CNS-Directed Therapy for Childhood ALL
Approximately 3% of patients have detectable central nervous system (CNS) involvement by conventional criteria at diagnosis (cerebrospinal fluid [CSF] specimen with ≥5 white blood cell [WBC]/μL 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 acute lymphoblastic leukemia (ALL) should receive systemic combination chemotherapy together with some form of CNS prophylaxis.
Because the CNS is a sanctuary site (i.e., an anatomic space that is poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.
Standard treatment options for CNS-directed therapy include the following:
All of these treatment modalities have a role in the treatment and prevention of CNS leukemia. The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for selective situations.
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 five or more WBC/µL and blasts in the CSF (CNS3), obtained at diagnosis.
- Patients with blasts in the CSF but fewer than 5 WBC/µL (CNS2) may be at increased risk of CNS relapse, although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.
- Patients with T-cell ALL, especially those with high presenting peripheral blood leukocyte counts.
- Patients who have a traumatic lumbar puncture showing blasts at the time of diagnosis may have an increased risk of CNS relapse. These patients receive more intensive CNS-directed therapy on some treatment protocols.[3,4]
CNS-directed treatment regimens for newly diagnosed childhood ALL are presented in Table 2:
|Disease Status||Standard Treatment Options|
|ALL = acute lymphoblastic leukemia; CNS = central nervous system; CNS3 = cerebrospinal fluid with five or more white blood cells/µL, cytospin positive for blasts, or cranial nerve palsies.|
|aThe drug itself is not CNS-penetrant, but leads to cerebrospinal fluid asparagine depletion.|
|Standard-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-directed systemic chemotherapy|
|High-dose methotrexate with leucovorin rescue|
|Escalating-dose intravenous methotrexate (no leucovorin rescue)|
|High-risk ALL||Intrathecal chemotherapy|
|Methotrexate with cytarabine and hydrocortisone|
|CNS-directed 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 and, in many protocols, continued throughout the maintenance phase.
Intrathecal chemotherapy typically consists of one of the following:
- Methotrexate alone.
- Methotrexate with cytarabine and hydrocortisone (triple intrathecal chemotherapy).
Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.
CNS-Directed 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:
- L-asparaginase (does not penetrate into CSF itself, but leads to CSF asparagine depletion).
- High-dose methotrexate with leucovorin rescue.
- Escalating dose intravenous (IV) methotrexate without leucovorin rescue.
Evidence (CNS-directed 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 another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.
- In a randomized clinical trial conducted by the former 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 of subsequent CNS relapse, such as those with documented CNS leukemia at diagnosis (as defined above) (>5 WBC/μL with blasts; CNS3) and/or T-cell phenotype with high presenting WBC count. In patients who do receive 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.[11,12] A meta-analysis of randomized trials of CNS-directed therapy has confirmed that radiation therapy can be replaced by intrathecal chemotherapy in most patients with ALL. Additional systemic therapy may be required depending on the agents and intensity used.[Level of evidence: 1iDi]
CNS Therapy for Standard-risk Patients
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, hydrocortisone, and cytarabine) with methotrexate as the sole intrathecal agent in nonirradiated patients.
- There was no significant difference in either CNS or non-CNS toxicities.
- Although 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), there was no difference in event-free survival (EFS).
- 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 EFS.
- The findings of this trial need to be interpreted within the context of other therapy administered to patients. Dexamethasone, which has been associated with lower CNS relapse rates and improved EFS in standard-risk patients in other trials,[7,20] was not used in CCG-1952 (prednisone was the only steroid administered to patients). It is not clear whether the results of the CCG-1952 trial are generalizable to protocols that include the use of dexamethasone and/or other CNS-directed systemic therapies.
- 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 and/or CNS3 disease).
Both the proportion of patients receiving radiation and the dose of radiation administered has 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.[11,12,24] 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 and intensified dosing of L-asparaginase,[11,12] 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/µL 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 hematopoietic stem cell transplant , which included total-body irradiation.
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).[16,18] Spinal radiation is no longer used.
Evidence (cranial radiation):
- SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[11,24] 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 higher cumulative doses of anthracycline than on Children’s Oncology Group (COG) trials, and frequent vincristine/dexamethasone pulses and intensified dosing of L-asparaginase, 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/µL and cytospin positive for blasts) patients.
- 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%.
- On the EORTC trial, the 8-year EFS of CNS3 patients (n = 49) treated without cranial radiation was 68%. The cumulative incidence of isolated CNS relapse for those patients was 9.4%.[Level of evidence: 2A]
Larger studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.
Presymptomatic CNS Therapy Options Under Clinical Evaluation
Treatment options under clinical evaluation include the following:
- NCI-2014-00712/AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This trial is for patients with T-cell ALL and is testing, in a nonrandomized fashion, reduction in the proportion of T-cell ALL patients who receive prophylactic cranial radiation. In this study, only very high-risk patients (those with M3 marrow at day 29 or MRD >0.1% at end of consolidation, regardless of initial CNS status) and any other patient who is CNS3 at diagnosis receive cranial radiation therapy. CNS3 patients receive 18 Gy of cranial radiation, while the other patients allocated to cranial radiation receive 12 Gy. It is estimated that 10% to 15% of T-cell ALL patients will receive cranial radiation on AALL1231, compared with 85% to 90% of T-cell ALL patients on predecessor COG trials.
- 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 triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether triple intrathecal chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy).
- 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.
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 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.[30-33] This modest decline is primarily seen in young children and girls.
Controversy exists about whether patients who receive dexamethasone have a higher risk of 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.[37-41] At doses of 18 Gy, it does not appear that irradiated patients have more severe neurocognitive impairments than ALL survivors who were treated without radiation. On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of late effects.
The following groups have been associated with neurocognitive and neuroendocrine sequelae after cranial radiation:
- Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae after cranial radiation.[42-44]
- Girls may be at a higher risk than boys of radiation-induced neuropsychologic and neuroendocrine sequelae.[43-45]
- 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.
- In another randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, cognitive function for both groups (assessed at a median of 6 years postdiagnosis) was in the average range, with only subtle differences noted between the groups in cognitive skills.[Level of evidence: 1iiC]
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, although high-grade lesions may occur.[27,48,49] 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 after cranial radiation because of the increased risk of neurologic sequelae, including leukoencephalopathy.
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