Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)
CNS-Directed Therapy for Childhood ALL
Successful treatment of children with acute lymphoblastic leukemia (ALL) requires the control of systemic disease (e.g., marrow, liver and spleen, lymph nodes), and the prevention or treatment of extramedullary disease, particularly in the central nervous system (CNS).
Approximately 3% of patients have detectable CNS involvement by conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with =5 white blood cell [WBC]/ÁL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, the majority of children will eventually develop overt CNS leukemia. Therefore, all children with ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
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. Standard treatment options for CNS-directed therapy include the following:
- Intrathecal chemotherapy.
- CNS-penetrant systemic chemotherapy.
- 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. Data suggest that the following groups of patients are at increased risk of CNS relapse:
- 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 intrathecal chemotherapy, especially during the induction phase.
- 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.[2,3]
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 2:
Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL
|Disease Status||Standard Treatment Options|
|ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with 5 or more white blood cells/ÁL and cytospin positive for blasts.|
|Standard-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-penetrant systemic chemotherapy|
|High-dose methotrexate with leucovorin rescue|
|High-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-penetrant systemic chemotherapy|
|High-dose methotrexate with leucovorin rescue|
A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.
All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation (four to eight doses of intrathecal chemotherapy given every 2–3 weeks), and, in certain protocols, continued throughout the maintenance phase.
Intrathecal chemotherapy typically consists of one of the following:
- Methotrexate alone.
- Methotrexate with cytarabine and hydrocortisone.
Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.
CNS-Penetrant Systemic Chemotherapy
In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis. The following systemically administered drugs provide some degree of CNS prophylaxis:
- High-dose methotrexate with leucovorin rescue.
Evidence (CNS-penetrant systemic chemotherapy):
- In a randomized Children's Cancer Group (CCG) study of standard-risk patients who all received the same dose and schedule of intrathecal methotrexate without cranial irradiation, oral dexamethasone was associated with a 50% decrease in the rate of CNS relapse compared with oral prednisone.
- In a standard-risk ALL trial (COG-1991), lower-dose intravenous methotrexate without rescue significantly reduced the CNS relapse rate compared with oral methotrexate given during each of two interim maintenance phases.
- In a randomized clinical trial conducted by the Pediatric Oncology Group, T-cell ALL patients who received high-dose methotrexate experienced a significantly lower CNS relapse rate than patients who did not receive high-dose methotrexate.
The proportion of patients receiving cranial radiation has decreased significantly over time. At present, most newly diagnosed children with ALL are treated without cranial radiation. Many groups administer cranial radiation only to those patients considered to be at highest risk for subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/ÁL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count. In patients still receiving cranial radiation, the dose has been significantly reduced.
Ongoing trials seek to determine whether radiation can be eliminated from the treatment of all children with ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.[10,11]
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.[10,11,12,13,14,15]
The use of cranial radiation does not appear to be a necessary component of CNS-directed therapy for these patients.[16,17]
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
- The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, prednisone, and cytarabine) with methotrexate as the sole intrathecal agent in nonirradiated patients.
- There was no significant difference in either CNS or non-CNS toxicities.
- Triple intrathecal chemotherapy was associated with a lower rate of isolated CNS relapse (3.4% ▒ 1.0% compared with 5.9% ▒ 1.2% for intrathecal methotrexate; P = .004).
- This effect was especially notable in patients with CNS2 status at diagnosis (lymphoblasts seen in CSF cytospin, but with <5 WBC/high-power field [hpf] on CSF cell count); the isolated CNS relapse rate was 7.7% ▒ 5.3% for CNS2 patients who received triple intrathecal chemotherapy compared with 23.0% ▒ 9.5% for those who received intrathecal methotrexate alone (P = .04).
- There were more bone marrow relapses in the group that received the triple intrathecal chemotherapy, leading to a worse overall survival (OS) (90.3% ▒ 1.5%) compared with the intrathecal 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 intrathecal chemotherapy in terms of rates of CNS relapse rate, OS, or event-free survival (EFS).
- In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[Level of evidence: 1iiC]
CNS Therapy for High-Risk Patients
Controversy exists as to which 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 the following:
- Patients with T-cell phenotype and high initial WBC count.
- Patients with high-risk precursor B-cell ALL (e.g., extremely high presenting leukocyte counts and/or adverse cytogenetic abnormalities).
Both the proportion of patients receiving radiation and the dose of radiation administered have decreased over the last 2 decades.
Evidence (cranial radiation):
- In a trial conducted between 1990 and 1995, the Berlin-Frankfurt-Münster (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 the BFM 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.
- Several groups, including the St. Jude Children's Research Hospital (SJCRH), the Dutch Childhood Oncology Group (DCOG), and the European Organization for Research and Treatment of Cancer (EORTC), have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[10,11,21] Most of these trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH and DCOG studies also included frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy,[10,11] while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with =5 WBC/ÁL and cytospin positive for blasts) patients.
- The 5-year cumulative incidence of isolated CNS relapse on those trials was between 2% and 4%, 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 the SJCRH study was 85.6% and 81% for the DCOG study, both in line with outcomes achieved by contemporaneously conducted clinical trials on which some patients received prophylactic radiation, but was lower on the EORTC trial (8-year EFS, 69.6%).
- Of note, on the SJCRH study, 33 of 498 (6.6%) patients in first remission with high-risk features (including 26 with high minimal residual disease, six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic stem cell transplant (SCT), which included total-body irradiation.
Toxicity of CNS-Directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
- Acute/subacute toxicities (e.g., seizures, stroke, somnolence syndrome, and ascending paralysis).
- Late-developing toxicities (e.g., meningiomas and other second neoplasms; leukoencephalopathy; and a range of neurocognitive, behavioral, and neuroendocrine disturbances).[22,23,24]
The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal 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 intrathecal 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.
In general, patients who receive intrathecal 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.[27,28,29,30] This modest decline is primarily seen in young children and girls.
A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[Level of evidence: 3iiiC]
Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances. 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.
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.[34,35,36,37,38]
The following groups have been associated with neurocognitive and neuroendocrine sequelae following cranial radiation:
- Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[39,40,41]
- Girls may be at a higher risk than boys of radiation-induced neuropsychologic and neuroendocrine sequelae.[40,41,42]
- Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24–28 Gy) on clinical trials conducted in the 1970s and 1980s.
Evidence (toxicity of cranial radiation):
- In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; 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.
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.[24,45,46] 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
Treatment options under clinical evaluation include the following:
- COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): In the Children's Oncology Group (COG) COG-AALL0434 protocol for patients with T-cell ALL, low-risk T-cell patients (those with NCI standard-risk features and a rapid response to induction therapy) are treated without cranial radiation, and intermediate-risk T-cell patients receive 12 Gy (instead of 18 Gy) cranial radiation. High-risk T-cell patients continue to receive 18 Gy cranial radiation. All patients are randomly assigned to receive either high-dose methotrexate (5 g/m2 over 24 hours) with leucovorin rescue or escalating-dose methotrexate without leucovorin rescue during the initial interim maintenance phase of therapy.
- COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of intrathecal triple chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether intrathecal triple chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy). Patients with induction failure or low hypodiploidy are eligible for allogeneic SCT in first remission.
- SJCRH Total XVI (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): Patients receive both intrathecal chemotherapy and high-dose methotrexate without radiation therapy. Certain patients with high-risk features, including those with a t(1;19) translocation, receive intensified intrathecal therapy.
CNS Therapy for Patients With CNS Involvement (CNS3 Disease) at Diagnosis
Therapy for ALL patients with clinically evident CNS disease (>5 WBC/hpf with blasts on cytospin; CNS3) at diagnosis typically includes intrathecal chemotherapy and cranial radiation (usual dose is 18 Gy).[15,17] Spinal radiation is no longer used.
Evidence (cranial radiation):
- 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 this study, CNS-leukemia at diagnosis (defined as CNS3 status or traumatic lumbar puncture with blasts) was an independent predictor of inferior EFS.
- On the DCOG-9 trial, the 5-year EFS of CNS3 patients (N = 21) treated without cranial radiation was 67% ▒ 10%.
- SJCRH and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[10,21] These trials have included at least four doses of high-dose methotrexate during postinduction consolidation and an increased frequency of intrathecal chemotherapy. The SJCRH study also included frequent vincristine/dexamethasone pulses during the first 1 to 2 years of therapy,, while the EORTC trials included additional high-dose methotrexate and multiple doses of high-dose cytarabine, during postinduction treatment phases for CNS3 (CSF with =5 WBC/ÁL and cytospin positive for blasts) patients.
- The long-term EFS for CNS3 patients on these trials ranged from 43% (SJCRH) to 68% (EORTC).
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
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