miércoles, 1 de mayo de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 6/8 —Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

CNS-Directed Therapy for Childhood ALL

At diagnosis, approximately 3% of patients have central nervous system 3 (CNS3) disease (defined as cerebrospinal fluid [CSF] specimen with ≥5 white blood cells [WBC]/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. 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.[1]
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 5 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,[2] although this risk appears to be nearly fully abrogated if they receive more doses of intrathecal chemotherapy, especially during the induction phase.[3]
  • 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 4:
Table 4. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL
Disease StatusStandard 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 ALLIntrathecal chemotherapy
 Methotrexate alone
 Methotrexate with cytarabine and hydrocortisone
CNS-directed systemic chemotherapy
 Dexamethasone
 L-asparaginasea
 High-dose methotrexate with leucovorin rescue
 Escalating-dose intravenous methotrexate (no leucovorin rescue)
High-risk and very high-risk ALLIntrathecal chemotherapy
 Methotrexate alone
 Methotrexate with cytarabine and hydrocortisone
CNS-directed systemic chemotherapy
 Dexamethasone
 L-asparaginasea
 High-dose methotrexate with leucovorin rescue
Cranial radiation
A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

Intrathecal Chemotherapy

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:[5]
  1. Methotrexate alone.
  2. 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.[6]

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:
  • Dexamethasone.
  • 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):
  1. 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.[7]
  2. In another standard-risk ALL trial (COG-1991), escalating dose IV methotrexate without leucovorin rescue significantly reduced the CNS relapse rate compared with standard, low-dose, oral methotrexate given during each of two interim maintenance phases.[8]
  3. 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.[9]

Cranial Radiation

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.[10] In patients who do receive radiation, the cranial radiation dose has been significantly reduced and administration of spinal irradiation is not standard.
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.[13]; [1][Level of evidence: 1iDi]

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.[11,12,14-17]
The use of cranial radiation is not a necessary component of CNS-directed therapy for these patients.[18,19] Some regimens use triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone), while others use intrathecal methotrexate alone throughout therapy.
Evidence (triple intrathecal chemotherapy vs. intrathecal methotrexate):
  1. The CCG-1952 study for National Cancer Institute (NCI) standard-risk patients compared the relative efficacy and toxicity of triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with methotrexate as the sole intrathecal agent in nonirradiated patients.[20]
    1. There was no significant difference in either CNS or non-CNS toxicities.
    2. 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).
      • The reduction in CNS relapse rate 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,[7,21] was not used in CCG-1952 (prednisone was the only steroid administered to patients).[22] 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.
    3. In a follow-up study of neurocognitive functioning in the two groups, there were no clinically significant differences.[23][Level of evidence: 1iiC]

CNS Therapy for High-risk and Very High-risk Patients

Controversy exists as to whether high-risk and very 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:[10]
  • 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):
  1. 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.[24]
  2. 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.[17]
    • 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.
  3. 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.[11,12,25] 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 pegaspargase,[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.[25]
    • 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.[11]
    • 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%).[25]
    • 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 (MRD), six with Philadelphia chromosome-positive ALL, and one with near haploidy) received an allogeneic hematopoietic stem cell transplant , which included total-body irradiation.[11]
  4. In a meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups, the use of cranial radiation therapy did not appear to impact 5-year OS or cumulative incidence of any event.[13]
    • In subgroup analyses of high-risk subsets, only those with CNS3 status at diagnosis appeared to benefit from cranial radiation, with a significantly lower rate of CNS relapses (isolated/any) in irradiated patients; however, even within this subgroup, OS was similar with or without the use of radiation therapy.
    • This study suggests that cranial radiation therapy may not be an essential component of treatment, even for high-risk patients; however, interpretation is limited by the considerable variation in treatment administered to patients by the different cooperative groups.

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).[17,19] Spinal radiation is no longer used.
Evidence (cranial radiation):
  1. SJCRH, DCOG, and the EORTC have published results of trials that omitted cranial radiation for all patients, including high-risk subsets.[11,25] 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 pegaspargase,[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/µL and cytospin positive for blasts) patients.[25]
    • On the SJCRH Total XV (TOTXV) study, patients with CNS3 status (N = 9) were treated without cranial radiation (observed 5-year EFS, 43% ± 23%%; OS, 71% ± 22%).[11] 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%.[12]
    • 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%.[25][Level of evidence: 2A]
  2. A meta-analysis of aggregated data from more than 16,000 patients treated between 1996 and 2007 by ten cooperative groups evaluated whether the use of cranial radiation therapy affected outcome in high-risk patient subsets.[13]
    • In subgroup analyses of high-risk subsets, only those with CNS3 status at diagnosis appeared to benefit from cranial radiation therapy, with a significantly lower rate of CNS relapses (isolated/any) in irradiated patients; however, even within this subgroup, OS was similar with or without the use of radiation therapy.
Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation in CNS3 patients.

Presymptomatic CNS Therapy Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  1. 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.
  2. SJCRH Total XVI (TOTXVI; NCT00549848) (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 acute and subacute or late developing. (Refer to the Late Effects of the Central Nervous System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Acute and subacute toxicities

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.[11] Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy.[26] Intrathecal and high-dose intravenous methotrexate has also been associated with a stroke-like syndrome, which, in most cases, appears to be reversible.[27]
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.[28] Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.[28]

Late-developing toxicities

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.
Subsequent neoplasms are observed primarily in survivors who received cranial radiation. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur. In a SJCRH retrospective study of more than 1,290 ALL patients who had never relapsed, the 30-year cumulative incidence of a subsequent neoplasm occurring in the CNS was 3%; excluding meningiomas, the 30-year cumulative incidence was 1.17%.[29] Nearly all of these CNS subsequent neoplasms occurred in previously irradiated patients.
Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy. In general, patients treated without cranial radiation 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] For patients who receive cranial radiation therapy, the frequency and severity of toxicities appear dose-related; patients treated with 18 Gy of cranial radiation therapy appear to be at lower risk of severe impairments compared with those treated with doses of 24 Gy or higher. Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.[34]
Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[23][Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances.[35] In a SJCRH study of nonirradiated long-term survivors, treatment with dexamethasone was associated with increased risk of impairments in attention and executive function.[36] Conversely, 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.[37]
Evidence (neurocognitive late effects of cranial radiation):
  1. A SJCRH study of 567 adult long-term survivors of childhood ALL underwent neurocognitive testing (mean time from diagnosis, 26 years).[36]
    • Patients treated with 24 Gy of cranial radiation showed the highest rates of impairment. Up to one-third of these patients demonstrated impairments (defined as test scores 2 or more standard deviations below age-adjusted national norms) in attention, memory, processing speed, and executive function.
    • Significantly fewer patients who had received 18 Gy of cranial radiation demonstrated severe impairments compared with those who had received 24 Gy. In general, there was no significant difference in rates of impairment between nonirradiated survivors and those who received 18 Gy of cranial radiation; however, the 18-Gy group was at increased risk of academic problems.
    • In addition to being dose-related, the neurocognitive impact of cranial radiation was also dependent on age at diagnosis, with higher frequency of impairments in patients diagnosed at a younger age.
  2. A study compared memory impairment in patients receiving 18 Gy of cranial radiation (n = 127) versus 24 Gy of cranial radiation (n = 138).[38]
    • Long-term survivors who received 24 Gy, but not 18 Gy, of cranial radiation demonstrated significant impairments in immediate and delayed memory.
  3. In a randomized trial comparing irradiated (at a dose of 18 Gy) and nonirradiated standard-risk ALL patients, the following was observed: [30][Level of evidence: 1iiC]
    • 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.
  4. 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.[39]
Evidence (neurocognitive late effects in nonirradiated patients):
  1. In the SJCRH long-term follow-up study of 567 adult long-term survivors, some nonirradiated patients also demonstrated neurocognitive impairments.[36]
    • The age-adjusted mean test scores for nonirradiated patients were very similar to that of expected national norms; however, approximately 15% of the nonirradiated survivors participating in this study demonstrated impairments in some domains, including attention, memory, processing speed, and executive function.
    • Despite the impairments noted on neurocognitive testing, overall, the educational attainment and employment status of the tested ALL survivors were similar to age- and sex-adjusted expected proportions using census data for the U.S. population.
  2. In a second study from SJCRH, patients enrolled on Total Study XV (which omitted cranial radiation in all patients) underwent comprehensive neuropsychological assessments at induction, end of maintenance, and 2 years after completion of therapy.[40]
    • Neurocognitive function was largely age appropriate 2 years after completing therapy, without evidence of excess impairment on measures of intellectual functioning, academic abilities, learning, and memory. Problems with sustained attention were observed at an increased frequency in this population compared with normative expectations.
    • High-risk patients who received more intensive CNS-directed chemotherapy (including high-dose methotrexate and more doses of intrathecal chemotherapy) were at greater risk of difficulties in attention, processing speed, and academics.
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