|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-08-2454.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Pediatric Oncology, Children's
Hospitals and Clinics, Minneapolis, MN; the Department of Preventive
Medicine, Keck School of Medicine, University of Southern California,
Los Angeles, CA; the Children's Oncology Group, Arcadia, CA; Childrens
Hospital Los Angeles, Los Angeles, CA; Childrens Hospital of Columbus,
Columbus, OH; PRACS Institute, Ltd, Fargo, ND; University of
North Carolina, Chapel Hill, NC; C. S. Mott Children's Hospital,
Ann Arbor, MI; Columbus Regional Medical Center, Columbus, GA; and
Christiana Care Health Services, Wilmington, DE.
Conventional therapy for childhood acute
lymphoblastic leukemia (ALL) includes prednisone and oral
6-mercaptopurine. Prior observations suggested potential advantages for
dexamethasone over prednisone and for intravenous (IV) over oral
6-mercaptopurine, which remain to be validated. We report the results
of a randomized trial of more than 1000 subjects that examined the
efficacy of dexamethasone and IV 6-mercaptopurine. Children with
National Cancer Institute standard-risk ALL were randomly assigned in a 2 × 2 factorial design to receive dexamethasone (6 mg/m2/d) for 28 days in induction, plus taper, compared
with prednisone (40 mg/m2/d). The second randomized
assignment was for daily oral or weekly IV 6-mercaptopurine during
consolidation. During maintenance, 5 days of the randomized steroid was
given monthly, at the same dose, and all patients received daily oral
6-mercaptopurine. During delayed intensification, all patients received
a dexamethasone dosage of 10 mg/m2/d for 21 days, with
taper. Intrathecal (IT) methotrexate was the sole central nervous
system-directed therapy. Patients randomly assigned to receive
dexamethasone had a 6-year isolated central nervous system-relapse
rate of 3.7% ± 0.8%, compared with 7.1% ± 1.1% for prednisone
(P = .01). There was also a trend toward fewer isolated
bone marrow relapses with dexamethasone. The 6-year event-free survival
(EFS) was 85% ± 2% for dexamethasone and 77% ± 2% for
prednisone (P = .002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had
decreased survival after relapse.
(Blood. 2003;101:3809-3817) According to current National Cancer Institute
(NCI) criteria,1 children older than 1 year and younger
than 10 years who have white blood cell (WBC) counts lower than
50 × 109/L are considered at standard risk. In this
report, we detail treatment outcomes for standard-risk acute
lymphoblastic leukemia (ALL) patients treated on the Children's Cancer
Group (CCG)-1922 trial. All patients received a 3-drug induction phase
and experienced a 3-month consolidation phase with 6-mercaptopurine
(6-MP), methotrexate, vincristine and steroid; a 2-month delayed
intensification (DI) phase2; and a 20- or 32-month
maintenance phase for girls and boys, respectively. The details of
therapy are depicted in Figure 1.
In CCG-1922, 2 hypotheses were tested. The first hypothesis was
that dexamethasone will be superior to prednisone in preventing central
nervous system (CNS) relapse and provide better event-free survival
(EFS). Dexamethasone provides better CNS penetration than
prednisone.3 The superior cytotoxicity of dexamethasone is
not explained fully by the conventional 6:1 to 7:1 ratio of glucocorticoid activity.4 Although overall EFS was
similar, Cancer and Leukemia Group B (CALGB) found that children
randomly assigned to dexamethasone had a lower CNS relapse rate than
those assigned to prednisone.5 The Dutch ALL Study VI and
Dana Farber Consortium replaced prednisone with dexamethasone and found
better outcomes than a historical control.6-9 The second
hypothesis was that weekly intravenous (IV) 6-MP will provide higher
intracellular accumulation of thioguanine nucleotides, resulting in
better EFS than daily oral 6-MP. Poor outcome has been linked to a
lesser accumulation of intracellular thioguanine
nucleotides.10,11 Intravenous administration of 6-MP
provides better bioavailability and less interpatient
variability.12-14 Preliminary results from a feasibility
trial showed a striking benefit from IV 6-MP.15,16 Thus,
patients on CCG-1922 were assigned randomly to receive dexamethasone or
prednisone during induction, consolidation, and maintenance and daily
oral or weekly IV 6-mercaptopurine during consolidation. All patients
received dexamethasone during delayed intensification and daily oral
6-mercaptopurine during maintenance.
Patients
During the first 6 months of the CCG-1922 study, a subset of
standard-risk patients (aged 1 to less than 2 years with WBC counts
lower than 50 × 109/L; aged 2 to less than 10 years with
WBC counts of 10 × 109 to less than
50 × 109/L; and boys aged 2 to less than 10 years with
WBC counts less than 10 × 109/L and platelet counts less
than 100 × 109/L) was enrolled in the CCG-1891 study for
patients with intermediate-risk ALL until accrual goals were
met.17 After the closure of CCG-1891 and for the remainder
of the study period, all NCI-defined standard-risk patients were
enrolled in CCG-1922, excluding those with lymphoma syndrome. Diagnosis
of ALL was based on morphologic, biochemical, and flow cytometric
features of leukemic cells, including lymphoblast morphology on
Wright-Giemsa-stained bone marrow smears, negative staining for
myeloperoxidase, and reactivity with monoclonal antibodies to
B-lineage-associated or T-lineage-associated lymphoid differentiation antigens, as described before.18
Treatment protocol
Therapy modifications for toxicity Treatment was modified to adjust for morbidity and to optimize delivery. Chemotherapy was not interrupted unless hepatic transaminases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) levels were higher than 1000 units/L on 2 determinations at least 1 week apart or the total bilirubin level was higher than 0.02 g/L. Maintenance chemotherapy was not interrupted unless the absolute neutrophil count fell to lower than 750 × 106/L or the platelet count to lower than 75 × 109/L. Therapy was not increased above prescribed doses for patients with persistent elevations of absolute neutrophil count.Toxicity grading To evaluate better the morbidity anticipated from the experimental interventions, specific toxicity questions were added to the data forms 14 months after initiation of the study. The specific toxicities evaluated included avascular necrosis, clinically significant infections determined by treating physician, grade 3 or 4 pancreatitis, steroid-associated proximal myopathy, any CNS toxicity, and hematuria or renal stones.19 The percentage of patients by phase for whom these data were available was 69% for induction; 79% for consolidation; 87% for delayed intensification; and 93+% for maintenance.Karyotype analysis Leukemic karyotypes were accepted after central review of studies performed at the local institutions.20Statistical methods Sample size and power calculations were based on a proportional hazard assumption for the treatment regimen, with few treatment failures assumed after 5 years of follow-up. The study used a 2 × 2 factorial design for examining effects of (1) oral versus IV 6MP in the consolidation phase, and (2) dexamethasone versus prednisone in induction, consolidation, and maintenance. An accrual of 1050 randomized patients was planned to have in excess of 80% power (2-sided log-rank test) for detecting a change in 5-year EFS from an assumed 80% baseline to 87.5%, representing a relative risk (RR) of 0.598 for the better regimen. The study also had power above 80% (2-sided Gray statistic) for detecting a change in the incidence of CNS relapse from 10% to 5%, representing an RR of 0.487 for the better regimen. The study was not designed to detect significant differences in bone marrow relapses.Assignments were randomized at study entry. Data were analyzed in July 2001 using a January 2001 cutoff. The primary end point used for life table comparisons of treatment regimen outcomes and prognostic factor effects was EFS, which was defined as the time to first occurrence of any one of the following events: induction death, no response to induction therapy, relapse after remission at any site, death in remission, or second malignant neoplasm. A secondary end point of interest was incidence of isolated CNS relapse as the initial event. Analysis of CNS incidence was done using a cumulative incidence function.21 Selected comparisons of overall survival outcomes also are provided. Comparison of treatment regimen outcomes was done with the intent-to-treat approach. EFS and survival life table estimates were done with the Kaplan-Meier (KM) method,22 and these estimates are provided at 6 years of follow-up. The standard deviation of the KM estimate was calculated using the Peto variance formula.23 Relative hazard rates were estimated by the log-rank observed divided by expected (O/E) method. Chi-square tests for homogeneity of distributions were used in some comparisons (similarity of patient characteristics, patterns of outcome events, etc). Multivariate analysis of prognostic factors was done with the Cox proportional hazards model.24
Patient characteristics Among 1080 patients entered on study, 19 were deemed ineligible because of lack of adequate consent or incorrect diagnosis, and one was not assigned randomly. Among the 1060 remaining patients, 530 were assigned randomly to dexamethasone and 530 to prednisone. Canadian institutions that participated in this study were unable to administer IV 6-mercaptopurine on an outpatient basis, and all 30 patients treated at Canadian institutions were not assigned randomly with respect to the 6-MP question. Among 1030 patients assigned randomly with respect to the 6-MP route, 514 were assigned to receive daily oral administration and 516 were randomized to receive weekly IV administration. Presenting characteristics were not significantly different in the treatment groups and are detailed in Table 2.
Treatment outcome Blast percentage in marrow was determined on day 7 of induction therapy. Overall, 53% of all patients achieved M1 marrow status (fewer than 5% blasts); 25% of patients had M2 marrow status (5%-25% blasts); and 22% had M3 status (more than 25% blasts). There was no difference in day-7 marrow response or induction end marrow status by randomized steroid. At the end of the induction phase, 99% of patients had M1 marrow status, 10 had M2 marrow status, and one had M3 marrow status. The 6-year EFS rate for the entire cohort of patients treated on CCG-1922 was 81% ± 2% with a 6-year survival rate of 92% ± 1%.Outcome was significantly improved for patients assigned to
dexamethasone (6-year EFS = 85% ± 2%) compared with that of
patients assigned to prednisone (6-year EFS = 77% ± 2%;
P = .002; RR = 0.65; Figure
2A). Survival was similar between
patients treated with dexamethasone and prednisone, with 6-year
estimates of 93% ± 1% and 91% ± 1%, respectively
(P = .17; RR = 0.74). For the randomized comparison of
daily oral and weekly IV 6-MP, 6-year EFS was 82% ± 2% and
80% ± 2%, respectively (P = .2; RR = 0.83; Figure
2B). Survival was worse for patients treated with IV versus oral 6-MP,
with 6-year estimates of 90% ± 1% and 94% ± 1%, respectively (P = .02; RR = 1.7).
We found no evidence of an interaction between the 2 assigned treatment comparisons. As such there was no difference in EFS between patients assigned to receive oral or IV 6-MP within the dexamethasone or prednisone subsets. Likewise, the significant improvement in EFS for the overall cohort of patients assigned to receive dexamethasone compared with those assigned to receive prednisone was preserved among subsets of patients treated with daily oral or weekly IV 6-MP. The survival advantage observed among the overall cohort of patients treated with oral 6-MP was preserved among patients who received dexamethasone or prednisone. Also, survival for patients who received dexamethasone or prednisone was similar within the subsets of patients treated with oral or intravenous 6-MP. The 6-year EFS by regimen was OD (oral mercaptopurine/dexamethasone) 86% ± 2%; ID (intravenous mercaptopurine/dexamethasone) 84% ± 2%; OP (oral mercaptopurine/prednisone) 78% ± 3%; and IP (intravenous mercaptopurine/prednisone) 77% ± 3% (P = .01). The primary reason for treatment failure was marrow relapse. Table
3 lists first events by treatment
regimen. As hypothesized, the cumulative incidence of isolated CNS
relapse was lower for dexamethasone patients than for prednisone
patients, with 6-year cumulative estimates of 3.7% ± 0.8% and
7.1% ± 1.1%, respectively (P = .01; Figure
3). In addition, dexamethasone patients
had a trend toward fewer marrow relapses, with 6-year estimates of
7.9% ± 1.3% and 11.1% ± 1.5%, respectively
(P = .08). The cumulative incidence of isolated CNS or
bone marrow relapse was similar for patients who received oral or IV
6-MP (data not shown). Thus far, 3 second malignancies have been
reported (Table 3).
Prognostic factors Univariate analysis of a large number of clinical and laboratory presenting features found adverse prognostic significance of age, spleen enlargement, hypodiploidy, and low hyperdiploidy. Children in the 2-to-5-year age range had only about half as many events as those in the 1-year age group or the older than 6 years age group (RR = 0.51 and 0.56, respectively, P = .0001). The WBC count had a minimal prognostic effect (P = .20) in the restricted WBC eligibility range for this study. Trisomy 10 and double trisomies 10 and 17 had favorable prognostic significance (P = .03 and .007, respectively) in 379 patients who had adequate banded karyotype analysis. Outcomes were similar for patients with or without acceptable karyotypes. The 6-year EFS results were 92% ± 5% for trisomy 10 and 81% ± 3% for those without trisomy 10 independent of other trisomy status (log-rank, P = .03). For the analysis of combined trisomy 10/17 status (P = .03), the 6-year results were 96% ± 4% for combined trisomy 10/17 and 81% ± 3% for those not having both trisomy 10 and trisomy 17 (P = .007) (Figure 4).
The favorable prognostic significance of trisomy 10 was observed among dexamethasone and IV 6-MP patients (P = .03 and .03, respectively), but not in those assigned to oral 6-MP or prednisone (P = .19 and .47, respectively). None of the 29 patients with trisomy 10 who were assigned to dexamethasone have relapsed. Marrow response on day 7 of therapy also was a significant prognostic
factor (P = .002; Figure 5).
We found worse outcomes for patients with M2 (RR = 1.59) or M3
(RR = 1.82) versus M1 marrow status. Similar trends were observed in
the IV 6-MP, prednisone, and dexamethasone subsets but not in the oral
6-MP subset. Dexamethasone was superior to prednisone for patients with
day 7 M1 marrow status (6-year EFS estimates of 89% ± 2% versus
82% ± 3%), M2 marrow status (6-year EFS estimates of 83% ± 4%
versus 77% ± 4%), and M3 marrow status (6-year EFS estimates of
82% ± 4% versus 71% ± 4%). Outcomes were similar within day-7
marrow status subsets for oral and IV 6-MP patients.
Toxicities Infectious complications and deaths. Patients assigned to dexamethasone or prednisone had identical incidence of bacteremia during induction (13%). Fungal infections were found in 6 dexamethasone patients and 10 prednisone patients. Viral infections were found in 11 dexamethasone patients and 14 prednisone patients. Incidence of fever and neutropenia and duration of hospital stay were similar between steroid groups, as were supportive care interventions. Six patients died from infections during induction or the month after (0.6%): 2 prednisone patients (Staphylococcus aureus, varicella) and 4 dexamethasone patients (adult respiratory distress syndrome in 3, 2 of whom also had alpha-streptococcal sepsis, and parainfluenza pneumonia in one). During delayed intensification, when all patients receive dexamethasone, 5 patients died from infections: 4 prednisone-assigned patients and one dexamethasone-assigned patient. Infectious deaths during maintenance included 2 patients in the prednisone group (Pseudomonas; alpha-streptococcus) and one in the dexamethasone group (varicella). Steroid myopathy. Reversible proximal myopathy was seen during induction, early consolidation, and delayed intensification, but not in maintenance. No patient had grade 4 toxicity (ie, respiratory embarrassment). Incidence of grades 1 to 3 steroid myopathy during induction and early consolidation was 1.5% in prednisone patients and 6.3% in dexamethasone patients (P < .0001 by chi-square). Grade 3 weakness (ie, inability to ambulate) was seen in 22 dexamethasone patients (4.1%) and only 2 prednisone patients (0.3%; P < .0001 by chi-square). Grade 3 myopathy was more common in younger children and boys. During delayed intensification, when all patients received dexamethasone, incidence of myopathy was 0.7% and was the same for prednisone- and dexamethasone-assigned patients. Weakness was reversible when the steroid was discontinued, and none recurred during monthly 5-day steroid pulses in maintenance. Pancreatitis. Incidence of grade 3 or 4 amylase elevation in induction was 1.3% (7 of 528) in dexamethasone patients and 0.4% (2 of 529) in prednisone patients (P = .09). Symptomatic pancreatitis was reported in 5 dexamethasone patients and one prednisone patient. All recovered without sequelae. Isolated hepatic transaminase elevations. The incidence of grade 3 or 4 ALT elevations was similar among prednisone and dexamethasone patients. During consolidation, elevations were more common among daily oral 6-MP patients (19%; 104/537) than among weekly IV 6-MP patients (13%; 64/500; P = .003). Hyperglycemia. Patients who received dexamethasone had a significantly higher incidence of reversible grade 3 or 4 hyperglycemia (26/528; 5%) versus those who received prednisone (8/529; 1.5%; P = .001). Data on specific use of insulin for hyperglycemia was not collected. Avascular osteonecrosis. Two prednisone patients and one dexamethasone patient were diagnosed with avascular necrosis of the ankles early in maintenance therapy. Neuropsychiatric effects. Two patients had consistent dysesthesia and agitation with each 5-day course of dexamethasone in maintenance. These symptoms were unresponsive to sedatives and to reduction of steroid dosage by 50%. Both patients were switched to prednisone with no or less intense reactions. Four patients were switched from dexamethasone to prednisone at their parents' requests because of similar reactions. Other toxicity. There were no apparent differences in incidence of other rare toxicities by assigned treatment, including seizures, CNS hemorrhage, thrombotic stroke, hematuria, and renal stones. Incidence and severity of other toxicities noted on the CCG Toxicity Rating Scale were not different by steroid or 6-MP route randomization.
Dexamethasone versus prednisone Against a background of 11-drug therapy, replacement of prednisone with dexamethasone at conventional equivalence provided a 34% reduction in risk of any relapse for children with standard-risk ALL. Corticosteroids are one of the mainstays in therapy for acute lymphoblastic leukemia.4,25 Attempts to delay corticosteroids until after induction have resulted in inferior results.26 The Berlin-Frankfurt-Münster (BFM) group, the Children's Cancer Group, and United Kingdom Acute Lymphoblastic Leukemia (UKALL) have used dexamethasone as part of successful postinduction intensification strategies.27-30 In the current randomized comparison, we observed a statistically significant and clinically important decrease in rate of isolated CNS relapses and an increase in EFS with dexamethasone, as hypothesized. The study was not designed with a sample sufficient to determine a statistically significant reduction in bone marrow relapses. However, the absolute reduction in bone marrow relapses with dexamethasone was identical to the reduction in CNS relapses, in the range of 3% to 4%. The benefit of dexamethasone was apparent for oral and IV 6-MP patients and for day-7 M1, M2, and M3 marrow status patients.Although no differences were found in duration of hospitalization or supportive care interventions, the substitution was not truly isotoxic. Published equivalency tables suggest that dexamethasone is approximately 7-fold more potent than prednisone. We chose a dose of 6 mg/m2/d to replace 40 mg/m2/d of prednisone. However, in vitro assays of phytohemagglutinin-induced lymphocyte proliferation suppression have shown dexamethasone to be 10-fold more active than prednisolone.31 In vitro assays of cytotoxicity have shown dexamethasone to be 6 to 16 times more potent against ALL blast cells.32,33 In vivo, dexamethasone has a longer biologic half-life.34 Thus, the superior results that we have obtained with dexamethasone may follow, in part, from the fact that 6 mg/m2/d of dexamethasone might be biologically equivalent to at least 100 mg/m2/d of prednisone. We observed a higher incidence of reversible corticosteroid-induced side effects (hyperglycemia and myopathy) in dexamethasone patients. Our studies have shown clearly that dexamethasone at a dose of 6 mg/m2 was superior to prednisone at 40 mg/m2. Steroid-related complications Infectious complications. Hurwitz et al described an increased incidence of gram-negative bacteremia and induction death in a group of patients who received dexamethasone during induction compared with historical controls who received prednisone.35 In contrast, we did not see any differences in infectious complications during induction or any other phase of therapy. Hurwitz et al used doxorubicin during induction, unlike this trial, which might have deepened neutropenia and delayed neutrophil recovery. In addition, dexamethasone may blunt the febrile response to infection, delaying recognition of fever and initiation of antibiotic therapy, thus increasing risk of death. Although CCG and others have used dexamethasone with anthracycline in delayed intensification for more than 20 years, we concur with Hurwitz et al's caution about prolonged exposure to dexamethasone in conjunction with myelosuppressive chemotherapy. Skeletal complications. Avascular necrosis of bone is a known complication of corticosteroids. Mattano et al36 found an incidence of 14% in patients older than 10 years versus 1% in younger patients. Factors increasing risk include being older than 10, female, and white, as well as the number of dexamethasone-containing delayed intensification courses.36 Others have suggested that avascular necrosis may be related to the combination of agents used in delayed intensification and not to dexamethasone alone.37 All patients in the current study were younger than 10 years at diagnosis, and only 3 were diagnosed with symptomatic avascular osteonecrosis, all after receiving dexamethasone in the delayed intensification phase. However, there was no difference in this rare occurrence by randomized steroid received. Patients who receive therapy for ALL are at risk of other skeletal abnormalities including osteopenia, osteoporosis, and symptomatic and asymptomatic fractures. Disease status and use of intensive corticosteroids may contribute to that risk.38 Atkinson et al found increased subclinical fractures in patients who received dexamethasone during induction versus historical controls who received prednisone and otherwise identical therapy.38 Strauss et al also found increased bony morbidity, including osteonecrosis, when dexamethasone was substituted for prednisone.39 In the current study, clinical fractures were not reported for any patient. We did not screen for subclinical fractures.Steroid myopathy. Proximal myopathy is a complication of corticosteroid therapy.40 Vincristine, usually given with corticosteroids during ALL therapy, also may cause or exacerbate neuropathy.40 Myopathy may be more prevalent with dexamethasone than with other corticosteroids.41 Patients assigned to dexamethasone had significantly greater incidence of proximal muscle weakness during or immediately after induction therapy in which they received 28 days of corticosteroid, followed by a taper. Male sex and younger age were risk factors for development of more severe weakness. Weekly vincristine was given during induction. It may be difficult to clinically differentiate corticosteroid myopathy from vincristine neuropathy, so it is possible that those patients may have had weakness from both effects. In most affected patients, ambulation was impaired. However, all patients recovered completely without recurrence during corticosteroid pulses in maintenance. Neuropsychiatric effects. Agitation and even frank psychosis are known complications of corticosteroid use.42,43 The mechanism is multifactorial because of effects on levels of biogenic amines, pro-opiomelanocortin (POMC)-related peptides and somatostatin, and on brain electrophysiology.44 Risk depends upon corticosteroid dose, potency, and individual susceptibility. Although a rare occurrence, 2 patients in the current study were unable to tolerate dexamethasone pulses in maintenance because of severe agitation, and 4 others were switched to prednisone at their parents' requests. In some cases, we found that concomitant sedatives and potassium supplements may decrease agitation level. Otherwise, a change to prednisone reduced or eliminated symptoms. Waber et al linked dexamethasone with cognitive dysfunction after comparing 2 cohorts of children who received one drug or the other.45 Methodologic considerations led Loring and Meador to state in an accompanying editorial that "The results do not answer the question regarding the presence of differential long-term cognitive side effects of dexamethasone versus prednisone."46 (p195) The dexamethasone and prednisone patients were populations of convenience. In the report by Waber et al,45 70% of the dexamethasone patients received prophylactic cranial radiation, as did half the prednisone patients. The dexamethasone patients were younger at diagnosis and fewer had parents who had gone to college. In the current study, no patient received prophylactic cranial radiation. Craniospinal irradiation was reserved for the less than 1% with overt CNS leukemia at diagnosis. Dexamethasone doses differed from doses in the current study. Neuropsychologic testing in a cohort of long-term survivors of this trial would address the question most productively.Intravenous 6-mercaptopurine Daily oral 6-mercaptopurine is a mainstay in the treatment of childhood ALL.47 In vitro studies also have shown correlation between blast sensitivity to thiopurines and risk of relapse.48 Some have shown a link between intracellular accumulation of thioguanine nucleotides and outcome. Others have linked more myelosuppression during maintenance therapy with daily oral 6-MP and weekly oral methotrexate with better EFS, which suggests that biologic activity of these drugs has an important bearing on outcome.11,49-51 More recently, against a background of more effective therapy, Relling et al52 found that prolonged interruptions of oral 6-MP and methotrexate are linked to lesser dose intensity and inferior outcome. Van Eys and coworkers were unable to improve outcome by escalating the dose of oral 6-MP to modest levels of leukopenia.53The bioavailability of oral 6-MP is poor, and its interpatient variability is wide. Intravenous 6-MP has better bioavailability and less interpatient variability.47,54 The Pediatric Oncology Group (POG) reported favorable outcomes with alternating weeks of IV 6-MP (1000 mg/m2 over 6 hours) and oral 6-MP (50 mg/m2/d × 7 days) in conjunction with IV methotrexate for early intensification in standard-risk patients.15,16,55 However, recently published randomized trials showed no difference or worse outcomes for patients treated with IV versus oral 6-MP.56 In the current trial, we found no difference in EFS. We did observe a significantly improved overall survival for oral 6-MP patients because of an increased risk of death after relapse in IV 6-MP patients.57 Daily use may be superior to more intermittent IV bolus use because of the antiangiogenic properties of 6-MP metabolites.58 Weekly IV 6-MP does not improve outcome despite reports of superior bioavailability in the literature. In fact, IV 6-MP patients have unexplained shorter survival after relapse than oral 6-MP patients. In contrast, dexamethasone significantly improves outcomes of children with standard-risk ALL by decreasing relapses without causing undo short-term toxicity. This improvement was apparent even though all patients received dexamethasone during delayed intensification. In this standard-risk population younger than 10 years who received no anthracycline during induction, neither infectious complications nor avascular necrosis of bone were problematic. For older patients at higher risk of avascular necrosis, and for patients who receive anthracycline in induction, dexamethasone should be introduced only in the context of a clinical trial where benefits and harms may be assessed accurately.
Submitted August 12, 2002; accepted December 15, 2002.
Prepublished online as Blood First Edition Paper, January 16, 2003; DOI 10.1182/blood-2002-08-2454.
Supported in part by research grants including Children's Cancer Group Chairman's Grant No. CA-13539 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Bruce C. Bostrom, c/o Children's Oncology Group, Attn Shaun Mason, PO Box 60012, Arcadia, CA 91066-6012; e-mail: bostrom{at}childrenshc.org; cc: smason{at}childrensoncologygroup.org.
1. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14:18-24[Abstract].
2.
Tubergen DG, Gilchrist GS, O'Brien RT, et al.
Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: a Children's Cancer Group phase III trial.
J Clin Oncol.
1993;11:527-537 3. Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack DG. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol. 1987;5:202-207[Abstract]. 4. Gaynon PS, Lustig RH. The use of glucocorticoids in acute lymphoblastic leukemia of childhood: molecular, cellular, and clinical considerations. J Pediatr Hematol Oncol. 1995;17:1-12[Medline] [Order article via Infotrieve]. 5. Jones B, Freeman AI, Shuster JJ, et al. Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol. 1991;19:269-275[Medline] [Order article via Infotrieve]. 6. Veerman AJ, Hahlen K, Kamps WA, et al. Dutch Childhood Leukemia Study Group: early results of study ALL VI (1984-1988). Hamatol Bluttransfus. 1990;33:473-477.
7.
Veerman AJ, Hahlen K, Kamps WA, et al.
High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: results of protocol ALL VI from the Dutch Childhood Leukemia Study Group.
J Clin Oncol.
1996;14:911-918 8. Silverman LB, Gelber RD, Kimball-Dalton V, Young ML, Sallan SE. Results of the Dana-Farber Cancer Institute (DFCI) Consortium Protocol 91-01 for Children with Acute Lymphoblastic Leukemia (ALL) [abstract]. Blood. 1998;92:483a.
9.
Silverman LB, Gelber RD, Dalton VK, et al.
Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01.
Blood.
2001;97:1211-1218 10. Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. 1989;7:1816-1823. 11. Schmiegelow K, Bruunshuus I. 6-Thioguanine nucleotide accumulation in red blood cells during maintenance chemotherapy for childhood acute lymphoblastic leukemia, and its relation to leukopenia. Cancer Chemother Pharmacol. 1990;26:288-292[Medline] [Order article via Infotrieve].
12.
Zimm S, Ettinger LJ, Holcenberg JS, et al.
Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion.
Cancer Res.
1985;45:1869-1873 13. Adamson PC, Zimm S, Ragab AH, et al. A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors. Cancer Chemother Pharmacol. 1990;26:343-344[Medline] [Order article via Infotrieve].
14.
Balis FM, Holcenberg JS, Poplack DG, et al.
Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.
Blood.
1998;92:3569-3577 15. Camitta B, Leventhal B, Lauer S, et al. Intermediate-dose intravenous methotrexate and mercaptopurine therapy for non-T, non-B acute lymphocytic leukemia of childhood: a Pediatric Oncology Group study. J Clin Oncol. 1989;7:1539-1544[Abstract]. 16. Camitta B, Mahoney D, Leventhal B, et al. Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: a Pediatric Oncology Group study. J Clin Oncol. 1994;12:1383-1389[Abstract].
17.
Lange BJ, Bostrom BC, Cherlow JM, Sensel MG, La MK, Rackoff W, Heerema NA, Wimmer RS, Trigg ME, Sather HN.
Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.
Blood.
2002;99:825-833
18.
Uckun FM, Muraguchi A, Ledbetter JA, et al.
Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues.
Blood.
1989;73:1000-1015 19. Duttera MJ, Carolla RL, Gallelli JF, Gullion DS, Keim DE, Henderson ED. Hematuria and crystalluria after high-dose 6-mercaptopurine administration. N Engl J Med. 1972;287:292-294[Medline] [Order article via Infotrieve].
20.
Heerema NA, Sather HN, Sensel MG, et al.
Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes).
J Clin Oncol.
2000;18:1876-1887 21. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY: John Wiley and Sons; 1980. 22. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 23. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples. Br J Cancer. 1977;35:1-39[Medline] [Order article via Infotrieve]. 24. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220. 25. Gaynon PS, Carrel AL. Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol. 1999;457:593-605[Medline] [Order article via Infotrieve]. 26. Ekert H, Waters KD, Matthews RN, et al. A randomized study of corticosteroid and non-corticosteroid containing regimens in induction therapy of childhood ALL. Cancer Therapy and Control. 1990;1:87-95. 27. Henze G, Langermann HJ, Fengler R, et al. Acute lymphoblastic leukemia therapy study BFM 79/81 in children and adolescents: intensified reinduction therapy for patients with different risks for relapse. Klin Padiatr. 1982;194:195-203[Medline] [Order article via Infotrieve]. 28. Henze G, Fengler R, Reiter A, Ritter J, Riehm H. Impact of early intensive reinduction therapy on event-free survival in children with low-risk acute lymphoblastic leukemia. Hamatol Bluttransfus. 1990;33:483-438[Medline] [Order article via Infotrieve]. 29. Gaynon PS, Bostrom BC, Reaman GH, et al. Children's Cancer Group (CCG) initiatives in childhood acute lymphoblastic leukemia. Int J Pediatr Hematol Oncol. 1998;5:99-114. 30. Hann I, Vora A, Richards S, et al. Benefit of intensified treatment for all children with acute lymphoblastic leukaemia, results from MRC UKALL XI and MRC ALL97 randomised trials: UK Medical Research Council's Working Party on Childhood Leukaemia. Leukemia. 2000;14:356-363[CrossRef][Medline] [Order article via Infotrieve].
31.
Cantrill HL, Waltman SR, Palmberg PF, Zink HA, Becker B.
In vitro determination of relative corticosteroid potency.
J Clin Endocrinol Metab.
1975;40:1073-1077 32. Ito C, Evans WE, McNinch L, et al. Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol. 1996;14:2370-2376[Abstract]. 33. Kaspers GJ, Veerman AJ, Popp-Snijders C, et al. Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 1996;27:114-121[CrossRef][Medline] [Order article via Infotrieve]. 34. Meikle AW, Tyler FH. Potency and duration of action of glucocorticoids: effects of hydrocortisone, prednisone and dexamethasone on human pituitary-adrenal function. Am J Med. 1977;63:200-207[CrossRef][Medline] [Order article via Infotrieve]. 35. Hurwitz CA, Silverman LB, Schorin MA, et al. Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer. 2000;88:1964-1969[CrossRef][Medline] [Order article via Infotrieve].
36.
Mattano LA Jr, Sather HN, Trigg ME, Nachman JB.
Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group.
J Clin Oncol.
2000;18:3262-3272 37. Tan ML, Kardos G, Veerman AJP, van der Does-van den Berg A, Kamps WA. Avascular osteonecrosis as side effect of treatment in childhood ALL may not be dependent upon dexamethasone dose. Med Pediatr Oncol. 1999;33:246. 38. Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and mineral abnormalities in childhood acute lymphoblastic leukemia: influence of disease, drugs and nutrition. Int J Cancer Suppl. 1998;11:35-39[Medline] [Order article via Infotrieve].
39.
Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB.
Bony morbidity in children treated for acute lymphoblastic leukemia.
J Clin Oncol.
2001;19:3066-3072 40. Macdonald DR. Neurologic complications of chemotherapy. Neurol Clin. 1991;9:955-967[Medline] [Order article via Infotrieve].
41.
Dropcho EJ, Soong SJ.
Steroid-induced weakness in patients with primary brain tumors.
Neurology.
1991;41:1235-1239 42. Shuster J. Psychiatric complications of corticosteroids. Nursing. 1999;29:31[Medline] [Order article via Infotrieve]. 43. Sutor B, Wells LA, Rummans TA. Steroid-induced depressive psychosis responsive to electroconvulsive therapy. Convuls Ther. 1996;12:104-107[Medline] [Order article via Infotrieve]. 44. Wolkowitz OM. Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology. 1994;19:233-255[CrossRef][Medline] [Order article via Infotrieve]. 45. Waber DP, Carpentieri SC, Klar N, et al. Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol. 2000;22:206-213[CrossRef][Medline] [Order article via Infotrieve]. 46. Loring DW, Meador KJ. Corticosteroids and cognitive function in humans: methodological considerations. J Pediatr Hematol Oncol. 2000;22:193-196[CrossRef][Medline] [Order article via Infotrieve].
47.
Pinkel D.
Intravenous mercaptopurine: life begins at 40.
J Clin Oncol.
1993;11:1826-1831 48. Pieters R, Huismans DR, Loonen AH, et al. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet. 1991;338:399-403[CrossRef][Medline] [Order article via Infotrieve]. 49. Lennard L, Rees CA, Lilleyman JS, Maddocks JL. Childhood leukaemia: a relationship between intracellular 6-mercaptopurine metabolites and neutropenia. Br J Clin Pharmacol. 1983;16:359-363[Medline] [Order article via Infotrieve]. 50. Silberman T, Robison LL, Nesbit ME. Association between outcome in childhood acute lymphoblastic leukemia and amount of maintenance 6-mercaptopurine. Proc Amer Soc Clin Oncol. 1985;4:166.
51.
Dolan G, Lilleyman JS, Richards SM.
Prognostic importance of myelosuppression during maintenance treatment of lymphoblastic leukaemia: Leukaemia in Childhood Working Party of the Medical Research Council.
Arch Dis Child.
1989;64:1231-1234
52.
Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE.
Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.
Blood.
1999;93:2817-2823 53. Van Eys J, Berry D, Crist W, et al. Treatment intensity and outcome for children with acute lymphocytic leukemia of standard risk: a Pediatric Oncology Group Study. Cancer. 1989;63:1466-1471[CrossRef][Medline] [Order article via Infotrieve]. 54. Kamen BA. Why more 6-mercaptopurine? Semin Hematol. 1991;28:12-14[Medline] [Order article via Infotrieve].
55.
Mahoney DH Jr, Shuster J, Nitschke R, et al.
Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial.
J Clin Oncol.
1998;16:246-254 56. Van der Werff Ten Bosch J, Suciu S, Philippe N, et al. The value of 6-MP i.v. during maintenance treatment in childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL): results of the randomized phase III trial 58881 of the EORTC Childhood Leukemia Cooperative Group (CLCG). Blood. 1999;94:628a. 57. Tolar J, Bostrom BC, Lee M, Sather H. Oral 6-mercaptopurine protects against fatal relapses in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group study CCG 1922. J Pediatr Hematol Oncol. 2000;22:378.
58.
Presta M, Rusnati M, Belleri M, Morbidelli L, Ziche M, Ribatti D.
Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process.
Cancer Res.
1999;59:2417-2424
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  C.-H. Pui, D. Campana, D. Pei, W. P. Bowman, J. T. Sandlund, S. C. Kaste, R. C. Ribeiro, J. E. Rubnitz, S. C. Raimondi, M. Onciu, et al. Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation N. Engl. J. Med., June 25, 2009; 360(26): 2730 - 2741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. S. Kadan-Lottick, I. Dinu, K. Wasilewski-Masker, S. Kaste, L. R. Meacham, A. Mahajan, M. Stovall, Y. Yasui, L. L. Robison, and C. A. Sklar Osteonecrosis in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study J. Clin. Oncol., June 20, 2008; 26(18): 3038 - 3045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. French, L. H. Hamilton, L. A. Mattano Jr, H. N. Sather, M. Devidas, J. B. Nachman, and M. V. Relling A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group Blood, May 1, 2008; 111(9): 4496 - 4499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Moricke, A. Reiter, M. Zimmermann, H. Gadner, M. Stanulla, M. Dordelmann, L. Loning, R. Beier, W.-D. Ludwig, R. Ratei, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95 Blood, May 1, 2008; 111(9): 4477 - 4489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Sanford, J. O. Okuma, J. Pan, D. K. Srivastava, N. West, L. Farr, and P. S. Hinds Gender Differences in Sleep, Fatigue, and Daytime Activity in a Pediatric Oncology Sample Receiving Dexamethasone J. Pediatr. Psychol., April 1, 2008; 33(3): 298 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Relling, W. E. Evans, and C.-H. Pui Continue to study childhood ALL Blood, January 1, 2008; 111(1): 468 - 469. [Full Text] [PDF]
|
|
|
|
|
|
S. Malempati, P. S. Gaynon, H. Sather, M. K. La, and L. C. Stork Outcome After Relapse Among Children With Standard-Risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study CCG-1952 J. Clin. Oncol., December 20, 2007; 25(36): 5800 - 5807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Felder-Puig, C. Scherzer, M. Baumgartner, M. Ortner, C. Aschenbrenner, C. Bieglmayer, T. Voigtlander, E. R. Panzer-Grumayer, W. J.E. Tissing, J. W. Koper, et al. Glucocorticoids in the Treatment of Children with Acute Lymphoblastic Leukemia and Hodgkin's Disease: A Pilot Study on the Adverse Psychological Reactions and Possible Associations with Neurobiological, Endocrine, and Genetic Markers Clin. Cancer Res., December 1, 2007; 13(23): 7093 - 7100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Rowe and A. H. Goldstone How I treat acute lymphocytic leukemia in adults Blood, October 1, 2007; 110(7): 2268 - 2275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Feusner "Lesser" ALL: treat less or study less? Blood, August 15, 2007; 110(4): 1086 - 1086. [Full Text] [PDF]
|
|
|
|
|
|
A. R. Chauvenet, P. L. Martin, M. Devidas, S. B. Linda, B. A. Bell, J. Kurtzberg, J. Pullen, M. J. Pettenati, A. J. Carroll, J. J. Shuster, et al. Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201 Blood, August 15, 2007; 110(4): 1105 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Butturini, F. J. Dorey, B. J. Lange, D. W. Henry, P. S. Gaynon, C. Fu, J. Franklin, S. E. Siegel, N. L. Seibel, P. C. Rogers, et al. Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia J. Clin. Oncol., May 20, 2007; 25(15): 2063 - 2069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Niinimaki, A. H. Harila-Saari, A. E. Jartti, R. M. Seuri, P. V. Riikonen, E. L. Paakko, M. I. Mottonen, and M. Lanning High Body Mass Index Increases the Risk for Osteonecrosis in Children With Acute Lymphoblastic Leukemia J. Clin. Oncol., April 20, 2007; 25(12): 1498 - 1504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Karimova, S. N. Rai, S. C. Howard, M. Neel, L. Britton, C.-H. Pui, and S. C. Kaste Femoral Head Osteonecrosis in Pediatric and Young Adult Patients With Leukemia or Lymphoma J. Clin. Oncol., April 20, 2007; 25(12): 1525 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Schultz, D. J. Pullen, H. N. Sather, J. J. Shuster, M. Devidas, M. J. Borowitz, A. J. Carroll, N. A. Heerema, J. E. Rubnitz, M. L. Loh, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) Blood, February 1, 2007; 109(3): 926 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Stock and N. L. Seibel Acute lymphoblastic leukemia and lymphoblastic lymphoma ASH Self-Assessment Program, January 1, 2007; 2007(1): 253 - 264. [Full Text] [PDF]
|
|
|
|
|
|
Y. Matloub, S. Lindemulder, P. S. Gaynon, H. Sather, M. La, E. Broxson, R. Yanofsky, R. Hutchinson, N. A. Heerema, J. Nachman, et al. Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group Blood, August 15, 2006; 108(4): 1165 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Karimova, S. N. Rai, X. Deng, D. J. Ingle, A. C. Ralph, M. D. Neel, and S. C. Kaste MRI of Knee Osteonecrosis in Children with Leukemia and Lymphoma: Part 1, Observer Agreement Am. J. Roentgenol., February 1, 2006; 186(2): 470 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui and W. E. Evans Treatment of Acute Lymphoblastic Leukemia N. Engl. J. Med., January 12, 2006; 354(2): 166 - 178. [Full Text] [PDF]
|
|
|
|
 |
|
 A. J Murphy, J. C. Wells, J. E Williams, M. S Fewtrell, P. S. Davies, and D. K Webb Body composition in children in remission from acute lymphoblastic leukemia Am. J. Clinical Nutrition, January 1, 2006; 83(1): 70 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Pui Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment Hematology, January 1, 2006; 2006(1): 142 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Jabbour, S. Faderl, and H. M. Kantarjian Adult Acute Lymphoblastic Leukemia Mayo Clin. Proc., November 1, 2005; 80(11): 1517 - 1527. [Abstract] [PDF]
|
|
|
|
|
|
S. Igarashi, A. Manabe, A. Ohara, M. Kumagai, T. Saito, Y. Okimoto, T. Kamijo, K. Isoyama, M. Kajiwara, M. Sotomatsu, et al. No Advantage of Dexamethasone Over Prednisolone for the Outcome of Standard- and Intermediate-Risk Childhood Acute Lymphoblastic Leukemia in the Tokyo Children's Cancer Study Group L95-14 Protocol J. Clin. Oncol., September 20, 2005; 23(27): 6489 - 6498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Pine, C. Yin, Y. H. Matloub, H. E. Sabaawy, C. Sandoval, O. Levendoglu-Tugal, M. F. Ozkaynak, and S. Jayabose Detection of Central Nervous System Leukemia in Children with Acute Lymphoblastic Leukemia by Real-Time Polymerase Chain Reaction J. Mol. Diagn., February 1, 2005; 7(1): 127 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. DeAngelo The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia Hematology, January 1, 2005; 2005(1): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui, J. T. Sandlund, D. Pei, D. Campana, G. K. Rivera, R. C. Ribeiro, J. E. Rubnitz, B. I. Razzouk, S. C. Howard, M. M. Hudson, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital Blood, November 1, 2004; 104(9): 2690 - 2696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Relling, W. Yang, S. Das, E. H. Cook, G. L. Rosner, M. Neel, S. Howard, R. Ribeiro, J. T. Sandlund, C.-H. Pui, et al. Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia J. Clin. Oncol., October 1, 2004; 22(19): 3930 - 3936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Hawkins, J. R. Park, B. G. Thomson, J. L. Felgenhauer, J. S. Holcenberg, E. H. Panosyan, and V. I. Avramis Asparaginase Pharmacokinetics After Intensive Polyethylene Glycol-Conjugated L-Asparaginase Therapy for Children with Relapsed Acute Lymphoblastic Leukemia Clin. Cancer Res., August 15, 2004; 10(16): 5335 - 5341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui, M. Schrappe, R. C. Ribeiro, and C. M. Niemeyer Childhood and Adolescent Lymphoid and Myeloid Leukemia Hematology, January 1, 2004; 2004(1): 118 - 145. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
