In one study, 108 children (mean age, 5 years) with high-risk relapsed B-ALL received one cycle of reinduction chemotherapy and two cycles of consolidation chemotherapy. Participating investigators could choose from established chemotherapy regimens.
The vast majority of patients (97%) had M1 marrow (<5% blasts). They were randomly allocated to blinatumomab (15 ug/m2/d for four weeks, continuous intravenous infusion) or to a third cycle of consolidation chemotherapy with the intent to proceed to allogeneic hematopoietic stem cell transplant (HSCT) if they had complete remission. There were 54 patients in each group.
The study was stopped early because it met the prespecified criterion to declare superiority of the blinatumomab group, Dr. Franco Locatelli of the University of Rome and colleagues report in JAMA.
After a median follow-up of 22 months, the incidence of events (relapse, death, second malignancy, or failure to achieve complete remission) was significantly lower in the blinatumomab group than in the consolidation chemotherapy group (31% vs. 57%; log-rank P<0.001).
The two-year estimated event-free survival rate was 66% in the blinatumomab group versus 27% in the chemotherapy group (hazard ratio, 0.33; 95% confidence interval, 0.18 to 0.61).
The statistically significant benefit of blinatumomab was seen in all analyzed subgroups and was particularly apparent for patients relapsing less than 18 months from diagnosis (HR, 0.21; 95% CI, 0.07 to 0.59).
There were eight deaths (15%) in the blinatumomab group and 16 (30%) in the consolidation-chemotherapy group (HR, 0.43; 95% CI, 0.18 to 1.01).
Significantly more patients in the blinatumomab than consolidation-chemotherapy group achieved remission with no minimal residual disease (90% vs. 54%) and more patients proceeded to HSCT (89% vs. 70%).
There were no fatal adverse events, and blinatumomab was associated with fewer serious adverse events (24.1% vs. 43.1%) and fewer adverse events of grade 3 or higher (57% vs. 82%).
"The take-home message is that in children with B-cell ALL experiencing high-risk first relapse, a pre-transplant consolidation therapy based on the use of blinatumomab is superior to chemotherapy in terms of better probability of event-free survival, lower cumulative incidence of leukemia recurrence, improved clearance of minimal residual disease and better probability of being transplanted in second remission," Dr. Locatelli told Reuters Health by email.
"Moreover, blinatumomab is superior to a course of consolidation chemotherapy for the incidence of some severe side effects, including febrile neutropenia and neutropenia. The advantage offered by the use of blinatumomab was confirmed also in the very challenging subset of patients relapsing within 18 months from diagnosis," he added.
"This is a practice-changing study," said Dr. Locatelli, "because now patients experiencing high-risk first relapse of B-ALL, after receiving induction therapy and initial consolidation therapy, should be treated with a last consolidation based on the use of blinatumomab before being offered an allograft. This approach now represents the standard of care for this specific subset of children with relapsed B-ALL."
The other study, also in JAMA, included 208 children, adolescents, and young adults (mean age, 9 years) with high- and intermediate-risk first-relapse B-ALL. All participants received a four-week reinduction chemotherapy course, followed by either two cycles of blinatumomab (105 patients) or two cycles of multiagent chemotherapy (103 patients), each followed by HSCT if possible.
The trial was stopped early based on a combined assessment of disease-free survival and the predefined secondary and exploratory end points of overall survival, minimal residual disease, and comparative adverse event profiles, "all of which favored blinatumomab over chemotherapy. The data and safety monitoring committee concluded that the totality of data demonstrated a loss of clinical equipoise," report Dr. Patrick Brown of Johns Hopkins University School of Medicine, in Baltimore, Maryland, and colleagues.
The two-year disease-free survival rate was 54% in the blinatumomab group versus 39% in the chemotherapy group (HR for disease progression or mortality, 0.70; 95% CI, 0.47 to 1.03). The difference in disease-free survival was not statistically significant, although early termination may have decreased the power to detect a difference, the authors say.
The differences between the blinatumomab group and the chemotherapy group in overall survival (71% vs. 58%) and minimal residual disease negativity (75% vs. 32%) were statistically significant.
The rates of adverse events and serious adverse events and the percentage of patients proceeding to transplant (70% vs. 43%) also favored favor blinatumomab group.
“This is definitely a practice-changing study,” Dr. Brown told Reuters Health by email. “Blinatumomab is more effective and less toxic than chemotherapy as post-reinduction consolidation prior to transplant for higher risk first relapse of B-lymphoblastic leukemia in children, adolescents and young adults. Blinatumomab should now be considered standard-of-care in this patient population.”
In an editorial, Dr. Neerav Shukla and Dr. Maria Luisa Sulis of Memorial Sloan Kettering Cancer Center, in New York City, say these two randomized clinical trials "affirm the benefit of blinatumomab in pediatric patients with high-risk first relapse of B-ALL with chemotherapy-responsive disease, and the findings suggest that blinatumomab provides a more effective and less toxic therapeutic regimen."
"Although only the study by Locatelli et al demonstrated a statistically significant difference in event-free survival in favor of blinatumomab, both studies showed an advantage in overall survival," they point out.
"Furthermore, several conclusions supporting a change in clinical practice can be drawn from the results reported," they write.
"First, regardless of the timing of randomization or type of chemotherapy given, blinatumomab was significantly less toxic than chemotherapy. In particular, life-threatening complications frequently responsible for delay in proceeding to HSCT, such as infections and sepsis, were less common with blinatumomab."
"Second, the MRD negativity rates in the blinatumomab groups in both studies were greater than the chemotherapy-only groups. This is a critical end point because the posttransplant survival outcome is highly dependent on the extent of disease control at time of transplant. Third, as a result, patients who received blinatumomab as consolidation chemotherapy were more likely to proceed to HSCT compared with patients who received chemotherapy," the editorialists note.
The study by Dr. Locatelli et al. was funded by Amgen Inc, which markets blinatumomab as Blincyto. The study by Dr. Brown et al. was funded by grants from the National Institutes of Health/National Cancer Institute and the St Baldrick's Foundation. Blinatumomab was provided by Amgen via a collaborative research-and-development agreement with the NIH/NCI. Several authors have disclosed relationships with Amgen and other pharmaceutical companies.
SOURCE: https://bit.ly/3rgtLyc, https://bit.ly/3b7r8ZG and https://bit.ly/3uI5tPL JAMA, March 2, 2021.
By Megan Brooks
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