Researchers led by a team from the Netherlands have shown that adding the immunotherapy blinatumomab to chemotherapy delays progression and improves survival for infants with an aggressive type of acute lymphoblastic leukemia (ALL).
The study, published in the New England Journal of Medicine, found that the treatment, which has already been demonstrated as safe and efficacious in older children and adults with relapsed or refractory B-lineage ALL after intensive chemotherapy, was also well-tolerated by the younger patients. It is now being incorporated into treatment regimens around the world.
Professor Rob Pieters, medical director and pediatric oncologist at the Princess Máxima Center for pediatric oncology in Utrecht, leads the research group that carried out the study. He said in a press release:
“The survival of children with acute lymphoblastic leukemia has risen to more than 90% in recent decades, but the cure rate for babies has lagged behind.
“Babies with leukemia often have a recurrence early in treatment. That’s why it was important to give the immunotherapy right at the start of the treatment. It’s wonderful to see that this is yielding such a good result, and that we are implementing the addition of immunotherapy into worldwide standard treatment straight away.”
The study included 30 patients younger than 1 year of age from nine countries who had newly diagnosed KMT2A-rearranged ALL. This rearrangement in the gene that encodes histone–lysine N-methyltransferase 2A (formerly known as mixed-lineage leukemia) is found in 75% of infants with leukemia and is associated with poor outcomes due to increased resistance to standard chemotherapy. The 3-year event-free survival rate among infants with KMT2A-rearranged ALL is below 40% and around 90% of relapses occur within 2 years of diagnosis. The survival rate after relapse is just 20%.
At present, infants with KMT2A-rearranged ALL may be treated with the Interfant-06 protocol, a multistep treatment regimen that involves several different chemotherapyd agents throughout the induction, treatment, and maintenance phases.
In the current study, first author Inge van der Sluis, pediatric oncologist and clinical pharmacologist also at the Princess Máxima Center for pediatric oncology, and colleagues investigated whether outcomes could be improved with addition of blinatumomab. They explain that the drug is designed to link CD19+ B cells and CD3+ T cells, which results in T-cell activation and a cytotoxic T-cell response against CD19+ B cells. Leukemic cells in infant ALL are immature B-lineage cells that express CD19.
The participants were given the chemotherapy according to the Interfant-06 regimen with the addition of one postinduction course of blinatumomab (15 μg/m2 of body-surface area per day as a 28-day continuous infusion).
All patients received the the full 4-week course of blinatumomab and during a median 26.3 months of follow-up the toxicity profile was similar to that seen in older patients treated with the immunotherapy agent.
The most common grade 3 or worse adverse events (AEs) were anaemia, which occurred in in 17% of patients, and febrile neutropenia, neutropenia, and elevated γ-glutamyltransferase levels, which occurred in 7% each. The were no fatal AEs and no patients had neurologic events.
At the end of blinatumomab infusion, 93% of patients had either no evidence of minimal residual disease (MRD) or low levels of MRD (<5 leukemic cells per 10,000 normal cells). All patients who continued chemotherapy became MRD-negative during further treatment.
The researchers report that the 2-year disease-free survival rate was 81.6%while the 2-year overall survival rateswas 93.3%. By comparison, the rates were 49.4% and 65.8%, respectively, among 214 historic controls who took part in the Interfant-06 trial.
The corresponds to a significant 78% reduction in the risk for disease progression or death and an 85% reduction in the risk for death with the addition of blinatumomab.
The authors say that the data “indicate a higher level of antileukemic activity than the Interfant-06 protocol, as reflected by good responses with respect to MRD and improved short-term survival.”
They continued: “Although the follow-up time was relatively short, it included the period historically defined as the period of increased risk of relapse. These outcome data are very promising, given the poor survival and lack of improvements in outcomes among infants with KMT2A-rearranged ALL in recent decades.”
Van der Sluis told Inside Precision Medicine that the patients will continue to be followed-up but “more importantly a larger study with 160 patients is planned (Interfant-21) to confirm these results.”
This study will be open in 27 countries worldwide and has recently recruited the first patients in the Netherlands. In the study, blinatumomab will replace chemotherapy rather than being added to the Interfant-06 backbone but high-risk patients will still be treated with induction chemotherapy plus one course of blinatumomab, followed by stem cell transplantation.
“We expect that replacing chemotherapy blocks with immunotherapy will lead to fewer side effects and a more efficacious treatment,” van der Sluis remarked.
She added that, as a result of the current study, “all babies with this form of leukemia are now receiving immunotherapy as part of standard treatment.” Although, she stresses that blinatumomab is not registered for first-line treatment in infants and they can therefore currently only be treated within study protocols to get access to blinatumomab.