Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD⁸¹⁶) was associated with a high white blood cell count at diagnosis (median, 29.60 × 10⁹/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD⁸¹⁶ mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT^–) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD⁸¹⁶ (n = 7) and the c-KIT^– patients. These findings indicate that c-KIT TKD⁸¹⁶ mutation has a negative impact on the outcome of AML with t(8;21).

Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL.

Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features.Diagnostic and prognostic charactrization in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications.Treatment choice in Waldemstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, disease characteristics, risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation.Therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents an important step forward for a better management of the disease.

In patients with acute myeloid leukemia (AML), age has generally been considered as the main factor to determine if intensive chemotherapy can be carried out (fitness). However, this has been gradually changing in recent years. In addition to age, comorbidities and overall performance status are also important in determining if the patient should undergo intensive chemotherapy and have an important role in tailoring therapeutic options. Consensus criteria to define eligibility for intensive and nonintensive chemotherapy in patients with AML have been proposed, which have been shown to correlate well with expected outcomes. Today, given the evolution of the treatment armamentarium, assessment of a patient’s ‘fitness’ is compulsory to select the most appropriate treatment for each patient.