Fulvio Massaro

Sudden sensorineural hearing loss: A vascular cause? Analysis of prothrombotic risk factors in head and neck

Abstract Objective: This aim of this study was to determine the prevalence of thrombophilic risk factors in sudden sensorineural hearing loss, central retinal vein occlusion, and stroke associated with small vessel disease, with the purpose of investigating and reinforcing the vascular hypothesis in the pathogenesis of sudden sensorineural hearing loss. Design: Case-control study. Genetic and acquired risk factors of these three groups were compared with healthy controls. Study sample: Forty-nine, 60, and 101 patients affected respectively by sudden sensorineural hearing loss, central retinal vein occlusion, or stroke associated with small vessel disease, enrolled during a three-year period were compared with 210 healthy controls. Results: The frequency of hyperhomocysteinemia (homocysteine ≥ 15 μmol/L) was higher in each disease group than in controls. A statically significant, albeit weak, correlation between the MTHFR C677T mutation and hyperhomocysteinemia was found in all three diseases. Conclusions: Hyperhomocysteinemia proved to be a risk factor for sudden sensorineural hearing loss. Based on these results, we propose to analyse homocysteine in sudden sensorineural hearing loss patients and, if its values are high, to evaluate the presence of MTHFR C677T mutation.

How ruxolitinib modified the outcome in myelofibrosis: focus on overall survival, allele burden reduction and fibrosis changes

ABSTRACT Introduction: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has shown superiority as compared to available conventional chemotherapies, in terms of reduction in splenomegaly and improvement of symptoms and quality of life. Areas covered: Data published about overall survival in the major randomized sponsored trials and in independent series of patients were detailed. Indeed, data regarding action of ruxolitinib on allele burden reduction and potential activity of the drug on pathogenetic mechanisms involved in increased fibrosis has been reviewed. Expert commentary: Data extrapolated from clinical trials demonstrated an advantage of survival when the drug was compared to placebo or to best available therapy. Moreover, in the long-term, JAK2 allele burden was reduced during treatment and about 50% of patients achieved improvement or stabilization of fibrosis. For this latter activity, several pathways have been involved. In conclusion, ruxolitinib is able to modify the natural outcome of patients affected by myelofibrosis, independently from its nature, both in primary and secondary diseases.

Second line small molecule therapy options for treating chronic myeloid leukemia.

ABSTRACT Introduction: Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease. Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151. Ponatinib, active against all BCR-ABL1 mutants including T315I, became widely used for resistant patients in all phases of disease after previous therapies. Other drugs, such as ABL001, which targets the myristoyl pocket of the ABL1 kinase, are currently in development, to offer therapeutic alternatives for resistant patients to ATP-binders. Expert opinion: In this review, we summarize the efficacy of second line small molecules available. Specific safety profiles have emerged for each drug from sponsored clinical trials in the long-term. Stratification of patients according to comorbidities and cardiovascular risk is now needed to individualize second line treatment. Combinations of different drugs with different mechanisms of action will be used in the future to decrease the incidence of resistance.

Ponatinib: A Review of Efficacy and Safety

Ponatinib is a third generation kinase inhibitor designed to overcome the gatekeeper T315I mutation. In different trials this drug showed inhibitory activity against native BCR-ABL1 kinase and several ABL1 mutations. For this reason, ponatinib is currently indicated for the treatment of chronic myeloid leukaemia (CML) in every phase of disease resistant and/or intolerant to dasatinib and nilotinib and for whom imatinib is not indicated anymore or for patients with T315I mutation. The drug is also indicated for Ph+ acute lymphoblastic leukaemia (ALL). Ponatinib was temporarily suspended in 2013 for the occurrence of cardiovascular thrombotic events. Since then, different investigators analyzed baseline characteristics of patient candidates for ponatinib, especially cardiovascular profile, in order to describe general management recommendations in this setting. In this review, clinical trials data about the use of ponatinib in CML and Ph+ ALL patients will be discussed. It will be focused also about the safety and tolerability profile of the drug and future perspectives of employment.

How has treatment changed for blast phase chronic myeloid leukemia patients in the tyrosine kinase inhibitor era? A review of efficacy and safety

ABSTRACT Introduction: Management of chronic myeloid leukemia (CML) patients in advanced phases of disease has drastically changed since the introduction of tyrosine kinase inhibitors (TKIs) which provide tailored treatment strategies. Areas covered: In this review, efficacy data of different TKIs are reported and reviewed when used as single agent or in combination for the management of blast phase (BP) CML. Expert opinion: Although brilliant results were achieved, the outcome of BP patients did not change when TKIs were used as single agents. Newer strategies of association of TKI with intensified chemotherapy or new agents for different pathways are strongly needed as a bridge to possible allogeneic transplant.

Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy

ABSTRACT Introduction: Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment. Furthermore, TKIs are unable to eradicate leukemic stem cells, allowing the persistence of neoplastic clones. Therefore, there is still clinical need for new agents to overcome common resistance mechanisms to available drugs. This review explores the horizon of drugs actually under investigation for CML patients resistant to conventional treatment. Expert commentary: Radotinib is an ATP-competitive TKI that showed significant activity also in front-line setting and could find employment indications in CML. Asciminib, an allosteric ABL1 inhibitor, could demonstrate a higher capacity in overcoming common TKIs resistant mutations, including T315I, but clinical findings are needed. CML stem cell target will probably require new therapeutic strategies: combinations of several compounds acting with different mechanisms of action are actually under investigation.

Diagnostic and prognostic cytogenetics of chronic myeloid leukaemia: an update

ABSTRACT Introduction: Despite the advent of molecular assessment, banding cytogenetics and fluorescence in situ hybridization (FISH) still have a significant role in diagnostic and prognostic approaches to chronic myeloid leukaemia (CML). Area covered: At diagnosis and during treatment with tyrosine kinase inhibitors (TKIs), cytogenetics is used to detect the Philadelphia chromosome, with its typical translocation t(9;22)(q34;q11.2), and any additional or other chromosomal aberrations (ACAs and OCAs) that may arise in 5–10% of cases, the latter associated to transformation of the disease in blast phases. In this review, the potential role of banding cytogenetics and FISH is discussed through a review of published papers on the prognostic impact of these tools in CML treatment and monitoring. Expert commentary: Cytogenetic techniques, including banding cytogenetics and FISH, continue to maintain a crucial role in CML monitoring. At diagnosis and after 3 months of therapy, banding cytogenetics will continue to be an essential test to perform, but it will become redundant after the achievement of a major molecular response (MMR) assessed with molecular techniques. FISH analysis maintains its usefulness in monitoring the response to TKIs only in special situations.

The Eutos long-term survival score accurately predicts the risk of death in chronic myeloid leukaemia patients treated outside of clinical trials

gle center study with a small sample of pediatric patients receiving MSDT. Second, MFC based MRD detection does not have a uniform sensitivity across all cases. In summary, our results indicate that for pre-MRD positive cases, haplo-SCT should be chosen, and prophylaxis donor lymphocyte infusion (DLI) should be performed if MSDT is used. Our results, together with the available literature, suggest that monitoring MRD during the peri-transplantation period, in combination with MRD-directed prophylaxis or preemptive therapies, could reduce the incidence of morphologic relapse and improve survival.

Clinical results according to age in patients with chronic myeloid leukemia receiving imatinib frontline: The younger, the later, the worse?

To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML).

Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib

Deep molecular response in chronic myeloid leukemia (CML) patients treated with imatinib is a prerequisite for possible discontinuation. We identify clinico-biologic features linked with the probability of reaching MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS) as a stable response (confirmed on two or more consecutive determinations). In a series of 208 patients treated with imatinib first-line outside clinical trials, after a median follow-up of 7 years the incidence of stable MR4.5 was 34.6%, obtained in median time of 5.4 years. In univariate analysis, female gender (p = 0.02), lower median age (56.4 vs 58.6, p = 0.03), Sokal risk stratification (p = 0.01) and e14a2 type of transcript (43% vs 31%, p = 0.02) are associated to achievement of a stable MR4.5. In multivariate regression analysis, female gender (HR 1.6, 95% CI: 1.1–2.6; P = 0.022), Sokal risk (HR 1.4, 95% CI: 1.1–2.3; p = 0.03), type of transcript (e14a2 vs e13a2 type, HR 1.6, 95% CI: 1.3–2.9; P = 0.03) and achievement of an early molecular response (EMR) at 3 months (HR 1.5, 95% CI: 1.2–2.8; P = 0.01), retained statistical significance. These clinical and biologic features associated with the achievement of a stable deep molecular response should be taken into account at a time when treatment-free remission strategies are being actively pursued in the management of CML.