Two trials of blinatumomab (Blincyto) offered mixed results in pediatric relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), with one offering a boost in event-free survival while another could not show an uptick in disease-free survival.
In the first trial, among children (median age 5 years) with high-risk, first-relapse B-ALL, treatment with one cycle of blinatumomab before allogeneic hematopoietic stem cell transplant (HSCT) resulted in an improved event-free survival at a median of 22.4 months of follow-up versus pre-HSCT standard intensive multidrug chemotherapy, reported Franco Locatelli, MD, PhD, of Sapienza University of Rome, and co-authors in JAMA.
On the other hand, among young patients (median age 9 years) with high- and intermediate-risk first relapse of B-ALL, post-reinduction treatment with blinatumomab versus chemotherapy, followed by transplant, did not lead to a statistically significant difference in disease-free survival, according to Patrick A. Brown, MD, of Johns Hopkins University School of Medicine in Baltimore, and co-authors.
“However, study interpretation is limited by early termination with possible underpowering for the primary end point,” Brown’s group cautioned in JAMA, explaining that “Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred.”
In addition, Locatelli and colleagues noted that, in their trial, “Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule.”
Blinatumomab, a bispecific T-cell engager (BiTE), is FDA approved for the treatment of adults and children with relapsed/refractory B-ALL — the drug received accelerated approval for minimal residual disease (MRD)-positive B-ALL upon results from confirmatory trials, including the one performed by Brown and co-authors.
Early stops aside, the two current trials are “the first… to show a clear benefit of blinatumomab for children with high-risk relapsed B-ALL,” noted Maria Luisa Sulis, MD, and Neerav Shukla, MD, both of Memorial Sloan Kettering Cancer Center in New York City, in an accompanying editorial.
The positive findings are much needed, as “There is no standard therapy for the management of relapsed B-ALL. There are few randomized trials, and comparison between trials is difficult due to differences in end points and patient populations,” they said.
But thanks to previous research — ALL-REZ BFM, COG ASCT0431, COG AALL01P2, UKALL R3 — “the importance of achieving minimal residual disease (MRD) negativity (defined as <10 blasts on a bone marrow aspirate) prior to HSCT has been well established,” they explained.
Both of the current trials led to higher MRD negativity rates with blinatumomab versus chemotherapy only, and “This is a critical end point because the post-transplant survival outcome is highly dependent on the extent of disease control at time of transplant,” according to Sulis and Shukla, and more of these patients were able to proceed to HSCT.
They also highlighted a key difference between the two trials: Locatelli’s group demonstrated that patients with “very early relapse appear to benefit the most from the use of blinatumomab,” while Brown’s group found that “blinatumomab had limited activity in patients who had early treatment failure to reinduction therapy.”
“Perhaps alternative agents, such as inotuzumab ozogamicin or CD19-directed chimeric antigen receptor (CAR) T-cell therapies, will provide better outcomes for this subgroup of patients,” Sulis and Shukla suggested.
Locatelli and co-authors randomized 108 patients (median age, 5 years; 51.9% girls; 97.2% M1 marrow; majority white) with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow <5% blasts) or with M2 marrow (blasts 5% and <25%) at 47 centers in 13 countries. They underwent either one cycle of continuous IV blinatumomab at 15 µg/m2/d for 4 weeks (n=54) or chemotherapy (n=54) for the third consolidation.
The trials primary endpoint was event-free survival from relapse, death, second malignancy, or failure to achieve complete remission; secondary endpoints included overall survival (OS), MRD, and adverse events (AEs).
At a median of 22.4 months of follow-up, the authors reported:
- Incidence of events: 31% in the blinatumomab group versus 57% in the consolidation chemotherapy group (hazard ratio 0.33, 95% CI 0.18 to 0.61, log-rank P<0.001).
- Deaths: 14.8% versus 29.6%.
- OS: HR 0.43 (95% CI 0.18 to 1.01).
- MRD: 90% versus 54% for a 35.6% difference (95% CI 15.6% to 52.5%).
- Serious AEs: 24.1% versus 43.1%.
- AEs grade ≥3 57.4% versus 82.4%.
- AEs leading to treatment discontinuation: 3.7% (grade 3 nervous system disorder; grade 4 seizure) versus 0%.
- Fatal AEs: None in both groups.
Locatelli’s group also noted that “Two patients in the blinatumomab group and one in the consolidation chemotherapy group experienced cytokine release syndrome [CRS grade <3],” and that a previous study showed a grade 3-4 CRS in about one-third of patients.
“Because patients with ALL often need immediate treatment, a potential advantage of blinatumomab is that it is an already manufactured, immediately available drug, whereas [CAR T-cell] therapy requires patient-specific engineering and therefore may not be as readily available,” they suggested.
Study limitations included the fact that patients only underwent one cycle of consolidation therapy with blinatumomab, and all of the patients had high-risk first B-ALL relapse, so “studies are needed to evaluate the role of blinatumomab in pediatric patients experiencing standard-risk first relapse of B-ALL.”
In their phase III trial performed across 155 international centers, Brown and co-authors randomized 208 patients (median age, 9 years; 47% female; 83.1% white) to blinatumomab instead of intensive chemotherapy in consolidation therapy. All patients underwent a 4-week reinduction chemotherapy course, followed by randomization to two cycles of blinatumomab (n=105) or two cycles of multi-agent chemotherapy (n=103), each followed by HSCT.
The primary endpoint was disease-free survival, while the secondary endpoint was OS, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P<0.025.
Among all patients, 57% completed the therapy they were randomized to when randomization was stopped, leaving 80 of 131 planned events occurring. With 2.9 years of median follow-up, the authors reported:
- Two-year disease-free survival: 54.4% for the blinatumomab group versus 39.0% for the chemotherapy group (HR 0.70 for disease progression or mortality, 95% CI 0.47 to 1.03, 1-sided P=0.03).
- Two-year OS: 71.3% versus 58.4% (HR 0.62 for mortality, 95% CI 0.39 to 0.98, 1-sided P=0.02).
- Serious AEs: 15% versus 65% for infection; 5% versus 58% for febrile neutropenia; 2% versus 27% for sepsis; 1% versus 28% for mucositis.
- MRD negativity rate: 75% versus 32% after cycle 1 of randomized therapy for a 43% difference (95% CI 31% to 55%, P<0.001); 66% versus 32% after cycle 2 for a 34% difference (95% CI 21% to 46%, P<0.001).
Brown’s group also reported that, “among the 42 patients with early treatment failure, 20 went on to other therapies while 22 received salvage blinatumomab, and 23% of the latter had morphologic remission (<5% marrow blasts) after one cycle of salvage blinatumomab. Of these five patents, the majority had negative MRD after either one cycle and all had proceeded to transplant.”
As for inotuzumab, Brown and co-authors cited the INO-VATE study, which demonstrated increased median survival duration but no difference in survival with that agent in all-comers with relapsed/refractory ALL.
Besides being underpowered, another limitation of Brown et al’s study was that “the transplant procedures… were not fully standardized or prescribed, and thus varied among trial participants,” the authors noted.
Brown’s group pointed out that “The goal of treatment for participants in this trial was to provide a ’bridge’ to stem cell transplant, which is necessary to achieve durable remission… Given the high rate of MRD negativity after cycle 1 of blinatumomab and because some patients who had negative MRD after the first blinatumomab cycle reverted to having positive MRD after the second cycle, future trials should test proceeding directly to transplant after 1 blinatumomab cycle for patients that have MRD negativity.”
Sulis and Shukla said answers are still needed for questions on optimal blinatumomab timing and number of cycles, the agent’s role in extramedullary relapse, and how to handle patients when the first cycle of reinduction therapy fails.
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Treatment with a single cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant (HSCT) resulted in an improved event-free survival in children with high-risk first-relapse B-cell acute lymphoblastic leukemia (B-ALL).
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Post-reinduction treatment with blinatumomab compared with chemotherapy, followed by HSCT, did not result in a statistically significant difference in disease-free survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL.
Shalmali Pal, Contributing Writer, BreakingMED™
The study by Locatelli’s group was funded by Amgen. A co-author is a company employee. Locatelli reported support from, and/or relationships with, Amgen, Novartis, Bellicum Pharmaceuticals, Miltenyi Speakers’ Bureau, Jazz Pharmaceutical, Takeda, Neovii, and Medac. Co-authors reported multiple relationships with industry including Amgen.
The study by Brown’s group was funded by the National Cancer Institute (NCI), the National Clinical Trials Network Statistics and Data Center, and St Baldrick’s Foundation. Blinatumomab was provided by Amgen/NIH/NCI/Cancer Therapy and Evaluation Program. A co-author is an employee of Amgen Research. Brown reported relationships with Novartis, Kura, Kite, Amgen, Servier, Jazz Pharmaceuticals, and Janssen. Co-authors reported multiple relationships with industry including Amgen.
Sulis and Shukla reported no relationships relevant to the contents of this paper to disclose.
Cat ID: 466
Topic ID: 78,466,730,466,138,192,925
