Consolidation/Intensification
Maintenance
        Treatment options under clinical evaluation
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Once remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) sanctuary therapy follows. The intensity of the postinduction chemotherapy varies considerably, but all patients receive some form of intensification following achievement of remission and before beginning continuous maintenance therapy. Intensification may involve the use of intermediate-dose or high-dose methotrexate,[1-4] the use of similar drugs as those used to achieve remission,[2,5] the use of different drug combinations with little known cross resistance to the induction therapy drug combination,[2,6] the extended use of high-dose L-asparaginase,[7] or combinations of the above.[2,8-10]

In children with standard-risk disease, there has been an attempt to limit exposure to drugs, such as the anthracyclines and alkylating agents, that are associated with an increased risk of late toxic effects.[3,11,12] For example, regimens utilizing a limited number of courses of intermediate-dose or high-dose methotrexate have been used with good results for treating children with standard-risk acute lymphoblastic leukemia (ALL).[1,3,4,11] Extended use of high-dose asparaginase reduced patients' exposure to alkylating agents and anthracyclines.[7,13] Another treatment approach for decreasing late effects of therapy utilizes anthracyclines and alkylating agents but limits their cumulative dose to an amount not associated with substantial long-term toxicity. An example of this approach is the use of delayed intensification, in which patients receive an anthracycline-based reinduction regimen and a cyclophosphamide-containing reconsolidation regimen at approximately 3 months after remission is achieved. The use of delayed intensification improves outcome for children with standard-risk ALL, in comparison to that achieved without an intensification phase.[14-16] In a Children's Cancer Group (CCG) study, which included a three-drug induction and utilized prednisone as the corticosteroid throughout all treatment phases, two blocks of delayed intensification produced a small event-free survival (EFS) benefit compared with one block of delayed intensification in intermediate-risk patients.[17] The benefit of two blocks of delayed intensification, however, may depend, in part, on the type of corticosteroid used (prednisone vs. dexamethasone). In a subsequent CCG study for standard-risk ALL in which dexamethasone was used instead of prednisone, two blocks of delayed intensification were not associated with a survival benefit in patients who were rapid early responders.[18]

In high-risk patients, a number of different approaches have been used with comparable efficacy.[6,7,19-22][Level of evidence: 2Di] Treatment for high-risk patients generally includes blocks of intensified therapy, such as the delayed intensification blocks (reinduction/reconsolidation) used by the former CCG and by the German Berlin-Frankfurt-Munster (BFM) group.[2,8,19] For high-risk patients with slow early response to therapy (M3 marrow on day 7 of induction therapy), augmented BFM therapy has been shown to improve outcome, particularly for younger patients.[23] The augmented BFM regimen utilizes two courses of delayed intensification, while also intensifying therapy with repeated courses of intravenous methotrexate (without leucovorin rescue) given with vincristine and asparaginase as well as additional vincristine/L-asparaginase pulses during consolidation and delayed intensification phases. Similarly, in an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to prednisone.[24]

The augmented BFM regimen has also been evaluated in children with high-risk ALL and a rapid response to induction therapy. For these children, augmented intensity during consolidation, interim maintenance, and delayed intensification resulted in a higher EFS rate than that achieved with standard-intensity treatment. Increased duration of intensive therapy was not beneficial, and a single application of delayed intensification was as effective as two applications.[25][Level of evidence: 1iiA] Of note, there is a significant incidence of avascular necrosis of bone in teenaged patients who receive the augmented BFM regimen.[26]

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral methotrexate. If the patient has not had cranial radiation, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. Clinical trials generally call for giving oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS.[27] It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[28] Treating physicians must also recognize that some patients may develop severe hematopoietic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[29,30] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[29,30] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematopoietic toxicity than patients who are homozygous for the normal allele.[29] The use of continuous 6-thioguanine (6-TG) instead of 6-mercaptopurine (6-MP) during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[31-34] Because of the risk of hepatic complications, 6-TG is no longer utilized in maintenance therapy in any protocol. It remains unknown if short term use of 6-TG can improve outcome without excessive toxicity.

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of intensive, multiagent regimens remains somewhat controversial. A CCG randomized trial demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses,[35] and a meta-analysis combining data from six clinical trials showed an EFS advantage for vincristine/prednisone pulses.[36] However, in a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[37] When pulses are used during the maintenance phase, dexamethasone is preferred over prednisone for younger patients based on data from a CCG study, in which dexamethasone was compared to prednisone for children aged 1 to 9 years with lower-risk ALL.[14,38] On that trial, patients randomized to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.[14,38] In a Medical Research Council trial comparing dexamethasone versus prednisolone during induction and maintenance therapies in both standard- and high-risk patients, the EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.[39] The benefit of using dexamethasone in adolescents requires further investigation because of the increased risk of steroid-induced osteonecrosis and a higher incidence of bone fractures in this age group.[40,41]

Maintenance chemotherapy generally continues until 2 to 3 years of continuous complete remission. Extending the duration of maintenance therapy to 5 years does not improve outcome.[36]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk for treatment failure. The Cellular Classification and Prognostic Variables section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

The current COG standard-risk ALL study divides patients into rapid-responder and slow-responder subgroups. Rapid responders are assigned to two separate groups based on cytogenetics. Patients with triple trisomy (chromosomes 4, 10, and 17) or a TEL-AML1 translocation are considered low risk. These patients are randomly assigned to receive standard therapy (simple consolidation, interim maintenance, delayed intensification, and maintenance) with or without additional PEG-L-asparaginase during consolidation and interim maintenance. Patients with ALL and rapid response, who do not have triple trisomy or TEL-AML1 (classified as standard-risk average group), are randomly assigned to receive treatment in a 2 × 2 factorial design to evaluate various components of the hemiaugmented BFM regimen. Some regimens extend maintenance therapy for boys based on the high risk of relapse, however, it is not clear that longer maintenance reduces relapse risk in boys, especially in the context of current intense therapies.[22][Level of evidence: 2Di]

Standard-risk ALL patients with slow early response disease receive the fully augmented BFM regimen.

In the COG trials, patients with ALL and rapid response to induction therapy receive hemiaugmented BFM, while patients with slow response receive the fully augmented BFM regimen. There are two randomized groups in the COG high-risk precursor B-cell ALL protocol (AALL032). During induction, patients are randomly assigned to receive either dexamethasone (14 days) or prednisone (28 days). All patients receive dexamethasone during delayed intensification (DI) and maintenance phases. During the first interim maintenance phase, patients receive either Capizzi methotrexate or high-dose methotrexate with leucovorin rescue as given in BFM protocols.

The COG is evaluating high-dose intermittent chemotherapy, including high doses of methotrexate, high-dose cytosine arabinoside, and ifosfamide in patients with t(9;22), patients with hypodiploid ALL with fewer than 44 chromosomes, and patients with MLL gene rearrangements and slow early response who attain remission. Patients with induction failure are also eligible for this trial. Patients with a matched sibling donor will receive a bone marrow transplant in first remission.

• A study at St. Jude Children’s Research Hospital is testing intensified chemotherapy with antimetabolites and asparaginase including double-reinduction therapy to determine whether this regimen can increase overall survival and whether cranial radiation can be omitted in all patients.



• The Dana-Farber Cancer Institute Consortium Protocol 05-01 is comparing the relative efficacy and toxicity of intravenous PEG-L-asparaginase with intramuscular E. coli asparaginase during postinduction consolidation for patients in all risk groups. The protocol is also testing whether an intensified consolidation improves the outcome for very high-risk patients (patients with high minimal residual disease at the end of remission induction, MLL gene rearrangements, or hypodiploidy <45 chromosomes).

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood acute lymphoblastic leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Harris MB, Shuster JJ, Pullen DJ, et al.: Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study. J Clin Oncol 16 (8): 2840-7, 1998.  [PUBMED Abstract]
   
   
2. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000.  [PUBMED Abstract]
   
   
3. Veerman AJ, Hählen K, Kamps WA, et al.: 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 14 (3): 911-8, 1996.  [PUBMED Abstract]
   
   
4. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 18 (6): 1285-94, 2000.  [PUBMED Abstract]
   
   
5. Tubergen DG, Gilchrist GS, O'Brien RT, et al.: 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 11 (3): 527-37, 1993.  [PUBMED Abstract]
   
   
6. Richards S, Burrett J, Hann I, et al.: Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomised trials, UKALL X and UKALL XI. Medical Research Council Working Party on Childhood Leukaemia. Leukemia 12 (7): 1031-6, 1998.  [PUBMED Abstract]
   
   
7. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 97 (5): 1211-8, 2001.  [PUBMED Abstract]
   
   
8. Hann I, Vora A, Richards S, et al.: Benefit of intensified treatment for all children with acute lymphoblastic leukaemia: results from MRC UKALL XI and MRC ALL97 randomised trials. UK Medical Research Council's Working Party on Childhood Leukaemia. Leukemia 14 (3): 356-63, 2000.  [PUBMED Abstract]
   
   
9. Harris MB, Shuster JJ, Pullen J, et al.: Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group Study. Leukemia 14 (9): 1570-6, 2000.  [PUBMED Abstract]
   
   
10. Rizzari C, Valsecchi MG, Aricò M, et al.: Effect of protracted high-dose L-asparaginase given as a second exposure in a Berlin-Frankfurt-Münster-based treatment: results of the randomized 9102 intermediate-risk childhood acute lymphoblastic leukemia study--a report from the Associazione Italiana Ematologia Oncologia Pediatrica. J Clin Oncol 19 (5): 1297-303, 2001.  [PUBMED Abstract]
    
    
11. Chauvenet AR, Martin PL, Devidas M, et al.: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201. Blood 110 (4): 1105-11, 2007.  [PUBMED Abstract]
    
    
12. Gustafsson G, Kreuger A, Clausen N, et al.: Intensified treatment of acute childhood lymphoblastic leukaemia has improved prognosis, especially in non-high-risk patients: the Nordic experience of 2648 patients diagnosed between 1981 and 1996. Nordic Society of Paediatric Haematology and Oncology (NOPHO) Acta Paediatr 87 (11): 1151-61, 1998.  [PUBMED Abstract]
    
    
13. Pession A, Valsecchi MG, Masera G, et al.: Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 23 (28): 7161-7, 2005.  [PUBMED Abstract]
    
    
14. Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 14 (12): 2223-33, 2000.  [PUBMED Abstract]
    
    
15. Riehm H, Gadner H, Henze G, et al.: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Hamatol Bluttransfus 33: 439-50, 1990.  [PUBMED Abstract]
    
    
16. Hutchinson RJ, Gaynon PS, Sather H, et al.: Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881. J Clin Oncol 21 (9): 1790-7, 2003.  [PUBMED Abstract]
    
    
17. Lange BJ, Bostrom BC, Cherlow JM, et al.: Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 99 (3): 825-33, 2002.  [PUBMED Abstract]
    
    
18. Matloub Y, Angiolillo A, Bostrom B, et al.: Double delayed intensification (DDI) is equivalent to single DI (SDI) in children with National Cancer Institute (NCI) standard-risk acute lymphoblastic leukemia (SR-ALL) treated on Children's Cancer Group (CCG) clinical trial 1991 (CCG-1991). [Abstract] Blood 108 (11): A-146, 2006. 
    
    
19. Gaynon PS, Steinherz PG, Bleyer WA, et al.: Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Childrens Cancer Group Study CCG-106. J Clin Oncol 11 (11): 2234-42, 1993.  [PUBMED Abstract]
    
    
20. Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92 (2): 411-5, 1998.  [PUBMED Abstract]
    
    
21. Lauer SJ, Shuster JJ, Mahoney DH Jr, et al.: A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia 15 (7): 1038-45, 2001.  [PUBMED Abstract]
    
    
22. Möricke A, Reiter A, Zimmermann M, et al.: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111 (9): 4477-89, 2008.  [PUBMED Abstract]
    
    
23. Nachman J, Sather HN, Gaynon PS, et al.: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group. J Clin Oncol 15 (6): 2222-30, 1997.  [PUBMED Abstract]
    
    
24. Aricò M, Valsecchi MG, Conter V, et al.: Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin-Frankfurt-Muenster protocol II. Blood 100 (2): 420-6, 2002.  [PUBMED Abstract]
    
    
25. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (5): 2548-55, 2008.  [PUBMED Abstract]
    
    
26. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000.  [PUBMED Abstract]
    
    
27. Schmiegelow K, Glomstein A, Kristinsson J, et al.: Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 19 (2): 102-9, 1997 Mar-Apr.  [PUBMED Abstract]
    
    
28. Davies HA, Lilleyman JS: Compliance with oral chemotherapy in childhood lymphoblastic leukaemia. Cancer Treat Rev 21 (2): 93-103, 1995.  [PUBMED Abstract]
    
    
29. Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91 (23): 2001-8, 1999.  [PUBMED Abstract]
    
    
30. Andersen JB, Szumlanski C, Weinshilboum RM, et al.: Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 87 (1): 108-11, 1998.  [PUBMED Abstract]
    
    
31. Broxson EH, Dole M, Wong R, et al.: Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer 44 (3): 226-31, 2005.  [PUBMED Abstract]
    
    
32. De Bruyne R, Portmann B, Samyn M, et al.: Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44 (2): 407-10, 2006.  [PUBMED Abstract]
    
    
33. Vora A, Mitchell CD, Lennard L, et al.: Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet 368 (9544): 1339-48, 2006.  [PUBMED Abstract]
    
    
34. Jacobs SS, Stork LC, Bostrom BC, et al.: Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 49 (3): 250-5, 2007.  [PUBMED Abstract]
    
    
35. Bleyer WA, Sather HN, Nickerson HJ, et al.: Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol 9 (6): 1012-21, 1991.  [PUBMED Abstract]
    
    
36. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Childhood ALL Collaborative Group. Lancet 347 (9018): 1783-8, 1996.  [PUBMED Abstract]
    
    
37. Conter V, Valsecchi MG, Silvestri D, et al.: Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet 369 (9556): 123-31, 2007.  [PUBMED Abstract]
    
    
38. Bostrom BC, Sensel MR, Sather HN, et al.: 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 101 (10): 3809-17, 2003.  [PUBMED Abstract]
    
    
39. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005.  [PUBMED Abstract]
    
    
40. Ojala AE, Lanning FP, Pääkkö E, et al.: Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment. Med Pediatr Oncol 29 (4): 260-5, 1997.  [PUBMED Abstract]
    
    
41. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19 (12): 3066-72, 2001.  [PUBMED Abstract]
    
    

Back to Top

< Previous Section  |  Next Section >