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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Pediatric Oncology and
Biostatistical Science, Dana-Farber Cancer Institute (DFCI); the
Division of Hematology/Oncology, Children's Hospital; the Department
of Pediatrics, Harvard Medical School, Boston, MA; the Department of
Hematology/Oncology, University of Rochester Medical Center, Rochester,
NY; the Department of Pediatrics, McMaster University Medical Center,
Hamilton, Ontario, Canada; the San Jorge Children's Hospital, San
Juan, Puerto Rico; the Maine Children's Cancer Program, The Barbara
Bush Children's Hospital at Maine Medical Center, Portland, ME; the
Hospital Saint Justine, Montreal, and the Le Centre Hospitalier de
L'Universite, Laval, Quebec, Canada; the Department of Pediatrics,
Oschsner Institutions, New Orleans, LA; the Schneider Children's
Hospital, New Hyde Park, NY; and the Department of Pediatrics, Stanford
University School of Medicine, Palo Alto, CA.
The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic
leukemia (ALL) Consortium Protocol 91-01 was designed to improve the
outcome of children with newly diagnosed ALL while minimizing toxicity.
Compared with prior protocols, post-remission therapy was intensified
by substituting dexamethasone for prednisone and prolonging the
asparaginase intensification from 20 to 30 weeks. Between 1991 and
1995, 377 patients (age, 0-18 years) were enrolled; 137 patients were
considered standard risk (SR), and 240 patients were high risk (HR).
Following a 5.0-year median follow-up, the estimated 5-year
event-free survival (EFS) ± SE for all patients was 83% ± 2%,
which is superior to prior DFCI ALL Consortium protocols conducted
between 1981 and 1991 (P = .03). There was no significant difference in 5-year EFS based upon risk group (87% ± 3% for SR and 81% ± 3% for HR, P = .24). Age at diagnosis was
a statistically significant prognostic factor (P = .03),
with inferior outcomes observed in infants and children 9 years or
older. Patients who tolerated 25 or fewer weeks of asparaginase had a
significantly worse outcome than those who received at least 26 weeks
of asparaginase (P < .01, both univariate and
multivariate). Older children (at least 9 years of age) were
significantly more likely to have tolerated 25 or fewer weeks of
asparaginase (P < .01). Treatment on
Protocol 91-01 significantly improved the outcome of children with ALL, perhaps due to the prolonged asparaginase intensification and/or the
use of dexamethasone. The inferior outcome of older children may be
due, in part, to increased intolerance of intensive therapy.
(Blood. 2001;97:1211-1218) During the last decade investigators have
reported favorable outcomes for children with acute lymphoblastic
leukemia (ALL), with long-term event-free survival rates for unselected
patient populations ranging from 60% to 80%.1-4 Advances
in the treatment of childhood ALL have resulted from clinical trials
conducted by several multi-institutional groups. The Dana-Farber Cancer Institute (DFCI) ALL Consortium has conducted such trials since 1981. Treatment strategies include intensive, multi-agent induction therapy;
early intensification with weekly, high-dose asparaginase; frequent
pulses of vincristine and corticosteroids during continuation therapy;
and for high-risk (HR) patients, doxorubicin during intensification. We
have previously reported a 7-year overall event-free survival (EFS)
rate of 78% for children with ALL treated between 1985 and 1987.5 Acute toxicities from our treatment approach
include asparaginase-related allergic events and
pancreatitis.5,6 In long-term survivors we have observed
asymptomatic echocardiographic changes related to anthracycline
exposure7 as well as short stature and learning
disabilities of varying severity, presumably secondary to central
nervous system (CNS)-directed therapy.8
DFCI ALL Consortium Protocol 91-01 was open for enrollment between 1991 and 1995. The objective of the protocol was to improve outcome
while minimizing toxicity. Based upon the reports of other investigators that high-dose intravenous (IV) 6-mercaptopurine (6-MP)
improved the outcome of patients with B-lineage
ALL,9,10 Protocol 91-01 randomized patients to receive
pulses of either high-dose IV 6-MP or standard-dose oral 6-MP during
the first year of post-remission therapy. In addition, for all
patients, dexamethasone was substituted for prednisone during
post-remission therapy based upon in vitro and in vivo data, which
demonstrated that the former was associated with increased antileukemia
activity and enhanced CNS penetration.11-14 Also, the
duration of high-dose asparaginase intensification was extended from 20 weeks (in prior protocols) to 30 weeks. Patients participated in 3 additional randomizations designed to evaluate whether acute and late
toxicities could be reduced. The randomizations included a comparison
of (1) 2 asparaginase preparations, native and
polyethylene-glycosylated (PEG) Escherichia coli
asparaginase; (2) 2 doxorubicin infusion rates, continuous infusion and
bolus; and (3) 2 dosing schedules of cranial radiation (once daily and
twice daily fractionation). We report here the treatment outcome
results for DFCI ALL Consortium Protocol 91-01 at 5 years of median
follow-up.
Patients
Patients were enrolled from the following consortium institutions:
DFCI/Children's Hospital (Boston, MA), Hospital Saint Justine (Montreal, Quebec, Canada), University of Rochester Medical Center (Rochester, NY), McMaster University Medical Center (Hamilton, Ontario,
Canada), San Jorge Children's Hospital (San Juan, Puerto Rico), Maine
Children's Cancer Program (Portland, ME), University of Massachusetts
(Worcester, MA), Mount Sinai Medical Center (New York, NY), Le Centre
Hospitalier de L'Universite (Laval, Quebec, Canada) and Oschner
Institutions (New Orleans, LA). The institutional review boards of each
participating institution approved the protocol prior to
patient enrollment.
Therapy
Details of therapy are shown in Table 1.
For SR and HR patients, CNS therapy commenced during the first cycle of
intensification therapy. During that cycle, asparaginase and
dexamethasone were not administered. Cranial radiation was delivered to
SR boys and all HR patients. The dose of radiation was 1800 cGy, except
for those with CNS leukemia at diagnosis (CNS-2 or CNS-3), all of whom
received 1980 cGy. SR girls did not receive cranial radiation. Infant
HR patients received an additional month of intensive chemotherapy immediately after the remission induction phase, which included high-dose cytarabine and high-dose methotrexate.15 Cranial
radiation was delayed until 12 months of age.
Asparaginase preparation was switched after a mild allergic event (local reaction, rash). Patients receiving E coli asparaginase were switched to weekly PEG asparaginase, and those receiving PEG were switched to E coli asparaginase to complete 30 weeks of therapy. All patients were switched to twice-weekly Erwinia asparaginase (25 000 IU/m2 per dose) if they experienced a subsequent allergic event. Asparaginase therapy was held until resolution of mild pancreatitis or deep venous thrombosis, and the therapy was permanently stopped after severe allergic events (bronchospasm and/or lip or tongue swelling), severe pancreatitis (abdominal pain for at least 72 hours with elevated pancreatic enzymes), CNS thrombosis, or mild allergic events to all 3 preparations (E coli, PEG, and Erwinia). Therapy for all patients was discontinued after patients had achieved 24 months of continuous complete remission (CCR). Randomizations Patients were eligible to participate in the following 5 randomizations. All randomizations were performed centrally and occurred following enrollment, prior to the initiation of therapy.Investigational window. To determine differences in early leukemic cell kill, patients were randomized to receive one of 4 possible 3-day courses of corticosteroids prior to the initiation of multi-agent remission induction therapy: 40 mg/m2/d prednisolone or 6, 18, or 150 mg/m2/d dexamethasone. Asparaginase. To determine whether PEG asparaginase was associated with decreased toxicity, patients were randomized to receive either 2500 IU/m2 PEG asparaginase intramuscularly (IM) every other week for 15 doses or native 25 000 IU/m2 E coli asparaginase IM every week for 30 doses during the intensification phase of therapy. Because PEG asparaginase was not available in Canada, children treated at Canadian institutions (n = 127) were not eligible for the asparaginase randomization and were directly assigned to receive E coli L-asparaginase during intensification. 6-MP. To determine whether high-dose IV 6-MP would improve outcome, all patients were randomized to receive either (1) high-dose 1000 mg/m2 IV 6-MP delivered as a continuous infusion for 20 hours on weeks 1 and 2 of every 3-week chemotherapy cycle or (2) conventional 50 mg/m2/d oral 6-MP on days 1-14 of every 3-week cycle during the first year of post-remission therapy. Doxorubicin. To determine if continuous infusion doxorubicin was associated with a decreased incidence of late echocardiographic abnormalities, HR patients were randomized to receive doxorubicin either as a 48-hour continuous infusion or as a conventional IV bolus for 15 minutes during intensification. Cranial radiation. To determine whether hyperfractionated radiation was associated with a decreased incidence of neuropsychologic sequelae, those patients receiving cranial radiation (SR boys and all HR patients, including infants) were randomized to receive either twice-daily fractions of 90 cGy (hyperfractionated) or once-daily fractions of 180 cGy (conventional). Immunophenotype and cytogenetics BM cells from diagnostic aspirates were examined for cell surface antigens using standard indirect immunofluorescence assays and were cultured for cytogenetic analyses as previously described.15Statistical analysis Fisher exact tests were used to compare presenting characteristics among patient groups.16 Outcome events were death during induction therapy, failure to achieve complete remission (defined as persistent leukemia at day 52 after diagnosis), death during remission, and relapse. EFS was the time from complete remission to the first outcome event; induction failure and induction deaths were considered events at time zero. Leukemia-free survival (LFS) was the time from complete remission to relapse; induction failure was considered a relapse at time zero. Overall survival (OS) was the time from start of treatment to death from any cause. CNS LFS was the time from complete remission to a relapse involving the CNS (whether isolated or combined with other sites).EFS, LFS, and OS were estimated using the Kaplan-Meier method,17 and the Greenwood formula was used to calculate SE.18 Univariate analyses of differences in EFS, LFS, and OS were conducted with log-rank tests.19 Multiple regression was conducted using Cox proportional hazards regression models to assess prognostic factors for EFS, LFS, and OS.20 To determine the impact of a patient's ability to tolerate asparaginase on outcome, a landmark analysis was conducted21 that included all patients with non-Ph+chromosome who were alive and event-free 40 weeks after diagnosis. Primary randomized efficacy comparison was defined prospectively as the standard-dose versus high-dose 6-MP, and planned sample size was determined based upon this randomization. Recruitment and evaluation of 360 evaluable patients was required to detect a 45% reduction in the risk of an event with 80% power using a 2-sided 0.05 level test. Given smaller sample sizes available for other randomizations (lack of availability of PEG asparaginase in Canada, HR patients only in doxorubicin randomization, and SR girls excluded from radiation randomization), the other randomized comparisons were designed to detect reductions in toxicities. Specifically, the asparaginase randomization had 80% power to detect a reduction in the risk of toxic reaction from 20% to 8%. The doxorubicin randomization had an 80% power to detect a reduction in the incidence of echocardiographic abnormalities in long-term survivors from 50% to 25% (2-sided 0.05 level test for both). The radiation randomization had 80% power to detect a reduction in the incidence of neuropsychologic sequelae from 40% to 20% and 80% power to detect differences in CNS relapse rate (5% vs 13%) in HR patients (2-sided 0.05 level test for both).
Patient characteristics The presenting clinical characteristics of the 377 evaluable patients are summarized in Table 2. We classified 240 (64%) patients as HR (including 7 infants); the remaining 137 (36%) patients were classified as SR. Age at diagnosis ranged from 55 days to 17.9 years, with a median of 4.4 years. Initial WBC count ranged from 0.7 to 1076.4 × 109 cells per L (700 to 1 076 400 cells per µL), with a median leukocyte count of 9.8 × 109 cells per L (9800 cells per µL).
Treatment results The outcome of the 377 patients is presented in Table 3. As of November 1999, median follow-up was 5.0 years. There were 370 (98%) patients who achieved CR. Of the 7 patients who failed to achieve CR, 5 had persistent leukemia, and 2 patients died of sepsis. Nine (2%) patients experienced a remission death during chemotherapy, including 4 of 137 SR patients (all of sepsis) and 5 of 240 HR/infant HR patients (sepsis, n = 3; Pneumocystis carinii pneumonia, n = 1; and unknown, n = 1). Three (1%) other patients died in CR due to BMT-related toxicities (Ph+ chromosome, n = 2, and one infant). All remission deaths occurred in patients aged less than 9 years. There were 46 (12%) patients who relapsed and 312 (84%) patients who remained in CCR.
The estimated 5-year EFS ± SE was 83% ± 2% for the 377 children
treated on Protocol 91-01 (Table 3 and Figure
1). The 5-year EFS estimate according to
the risk group was 87% ± 3% for SR patients and 81% ± 3% for
HR patients (Figure 2). The difference in
EFS between SR and HR patients was not statistically significant
(P = .24). Excluding 7 infants and 6 patients with
Ph+-chromosome disease, the 5-year EFS for the remaining
227 HR patients was 82% ± 3%. The estimated 5-year CNS LFS by risk
group was 98% ± 1% for SR patients and 96% ± 1% for HR
patients.
We also retrospectively analyzed outcome according to the age and leukocyte count criteria proposed by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI), Bethesda, MD.20 By those criteria, the estimated 5-year EFS for 243 patients with standard-risk B-precursor ALL (age, between 1 and 10 years, and initial WBC count, 50 × 109 cells per L [less than 50 000 cell per µL]) was 85% ± 2%, and the EFS for 99 patients with high-risk B-precursor ALL (age, at least 10 years, and/or initial WBC count, 50 × 109 cells per L [at least 50 000 cells per µL]) was 82% ± 4%. For 28 noninfant patients with T-lineage ALL, the estimated 5-year EFS was 79% ± 8%. For 7 infants, the estimated 5-year EFS was 71% ± 17%. There was no significant difference in EFS comparing the 4 groups based upon NCI risk group criteria (P = .66). Special patient subgroups All 6 patients with Ph+-chromosome ALL achieved CR and subsequently were treated with an allogeneic BMT in first CR. Two patients received transplantations from human leukocyte antigen (HLA)-matched sibling donors, one from a mismatched parent, and 3 from matched unrelated donors. Transplants occurred between 3-10 months after diagnosis. Two patients died of BMT-related toxicities, one patient relapsed after transplantation, and 3 patients remained alive in CCR. The estimated 5-year EFS for Ph+-chromosome patients was 50% ± 20%.None of the 7 infants treated on Protocol 91-01 relapsed. One died in first CR of P carinii pneumonitis. Another was removed from protocol by his treating physician, received a matched unrelated donor BMT in first CR, and died of BMT-related toxicity. Five infants remained alive in CCR, with an estimated 5-year EFS of 71% ± 17%. Prognostic factors The results of the univariate analysis of prognostic factors for patients treated on Protocol 91-01 are presented in Table 2. Only age at diagnosis was a statistically significant prognostic factor (P = .03). The best outcome was achieved by those patients aged 12-23 months at diagnosis (n = 33), all of whom were classified and treated as HR, with a 5-year EFS of 97% ± 3%. The 5-year EFS of patients aged 12 months to less than 9 years was significantly superior to those aged 9-18 years (86% ± 2% vs 77% ± 5%; P = .03), as was the 5-year LFS (89% ± 2% vs 79% ± 5%; P = .01).Risk group status (defined either by DFCI or NCI criteria), initial WBC count, sex, immunophenotype, and CNS status at the time of diagnosis were not statistically significant predictors of EFS. For the 207 patients on whom cytogenetic data were obtained, there was no significant difference in outcome based upon the number of chromosomes present in blast cells at diagnosis (ploidy). In multiple regression models, including age, WBC count, sex, and immunophenotype, age was the only significant factor predicting EFS, LFS, and OS (P = .02, P = .01, and P = .004, respectively). EFS according to randomizations There were no significant differences in presenting features among randomized patients compared with nonrandomized patients or between randomized groups (data not shown). As shown in Table 4, there was no difference in EFS of randomized patients based upon investigational window corticosteroid (P = .73), asparaginase preparation (P = .29), 6-MP dosing (P = .90), or doxorubicin infusion rate (P = .23). For HR patients, the 5-year EFS and LFS were lower for those randomized to receive hyperfractionated cranial radiation (P = .05 and P = .02, respectively), although there was no difference in CNS LFS based upon randomized radiation schedule (P = .24). For SR males, there was no difference in EFS, LFS, or CNS LFS based upon CNS radiation randomization (P = .84, P = .79, and P = .36, respectively).
Toxicities Asparaginase-related toxicities were observed in 29% of the 377 patients. The most frequent toxicities included allergic reactions (15%), pancreatitis (7%), and coagulopathy (defined as thromboses or clinical bleeding) (4.5%). One percent of the patients experienced a CNS thrombosis. Patients aged 9-18 years were more likely to experience an asparaginase-related toxicity compared with those less than 9 years (48% vs 24%; P < .01). Patients aged 9-18 years had a higher incidence of pancreatitis than younger patients (15% vs 5%; P < .01). The older patients also had a higher incidence of thromboses, including strokes (15% vs 2%; P < .01), but not allergic events (14% vs 16%; P = 1.00). Of the patients randomized to PEG asparaginase, 25% experienced a toxic reaction compared with 36% of E coli-randomized patients (P = .09). PEG asparaginase was associated with a lower incidence of mild allergic reactions (P = .02). There was no difference between the 2 preparations in the rates of dose-limiting toxicities such as severe allergic reaction (P = .22), severe pancreatitis (P = .78), or CNS thrombosis (P = 1.00).There were 59 (16%) patients who experienced at least one bone fracture on therapy. There were no second malignancies or overt congestive heart failure observed in any patient. Follow-up time was insufficient to assess late CNS toxicity including growth parameters and neuropsychologic functioning as well as the incidence of late cardiac toxicity. Data regarding other toxicities, such as the incidence of seizures and osteonecrosis, were not prospectively collected. Asparaginase intolerance and outcome We analyzed the outcome of patients who were alive and in CR 40 weeks after diagnosis (and thus potentially could have received all 30 weeks of asparaginase intensification therapy) to determine whether asparaginase allergy and/or intolerance impacted subsequent outcome. Of the 352 patients included in the analysis, 54 (15%) patients experienced one or more allergic events. There was no difference in EFS when comparing those patients who developed an asparaginase allergy with those who did not (P = .31).Of the 352 patients, 43 (12%) patients received less than 25 weeks of asparaginase. The remaining 308 (88%) patients received at least 26 weeks of asparaginase. Of the 43 patients who received less than 25 weeks of asparaginase, 37 (86%) patients experienced an asparaginase-related dose-limiting toxicity including pancreatitis (39% of 43 patients), allergy to one or more preparations (19%), CNS thrombosis/hemorrhage (12%), non-CNS deep venous thrombosis (7%), hyperglycemia (5%), hyperlipidemia (2%), and hepatitis (2%). Six (14%) patients received truncated therapy for other reasons including 2 patients with toxicities not clearly related to asparaginase (parasthesias and sepsis), 2 patients with non-protocol alteration in therapy, and 2 patients for unknown reasons. Asparaginase intolerance was associated with older age at diagnosis, but not with initial type of asparaginase (PEG or native E coli). Of 76 patients aged 9-18 years, 18 (24%) patients received less than 25 weeks of asparaginase compared with 25 (9%) of 276 patients less than 9 years of age (P < .01). The 5-year EFS of patients who received less than 25 weeks of asparaginase therapy was significantly worse than those who received at least 26 weeks of asparaginase (73% ± 7% vs 90% ± 2%; P < .01) (Table 2). In multivariate Cox-proportional hazards model, including covariates for asparaginase intolerance, age, presenting WBC count, and immunophenotype, asparaginase intolerance was the only prognostically significant factor predicting EFS (P < .01). Comparison with prior DFCI Consortium protocols We compared EFS and LFS of patients treated on Protocol 91-01 with those achieved by patients treated on the 3 prior protocols conducted by the DFCI Consortium between 1981 and 1995. Details of Protocols 81-01 and 85-01 have been previously published.5,6 Risk group classification and presenting features were similar in all 4 protocols (Table 5). There was no significant difference in remission death rates (P = .74). EFS was significantly different when comparing the 4 protocols (P = .03), with the EFS and LFS for patients treated on Protocol 91-01 superior to those achieved by patients treated on prior DFCI ALL Consortium protocols conducted between 1981 and 1991 (P = .03 for EFS and P = .02 for LFS comparisons). The differences in EFS and LFS remained statistically significant when stratified by risk group (P = .03 and P = .02, respectively). EFS of Protocol 91-01 was significantly greater than Protocol 81-01 (P < .01), and there was a trend toward improved EFS on 91-01 that did not reach statistical significance when compared individually to Protocols 85-01 (P = .37) and 87-01 (P = .16).
Children with ALL treated on Protocol 91-01 had a superior outcome to those treated on prior DFCI ALL Consortium protocols. The estimated 5-year EFS ± SE rate of 83% ± 2% is also superior to results reported by other investigators for similar groups of unselected patients with ALL.1-3 We also observed a significant improvement in LFS achieved on Protocol 91-01 compared to prior protocols, indicating that the superior outcome was not simply due to a reduction in remission deaths associated with advances in supportive care during the last decade. We have previously demonstrated that early post-remission intensification with high-dose asparaginase improved outcome.22 On Protocol 91-01, duration of asparaginase intensification was extended from 20 to 30 weeks. Asparaginase intolerance (failure to receive at least 26 weeks of asparaginase) was an independent predictor of adverse outcome on multivariate analysis, suggesting that the prolongation of asparaginase therapy may have contributed to the improved outcome on Protocol 91-01. A prospective randomized trial comparing 20 versus 30 weeks of asparaginase intensification is necessary to confirm this finding. Although PEG asparaginase decreased the rate of mild allergic reactions, it was not associated with a decreased incidence of dose-limiting toxicities nor with improved outcome. Alternative asparaginase preparations or dosing strategies may mitigate severe toxicities, thereby allowing a greater proportion of patients to tolerate the extended intensification phase and improving outcome. The other major differences between Protocol 91-01 and prior DFCI ALL Consortium protocols was the use of dexamethasone instead of prednisone during post-remission therapy and the inclusion of 5 randomized studies. None of the investigational arms of the randomized studies were associated with a statistically significant superior outcome, although, by design, only the 6-MP randomization (high versus low) was powered sufficiently to detect EFS differences. The use of dexamethasone may have contributed to the improved outcome on Protocol 91-01, as other investigators have reported that dexamethasone has more potent in vitro antileukemic activity, higher free plasma levels, and enhanced CSF penetration, and dexamethasone may be more effective than prednisone or prednisolone in the treatment of childhood ALL.12,14,23,24 The relative toxicities of dexamethasone and prednisone have not been fully elucidated in patients with ALL. We have reported that the substitution of dexamethasone for prednisone during remission induction was associated with a high incidence of septic episodes and deaths25 and that post-remission dexamethasone may be associated with more severe neurocognitive late effects.26 The Children's Cancer Group recently reported a 9.3% incidence of osteonecrosis in patients treated with both prednisone and dexamethasone, with higher rates noted in patients receiving higher cumulative doses of dexamethasone.27 The incidence of osteonecrosis was not prospectively collected on Protocol 91-01, although we observed that 16% of patients experienced a fracture. We are currently conducting a prospective randomized comparison of dexamethasone and prednisone that could help clarify their relative efficacy and toxicity in the treatment of childhood ALL. We observed a very low CNS relapse rate, with a 5-year CNS LFS rate of 98% in SR patients and 96% in HR patients. All patients except SR girls (80% of patients) received 1800 cGy cranial radiation. SR boys received cranial radiation because we had observed a higher-than-expected CNS relapse rate in this population when they were treated without radiation on a prior protocol. Other investigators have successfully used alternative CNS treatment strategies including the use of high-dose antimetabolite therapy and/or intensive intrathecal chemotherapy in lower risk patients4,23,28,29 and lower cranial radiation doses (12 Gy) in higher risk patients.30 Although such treatments may offer comparable efficacy as conventionally fractionated 1800 cGy cranial radiation, the relative long-term neuropsychological sequelae of the various CNS treatment strategies remains unsettled.8,31,32 On Protocol 91-01 we investigated whether hyperfractionated cranial radiation might reduce late effects without compromising efficacy. While longer follow-up is needed to assess late effects, the use of hyperfractionated radiation therapy in HR patients was associated with an inferior outcome due to a higher marrow relapse rate, but not a higher CNS relapse rate. At this time we do not have an explanation for this unexpected finding. Currently, we are using intensive intrathecal therapy (without cranial radiation) in all SR patients. We have also adopted NCI age and WBC criteria to risk-stratify patients, thereby resulting in a higher proportion of patients being considered SR, so that only 40% of patients now considered HR receive cranial radiation. We are investigating whether the dose of cranial radiation can be decreased in HR patients without compromising efficacy, as has been reported by others.1 Other than ability to tolerate at least 26 weeks of asparaginase therapy, age at diagnosis was the only significant predictor of outcome on Protocol 91-01. The 2 age groups with relatively inferior prognoses were infants aged less than 1 year and children aged at least 9 years. The poor prognosis of infants with ALL has been reported by many investigators.33 We have previously demonstrated improved outcome for infants (50-month EFS, 54%) treated with therapy, which is nearly identical to that administered on Protocol 91-01, including the use of high-dose methotrexate and high-dose cytarabine.15 Building upon these results and those of others suggesting that cytarabine may be an important component of therapy for infants with ALL, we are currently enrolling infants on an international collaborative protocol that includes high- and low-dose cytarabine during several phases of therapy.33 Several other studies have also reported that older children and adolescents with ALL fare worse than younger patients.1,2 The inferior outcome of older children may be due to differences in the underlying biology of their disease, but also to an inability to tolerate the intensive 2-year regimen. While no patient aged 9-18 years experienced a remission death, older age at diagnosis was associated with an increased risk of developing a dose-limiting asparaginase-related toxicity, which may have negatively impacted subsequent outcome. Despite this increased vulnerability to dose-limiting toxicity, the outcome of older children on Protocol 91-01 (5-year EFS, 77%) compares favorably with recent reports by other investigators (EFS rates of 60% to 70% for similarly aged patients).1,2 There were no other statistically significant prognostic factors. For the first time, there was no significant difference in outcome based upon risk group status (P = .24). The results of Protocol 91-01 suggest that in the era of intensive multi-agent regimens, we are reaching the limits of prognostic significance of currently applied clinical risk factors. Other potentially important risk factors include early response to therapy,34,35 minimal residual disease levels at various time-points during therapy,36-38 and the presence of molecular abnormalities such as TEL-AML1 gene fusion.39-41 To meaningfully improve upon the results of Protocol 91-01, the prognostic significance of these and other factors needs to be established. In this way, more intensive regimens and novel therapies can be evaluated in children at highest risk of relapse, while attempts are made to diminish long-term toxicity in those who are successfully treated with current therapies.
We thank the patients, families, physicians, nurses, data managers, and all others who participated in this trial. We acknowledge the fundamental contributions of Kristin Barrett, Mia Donnelly, Jennifer Peppe, Molly Schwenn, Joyce Su, Sharon Thornhill, Stacy Waters, and Guangyong Zou.
Submitted August 1, 2000; accepted October 31, 2000.
Supported in part by grants CA 68484 and CA 06516 from the 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: Lewis B. Silverman, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: lewis_silverman{at}dfci.harvard.edu.
1.
Schrappe M, Reiter A, Ludwig WD, et al.
Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90: German-Austrian-Swiss ALL-BFM Study Group.
Blood.
2000;95:3310-3322 2. Rivera GK, Raimondi SC, Hancock ML, et al. Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet. 1991;337:61-66[CrossRef][Medline] [Order article via Infotrieve]. 3. Chessells JM, Bailey C, Richards SM. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X: Medical Research Council Working Party on Childhood Leukaemia. Lancet. 1995;345:143-148[CrossRef][Medline] [Order article via Infotrieve].
4.
Pui CH, Mahmoud HH, Rivera GK, et al.
Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia.
Blood.
1998;92:411-415 5. Schorin MA, Blattner S, Gelber RD, et al. Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital Acute Lymphoblastic Leukemia Consortium Protocol 85-01. J Clin Oncol. 1994;12:740-747[Abstract]. 6. Clavell LA, Gelber RD, Cohen HJ, et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med. 1986;315:657-663[Abstract]. 7. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med. 1991;324:808-815[Abstract]. 8. Waber DP, Tarbell NJ, Fairclough D, et al. Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol. 1995;13:2490-2496[Abstract]. 9. 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].
10.
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 11. 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]. 12. 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]. 13. 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]. 14. 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]. 15. Silverman LB, McLean TW, Gelber RD, et al. Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium. Cancer. 1997;80:2285-2295[CrossRef][Medline] [Order article via Infotrieve]. 16. Cox DR. Analysis of Binary Data. London: Methuen; 1970. 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 18. Greenwood M. The Natural Duration of Cancer: Reports on Public Health and Medical Subjects. Vol 33. London: Her Majesty's Stationary Office; 1926. 19. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1996;50:163-170. 20. Cox DR. Regression models and life-tables (with discussion). J R Stat Soc (B). 1972;34:187-220. 21. Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol. 1983;1:710-719[Abstract].
22.
Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei Ed, Nathan DG.
Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia.
Cancer Res.
1983;43:5601-5607
23.
Veerman AJP, 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 24. Bostrom B, Gaynon PS, Sather H, et al. Dexamethasone decreases central nervous system relapse and improves event-free survival in lower risk acute lymphoblastic leukemia. Proc Am Soc Clin Oncol. 1998;17:527a. 25. 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]. 26. 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].
27.
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
28.
Tubergen DG, Gilchrist GS, O'Brien RT, et al.
Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: a Children's Cancer Group report.
J Clin Oncol.
1993;11:520-526
29.
Pullen J, Boyett J, Shuster J, et al.
Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study.
J Clin Oncol.
1993;11:839-849 30. Schrappe M, Reiter A, Henze G, et al. Prevention of CNS recurrence in childhood ALL: results with reduced radiotherapy combined with CNSdirected chemotherapy in four consecutive ALL-BFM trials. Klin Padiatr. 1998;210:192-199[Medline] [Order article via Infotrieve]. 31. Mulhern RK, Fairclough D, Ochs J. A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation. J Clin Oncol. 1991;9:1348-1356[Abstract]. 32. Jankovic M, Brouwers P, Valsecchi MG, et al. Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia: ISPACC: International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet. 1994;344:224-227[CrossRef][Medline] [Order article via Infotrieve].
33.
Biondi A, Cimino G, Pieters R, Pui CH.
Biological and therapeutic aspects of infant leukemia.
Blood.
2000;96:24-33 34. Gaynon PS, Desai AA, Bostrom BC, et al. Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer. 1997;80:1717-1726[CrossRef][Medline] [Order article via Infotrieve].
35.
Nachman JB, Sather HN, Sensel MG, et al.
Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy.
N Engl J Med.
1998;338:1663-1671
36.
Cave H, van der Werff ten Bosch J, Suciu S, et al.
Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia: European Organization for Research and Treatment of Cancer 37. van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731-1738[CrossRef][Medline] [Order article via Infotrieve]. 38. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet. 1998;351:550-554[CrossRef][Medline] [Order article via Infotrieve].
39.
McLean TW, Ringold S, Neuberg D, et al.
TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia.
Blood.
1996;88:4252-4258
40.
Rubnitz JE, Downing JR, Pui CH, et al.
TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance.
J Clin Oncol.
1997;15:1150-1157
41.
Borkhardt A, Cazzaniga G, Viehmann S, et al.
Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials: Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster Study Group.
Blood.
1997;90:571-577
© 2001 by The American Society of Hematology.
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|
 |
|
  D. French, W. Yang, C. Cheng, S. C. Raimondi, C. G. Mullighan, J. R. Downing, W. E. Evans, C.-H. Pui, and M. V. Relling Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia Blood, May 7, 2009; 113(19): 4512 - 4520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Pieters, I. Appel, H.-J. Kuehnel, I. Tetzlaff-Fohr, U. Pichlmeier, I. van der Vaart, E. Visser, and R. Stigter Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: a randomized phase 2 clinical trial Blood, December 15, 2008; 112(13): 4832 - 4838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Teuffel, M. Stanulla, G. Cario, W. D. Ludwig, S. Rottgers, B. W. Schafer, M. Zimmermann, M. Schrappe, and F. K. Niggli Anemia and survival in childhood acute lymphoblastic leukemia Haematologica, November 1, 2008; 93(11): 1652 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Usvasalo, R. Raty, S. Knuutila, K. Vettenranta, A. Harila-Saari, E. Jantunen, M. Kauppila, P. Koistinen, K. Parto, P. Riikonen, et al. Acute lymphoblastic leukemia in adolescents and young adults in Finland Haematologica, August 1, 2008; 93(8): 1161 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dulucq, G. St-Onge, V. Gagne, M. Ansari, D. Sinnett, D. Labuda, A. Moghrabi, and M. Krajinovic DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL Blood, April 1, 2008; 111(7): 3692 - 3700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Oudot, M.-F. Auclerc, V. Levy, R. Porcher, C. Piguet, Y. Perel, V. Gandemer, M. Debre, C. Vermylen, B. Pautard, et al. Prognostic Factors for Leukemic Induction Failure in Children With Acute Lymphoblastic Leukemia and Outcome After Salvage Therapy: The FRALLE 93 Study J. Clin. Oncol., March 20, 2008; 26(9): 1496 - 1503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Goldstone, S. M. Richards, H. M. Lazarus, M. S. Tallman, G. Buck, A. K. Fielding, A. K. Burnett, R. Chopra, P. H. Wiernik, L. Foroni, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993) Blood, February 15, 2008; 111(4): 1827 - 1833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. Seibel Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents: Peaks and Pitfalls Hematology, January 1, 2008; 2008(1): 374 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Waber, J. Turek, L. Catania, K. Stevenson, P. Robaey, I. Romero, H. Adams, C. Alyman, C. Jandet-Brunet, D. S. Neuberg, et al. Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 J. Clin. Oncol., November 1, 2007; 25(31): 4914 - 4921. [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. Zhou, M. A Goldwasser, A. Li, S. E. Dahlberg, D. Neuberg, H. Wang, V. Dalton, K. D McBride, S. E. Sallan, L. B Silverman, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01 Blood, September 1, 2007; 110(5): 1607 - 1611. [Abstract] [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]
|
|
|
|
 |
|
 D. A. Williams A New Mechanism of Leukemia Drug Resistance? N. Engl. J. Med., July 5, 2007; 357(1): 77 - 78. [Full Text] [PDF]
|
|
|
|
|
|
S. Kishi, C. Cheng, D. French, D. Pei, S. Das, E. H. Cook, N. Hijiya, C. Rizzari, G. L. Rosner, T. Frudakis, et al. Ancestry and pharmacogenetics of antileukemic drug toxicity Blood, May 15, 2007; 109(10): 4151 - 4157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Paz-Priel, L. Long, L. J. Helman, C. L. Mackall, and A. S. Wayne Thromboembolic Events in Children and Young Adults With Pediatric Sarcoma J. Clin. Oncol., April 20, 2007; 25(12): 1519 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Douer, H. Yampolsky, L. J. Cohen, K. Watkins, A. M. Levine, A. P. Periclou, and V. I. Avramis Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia Blood, April 1, 2007; 109(7): 2744 - 2750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hijiya, M. M. Hudson, S. Lensing, M. Zacher, M. Onciu, F. G. Behm, B. I. Razzouk, R. C. Ribeiro, J. E. Rubnitz, J. T. Sandlund, et al. Cumulative Incidence of Secondary Neoplasms as a First Event After Childhood Acute Lymphoblastic Leukemia JAMA, March 21, 2007; 297(11): 1207 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Barry, D. J. DeAngelo, D. Neuberg, K. Stevenson, M. L. Loh, B. L. Asselin, R. D. Barr, L. A. Clavell, C. A. Hurwitz, A. Moghrabi, et al. Favorable Outcome for Adolescents With Acute Lymphoblastic Leukemia Treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols J. Clin. Oncol., March 1, 2007; 25(7): 813 - 819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Moghrabi, D. E. Levy, B. Asselin, R. Barr, L. Clavell, C. Hurwitz, Y. Samson, M. Schorin, V. K. Dalton, S. E. Lipshultz, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia Blood, February 1, 2007; 109(3): 896 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Ribera, J.-J. Ortega, A. Oriol, P. Bastida, C. Calvo, J.-M. Perez-Hurtado, M.-E. Gonzalez-Valentin, V. Martin-Reina, A. Molines, F. Ortega-Rivas, et al. Comparison of Intensive Chemotherapy, Allogeneic, or Autologous Stem-Cell Transplantation As Postremission Treatment for Children With Very High Risk Acute Lymphoblastic Leukemia: PETHEMA ALL-93 Trial J. Clin. Oncol., January 1, 2007; 25(1): 16 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. M. Saarinen-Pihkala, C. Heilmann, J. Winiarski, A. Glomstein, J. Abrahamsson, J. Arvidson, A. N. Bekassy, E. Forestier, G. Jonmundsson, H. Schroeder, et al. Pathways Through Relapses and Deaths of Children With Acute Lymphoblastic Leukemia: Role of Allogeneic Stem-Cell Transplantation in Nordic Data J. Clin. Oncol., December 20, 2006; 24(36): 5750 - 5762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Storring, J. Brandwein, V. Gupta, A. C. Schuh, A. Schimmer, K. Yee, R. A. Wells, J. H. Lipton, H. A. Messner, W. Xu, et al. Treatment of Adult Acute Lymphoblastic Leukemia (ALL) with a Modified DFCI Pediatric Regimen - The Princess Margaret Experience. Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 1875 - 1875. [Abstract] [PDF]
|
|
|
|
|
|
V. Caruso, L. Iacoviello, A. Di Castelnuovo, S. Storti, G. Mariani, G. de Gaetano, and M. B. Donati Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients Blood, October 1, 2006; 108(7): 2216 - 2222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Eapen, E. Raetz, M.-J. Zhang, C. Muehlenbein, M. Devidas, T. Abshire, A. Billett, A. Homans, B. Camitta, W. L. Carroll, et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research Blood, June 15, 2006; 107(12): 4961 - 4967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Loh, M. A. Goldwasser, L. B. Silverman, W.-M. Poon, S. Vattikuti, A. Cardoso, D. S. Neuberg, K. M. Shannon, S. E. Sallan, and D. G. Gilliland Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 Blood, June 1, 2006; 107(11): 4508 - 4513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Feusner Bcl-rambo: a maverick of apoptotic genes Blood, January 15, 2006; 107(2): 421 - 421. [Full Text] [PDF]
|
|
|
|
|
|
J. O'Neil, J. Calvo, K. McKenna, V. Krishnamoorthy, J. C. Aster, C. H. Bassing, F. W. Alt, M. Kelliher, and A. T. Look Activating Notch1 mutations in mouse models of T-ALL Blood, January 15, 2006; 107(2): 781 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Rowe, G. Buck, A. K. Burnett, R. Chopra, P. H. Wiernik, S. M. Richards, H. M. Lazarus, I. M. Franklin, M. R. Litzow, N. Ciobanu, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993 Blood, December 1, 2005; 106(12): 3760 - 3767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui, D. Pei, J. T. Sandlund, D. Campana, R. C. Ribeiro, B. I. Razzouk, J. E. Rubnitz, S. C. Howard, N. Hijiya, S. Jeha, et al. Risk of Adverse Events After Completion of Therapy for Childhood Acute Lymphoblastic Leukemia J. Clin. Oncol., November 1, 2005; 23(31): 7936 - 7941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. G. Einsiedel, A. von Stackelberg, R. Hartmann, R. Fengler, M. Schrappe, G. Janka-Schaub, G. Mann, K. Hahlen, U. Gobel, T. Klingebiel, et al. Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Munster Group 87 J. Clin. Oncol., November 1, 2005; 23(31): 7942 - 7950. [Abstract] [Full Text] [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]
|
|
|
|
|
|
G. Zaza, M. Cheok, W. Yang, J. C. Panetta, C.-H. Pui, M. V. Relling, and W. E. Evans Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment Blood, September 1, 2005; 106(5): 1778 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J Wright, V. Galea, and R. D Barr Proficiency of Balance in Children and Youth Who Have Had Acute Lymphoblastic Leukemia Physical Therapy, August 1, 2005; 85(8): 782 - 790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. C. Rocha, C. Cheng, W. Liu, S. Kishi, S. Das, E. H. Cook, J. T. Sandlund, J. Rubnitz, R. Ribeiro, D. Campana, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia Blood, June 15, 2005; 105(12): 4752 - 4758. [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]
|
|
|
|
|
|
S. E. Lipshultz, N. Rifai, V. M. Dalton, D. E. Levy, L. B. Silverman, S. R. Lipsitz, S. D. Colan, B. L. Asselin, R. D. Barr, L. A. Clavell, et al. The Effect of Dexrazoxane on Myocardial Injury in Doxorubicin-Treated Children with Acute Lymphoblastic Leukemia N. Engl. J. Med., July 8, 2004; 351(2): 145 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Waber, L. B. Silverman, L. Catania, W. Mautz, M. Rue, R. D. Gelber, D. E. Levy, M. A. Goldwasser, H. Adams, A. Dufresne, et al. Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity J. Clin. Oncol., July 1, 2004; 22(13): 2701 - 2707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Howard, M. Pedrosa, M. Lins, A. Pedrosa, C.-H. Pui, R. C. Ribeiro, and F. Pedrosa Establishment of a Pediatric Oncology Program and Outcomes of Childhood Acute Lymphoblastic Leukemia in a Resource-Poor Area JAMA, May 26, 2004; 291(20): 2471 - 2475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui, M. V. Relling, and J. R. Downing Acute Lymphoblastic Leukemia N. Engl. J. Med., April 8, 2004; 350(15): 1535 - 1548. [Full Text] [PDF]
|
|
|
|
|
|
T. M. Holling, E. Schooten, A. W. Langerak, and P. J. van den Elsen Regulation of MHC class II expression in human T-cell malignancies Blood, February 15, 2004; 103(4): 1438 - 1444. [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]
|
|
|
|
|
|
M. E. Ross, X. Zhou, G. Song, S. A. Shurtleff, K. Girtman, W. K. Williams, H.-C. Liu, R. Mahfouz, S. C. Raimondi, N. Lenny, et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling Blood, October 15, 2003; 102(8): 2951 - 2959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Goldberg, L. B. Silverman, D. E. Levy, V. K. Dalton, R. D. Gelber, L. Lehmann, H. J. Cohen, S. E. Sallan, and B. L. Asselin Childhood T-Cell Acute Lymphoblastic Leukemia: The Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Experience J. Clin. Oncol., October 1, 2003; 21(19): 3616 - 3622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsutsumi, T. Taketani, K. Nishimura, X. Ge, T. Taki, K. Sugita, E. Ishii, R. Hanada, M. Ohki, H. Aburatani, et al. Two Distinct Gene Expression Signatures in Pediatric Acute Lymphoblastic Leukemia with MLL Rearrangements Cancer Res., August 15, 2003; 63(16): 4882 - 4887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Pui, C. Cheng, W. Leung, S. N. Rai, G. K. Rivera, J. T. Sandlund, R. C. Ribeiro, M. V. Relling, L. E. Kun, W. E. Evans, et al. Extended Follow-up of Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia N. Engl. J. Med., August 14, 2003; 349(7): 640 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. K. Dalton, M. Rue, L. B. Silverman, R. D. Gelber, B. L. Asselin, R. D. Barr, L. A. Clavell, C. A. Hurwitz, A. Moghrabi, Y. Samson, et al. Height and Weight in Children Treated for Acute Lymphoblastic Leukemia: Relationship to CNS Treatment J. Clin. Oncol., August 1, 2003; 21(15): 2953 - 2960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C. Bostrom, M. R. Sensel, H. N. Sather, P. S. Gaynon, M. K. La, K. Johnston, G. R. Erdmann, S. Gold, N. A. Heerema, R. J. Hutchinson, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group Blood, May 15, 2003; 101(10): 3809 - 3817. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Clarke, P. Gaynon, I. Hann, G. Harrison, G. Masera, R. Peto, and S. Richards CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia: Childhood ALL Collaborative Group Overview of 43 Randomized Trials J. Clin. Oncol., May 1, 2003; 21(9): 1798 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
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N. Boissel, M.-F. Auclerc, V. Lheritier, Y. Perel, X. Thomas, T. Leblanc, P. Rousselot, J.-M. Cayuela, J. Gabert, N. Fegueux, et al. Should Adolescents With Acute Lymphoblastic Leukemia Be Treated as Old Children or Young Adults? Comparison of the French FRALLE-93 and LALA-94 Trials J. Clin. Oncol., March 1, 2003; 21(5): 774 - 780. [Abstract] [Full Text] [PDF]
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C.-H. Pui Toward Optimal Central Nervous System-Directed Treatment in Childhood Acute Lymphoblastic Leukemia J. Clin. Oncol., January 15, 2003; 21(2): 179 - 181. [Full Text] [PDF]
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 R. M. Stone The Difficult Problem of Acute Myeloid Leukemia in the Older Adult CA Cancer J Clin, November 1, 2002; 52(6): 363 - 371. [Abstract] [Full Text] [PDF]
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P. Ballerini, A. Blaise, M. Busson-Le Coniat, X. Y. Su, J. Zucman-Rossi, M. Adam, J. van den Akker, C. Perot, B. Pellegrino, J. Landman-Parker, et al. HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis Blood, July 18, 2002; 100(3): 991 - 997. [Abstract] [Full Text] [PDF]
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S. E. Lipshultz, A. L. Giantris, S. R. Lipsitz, V. K. Dalton, B. L. Asselin, R. D. Barr, L. A. Clavell, C. A. Hurwitz, A. Moghrabi, Y. Samson, et al. Doxorubicin Administration by Continuous Infusion Is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol J. Clin. Oncol., March 15, 2002; 20(6): 1677 - 1682. [Abstract] [Full Text] [PDF]
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B. J. Lange, B. C. Bostrom, J. M. Cherlow, M. G. Sensel, M. K. L. La, W. Rackoff, N. A. Heerema, R. S. Wimmer, M. E. Trigg, and H. N. Sather Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group Blood, February 1, 2002; 99(3): 825 - 833. [Abstract] [Full Text] [PDF]
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J. M. LeClerc, A. L. Billett, R. D. Gelber, V. Dalton, N. Tarbell, J. M. Lipton, R. Barr, L. A. Clavell, B. Asselin, C. Hurwitz, et al. Treatment of Childhood Acute Lymphoblastic Leukemia: Results of Dana-Farber ALL Consortium Protocol 87-01 J. Clin. Oncol., January 1, 2002; 20(1): 237 - 246. [Abstract] [Full Text] [PDF]
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D. Hoelzer, N. Gokbuget, O. Ottmann, C.-H. Pui, M. V. Relling, F. R. Appelbaum, J. J.M. van Dongen, and T. Szczepanski Acute Lymphoblastic Leukemia Hematology, January 1, 2002; 2002(1): 162 - 192. [Abstract] [Full Text] [PDF]
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A. J. Strauss, J. T. Su, V. M. K. Dalton, R. D. Gelber, S. E. Sallan, and L. B. Silverman Bony Morbidity in Children Treated for Acute Lymphoblastic Leukemia J. Clin. Oncol., June 15, 2001; 19(12): 3066 - 3072. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
Childhood Leukemia Cooperative Group.
N Engl J Med.
1998;339:591-598