Haploidentical Transplant with Post-Transplant Cyclophosphamide for Acute Myeloid Leukaemia and Myelodysplastic Syndromes Patients: The Role of Previous Lines of Therapy.

Background: Allogeneic haematopoietic stem-cell transplant is an option, potentially curative, for high-risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients. Post-transplant cyclophosphamide administration allows for the selection of haploidentical donors in patients who are eligible for the procedure but do not have a fully matched donor since it can overcome the HLA barrier. There is still an active debate on whether intensifying the conditioning regimen is necessary with haploidentical donors when peripheral blood stem cells are used as the graft source. Herein, we report our decennial experience of haploidentical stem-cell transplant using peripheral blood stem cells (haplo-PBSC) at King's College Hospital. Objectives: The primary objective was to evaluate overall survival (OS) following haplo-PBSC. Secondary objectives were total OS for patients with less than two previous lines of therapy, OS according to cytomegalovirus (CMV) reactivation, incidence of transplant-related mortality (TRM), graft-versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). Results: One-year and three-year total OS were 62% and 43%, respectively, with a median OS of 22 months. One-year and three-year OS for patients with ≤2 and those with >2 previous lines of therapy were 72% and 55%, and 60% and 22%, respectively (p-value=0.04). The median OS in patients with >2 previous and ≤2 lines of therapy was 16 and 49 months, respectively. Cumulative incidence (CI) of relapse was 25% with a median time to relapse of 5 months (range 1 - 38 months). Conclusions: Haploidentical haematopoietic stem-cell transplant is potentially curative in chemosensitive AML and MDS and offers a high rate of prolonged remission. Our cohort further confirms the role of consolidative haploidentical transplant in patients in complete remission and highlights that patients with heavily pre-treated disease may not benefit from this strategy.

Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity.

Major Adipokines and the -420C>G Resistin Gene Polymorphism as Predictors of Acute Ischemic Stroke Severity and In-Hospital Outcome.

BACKGROUND: The role of adiponectin, leptin, and resistin and the -420C>G polymorphism of the resistin gene promoter in the pathogenesis of ischemic stroke are controversial. We aimed to evaluate whether serum levels of these adipokines and the -420C>G polymorphism are associated with ischemic stroke severity and in-hospital outcome. METHODS: We prospectively studied 93 patients who were consecutively hospitalized for acute ischemic stroke (39.8% males, age 79.7 ± 6.3 years). Stroke severity was evaluated at admission by the National Institutes of Health Stroke Scale (NIHSS). In-hospital outcome was evaluated by dependency rates at discharge and in-hospital mortality. RESULTS: The G allele was more prevalent in patients with severe stroke (P < .05). Independent predictors of severe stroke were high-sensitivity C-reactive protein levels (relative risk [RR] 1.43, 95% confidence interval [CI] 1.08-1.91, P < .05). Patients with dependency at discharge had lower serum leptin levels (P < .05). Independent predictors of functional dependence were prior ischemic stroke (RR 7.55, 95% CI 1.69-33.58, P < .01), serum triglyceride levels (RR .98, 95% CI .96-0.99, P < .05), and NIHSS at admission (RR 1.47, 95% CI 1.17-1.84, P < .001). The G allele was more prevalent in patients who died (P < .05). Independent predictors of in-hospital mortality were systolic blood pressure (RR 1.09, 95% CI 1.01-1.19, P < .05) and NIHSS at admission (RR 1.26, 95% CI 1.08-1.48, P < .005). CONCLUSIONS: The G allele of the -420C>G polymorphism of the resistin gene promoter appears to be associated with more severe stroke and higher in-hospital mortality in patients with acute ischemic stroke. Higher leptin levels appear to be related to favorable functional outcome.

The role of adipokines in ischemic stroke risk stratification.

BACKGROUND: Adiponectin, leptin, and resistin are the most well-studied adipokines and play important roles in the regulation of glucose metabolism, subclinical inflammation, and cardiovascular homeostasis. Accordingly, measurement of adipokine levels might be useful in cardiovascular risk stratification. Moreover, the study of single-nucleotide polymorphisms of genes that encode these adipokines might also represent a valuable predictive tool in cardiovascular disease prevention strategies. AIMS: To summarize the biologic role of the adipokines adiponectin, leptin, and resistin and the prognostic value of their serum levels regarding the occurrence and outcome of ischemic stroke. We also discuss the relationship of single-nucleotide polymorphisms of the adiponectin, leptin genes, and the -420C > G polymorphism of resistin gene with stroke risk. SUMMARY OF REVIEW: Several studies in the general population evaluated the association between these adipokines and stroke risk, yielding conflicting results. There are more limited data regarding the effect of these adipokines on stroke severity and outcome. A small number of studies also assessed the predictive role of single-nucleotide polymorphisms of the adiponectin, leptin, and resistin genes regarding stroke risk, but the findings were also controversial. CONCLUSIONS: It is unclear whether adiponectin, leptin, and resistin levels or the single-nucleotide polymorphisms of their encoding genes are independently associated with stroke risk. However, given the role of these adipokines in the pathogenesis of atherosclerosis, larger prospective studies, both in the general population and in patients with a history of stroke, are needed to determine whether the measurement of serum levels of these adipokines or the evaluation of single-nucleotide polymorphisms in their encoding genes could improve stroke risk prediction. If this relationship is proven, therapeutic interventions targeting adipokine levels might represent a novel approach to reduce stroke-related mortality and disability.