Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)
Treatment for Newly Diagnosed Childhood ALL
Standard Treatment Options for Newly Diagnosed ALL
Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:
Remission induction therapy
Induction chemotherapy consists of the following drugs, with or without an anthracycline:
- Corticosteroid (prednisone or dexamethasone).
The Children's Oncology Group (COG) protocols do not administer anthracycline during induction to patients with National Cancer Institute standard-risk precursor B-cell ALL. This three-drug induction regimen results in a complete remission rate of greater than 95% for standard-risk patients.
Patients treated by other study groups receive a four-drug induction regimen regardless of presenting features:
- Berlin-Frankfurt-Münster Group in Europe.
- St. Jude Children's Research Hospital.
- Dana-Farber Cancer Institute ALL Consortium.
The most common four-drug induction regimen is vincristine, corticosteroid (either dexamethasone or prednisone), L-asparaginase, and either doxorubicin or daunorubicin. Some studies have suggested that this more intensive induction regimen may result in improved event-free survival (EFS) in patients presenting with high-risk features.[5,6] The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.
For patients who are at standard risk or low risk of treatment failure, four-drug or more induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[5,7,8]
Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy.
- The Children's Cancer Group conducted a randomized trial comparing dexamethasone and prednisone in standard-risk ALL patients.
- The trial reported that dexamethasone was associated with a superior EFS.
- Another randomized trial was conducted by the United Kingdom Medical Research Council.
- The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.
- Patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.
- Other randomized trials did not confirm an EFS advantage with dexamethasone.[11,12]
The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio is 1:5 to 1:7 have shown a better result for dexamethasone, while studies using a 1:10 ratio have shown similar outcomes.
While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may be more toxic, especially in the context of more intensive induction regimens and in adolescents.
Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving anthracycline-containing induction regimens.[15,16] The increased risk of infection with dexamethasone during the induction phase has not been noted with three-drug induction regimens (vincristine, dexamethasone, and L-asparaginase). Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone  and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.
Several forms of L-asparaginase are available in the United States for use in the treatment of children with ALL including the following:
- Native E. coli L-asparaginase.
- Erwinia L-asparaginase.
PEG-L-asparaginase, a form of L-asparaginase in which the Escherichia coli-derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients.
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion following a single injection.
A single intramuscular (IM) dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).
Studies have shown that a single dose of PEG-L-asparaginase given either IM or intravenously (IV) as part of multiagent induction results in serum enzyme activity (>100 IU/mL) in nearly all patients for at least 2 to 3 weeks.[20,21,22]
- A randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase was conducted and each agent was given for a 30-week period following achievement of remission. 
- Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.
- Another randomized trial of patients with standard-risk ALL assigned patients to receive either PEG-L-asparaginase or native E. coli asparaginase in induction and each of two delayed intensification courses.
- The use of PEG-L-asparaginase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase.
Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration. The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. It is safe to give IV PEG-L-asparaginase in pediatric patients.[21,22]
The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli (1.2 days) or PEG-L-asparaginase (5.7 days). If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose to achieve adequate asparagine depletion.
Evidence (Erwinia L-asparaginase):
- In two studies, newly diagnosed patients were randomly assigned to receive the same schedule and dosage of Erwinia L-asparaginase or E. coli L-asparaginase.[24,25]
- Patients who received Erwinia L-asparaginase had a significantly worse EFS.
- When administered more frequently (twice weekly), the use of Erwinia L-asparaginase did not adversely impact EFS in patients experiencing an allergic reaction to E. coli L-asparaginase.
Response to remission induction chemotherapy
More than 95% of children with newly diagnosed ALL will achieve a complete remission (CR) within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately half will experience a toxic death during the induction phase (usually due to infection) and the other half will have resistant disease (persistent morphologic leukemia).[25,27,28]; [Level of evidence: 3iA] Patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic stem cell transplant (SCT) once CR is achieved.[30,31,32] In a large retrospective series, the 10-year overall survival for patients with persistent leuekmia was 32%. A trend for superior outcome with allogeneic SCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and B-precursor patients younger than 6 years. B-precursor ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL translocation, BCR-ABL) had a relatively favorable prognosis, without any advantage in outcome with the utilization of SCT compared with chemotherapy alone.
For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, particularly the following:
- Morphologic persistence of marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with higher relapse risk, and has been used by the COG to risk-stratify patients.
- Similarly, end-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[35,36,37,38] Intensification of postinduction therapy for patients with high levels of end-induction MRD is under investigation by many groups.
- MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance.[37,39,40]
Refer to the Effect of response to initial treatment on prognosis section of this summary for more information.
(Refer to the CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia section of this summary for specific information about central nervous system therapy to prevent CNS relapse in children with newly diagnosed ALL.)
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood acute lymphoblastic leukemia. 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.
- Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 354 (2): 166-78, 2006.
- Möricke A, Zimmermann M, Reiter A, et al.: Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 24 (2): 265-84, 2010.
- Pui CH, Pei D, Sandlund JT, et al.: Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24 (2): 371-82, 2010.
- Silverman LB, Stevenson KE, O'Brien JE, et al.: Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 24 (2): 320-34, 2010.
- 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.
- 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.
- Veerman AJ, Kamps WA, van den Berg H, et al.: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10 (10): 957-66, 2009.
- 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.
- 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.
- 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.
- Igarashi S, Manabe A, Ohara A, et al.: No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol. J Clin Oncol 23 (27): 6489-98, 2005.
- De Moerloose B, Suciu S, Bertrand Y, et al.: Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood 116 (1): 36-44, 2010.
- McNeer JL, Nachman JB: The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol 149 (5): 638-52, 2010.
- Teuffel O, Kuster SP, Hunger SP, et al.: Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia 25 (8): 1232-8, 2011.
- Hurwitz CA, Silverman LB, Schorin MA, et al.: Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 88 (8): 1964-9, 2000.
- Belgaumi AF, Al-Bakrah M, Al-Mahr M, et al.: Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer 97 (11): 2898-903, 2003.
- Ahmed SF, Tucker P, Mushtaq T, et al.: Short-term effects on linear growth and bone turnover in children randomized to receive prednisolone or dexamethasone. Clin Endocrinol (Oxf) 57 (2): 185-91, 2002.
- 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.
- Asselin BL, Whitin JC, Coppola DJ, et al.: Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 11 (9): 1780-6, 1993.
- Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99 (6): 1986-94, 2002.
- Rizzari C, Citterio M, Zucchetti M, et al.: A pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia. Haematologica 91 (1): 24-31, 2006.
- Silverman LB, Supko JG, Stevenson KE, et al.: Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood 115 (7): 1351-3, 2010.
- 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.
- Duval M, Suciu S, Ferster A, et al.: Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood 99 (8): 2734-9, 2002.
- Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007.
- Vrooman LM, Supko JG, Neuberg DS, et al.: Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 54 (2): 199-205, 2010.
- Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.
- 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.
- Prucker C, Attarbaschi A, Peters C, et al.: Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group. Leukemia 23 (7): 1264-9, 2009.
- Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26.
- Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85 (6): 1395-404, 1999.
- Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 26 (9): 1496-503, 2008.
- Schrappe M, Hunger SP, Pui CH, et al.: Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 366 (15): 1371-81, 2012.
- Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997.
- van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998.
- Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 110 (5): 1607-11, 2007.
- Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008.
- Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010.
- Coustan-Smith E, Sancho J, Behm FG, et al.: Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100 (1): 52-8, 2002.
- Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27 (31): 5168-74, 2009.
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