They are pathologies characterized by a chronic initial phase, which can last many years. Unfortunately, however, in some cases they can progress to more advanced forms and become acute myeloid leukemia, one of the most difficult conditions to treat and associated with a particularly poor prognosis.
We are talking about myeloproliferative diseases. In recent years, the treatment of these pathological conditions has undergone profound changes. Although they are different diseases, polycythemia vera, essential thrombocytopenia and myelofibrosis share a common molecular mechanism: the anomalous and dysregulated activation of the JAK-STAT signaling pathway, fundamental for the normal production of blood cells.
The understanding of this mechanism, which occurred thanks to the discovery of the main mutations between 2005 and 2013, represented a decisive turning point also in terms of treatment as recently explained by Alessandro M. Vannucchi, Director of SOD Hematology, CRIMM, Research and Innovation Center for Myeloproliferative Diseases and Director of the Department of Oncology, Director of the School of Specialization in Hematology at the Careggi University Hospital and the University of Florence, on the occasion of National AIL Day.
Important to arrive early
Thanks to research, we now have molecular tools that allow us to identify these diseases with great precision and at a very early stage.
“Timely diagnosis probably represents the most important therapeutic strategy, since it allows early intervention with preventive measures, such as antithrombotic prophylaxis, considering that thrombosis is among the most frequent and early complications. Furthermore, it allows us to promote a correct lifestyle, accurate clinical-haematological monitoring and, if necessary, the adoption of the most appropriate therapy”
explains Vannucchi.
Molecular knowledge has made increasingly accurate risk stratification possible. This aspect is particularly relevant in myelofibrosis, the form with the most severe prognosis among the three, characterized by a median survival of approximately 6-7 years and for which transplant represents the only potentially curative option. Thanks to genetic information we can now identify patients destined for a more aggressive course and anticipate the need for transplantation when necessary.
In recent years, a further step forward has been taken: it has been demonstrated that some treatments can progressively reduce the mass of neoplastic cells. This effect is monitored by measuring the level of mutations responsible for the disease. Patients who achieve a molecular response show a lower incidence of complications and a reduced likelihood of disease progression.
“If we were to summarize the main innovations, we could identify three: an early and accurate diagnosis based on molecular markers, an increasingly precise and personalized risk stratification and molecular monitoring capable of evaluating the response to therapies with high accuracy”
comments Vannucchi.
Towards personalized medicine
The future of therapeutic strategies will be increasingly linked to the identification and targeting of specific molecular defects. The discovery that the JAK-STAT pathway is altered in all of these diseases, regardless of the mutation present, led to the development of JAK inhibitors.
“We currently have three drugs approved in Europe and four in the United States. These treatments have radically changed the therapeutic approach, significantly improving the quality of life of patients. In many cases they allow optimal control of symptoms and allow people to return to an almost normal life. However, we have understood that these drugs are not able to definitively eliminate the disease. For this reason, one of the most promising perspectives concerns the development of specific inhibitors for the mutated JAK2 protein, rather than for the simply activated protein. In hematology we have already an extraordinary example of success with chronic myelogenous leukemia. In that disease, the introduction of imatinib, a drug directed against the genetic alteration responsible for the pathology, has transformed a once fatal disease into a condition that, for many patients, can be considered essentially cured. For this reason, we are looking with great interest at the development of specific drugs against mutated JAK2. Some molecules are already in an advanced stage of testing and there are good reasons to be optimistic, even if we have to wait for further data on efficacy and safety”.
A second particularly promising line of research concerns patients carrying calreticulin mutations (CALR). The mutated protein is expressed on the surface of diseased cells and has different characteristics compared to the normal form. This has allowed the development of highly specific antibodies, capable of exclusively recognizing the mutated protein.
The first clinical studies are already underway and could lead to a real change in the therapeutic paradigm for the 20-30% of patients with essential thrombocythemia or myelofibrosis who carry the CALR mutation, although there still remains a portion of subjects who respond less well and for whom new molecules are being developed.
“Looking further ahead, if this approach proves effective, we could also develop CAR-T therapies directed specifically against cells that express mutated CALR. It is a very fascinating prospect on which we are already working and the first results obtained in the laboratory are encouraging”
concludes Vannucchi.
The AIL Scientific Committee is renewed
The Scientific Committee of the Italian Association against Leukemia, Lymphoma and Myeloma is renewed with the appointment of Professor Paolo Corradini as President of the body and the appointment of Professor Franco Locatelli as a new member.
Corradini, Full Professor of Hematology at the University of Milan, Director of Hematology and Acting Scientific Director of the National Cancer Institute of Milan, was elected President by the members of the Scientific Committee.
Franco Locatelli was also appointed new member of the AIL Scientific Committee; Director of the Clinical Area of Pediatric Onco-Hematology, Cellular Therapy, Gene Therapies and Hematopoietic Transplantation of the Bambino Gesù Children’s Hospital in Rome and Full Professor of Pediatrics at the Catholic University of the Sacred Heart of Rome, Locatelli is among the leading international experts in the field of pediatric hematology, hematopoietic stem cell transplantation and advanced cell therapies.
Following the renewal, the AIL Scientific Committee is composed of:
- Paolo Corradini, President
- Franco Locatelli
- Fabrizio Pane, Full Professor of Hematology, Director of the Department of Oncology, Hematology and Pathological Anatomy, Federico II University of Naples, Director of the Hematology and Bone Marrow Transplant Unit, AOU Federico II of Naples,
- Alessandro Rambaldi – Professor of Hematology, Scientific Director of the FROM Research Foundation, Papa Giovanni XXIII Hospital in Bergamo
- Giorgina Specchia – Professor of Hematology and President of the Puglia Hematology Network.
