PURPOSE Determine the efficacy and toxicity of higher dose versus standard

PURPOSE Determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate and pulses of high dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL). gm/m2 versus 2.5 gm/m2 and to cytosine arabinoside/teniposide versus high dose cytosine arabinoside/asparaginase during Rabbit polyclonal to WBP2.WW domain-binding protein 2 (WBP2) is a 261 amino acid protein expressed in most tissues.The WW domain is composed of 38 to 40 semi-conserved amino acids and is shared by variousgroups of proteins, including structural, regulatory and signaling proteins. The domain mediatesprotein-protein interactions through the binding of polyproline ligands. WBP2 binds to the WWdomain of Yes-associated protein (YAP), WW domain containing E3 ubiquitin protein ligase 1(AIP5) and WW domain containing E3 ubiquitin protein ligase 2 (AIP2). The gene encoding WBP2is located on human chromosome 17, which comprises over 2.5% of the human genome andencodes over 1,200 genes, some of which are involved in tumor suppression and in the pathogenesisof Li-Fraumeni syndrome, early onset breast cancer and a predisposition to cancers of the ovary,colon, prostate gland and fallopian tubes. intensified continuation therapy. RESULTS Patients receiving standard dose methotrexate experienced 5-yr DFS of 71.8 ± 2.4%; individuals receiving higher dose methotrexate experienced 5-yr DFS of 71.7 ± 2.4% (p=0.55). Results on cytosine arabinoside/teniposide (DFS of 70.4 ± 2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1 ± 2.3%) (p=0.41). OS rates were not different between methotrexate doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase. CONCLUSION Increasing methotrexate dosing to 2.5 gm/m2 did not improve outcomes in higher risk pediatric B-precursor ALL. Providing high dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant variations in outcomes allowing for teniposide to be removed from ALL therapy. Launch Survival of kids with severe lymphoblastic leukemia (ALL) provides increased dramatically within the last fifty years.1-14 Multiagent systemic chemotherapy prophylactic central nervous program therapy and intensive supportive treatment have contributed to the progress.15 Furthermore the capability to better identify children at higher risk of relapse offers led to risk-stratified treatment protocols. Using factors such as individual age white blood cell count (WBC) at analysis cytogenetics and DNA index a group of individuals with B-precursor ALL with a higher risk of relapse can be selected to receive intensified therapy.16 Early Pediatric Oncology Group (POG) protocols demonstrated that anti-metabolite therapy was inadequate for many higher risk individuals.4 17 In POG protocol 8602 (1986-1991) 5-12 months event free survival for higher risk individuals was 60% versus 80% for standard risk individuals.4 18 This study examined whether adding Cytarabine (cytosine arabinoside ara-C) or L-asparaginase to methotrexate (MTX)-based intensification therapy improved overall outcomes.18 19 Overall outcomes improved but it was unclear whether ara-C experienced any independent effect. POG 9006 (1991-1994) tested the Goldie-Coldman hypothesis of using revolving mixtures of anti-leukemic medicines (including ara-C) versus intensified intravenous mercaptopurine (6-MP) plus MTX (1 gm/m2) only during early consolidation.20 Early interim analysis showed that revolving intensified consolidation appeared to be more effective and the study was closed.20 After data maturation however there was no significant difference in leukemia-free survival between the two treatments.4 Although not seen in POG 9006 intensification with intermediate dose MTX (1 gm/m2) has improved BMS-740808 event-free survival in children with ALL.21-24 In 1994 BMS-740808 POG opened a group-wide randomized Phase III clinical trial (POG 9406) to study the part of intensified chemotherapy in children with higher risk B-precursor ALL. The primary objectives of the study were to (1) determine the effectiveness of higher dose (2.5 gm/m2 over 24 hours) versus standard dose (1 gm/m2 over 24 hours) intravenous MTX during intensified continuation therapy; and (2) determine whether pulses of high dose ara-C (3 gm/m2 × 4 doses) with asparaginase were superior to pulses of teniposide and ara-C (150 mg/m2/day time × 72 hours) during intensified continuation therapy. We survey the full total outcomes of the trial. Patients and strategies Sufferers POG 9406 enrolled sufferers between November 15 1994 and November 15 1999 Regional institutional review plank approval and created up to date consent from the individual and/or a mother or father were required ahead of enrollment. Eligibility Eligibility included (1) recently diagnosed B-precursor ALL; (2) enrollment over the POG 9400 classification research; and (3) conference the requirements for risky B-precursor ALL. Those requirements were (1) age group 10.00-21.99 years without trisomies of chromosomes 4 and 10 [if cytogenetic studies were informative (karyotypically abnormal)] or with DNA index ≤1.16 if cytogenetic research were uninformative; (2) any age group with existence of t(1;19) t(4;11) t(9;22) CNS leukemia or testicular disease; or (3) age BMS-740808 group 1.001- 9.99 years with initial WBC ≥50 0 without trisomies of chromosomes 4 and 10 or with DNA index ≤1.16 (if cytogenetic research were uninformative). Sufferers < a year of age weren't eligible. Description of disease and.