Correspondence
Treating Childhood Leukemia without Cranial Irradiation
N Engl J Med 2009; 361:1310-1312September 24, 2009
- Article
To the Editor:
Pui and colleagues (June 25 issue)1 report a high likelihood of event-free and overall survival among children with acute lymphoblastic leukemia (ALL) treated with an intensive regimen of intrathecal chemotherapy and systemic drugs that penetrate the central nervous system (CNS). Their goal was to eliminate cranial irradiation and its late toxic effects. Most other trials of treatment for childhood ALL already treat the majority of patients (80% or more) without cranial irradiation, with similarly favorable results. Indeed, only 14% of patients in the study reported on by Pui et al. would have received cranial irradiation in previous trials. In these patients, survival did not appear to be adversely affected by the elimination of irradiation. Although the overall outcome of this trial was favorable, some subgroups of patients remained at high risk for relapse. Also, the acute systemic and CNS toxic effects of the treatment were not insubstantial, and the long-term neurocognitive outcomes are unknown. Before this investigational approach can be considered the standard of care, its consequences should be more thoroughly evaluated, ideally in randomized trials with larger numbers of patients and longer follow-up.
1 ReferencesStephen E. Sallan, M.D.
Dana–Farber Cancer Institute, Boston, MA
stephen_sallan@dfci.harvard. edu Martin Schrappe, M.D.
University Medical Center Schleswig-Holstein, Kiel, GermanyLewis B. Silverman, M.D.
Dana–Farber Cancer Institute, Boston, MA1
Pui C-H ,Campana D ,Pei D , et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009;360:2730-2741
Full Text | Web of Science | Medline
To the Editor:
An association between thrombotic events and the use of asparaginase in children with ALL is well known. Asparaginase decreases the plasma level of antithrombin, which is an inhibitor of coagulation and thrombin regulation.1 Children with standard-risk and high-risk ALL in the study reported on by Pui and colleagues received a higher than usual dose of asparaginase, which could account for the increased incidence of thrombosis. In how many of these children did cortical vein thrombosis develop? Prophylactic antithrombin concentrate, which has been administered to children receiving asparaginase, may decrease the incidence of thrombosis.2 Would the authors consider incorporating prophylactic antithrombin concentrate in future clinical trials, since older children (>10 years of age) with standard-risk or high-risk ALL will receive a higher dose of asparaginase?
2 ReferencesHarris V. Naina, M.D.
Mayo Clinic, Rochester, MN
naina.harris@mayo. edu Samar Harris, M.D.
University of Missouri, Columbia, MOMrinal M. Patnaik, M.D.
Mayo Clinic, Rochester, MN1
Nowak-Gottl U ,Kenet G ,Mitchell LG . Thrombosis in childhood acute lymphoblastic leukaemia: epidemiology, aetiology, diagnosis, prevention and treatment. Best Pract Res Clin Haematol 2009;22:103-114
CrossRef | Web of Science | Medline2
Mitchell L ,Andrew M ,Hanna K , et al. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving L-asparaginase for acute lymphoblastic leukemia: results of the PAARKA study. Thromb Haemost 2003;90:235-244
Web of Science | Medline
Author/Editor Response
It is well established that cranial irradiation is associated with neurocognitive deficits, endocrinopathy, and, most importantly, second cancers, with the cumulative incidence of second neoplasms increasing steadily over a period of many decades after treatment.1,2 Our previous studies also showed that cranial irradiation is associated with excess late mortality and an increased unemployment rate.1 By contrast, children with ALL who have not received cranial irradiation and who have event-free survival for 10 years or more can expect a normal long-term survival and an employment rate similar to that of the general population.1 Patients treated in our Total Therapy XV study will not have these radiation-induced complications.
We are cognizant of the potential neurotoxicity induced by systemic and intrathecal chemotherapy, as raised by Sallan and colleagues. We have been prospectively performing longitudinal neurocognitive evaluations in patients treated in the Total Therapy XV study. We have completed evaluations at the end of therapy and 2 years after the cessation of therapy in 123 patients. We also studied 162 long-term survivors who received prophylactic cranial irradiation in our previous Total Therapy studies. All test results were converted into standard scores according to age (mean [±SD], 100±15). Within each group, the percentage of patients at or below the 10th percentile of national norms was calculated to quantify rates of impairment. As shown in Table 1Table 1
Results of Tests of Intelligence, Attention, and Memory., intelligence scores were normal in patients treated in the Total Therapy XV study, but they indicated impairment in the historical controls. Attention and memory scores indicated similar rates of impairment in the two cohorts; additional monitoring is required to determine the functional significance of these findings. These preliminary results are encouraging, since patients treated in our Total Therapy XV protocol had less neurocognitive impairment than patients treated with cranial irradiation in previous studies.In response to Naina et al.: in our study, cerebral thrombosis developed in 12 patients (2.4%) (3 patients with low-risk leukemia and 9 patients with standard-risk or high-risk leukemia). None of these thromboses contributed to mortality. The increased incidence of thrombosis among the higher-risk patients, especially those older than 10 years of age, could be attributed to both prolonged exposure to asparaginase during continuation therapy and increased systemic exposure to dexamethasone.3 We do not use antithrombin III for prophylaxis because data supporting its clinical usefulness are not conclusive.
3 ReferencesChing-Hon Pui, M.D.
Kevin Krull, Ph.D.
Mary Relling, Pharm.D.
St. Jude Children's Research Hospital, Memphis, TN
ching-hon.pui@stjude. org 1
Pui C-H ,Cheng C ,Leung W , et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 2003;349:640-649[Erratum, N Engl J Med 2003;349:1299.]
Full Text | Web of Science | Medline2
Hijiya N ,Hudson MM ,Lensing S , et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA 2007;297:1207-1215
CrossRef | Web of Science | Medline3
Yang L ,Panetta JC ,Cai X , et al. Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol 2008;26:1932-1939
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Wendy Stock, Dan Douer, Daniel J. DeAngelo, Martha Arellano, Anjali Advani, Lloyd Damon, Tibor Kovacsovics, Mark Litzow, Michael Rytting, Gautam Borthakur, Archie Bleyer. (2011) Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leukemia & Lymphoma 52:12, 2237-2253
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