Blood and Lymphatic Cancer-Targets and Therapy最新文献

Mutations in the FLT3 gene are associated with poor prognosis in patients with AML, even after consolidation with allogeneic hematopoietic cell transplantation (alloHCT) in first remission. Treatment failure in FLT3-mutated AML is largely driven by excessive risk of relapse compared to other genetic subtypes, including in patients post-alloHCT. As a result, there is substantial interest in studying posttransplant maintenance therapy in FLT3-mutated AML as an approach to optimize disease control and improve long-term outcomes. Clinical trials utilizing posttransplant FLT3 inhibitors, such as sorafenib and midostaurin, have shown feasibility, safety, and encouraging posttransplant outcomes, and there are ongoing studies using newer-generation tyrosine-kinase inhibitors as posttransplant maintenance therapy. Here, we review the toxicities and efficacy of FLT3 inhibitors as posttransplant maintenance, recommendations on the use of FLT3 inhibitors by international consensus guidelines, and highlight key remaining questions.

Epigenetic mechanisms such as DNA hypermethylation or histone deacetylation normally silence gene expression that regulates numerous cellular activities. Germinal center-derived lymphomas such as follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are characterized by frequent mutations of histone-modifying genes. EZH2 is essential to the formation of germinal center in the secondary lymphoid tissue (eg, lymph nodes and spleen) and is one of the most frequently mutated histone-modifying genes in human lymphomas. EZH2 encodes a histone methyltransferase, mediates transcriptional repression and acts as an oncogene that promotes the development and progression of a variety of human malignancies, including FL and DLBCL. Thus, recurrent mutations in the EZH2 and other non-histone epigenetic regulators represent important targets for therapeutic interventions. Recently, an orally active inhibitor of EZH2, tazemetostat, has received regulatory approval for patients with mutated EZH2 relapsed or refractory FL after ≥2 prior systemic therapies. It is also approved for those with relapsed or refractory FL who have no satisfactory alternative treatment options, regardless of their mutational status of EZH2. Currently, tazemetostat and its combination therapies for patients with relapsed or refractory germinal center-derived lymphomas, as well as frontline therapies for previously untreated patients, are in various phases of clinical investigations. Despite the promise of epigenetic therapies, potential pitfalls such as target selectivity, risk of oncogenic activation, risk of secondary malignancies associated with epigenetic therapies must be carefully monitored. Future applications of epigenetic approach that incorporate clinical and genomic features are needed to determine how individualized treatments can be used for these hematologic malignancies.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has changed significantly since the development of oral Bruton's tyrosine kinase (BTK) inhibitors. While chemoimmunotherapy was previously the standard of care for first-line treatment, BTK inhibitors have proven to be a highly effective and safe therapeutic option for CLL/SLL, and now constitute one of the preferred first-line options. Ibrutinib, the first approved covalent BTK inhibitor in CLL/SLL, has the most long-term data supporting its efficacy in CLL/SLL treatment although is associated with increased risk of cardiovascular and hemorrhage adverse events due to off-target kinase inhibition. The second-generation covalent BTK inhibitors, including acalabrutinib and zanubrutinib, are more selective to BTK with less off-target effects. Resistance to covalent BTK inhibitors may emerge over time due to mutations in BTK and downstream kinases. Novel non-covalent BTK inhibitors currently being studied are showing promising activities to overcome such resistance. In this review, we discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.

Intravascular large B cell lymphoma (IVL) is a rare subtype of diffuse large B cell lymphoma confined to small blood vessels with a predilection for CNS involvement. The prognosis of IVL with CNS involvement (CNS-IVL) is extremely poor. The optimal treatment for CNS-IVL is not well defined. Thus, we report three patients with CNS-IVL successfully treated with a CNS-centric approach consisting of high-dose methotrexate (HDMTX) and high-dose Ara-C (HiDAC) based CNS-directed chemoimmunotherapy (CIT) alternating with anthracycline-based CIT. Our rationale for intensifying the CNS-directed therapy is the presence of intracerebral bleeding in two of our patients which would result in extravasation of lymphoma cells into the cerebral parenchyma with the development of CNS lymphoma. All three patients have achieved excellent therapeutic outcomes. Two patients with intracerebral bleeding have been in complete remission (CR) for about 11 years and 4 years. One patient was successfully induced into CR about 10 months ago and currently is in CR. This unique therapeutic approach should be further explored for CNS-IVL.