Blinatumomab Improves Outcomes in B-Cell Acute Lymphoblastic Leukemia


Blinatumomab integration led to high complete response and minimal residual disease-negativity rates, especially in patients over 40 and Philadelphia chromosome-positive cases.

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku -

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku -

Integrating linatumomab (Blincyto) into pre-phase and consolidation chemotherapy led to improved outcomes compared with previous results reported from the HOVON-100 study (NCT01616238) among patients with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL). Findings from the HOVON-146 study (NCT03541083) were presented at the 2024 European Hematology Association (EHA) Annual Meeting.1

In the total population, which consisted of 71 patients, 60 (85%) achieved a complete response (CR). After pre-phase, early CR was reached in 45 (63%) of the 7 patients included in the study, and 24 (53%) of 45 patients attained minimal residual disease (MRD) negativity. Further, 57 (97%) of 59 patients had a CR after consolidation and 52 (91%) of 57 patients achieved MRD negativity.

“Blinatumomab in the pre-phase has a very early CR of 63%, of which half of the patients were already MRD negative. Although I remind you, in nearly 80% of the patients, they had high-risk disease,” explained Anita Rijneveld, MD, Erasmus MC Cancer Institute, Hematology, Rotterdam, the Netherlands, during a presentation of the data at the meeting. “I think that the addition of blinatumomab to the chemotherapy backbone suggests a favorable outcome compared with our former trial, and this is especially true for patients above 40 years of age and Ph [Philadelphia chromosome]-positive patients.”

Blinatumomab Safety

For safety, increased adverse effects (AEs) were observed among patients older than 60 years of age. These AEs required chemotherapy dose adjustments, which effectively mitigated additional significant safety concerns.

Seventy patients were given the full first course of blinatumomab, including 8 with interruption. Fifteen patients discontinued protocol prior to first blinatumomab consolidation due to refractory disease (n = 8), toxicity (n = 5), and death (n = 2).

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade were seen in 28 (39%) and 4 (5%) patients, respectively. While grade 3 CRS was observed in 3 (4%) patients and ICANS was seen in 2 (2%), higher grades of each were not noted.

Event-Free and Overall Survival

The first results of the HOVON-146 study showed MRD negativity after first blinatumomab consolidation to be seen in 91% of patients. The event-free survival (EFS) rate at 2 years was 64% following a median follow-up of 17.6 months. Experts sought to update these data following a median follow-up of 43 months (33-62 months).

At 4 years, the estimated EFS was 64% among patients younger than 40 and 40% for those over the age of 40. After 43 months of follow-up, the overall survival (OS) was 86% among patients younger than 40 (SE ± 7%), 86% for those between 40 and 60 years of age (SE ± 6%), and 50% for those older than 60 (SE ± 11%).

A total of 18 (25%) patients died.

Anita Rijneveld, MD, explained, “if you look at the 10 patients out of the 20 above 60 years of age who died, half of them died due to disease, the other half due to toxicity, and 1 due to a secondary malignancy.”

Among the 26 patients with PH-positive ALL included in the study, the EFS and OS rates at 43 months of follow-up were 75% and 85%. For those with Ph-negative ALL, the EFS and OS rates at 4 years were 64% and 70%, respectively.

Twenty-six patients underwent allogeneic hematopoietic stem cell transplantation. Another 12 patients continued with maintenance.

“In this protocol, although we did not reduce the chemotherapy, the outcome for the Ph-positive adult patient is quite impressive,” added Rijneveld.

Researchers also compared these findings to what was observed in the standard arm of the preceding HOVON-100 trial, which had a median follow-up of 70 months and utilized the same backbone without blinatumomab.

Compared with the HOVON-100 study, the 4-year OS for those 40 years of age and older was 86% in the current vs 74 % in the former trial. The EFS rates at 4 years in both studies were 61%. Moreover, for patients younger than 40, OS at 4 years was 71% in the current study vs 51% in the HOVON-100 study, and EFS rates were 54% vs 43%, respectively.

“Yes, there is a remarkable improvement, but I have to say that the backbone in [HOVON]-100 for elderly patients is slightly different from the backbone we used in the new [HOVON]-146 study. So whether this improvement is due to the addition of blinatumomab, probably also due to the intensification, we cannot differentiate,” stated Rijneveld.

HOVON-146 Study

The HOVON-146 trial was a single-arm, phase 2 trial which evaluated blinatumomab added to pre-phase and consolidation therapy in newly diagnosed patients with CD19-positive ALL, including those with Ph-positive disease. Patients ranged between 18 and 70 years of age and were required to have a World Health Organization performance status of 0, 1, or 2, and a negative pregnancy test at inclusion, if applicable.2

The primary end point of the study is MRD, which was measured by molecular MRD Ig/TCR gene rearrangements and flow cytometry centrally. The threshold for MRD negativity was below 10-4.

During pre-phase, 5 days of dexamethasone were given, which extended to another 5 days in combination with blinatumomab in a regular step-up dosing schedule. Two 4-week courses of blinatumomab were added, respectively, during consolidation and intensification. Elderly patients required dose reductions, and rituximab (Rituxan) was added when patients with CD20-positive or Ph-positive disease were included. There, only a tyrosine kinase inhibitor was added as no dose reduction was given.1

A total of 71 patients with a median age of 53 years (range, 18-70) were included in the study. Twenty-two (31%) patients were aged 40 years or younger, 29 (41%) patients were between 40 and 60 years of age, and 20 (28%) patients were older than 60. In 55 of the 71 patients (77%), at least 1 high-risk factor was present. Eighty-seven percent of patients (n = 62) had more than 50% leukemic blasts in their bone marrow.

Key Takeaways

Overall, the continued investigation of blinatumomab as a potential substitute to chemotherapy, especially in Ph-positive and elderly, patients represents a promising future direction and continues to be explored, Rijneveld said.

“I think that substituting chemotherapy, as we have heard already before, with blinatumomab, especially in elderly and Ph-positive [patients], is an important next step to reduce toxicity, to improve the depth of the response, and improve the outcomes,” he concluded.

1. Van Baalen E, Gradowska P, Bellido M, et al. Blinatumomab added to prephase and consolidation therapy in adult B-ALL: a comparison of the consecutive HOVON-100 and H-146 studies. Presented at: European Hematology Association 2024 Hybrid Congress; June 13-14, 2023; Madrid, Spain. Abstract S113.
2. Blinatumomab added to prephase and consolidation therapy in precursor B-acute lymphoblastic leukemia in adults. (HOVON146ALL). Updated July 13, 2023. Accessed June 14, 2024.
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