Philadelphia-positive acute lymphoblastic leukaemia (Ph+ ALL) is the most common subgroup of this type of blood cancer in adults, and its incidence increases with age. After the age of 50, it can affect one in two people. In the past, it was considered to be the haematological malignancy with the worst prognosis, as it did not respond well to chemotherapy. The only potentially curative strategy was linked to the possibility of allogeneic haematopoietic stem cell transplantation, a procedure that was rarely feasible due to the poor sensitivity to chemotherapy and the advanced age of many patients.

The prognosis has changed since the early 2000s with the introduction into clinical practice of tyrosine kinase inhibitors, a therapy that targets the genetic lesion that characterises Ph+ ALL. In all the national protocols of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) cooperative group, it was decided to treat patients with a tyrosine kinase inhibitor in the first phase - the so-called 'induction' phase - in combination with steroid therapy, without chemotherapy. This strategy achieved very high rates of clinical remission and limited side effects in patients of all ages. It is also important to note that tyrosine kinase inhibitors are administered orally and are therefore often taken at home, which is beneficial for patients' quality of life.

The group led by Robin Foà of Sapienza University of Rome then used a second-generation tyrosine kinase inhibitor (dasatinib) followed by a consolidation treatment with a bispecific monoclonal antibody (blinatumomab) capable of recognising two antigens, one on tumour cells and one on lymphocytes that are thus activated against the tumour. The combined use of the two drugs resulted in a complete remission of leukaemia in 98% of patients, of all ages, without significant side effects and the need for systemic chemotherapy. The results of the GIMEMA LAL2116 (D-ALBA) clinical trial, supported by the AIRC Foundation's “5 per mille” programme and Amgen's contribution, were published in the New England Journal of Medicine in 2020.

Today comes data from more than four years of patient follow-up (53 months), published by the same group in the Journal of Clinical Oncology. The results confirm the efficacy of this treatment strategy with survival rates between 75% and 80%. The study also showed that 50% of patients were treated with the combination therapy alone, without chemotherapy or transplantation. Disease was monitored during treatment using molecular biology techniques and none of the patients with an early deep molecular response relapsed.

This therapeutic strategy can largely be administered at home; the clinical protocol was indeed able to continue even during the COVID-19 pandemic lockdown, which began in March 2020.

"These results", says Robin Foà, Professor Emeritus of Haematology at Sapienza University of Rome, "are the best to date because they have been maintained over time and, above all, regardless of the age of the patients. This shows that this therapeutic strategy, based on tyrosine kinase inhibitor therapy targeting the genetic alteration characteristic of Ph+ ALL and combined with a bispecific immunotherapeutic antibody, truly represents the future of therapy for patients with Ph+ ALL of all ages. Chemotherapy and transplantation can be avoided in a large number of patients".

This last point will be definitively documented by the new multicentre GIMEMA phase 3 clinical protocol currently underway in our country for Ph+ ALL adult patients of all ages.

References:

Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL - Robin Foà, Renato Bassan, Loredana Elia, Alfonso Piciocchi, Stefano Soddu, Monica Messina, Felicetto Ferrara, Monia Lunghi, Antonino Mulè, Massimiliano Bonifacio, Nicola Fracchiolla, Prassede Salutari, Paola Fazi, Anna Guarini, Alessandro Rambaldi, Sabina Chiaretti - Journal of Clinical Oncology, 2023 doi: 10.1200/JCO.23.01075

Further Information

Robin Foà
Department of Translational and Precision Medicine
rfoa@bce.uniroma1.it