Postinduction Treatment for Childhood ALL
Standard Postinduction Treatment Options for Childhood ALL
Standard treatment options for consolidation/intensification and maintenance therapy include the following:
Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children’s Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (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 acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.)Consolidation/intensification therapy
Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.
The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:
- An initial consolidation (sometimes referred to as “Induction IB”) immediately after the initial induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and a thiopurine (mercaptopurine or thioguanine).
- An interim maintenance phase, which includes multiple doses of either intermediate-dose or high-dose methotrexate (1–5 g/m2) with leucovorin rescue or escalating doses of methotrexate (starting dose 100 mg/m2) without leucovorin rescue.
- Reinduction (or delayed intensification), which typically includes the same agents used during the induction and initial consolidation phases.
- Maintenance, typically consisting of mercaptopurine, low-dose methotrexate, and sometimes, vincristine/steroid pulses.
This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:
- Intensification for higher-risk patients by including additional interim maintenance and/or reinduction phases and administering additional agents during some phases (e.g., vincristine and L-asparaginase added to interim maintenance phases).
- Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.
Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases:
- Pediatric Oncology Group (POG): Protocols conducted by the former POG included intensification with high-dose antimetabolite therapy (e.g., multiple doses of intermediate-dose or high-dose methotrexate with leucovorin rescue), but no reinduction/delayed intensification phase.
- DFCI: The DFCI ALL Consortium protocols include 20 to 30 weeks of L-asparaginase beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, low-dose methotrexate, nightly mercaptopurine). These protocols also do not include a delayed intensification phase, but high-risk patients do receive additional doses of doxorubicin (instead of methotrexate) during intensification.
- SJCRH: SJCRH follows a BFM-backbone but intensifies maintenance for some patients using rotating drug pairs.
In children with standard-risk ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[5-7] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes. Favorable outcomes for standard-risk patients have also been reported by the POG, utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase),[6,9,10] and by the DFCI ALL Consortium utilizing multiple doses of L-asparaginase (20–30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[11,12]
Evidence (intensification for standard-risk ALL):
- Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[13-15] The delayed intensification phase on such regimens, including those of the COG, consists of a 3-week reinduction (including anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 3 months after remission is achieved.[13,16,17]
- A Children's Cancer Group study (CCG-1991/COG-1991) for standard-risk ALL utilized dexamethasone for induction and a second delayed intensification phase. This study also compared escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination including oral methotrexate given during two interim maintenance phases.[Level of evidence: 1iiDi]
- A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).
- Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in event-free survival (EFS), which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.
- In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified based on minimal residual disease (MRD) level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low-risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[Level of evidence: 1iiDi]
- There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.
- There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.
In high-risk patients, a number of different approaches have been used with comparable efficacy.[11,19]; [Level of evidence: 2Di] Treatment for high-risk patients generally is more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.
Evidence (intensification for high-risk ALL):
- The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and L-asparaginase during interim maintenance and additional vincristine and L-asparaginase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, National Cancer Institute (NCI) high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.
- The augmented therapy regimen in the CCG-1882 trial produced a significantly better EFS than did standard CCG modified BFM therapy.
- There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).
- 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 a prednisone prophase.
- The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
- Augmented therapy was associated with an improvement in EFS; there was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[Level of evidence: 1iiA]
- The cumulative incidence of osteonecrosis of bone at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[Level of evidence: 1iiC]
- The use of the cardioprotectant agent dexrazoxane has been shown to prevent cardiac toxic effects without adversely impacting EFS in high-risk ALL patients. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[25,26]
- The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
- A greater long-term protective effect was noted in girls than in boys.
- The Pediatric Oncology Group (POG)-9404 trial also demonstrated no difference in EFS between patients with T-cell ALL who were treated with dexrazoxane and patients who did not receive dexrazoxane.
- Patients with adverse cytogenetic abnormalities, including t(9;22), MLL gene rearrangements, and low hypodiploidy (<44 chromosomes).
- Patients who achieve complete remission but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high minimal residual disease (MRD) levels at the end of induction (week 4) or later time points (e.g., week 12).
- Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve complete remission.
COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM-backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide. However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[17,29]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, [29-31] although it is not clear whether outcomes are better with transplantation.
Evidence (allogeneic HSCT in first remission for very high-risk patients):
- In a European cooperative group study, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22) or t(4;11), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells [WBC] >100,000/μL) were assigned to receive either an allogeneic HSCT in first remission (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.
- Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year disease-free survival (DFS) compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant versus 41% ± 3% for chemotherapy, P = .02)
- There was no significant difference in overall survival (OS) (56% ± 6% for transplant versus 50% ± 3% for chemotherapy, P = .12).
- For patients with T- cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.
- In another study of very high-risk patients that included children with extremely high presenting leukocyte counts and those with adverse cytogenetic abnormalities and/or initial induction failure (M2 marrow [between 5% and 25% blasts]), allogeneic HSCT in first remission was not associated with either a DFS or OS advantage.
- In a large retrospective series of patients with initial induction failure, the 10-year OS 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 with B-precursor ALL who were older than 6 years.
- Patients with B-precursor ALL 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.
- In a Dutch and Australian trial of 111 children with high-risk features or high MRD, patients received three novel intensive chemotherapy agents followed by allogeneic transplantation. Thirty of these patients were high risk by MRD and had a 5-year EFS of 64%.
Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical trials generally call for the administration of oral mercaptopurine in the evening, which is supported by evidence that this practice may improve EFS. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. 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. Nonadherence to treatment with 6-mercaptopurine (6-MP) in the maintenance phase is associated with a significant increase in the risk of relapse.
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.[36,37] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[36,37] 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 do patients who are homozygous for the normal allele.
Evidence (maintenance therapy):
- In a meta-analysis of randomized trials that compared thiopurines, 6-thioguanine (6-TG) did not improve the overall EFS, although particular subgroups may benefit from its use. The use of continuous 6-TG instead of 6-MP during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[39-43] Because of the increased toxicity of 6-TG, 6-MP remains the standard drug of choice.
- Another approach is an intensified maintenance phase that consists of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins, along with more standard maintenance agents.
- The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia  and a higher risk of secondary acute myelogenous leukemia, especially when epipodophyllotoxins are included.
SJCRH has modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).
- The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia  and a higher risk of secondary acute myelogenous leukemia, especially when epipodophyllotoxins are included.
- A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.
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 controversial.
Evidence (vincristine/corticosteroid pulses):
- A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients receiving monthly vincristine/prednisone pulses. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[48,49]
- A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy.
- 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.
- A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[Level of evidence: 1iiA]
For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents. Dexamethasone has not been associated with an increased frequency of these complications in younger patients.[13,52-55]
Evidence (dexamethasone vs. prednisone):
- In a CCG study, dexamethasone was compared with prednisone for children aged 1 to younger than 10 years with lower-risk ALL.[13,52]
- Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
- In a Medical Research Council trial, dexamethasone was compared with prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients.
- The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.
- Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.
- In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.
- Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.
Maintenance chemotherapy generally continues until 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls; on others, there is no difference in the duration of treatment based on gender.[11,17] It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.Adherence to maintenance therapy
Nonadherence to treatment with 6-MP in maintenance is associated with a significant increase in the risk of relapse.
Evidence (adherence to treatment):
- The COG studied the impact of non-adherence to 6-MP during maintenance in 327 children and adolescents of different ethnic backgrounds.
- Adherence declined from 95% to 90% over the 6-month observation period.
- Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households.
- Lower adherence to 6-MP was associated with a significantly higher risk of relapse. After adjusting for other prognostic factors (including NCI risk group and chromosomal abnormalities), a progressive increase in relapse was observed with decreasing adherence.
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 of treatment failure. The Risk-based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.
Ongoing clinical trials include the following:COG studies for B-precursor ALL
- COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL):
This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/WBC, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).
All patients will receive a three-drug induction (dexamethasone, vincristine, and IV PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive one of the following:
- A regimen based on POG-9904, including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines.
- A modified BFM backbone including two interim maintenance phases with escalating doses of IV methotrexate (no leucovorin) and one delayed intensification phase.
The objective is not to prove superiority of either regimen, but rather, to determine whether excellent outcomes (at least 95% 5-year DFS) can be achieved.
All average-risk patients will receive a modified BFM-backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.
- COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL):
This protocol is open to patients aged 30 years or younger. Patients treated on this trial are classified as either high risk or very high risk. The presence of any of the following is sufficient to classify a patient as very high risk:
- Age 13 years or older.
- CNS3 at diagnosis.
- M3 marrow at day 29.
- Unfavorable genetics (e.g., iAMP21, low hypodiploidy, MLL gene rearrangements).
- High marrow MRD (>0.01% by flow cytometry) at day 29 (with the exception of NCI standard-risk patients with favorable genetics).
The high-risk group includes patients with NCI high-risk ALL who lack very high-risk features, and two groups of NCI standard-risk patients who otherwise lack very high-risk features: (1) those without favorable genetics (no ETV6-RUNX1 or double trisomies 4 and 10), and with day 8 peripheral blood MRD >1%; and (2) those with favorable cytogenetics and with high marrow MRD at day 29. Patients with BCR-ABL (Philadelphia chromosome–positive) are treated on a separate clinical trial.
Patients on this trial will receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV PEG-L-asparaginase) with intrathecal chemotherapy. Patients younger than 10 years receive dexamethasone during induction, and those aged 10 years and older receive prednisone. Postinduction therapy consists of a modified BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase. Very high-risk patients receive a second interim maintenance phase before beginning more standard maintenance. Only patients with CNS3 status at diagnosis receive cranial radiation. Those with M3 marrow at day 29 or low hypodiploidy are eligible for allogeneic HSCT in first remission.
For high-risk patients, the study will compare, in a randomized fashion, triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS.
For very high-risk patients, the study will test, in a randomized fashion, whether intensified consolidation phases (including either cyclophosphamide/etoposide or clofarabine/cyclophosphamide/etoposide) improves 4-year DFS compared with the standard consolidation phase.
- Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at SJCRH is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) PEG-L-asparaginase during postremission therapy.
- DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma): A DFCI ALL Consortium protocol is comparing the pharmacokinetics and toxicity of two forms of IV PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also examining the following:
- Whether an intensified consolidation including high-dose cytarabine and etoposide improves the outcome for very high-risk patients (patients with high MRD at the end of remission induction, MLL translocations, or hypodiploidy [<44 chromosomes]).
- Whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase.
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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
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