It was the year 2000 when in Italy the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) (Italian Group for Haematological Diseases of Adults) inaugurated the first clinical protocol for the treatment without chemotherapy of elderly patients suffering from Philadelphia-positive acute lymphoblastic leukaemia (Ph+ ALL) the haematological tumour with the worst prognosis at that time. The study was supported by the then Associazione Italiana per la Ricerca sul Cancro, today the AIRC foundation.

Patients were treated with imatinib - a tyrosine kinase inhibitor (TKI) targeting the genetic defect (BCR:ABL) of the disease - and steroids, all achieving disease remission.

Since then and to date, in all subsequent GIMEMA national protocols, a first (imatinib), second (dasatinib) or third generation (ponatinib) TKI has been used for induction therapy, always without systemic chemotherapy. This therapeutic strategy, based on a steroid-associated TKI, achieved response rates in 94-100% of adult patients of all ages with Ph+ ALL with very low toxicity.

Over the years, the all-Italian research of the group coordinated by Robin Foà - Professor Emeritus of Haematology at Sapienza University of Rome - has taken further steps forward: the next step was to add the bispecific monoclonal antibody blinatumomab in consolidation after induction therapy with TKI. This drug acts on the one hand by binding to an antigen, CD19, expressed by leukaemic cells, and on the other by activating an immune response in the body, binding to the CD3 receptor present on the patient's T lymphocytes.

The “chemo-free” approach, based on the combination of an initial induction therapy (dasatinib and steroid) followed by an immunotherapeutic consolidation strategy (blinatumomab), led to remission in 98% of patients and, more importantly, to molecular remissions in up to 80% of cases (“New England Journal of Medicine”, October 22, 2020).

At a follow-up of almost five years - the results of which were published on December 21, 2023 in the Journal of Clinical Oncology - survival rates between 75% and 80% were observed, results never achieved with previous treatment protocols. Moreover, for the first time it was reported that 50% of patients were treated with TKI and immunotherapy alone, without chemotherapy or transplantation.

The research continued with the latest GIMEMA protocol, in which the third-generation TKI ponatinib followed by the drug blinatumomab was used. The first promising results of the protocol, which closed enrolment in January 2025, have already been presented at the American Society of Haematology (ASH) Congress in San Diego in 2024 by Sabina Chiaretti, professor at Sapienza University's Department of Translational and Precision Medicine.

In light of the results obtained over the past 25 years, the New England Journal of Medicine asked Professor Foà to write a review on how the treatment and prognosis of Ph+ ALL has changed over the years.

The review, titled “Ph+ Acute Lymphoblastic Leukemia - 25 Years of Progress” and published on May 15, 2025, reconstructs the history of these 25 years of research, which have led to a radical change in the therapeutic approach and prognosis of adult Ph+ ALL patients by proposing therapies that do not resort to chemotherapy.

In addition to the limited side effects of the “chemo-free” approach, the review highlights the marked immunomodulation that the therapy induces in patients, even going so far as to speculate on the possibility, unthinkable until a few years ago, of discontinuing the treatment.

Finally, the analysis highlights the discrepancy between what one would like to be able to do for all patients and the actual situation: one speaks, in this case, of “Recommended Frontline Strategy” and “Real-Life Frontline Strategy”, highlighting how, despite the brilliant results obtained, one is too often faced with the impossibility of implementing the optimal first-line therapy.

"In our country, there is every possibility of significantly improving the treatment and prognosis for patients," says Robin Foà. "But it is paradoxical that we, in fact, cannot treat patients with the strategy that has led to a radical change in the prognosis for Ph+ ALL. We cannot even activate a new clinical protocol, despite our intentions."

References:

Robin Foà - Philadelphia-Positive Acute Lymphoblastic Leukemia  – 25 Years of Progress -  New England Journal of Medicine 2025;392:1941-1952.

Further Information:

Robin Foà

Department of Translational and Precision Medicine

rfoa@bce.uniroma1.it