Almost twenty years have passed since a substance, imatinib, belonging to a new class of targeted anti-cancer drugs, was first tested in Italy in patients with acute lymphoblastic leukaemia (ALL) associated with a Philadelphia chromosome alteration (LAL Ph+) for the initial treatment of these patients. As this was a revolutionary therapeutic approach, only elderly patients over 60 years old, for many of whom only palliative therapies were offered, were enrolled for this trial.

After being treated with a combination of imatinib, tyrosine kinase inhibitor (TKI) and steroid, all patients achieved disease remission.

Since then, this initial therapeutic strategy based only on a TKI (plus steroid) has resulted in response rates in 94-100% of adult patients of all ages with LAL Ph+, without resorting to systemic chemotherapy (only CNS prophylaxis) and with very low toxicity for patients.

Over the years, the research of the group coordinated by Robin Foà (Professor Emeritus of Haematology at Sapienza University of Rome) has been going on with the aim of curing patients suffering from this haematological pathology.

That is why the prestigious New England Journal of Medicine asked Professor Foà to describe the most important results achieved and published in these twenty years on LAL Ph+ and how the natural history of this disease, once considered the most inauspicious haematological neoplasm, has changed. The review 'Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia', published on June 23, retraces precisely the milestones of this all-Italian success in medical research.

After the first trial of imatinib in patients with LAL Ph+, it was progressively realised that, in order to avoid a disease relapse and improve the chances of cure, a haematological remission was not sufficient, but it was essential to achieve a state of minimal residual disease (MRD) negativity.

In 2016, the first Italian multicentre study for adult patients with LAL Ph+ (no age limit) began in which blinatumomab was added to the TKI, the first drug in the BiTE® class of bi-specific antibodies, which act by stimulating a dual reaction: on the one hand, blinatumomab binds to the protein expressed by leukaemic cells and, on the other, activates an immunological response in the body.

This chemo-free approach, based on the combination of initial TKI-targeted therapy (dasatinib) and steroid (induction), followed by an immunotherapeutic strategy (blinatumomab, which activates the patient's own T-lymphocytes) as consolidation therapy, led to remissions in 98% of patients and, more importantly, to molecular remissions in up to 80% of cases. The study results were published on October 22 in the New England Journal of Medicine. It should also be mentioned that encouraging results are being obtained with blinatumomab in another Italian study for patients with LAL Ph- and that a more manageable subcutaneous formulation is in development.

The review discusses the use over the years of second-and third-generation TKIs, alone or together with reduced doses of chemotherapy, in the first-line treatment of patients with LAL Ph+, how to consolidate the responses obtained with TKIs, and how immunotherapy with blinatumomab significantly enhanced the responses obtained with TKIs. The management of relapses based on new therapeutic perspectives is also discussed, and the role of allogeneic stem cell transplantation is evaluated in light of the results obtained by combining targeted therapy with immunotherapy.

A paragraph is dedicated to the 'Role of Laboratory Testing in Management' as the results obtained in LAL Ph+ (as in many other haematological pathologies where, moreover, Italy has always made significant contributions) were and are only possible through the availability of certified laboratories using standardised methods (and with quality controls).

For Ph+ LALs, it is essential to obtain an accurate molecular diagnosis within the first week after the diagnosis of LAL, so that treatment with a TKI can be started promptly. In addition, a molecular study should be carried out to define whether or not a patient has an unfavourable genetic profile, the possible presence of mutations conferring resistance to certain TKIs should be investigated, MRD should be accurately monitored with quantitative PCR techniques and now also with more sensitive techniques (such as droplet digital PCR), and the modulations induced by treatment with TKIs and blinatumomab on the immune compartment of treated patients should be monitored. A very demanding organisational effort but essential for obtaining results.

This complex network is, of course, unavailable globally, and it is becoming increasingly difficult to manage patients. Co-operative studies, present in several countries, are therefore essential. These include GIMEMA for adults and AIEOP for children in Italy. In the GIMEMA protocols for LAL, all samples from enrolled patients have been centralised since 1996 (at diagnosis and follow-up) at the haematology laboratories of the Policlinico Umberto I General Hospital to ensure that all patients are studied uniformly. This is only possible with qualified and adequately trained staff, who ensure that all the necessary complex tests are properly performed in certified laboratories.

The review also deals with the issue of 'Accessibility and Sustainability'. How many patients have access to this? In terms of laboratory tests and access to drugs? Even today, the availability of TKIs is limited in many parts of the world. In fact, all too often, access to laboratories for the necessary tests and treatment is only possible for those who can afford it.

This approach of induction and consolidation without systemic chemotherapy was also particularly important during the first peak of the Covid-19 pandemic, because it allowed patients to reduce hospitalisation time and, above all, not to interrupt treatment.

In the review's concluding paragraph, it is finally clarified that ongoing studies - primarily the new GIMEMA protocol open for enrolment - will be able to conclusively establish whether a proportion of patients with LAL Ph+ can be treated without systemic chemotherapy and transplantation in the future.

'An achievement that was unthinkable even just a few years ago,' says Robin Foà, 'which leads me to tell the younger generation to believe in their ideas, especially if they are original, and to pursue them with obstinacy. It was not easy for us at the beginning either, but this all-Italian story teaches us that dreams often come true'.

References:

Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia - Robin Foà, Sabina Chiaretti - New England Journal of Medicine (2022) https://doi.org/10.1056/NEJMra2113347

Further Information

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