THIS YEAR, the “National day for the fight against leukemia, lymphomas and myeloma “ of the AIL, which is celebrated on 21 June, is dedicated to 4 rare tumors affecting the bone marrow, subtle and silent: the myeloproliferative neoplasms. Let’s talk about chronic myeloid leukemia, policitemia vera, essential thrombocythemia e idiopathic myelofibrosis. They all fit into a single hat because they share common traits: they increase the risk of thrombosis, are often difficult to diagnose, because they are silent for a long time, and can evolve into different and more serious forms. They are also, however, increasingly treatable. For all of them, in fact, there has been a change of pace in recent decades on the front of therapies, thanks to the knowledge of the molecular basis that are at their origin.
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“The AIL Day was born when precision medicine was only in its infancy, with the first drugs capable of targeting the molecular targets at the origin of tumors”, he recalls Sergio Amadori, national president of the association: “Today, however, targeted therapies are a reality, even for myeloproliferative neoplasms”. Precisely on June 21, the toll-free number of the AIL (800226524 from 8 to 20) will answer the haematologists to give information on these diseases and new therapies. “The patient’s needs are only to heal, yes, but not only,” he recalls Giampiero Garuti, patient and Ail volunteer today: “A patient also needs to have correct information to be aware of their disease, to share therapeutic choices and actively participate in treatment. It is true that the doctor makes choices and advises the patient on therapeutic paths, but the latter cannot be just a passive subject, because any therapeutic action must be shared “.
Chronic myeloid leukemia: a new drug targeted for those who do not respond to standard therapy
What, then, are the new perspectives of treatment for myeloproliferative neoplasms? Let’s take chronic myeloid leukemia, for example. Today this disease has a survival of more than 80% at ten years and is much less scary than in the past, thanks to the arrival of tyrosine kinase inhibitors (TKI, which act on the mutated protein at the origin of the disease). For some patients, therapy may even be suspended. However, 20% of patients remain for whom these therapies do not work: “These are patients for whom other drugs are needed – he explained Fabrizio Pane, Professor of Hematology and Director of the Hematology and Transplantation Unit AOU Federico II of Naples. Who I am? “Patients – continues Pane – who recognize risk factors at diagnosis, such as the presence of other chromosomal alterations in addition to that typical of the disease, or other factors that determine a higher propensity for disease instability”. But the therapeutic scene, Pane continues, is getting richer, and he cites, for example, the case of asciminib, a tyrosine kinase inhibitor with a new mechanism of action: “The drug has shown almost double efficacy compared to a standard inhibitor, bosutinib, in patients resistant or intolerant to TKIs, previously treated with at least two TKIs, all with a very favorable safety profile “.
Myelofibrosis, new hope thanks to JAK inhibitors
But not only the history of chronic myeloid leukemia has changed over the years. Even in myelofibrosis – primary, or secondary, as the evolution of an essential thrombocythemia or polycythemia vera – progress has been made: “Even today, the median survival of these patients is around 6/7 years – he explains Alessandro Maria Vannucchi, Director of SOD Hematology Careggi University Hospital of Florence and Head of CRIM – Research and Innovation Center for Myeloproliferative Diseases – but the good news is that evidence is beginning to accumulate so that, thanks to a new approach that facilitates diagnosis, stratification according to risk and new drugs, survival is beginning to increase, albeit less rapidly than we would like ”. Unlike other myeloproliferative neoplasms, such as polycythemia vera and essential thrombocythemia, it is hardly a disease diagnosed by chance, because fatigue, night sweats and symptoms related to an enlarged spleen often lead patients to the doctor. “Thanks to the discoveries of molecular alterations, such as JAK2, MPL and CAR, today we know where to hit – explains the expert – in fact, we hit a molecular pathway of JAK2 with JAK inhibitor drugs, such as ruxolitinib, available for several years, and European Medicines Agency (EMA) recently approved another JAK-inhibitor, fedratinib, which we hope will soon be available in Italy too ”. However, the expert goes on, none of these drugs heals the disease, so stem cell transplantation remains as a treatment option, especially for some patients, such as those most at risk of rapid progression: “Here too, genetics help us, favoring the selection of the patient who must be referred for transplantation, such as young and high-risk ones, because we still have to balance the high mortality associated with the transplant procedure “. Research is active, Vannucchi points out, even for those who no longer respond to ruxolitinib, and this is good for patients to know, perhaps to turn to those centers that conduct clinical trials.
Polycythemia vera and essential thrombocythemia: therapy depends on the risk of thrombosis
Knowing the genetics is also important in other myeloproliferative neoplasms, because it allows to differentiate the risk, and therefore the pharmacological treatment. As happens for example in the case of polycythemia vera and essential thrombocythemia, he recalled Tiziano Barbui, Chief Emeritus of Clinical Hematology, Scientific Director of the FROM Foundation Research Foundation of Bergamo Hospital. Pathologies less serious than myelofibrosis, explains the expert, but which can evolve and whose management depends on the characteristics of the patient: “It must be remembered that the average age at diagnosis of these patients is around 60/65 years and that the ‘advanced age is a vascular risk factor as are previous thrombosis episodes – said Barbui – The haematologist uses drugs directed against these two diseases only if the vascular risk requires it. For example, patients with low vascular risk polycythemia vera are treated with bloodletting and aspirin, cytoreductive drugs are not used; these are used only in high-risk patients. The definition of risk is based on scores for both TE and PV and the genetics of these diseases (JAK2, CALR and MPL mutations) contribute significantly. The risk of a patient with TE who does not have the JAK2 mutation is different from those who have it; or if it has changed due to calreticulin or MPL ”. There are basically three drugs aimed at controlling bone marrow cell proliferation: the standard of care is hydroxyurea and the new drugs are interferon and JAK2 inhibitors. “The latter – underlines Barbui – are not indicated in TE, except in exceptional cases, while they can be used in patients with PV who have shown resistance to hydroxyurea. Interferon is now the subject of numerous studies and used in young people, of childbearing age or in pregnancy “.
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