No abstract

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

Aim: There is lack of evidence of the role of sacral root neuromodulation (SNM) in the management of chronic pelvic pain syndrome (CPPS). We evaluated the effectiveness of cycling sacral root neuromodulation (CSNM) in the management of CPPS in patients non responders to conservative treatment. Methods:A prospective, single center, cohort study was carried out on all patients with CPPS refractory to conventional treatment, who underwent test stimulation using the tined lead between February 2012 and March 2016. During test stimulation the tine lead was positioned along the third sacral nerve, on the side where they reported more pain. Success was defined as >50% improvement of pain and concurrent urinary symptoms. After a successful SNM test period of 4 weeks, patients received a permanent implant. We also included 9 more patients already with a permanent implant and partial responders to continuous mode in neuromodulator programming. To assess pain and quality of life, all patients filled-in a VAS scale and SF-36 and McGill questionnaires, at baseline, after the 4-week test period ad after the permanent implant.Results: Overall 22 consecutive adult patients were suitable to undergo a cycling test stimulation; 19 out of them (86.3%) underwent a permanent implant after a satisfactory test phase, using a codified cycling mode of programming. Eighteen naive patients out of nineteen (94.7%) maintained the benefits of the test stimulation at a mean follow up of 21.3 months. VAS scale, McGill and SF-36 questionnaires scores improved significantly in all domains with a 95% satisfaction rate; 7 out of the 9 already implanted patients (77.7%) significantly improved their pain control.Conclusion: CSRN appears to be effectiveness in treating CPPS in both naïve and previous implanted partial responder patients.

The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML.