Leukemia, from the imatinib breakthrough to the dream of a cure without chemo

It traces the fundamental stages of twenty-year research – all Italian – which with the use of a tyrosine kinase inhibitor (Tki) has led to a radical change in the treatment and prognosis of patients with Philadelphia-positive acute lymphoblastic leukemia (Lal Ph +). article recently published in the ‘New England Journal of Medicine’ (Nejm) by Robin Foà and Sabina Chiaretti of the La Sapienza University of Rome. When, about twenty years ago, acute lymphoblastic leukemia (Lal) associated with an alteration of the Philadelphia chromosome (Ph +) was ‘an incurable disease’ – recalls the university – it was tested in Italy, for the first time, ‘imatinib, the first in a new class of targeted anticancer drugs, the Tki. Being a revolutionary therapeutic approach, in the first trial only elderly patients, over 60 years old, who in many cases had only palliative therapies as their cure, were enrolled. After administration of a combination of imatinib and steroid, all patients achieved disease remission. Since then this initial therapeutic strategy based only on a Tki (plus the steroid) has made it possible to obtain response rates in 94-100% of adult patients of all ages with Lal Ph +, without resorting to systemic chemotherapy (only prophylaxis of the nervous system central) and with very low toxicity for patients.Over the years the research of the group coordinated by Foà, professor emeritus of Hematology of Sapienza, has gone ahead with the aim of reaching the recovery of patients suffering from this haematological pathology. For this reason, the Nejm asked the specialist to describe the most important results achieved and published in these twenty years on the Lal Ph + and how the natural history of this disease, once considered the most unfortunate haematological neoplasm, has changed. The review ‘Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia’, published on 23 June last, traces the fundamental stages of this all-Italian success of medical research.After the first experimentation of imatinib in patients with Lal Ph +, it has been progressively understood how , to avoid a recurrence of the disease and improve the chances of recovery, a hematological remission was not enough, but it was essential to obtain a state of negativity of the minimal residual disease (Mrd, Minimal residual disease). adult patients with Lal Ph +, without age limits, in which blinatumomab has been added to Tki, the first drug in the class of bi-specific antibodies BiTE, which acts by stimulating a double reaction: on the one hand, blinatumomab binds to the protein expressed by the cells leukemic, on the other hand activates an immunological response in the organism. This chemo-free approach, based on the combination of an initial targeted induction therapy on a Tki (dasatinib) and steroid, followed by an immunotherapy strategy (blinatumomab, which activates the patient’s T cells) as consolidation therapy, resulted in remissions. in 98% of patients and, above all, in molecular remissions up to 80% of cases. The results of the study were published on October 22, 2020, again in the Nejm. Encouraging results are being obtained with blinatumomab in another Italian study for patients with Lal Ph- and a more manageable subcutaneous formulation is being developed. treatment with a Tki. Furthermore, a molecular study must be carried out on the genetic profile of the patient and the possible presence of mutations that confer resistance to the treatments. All this requires a very demanding organizational effort, but essential for obtaining results. Cooperative studies, present in various countries, are also essential – reads the note from Sapienza. Among these, in Italy there are the Gimema for adults and the Aieop for children. In the Gimema protocols for Lal all the samples of the enrolled patients have been centralized since 1996 (at diagnosis and in the follow-up) at the hematology laboratories of the Umberto I University Hospital in Rome, to ensure that all patients are studied in a uniform way. This is only possible with qualified and adequately trained personnel, who make sure that all the necessary complex tests are properly carried out in certified laboratories.The induction and consolidation approach without systemic chemotherapy was particularly important even during the first peak of the Covid pandemic. -19, because it allowed patients to reduce hospitalization times and above all not to interrupt treatment, it is pointed out in the note. ‘enrollment – will be able to establish conclusively whether a proportion of patients with Lal Ph + can be treated in the future without systemic chemotherapy and transplantation. “An unthinkable result even just a few years ago – comments Foà – which leads me to tell young people to believe in their ideas, especially if they are original, and to pursue them with obstinacy. It was not easy for us too at the beginning, but this story all Italian teaches us that dreams often come true “.