Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)
IN THIS ARTICLE
Remission Induction for Newly Diagnosed ALL
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses 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.)
Three-drug induction therapy using vincristine, corticosteroid (prednisone or dexamethasone), and L-asparaginase in conjunction with intrathecal (IT) therapy, results in complete remission (CR) rates of greater than 95%. For patients presenting with high-risk features, a more intensive induction regimen (four or five agents) may result in improved event-free survival (EFS).[2,3] Such patients generally receive induction therapy that includes an anthracycline (e.g., daunorubicin) in addition to vincristine, prednisone/dexamethasone, plus L-asparaginase. For patients who are at standard risk or low risk of treatment failure, four or more drug induction therapy does not appear necessary for favorable outcome provided that adequate postremission intensification therapy is administered.[2,4,5] The Children's Oncology Group (COG) protocols risk stratify at diagnosis and do not administer anthracycline during induction to patients with National Cancer Institute (NCI) standard-risk precursor B-cell acute lymphoblastic leukemia (ALL). While other groups, such as the Berlin-Frankfurt-Muenster (BFM) Group in Europe, St. Jude Children's Research Hospital (SJCRH), and the Dana-Farber Cancer Institute (DFCI) ALL Consortium, utilize either a four- or five-drug induction for all patients, regardless of presenting features.[6,7,8]
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 ALL patients, and reported that dexamethasone was associated with a superior EFS. 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. 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. However, other randomized trials did not confirm an EFS advantage with dexamethasone. It appears that 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 also 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.[13,14] 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 for use in the treatment of children with ALL in the United States. 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.[18,19,20] The toxicity of PEG-L-asparaginase seems to be similar to that observed with native E. coli asparaginase. In a randomized comparison of PEG-L-asparaginase versus native E. coli asparaginase in which each agent was to be 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. 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. It is safe to give IV PEG-L-asparaginase in pediatric patients.[19,20] Pharmacokinetics and toxicity profiles are similar for IV and IM PEG-L-asparaginase administration.
Patients with an allergic reaction to PEG-L-asparaginase should be switched to Erwinia 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 and a higher dose to achieve adequate asparagine depletion. In two studies, newly diagnosed patients randomly assigned to receive Erwinia L-asparaginase on the same schedule and dosage as E. coli L-asparaginase had a significantly worse EFS.[22,23] However, when administered more frequently (twice weekly), the use of Erwinia asparaginase did not adversely impact EFS in patients experiencing an allergic reaction to E. coli L-asparaginase.
More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of the 2% to 4% of patients 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).[23,25,26]; [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 once CR is achieved.[28,29,30]
For patients who achieve CR, measures of the rapidity of blast clearance and minimal residual disease (MRD) determinations have important prognostic significance, as discussed in the Cellular Classification and Prognostic Variables section of this summary. 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.[32,33,34,35] 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.[34,36,37]
Central Nervous System (CNS) Therapy
Historically, survival rates for children with ALL did not improve until CNS-directed therapy was instituted. The early institution of adequate CNS therapy is critical for eliminating clinically evident CNS disease at diagnosis and for preventing CNS relapse in all patients. Options for CNS-directed therapy include IT chemotherapy, CNS-penetrant systemic chemotherapy, and cranial radiation. The type of CNS-therapy that is used is based on a patient's risk of CNS-relapse, with higher-risk patients receiving more intensive treatments. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurotoxicity and other late effects. The proportion of patients receiving cranial radiation has decreased significantly over time. In patients still receiving cranial radiation, the dose has been significantly reduced.
All therapeutic regimens for childhood ALL include IT chemotherapy. IT chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of IT given every 2–3 weeks), and, in certain protocols, continued throughout the maintenance phase. IT chemotherapy typically consists of either methotrexate alone or methotrexate with cytarabine and hydrocortisone. Unlike IT cytarabine, IT methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. Systemically administered drugs, such as dexamethasone, L-asparaginase, and high-dose methotrexate with leucovorin rescue, provide some degree of CNS prophylaxis. For example, in a randomized CCG study of standard-risk patients who all received the same dose and schedule of IT methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone. In a recent standard-risk ALL trial (COG-1991), lower-dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared to oral methotrexate given during each of two interim maintenance phases.[abstract]
CNS therapy for standard-risk patients
Intrathecal chemotherapy without cranial radiation, given in the context of appropriate systemic chemotherapy, results in CNS relapse rates of less than 5% for children with standard-risk ALL.[4,25,40,41,42,43] The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[23,44]
The CCG-1952 study for NCI standard-risk patients compared the relative efficacy and toxicity of triple IT chemotherapy (methotrexate, prednisone, and cytarabine) with methotrexate as the sole IT agent in nonirradiated patients. There was no significant difference in either CNS or non-CNS toxicities. Triple IT chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ▒ 1.0% compared with 5.9% ▒ 1.2% for IT methotrexate; P = .004). This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in cerebrospinal fluid [CSF] cytospin, but with <5 WBC/hpf on CSF cell count); the isolated CNS relapse rate was 7.7% ▒ 5.3% for CNS2 patients who received triple IT chemotherapy compared with 23.0% ▒ 9.5% for those who received IT methotrexate alone (P = .04). There were, however, more bone marrow relapses in the group that received the triple IT therapy, leading to a worse overall survival (OS) (90.3% ▒ 1.5%) compared with the IT methotrexate 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 terms of rates of CNS relapse rate, OS, or EFS. In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[Level of evidence: 1iiC]
Patients with blasts in the CSF but fewer than 5 WBC/ÁL (CNS2) are at increased risk of CNS relapse, although this risk appears to be nearly fully abrogated if they receive more intensive IT chemotherapy, especially during the induction phase. Data also suggest that patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis have an increased risk of CNS relapse, and these patients receive more intensive CNS-directed therapy on some treatment protocols.[48,49]
CNS therapy for high-risk patients
Controversy exists as to which, if any, high-risk patients should be treated with cranial radiation. Depending on the protocol, up 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. Patients receiving cranial radiation on many treatment regimens include those with T-cell phenotype and high initial WBC count and certain patients with high-risk precursor B-cell ALL (e.g., those with extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities).
Both the proportion of patients receiving radiation and the dose of radiation administered has decreased over the last 2 decades. For example, in a trial conducted between 1990 and1995, the BFM group demonstrated that a reduced dose of prophylactic radiation (12 Gy instead of 18 Gy) provided effective CNS prophylaxis in high-risk patients. In the follow-up trial conducted by that group between 1995 and 2000 (BFM-95), cranial radiation was administered to approximately 20% of patients (compared with 70% on the previous trial), including patients with T-cell phenotype, a slow early response (as measured by peripheral blood blast count after a 1-week steroid prophase), and/or adverse cytogenetic abnormalities. While the rate of isolated CNS relapses was higher in the nonirradiated higher-risk patients compared with historic (irradiated) cohorts, their overall EFS rate was not significantly different.
Two studies, one conducted by the SJCRH and the other by the Dutch Childhood Oncology Group (DCOG), omitted cranial radiation for all patients.[4,43] Each of these studies included four doses of high-dose methotrexate administered every 2 weeks during postinduction consolidation, as well as an increased frequency of IT triple chemotherapy (cytarabine, methotrexate, and hydrocortisone) and frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy. The 5-year cumulative incidence of isolated CNS relapse on each trial was between 2% and 3%, although some patient subsets had a significantly higher rate of CNS relapse. On the SJCRH study, clinical features associated with a significantly higher risk of isolated CNS relapse included T-cell phenotype, the t(1;19) translocation, or the presence of blasts in the CSF at diagnosis. The overall EFS for these studies was 85.6% (SJCRH) and 81% (DCOG), in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation. Of note, on the SJCRH study 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high MRD, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic stem cell transplant, which included total-body irradiation.
Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes IT chemotherapy and cranial radiation (usual dose is 18 Gy).[23,42] Spinal radiation is no longer used. On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ▒ 23%). On that study, CNS-leukemia at diagnosis (defined as CNS3 status or traumatic LP with blasts) was an independent predictor of inferior EFS. The 5-year EFS of CNS3 patients (N = 21) treated without cranial radiation on the DCOG-9 trial was 67% ▒ 10%. Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Toxicity of CNS-directed therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
The most common acute side effect associated with IT chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of IT chemotherapy will have at least one seizure during therapy. Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to IT chemotherapy. 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. Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[56,57,58,59,60] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[61,62,63] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[62,63,64] Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24 Gy–28 Gy) on clinical trials conducted in the 1970s and 1980s. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; in fact, cognitive function for both groups was not significantly impaired.; [Level of evidence: 1iiC] On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose (12 Gy). Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae.
In general, patients who receive IT chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[67,68,69,70] This modest decline is primarily seen in young children and girls. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple IT therapy showed no clinically meaningful difference.[Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances, although long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.
Cranial radiation has also been associated with an increased risk of second neoplasms, many of which are benign or of low malignant potential, such as meningiomas.[53,74,75] Leukoencephalopathy has been observed after cranial radiation in children with ALL, but appears to be more common with higher doses than are currently administered. In general, systemic methotrexate doses greater than 1 g/m2 should not be given following cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
Presymptomatic CNS therapy options under clinical evaluation
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.
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.
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