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 COG A5971

Abstract The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival. From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification. The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here). Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms. These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

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6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Leukemia ◽

10.1038/sj.leu.2401986 ◽

2001 ◽

Vol 15 (1) ◽

pp. 74-79 ◽

Cited By ~ 22

Author(s):

K Schmiegelow ◽

U Bretton-Meyer

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Bone Marrow Toxicity ◽

High Dose Methotrexate ◽

Dose Methotrexate

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Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group.

Journal of Clinical Oncology ◽

10.1200/jco.1987.5.10.1646 ◽

1987 ◽

Vol 5 (10) ◽

pp. 1646-1654 ◽

Cited By ~ 33

Author(s):

J A Ortega ◽

M E Nesbit ◽

H N Sather ◽

L L Robison ◽

G J D'Angio ◽

...

Keyword(s):

Bone Marrow ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

Current Status ◽

Intrathecal Methotrexate ◽

Childhood All ◽

Cns Disease ◽

Cns Prophylaxis ◽

Cns Relapse ◽

Significant Difference

The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

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Outcome of 136 Children with Advanced Lymphoblastic Lymphoma Receiving an BFM-Type Therapy with Intensified Maintenance: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study

Blood ◽

10.1182/blood.v124.21.3049.3049 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3049-3049

Author(s):

Shosuke Sunami ◽

Masahiro Sekimizu ◽

Tetsuya Takimoto ◽

Tetsuya Mori ◽

Tetsuo Mitsui ◽

...

Keyword(s):

Maintenance Therapy ◽

Lymphoblastic Leukemia ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

Induction Phase ◽

Pediatric Leukemia ◽

Cns Disease ◽

Stage 4 ◽

Mediastinal Disease ◽

Significant Difference

Abstract BACKGROUND: Lymphoblastic lymphoma (LBL) accounts for 30% of childhood non Hodgkin’s lymphoma in Japan. From European and North American groups, favorable results have been reported, using treatment strategies for acute lymphoblastic leukemia, over 80% of event free survival rate even in advanced LBL. However there were few data on Japanese or Asian patients with LBL. Here we report final outcome of first nation-wide prospective study over one hundred cases with advanced childhood LBL from Japan. PATIENTS & METHOD: Patients with stage 3 or 4 LBL received for 9 weeks induction phase, which consisted of 7 drugs and triple IT , followed by three courses of high dose MTX(5g/m2). After high dose MTX, re-induction, early maintenance, and late maintenance phase were administered. With an attempt to intensify maintenance therapy,early maintenance was consisted by two cycles of four courses of six drugs(MTX, PSL,VCR, L-ASP, 6MP, THP#) and late maintenance was five cycles of five drugs(MTX, PSL,VCR, 6MP,AraC). We omitted local radiotherapy including prophylactic cranial radiotherapy except patient with initial central nervous system (CNS) disease. The total duration of the treatment was 24 month. RESULTS: From November 2004 to October 2010, 154 children with newly diagnosed advanced stage LBL were entered in this study. A total of 136 cases were eligible. Ages ranged from four month to 15 years, with a median of 9.07 years. Of the 136 patients, 36 were girls and 100 were boys. The distribution of clinical stage 3 and stage 4 was 82 and 54 patients respectively. 94 patients had primary mediastinal disease. 41 patients had BM disease, 31 patients had CNS disease and 8 patients had BM and CNS disease. 104 patients (76.5%) had precursor T LBL (T-LBL), 31 patients (22.8%) had precursor B LBL (B-LBL), onepatient (0.7%) had bi phenotype LBL. The follow-up time ranged from 2.8 to 94 months, with a median 58 months. For the 136 patients analyzed in this study, 5-year OS was 82.9% and 5-year EFS was 77.9%. There was no significant difference in outcome by gender (5-year EFS, male 78.2% vs. female 73.0%), or by immunophenotype (5-year EFS, B-LBL 80.7% vs. T-LBL 76.9%). Of note, the 5-year EFS for stage 3 T-LBL patients were worse than that of stage 4 T-LBL patients (70.6% vs. 88.9%, P=0.031). There were also significant difference in 5-year EFS for T-LBL patients who achieved CR and CRu at end of induction, 86.9%, and 69.7% (P=0.034), respectively.Most events were observed as mediastinum enlargement before initiation of intensified maintenance therapy. CONCLUSIONS: Our firstnationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve survival outcome. Our result also emphasize the significant difference between T-LBL stage 3 and stage 4 and might suggest the difference in ethnicity for the composition of biological subgroup in T-LBL. THP: Pirarubicin Disclosures No relevant conflicts of interest to declare.

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Shortening Infusion Time for High-Dose Methotrexate Alters Antileukemic Effects: A Randomized Prospective Clinical Trial

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.5340 ◽

2011 ◽

Vol 29 (13) ◽

pp. 1771-1778 ◽

Cited By ~ 33

Author(s):

Torben S. Mikkelsen ◽

Alex Sparreboom ◽

Cheng Cheng ◽

Yinmei Zhou ◽

James M. Boyett ◽

...

Keyword(s):

Bone Marrow ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

The United States ◽

Leukemia Cells ◽

High Dose ◽

Infusion Time ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Infusion Duration

Purpose To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m2) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG1-7) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes. Methods From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m2) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG1-7 in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells). Results The 24-hour infusion resulted in significantly higher amounts of MTXPG1-7 in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/109 cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect on MTXPG1-7 accumulation in hyperdiploid ALL (median: 3,919 v 2,417 pmol/109 cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG1-7 but greater antileukemic effects with the longer infusion (median decrease in leukemia cells: 88.4% v 51.8%, P = .0075). In contrast, infusion duration had no significant impact on MTXPG1-7 accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation. Conclusion Shortening the infusion time of HDMTX reduces accumulation of active methotrexate in leukemia cells and decreases antileukemic effects, with differing consequences among major ALL subtypes.

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Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)

Blood ◽

10.1182/blood-2010-06-292615 ◽

2011 ◽

Vol 118 (4) ◽

pp. 874-883 ◽

Cited By ~ 105

Author(s):

Barbara L. Asselin ◽

Meenakshi Devidas ◽

Chenguang Wang ◽

Jeanette Pullen ◽

Michael J. Borowitz ◽

...

Keyword(s):

T Cell ◽

Lymphoblastic Leukemia ◽

Randomized Study ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Oncology Group ◽

Dose Methotrexate ◽

Increased Risk ◽

The Difference

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.

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Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)

Yearbook of Pediatrics ◽

10.1016/j.yped.2011.10.011 ◽

2013 ◽

Vol 2013 ◽

pp. 497-499

Author(s):

J.A. Stockman

Keyword(s):

T Cell ◽

Lymphoblastic Leukemia ◽

Randomized Study ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

Advanced Stage ◽

High Dose Methotrexate ◽

Oncology Group ◽

Dose Methotrexate

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Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

Supportive Care in Cancer ◽

10.1007/s00520-021-06395-3 ◽

2021 ◽

Author(s):

Riitta Niinimäki ◽

Henri Aarnivala ◽

Joanna Banerjee ◽

Tytti Pokka ◽

Kaisa Vepsäläinen ◽

...

Keyword(s):

Folinic Acid ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Optimal Dosage ◽

High Dose Methotrexate ◽

Reduced Dose ◽

Dose Methotrexate ◽

Antileukemic Effect ◽

Folinic Acid Rescue ◽

High Doses

Abstract Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

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