Proportion Of Refractory Patients Research Articles

Antiseizure medication discovery: Recent and future paradigm shifts.

Despite the ever‐increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms are required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first‐in‐class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi‐target agents and low‐affinity ligands.

Expression of Programmed Death Ligand-1 (PD-L1) in Human Acute Leukemia and Its Clinical Significance

To explore the expression of PD-L1 in acute leukemia patients, and to analyze the relationship of PD-L1 expression with the patients' clinical characteristics and prognosis. The expression of PD-L1 in leukemia cells of 75 patients including 59 de novo patients and 16 relapse/refractory patients with acute leukemia was detected by the flow cytometry, the clinical information was collected, and the therapeutic efficacy of de novo patients was analyzed. The PD-L1 was expressed in human acute leukemia cells with total expression rate 32% (24/75), and its expression level in AML-M5 was higher than that in other leukemias [56.3% (9/16) vs 25.4% (15/59)], there was statistical significance (P = 0.019). The PD-L1 possitive rate in relapse/refractory group was higher than that in de novo patient group [(56.3% (9/16) vs 25.4% (15/59)], and there was statistical significance (P = 0.019). In 59 de novo patients, the CR rate of PD-L1 positive group after 1 course of chemotherapy was lower than that in PD-L1 negative group (66.7% vs 71.4%), the CR rate of PD-L1 positive group after 2 courses of chemotherapy was also lower than that in PD-L1 negative group (70% vs 88.6%). The relapse rate and the proportion of refractory patients in PD-L1 possitive group were higher than those in PD-L1 negative group. The expression of PD-L1 did not correlated with the clinical parameters, such as sex, age, extramedullary infiltration, percentage of blast cells in bone marrow, counts of WBC, RBC and platelet, as well as molecular biological features and cytogenetical characteristics. PD-L1 is expressed in human acute leukemia cells, and may be involved in the immune escape and primary resistant mechanisms, PD-L1 may be used as an indicator for evaluation of the the patients' prognosis and reocurrence.

Influence of NPM1 and FLT3-ITD Status On Outcome in Relapsed/Refractory AML Patients with Normal Karyotype and Receiving Salvage Therapy Including Gemtuzumab Ozogamicin (GO).

Abstract 3110Poster Board III-47The aim of this study was to investigate the influence of the NPM1/FLT3-ITD status on outcome in relapsed/refractory AML patients with normal karyotype who received a salvage regimen using GO as monotherapy or in combination with other agents.For this purpose, we analyzed the outcome of 57 AML patients with normal karyotype treated between 2001 and 2009. Patients received GO as monotherapy or in combination with other chemotherapeutic agents at time of relapse (n=36) or in the setting of refractory disease (n=21). There were 26 males and 31 females with a median age of 52 (range, 20-70) years at time of leukemia diagnosis. The FAB distribution included 2, 13, 15, 11, 12 and 1 AML cases from the M0, M1, M2, M4, M5 and M6 subgroups, respectively. Three cases were considered as unclassified. In addition, 5 patients had secondary AML. All patients were CD33 positive with a median CD33 expression level of 98%. As salvage treatment, 46 patients received the MIDAM regimen (GO: 9 mg/m2 at day 4 + Cytarabine 1g/m2/12 hours day 1-5 + Mitoxantrone 12 mg/m2/day day 1-3).3 In 2 patients receiving the MIDAM regimen, Mitoxantrone was omitted to avoid cardiac toxicity. Four patients received GO as monotherapy at 9 mg/m2 (n=3) or at 6 mg/m2 (n=1). The 5 remaining patients received GO 3 to 9 mg/m2 combined with other chemotherapeutic agents (Cytarabine + VP16 + GO, n=2; Cytarabine + Idarubicine + GO, n=2; Cytarabine + Amsacrine + GO, n=1). After salvage therapy, 25 patients could proceed and receive consolidation with an allogeneic stem cell transplant.In this series, all patients could be screened in the blood or bone marrow for mutations in the NPM1 and in the FLT3 gene (ITD mutations) at diagnosis. Numbers of patients according to NPM1/FLT3-ITD status were as follow: (+/−): n=14, (+/+): n=9, (−/−): n=19, (−/+): n=15. The same proportion of refractory patients was observed in the favourable NPM1+/FLT3-ITD- sub-group as compared to the other sub-groups (36%, n=5/14 vs 37%, n=16/43).With a median follow-up of 23.3 (range, 2.3-94.5) months for surviving patients, OS was 46.5% (95%CI, 33.6-59.9%) at 2 years. CR, relapse and death rates according to NPM1/FLT3-ITD status were as follow: CR: (+/−): 85%, (+/+): 66%, (−/−): 47%, (−/+): 73%, P=NS; Relapses: (+/−): 33%, (+/+): 33%, (−/−): 33%, (−/+): 54%, P=NS; Deaths: (+/−): 28%, (+/+): 78%, (−/−): 58%, (−/+): 66%, P=0.02 Also, the death rate was significantly lower in FLT3-ITD- patients as compared to FLT3-ITD+ cases (45% vs. 71%, P=0.05). OS was significantly higher in the NPM1+/FLT3-ITD- sub-group as compared to other patients (78% vs. 36% at 2 years, P=0.026).In conclusion, and although this needs to be confirmed in a prospective setting, refractory/relapsed AML patients combining a normal karyotype and a NPM1+/FLT3-ITD- molecular status are likely to remain in a “favorable prognosis” category when receiving salvage therapy. Such information is of major interest for patients counselling and for the design of salvage therapy approaches. DisclosuresNo relevant conflicts of interest to declare.