RESUMO
Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) with a poor prognosis, at high risk of relapse after conventional treatment. MCL-associated tumour microenvironment (TME) is characterized by M2-like tumour-associated macrophages (TAMs), able to interact with cancer cells, providing tumour survival and resistance to immuno-chemotherapy. Likewise, monocyte-derived nurse-like cells (NLCs) present M2-like profile and provide proliferation signals to chronic lymphocytic leukaemia (CLL), a B-cell malignancy sharing with MCL some biological and phenotypic features. Antibodies against TAMs targeted CD47, a 'don't eat me' signal (DEMs) able to quench phagocytosis by TAMs within TME, with clinical effectiveness when combined with Rituximab in pretreated NHL. Recently, CD24 was found as valid DEMs in solid cancer. Since CD24 is expressed during B-cell differentiation, we investigated and identified consistent CD24 in MCL, CLL and primary human samples. Phagocytosis increased when M2-like macrophages were co-cultured with cancer cells, particularly in the case of paired DEMs blockade (i.e. anti-CD24 + anti-CD47) combined with Rituximab. Similarly, unstimulated CLL patients-derived NLCs provided increased phagocytosis when DEMs blockade occurred. Since high levels of CD24 were associated with worse survival in both MCL and CLL, anti-CD24-induced phagocytosis could be considered for future clinical use, particularly in association with other agents such as Rituximab.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma de Célula do Manto , Adulto , Humanos , Rituximab/farmacologia , Rituximab/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma de Célula do Manto/tratamento farmacológico , Antígeno CD47 , Recidiva Local de Neoplasia , Fagocitose , Microambiente Tumoral , Antígeno CD24RESUMO
PURPOSE OF REVIEW: Patients with relapsed/refractory primary central nervous system lymphoma (rrPCNSL) have poor prognosis, with a median survival after relapse of 6.8âmonths. In this review, we discuss the evolving landscape and the possible future directions related to this important unmet clinical need. RECENT FINDINGS: The modern two-phase approach for newly diagnosed PCNSL based on an induction using high-dose methotrexate (HD-MTX) combinations and a subsequent consolidation, has significantly improved the outcome in this setting. However, this strategy is able to cure more or less 50% of patients. rrPCNSL patients have a very poor prognosis with a reported 5-year overall survival of 18%. Late relapses (after third year) and use of high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) represent important factors associated with a better outcome in this setting. On the basis of the growing acquisition of knowledge on the molecular characteristics of PCNSL, the use of non-chemotherapeutic drugs such as bruton tyrosine kinase inhibitors (BTK-is), immunomodulatory drugs (IMiDs) and immune checkpoint blockers (ICBs) is increasing in the last years along with the introduction of novel approaches (CAR-T cells and blood--brain barrier disruption). However, despite high responses in some cases, durations are often short, translating in outcome results still unsatisfactory. SUMMARY: Treatment of rrPCNSL patients is challenging. As no standard of care exist in this setting, it is of paramount importance to acquire new knowledge related to this condition and start multidisciplinary collaboration in order to improve pts outcome.
Assuntos
Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Transplante Autólogo , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Sistema Nervoso Central/patologia , Terapia CombinadaAssuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Crizotinibe/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Anaplásico de Células Grandes , Inibidores de Proteínas Quinases/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de SobrevidaRESUMO
Acute myeloid leukemia (AML) identifies a heterogeneous group of clonal disorders, both clinically and genetically. A large number of mutations have been described in AML, although only a few are currently employed in clinical practice. Next generation sequencing (NGS) allows for better understanding of the complex genetic background in AML and may direct individualized therapies. In this study, we aim to identify molecular aberrations that are not routinely investigated in AML using an NGS-based panel encompassing 101 genes and to evaluate how their oncogenic potential correlates with survival. Forty consecutive patients with newly diagnosed AML were enrolled between January 2018 and April 2020. We performed targeted NGS and detected 96 mutations in 36 patients (90%), while 14 fusion genes were detected in 13 patients (32%). Each mutation was weighed using OncoScore, a text-mining tool ranking genes according to their oncogenic potential. An OncoScore ≥ 100 was associated with shorter PFS among our patients (p = 0.05). In 11 patients with no available MRD markers at diagnosis, we were able to perform NGS-based MRD monitoring using targeted deep sequencing. Overall, our study shows that NGS is a powerful tool in AML and should be employed both in routine diagnostic workup and follow up.