Reduced Vincristine/Dexamethasone Dosing Schedule Shows Impressive Outcomes, Improved QoL in Pediatric B-ALL

Anne Angiolillo, MD

A reduced frequency of maintenance vincristine and dexamethasone led to a 5-year overall survival (OS) rate of 98.6% and improved quality of life (QoL) in pediatric patients with newly diagnosed, standard-risk B-cell acute lymphoblastic leukemia (B-ALL), according to results of a Children’s Oncology Group (COG) study that was published in the Journal of Clinical Oncology.

In the 2x2 factorial design COG AALL0932 study, investigators enrolled 9229 patients with newly diagnosed B-ALL; 2364 average-risk patients were randomized to receive maintenance vincristine/dexamethasone pulses at the standard every-4-week schedule or every 12 weeks, along with a starting dose of oral methotrexate at 20 mg/m² or 40 mg/m² once weekly. Researchers aimed to determine whether the change in schedule would reduce toxicities without sacrificing efficacy.

Data showed that the 5-year disease-free survival (DFS) rate in those who received the standard vincristine/dexamethasone schedule was 94.1% versus 95.1% for patients treated at the every-12-week frequency. Additionally, the 5-year OS rates were 98.3% and 98.6%, respectively.

In patients treated with the 20 mg/m² of methotrexate, the 5-year DFS and OS rates were 95.1% and 98.8% versus 94.2% and 98.1% for those who received methotrexate at 40 mg/m².

The results have had a major effect on the dosing schedule for this population, said lead study author, Anne Angiolillo, MD, adding that they will ultimately translate on QoL with the child as they receive their maintenance therapy.

"I'm really excited that the results from COG AALL0932 will have a major effect on the schedule of maintenance therapy for children with standard-risk and high-risk B-cell acute lymphoblastic leukemia within COG,” said Angiolillo. “We have taken these data already and incorporated it into our newest frontline trials. It was a huge shift for thousands of providers and patients, and most importantly, the child and their quality of life will be improved."

In an interview with OncLive, Angiolillo, who is director of the Leukemia and Lymphoma Program of Children’s National, discussed the impressive findings in detail and how they can be immediately applied to clinical practice of pediatric patients with B-ALL.

OncLive: This study evaluated a reduced frequency of vincristine and dexamethasone pulses in standard-risk B-ALL. What was the rationale to create this kind of study? What is the unmet need of this population?

Angiolillo: AALL0932 was a phase 3 clinical trial open within COG that enrolled more than 9000 patients in over 200 centers. It was designed just for patients with newly diagnosed, standard-risk B-ALL. Its main objective was to explore the delivery of maintenance therapy. As a pediatric oncologist, we're so proud that for children with this diagnosis, their actual OS and DFS was quite good at the start of the trial.

Our main goal was: how can we maintain these excellent outcomes while, hopefully, reducing the burden of therapy? It has 2 maintenance questions. What would happen if we increased standard methotrexate dosing from the standard 20 mg/m² to 40 mg/m², with and without altering the frequency of the standard vincristine/dexamethasone pulses?

Traditionally, within COG for decades, it was given every 4 weeks, and we explored what would happen if we gave it every 12 weeks. It was a 2x2 multifactorial design, where the children received either 20 mg/m² or 40 mg/m² and methotrexate each week, plus or minus the alteration in the frequency of the vincristine/dexamethasone between every 4 or every 12 weeks. The main goal was how can we improve QoL for these children, and could we administer an alternative to our standard maintenance therapy while maintaining excellent outcomes?

How would you define this patient population? What are the typical adverse events that they endure from the standard chemotherapy schedule?

B-ALL is actually the most common childhood cancer that we treat. In my lifetime, I'm so proud to say went from actually a pretty tragic, very low survival rate over the decades to survival rates for the standard-risk, mainstay patient to roughly over 90% to 95%. [These are] excellent outcomes.

We are really interested in pushing that envelope with lessening the burden of therapy, because frequently, and we know from our experience of taking care of thousands of children, getting this vincristine/dexamethasone pulse every 4 weeks was frought with side effects from the dexamethasone and can cause a child to be moody, irritable, have increased appetite, sleep disturbance, and bone joint pain. Parents would come into the clinic and report these deleterious effects.

Also, with vincristine, one of the main side effects is both sensory and motor neuropathy. Both of those toxicity profiles are just our reality. Therefore, going into this was a real challenge, because we had excellent outcomes—so how can we push the envelope even further with reducing toxicity? Our main goal is to improve the QoL for children.

In examining the results of this study, what was most significant? How did this adjusted dose schedule impact patients?

Before starting maintenance, the children were randomized to one of these arms, that I described earlier, and I'm really proud to say that the 5-year DFS rate was 95% approximately in each arm and the 5-year OS rate was 98%. We learned that this alternative approach to maintenance therapy, by lessening the burden of therapy, could maintain excellent outcomes while reducing side effects and toxicity, and therefore ultimately improving QoL for our kids.

Will there be patient-reported outcome analyses from this study, or other QoL assays for this population?

COG AALL0932 was one of the first trials within COG where we had embedded 2 QoL initiatives. We are currently looking at those data and are anxious to publish that in the next manuscript. The two areas of interest were first on QOL, and if parents gave consent or participate in that, the parents filled out questionnaires throughout certain phases of the trial and it looked at that parental perception of how their child was doing. Did they miss days of school, work, or day care? There was that sort of vulnerability assessment.

Then, the second QoL trial was an initiative to examine the toxicity from vincristine specifically, regarding both the sensory and motor components. We are looking at those data. We have data now that will really inform us and be scientifically rigorous to answer that question. We are analyzing that data now, and that will be the subject matter for our next manuscript.

Reference

Angiolillo AL, Schore RJ, Kairalla JA, et al. Excellent outcomes with reduced frequency of vincristine and dexamethasone pulses in standard-risk b-lymphoblastic leukemia: results from Children's Oncology Group AALL0932. J Clin Oncol. Published online January 7, 2021. doi:10.1200/JCO.20.00494