr 20;264:790-3. link to original article PubMed
Subsequent lines of therapy
CAP
back to top |
CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Johnson et al. 1996 | 1990-1992 | Phase III (C) | Fludarabine | Seems to have inferior ORR (*) |
Note: the inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
1-month cycle for 6 cycles
References
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; The French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains protocol PubMed
Fludarabine monotherapy
back to top |
F: Fludarabine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Keating et al. 1989 | 1985-1987 | Non-randomized (RT) | ||
Grever et al. 1990 | NR in abstract | Phase I/II (RT) | ||
Johnson et al. 1996 | 1990-1992 | Phase III (E-de-esc) | CAP | Seems to have superior ORR (*) |
Note: the superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5
28-day cycle for 6 cycles
References
- Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989 Jul;74(1):19-25. link to original article PubMed
- Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, Malspeis L. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990 Oct;17(5 Suppl 8):39-48. PubMed
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; The French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains protocol PubMed
FC
back to top |
FC: Fludarabine, Cyclophosphamide
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
O'Brien et al. 2007 | Phase III (C) | OBL-FC | Seems to have inferior ORR |
Robak et al. 2010 (REACH) | Phase III (C) | R-FC | Inferior PFS |
Robak et al. 2016 (COMPLEMENT 2) | Phase III (C) | O-FC | Inferior PFS |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 1 to 3
Supportive medications
- Note: varied according to reference.
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7
- Some patients received:
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per week
- Valacyclovir (Valtrex) 500 mg PO once per day
28-day cycle for 6 cycles
References
- O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114-20. Epub 2007 Feb 12. Erratum in: J Clin Oncol. 2008 Feb 10;26(5):820. link to original article contains protocol PubMed
- Update: O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, Chanan-Khan AA, Seymour JF, Gribben J, Itri LM, Rai KR. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009 Nov 1;27(31):5208-12. Epub 2009 Sep 8. link to original article link to PMC article PubMed
- REACH: Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, Montillo M, Zyuzgin I, Ganly PS, Dartigeas C, Rosta A, Maurer J, Mendila M, Saville MW, Valente N, Wenger MK, Moiseev SI. 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 Apr 1;28(10):1756-65. Epub 2010 Mar 1. link to original article contains protocol PubMed content property of HemOnc.org
- COMPLEMENT 2: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kryachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. Epub 2016 Oct 12. link to original article PubMed
HDMP
back to top |
HDMP: High Dose, MethylPrednisolone
Regimen
Study | Evidence |
---|---|
Burningham et al. 1964 | Non-randomized, <20 pts |
Chemotherapy
References
- Burningham RA, Restrepo A, Pugh RP, Brown EB, Schlossman SF, Khuri PD, Lessner HE, Harrington WJ. Weekly high-dosage glucocorticosteroid treatment of lymphocytic leukemias and lymphomas. N Engl J Med. 1964 May 28;270:1160-6. link to original article PubMed
Tisagenlecleucel monotherapy
back to top |
Regimen
Study | Evidence |
---|---|
Porter et al. 2011 | Pilot |
Note: this regimen is of historic interest in this context, this being the first clinical use of CAR-T-cell therapy. It is not FDA approved for this indication.
Immunotherapy
References
- Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed
- Update: Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95ra73. link to original article link to PMC article PubMed
- Update: Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. link to original article link to PMC article PubMed