B-cell acute lymphoblastic leukemia, pediatric - 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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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 pediatric B-ALL page for current regimens.

17 regimens on this page 17 variants on this page

Upfront induction therapy

Aminopterin monotherapy

Regimen

Study	Dates of enrollment	Evidence
Farber et al. 1948	1947-1948	Non-randomized pilot

Note: This regimen is 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

• Aminopterin

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

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Anderson et al. 1983	1977-1979	Phase 3 (E-de-esc)	Modified LSA2-L2	Seems not superior

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Vincristine (Oncovin)
• Methotrexate (MTX)

Glucocorticoid therapy

• Prednisone (Sterapred)

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

Cytarabine, Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Pieters et al. 2007 (Interfant-99)	1999-2005	Non-randomized portion of RCT

Preceding treatment

• Prednisone pre-phase

Chemotherapy

• Cytarabine (Ara-C)
• Daunorubicin (Cerubidine)
• Asparaginase (Elspar)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Dexamethasone (Decadron)

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 NCT00015873

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

Regimen

Study	Dates of enrollment	Evidence
Rivera et al. 1991	NR in abstract	Non-randomized portion of RCT
Evans et al. 1998	1988-1991	Non-randomized portion of RCT

Chemotherapy

• Cytarabine (Ara-C)
• Daunorubicin (Cerubidine)
• Asparaginase (Elspar)
• Teniposide (Vumon)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisone (Sterapred)

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

Daunorubicin, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Halazun et al. 1974 (ALGB 6801)	1968-1971	Phase 3 (E-RT-esc)	Vincristine & Prednisone	Did not meet primary endpoint of CR rate

Chemotherapy

• Daunorubicin (Cerubidine)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisone (Sterapred)

References

1. Mathé G, Hayat M, Schwarzenberg L, Amiel JL, Schneider M, Cattan A, Schlumberger JR, Jasmin C. Acute lymphoblastic leukaemia treated with a combination of prednisone, vincristine, and rubidomycin: Value of pathogen-free rooms. Lancet. 1967 Aug 19;2(7512):380-2. link to original article PubMed
2. ALGB 6801: Halazun JF, Wagner HR, Gaeta JF, Sinks LF. Proceedings: Daunorubicin cardiac toxicity in children with acute lymphocytic leukemia. Cancer. 1974 Feb;33(2):545-54. link to original article PubMed

Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence
Vrooman et al. 2013 (DFCI 00-01)	2000-2004	Non-randomized portion of phase 3 trial

Note: the MTX dose reported in the manuscript appears to be erroneous, but is replicated here.

Chemotherapy

• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 0 & 1
• Methotrexate (MTX) 4 mg/m² IV once, given 8 to 24 hours after doxorubicin
• Asparaginase (Elspar) 25,000 units/m² IM once (day not specified)
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m²/day IV or PO on days 0 to 28

Supportive therapy

• High-risk patients: Dexrazoxane (Zinecard) 300 mg/m² IV once per day on days 0 & 1

29-day course

Subsequent treatment

• Intensification

References

1. DFCI 00-01: Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL, Athale UH, Clavell LA, Kelly KM, Kutok JL, Laverdière C, Lipshultz SE, Michon B, Schorin M, Relling MV, Cohen HJ, Neuberg DS, Sallan SE, Silverman LB. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013 Mar 20;31(9):1202-10. Epub 2013 Jan 28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00165178

Doxorubicin, Methotrexate, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence
Clavell et al. 1986	1981-1985	Non-randomized

Chemotherapy

• Doxorubicin (Adriamycin)
• Methotrexate (MTX)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisone (Sterapred)

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Veerman et al. 1996 (DCOG ALL-VI)	1984-1988	Non-randomized
Bostrom et al. 2003 (CCG-1922)	1993-1995	Phase 3 (E-switch-ic)	L-asparaginase, Vincristine, Prednisone	Superior EFS
Mitchell et al. 2005 (UK MRC ALL97)	1997-2002	Phase 3 (E-switch-ic)	L-asparaginase, Vincristine, Prednisolone	Superior EFS
Veerman et al. 2009 (DCOG ALL-9)	1997-2004	Non-randomized

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Dexamethasone (Decadron)

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; Dutch Childhood Oncology Group. 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 NCT00003437
   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 original article PubMed NTR460

L-Asparaginase, Vincristine, Prednisolone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hann et al. 2000 (MRC UKALL XI)	1990-1997	Non-randomized portion of RCT
Mitchell et al. 2005 (UK MRC ALL97)	1997-2002	Phase 3 (C)	L-asparaginase, Vincristine, Dexamethasone	Inferior EFS

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisolone (Millipred)

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 NCT00003437
   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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ortega et al. 1977 (CCG 101/143)	1971-NR	Non-randomized (RT)
van der Does-van den Berg et al. 1989 (DCLSG ALL V)	1979-1982	Phase 3 (C)	DOLP	Seems not superior
Eden et al. 1991 (MRC UKALL VIII)	1979-1982	Phase 3 (C)	DOLP	Seems not superior
Tubergen et al. 1993 (CCG-105)	1983-1989	Phase 3 (C)	DOLP	Not reported
Bostrom et al. 2003 (CCG-1922)	1993-1995	Phase 3 (C)	L-asparaginase, Vincristine, Dexamethasone	Inferior EFS
Matloub et al. 2006 (CCG-1952)	1996-2000	Non-randomized portion of phase 3 RCT

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisone (Sterapred)

28-day course

Subsequent treatment

• CCG-1952: Consolidation

References

1. CCG 101/143: Ortega JA, Nesbit ME Jr, Donaldson MH, Hittle RE, Weiner J, Karon M, Hammond D. L-Asparaginase, vincristine, and prednisone for induction of first remission in acute lymphocytic leukemia. Cancer Res. 1977 Feb;37(2):535-40. link to original article PubMed
2. 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; Dutch Childhood Leukemia Study Group. 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
3. 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
4. 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
5. 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
6. CCG-1952: Matloub Y, Lindemulder S, Gaynon PS, Sather H, La M, Broxson E, Yanofsky R, Hutchinson R, Heerema NA, Nachman J, Blake M, Wells LM, Sorrell AD, Masterson M, Kelleher JF, Stork LC; Children's Oncology Group. Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group. Blood. 2006 Aug 15;108(4):1165-73. Epub 2006 Apr 11. link to original article link to PMC article PubMed NCT00002744

Mercaptopurine & Methotrexate

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Frei et al. 1958 (ALGB 01)	NR	Randomized (E-switch-ic)	6-MP & MTX; alternate dosing	Seems not superior
Frei et al. 1961 (ALGB 03)	1957-1960	Randomized (E-esc)	1. 6-MP 2. MTX	Seems not superior
Frei et al. 1965	NR	Non-randomized

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

Chemotherapy

• Mercaptopurine (6-MP)
• Methotrexate (MTX)

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fernbach et al. 1966	1960-1962	Randomized (C)	Cyclophosphamide & Prednisone	Seems not superior

Chemotherapy

• Mercaptopurine (6-MP)

Glucocorticoid therapy

• Prednisone (Sterapred)

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

Consolidation after upfront therapy

Mercaptopurine & Methotrexate

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Evans et al. 1986	1979-1982	Randomized (E-switch-ooc)	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

• L-Asparaginase, Vincristine, Prednisone induction

Chemotherapy

• Mercaptopurine (6-MP)
• Methotrexate (MTX)

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

Maintenance after upfront therapy

Methotrexate monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Selawry & Holland 1965 (ALGB 6313)	1963	Randomized (E-switch-ic)	MTX; oral	Superior RFS
Burgert et al. 1969 (ALGB 6311)	NR	Randomized (E-switch-ic)	MTX; oral	Seems not superior

Preceding treatment

• Vincristine & Prednisone induction

Chemotherapy

• Methotrexate (MTX) IV or IM

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

Cyclophosphamide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Fernbach et al. 1962	NR in abstract	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan)

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

Regimen

Study	Dates of enrollment	Evidence
Holton et al. 1969	NR	Non-randomized

Chemotherapy

• Daunorubicin (Cerubidine)

Glucocorticoid therapy

• Prednisone (Sterapred)

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

L-Asparaginase, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Anderson et al. 1981	NR in abstract	Phase 3 (C)	L-Asparaginase, Vindesine, Prednisone	Seems not superior

Chemotherapy

• Asparaginase (Elspar)
• Vincristine (Oncovin)

Glucocorticoid therapy

• Prednisone (Sterapred)

References

1. Anderson J, Krivit W, Chilcote R, Pyesmany A, Chard R, Hammond D. Comparison of the therapeutic response of patients with childhood acute lymphoblastic leukemia in relapse to vindesine versus vincristine in combination with prednisone and L-asparaginase: a phase III trial. Cancer Treat Rep. 1981 Nov-Dec;65(11-12):1015-9. PubMed