In patients with Ph-negative acute lymphoblastic leukemia (ALL) and no trace of detectable disease (MRD-negative) after initial treatment, the addition of the bispecific antibody blinatumomab to consolidation chemotherapy significantly increases survival. The news, which comes from the results of the E1910 clinical study, recently published in the New England Journal of Medicine (NEJM), opens the prospect of a new standard of care for adults diagnosed with ALL. Specifically – we read in a note released by Amgen – the addition of immunotherapy to the first-line treatment scheme allowed a reduction in the risk of death by 59%: at approximately three and a half years, 85% of patients treated with blinatumomab is still alive, compared to 68% of patients treated with chemotherapy alone.
ALL is a rapidly progressive blood cancer with high mortality. In Italy, approximately 800 new cases among adults and children are estimated per year. Currently, the standard front-line treatment of Ph-negative ALL is chemotherapy, administered in three phases: induction, consolidation and maintenance. In Italy, thanks to the first-line chemotherapy protocol (Gimema Lal 1913), it has been possible to obtain important results in clinical practice in adult patients with Ph-negative B-ALL: at 3 years 64.9% of patients are still alive (Os ) and 61.4% show no signs of disease (Dfs). But, following a relapse of the disease, patients still have unsatisfactory outcomes. Precisely for this reason, it is essential to prevent relapses and improve responses from the beginning of treatment, introducing effective and innovative therapies at the forefront.
“This study – states Robin Foà, professor emeritus of Hematology, Sapienza University of Rome – represents an important step forward in the treatment of ALL because, for the first time, it demonstrates that blinatumomab administered in the front line improves the prognosis of patients with B-ALL Ph negative Mrd negative. It is a relevant result because, even for these patients, the risk of recurrence remains high and therefore this scheme could become the new standard of care. In fact, in light of these results, last June, the FDA “approved, in the United States, treatment with blinatumomab for patients with first-line Ph-negative B-ALL, including MRD. negative.”
ALL is a heterogeneous pathology that includes different types, each with variable sensitivity to treatments. For this reason, characterizing it from the beginning and monitoring MRD allows us to predict the progress of the pathology and guide the clinician in the most appropriate therapeutic choices. “Thanks to the evidence of this study – observes Alessandro Rambaldi, full professor of Hematology, State University of Milan – blinatumomab could be used in the first line of treatment, before recurrence occurs. In this way, the innovation brought by blinatumomab would fulfill the main task that we hematologists are called upon to do, namely that of improving clinical results and reducing the toxicity caused by chemotherapy. But to bring about the desired effects there is another very important aspect to take into consideration, namely that of applying the molecular evaluation techniques of MRD to all patients, an indispensable condition for guiding clinicians’ therapeutic choices.”
MRD is an indicator that signals the presence of a minimal amount of tumor cells not visible with traditional diagnostic methods, despite the patient having achieved complete remission. “The development of MRD evaluation techniques – adds Rambaldi – with molecular biology is one of the most significant advances of the last 20 years. When we detect the persistence of MRD in a patient apparently in remission, we can anticipate a possible relapse and select the best strategy for treatment.” Even a small error in MRD monitoring can make a difference to patient survival.
“In a pathology like ALL, monitoring MRD is fundamental – Foà points out – Even when the patient tests negative MRD, the test must be repeated several times over time. To obtain precise and reliable data, it is essential that the investigations are carried out in certified laboratories, with quality controls, standardized techniques and strict deadlines. For this reason, in Italy, since 1996, the study of the biological samples of LLA included in the protocols has been centralized, including the monitoring of MRD”. Blinatumomab, the first bispecific monoclonal antibody, authorized by the European Medicines Agency (EMA) in 2015, is revolutionizing the treatment of this insidious disease. Already approved for adults and children in the advanced stages of the disease and to eradicate MRD, new data now show promising results even in early lines, with new treatment prospects. The first immunotherapy developed with Amgen’s Bite* (Bi-specific T-cell engager) platform, blinatumomab enhances the ability of the patient’s immune system to eliminate tumor cells. This year, the drug received the Prix Galien Italia, the most prestigious award for innovation in the pharmacological field, in the category of orphan drugs.
“This important evidence – comments Alessandra Brescianini, medical director of Amgen Italia – arises from the constant collaboration with the scientific community, in particular with Italian hematologists, who have made a fundamental contribution at an international level to the development of this treatment, enhancing their vocation of experimenters. Our commitment to the development of this therapy continues with significant results and with the aim of continuing to improve the lives of patients with ALL. By exploiting all the potential of this innovation, we want to offer a very different future to those who face this complex pathology.”
Clinical research is constantly evolving. In Italy, in fact, experience has been gained with a first-line treatment protocol (Gimema Lal 2317) in adult patients with Ph-negative B-ALL who were administered blinatumomab. The data from this study were preliminarily presented and welcomed by the American Society of Hematology (ASH) with much interest in December 2023. They have, in fact, demonstrated that globally the outcome of all adult patients with Ph-negative B-ALL is both MRD positive and negative, is improving significantly, and in this blinatumomab is confirming an important role.
Furthermore, as demonstrated by Italian studies published in Nejm and in the Journal of Clinical Oncology, the combination of blinatumomab with first-line molecular targeted therapy has also demonstrated its effectiveness for patients with Ph-positive ALL. This strategy allowed achieving complete remission in 98% of patients, and long-term survival in 75-80% of cases. Half of the patients did not have to resort to chemotherapy and transplantation, opening the door to a ‘chemo-free’ approach.
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