Induction Chemotherapy
        Options under clinical evaluation for end-induction treatment assignment
Central Nervous System Therapy
        No clinical evidence of CNS involvement at diagnosis
        Clinically evident CNS involvement at diagnosis
Current Clinical Trials

Induction Chemotherapy

Three-drug induction therapy using vincristine, prednisone/dexamethasone, plus L-asparaginase in conjunction with intrathecal therapy (IT), results in complete remission rates of greater than 95%.[1] For patients at high risk of treatment failure, a more intense induction regimen (four or five agents) may result in improved event-free survival (EFS),[2-4] and high-risk patients generally receive induction therapy that includes an anthracycline (e.g., daunomycin) in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For patients who are at standard risk or low risk of treatment failure, four-drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[2,5,6] Because of the likelihood of increased toxicity with four-drug induction therapy, Children's Oncology Group (COG) protocols for National Cancer Institute (NCI) standard-risk precursor B-cell ALL currently utilize dexamethasone, vincristine, and L-asparaginase. Induction regimens using four or more agents are reserved for higher risk patients.[2,5,7]

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy. The Children's Cancer Group (CCG) conducted a randomized trial comparing dexamethasone and prednisone in standard-risk patients, and reported that dexamethasone was associated with a superior EFS.[8] Results from another randomized trial conducted by the United Kingdom Medical Research Council (MRC) demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.[9] In the MRC trial, patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than patients who received prednisolone.[9] However, a third randomized trial (conducted in Japan) did not confirm a survival advantage with dexamethasone.[10] This discrepant result might have been due to the use of a higher dose of prednisolone during induction therapy, the use of a more intensive backbone chemotherapy regimen, and/or the smaller number of patients included in that trial.

While dexamethasone may be more effective than prednisone, data also suggest that dexamethasone may also be more toxic, especially in the context of more intensive induction regimens. Several reports indicate that dexamethasone may increase the frequency and severity of infections and/or other complications in patients receiving intensive (more than three drugs) induction regimens.[11,12] The Berlin-Frankfurt-Muenster (BFM) group observed increased mortality in adolescent patients who received dexamethasone instead of prednisone during a four-drug induction regimen. However, the MRC group did not observe any toxicity or mortality differences between dexamethasone and prednisone during a four-drug induction regimen.[3] Dexamethasone appears to have a greater suppressive effect on short-term linear growth than prednisone,[13] and has been associated with a higher risk of osteonecrosis, especially in adolescent patients.[14]

Several forms of L-asparaginase are available for use in the treatment of children with ALL, with Eschericia coli (E. coli) L-asparaginase being most commonly used. PEG-L-asparaginase is an alternative form of L-asparaginase in which the E. coli enzyme is modified by the covalent attachment of polyethylene glycol. PEG-L-asparaginase has a much longer serum half-life than native E. coli L-asparaginase, allowing it to produce asparagine depletion with less frequent administration.[15] A single intramuscular dose of PEG-L-asparaginase given in conjunction with vincristine and prednisone during induction therapy appears to have similar activity and toxicity as nine doses of intramuscular E. coli L-asparaginase (three times a week for 3 weeks).[16] In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be given over a 30-week period following achievement of remission, similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.[17] In another randomized trial in which patients with standard-risk ALL were randomly assigned to receive PEG-L-asparaginase versus 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.[16] Current COG protocols use PEG-L-asparaginase during induction for all patients with ALL. Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia L-asparaginase. If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration and a higher dose. In two studies, patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[18,19]

More than 95% of children with newly diagnosed ALL will achieve a complete remission within the first 4 weeks of treatment. Of the 2% to 4% of patients who fail to achieve complete remission 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).[19-21] Patients who require more than 4 weeks to achieve remission have a poor prognosis and may benefit from an allogeneic stem cell transplant once complete remission is achieved.[22-24] Outcome is also less favorable for patients who demonstrate more than 25% blasts in the bone marrow or persistent blasts in the peripheral blood after 1 week of intensive multiagent induction therapy,[3,25,26] and protocols of the former CCG-based treatment decisions on the day 7 bone marrow response (for high-risk patients) or day 14 bone marrow response (for standard-risk patients).[27]

The COG is evaluating a new end-induction classification system. Standard-risk patients (aged 1–9.99 years, <50,000 white blood cell count (WBC)/µL, precursor B-cell ALL) receive a three-drug induction regimen with dexamethasone, PEG-L-asparaginase, and vincristine. High-risk precursor B-cell ALL patients receive a four-drug induction regimen including daunomycin and are randomly assigned to receive either dexamethasone for 14 days or prednisone for 28 days. Patients with T-cell ALL receive a four-drug induction regimen with prednisone as the induction steroid. Patients with ALL undergo an evaluation on day 28 that includes a bone marrow biopsy/aspiration for morphology and minimal residual disease (MRD) determinations. On the basis of day 14 marrow morphology, day 28 marrow morphology, and day 28 MRD determination, ALL patients are classified as rapid responders, slow responders, very slow responders, or induction failures. Patients with t(9;22) and hypodiploidy with fewer than 44 chromosomes move to the very high-risk protocol at the end of induction therapy, regardless of response classification. Patients with MLL gene rearrangements who do not show a rapid response also move to the very high-risk treatment protocol. Patients with ALL and slow or rapid response to induction receive consolidation on the appropriate standard or high-risk precursor B-cell ALL or T-cell treatment protocol. Patients with very slow response to induction therapy receive an additional 2 weeks of induction therapy and then have a day 42 bone marrow evaluation for morphology and MRD. Patients with an M1 day 42 marrow and less than 0.1 MRD go onto consolidation therapy; all other patients are considered induction failures and move to the very high-risk treatment protocol.

The Dana-Farber Cancer Institute (DFCI) ALL Consortium is also testing a new risk classification system for patients with precursor B-cell ALL. All patients are initially risk classified as either standard risk or high risk based upon age, presenting leukocyte count, and presence or absence of CNS disease. At the completion of a five-drug remission induction regimen (4 weeks from diagnosis), the level of MRD is determined. Patients with high MRD (≥0.1%) are classified as very high risk and receive a more intensive postremission consolidation. Patients with low MRD (<0.1%) continue to receive treatment based on their initial risk group classification. The goal of this new classification schema is to determine whether intensification of therapy will improve the outcome of patients with high MRD at the end of remission induction. Patients with T-cell ALL are treated as high risk, regardless of MRD status. All patients with MLL translocations or hypodiploidy (<45 chromosomes) are classified as very high-risk, regardless of MRD status or phenotype. Patients with the Philadelphia chromosome are treated as high risk, but receive an allogeneic stem cell transplant in first remission.

The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in patients without overt CNS involvement at diagnosis. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (4–8 doses of IT given every 2–3 weeks), and often continued throughout maintenance. A current goal of ALL therapy design is to achieve effective CNS therapy while minimizing neurotoxicity. Every patient with ALL receives IT chemotherapy with methotrexate alone or methotrexate with cytarabine plus hydrocortisone.[28] IT methotrexate may also have a significant systemic effect that could result in a decrease in marrow relapse rate.[29] Historically, significant control of bone marrow relapse did not occur until CNS therapy was instituted. Conversely, the type and extent of systemic intensification also appears to influence the efficacy of the CNS therapy. Systemically administered drugs such as dexamethasone, L-asparaginase, high-dose methotrexate, and high-dose cytarabine may provide some degree of CNS protection. For example, in a CCG study of patients with standard-risk ALL, oral dexamethasone decreased the CNS relapse rate by 50% compared with patients receiving oral prednisone (patients received IT methotrexate alone for CNS prophylaxis).[8]

IT chemotherapy may be the sole form of presymptomatic CNS therapy, or it may be combined with systemic moderate-dose to high-dose infusions of methotrexate with leucovorin rescue and/or cranial radiation (12–18 Gy).[30] The DFCI ALL Consortium 95-01 trial randomized lower risk patients to receive either 18 Gy of cranial irradiation with IT chemotherapy or more frequently dosed IT chemotherapy alone (no radiation therapy) and demonstrated no significant difference in EFS.[19] Appropriate systemic therapy combined with IT chemotherapy resulted in CNS relapse rates of less than 5% for children with standard-risk ALL.[5,20,31,32] The question of whether to use triple (methotrexate, prednisone, cytarabine) IT therapy or single (methotrexate) IT therapy in nonirradiated standard-risk patients was studied as a randomized question in the CCG-1952 clinical trial.[33] The results showed an isolated CNS relapse rate of 3.4 ± 1.0% for triple IT therapy and 5.9 ± 1.2% for single IT therapy (P = .004). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) in this group (90.3 ± 1.5%) compared with the single IT therapy group (94.4 ± 1.1%; P = .01). When the analysis was restricted to patients with precursor B-cell ALL and rapid early response (M1 marrow on day 14), there was no difference between triple and single IT therapy in CNS relapse rate, OS, or EFS.[33] Patients with blasts in the cerebrospinal fluid (CSF) but less than 5 WBC/µL (CNS2) are at increased risk of CNS relapse and may require more intensive IT chemotherapy (but not cranial radiation).[34,35] Data also suggest that a traumatic lumbar puncture with blasts at the time of diagnosis is associated with an increased risk of CNS relapse, however, with more intensive IT chemotherapy, the risk is abrogated.[35,36]

Approximately 5% to 20% of children with ALL receive cranial radiation as part of their CNS-directed therapy, even if they present without CNS involvement at diagnosis, including those with T-cell phenotype and subsets of patients with high-risk precursor B-cell ALL.[37,38] Whether some or all of these patients could be as effectively treated without radiation is controversial and is currently under investigation.[39]

Toxic effects of CNS-directed therapy for childhood ALL can be divided into two broad groups. Acute/subacute toxicities include seizures, stroke, somnolence syndrome, and ascending paralysis. Chronic and late toxicities include meningiomas, leukoencephalopathy and a range of neurocognitive, behavioral, and neuroendocrine disturbances.[40,41]

Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years.[42] Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[43-47] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[48-50] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[49-51] In general, high-dose methotrexate should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy. In addition, radiation has been associated with the development of second neoplasms (many of which are benign or of low malignant potential).[47,52] Attempts at reducing the adverse sequelae of cranial radiation have included lowering the dose and utilizing alternative fractionation schedules. Children receiving 18 Gy of cranial radiation may be at diminished risk of neurologic toxicity compared with those receiving 24 Gy,[53] although neurocognitive and neuroendocrine effects, as well as development of second malignant neoplasms have been noted at this lower dose.[21,48,54] In the German BFM and DFCI ALL Consortium studies, many of the patients treated with cranial radiation receive a dose of only 12 Gy.[21] Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation, although cognitive function for both groups was not significantly impaired.[55,56][Level of evidence: 1iiC]

The most common toxicity associated with IT chemotherapy alone is seizures. Approximately 5% to 10% of patients with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy.[7] Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.[57] Valproic acid or gabapentin are alternative anticonvulsants with less enzyme-inducing capabilities.[57] In general, patients who receive IT chemotherapy without cranial radiation as CNS therapy appear to have a low incidence of neurocognitive sequelae, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[58-60] This modest decline is especially seen in young children and girls.[61] Regimens that utilize a biweekly schedule of 12 doses of intravenous high-dose methotrexate with leucovorin rescue and IT chemotherapy in the off-week have been associated with excessive neurologic toxicity.[62] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances.[63]

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.

• In the COG-AALL0232 study, patients with high-risk precursor B-cell ALL receive either IT methotrexate alone (rapid early responders) or IT methotrexate with cranial radiation (slow early responders). One goal of this study is to determine whether oral dexamethasone, high-dose methotrexate, or both agents will decrease the incidence of CNS relapse.



• In the COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients will be treated without cranial radiation, and intermediate-risk T-cell patients will receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients will continue to receive 18 Gy cranial radiation.



• A clinical trial at St. Jude Children's Research Hospital is testing whether intensive IT and systemic chemotherapy without radiation can be used for CNS prophylaxis in all patients regardless of initial CNS status.



• DFCI ALL Consortium Protocol 05-01 is testing whether IT chemotherapy alone can replace cranial radiation in some high-risk patients. Approximately 20% of patients will receive cranial radiation, including B-lineage patients with high presenting leukocyte counts (≥100,000 μ/L), CNS3 disease at diagnosis, or high MRD levels at the end of remission induction, and all T-cell ALL patients. The remaining 80% of patients will receive triple IT chemotherapy, but no radiation. The goal of this treatment schema is to reduce neurotoxicity and other CNS late effects without compromising efficacy by limiting the number of patients exposed to radiation and by lowering the radiation dose (12 Gy instead of 18 Gy) to those still receiving radiation.

Standard treatment for ALL patients with clinically evident CNS disease (>5 WBC/μL with blasts on cytospin; CNS3) at diagnosis includes IT chemotherapy and cranial radiation (usual dose: 18 Gy). Spinal radiation is no longer used.

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

• A clinical trial at St. Jude Children's Research Hospital is testing whether patients with clinically evident CNS disease at diagnosis can be treated with intensive IT and systemic chemotherapy without radiation.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

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