Adding Brentuximab Vedotin to Chemotherapy Improves Outcomes in Pediatric ALK-Positive ALCL

The addition of brentuximab vedotin to chemotherapy led to favorable overall survival (OS) and event-free survival (EFS) in children with ALK-positive anaplastic large cell lymphoma (ALCL), according to results published in Blood. These outcomes were comparable to those seen with the use of conventional chemotherapy, the authors, led by Eric Lowe, MD, of the Children’s Hospital of The King’s Daughters in Norfolk, Virginia, noted.

ANHL12P1, a randomized phase II study, enrolled a total of 68 pediatric patients with newly diagnosed, nonlocalized ALK-positive/CD30+ ALCL. At time of enrollment, the patients’ median age was 12 years (range = 2-21 years).

Patients were treated according to the ALCL99 protocol, as described in the TABLE. Treatment consisted of prophase for five days, followed by six alternating cycles of chemotherapy administered every 21 days. On day one of each of the six cycles, patients also received brentuximab vedotin intravenously, starting at a dose of 1.8 mg/kg, with a maximum dose of 180 mg, for 30 minutes before other chemotherapy. If certain toxicities occurred – including grade 2 pancreatitis, grades 2 or 3 peripheral neuropathy, grade 2 pneumonitis, or grades 3 or 4 nonhematologic events – doses were reduced to 1.2 mg/kg (maximum of 120 mg), followed by 0.8 mg/kg (maximum of 80 mg). The overall duration of treatment was five months.

If patients experienced any grade of anaphylaxis or progressive multifocal leukoencephalopathy, grades 3 or 4 pancreatitis, grade 4 peripheral neuropathy, grades 3 or 4 pneumonitis, or severe renal impairment, brentuximab vedotin was permanently discontinued.

Response evaluation occurred after cycles two and six, as well as at cycle four in patients who did not experience a complete response (CR) following the second cycle.

The primary endpoints of the study included the incidence of grade ≥3 nonhematologic adverse events and EFS.

A total of 66 patients completed all six cycles of chemotherapy, providing investigators with 399 evaluable treatment cycles. In the evaluable patients, there were no incidences of toxic deaths or cases of progressive multifocal leukoencephalopathy syndrome. No cases of grades 3 or 4 neuropathy were observed in the study group.

These safety findings are notable, the authors wrote, given that some of the major concerns regarding the addition of new agents to conventional chemotherapy center on an increased risk of toxicity. The investigators posit that the younger age of this cohort may have been protective against side effects, or that the six doses used in the study were not enough to cause neuropathy or other toxic effects.

Relapses were recorded in 14 patients. “Like previous pediatric ALCL trials, the vast majority of relapses occurred shortly after the completion of chemotherapy,” the authors wrote, at a median of 7.5 months from diagnosis (range = 5.5-22 months), with 11 (79%) occurring within 10 months of initial diagnosis. Only one patient experienced a relapse prior to off-therapy evaluation.

The estimated two-year rates of OS and EFS in the patient population were 97.0% and 79.1%, respectively. Among patients who underwent evaluation after cycle two, the CR rate was 62%. Nearly all patients experienced a CR (97%) at cycle six evaluation.

The only prognostic factor for EFS that was identified in a univariate analysis was lung involvement (p=0.026). Minimal disseminated disease (MDD), as measured in peripheral blood by quantitative reverse transcription polymerase chain reaction using >10 normalized copy number as positive, was also considered highly predictive of outcome and two-year EFS (p=0.0004). In patients who were MDD-negative, the estimated two-year EFS rate was 89.0%, compared with 52.6% in MDD-positive patients.

The authors concluded that, “our study has reaffirmed the potential use of MDD in peripheral blood to establish risk categories and the need for quantitative MDD analysis to be harmonized across research groups in the future.”

Study authors report no relevant conflicts of interest.

Reference

Lowe EJ, Reilly AF, Lim MS, et al. Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ALCL: Results of COG trial ANHL12P1. [published online ahead of print, 2021 Mar 8]. Blood. doi: 10.1182/blood.2020009806.