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

252

201

Key Points• Largest prospective trial for adult Burkitt lymphoma/ leukemia patients. • Substantial cure rates and high treatment-realization rates in all age groups.This largest prospective multicenter trial for adult patients with Burkitt lymphoma/ leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P 5 .0005), age-adjusted IPI score (0-1 vs 2-3; P 5 .0001), and gender (male vs female; P 5 .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082. (Blood. 2014;124(26):3870-3879)

Section: Discussionmentioning

confidence: 96%

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Hoelzer

Walewski

Döhner

et al. 2014

252

201

“…72 Although the optimal dosage and number of courses of high-dose methotrexate remain to be determined for individual subtypes of ALL, based on current evidence and pharmacologic studies in ALL subtypes, we recommend the infusion of high dose (ϳ 5 g/m 2 ) over 24 hours for T-cell cases and those with TCF3-PBX1 fusion. 69,73 For patients who PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA 1169 BLOOD, 9 AUGUST 2012 ⅐ VOLUME 120, NUMBER 6…”

Section: Selecting Effective Consolidation/intensification/ Reinductimentioning

confidence: 99%

“…Among different strategies of intensification of methotrexate, extended intravenous infusion (ie, over 24 hours) at high doses (eg, 5 g/m 2 ) has been widely used for patients with T-cell ALL. 69,70 Although the addition of escalating intravenous methotrexate (initial dose 100 mg/m 2 , increasing by 50 mg/m 2 every 10 days for 4 doses) without leucovorin rescue has been shown to improve the outcome of standard-risk ALL, 71 it was not as effective or less toxic than high-dose methotrexate with leucovorin rescue in a recent COG study for high-risk ALL. 72 Although the optimal dosage and number of courses of high-dose methotrexate remain to be determined for individual subtypes of ALL, based on current evidence and pharmacologic studies in ALL subtypes, we recommend the infusion of high dose (ϳ 5 g/m 2 ) over 24 hours for T-cell cases and those with TCF3-PBX1 fusion.…”

Section: Selecting Effective Consolidation/intensification/ Reinductimentioning

confidence: 99%

“…72 Although the optimal dosage and number of courses of high-dose methotrexate remain to be determined for individual subtypes of ALL, based on current evidence and pharmacologic studies in ALL subtypes, we recommend the infusion of high dose (ϳ 5 g/m 2 ) over 24 hours for T-cell cases and those with TCF3-PBX1 fusion. 69,73 For patients who receive such high dose, we would also individualize the dosage to achieve the desired steady-state plasma concentration (65M) not only to optimize antileukemic effects but also to reduce toxicity ( Figure 3). …”

Section: Selecting Effective Consolidation/intensification/ Reinductimentioning

confidence: 99%

See 1 more Smart Citation

Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?

Pui

Mullighan

Evans

et al. 2012

Self Cite

449

339

Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients. (Blood. 2012;120(6):1165-1174) IntroductionOptimal use of existing antileukemic agents and improved supportive care in contemporary clinical trials have improved the 5-year survival rate of childhood acute lymphoblastic leukemia (ALL) above 85% in developed countries (Table 1). [1][2][3][4][5][6][7][8] Further advances in survival and quality of life will require a better understanding of ALL pathobiology, the mechanisms of drug resistance, and drug disposition in the host, together with the development of innovative therapeutics. To this end, the advent of high-resolution genomewide analyses of gene expression, DNA copy number alterations, and epigenetic changes, and more recently, next-generation wholegenome and transcriptome sequencing have provided new insights into leukemogenesis, drug resistance, and host pharmacogenomics, identified novel subtypes of leukemia, and suggested potential targets for therapy. 9,10 Paralleling these advances has been the development of novel monoclonal antibodies, small molecule inhibitors, chemotherapeutics, and cell-based treatment strategies. 9 Here we discuss some of the current challenges and future directions in pediatric ALL research. Emerging leukemia subtypesTraditionally, ALL has been classified into precursor T (or T-cell), precursor B, and B-cell (Burkitt) phenotypes, which are then further subdivided according to recurrent karyotypic abnormalities, including aneuploidy and translocations. 9,11 Detailed profiling of submicroscopic alterations and mutational analyses have allowed refinement of these classification schema, identification of genetic alterations that coexist and cooperate with chromosomal alterations in leukemogenesis, and discovery of new ALL subtypes that lack alterations on cytogenetic analysis. Like acute myeloid leukemia, 12 many ALL subtypes are characterized by genetic alterations that perturb multiple key cellular pathways, including hematopoietic development, signaling or proliferation, and epigenetic regulation. Recent studies have identified a novel high-risk immature T-cell subtype, termed "early T-cell precursor" ALL, which is characterized by immunologic markers and a gene expression profile reminiscent of double-negative 1 thymocytes that retain the ability to differentiate into both T-cell and myeloid, but not B-cell, lineages. 13 Whole genome sequencing showed that the mutational spectru...

“…[1][2][3][4] Mikkelsen et al 5 showed that a 1 g/m 2 dose given over 24 hours resulted in significantly greater active methotrexate polyglutamates in leukemic cells than the same dose given over 4 hours. In a randomized clinical trial, investigators from the Children's Oncology Group (COG) tested the efficacy and toxicity of a 2 g/m 2 dose over 4 hours versus a 1 g/m 2 dose over 24 hours.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide study of methotrexate clearance replicates SLCO1B1

Ramsey

Panetta

Smith

et al. 2013

Self Cite

181

150

Key Points• A genome-wide study of the association of over 5 million SNPs with methotrexate clearance in 1279 patients treated with HDMTX in multicenter COG trials 9904 and 9905.• We replicated the finding that inherited variations in SLCO1B1 are the most important genetic variations influencing methotrexate clearance.Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m 2 dose or 4-hour infusion of a 2 g/m 2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P ‫؍‬ 7 ؋ 10 ؊7 ), girls (P ‫؍‬ 2.7 ؋ 10 ؊4 ), and those who received a delayed-intensification phase (P ‫؍‬ .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P ‫؍‬ 2.1 ؋ 10 ؊11 ). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 ؋ 10 ؊19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. IntroductionHigh-dose methotrexate (HDMTX) is an important element of chemotherapy in the treatment of acute lymphoblastic leukemia (ALL) and other malignancies. [1][2][3][4] Mikkelsen et al 5 showed that a 1 g/m 2 dose given over 24 hours resulted in significantly greater active methotrexate polyglutamates in leukemic cells than the same dose given over 4 hours. In a randomized clinical trial, investigators from the Children's Oncology Group (COG) tested the efficacy and toxicity of a 2 g/m 2 dose over 4 hours versus a 1 g/m 2 dose over 24 hours. 6,7 The systemic exposure to methotrexate (ie, plasma concentration over time) is related to cure and toxicity in children with ALL. 8,9 In a group of children with ALL who were treated and monitored at a single institution (St Jude Children's Research Hospital), with extensive prospective therapeutic drug monitoring, even including pharmacokinetically guided dosage adjustments, we identified variants in the SLCO1B1 gene that were associated with methotrexate clearance in a genome-wide association study (GWAS). 10,11 Herein, we sought to test whether we could replicate these GWAS findings in a large cohort of patients treated with alternative HDMTX schedules on the COG multi-institutional trials P9904 and P9905. MethodsThis study was approved by the institutional review boards of all participating institutions, and informed consent was obtained in accordance with the Declaration of Helsinki. Patients in P9904 included National Cancer Institute (NCI) standard-risk (age 1.00-9.99 years and initial white blood cell count [WBC]Ͻ 50 000/L) patients with an ETV6-RUNX1 translocation or simultaneous trisomies of chromosomes 4 and 10, whereas patients in P9905 included a mixture of NCI standard-risk patients without favorable genetic lesions, NCI high-risk (age...