Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: A report from the children's oncology group

Abstract

Background Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis. Intensification of therapy has resulted in fewer relapses but increased early deaths, resulting in failure to improve survival. Procedure AALL0631 is a Phase 3 study for infants (< 366 days of age) with newly diagnosed ALL. Induction initially (Cohort 1) consisted of 3 weeks of therapy based on COG P9407. Due to excessive early mortality, induction was amended to a less intensive 5 weeks of therapy based on Interfant-99. Additionally, enhanced supportive care guidelines were incorporated with hospitalization during induction until evidence of marrow recovery and recommendations for prevention/treatment of infections (Cohort 2). Results Induction mortality was significantly lower for patients in Cohort 2 (2/123, 1.6%) versus Cohort 1 (4/26, 15.4%; p=0.009). All induction deaths were infection related except one due to progressive disease (Cohort 2). Sterile site infections were lower for patients in Cohort 2 (24/123, 19.5%) versus Cohort 1 (15/26, 57.7%; p=0.0002), with a significantly lower rate of Gram positive infections during induction for patients in Cohort 2, p=0.0002. No clinically significant differences in grades 3–5 non-infectious toxicities were observed between the two cohorts. Higher complete response rates were observed at end induction intensification for Cohort 2 (week 9, 94/100, 94%) versus Cohort 1 (week 7, 17/25, 68%; p=0.0.0012). Conclusion De-intensification of induction therapy and enhanced supportive care guidelines significantly decreased induction mortality and sterile site infections, without decreasing complete remission rates.

Factors associated with a prolonged hospital stay during induction chemotherapy in newly diagnosed high risk pediatric acute lymphoblastic leukemia

“…On univariable analysis ( Approximately, one third of patients in both groups experienced unplanned readmissions within 30 days due to varied reasons. Despite this high readmission rate, we noted a low overall induction mortality of 2.7% (n=2), similar to previously reported studies 11,19 .…”

“…Pediatric and young adults with HR, VHR ALL, and Tlymphoblastic leukemia (T-ALL), are initially treated with a standard 4 drug induction regimen 2 , aimed at achieving a MRD negativity by day 29 8 . Induction therapy is often associated with a high burden of care due to increased therapy-related adverse events that require pediatric intensive care unit (PICU) care or a prolonged inpatient length of stay (LOS) [9][10][11][12] . However, despite standard induction regimens, there is a high variability amongst institutions with regards to timing of discharge for patients who appear clinically well 13 .…”

“…Neutropenia usually results from leukemic infiltration into the bone marrow or from bone marrow suppression secondary to ongoing infection at the time of leukemia diagnosis. ANC <200/mm3 has been identified as a risk factor for readmission and infection during induction chemotherapy 11,14,26 . However, these studies included both low risk (receiving 3-drug induction) and HR/VHR patients in their analysis 14 .…”

Treatment of infant leukemias: challenge and promise

“…22 Remarkably, the early death rate increased again on the successor COG trial AALL0631, with 4 of the first 26 patients (15%) dying from infections, although the only change to induction therapy was to substitute a single dose of PEG asparaginase for native E coli asparaginase. 23 Similar issues have been reported in infants with AML. Induction mortality on the Medical Research Council (MRC) protocols AML10 and AML12 was 12% and 3% for infants and older children, respectively.…”

Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib

“…This study was approved by the Institutional Review Board of Cincinnati Children's Hospital Medical Center. Patients were treated according to Children's Oncology Group protocols AALL0031, AALL0232, AALL0622, AALL1122, AALL0434, AALL1131 (2 g/m 2 dosing for patients with Down syndrome, 5 g/m 2 dosing for all others), AALL0631 (4 g/m 2 dosing), or AALL0932 (1 g/m 2 dosing, LR‐M arm). Dose reductions or omissions due to toxicity were made for subsequent HDMTX courses per protocol criteria or physician discretion in certain cases.…”