This article is more than 5 years old. Information may no longer be current.
Dasatinib, chemotherapy combination appears effective in pediatric patients with leukemia subtype
ATLANTA — The addition of dasatinib to imatinib plus chemotherapy conferred survival benefit and appeared safe in pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, according to results of a phase 2 study presented at the ASH Annual Meeting and Exposition.
Stephen P. Hunger, MD, chief of the Division of Oncology, director of the Center for Childhood Cancer Research, and Jeffrey E. Perelman Distinguished Chair in Pediatrics at Children’s Hospital of Philadelphia, and colleagues conducted a phase 2 trial of dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) added to the chemotherapy regimen used in the EsPhALL trial in pediatric patients with Philadelphia chromosome-positive (Ph+) ALL at Children’s Oncology Group sites across North America and Australia and EsPhALL sites in Italy and the United Kingdom.
Biondi and colleagues demonstrated, through the 2012 EsPhALL trial, that the addition of imatinib (Gleevec, Novartis) to various intensive chemotherapy regimens improved event-free and overall survival in pediatric patients with Ph+ALL.
However, dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) emerged as a possible treatment option because, as background data indicated, the therapy is 300-times more potent than imatinib in vitro and it is active against most mutations that can cause imatinib resistance.
Hunger and colleagues measured minimal residual disease (MRD) by assessing immunoglobulin (Ig) and T-cell receptor (TCR) genes through polymerase chain reactions, as well as flow cytometry. Patients with MRD 0.05% at the end of day 78 and those with MRD 0.005-0.05% at end of day 78 who remained MRD-positive at any detectable level after three additional high-risk chemotherapy blocks underwent HSCT during first remission.
Three-year event-free survival served as the primary endpoint.
From April 2012 to May 2014, 109 (median age, 9 years; range, 1-17; 80% white) patients enrolled in the study. However, three did not meet inclusion criteria and did not receive any therapies.
Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy.
Every patient was included in the safety analysis; however, two patients were not included in the efficacy analysis because of a retrospective diagnosis of blast-crisis chronic myeloid leukemia.
Seventy-five percent of patients completed 3 or more years of follow-up.
Nineteen patients met study criteria for HSCT, and 14.2% received HSCT during first remission.
The remaining 85.8% of patients received EsPhALL chemotherapy plus dasatinib without HSCT.
The most common toxicities included febrile neutropenia and infection. Grade 3 or higher febrile neutropenia occurred in 75.5% of patients and 18.9% of patients experienced a grade 3 or higher case of sepsis.
Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious grade 3 or higher dasatinib-related adverse events reported in more than 10% of patients
Relevant grade 3 or higher non-hematologic, non-infectious toxicities that were dasatinib-related included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%) and cardiac failure (0.8%).
Every patient reached complete remission.
Thirty-three events occurred, including five deaths – three occurring in the third high-risk chemotherapy regimen and two in reinduction – due to proven or suspected infection among the 91 patients receiving dasatinib plus chemotherapy. Two additional deaths occurred from infection post-HSCT in the 15 patients who underwent HSCT.
“Early in the conduct of the study we saw significant infectious toxicity and a few deaths from infection during the phases of therapy that include intensive chemotherapy, high dose corticosteroids and TKIs,” Hunger told HemOnc Today. “Similar issues were seen with imatinib combined with the same chemotherapy regimen. We amended the trial to augment the supportive care recommendations and no longer had significant problems with treatment related mortality.”
Three-year EFS was 66% and the 3-year OS was 92.3%.
“These results need longer follow-up but are similar to the results of [previous] trials of TKI [treatments] for pediatric ALL despite having the lowest rates of SCT and cranial irradiation,” Hunger said in the interview. “One key finding is that many patients that relapse after treatment with chemotherapy plus TKI can be salvaged with second-line therapy, which makes us comfortable limiting the use of SCT in first remission.”
Combined with the results from previous trials of TKI therapies – three with imatinib and two with dasatinib – outcomes for this patient populations are significantly better than they were prior to the use of TKIs, according to Hunger.
“There is still a relatively high relapse risk, but many patients can be cured after second-line therapy so that overall survival rates approach those seen in other pediatric ALL subsets,” he said. “We need to develop better predictors to identify patients who do or do not need SCT in first remission and we need to address whether or not TKI therapy should be continued for longer than 2 years.” – by Ryan McDonald
Reference:
Biondi A, et al. Lancet Oncol. 2012;doi:10.1016/S1470-2045(12)70377-7.
Hunger SP, et al. Abstract 98. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Hunger reports consultant roles with Amgen, Erytech Pharmaceuticals and Novartis. Hunger also reports honoraria from Jazz Pharmaceuticals, and equity ownership in Amgen.