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B-cell acute lymphoblastic leukemia - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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? See the main B-ALL page for current regimens.

21 regimens on this page
21 variants on this page


Contents

Upfront induction therapy

Aminopterin monotherapy

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Regimen

Study Evidence
Farber et al. 1948 Non-randomized pilot

Of major historical interest, being one of the first published cancer chemotherapy experiments in man that led to an active non-clinical-trial intervention (to be distinguished from the trial of diopterin and teropterin published in Science in 1947). This agent is no longer available but was used clinically for several decades.

Chemotherapy

References

  1. Farber S, Mercer RD, Sylvester RF, Wolff JA, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948 Jun 3;238(23):787-93. link to original article PubMed

COMP

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COMP: Cyclophosphamide, Oncovin (Vincristine), Methotrexate, Prednisone

Regimen

Study Evidence Comparator Comparative Efficacy
Anderson et al. 1983 Phase III (E) Modified LSA2-L2 Seems not superior

Chemotherapy

References

  1. Anderson JR, Wilson JF, Jenkin DT, Meadows AT, Kersey J, Chilcote RR, Coccia P, Exelby P, Kushner J, Siegel S, Hammond D. Childhood non-Hodgkin's lymphoma: the results of a randomized therapeutic trial comparing a 4-drug regimen (COMP) with a 10-drug regimen (LSA2-L2). N Engl J Med. 1983 Mar 10;308(10):559-65. link to original article PubMed

Cyclophosphamide, Doxorubicin, L-Asparaginase, Vincristine, Prednisolone

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Regimen

Study Evidence
Takeuchi et al. 2002 (JALSG-ALL93) Non-randomized

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. JALSG-ALL93: Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, Asou N, Ino T, Okamoto T, Usui N, Nishimura M, Shinagawa K, Fukushima T, Taguchi H, Morii T, Mizuta S, Akiyama H, Nakamura Y, Ohshima T, Ohno R. Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia. 2002 Jul;16(7):1259-66. link to original article PubMed

Cytarabine, Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone

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Regimen

Study Evidence
Pieters et al. 2007 (Interfant-99) Non-randomized portion of RCT

Preceding treatment

  • Prednisone pre-phase

Chemotherapy

Subsequent treatment

  • MARAM consolidation

References

  1. Interfant-99: Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, Hovi L, LeBlanc T, Szczepanski T, Ferster A, Janka G, Rubnitz J, Silverman L, Stary J, Campbell M, Li CK, Mann G, Suppiah R, Biondi A, Vora A, Valsecchi MG. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007 Jul 21;370(9583):240-250. link to original article PubMed

Cytarabine, Daunorubicin, L-Asparaginase, Teniposide, Vincristine, Prednisone

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Regimen

Study Evidence
Rivera et al. 1991 Non-randomized portion of RCT
Evans et al. 1998 Non-randomized portion of RCT

Chemotherapy

Subsequent treatment

  • High-dose MTX

References

  1. Rivera GK, Raimondi SC, Hancock ML, Behm FG, Pui CH, Abromowitch M, Mirro J Jr, Ochs JS, Look AT, Williams DL, Murphy SB, Dahl GV, Kalwinsky DK, Evans WE, Kun LE, Simone JV, Crist WM. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet. 1991 Jan 12;337(8733):61-6. link to original article PubMed
  2. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998 Feb 19;338(8):499-505. link to original article PubMed

Doxorubicin, Methotrexate, Vincristine, Prednisone

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Regimen

Study Evidence
Clavell et al. 1986 Non-randomized

Chemotherapy

References

  1. Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S, Cassady JR, Tarbell NJ, Blattner SR, Tantravahi R, Leavitt P, Sallan SE. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med. 1986 Sep 11;315(11):657-63. link to original article PubMed

L-Asparaginase, Vincristine, Dexamethasone

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Regimen

Study Evidence Comparator Comparative Efficacy
Veerman et al. 1996 (DCOG ALL-VI) Non-randomized
Bostrom et al. 2003 (CCG-1922) Phase III (E) L-asparaginase, Vincristine, Prednisone Superior EFS
Mitchell et al. 2005 (UK MRC ALL97) Phase III (E) L-asparaginase, Vincristine, Prednisolone Superior EFS
Veerman et al. 2009 (DCOG ALL-9) Non-randomized

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. DCOG ALL-VI: Veerman AJ, Hählen K, Kamps WA, Van Leeuwen EF, De Vaan GA, Solbu G, Suciu S, Van Wering ER, Van der Does-Van der Berg A. High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol. 1996 Mar;14(3):911-8. link to original article PubMed
  2. CCG-1922: Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed
  3. UK MRC ALL97: Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed
    1. Update: Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, Richards SM; Medical Research Council; National Cancer Research Network Childhood Leukaemia Working Party. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006 Oct 14;368(9544):1339-48. link to original article PubMed
  4. DCOG ALL-9: Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bökkerink JP, Bruin MC, van den Heuvel-Eibrink MM, Korbijn CM, Korthof ET, van der Pal K, Stijnen T, van Weel Sipman MH, van Weerden JF, van Wering ER, van der Does-van den Berg A; Dutch Childhood Oncology Group. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol. 2009 Oct;10(10):957-66. Epub 2009 Sep 9. link to SD article PubMed

L-Asparaginase, Vincristine, Prednisolone

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Regimen

Study Evidence Comparator Comparative Efficacy
Hann et al. 2000 (MRC UKALL XI) Non-randomized portion of RCT
Mitchell et al. 2005 (UK MRC ALL97) Phase III (C) L-asparaginase, Vincristine, Dexamethasone Inferior EFS

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. MRC UKALL XI: Hann I, Vora A, Richards S, Hill F, Gibson B, Lilleyman J, Kinsey S, Mitchell C, Eden OB; UK Medical Research Council's Working Party on Childhood Leukaemia. Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. Leukemia. 2000 Mar;14(3):356-63. link to original article PubMed
  2. UK MRC ALL97: Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol. 2005 Jun;129(6):734-45. link to original article PubMed
    1. Update: Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, Richards SM; Medical Research Council; National Cancer Research Network Childhood Leukaemia Working Party. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006 Oct 14;368(9544):1339-48. link to original article PubMed

L-Asparaginase, Vincristine, Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Henderson et al. 1979 (CALGB 7113) Non-randomized
Gottlieb et al. 1984 (CALGB 7612) Randomized (C) DOLP Inferior CR rate
van der Does-van den Berg et al. 1989 (DCLSG ALL V) Phase III (C) DOLP Seems not superior
Eden et al. 1991 (MRC UKALL VIII) Phase III (C) DOLP Seems not superior
Tubergen et al. 1993 (CCG-105) Phase III (C) DOLP Not reported
Bostrom et al. 2003 (CCG-1922) Phase III (C) L-asparaginase, Vincristine, Dexamethasone Inferior EFS

Unlikely to be completed, here for historic context only.

Chemotherapy

References

  1. CALGB 7113: Henderson ES, Scharlau C, Cooper MR, Haurani FI, Silver RT, Brunner K, Carey RW, Falkson G, Blom J, Nawabi IV, Levine AS, Bank A, Cuttner J, Cornwell GG 3rd, Henry P, Nissen NI, Wiernik PH, Leone L, Wohl H, Rai K, James GW, Weinberg V, Glidewell O, Holland JF. Combination chemotherapy and radiotherapy for acute lymphocytic leukemia in adults: results of CALGB protocol 7113. Leuk Res. 1979;3(6):395-407. link to SD article PubMed
  2. CALGB 7612: Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Terebelo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchinson JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF. Efficacy of daunorubicin in the therapy of adult acute lymphocytic leukemia: a prospective randomized trial by Cancer and Leukemia Group B. Blood. 1984 Jul;64(1):267-74. link to original article PubMed
  3. DCLSG ALL V: van der Does-van den Berg A, van Wering ER, Suciu S, Solbu G, van 't Veer MB, Rammeloo JA, de Koning J, van Zanen GE. Effectiveness of rubidomycin in induction therapy with vincristine, prednisone, and L-asparaginase for standard risk childhood acute lymphocytic leukemia: results of a Dutch phase III study (ALL V); A report on behalf of the Dutch Childhood Leukemia Study Group (DCLSG). Am J Pediatr Hematol Oncol. 1989 Summer;11(2):125-33. PubMed
  4. MRC UKALL VIII: Eden OB, Lilleyman JS, Richards S, Shaw MP, Peto J. Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood). Br J Haematol. 1991 Jun;78(2):187-96. link to original article PubMed
  5. CCG-105: Tubergen DG, Gilchrist GS, O'Brien RT, Coccia PF, Sather HN, Waskerwitz MJ, Hammond GD. Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Childrens Cancer Group phase III trial. J Clin Oncol. 1993 Mar;11(3):527-37. link to original article PubMed
  6. CCG-1922: Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME; Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. Epub 2003 Jan 16. link to original article PubMed

Mercaptopurine & Methotrexate

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Regimen

Study Evidence Comparator Comparative Efficacy
Frei et al. 1958 (ALGB 01) Randomized (E) 6-MP & MTX (alternate dosing) Seems not superior
Frei et al. 1961 (ALGB 03) Randomized (E) 1. 6-MP
2. MTX
Seems not superior
Frei et al. 1965 Non-randomized

Note: this is one of the first combination regimens in hematology/oncology.

Chemotherapy

References

  1. ALGB 01: Frei E 3rd, Holland JF, Schneiderman MA, Pinkel D, Selkirk G, Freireich EJ, Silver RT, Gold GL, Regelson W. A comparative study of two regimens of combination chemotherapy in acute leukemia. Blood. 1958 Dec;13(12):1126-48. link to original article PubMed
  2. ALGB 03: Frei E, Freireich EJ, Gehan E, Pinkel D, Holland JF, Selawry O, Haurani F, Spurr CL, Hayes DM, James GW, Rothberg H, Sodee DB, Rundles RW, Schroeder LR, Hoogstraten B, Wolman IJ, Traggis DG, Cooper T, Gendel BR, Ebaugh F, Taylor R. Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate. Blood. 1961;18(4):431-454. link to original article
  3. Frei E 3rd, Karon M, Levin RH, Freireich EJ, Taylor RJ, Hananian J, Selawry O, Holland JF, Hoogstraten B, Wolman IJ, Abir E, Sawitsky A, Lee S, Mills SD, Burgert EO Jr, Spurr CL, Patterson RB, Ebaugh FG, James GW 3rd, Moon JH. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965 Nov;26(5):642-56. link to original article PubMed

Mercaptopurine & Prednisone

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Regimen

Study Evidence Comparator Comparative Efficacy
Fernbach et al. 1966 Randomized (C) Cyclophosphamide & Prednisone Seems not superior

Chemotherapy

References

  1. Fernbach DJ, Griffith KM, Haggard ME, Holcomb TM, Sutow WW, Vietti TJ, Windmiller J. Chemotherapy of acute leukemia in childhood: comparison of cyclophosphamide and mercaptopurine. N Engl J Med. 1966 Sep 1;275(9):451-6. link to original article PubMed

Prednisolone monotherapy

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Regimen

Study Evidence
Shanbrom & Miller 1962 Non-randomized

Chemotherapy

References

  1. Shanbrom E, Miller S. Critical evaluation of massive steroid therapy of acute leukemia. N Engl J Med. 1962 Jun 28;266:1354-8. link to original article PubMed

Prednisone monotherapy

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Regimen

Study Evidence
Granville et al. 1958 Non-randomized

Chemotherapy

References

  1. Granville NB, Rubio F Jr, Unugur A, Schulman E, Dameshek W. Treatment of acute leukemia in adults with massive doses of prednisone and prednisolone. N Engl J Med. 1958 Jul 31;259(5):207-13. link to original article PubMed

Consolidation after upfront therapy

Mercaptopurine & Methotrexate

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Regimen

Study Evidence Comparator Comparative Efficacy
Evans et al. 1986 Randomized (E) WBRT, then 6-MP & MTX (conventional dosing) Not reported

Note: although this is a randomized trial, the report focuses on this arm, which includes HD-MTX, and not the comparison.

Preceding treatment

Chemotherapy

References

  1. Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP, George SL, Pui CH. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia: identification of a relation between concentration and effect. N Engl J Med. 1986 Feb 20;314(8):471-7. link to original article PubMed

Late intensification

POMP

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POMP: Purinethol (Mercaptopurine), Oncovin (Vincristine), Methotrexate, Prednisone

Regimen

Study Evidence
Bodey et al. 1976 Non-randomized, <20 pts

Note: POMP is still used in maintenance settings; this is marked historic because it is late intensification.

Chemotherapy

References

  1. Bodey GP, Freireich EJ, Gehan E, McCredie KB, Rodriguez V, Gutterman J, Burgess MA. Late intensification therapy for acute leukemia in remission: chemotherapy and immunotherapy. JAMA. 1976 Mar 8;235(10):1021-5. link to original article PubMed

Maintenance after upfront therapy

Methotrexate monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Selawry & Holland 1965 (ALGB 6313) Randomized (E) PO MTX Superior RFS
Burgert et al. 1969 (ALGB 6311) Randomized (E) PO MTX Seems not superior

Preceding treatment

  • Vincristine & Prednisone induction

Chemotherapy

References

  1. ALGB 6313: Selawry OS, Holland JF; Acute Leukemia Group B. New treatment schedule with improved survival in childhood leukemia: intermittent parenteral vs daily oral administration of methotrexate for maintenance of induced remission. JAMA. 1965 Oct 4;194(1):75-81. link to original article PubMed
  2. ALGB 6311: Burgert EO, Valvo F, Petzold G, Holland JF; Acute Leukemia Group B. Acute lymphocytic leukemia in children: maintenance therapy with methotrexat administered intermittently. JAMA. 1969 Feb 3;207(5):923-8. link to original article PubMed

Relapsed or refractory

Bacillus Calmette-Guérin (BCG) monotherapy

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Regimen

Study Evidence
Mathé et al. 1969 Non-randomized

Immunotherapy

References

  1. Mathé G, Amiel JL, Schwarzenberg L, Schneider M, Cattan A, Schlumberger JR, Hayat M, De Vassal F. Active immunotherapy for acute lymphoblastic leukaemia. Lancet. 1969 Apr 5;1(7597):697-9. link to SD article PubMed

Cyclophosphamide monotherapy

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Regimen

Study Evidence
Fernbach et al. 1962 Non-randomized

Chemotherapy

References

  1. Fernbach DJ, Sutow WW, Thurman WG, Vietti TJ. Clinical evaluation of cyclophosphamide: a new agent for the treatment of children with acute leukemia. JAMA. 1962 Oct 6;182:30-7. link to original article PubMed

Daunorubicin & Prednisone

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Regimen

Study Evidence
Holton et al. 1969 Non-randomized

Chemotherapy

References

  1. Holton CP, Vietti TJ, Nora AH, Donaldson MH, Stuckey WJ Jr, Watkins WL, Lane DM. Clinical study of daunomycin and prednisone for induction of remission in children with advanced leukemia. N Engl J Med. 1969 Jan 23;280(4):171-4. link to original article PubMed

Pentostatin monotherapy

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Regimen

Study Evidence
Prentice et al. 1981 Pilot

Chemotherapy

References

  1. Prentice HG, Russell NH, Lee N, Ganeshaguru K, Blacklock H, Piga A, Smyth JF, Hoffbrand AV. Therapeutic selectivity of and predication of response to 2'-deoxycoformycin in acute leukaemia. Lancet. 1981 Dec 5;2(8258):1250-4. link to original article PubMed

TBI, then auto HSCT

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TBI: Total Body Irradiation

Regimen

Study Evidence
McGovern et al. 1959 Pilot

This is of historic interest and likely the first reported use of autologous HSCT in the treatment of malignancy.

Radiotherapy

References

  1. McGovern JJ Jr, Russell PS, Atkins L, Webster EW. Treatment of terminal leukemic relapse by total-body irradiation and intravenous infusion of stored autologous bone marrow obtained during remission. N Engl J Med. 1959 Apr 2;260(14):675-83. link to original article PubMed