Introduction: The Hedgehog (HH) pathway constitutes a collection of signaling molecules which critically influence embryogenesis. In adults, however, the HH pathway remains integral to the proliferation, maintenance, and apoptosis of adult stem cells including hematopoietic stem cells.
Areas covered: We discuss the current understanding of the HH pathway as it relates to normal hematopoiesis, the pathology of acute myeloid leukemia (AML), the rationale for and data from combination therapies including HH pathway inhibitors, and ultimately the prospects that might offer promise in targeting this pathway in AML.
Expert opinion: Efforts to target the HH pathway have been focused on impeding this disposition and restoring chemosensitivity to conventional myeloid neoplasm therapies. The year 2018 saw the first approval of a HH pathway inhibitor (glasdegib) for AML, though for an older population and in combination with an uncommonly-used therapy. Several other clinical trials with agents targeting modulators of HH signaling in AML and MDS are underway. Further study and understanding of the interplay between the numerous aspects of HH signaling and how it relates to the augmented survival of AML will provide a more reliable substrate for therapeutic strategies in patients with this poor-risk disease. 相似文献
Refractory acute myeloid leukemia (AML) includes AML includes failure of disease to respond to standard induction chemotherapy, relapse within 6 months after first CR, and 2 or more relapses. The outcome of these patients is usually very poor; only a small proportion can be rescued by allogenic hematopoietic stem-cell transplantation (allo-HSCT). The aim of this study was to evaluate the efficacy and feasibility of allo-HSCT in patients with refractory AML.
Patients and Methods
We retrospectively analyzed the clinical outcome of 91 patients who were diagnosed with treatment-refractory AML at Hacettepe University Hospital between January 2002 and June 2018. Patients' disease status included refractory AML, defined as failure to respond to standard induction chemotherapy and relapse within 6 months after first complete remission.
Results
The median follow-up was 12 months (range, 0.5-184 months) for the entire group. Kaplan-Meier estimates of the 3-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 67% and 12%, respectively. Additionally, the Kaplan-Meier estimates of 5-year overall survival for patients who underwent allo-HSCT and patients who received only salvage chemotherapy were 44% and 4%, respectively (P < .001). Complete remission was obtained in 25 patients (83.3%) who underwent allo-HSCT; however, the disease of only 3 patients (3.8%) exhibited complete response after salvage chemotherapy.
Conclusion
Allo-HSCT is still the best-known treatment option with curative potential in patients with treatment-refractory AML. Therefore, all efforts should be made in an attempt to find a suitable matched donor in order to perform allo-HSCT. 相似文献
Acute myeloid leukaemia (AML) is one of the deadliest haematological malignancies. During pregnancy it is a rare comorbidity and can lead to adverse outcomes, such as death, without adequate treatment. The management of AML during pregnancy remains a challenge. We report the case of a primigravida 34-year-old, with 18 weeks of amenorrhoea, who attended the emergency department presenting with pain and hypertrophy of the oral mucosa, accompanied by intense asthenia. Acute myeloblastic leukaemia was diagnosed. The possibility of terminating the pregnancy was offered given the lack of evidence regarding the maternal-foetal outcome, but the patient rejected it, so chemotherapy treatment was started. In the ultrasound controls there was no evidence of teratogenic alterations nor foetal growth restriction, and there were no alterations in Doppler flow values. It was decided to end the pregnancy at 32 + 3 GW. A preterm male was born through eutocic delivery with a normal Apgar test and umbilical cord pH, and did not require resuscitation. The puerperium was favourable and 15 days following discharge she was admitted for a bone marrow transplant from her HLA identical sister. The patient died due to rejection of the transplant and the complications derived from this event. 相似文献
Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions. 相似文献
The ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials showed that the adjuvanted recombinant zoster vaccine (RZV) was ≥90% efficacious in preventing herpes zoster in adults. Here we present a comprehensive overview of the safety data from these studies.
Methods
Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomly vaccinated with RZV or placebo. Safety analyses were performed on the pooled total vaccinated cohort, consisting of participants receiving at least one dose of RZV or placebo. Solicited and unsolicited adverse events (AEs) were collected for 7 and 30?days after each vaccination, respectively. Serious AEs (SAEs) were collected from the first vaccination until 12?months post-last dose. Fatal AEs, vaccination-related SAEs, and potential immune-mediated diseases (pIMDs) were collected during the entire study period.
Results
Safety was evaluated in 14,645 RZV and 14,660 placebo recipients. More RZV than placebo recipients reported unsolicited AEs (50.5% versus 32.0%); the difference was driven by transient injection site and solicited systemic reactions that were generally seen in the first week post-vaccination. The occurrence of overall SAEs (RZV: 10.1%; Placebo: 10.4%), fatal AEs (RZV: 4.3%; Placebo: 4.6%), and pIMDs (RZV: 1.2%; Placebo: 1.4%) was balanced between groups. The occurrence of possible exacerbations of pIMDs was rare and similar between groups. Overall, except for the expected local and systemic symptoms, the safety results were comparable between the RZV and Placebo groups irrespective of participant age, gender, or race.
Conclusions
No safety concerns arose, supporting the favorable benefit-risk profile of RZV. 相似文献
FGFR–TACC, found in different tumor types, is characterized by the fusion of a member of fibroblast grown factor receptor (FGFR) tyrosine kinase (TK) family to a member of the transforming acidic coiled-coil (TACC) proteins. Because chromosome numerical alterations, hallmarks of FGFR–TACC fusions are present in many hematological disorders and there are no data on the prevalence, we studied a series of patients with acute myeloid leukemia and myelodysplastic syndrome who presented numerical alterations using cytogenetic traditional analysis. None of the analyzed samples showed FGFR3–TACC3 gene fusion, so screening for this mutation at diagnosis is not recommended. 相似文献
Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease. 相似文献
Cytogenetic abnormalities are observed in approximately two‐thirds of patients with acute myeloid leukemia (AML). Chromosome rearrangements are associated with specific subtypes of AML and associated prognosis. We report a patient with AML, M2, who was primarily refractory to standard induction chemotherapy with idarubicin and cytarabine. Flow cytometry of a bone marrow aspirate showed aberrant expression of B‐cell markers including CD19. Cytogenetic studies disclosed a translocation between 5q35 and 11q13. Fluorescence in situ hybridization analyses demonstrated that neither the NSD1 nor MLL genes were involved in this case. Further study is required to define conclusively the genes involved and their contribution to pathogenesis in this case. 相似文献