Abstract

The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m2 as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM (P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis.

Introduction

Lymphoid malignancies with a T-cell immunophenotype are associated with distinctive biologic, cytogenetic, and clinical features which set them apart from non-T lymphoid malignancies.1-5  Historically, the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic non-Hodgkin lymphoma (T-NHL) predicted a higher risk of induction failure, early relapse, and worse event-free survival (EFS) for patients with T-cell compared with B-precursor childhood leukemia or lymphoma.6-11  With increasingly intensive regimens of multi-agent chemotherapy, survival rates have improved to > 70%.12-22  Although these regimens all demonstrate some degree of efficacy in T-cell disease, true lineage-specific, highly efficacious therapy has not been identified.

Methotrexate, a folate analog which inhibits intracellular folate-requiring enzymes, has been a vital component of successful ALL treatment regimens regardless of immunophenotype. Doses have ranged from 20 mg/m2 given orally on a weekly schedule to 33.6 g/m2 given by 24-hour intravenous infusion.14,19,23-26  The optimal dose and route of administration are still debated. Higher systemic doses have contributed to improved control of testicular and medullary disease, but not of CNS disease.27  Of interest is whether early leucovorin rescue interferes with the potential CNS protection that might be offered by higher doses of methotrexate.28  Multiple investigators have reported that T-lineage blasts required a higher concentration of extracellular methotrexate to achieve the same intracellular levels as in B-lineage blasts,29,30  and in a study from St Jude, intracellular levels of methotrexate correlated with leukemic cell killing effect.31  In 2 successive multicenter trials, the Berlin-Frankfurt-Muenster Group (BFM) showed improved EFS of children with T-ALL after introduction of high-dose methotrexate.18,19,32  Although these were successive trials, with higher doses of methotrexate included as a nonrandomized change to treatment, these data suggest that higher dose methotrexate may improve the treatment of T-lineage lymphoid malignancies. The present study was designed to evaluate, in a randomized fashion, the benefit of 4 cycles of high-dose methotrexate (HDM).

The Dana-Farber Leukemia Consortium (DFCI) has shown excellent outcomes for patients with advanced stage T-cell malignancies when treated on the same regimens used for high-risk patients with B-precursor disease.15,33  Their data suggested, albeit in small numbers, that event-free survival rates were not significantly worse for T-ALL compared with B-precursor ALL although the children with T-ALL did have higher rates of induction failure, CNS relapse, and a shorter time to relapse. When the current trial was designed, the backbone of therapy used in the DFCI studies was selected because of the excellent outcomes for patients with T-cell disease (5-year EFS = 75%) without use of alkylating agents or epipodophyllotoxins.

The rationale for the current study was based on the excellent outcomes reported by both the DFCI and the BFM groups in treatment of patients with T-ALL and T-NHL. The POG 9404 protocol tested whether addition of 4 cycles of HDM to the standard multi-agent DFCI chemotherapy would reduce the number of early events and subsequently prolong EFS. Because the DFCI treatment regimen included intensive use of the anthracycline, doxorubicin, a second objective of the 9404 study was to examine the effectiveness of the cardioprotectant drug, dexrazoxane (Zinecard), in prevention of anthracycline-induced cardiomyopathy. Here, we report only the efficacy and toxicity results of methotrexate treatment. The outcomes of the dexrazoxane question will be reported separately.

Methods

Patients

The protocol was approved by the National Cancer Institute (NCI) and the institutional review boards of each participating institution before patient enrollment. Informed consent was obtained before registration from patients, their parents, and/or legal guardians in accordance with local institutional regulations, Department of Health and Human Services guidelines, and the Declaration of Helsinki.

Eligibility criteria for patients with T-ALL included age 1-21 years, presence of > 25% blasts in the bone marrow regardless of nodal disease, T-cell immunophenotype with confirmation by central reference laboratory flow cytometric studies and no prior therapy except for < 48 hours of corticosteroids or emergency radiation to the mediastinum in patients with severe respiratory distress. Patients with biopsy-proven diffuse lymphoblastic lymphoma (confirmed by central pathology review) regardless of T- or B-cell immunophenotype were eligible if they were < 22 years old, had Murphy stage III or IV disease (> 5% but < 25% blasts in the marrow, blasts in the CNS, or both), and had received no prior therapy except for < 48 hours of corticosteroids or emergency mediastinal radiation for severe respiratory distress.

In September 2000, interim analysis showed significantly better outcomes in patients randomized to receive HDM.34  The POG Data Safety Monitoring Committee therefore recommended discontinuation of the methotrexate randomization. All patients enrolled subsequently were assigned to the HDM arm. The second randomization that assigned patients to treatment with or without dexrazoxane remained open.

Treatment

The standard treatment protocol (Table 1) was modified from the DFCI protocol 87-01, which has been previously published.33,35  All patients received 6-week induction therapy with vincristine, doxorubicin, prednisone, a single low dose of methotrexate, mercaptopurine, and triple intrathecal chemotherapy. Consolidation therapy was administered as repeating 3-week pulses of vincristine, prednisone, mercaptopurine, and doxorubicin to a cumulative dose of 360 mg/m2 with 20 weekly doses of asparaginase. After completion of the prescribed doxorubicin, patients received 74 weeks of continuation therapy that included weekly methotrexate in addition to continued 3-week pulses of prednisone, vincristine, and mercaptopurine. Drug doses for doxorubicin, dexrazoxane, methotrexate, mercaptopurine, and prednisone were capped at maximum body surface area of 2.0 m2 because of concerns for potential toxicity in older, overweight patients. Total duration of therapy was 2 years from the date of documented complete remission.

Table 1

Treatment regimen

Treatment regimen
Induction, weeks 1-6 
    Vincristine 1.5 mg/m2 IVP weekly × 4, days 1, 8, 15, 22 
    Prednisone 40 mg/m2/d × 21 days, days 1-22 then stop 
    Doxorubicin 30 mg/m2 IV × 2, days 1 and 2* 
    (Randomized ± dexrazoxane as cardioprotectant) 
    Methotrexate 40 mg/m2 × 1, day 2 (8-24 hours after dox) 
    Triple intrathecal drugs × 4, days 1, (8), 15, 22, 29, and 36 
    Doxorubicin 30 mg/m2 × 1, day 22* 
    ± HDM per randomized assignment, day 22 
    Mercaptopurine 50 mg/m2/d PO × 14 days, days 22-36 
Consolidation, weeks 7-33 
    3-week cycles (start day 43) 
    Vincristine 2.0 mg/m2 IVP q3 weeks 
    Prednisone 120 mg/m2/d PO × 5 days 
    Doxorubicin 30 mg/m2 IV q3 weeks *(to a total of 360 mg/m2
    Mercaptopurine 50 mg/m2/d PO × 14 days 
    Asparaginase 25 000 IU/m2 IM weekly × 20 doses 
    Triple intrathecal drugs, weeks 10, (16), 22 
    ± HDM per randomized assignment, weeks 7, 10, and 13 
CNS prophylaxis (for all patients) 
    Cranial radiation 1800 cGy in 9 fractions, start week 22 
    Triple intrathecal drugs (doses by age) × 11 doses 
     (CNS-2 and -3 received 2 additional doses, day 8 of induction and week [16] of consolidation) 
Continuation, weeks 34-108 (repeat 3-week cycle until 2 years from date of documented complete remission) 
    3-week cycles 
    Vincristine 2.0 mg/m2 IVP q3 weeks 
    Prednisone 120 mg/m2/d PO × 5 days 
    Methotrexate 30 mg/m2 IV/IM weekly 
    Mercaptopurine 50 mg/m2/d PO × 14 days 
    Triple intrathecal drugs, weeks 40, 58, 76, and 94 
Randomizations, at enrollment 
    Standard therapy ± dexrazoxane ± HDM 
    Start leucovorin rescue 75 mg/m2 at hour 36 then 15 mg/m2 q6 hours at hours 42, 48, 54, 60, 66, and 72, and until serum methotrexate level ≤ 0.1μM§ 
Treatment regimen
Induction, weeks 1-6 
    Vincristine 1.5 mg/m2 IVP weekly × 4, days 1, 8, 15, 22 
    Prednisone 40 mg/m2/d × 21 days, days 1-22 then stop 
    Doxorubicin 30 mg/m2 IV × 2, days 1 and 2* 
    (Randomized ± dexrazoxane as cardioprotectant) 
    Methotrexate 40 mg/m2 × 1, day 2 (8-24 hours after dox) 
    Triple intrathecal drugs × 4, days 1, (8), 15, 22, 29, and 36 
    Doxorubicin 30 mg/m2 × 1, day 22* 
    ± HDM per randomized assignment, day 22 
    Mercaptopurine 50 mg/m2/d PO × 14 days, days 22-36 
Consolidation, weeks 7-33 
    3-week cycles (start day 43) 
    Vincristine 2.0 mg/m2 IVP q3 weeks 
    Prednisone 120 mg/m2/d PO × 5 days 
    Doxorubicin 30 mg/m2 IV q3 weeks *(to a total of 360 mg/m2
    Mercaptopurine 50 mg/m2/d PO × 14 days 
    Asparaginase 25 000 IU/m2 IM weekly × 20 doses 
    Triple intrathecal drugs, weeks 10, (16), 22 
    ± HDM per randomized assignment, weeks 7, 10, and 13 
CNS prophylaxis (for all patients) 
    Cranial radiation 1800 cGy in 9 fractions, start week 22 
    Triple intrathecal drugs (doses by age) × 11 doses 
     (CNS-2 and -3 received 2 additional doses, day 8 of induction and week [16] of consolidation) 
Continuation, weeks 34-108 (repeat 3-week cycle until 2 years from date of documented complete remission) 
    3-week cycles 
    Vincristine 2.0 mg/m2 IVP q3 weeks 
    Prednisone 120 mg/m2/d PO × 5 days 
    Methotrexate 30 mg/m2 IV/IM weekly 
    Mercaptopurine 50 mg/m2/d PO × 14 days 
    Triple intrathecal drugs, weeks 40, 58, 76, and 94 
Randomizations, at enrollment 
    Standard therapy ± dexrazoxane ± HDM 
    Start leucovorin rescue 75 mg/m2 at hour 36 then 15 mg/m2 q6 hours at hours 42, 48, 54, 60, 66, and 72, and until serum methotrexate level ≤ 0.1μM§ 

Maximum dosage recommendations: vincristine 2 mg/dose; doxorubicin 60 mg/dose; dexrazoxane 600 mg/dose; HDM 10 g/24-hour infusion; prednisone 80 mg/d during induction and 240 mg/d during consolidation and continuation; mercaptopurine 100 mg/d all phases; and methotrexate 80 mg/dose day 2 of induction and continuation.

IVP indicates intravenous push; dox, doxorubicin; HDM, high-dose methotrexate; q, every; and PO, orally.

*

Dexrazoxane 300 mg/m2 IV immediately before each dose of doxorubicin.

August 1999, protocol amended intrathecal drugs to cytarabine alone on induction days 1, (8), and 15. Doses on weeks 5 and 6 were omitted. All other intrathecal doses were methotrexate/cytarabine given weeks 4, 7, 10, (16), 22, 40, 58, 76, and 94.

HDM = Methotrexate 5 g/m2 IV infusion as a bolus of 0.5 gm/m2 over 0.5 hours then 4.5 g/m2 over 23.5 hours

§

Prior to March 1997, the hour-36 leucovorin dose was 15 mg/m2, repeated every 6 hours × 5 doses minimum. If the 72-hour serum MTX level was > 0.1μM, then leucovorin continued at 5 mg/m2 every 6 hours until the MTX level was < 0.1μM.

At diagnosis, patients were randomized to receive standard therapy with or without HDM and with or without dexrazoxane. Patients assigned to receive HDM were given 5 g/m2 as a 24-hour infusion at week 4 (during induction therapy) and weeks 7, 10, and 13 (during consolidation therapy). The HDM and leucovorin rescue schedule (Table 1) were modified from the ALL-BFM 86 trial.19  Because of excessive systemic toxicities observed in the first 9 months of study the leucovorin dosage was increased (originally 15 mg/m2 every 6 hours × 6 starting at hour 36 then 5 mg/m2 every 6 hours until the methotrexate level was < 0.1μM) to 75 mg/m2 at hour 36 followed by 15 mg/m2 every 6 hours for a minimum of 6 doses and until the methotrexate level was < 0.1μM. Based on randomized assignment, one half of the patients received dexrazoxane immediately before every dose of doxorubicin.

CNS prophylaxis consisted of 11 doses of triple intrathecal chemotherapy (Table 1) as well as cranial radiation (1800 cGy) at week 22 of consolidation. Doses of intrathecal medications were based on age. Patients with CNS involvement (CNS-2 or -3) at initial diagnosis received 2 additional doses of intrathecal medication during induction (day 8) and consolidation (week 16). CNS-2 was defined as < 5 cells/μL cerebrospinal fluid with identifiable blasts. CNS-3 was defined as 5 or more nucleated cells/μL cerebrospinal fluid with identifiable blasts and/or cerebral infiltrates on imaging studies and/or cranial nerve palsy. Delay of cranial radiation from week 4 to week 22 was the primary treatment modification from the standard practice in the DFCI protocols, because of concern for additive neurotoxicity if HDM was given following cranial radiation. Thus, the delay in cranial radiation allowed for a 9-week interval between the last HDM cycle and radiation.

In August 1999, the original 9404 regimen was amended because of an unanticipated rate of severe neurotoxicity, primarily seizures, among all POG ALL trials. To more closely reflect the DFCI regimens, which had not been associated with excess neurotoxicity, therapy was amended to use intrathecal cytosine arabinoside alone on days 1 and 15 of induction and intrathecal methotrexate and cytosine arabinoside during consolidation and continuation (Table 1).

Complete remission was defined as < 5% blasts in the marrow with no extramedullary disease on day 43 of therapy. The presence of > 25% blasts in the marrow at day 22 or > 5% blasts in the marrow (M2 or M3) on day 43, or the presence of biopsy-proven residual extramedullary disease at day 43 was considered an induction failure. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 2.0. All events of grade 3 or 4, and specifically any central neurotoxicity, grade 2 or higher, were reported.

Statistical analysis

This study had a 2 × 2 randomized factorial design with the DFCI 87-01 regimen35  as standard therapy, with or without HDM, and with or without dexrazoxane as a cardioprotectant. Randomization was stratified by disease (ALL vs NHL) and presence of CNS disease at diagnosis. The primary end point for the HDM question was EFS, calculated as the time from diagnosis to first event (induction failure, relapse at any site, secondary malignancy, or death from any cause). The log-rank test was used to compare survival curves (1-sided test). EFS curves were constructed by the method of Kaplan and Meier.36  Because the study was designed to compare overall outcomes between regimens, specific subset inferences (eg, by disease) will not have sufficient power. The Fisher exact test was used for comparison of proportions. Alpha was set at 0.05.

Results

Patient characteristics

Between June 1996 and September 2001, 573 patients with newly diagnosed T-ALL or advanced-stage T-NHL were entered on POG 9404 (Figure 1). Data current as of June 2009 are used in this report. Thirty-five patients were excluded (reasons detailed in Figure 1); leaving 537 eligible, evaluable patients. In September 2000, based on results of interim analysis the methotrexate randomization was closed by the POG Data Monitoring Committee, and all patients enrolled subsequently were assigned directly to receive HDM. The second randomization that assigned patients to treatment with or without dexrazoxane remained open. Before the closure of the methotrexate randomization in September 2000, 219 and 217 eligible patients were randomized to HDM and no HDM, respectively (Figure 1), and are included in this report. Minimal follow-up for randomized patients is 8.7 years. An additional 101 patients enrolled during the remaining year were assigned to receive HDM.

Figure 1

Patient enrollment in POG 9404.

Figure 1

Patient enrollment in POG 9404.

Table 2 gives the patient characteristics for all of the randomized patients by disease stratum and regimen (HDM and no HDM). Overall, 47% of patients were over 10 years of age, 75% were male, and 77% were white. Among the T-ALL patients, 58% had WBC ≥ 50 000/μL, while all the T-NHL patients had WBC < 50 000/μL. Patient characteristics were similar for the randomized and directly assigned (postclosure of HDM randomization) patients (data not shown).

Table 2

Patient characteristics (randomized patients only)

T-cell leukemia
NHL
Total
No HDMHDMNo HDMHDM
Age at diagnosis, y      
    Younger than 10 85 78 31 38 232 
    10 or older 66 70 35 33 204 
Sex      
    Male 109 111 52 55 327 
    Female 42 37 14 16 109 
Race      
    White 113 116 51 56 336 
    Black 32 23 11 10 76 
    Other 23 
    Unknown 
CNS status      
    No data 
    CNS 1 102 109 60 69 340 
    CNS 2 34 24 58 
    CNS 3 12 25 
    Bloody tap, blasts 
    Bloody tap, cannot interpret 
    Cranial nerve involvement only 
WBC, × 1000/μL      
    < 50 61 64 66 71 262 
    50+ 90 84 174 
Lymphadenopathy      
    Missing 
    No 27 38 26 21 112 
    Yes 124 110 37 48 319 
Mediastinal mass      
    No 59 63 11 13 146 
    Yes 92 85 55 58 290 
Bulky disease (lymphadenopathy and mediastinal mass)      
    Missing 
    No 73 86 34 33 226 
    Yes 78 62 29 36 205 
Splenomegaly (spleen palpable below umbilicus)      
    Missing 
    No 106 100 57 64 121 
    Yes 45 48 14 
Stage (T-NHL only)      
    Missing   
    III   44 46 90 
    IV   23 26 49 
T-cell leukemia
NHL
Total
No HDMHDMNo HDMHDM
Age at diagnosis, y      
    Younger than 10 85 78 31 38 232 
    10 or older 66 70 35 33 204 
Sex      
    Male 109 111 52 55 327 
    Female 42 37 14 16 109 
Race      
    White 113 116 51 56 336 
    Black 32 23 11 10 76 
    Other 23 
    Unknown 
CNS status      
    No data 
    CNS 1 102 109 60 69 340 
    CNS 2 34 24 58 
    CNS 3 12 25 
    Bloody tap, blasts 
    Bloody tap, cannot interpret 
    Cranial nerve involvement only 
WBC, × 1000/μL      
    < 50 61 64 66 71 262 
    50+ 90 84 174 
Lymphadenopathy      
    Missing 
    No 27 38 26 21 112 
    Yes 124 110 37 48 319 
Mediastinal mass      
    No 59 63 11 13 146 
    Yes 92 85 55 58 290 
Bulky disease (lymphadenopathy and mediastinal mass)      
    Missing 
    No 73 86 34 33 226 
    Yes 78 62 29 36 205 
Splenomegaly (spleen palpable below umbilicus)      
    Missing 
    No 106 100 57 64 121 
    Yes 45 48 14 
Stage (T-NHL only)      
    Missing   
    III   44 46 90 
    IV   23 26 49 

NHL indicates non-Hodgkin lymphoma; and HDM, high-dose methotrexate.

Event-free and overall survival

Five-year EFS for the 436 patients who participated in the methotrexate randomization was 76.9% ± 2.1% (10-year EFS 75.4% ± 3.3%; Figure 2). EFS at 5 years for T-ALL patients were 73.4% ± 2.6% and 84.6% ± 3.2% for T-NHL (Figure 3). The 10-year rates were 71.6% ± 4.2% and 83.7% ± 5.0%, respectively. The 5-year EFS rates for all patients randomized to HDM versus no HDM were 80.2% ± 2.8% and 73.6% ± 3.1%, respectively (P = .17; Figure 4A). The corresponding 10-year EFS rates were 78.1% ± 4.3% and 72.6% ± 5.0%. For the T-ALL patients, EFS was significantly better for those randomized to HDM (5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%; n = 148) compared with no HDM (5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; n = 151), P = .047 (Figure 4B). In contrast, the T-NHL patients had nonsignificantly lower EFS with HDM (5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5%; n = 71) compared with the no HDM group (5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; n = 66), P = .38 (Figure 4C). Overall overall survival (OS) rates for the randomized patients were: 81.7% ± 1.9% at 5 years and 80.1% ± 3.1% at 10 years (Figure 2). The OS rates for T-ALL patients randomized to HDM versus no HDM were: 84.3% ± 3.1% versus 74.7% ± 3.7% at 5 years; and 80.5% ± 5.0% versus 74.7% ± 6.1% at 10 years (P = .22). For the T-NHL patients, 5-year OS rates were HDM (84.5% ± 4.6%) versus no HDM (89.2% ± 4.0%), P = .31. Ten-year rates for these patients were 82.6% ± 7.0% versus 89.2% ± 6.1%.

Figure 2

Event-free and overall survival for all randomized patients.

Figure 2

Event-free and overall survival for all randomized patients.

Figure 3

Event-free survival based on diagnosis of T-ALL or T-NHL.

Figure 3

Event-free survival based on diagnosis of T-ALL or T-NHL.

Figure 4

Event-free survival for all eligible patients according to methotrexate randomization and disease. (A) EFS curves based on treatment with (HDM) or without (no HDM) HDM. (B) EFS for T-ALL patients by treatment (HDM vs no HDM). (C) EFS for T-NHL patients by treatment (HDM vs no HDM).

Figure 4

Event-free survival for all eligible patients according to methotrexate randomization and disease. (A) EFS curves based on treatment with (HDM) or without (no HDM) HDM. (B) EFS for T-ALL patients by treatment (HDM vs no HDM). (C) EFS for T-NHL patients by treatment (HDM vs no HDM).

Overall outcomes at 5 years for the 101 patients nonrandomly assigned to the HDM arm were: EFS of 74.2% ± 4.8% and OS of 83.9% ± 4.0%. When looked at as separate groups, the T-ALL patients (n = 63) had 5-year EFS of 76.2% ± 5.8%, and OS of 87.0% ± 4.6%. For the 38 patients in the T-NHL subgroup, the 5-year EFS was 71.1% ± 8.2%, and OS was 78.6% ± 7.3%. These outcomes were similar to those for the randomized HDM groups, but with poorest outcome in the small T-NHL subgroup (data not shown).

Treatment failures

The complete remission (CR) rate was 94% overall: 92% for patients with T-ALL and 98.5% for patients with T-NHL. Overall 3.7% on the HDM arm and 6.9% on the no HDM arm suffered induction failures. Table 3 gives a summary of failures by treatment and diagnosis. For patients with T-ALL, the major site of relapse was the CNS (26/48 = 54%) with 17 isolated CNS relapses, 8 combined marrow/CNS, and 1 combined CNS/eye compared with 12 isolated marrow relapses, and 5 involving marrow and an extramedullary, non-CNS site (17/48 = 35%). Although more than half of these patients had a mediastinal mass at diagnosis (n = 177/299 = 59%), relapse in the mediastinum occurred in only 3 patients. In contrast, relapses in the lymphoma patient group were more evenly distributed with 3 isolated CNS relapses, 5 marrow relapses, and 5 mediastinal/chest relapses.

Table 3

Distribution of treatment failures (randomized patients only)

T-ALL
T-NHL
Total
No HDM (n = 151)HDM (n = 148)No HDM (n = 66)HDM (n = 71)No HDM (n = 217)HDM (n = 219)
Total failures 50 35 14 59 49 
Induction failures 14 15 
Induction deaths 
Relapse 28 20 10 33 30 
    Marrow only 
    Marrow + CNS 
    Marrow + testicular 
    Marrow + Mediastinal 
    Marrow + other 1* 1 1* 
    Isolated CNS 11 7 12 
    Isolated testicular 
    Mediastinal ± other 2§ 3 
    Lymph 
    Unspecified 
Second malignancy 
Remission deaths 
T-ALL
T-NHL
Total
No HDM (n = 151)HDM (n = 148)No HDM (n = 66)HDM (n = 71)No HDM (n = 217)HDM (n = 219)
Total failures 50 35 14 59 49 
Induction failures 14 15 
Induction deaths 
Relapse 28 20 10 33 30 
    Marrow only 
    Marrow + CNS 
    Marrow + testicular 
    Marrow + Mediastinal 
    Marrow + other 1* 1 1* 
    Isolated CNS 11 7 12 
    Isolated testicular 
    Mediastinal ± other 2§ 3 
    Lymph 
    Unspecified 
Second malignancy 
Remission deaths 

T-ALL indicates T-cell acute lymphoblastic leukemia; T-NHL, T-cell lymphoblastic non-Hodgkin lymphoma; and HDM, high-dose methotrexate.

*

One lymph.

One spleen.

One eye.

§

One pleura.

One lung.

CNS relapse accounted for 33% of all relapses in the HDM and 58% in the no HDM groups, respectively (P = .08). The cumulative incidence of CNS relapse, isolated or with concurrent other site (Figure 5) was significantly higher in T-ALL patients treated with no HDM (P = .044), but no different in the methotrexate randomized groups when analyzed for T-NHL patients (P = .61) or all patients (P = .075). Neither cumulative incidence of CNS relapse or EFS was associated with CNS status at diagnosis (P = .71 and 0.81, respectively, data not shown). For the 38 patients treated before the amendment of leucovorin dosage, cumulative incidence of CNS relapse (isolated + combined) was not significantly different from that of the 181 patients treated postamendment (P = .089, data not shown).

Figure 5

Cumulative incidence (CI) of CNS relapse (isolated and concurrent with other sites) for patients according to methotrexate randomization. (A) CI for T-ALL patients. (B) CI for T-NHL patients. (C) CI for all patients.

Figure 5

Cumulative incidence (CI) of CNS relapse (isolated and concurrent with other sites) for patients according to methotrexate randomization. (A) CI for T-ALL patients. (B) CI for T-NHL patients. (C) CI for all patients.

Death was the first event for 8 T-ALL patients and 3 T-NHL patients. Induction deaths occurred in 3 children (fatal pulmonary hemorrhage with Gram-negative sepsis on day 8; tumor lysis syndrome and infection on day 3; and fatal infection with presumed septic shock on day 16). During consolidation and continuation, 4 patients receiving HDM died (bacterial and fungal infection at day 102; Gram-negative sepsis at day 140; pancreatitis with septic shock at day 89; and hemorrhage as complication of Gram-negative sepsis and pancreatitis at day 91). Four remission deaths occurred in patients treated with no HDM (Gram-negative sepsis at day 191; fatal infection at day 194; unknown, suspected pulmonary embolism at day 140; ataxia telangiectasia). There was no difference in either induction (0.91% vs 0.46%) or remission deaths (1.84% vs 1.84%) between the 2 regimens.

Of 11 second malignancies as a first event, 6 were in the no HDM group, and 5 in the HDM group. Eight of these second malignancies occurred in patients with T-ALL: 4 in the HDM (diffuse large cell lymphoma 5 years after diagnosis; acute myeloid leukemia at 1 year from diagnosis during continuation therapy; acute myelomonocytic leukemia 4 years postdiagnosis; and glioblastoma 12 years after diagnosis) and 4 in the no HDM group (acute myeloid leukemia 1 year after diagnosis while on continuation therapy, diffuse large cell lymphoma at 16 months after diagnosis during continuation therapy; medulloblastoma 9 years postdiagnosis; and myelodysplastic syndrome 4 years postdiagnosis). There were 3 second malignancies among the T-NHL patients: 1 on HDM (astrocytoma 6 years postdiagnosis) and 2 on no HDM arm (myeloid sarcoma 11 months from diagnosis while on continuation therapy; papillary carcinoma 10 years postdiagnosis).

Prognostic factors

Among patients with T-ALL, patients ≥ 10 years of age at diagnosis did poorly compared with younger patients (5-year EFS: 66.9% ± 4.2% vs 79.0% ± 3.3%, P = .01; Table 4). Similarly, high WBC (≥ 50 000/μL) was also a significant adverse prognostic factor (67.6% ± 3.6% vs lower WBC 81.5% ± 3.6%, P = .009). Patients with NCI standard risk features fared better than did those with high-risk features (EFS 85.5% ± 4.4% vs 69.8% ± 3.1%, P = .02). The presence of a mediastinal mass, CNS disease, and bulky adenopathy or splenomegaly, did not significantly correlate with prognosis in patients with either leukemia or lymphoma (P = .42 and 0.08, respectively). There was no prognostic significance for stage (stage III vs stage IV) among the lymphoma patients (P = .43). Table 4 gives 5-year EFS results on HDM versus no HDM arms by various prognostic factors and univariate Cox regression analyses adjusting for each prognostic factor for T-ALL (age, WBC, NCI risk, sex, and race) and T-NHL (stage).

Table 4

Univariate analyses of outcome by prognostic factors

Prognostic factor% No HDM 5-year EFS ± SE (n)% HDM 5-year EFS ± SE (n)Hazard ratioP
T-ALL     
    Age, y     
        Younger than 10 72.9 ± 4.9 (85) 85.6 ± 4.1 (78) 1.73 .01 
        10 or older 60.6 ± 6.3 (66) 72.8 ± 5.6 (70)   
    WBC     
        < 50 81.9 ± 5.1 (61) 81.2 ± 5.2 (64) 1.85 .01 
        ≥ 50 57.7 ± 5.4 (90) 78.4 ± 4.6 (84)   
    NCI risk     
        Standard 83.9 ± 6.7 (31) 86.8 ± 5.8 (38) 2.21 .01 
        High 63.3 ± 4.6 (120) 77.1 ± 4.2(110)   
    Sex     
        Male 61.4 ± 4.8 (109) 79.1 ± 4.0(111) 0.56 .03 
        Female 83.3 ± 5.8 (42) 80.7 ± 6.8 (37)   
    Race     
        White 68.0 ± 4.5 (113) 81.8 ± 3.7(116)   
        Black 65.6 ± 8.6 (32) 64.9 ± 11.6(23) 1.49 .33 
        Other 66.7 ± 19.3 (6) 88.9 ± 10.5 (9) 0.99  
T-NHL     
    Stage III 88.1 ± 5.1 (43) 79.9 ± 6.2 (45) 0.69 .43 
    Stage IV 87.0 ± 7.4 (23) 88.0 ± 7.2 (26)   
Prognostic factor% No HDM 5-year EFS ± SE (n)% HDM 5-year EFS ± SE (n)Hazard ratioP
T-ALL     
    Age, y     
        Younger than 10 72.9 ± 4.9 (85) 85.6 ± 4.1 (78) 1.73 .01 
        10 or older 60.6 ± 6.3 (66) 72.8 ± 5.6 (70)   
    WBC     
        < 50 81.9 ± 5.1 (61) 81.2 ± 5.2 (64) 1.85 .01 
        ≥ 50 57.7 ± 5.4 (90) 78.4 ± 4.6 (84)   
    NCI risk     
        Standard 83.9 ± 6.7 (31) 86.8 ± 5.8 (38) 2.21 .01 
        High 63.3 ± 4.6 (120) 77.1 ± 4.2(110)   
    Sex     
        Male 61.4 ± 4.8 (109) 79.1 ± 4.0(111) 0.56 .03 
        Female 83.3 ± 5.8 (42) 80.7 ± 6.8 (37)   
    Race     
        White 68.0 ± 4.5 (113) 81.8 ± 3.7(116)   
        Black 65.6 ± 8.6 (32) 64.9 ± 11.6(23) 1.49 .33 
        Other 66.7 ± 19.3 (6) 88.9 ± 10.5 (9) 0.99  
T-NHL     
    Stage III 88.1 ± 5.1 (43) 79.9 ± 6.2 (45) 0.69 .43 
    Stage IV 87.0 ± 7.4 (23) 88.0 ± 7.2 (26)   

T-ALL indicates T-cell acute lymphoblastic leukemia; T-NHL, T-cell lymphoblastic non-Hodgkin lymphoma; EFS, event-free survival; NCI, National Cancer Institute; and HDM, high-dose methotrexate.

Age 10 years or older, WBC at diagnosis ≥ 50 000/μL, NCI high risk, and male sex were each individually associated with worse outcomes. However, these differences were most pronounced in the no HDM group. Thus, patients with these higher-risk features demonstrated significant benefit when treated with HDM versus no HDM. Patients with lower risk features (ie, age younger than 10 years, WBC < 50 000/μL, NCI standard risk, and females) showed no significant difference in outcome based on treatment group with or without methotrexate.

Results of multivariate Cox regression analyses, restricted to T-ALL patients are presented in Table 5. Treatment regimen, age group, sex, NCI risk, WBC, and race were included in the model. Treatment regimen without HDM, older age group (10 years or older), and high WBC (≥ 50 000 μL) contributed to poor prognosis.

Table 5

Multivariate analysis (randomized T-ALL patients only)

Multivariate analysisRHR95% CI
Treatment   
    No HDM   
    HDM 0.606 0.389, 0.944 
Age group, y   
    Younger than 10   
    10 or older 2.013 1.198, 3.381 
Sex   
    Male   
    Female 0.587 0.334, 1.033 
NCI risk   
    Standard   
    High 0.629 0.243, 1.626 
WBC   
    < 50 000   
    ≥ 50 000 2.364 1.233, 4.533 
Race   
    White   
    Black 1.558 0.931, 2.607 
    Other 1.082 0.391, 2.999 
Multivariate analysisRHR95% CI
Treatment   
    No HDM   
    HDM 0.606 0.389, 0.944 
Age group, y   
    Younger than 10   
    10 or older 2.013 1.198, 3.381 
Sex   
    Male   
    Female 0.587 0.334, 1.033 
NCI risk   
    Standard   
    High 0.629 0.243, 1.626 
WBC   
    < 50 000   
    ≥ 50 000 2.364 1.233, 4.533 
Race   
    White   
    Black 1.558 0.931, 2.607 
    Other 1.082 0.391, 2.999 

RHR indicates relative hazard ratio; NCI, National Cancer Institute; and CI, confidence interval.

Toxicity

Toxicities were significant but manageable. Postinduction hematologic toxicities with severe grade 3 or 4 neutropenia, anemia and/or thrombocytopenia) were common in both treatment groups (94.4% HDM vs 91.5% no HDM; P = .26). Many patients experienced grade 3 or 4 infections, but they were not significantly more frequent in the HDM group compared with the no HDM patients (66.2% vs 65.7%; P = .9). Mucositis was significantly more frequent in the HDM regimen (17.8% HDM, 8.0% no HDM; P = .003). Neurologic toxicities were predominantly single episodes of seizure following intrathecal medications, but the incidence was not significantly different between treatment groups (12.2% HDM vs 8.0% no HDM; P = .15). Somnolence syndrome following cranial radiation therapy was reported in 1.62% and 0% of the HDM and no HDM patients, respectively (P = .16) and was generally mild and time limited.

Discussion

T-cell ALL and advanced stage lymphoblastic lymphomas are aggressive malignancies once associated with a very poor prognosis. In the 1980s, the POG adopted a strategy of lineage-specific treatment for T-ALL and T-NHL using protocols different from those used to treat patients with B lineage disease.20,22  The POG 8704 study (1987-1992) demonstrated an improved outcome for patients with T-ALL or T-NHL who were randomized to receive intensive high-dose asparaginase during consolidation (continuous complete remission 71% vs 58%; P < .001).20  This confirmed the findings of the DFCI protocols that used weekly high-dose asparaginase during postinduction therapy.33  On the basis of the excellent outcomes of DFCI ALL Consortium trials between 1981 and 1995 (aggregate 5-year EFS of 75% for T-ALL patients),15  we designed the current POG study to use this DFCI ALL Consortium backbone. The 5-year EFS of 68% for the T-ALL patients treated without HDM (control) arm of our study is lower than expected, and likely results from the changes in CNS prophylaxis that were made to accommodate the addition of HDM. The 5-year EFS of 88% for the patients with T-NHL on the control arm of our study without HDM is similar to those observed on the DFCI protocols. The results in the nonrandomized patients treated with HDM were similar to those in patients randomized to that treatment. Overall, the results of the current study compare favorably with results for T-lineage patients treated by other investigators.17-22 

The rationale for evaluating the efficacy of HDM was based on prior studies demonstrating differences in methotrexate pharmacology associated with leukemia cell immunophenotype.29,30  In 1990, Whitehead et al reported a favorable prognosis in children with ALL whose blasts accumulated high levels of methotrexate polyglutamates (MTX-PG) in vitro.37  Goker et al observed a lower accumulation of total methotrexate and methotrexate polyglutamates by T-lineage blasts compared with B-lineage blasts.38  The St Jude Total Therapy XIII study also showed lower methotrexate-polyglutamate accumulation in the blasts of T-ALL patients, following a single in vivo dose of methotrexate as initial treatment after diagnosis.29,30  The latter study also demonstrated that 1 g/m2 methotrexate infused over 24 hours resulted in higher blast methotrexate polyglutamate concentrations than divided dose oral methotrexate (180 mg/m2/course), and that the intracellular MTX-PG levels achieved in T-lineage blasts with the higher dose methotrexate were comparable with levels observed in B-lineage blasts following the low dose methotrexate. Most importantly, this study demonstrated that higher concentrations of MTX-PGs are associated with greater in vivo antileukemic effect.31  It is not known whether T-lineage blasts require higher intracellular MTX-PG concentrations to produce the same degree of antileukemic effect as in B-precursor blasts, but the improvement seen with increased methotrexate dose in the successive, nonrandomized, ALL-BFM trials was lineage-related. Specifically, the increase in MTX dose from 0.5 g/m2 in BFM-83 to 5.0 g/m2 in BFM-86 was associated with an improvement in the EFS of patients with T-ALL (52.7% vs 71.3%, respectively), not with B-precursor ALL (63.2% vs 69.8%, respectively).39  It is possible that methotrexate doses > 1 g/m2 would produce higher MTX-PG concentrations and thus a further enhanced antileukemic effect in patients with T-ALL.

Our study demonstrated a significantly improved outcome for T-ALL, but not lymphoblastic lymphoma in patients who received HDM. In 2000, the methotrexate randomization was closed based on an interim analysis that showed 3-year EFS of 72% ± 7% for no HDM and 86% ± 6% for HDM treatment groups (P = .002). With longer follow-up, the benefit of HDM was only seen in the leukemia patients and disappeared for the lymphoma patients. The benefit was most striking in T-ALL patients with additional high-risk features, specifically those older than age 10 years, those with initial WBC > 50 000/μL and male sex. Outcome for patients without these higher-risk features showed insignificant improvement with HDM but was in the same direction as in higher-risk patients. Among T-ALL patients the benefit of HDM was seen primarily in a decreased number of CNS relapses but not marrow or other sites. This is in contrast to the findings of a meta-analysis that suggested that the primary contribution of addition of higher doses of methotrexate was in control of systemic disease not CNS disease.27 

Overall outcomes for patients with T-NHL were better than T-ALL, and independent of stage of disease or CNS status. We have no clear explanation for the worse outcomes for patients with T-NHL treated with HDM. The events primarily were disease-related and not a result of increased toxicity from the additional HDM doses. Results from the Children's Cancer Group study A5971 also showed no improvement in EFS for patients with T-NHL with addition of HDM to a modified BFM backbone.40  The statistical power to detect a meaningful difference in EFS was low, however, because so few patients had T-NHL; thus, a benefit of HDM cannot be excluded. Because the study was designed to compare outcomes between regimens, the number of NHL patients in subgroups defined by disease, disease stage, CNS status, or pre- and post-amendments are insufficient to allow conclusions regarding specific subsets.

Cranial radiation was prescribed for all patients. The major treatment modification in adapting the DFCI regimen for our study was a delay of the cranial radiation from week 4 to week 22. We hypothesized that HDM and intrathecal chemotherapy doses would provide adequate protection of the CNS during the postinduction phase before radiation therapy. In addition, the series of 4 intrathecal doses given over 2 weeks as part of traditional DFCI postinduction CNS prophylaxis was spread out over 18 weeks with the net effect of reducing the total number of intrathecal doses from 11 to 10 (2 additional doses for CNS-2 and CNS-3 disease) given over 2 years. This decreased dose intensity of CNS prophylaxis may have contributed to the lower than expected event-free survival of patients on the control regimen (68% vs 75% in the DFCI studies). In comparison to other treatment protocols, especially those that omit cranial radiation, POG 9404 used fewer doses of intrathecal medications. For example, the ALL-BFM trials which have used HDM since 1986, have reduced the cranial radiation dose in a stepwise fashion while increasing the number of intrathecal methotrexate doses to 13 (all given by the end of reinduction without an increase in the CNS relapse rate).16,19,39 

CNS relapse was the most common single event in all treatment arms. One-third of the relapses involving the CNS occurred in the first 6 months of treatment. Although the total number of CNS relapses in the HDM group was smaller, the proportion of patients with early CNS events was the same as observed in the No HDM group suggesting the importance of cranial irradiation as a component of CNS disease prevention. The addition of HDM was inadequate early CNS disease prophylaxis for many patients. A possible explanation for the higher than expected early CNS failures is the decreased intensity of intrathecal chemotherapy given in the early intensification phase of therapy before cranial irradiation. In the successful ALL-BFM trials where cranial radiation therapy is administered at 6-7 months postdiagnosis the intensity of both intrathecal and systemic CNS prophylaxis was increased in comparison to our trial. Another potential contributing factor is interference by leucovorin with the antileukemia effects of HDM. For the majority of patients on this study, the leucovorin rescue schedule included an initial dose at 36 hours of 75 mg/m2 which was a modification of the ALL-BFM 86 trial.19  This is higher than the rescue doses of 15 mg/m2 at hours 42, 48, and 54 used on subsequent BFM regimens.16  Thus, the full benefits of HDM were potentially offset by a decrease in early treatment intensity, specifically delay in cranial radiation therapy, decreased number of intrathecal doses, and increased leucovorin rescue.

Identifying reliable prognostic factors for T-ALL treatment planning has been considerably more difficult than for B-precursor ALL.41  Nevertheless, within this trial, age, WBC at diagnosis, and gender were prognostic. For example, the addition of HDM in the group of patients > 10 years of age resulted in EFS of 78% which is essentially the same as the EFS seen in a lower-risk group of patients < 10 years who did not receive the additional courses of methotrexate. Minimal residual disease (MRD) was not evaluated in this study because the POG central laboratory had not developed a validated method in T-ALL. Other investigators have reported the value of higher MRD as a predictor of risk of relapse.42-44  Given the high intensity of treatment in this regimen and those used by other cooperative groups, it would be ideal to identify patients who may be cured by less toxic therapies. The converse is also true: patients identified as very high risk could be treated more intensively (eg, with allogeneic stem cell transplantation in first remission). The possible benefit of this approach was recently reported by the BFM group.45 

This study demonstrates the feasibility and benefits of addition of 4 cycles of HDM to a multi-agent chemotherapy regimen. Several elements of this treatment protocol, specifically the high-dose asparaginase and HDM have been shown to significantly benefit patients with T-lineage disease, eliminating the negative prognostic significance of T- versus precursor B-lineage. Although this regimen is not truly lineage specific, our results confirm the efficacy of this treatment for T-ALL.

Despite the improvements of the past 3 decades, outcomes for patients with T-ALL and T-NHL are not optimal. Relapse remains the major cause of treatment failure. Our data show minimal changes in outcomes after 5 years. In fact, events occurring beyond year 2 are rare. As expected, the salvage rates for patients with early failures are poor. Thus interventions to improve outcomes must occur early to prevent recurrence. Possible measures include: better risk stratification, prospective application of MRD measurements and early introduction of new agents. Recent trials suggest that evaluation of rapidity of response,21,33,39,46  and postinduction minimal disease measurements,42-44  as well as host pharmacogenomics47-49  may allow tailoring of treatment to the risk of disease recurrence rather than treating all children with T-ALL with increasingly intensive regimens. In the future, T-specific therapy may be developed that will add to the efficacy of treatment without a significant increase in toxicity. Nelarabine50  is an example of a T-specific drug that is currently being tested by the Children's Oncology Group in patients with T-ALL and T-NHL. The current COG front line trial is designed to evaluate the addition of 4 cycles of HDM to an augmented BFM regimen,21  with omission of prophylactic cranial radiation for a subset of lower risk patients, randomized assignment to nelarabine for higher-risk patients, and prospective use of MRD for risk assignment.

Presented in abstract form at the 37th annual meeting of the American Society of Clinical Oncology, San Francisco, CA, May 14, 2001.

The online version of this article contains a data supplement.

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 USC section 1734.

Acknowledgments

The authors thank Drs. William Carroll, Naomi Winick, and Stephen Hunger for their suggestions, insight, and support in development of this manuscript.

This work was supported in part by the Clinical Trials Evaluation Program of the National Cancer Institute, National Institutes of Health grant U10 CA098543. A complete listing of grant support for research conducted by the POG and Children's Cancer Group before initiation of the COG grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm.

National Institutes of Health

Authorship

Contribution: B.L.A., as study chair, designed and supervised the study, and wrote the manuscript; M.D. analyzed the data and wrote the “Results” section of the manuscript; C.W. assisted with data analysis and construction of data tables and graphs; J.P. contributed to the design and the conduct of the study and edited the manuscript; M.J.B. contributed to the design and performed flow cytometric studies to confirm T-cell immunophenotype, and edited the manuscript; R.H. performed centralized pathology review of all lymphoma biopsies at diagnosis to confirm lymphoblastic histology; S.E.L. contributed to the design of the study, monitored all aspects of cardiac studies, and edited the manuscript; and B.M.C. designed the study, chaired the POG ALL Committee, participated in the conduct of the study, and edited the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

A complete list of participants in the Children's Oncology Group is available in the supplemental Appendix (available on the Blood Web site; see the Supplemental Materials link at the top of the online article).

Correspondence: Barbara L. Asselin, Department of Pediatrics, Box 667, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642; e-mail: barbara_asselin@urmc.rochester.edu.

References

References
1
Sen
 
L
Borella
 
L
Clinical importance of lymphoblasts with T markers in childhood acute leukemia.
N Engl J Med
1975
, vol. 
292
 
16
(pg. 
828
-
832
)
2
Dowell
 
BL
Borowitz
 
MJ
Boyett
 
JM
, et al. 
Immunologic and clinicopathologic features of common acute lymphoblastic leukemia antigen-positive childhood T-cell leukemia: a Pediatric Oncology Group study.
Cancer
1987
, vol. 
59
 
12
(pg. 
2020
-
2026
)
3
Pui
 
CH
Christ
 
WM
Look
 
AT
Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia.
Blood
1990
, vol. 
76
 
8
(pg. 
1449
-
1463
)
4
Steinherz
 
PG
Siegel
 
SE
Bleyer
 
WA
, et al. 
Lymphomatous presentation of childhood acute lymphoblastic leukemia. A subgroup at high risk of early treatment failure.
Cancer
1991
, vol. 
68
 
4
(pg. 
751
-
758
)
5
Uckun
 
FM
Sensel
 
MG
Sun
 
L
, et al. 
Biology and treatment of childhood T-lineage acute lymphoblastic leukemia.
Blood
1998
, vol. 
91
 
3
(pg. 
735
-
746
)
6
Pullen
 
DJ
Sullivan
 
MP
Falletta
 
JM
, et al. 
Modified LSA2-L2 treatment in 53 children with E-rosette-positive T-cell leukemia: results and prognostic factors (a Pediatric Oncology Group study).
Blood
1982
, vol. 
60
 
5
(pg. 
1159
-
1168
)
7
Borowitz
 
MJ
Dowell
 
BL
Boyett
 
JM
, et al. 
Clinicopathologic aspects of E rosette negative T cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.
J Clin Oncol
1986
, vol. 
4
 
2
(pg. 
170
-
177
)
8
Crist
 
WM
Shuster
 
JJ
Falletta
 
J
, et al. 
Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiaion.
Blood
1988
, vol. 
72
 
6
(pg. 
1891
-
2081
)
9
Shuster
 
JJ
Falletta
 
JM
Pullen
 
DJ
, et al. 
Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.
Blood
1990
, vol. 
75
 
1
(pg. 
166
-
173
)
10
Pui
 
CH
Behm
 
FG
Singh
 
B
, et al. 
Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia.
Blood
1990
, vol. 
75
 
1
(pg. 
174
-
179
)
11
Pui
 
CH
Behm
 
FG
Christ
 
WM
, et al. 
Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia.
Blood
1993
, vol. 
82
 
2
(pg. 
343
-
362
)
12
Uckun
 
F
Reaman
 
G
Steinherz
 
P
, et al. 
Improved outcome for children with T-lineage acute lymphoblastic leukemia after contemporary chemotherapy: a Children's Cancer Group study.
Leuk Lymphoma
1996
, vol. 
24
 
1–2
(pg. 
57
-
70
)
13
Gaynon
 
P
Steinherz
 
P
Bleyer
 
WA
, et al. 
Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: a follow-up report of the Children's Cancer Group study CCG-106.
J Clin Oncol
1993
, vol. 
11
 
11
(pg. 
2234
-
2242
)
14
Schorin
 
MA
Blattner
 
S
Gelber
 
RD
, et al. 
Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber Cancer Institute/Children's Hospital ALL Consortium protocol 85-01.
J Clin Oncol
1994
, vol. 
12
 
4
(pg. 
740
-
747
)
15
Goldberg
 
JM
Silverman
 
LB
Levy
 
DE
, et al. 
Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience.
J Clin Oncol
2003
, vol. 
21
 
19
(pg. 
3616
-
3622
)
16
Schrappe
 
M
Reiter
 
A
Ludwig
 
W-D
, et al. 
Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90.
Blood
2000
, vol. 
95
 
11
(pg. 
3310
-
3322
)
17
Conter
 
V
Schrappe
 
M
Arieo
 
M
, et al. 
Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone.
J Clin Oncol
1997
, vol. 
15
 
8
(pg. 
2786
-
2791
)
18
Reiter
 
A
Schrappe
 
M
Ludwig
 
W-D
, et al. 
Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM Group report.
Blood
2000
, vol. 
95
 
2
(pg. 
416
-
421
)
19
Reiter
 
A
Schrappe
 
M
Ludwig
 
W-D
, et al. 
Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86.
Blood
1994
, vol. 
84
 
9
(pg. 
3122
-
3133
)
20
Amylon
 
MD
Shuster
 
J
Pullen
 
J
, et al. 
Intensive high dose asparaginase consolidation improves survival for pediatric patients with T-cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study.
Leukemia
1999
, vol. 
13
 (pg. 
335
-
342
)
21
Seibel
 
NL
Steinherz
 
PG
Sather
 
HN
, et al. 
Early postinduction intensification therapy improves survival for children and adolescents with high risk acute lymphoblastic leukemia: a report from the Children's Oncology Group.
Blood
2008
, vol. 
111
 
5
(pg. 
2548
-
2555
)
22
Winter
 
SS
Holdsworth
 
MT
Devidas
 
M
, et al. 
Antimetabolite-based therapy in childhood T-cell acute lymphoblastic leukemia:a report of POG study 9296.
Pediatr Blood Cancer
2006
, vol. 
46
 
2
(pg. 
179
-
186
)
23
Niemeyer
 
CM
Gelber
 
RD
Tarbell
 
NJ
, et al. 
Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (protocol 81-01 update).
Blood
1991
, vol. 
78
 
10
(pg. 
2514
-
2519
)
24
Chessells
 
JM
Bailey
 
C
Richards
 
SM
Intensification of treatment and survival in all children with acute lymphoblastic leukemia: results of UK Medical Research Council trial UKALL X.
Lancet
1995
, vol. 
345
 
8943
(pg. 
143
-
148
)
25
Pui
 
CH
Simone
 
JV
Hancock
 
ML
, et al. 
Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children: long-term results of St. Jude total therapy study X.
Leukemia
1992
, vol. 
6
 
2
(pg. 
150
-
157
)
26
Nathan
 
PC
Whitcomb
 
T
Wolters
 
PL
, et al. 
Very high-dose methotrexate (33.6 g/m2) as central nervous system preventive therapy for childhood acute lymphoblastic leukemia: results of National Cancer Institute/Children's Cancer Group trials CCG-191P, CCG-134P, and CCG-144P.
Leuk Lymphoma
2006
, vol. 
47
 
12
(pg. 
2488
-
2504
)
27
Clarke
 
M
Gaynon
 
P
Hann
 
I
, et al. 
CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Cooperative Group overview of 43 randomized trials.
J Clin Oncol
2003
, vol. 
21
 
9
(pg. 
1798
-
1809
)
28
Borsi
 
JD
Sagen
 
E
Romslo
 
I
Moe
 
PJ
Rescue after intermediate and high-dose methotrexate: background, rationale, and current practice.
Pediatr Hematol Oncol
1990
, vol. 
7
 
4
(pg. 
347
-
363
)
29
Barredo
 
JC
Synold
 
TW
Laver
 
J
, et al. 
Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia.
Blood
1994
, vol. 
84
 
2
(pg. 
564
-
569
)
30
Synold
 
TW
Relling
 
MV
Boyett
 
JM
, et al. 
Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.
J Clin Invest
1994
, vol. 
94
 
5
(pg. 
1996
-
2001
)
31
Masson
 
E
Relling
 
MV
Synold
 
TW
, et al. 
Accumlation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high dose methotrexate.
J Clin Invest
1996
, vol. 
97
 
1
(pg. 
73
-
80
)
32
Riehm
 
H
Gadner
 
H
Henze
 
G
, et al. 
Results and significance of six randomized trials in four consecutive ALL-BFM trials.
Haematol Blood Transfus
1990
, vol. 
33
 (pg. 
439
-
450
)
33
Silverman
 
LB
Declerck
 
L
Gelber
 
RD
, et al. 
Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).
Leukemia
2000
, vol. 
14
 
12
(pg. 
2247
-
2256
)
34
Asselin
 
B
Shuster
 
J
Amylon
 
M
, et al. 
Improved event-free survival with high dose methotrexate in T-cell lymphoblastic leukemia and advanced lymphoblastic lymphoma [abstract].
J Clin Oncol
2001
, vol. 
20
 pg. 
367a
  
Abstract 1464
35
LeClerc
 
JM
Billett
 
AL
Gelber
 
RD
, et al. 
Treatment of childhood acute lymphoblastic leukemia: results of the Dana-Farber ALL Consortium protocol 87-01.
J Clin Oncol
2002
, vol. 
20
 
1
(pg. 
237
-
246
)
36
Kaplan
 
E
Meier
 
P
Nonparametric estimation from incomplete observations.
J Amer Statist Assoc
1958
, vol. 
53
 (pg. 
457
-
481
)
37
Whitehead
 
VM
Rosenblatt
 
DS
Vuchich
 
M-J
Shuster
 
JJ
Witte
 
A
Beaulieu
 
D
Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis.
Blood
1990
, vol. 
76
 
1
(pg. 
44
-
49
)
38
Goker
 
E
Lin
 
JT
Trippett
 
T
, et al. 
Decreased polyglutamation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease.
Leukemia
1993
, vol. 
7
 
7
(pg. 
1000
-
1004
)
39
Schrappe
 
M
Reiter
 
A
Zimmermann
 
M
, et al. 
Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995.
Leukemia
2000
, vol. 
14
 
12
(pg. 
2205
-
2222
)
40
Abromowitch
 
M
Termuhlen
 
A
Chang
 
M
, et al. 
High-dose methotrexate and early intensification of therapy do not improve 3 year EFS in children and adolescents with disseminated lymphoblastic lymphoma. Results of the randomized arms of A5971 [abstract].
Blood (ASH Annual Meeting Abstracts)
2008
, vol. 
112
 
11
pg. 
1235a
  
Abstract 3610
41
Pullen
 
J
Shuster
 
JJ
Link
 
M
, et al. 
Significance of commonly used prognostic factors differs for children with T cell acute lymphoblastic leukemia (ALL), as compared to those with B-precursor ALL. A Pediatric Oncology Group (POG) study.
Leukemia
1999
, vol. 
13
 (pg. 
1696
-
1707
)
42
Chen
 
X
Pan
 
Q
Stow
 
P
, et al. 
Quantification of minimal residual disease in T-lineage acute lymphoblastic leukemia with the TAL-1 deletion using a standardized real-time PCR assay.
Leukemia
2001
, vol. 
15
 
1
(pg. 
166
-
170
)
43
Willemse
 
MJ
Seriu
 
T
Hettinger
 
K
, et al. 
Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL.
Blood
2002
, vol. 
99
 
12
(pg. 
4386
-
93
)
44
Kerst
 
G
Kreyenberg
 
H
Roth
 
C
, et al. 
Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia by flow cytometry and real-time PCR.
Br J Haematol
2005
, vol. 
128
 (pg. 
774
-
82
)
45
Schrauder
 
A
Reiter
 
A
Gadner
 
H
, et al. 
Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95.
J Clin Oncol
2006
, vol. 
24
 
36
(pg. 
5742
-
49
)
46
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
, vol. 
338
 
23
(pg. 
1663
-
1671
)
47
Relling
 
MV
Dervieux
 
T
Pharmacogenetics and cancer therapy.
Nat Rev Cancer
2001
, vol. 
1
 
2
(pg. 
99
-
108
)
48
Evans
 
WE
McLeod
 
HL
Pharmacogenomics–drug disposition, drug targets, and side effects.
N Engl J Med
2003
, vol. 
348
 
6
(pg. 
538
-
549
)
49
Evans
 
WE
Relling
 
MV
Moving towards individualized medicine with pharmacogenomics.
Nature
2004
, vol. 
429
 
6990
(pg. 
464
-
468
)
50
Kurtzberg
 
J
Ernst
 
TJ
Keating
 
MJ
, et al. 
Phase I Study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies.
J Clin Oncol
2005
, vol. 
23
 
15
(pg. 
3396
-
3403
)