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.

1998 ◽  
Vol 16 (1) ◽  
pp. 246-254 ◽  
Author(s):  
D H Mahoney ◽  
J Shuster ◽  
R Nitschke ◽  
S J Lauer ◽  
N Winick ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lower Risk ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Dose Oral ◽  
B Lineage ◽  
Prevention Of Relapse

PURPOSE To determine whether early intensification with 12 courses of intravenous methotrexate and intravenous mercaptopurine (IVMTX/IVMP) is superior to 12 courses of repetitive, low-dose oral MTX with I.V. MP (LDMTX/IVMP) for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Seven hundred nine patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction. Patients were randomized to receive intensification with either IVMTX 1,000 mg/m2 plus IVMP 1,000 mg/m2 (regimen A) or LDMTX 30 mg/m2 every 6 hours for six doses with IVMP 1,000 mg/m2 (regimen B). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy (TIT) was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and TIT every 12 weeks for 2 years. RESULTS Six hundred ninety-nine (99%) patients achieved remission. Three hundred forty-nine were assigned to regimen A and 350 to regimen B. The estimated 4-year continuous complete remission (CCR) rate for patients treated with regimen A is 80.3% (SE = 2.9%) and with regimen B is 75.9% (SE = 3.1%). By log-rank analysis, regimen A demonstrated superior CCR (P = .013). Transient neutropenia/thrombocytopenia, bacterial sepsis, neurotoxicity, stomatitis, and hospitalizations were more frequent among patients treated on regimen A. CONCLUSION Intensification with IVMTX/IVMP is more effective than LDMTX/IVMP for prevention of relapse in children with B-precursor ALL at lower risk for relapse.

Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

2000 ◽  
Vol 18 (6) ◽  
pp. 1285-1294 ◽  
Author(s):  
Donald H. Mahoney ◽  
Jonathan J. Shuster ◽  
Ruprecht Nitschke ◽  
Stephen Lauer ◽  
C. Philip Steuber ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lower Risk ◽  
Lymphoblastic Leukemia ◽  
Effective Therapy ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Continuation Therapy ◽  
Increased Risk ◽  
Significant Difference ◽  
Prevention Of Relapse

PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m2 plus IV MP 1,000 mg/m2 (regimen A) or IV MTX 1,000 mg/m2 alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P = .5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study.

1994 ◽  
Vol 12 (7) ◽  
pp. 1383-1389 ◽  
Author(s):  
B Camitta ◽  
D Mahoney ◽  
B Leventhal ◽  
S J Lauer ◽  
J J Shuster ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Free Survival ◽  
Continuation Therapy ◽  
Potential Efficacy ◽  
Patients At Risk ◽  
B Lineage

PURPOSE To determine the potential efficacy and toxicity of intravenous (i.v.) methotrexate (MTX) and mercaptopurine (MP) as postremission intensification treatment for children with B-lineage acute lymphoblastic leukemia (ALL) at higher risk to relapse. PATIENTS AND METHODS Eighty-three patients (age 1 to 20 years) with higher-risk B-lineage ALL were entered onto this protocol. Following standard four-drug remission induction, 80 patients received 12 intensive 2-week cycles of MTX/MP: MTX 200 mg/m2 i.v. push, then 800 mg/m2 i.v. 24-hour infusion on day 1; MP 200 mg/m2 i.v. in 20 minutes, then 800 mg/m2 i.v. 8-hour infusion day 2; MTX 20 mg/m2 intramuscularly day 8; and MP 50 mg/m2 by mouth days 8 to 14. Age-based triple intrathecal therapy (MTX, hydrocortisone, and cytarabine) was administered for CNS prophylaxis. Continuation therapy was weekly MTX/MP (as on days 8 to 14) for 2 years. RESULTS Eighty-one patients (98%) entered remission. There were 28 relapses (marrow, n = 11; marrow and CNS, n = 2; isolated CNS, n = 9; testes, n = 5; ovaries, n = 1). No overt relapse occurred during the intensive phase of therapy. The event-free survival (EFS) rate at 4 years is 57.4% +/- 9.1% (SE). Hematologic, mucosal, and infectious toxicities were seen in 12%, 9%, and 5% of intensive MTX/MP courses, but were generally mild. CONCLUSION Combined data from this and our previous trial suggest that intensive MTX/MP may produce long-term disease-free survival in 70 to 75% of children with B-lineage ALL. In comparison to other intensive regimens, intensive MTX/MP is easy to administer, effective, and relatively nontoxic. If patients at risk for failure of MTX/MP can be identified prospectively, more aggressive regimens could be restricted to this smaller (25% to 30%) cohort.

scholarly journals Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2740-2748 ◽  
Author(s):  
Linda C. Stork ◽  
Yousif Matloub ◽  
Emmett Broxson ◽  
Mei La ◽  
Rochelle Yanofsky ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Occlusive Disease ◽  
Intrathecal Methotrexate ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Cancer Group ◽  
Starting Dose ◽  
Standard Risk

Abstract The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (± 1.8%) and to MP was 79.0% (± 2.1%; P = .004 log rank), although overall survival was 91.9% (± 1.4%) and 91.2% (± 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m2 per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m2 (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2690-2696 ◽  
Author(s):  
Ching-Hon Pui ◽  
John T. Sandlund ◽  
Deqing Pei ◽  
Dario Campana ◽  
Gaston K. Rivera ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Dose ◽  
Lower Risk ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Intrathecal Chemotherapy ◽  
Remission Induction ◽  
Cns Relapse ◽  
Risk Patients ◽  
Total Therapy

Abstract St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 × 109/L or more, or CNS-3 (5 or more leukocytes/μL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% ± 2.6% (SE); the 8-year rate was 78.6% ± 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% ± 0.8%, and that of isolated plus combined CNS relapse was 3.0% ± 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% ± 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m2 and 5.0% ± 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m2 (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether. (Blood. 2004;104:2690-2696)

scholarly journals Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2514-2519 ◽  
Author(s):  
CM Niemeyer ◽  
RD Gelber ◽  
NJ Tarbell ◽  
M Donnelly ◽  
LA Clavell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Childhood All ◽  
To Receive

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

A Report of the Event-Free Survival (EFS) and Neurotoxicity for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) on Pediatric Oncology Group (POG) Protocol 9405.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 882-882 ◽  
Author(s):  
Stephen Rodes ◽  
Beverly A. Bell ◽  
Sharon B. Abish ◽  
Jeanette Pullen ◽  
Allen Chauvenet ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
Preliminary Review ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Event Free Survival ◽  
Phase Dependence ◽  
Free Survival ◽  
Significant Difference ◽  
Standard Risk

Abstract POG 9405, a randomized phase III study for children with standard risk ALL, opened in 1994. The primary objectives were to determine effects on event-free survival (EFS) of: 1) higher (2.5g/m2) vs. standard (1g/m2) dose methotrexate (MTX) infusions during consolidation (in an attempt to obtain a plasma MTX target of 12 μmol) and (2) once vs. twice daily 6- mercaptopurine (MP) dosing during continuation (to improve the efficacy of MP based on its short half-life and S-phase dependence). Following remission induction, patients were randomized to: Regimens (Reg) A/B (MTX 1 g/m2 IV) or C/D (MTX 2.5 g/m2), all with MP 1g/m2 IV, q2 weeks (wk) x 12. Leucovorin 5 mg/m2 q6h x 5 began at hour 48 and continued until MTX level was <0.3μmol. MTX 20 mg/m2/wk IM and MP 75 mg/m2/day p.o. were given on alternate wks. Continuation was MTX 20 mg/m2/wk IM for all patients and MP 75 mg/m2 daily p.o. for A/C and 37.5 mg/m2 p.o. b.i.d for B/D. CNS prophylaxis was age-adjusted triple intrathecal therapy (TIT) for a total of 14–19 doses due to protocol modifications made because of concerns about neurotoxicity. Total treatment duration was 130 wks. 295 patients entered consolidation therapy. Reg A: 77, Reg B: 77, Reg C: 70, Reg D: 71. The overall 6 year EFS for the study was 80% ±2.4% (s.e.). The study closed prematurely in 1996 due to issues pertaining to neurotoxicity. There was no significant difference in EFS between the two 6-MP dosing regimens [once-daily 78% vs. twice-daily 83%; p = 0.222]. Only 36% of patients on Reg C/D received the full 12 courses of higher dose MTX due to above noted protocol modifications. Neither the efficacy nor the toxicity of higher dose MTX can be fully evaluated for this study. 57 Patients (19%) reported one or more grade 2–4 neurotoxicity event using the Common Toxicity Criteria (CTC) version 2.0. These events included: cortical toxicity 37 events (including 33 seizures), cerebellar 15, cognitive dysfunction 6, headaches 4, motor 3, and significant fatigue in 3 children. Preliminary review indicates no difference in neurotoxicity incidence based on MTX dose. This antimetabolite based study highlights the importance of monitoring for neurotoxicity, as well as other unexpected adverse events on subsequent leukemia treatment protocols.

scholarly journals Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2514-2519 ◽  
Author(s):  
CM Niemeyer ◽  
RD Gelber ◽  
NJ Tarbell ◽  
M Donnelly ◽  
LA Clavell ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Childhood All ◽  
To Receive

Abstract We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

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