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:
The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed B-precursor ALL achieve CR by the end of this phase, with somewhat lower rates in patients with T-cell ALL or high presenting leukocyte counts.[1-5]
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.
Patients treated by the following study groups receive an induction regimen with four or more drugs 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. In a randomized trial of doxorubicin and daunorubicin during induction, there were no differences between these two agents in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[Level of evidence: 1iiDiv] 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, but it may not be necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[7,8] The COG reserves the use of a four-drug induction for patients with high-risk B-precursor ALL and T-cell ALL.Corticosteroid therapy
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 that compared 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 was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used 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 patients aged 10 years and older.L-asparaginase
Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:
- Erwinia L-asparaginase.
- Native E. coli L-asparaginase.
Only PEG-L-asparaginase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.PEG-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 may be given either intramuscularly (IM) or intravenously (IV). Pharmacokinetics and toxicity profiles are similar for IM and IV PEG-L-asparaginase administration. There is no evidence that IV administration of PEG-L-asparaginase is more toxic than IM administration.[18,19]
PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.
Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of PEG-L-asparaginase given either IM or IV as part of multiagent induction results in serum enzyme activity (>0.1 IU/mL) in nearly all patients for at least 2 to 3 weeks.[18,19,21]
Evidence (use of PEG-L-asparaginase instead of native E. coli L-asparaginase):
- A randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR.
- 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.
- A single 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).
- 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.Erwinia L-asparaginase:
Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or PEG-L-asparaginase.
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 to achieve adequate asparagine depletion.
Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):
- 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.[23,24]
- 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 who had experienced an allergic reaction to E. coli L-asparaginase.
- A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to PEG L-asparaginase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL). On that trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days and 85% did so at 3 days.
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-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).[24,27,28]; [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 hematopoietic stem cell transplant (HSCT) once CR is achieved.[30,31,4] In a large retrospective series, the 10-year overall survival for patients with persistent leukemia was 32%. A trend for superior outcome with allogeneic HSCT 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 HSCT compared with chemotherapy alone.
For patients who achieve CR, measures of the rapidity of blast clearance and 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 in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.[34,35]
- End-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[34,36-38] 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.[34,38-41]
(Refer to the Response to initial treatment affecting 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 CNS 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.References
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