Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: A comparison to other agents

This study characterized the novel neurokinin (NK)₁ antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK₁ receptors (pK_i, 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK₁ receptors in gerbils (Inhibitory Dose₅₀, 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK₁ agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK₁ receptor antagonist: its actions support the utility of NK₁ receptor blockade in the alleviation of anxiety and, possibly, depression.     

Growth factor-associated graft-versus-host disease and mortality 10 years after allogeneic bone marrow transplantation

This study analysed the effects of growth factor on outcome after haematopoietic stem‐cell transplantation (HSCT) with >9 years follow‐up. Of 1887 adult patients with acute leukaemia who received bone marrow from human leucocyte antigen (HLA)‐identical siblings and were treated with myeloablative conditioning, 459 (24%) were treated with growth factor. Growth factor hastened engraftment of neutrophils (P < 0·0001), but reduced platelet counts (P = 0·0002). Graft‐versus‐host disease (GVHD)‐free survival (no acute GVHD grade II–IV or chronic GVHD) at 10 years was 12 ± 2% (±SE) in the growth factor group, as opposed to 17 ± 2% in the controls [hazard ratio (HR) 0·81, P = 0·001]. Similar differences in GVHD‐free survival were seen in patients with or without conditioning with total body irradiation (TBI). Non‐relapse mortality (NRM) was higher in the growth factor group irrespective of whether or not TBI conditioning was included [HR = 1·48; 95% confidence interval (CI): 1·15–1·9; P = 0·002; HR = 1·59; 95% CI: 1·07–2·37; P = 0·02, respectively]. Both groups had similar probabilities of leukaemic relapse (HR = 0·96; 95% CI: 0·78–1·18; P = 0·71). Leukaemia‐free survival (LFS) at 10 years was 35 ± 2% in those receiving growth factor prophylaxis, as opposed to 44 ± 1% in the controls (HR = 0·70; 95% CI: 0·60–0·82; P = 0·00001). Prophylaxis with growth factor increases the risk of GVHD, does not affect relapse, increases NRM and reduces LFS > 10 years after HSCT, regardless of conditioning with TBI.     

Results from a clofarabine-busulfan-containing,reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial

We prospectively evaluated the safety and efficacy of a clofarabine, intravenous busulfan and antithymocyte globulin-based reduced-toxicity conditioning (CloB2A2) regimen before allogeneic stem cell transplantation. Thirty high-risk patients (median age: 59 years; acute myeloid leukemia n=11, acute lymphoblastic leukemia n=13; myelodysplastic syndrome n=5, bi-phenotypic leukemia n=1) were included in this phase 2 study. At time of their transplant, 20 and seven patients were in first and second complete remission, respectively, while three patients with myelodysplastic syndrome were responding to chemotherapy or who had not been previously treated. The CloB2A2 regimen consisted of clofarabine 30 mg/m²/day for 4 days, busulfan 3.2 mg/kg/day for 2 days and antithymocyte globulin 2.5 mg/kg/day for 2 days. The median follow-up was 23 months. Engraftment occurred in all patients. The 1-year overall survival, leukemia-free survival, relapse incidence and non-relapse mortality rates were 63±9%, 57±9%, 40±9%, and 3.3±3%, respectively. Comparing patients with acute myeloid leukemia/myelodysplastic syndrome versus those with acute lymphoblastic leukemia/bi-phenotypic leukemia, the 1-year overall and leukemia-free survival rates were 75±10% versus 50±13%, respectively (P=0.07) and 69±12% versus 43±13%, respectively (P=0.08), while the 1-year relapse incidence was 25±11% versus 57±14%, respectively (P=0.05). The CloB2A2 regimen prior to allogeneic stem cell transplantation is feasible, allowing for full engraftment and low toxicity. Disease control appears to be satisfactory, especially in patients with acute myeloid leukemia/myelodysplastic syndrome. The trial was registered at www.clinicaltrials.gov no. {"type":"clinical-trial","attrs":{"text":"NCT00863148","term_id":"NCT00863148"}}NCT00863148.     

Low non-relapse mortality and long-term preserved quality of life in older patients undergoing matched related donor allogeneic stem cell transplantation: a prospective multicenter phase II trial

Allogeneic transplantation is a challenge in patients of advanced age because of a high risk of non-relapse mortality and potential long-lasting impairment of health-related quality of life. The development of reduced-intensity conditioning regimens has allowed the use of allogeneic transplantation in this population, but the optimal regimen remains undefined. We conducted a multicenter phase II trial evaluating the safety and efficacy of a reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins in patients older than 55 years of age transplanted from matched-related donor. In addition, health-related quality of life was prospectively measured. Seventy-five patients with a median age of 60 years (range 55–70) were analyzed. Grade III-IV acute and extensive chronic graft-versus-host diseases were found in 3% and 27% of patients, respectively. The day 100 and 1-year non-relapse mortality incidences were 1% and 9%, respectively. The cumulative incidences of relapse, progression-free survival and overall survival at two years were 36%, 51% and 67%, respectively, with a median follow up of 49 months. Global health-related quality of life, physical functioning, emotional functioning, and social functioning were not impaired compared to baseline for more than 75% of the patients (75%, 81.4%, 82.3%, and 75%, respectively). Thirty-four of the 46 (74%) progression-free patients at one year were living without persistent extensive chronic graft-versus-host disease. We conclude that the reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins is well tolerated in patients older than 55 years with low non-relapse mortality and long-term preserved quality of life.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.     

Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia

Ongoing studies in B-cell chronic lymphocytic leukemia are evaluating autologous peripheral blood stem cell (PBSC) transplantation in first remission following fludarabine therapy. However, fludarabine could impair PBSC harvest. In 38 patients after frontline oral fludarabine and cyclophosphamide (FDR-CY) therapy, we prospectively evaluated steady state filgrastim- or lenograstim-primed PBSC mobilization to collect 2.0 x 106/kg or more CD34 cells. The first mobilization, performed a median of 178 days (range, 69-377 days) from the last FDR-CY course, was unsuccessful in 32 patients. This result was significantly associated with a low platelet count before mobilization but not with age, interval from last FDR-CY course, initial stage, remission status, or other blood parameters. Finally, after 1, 2, and 3 mobilizations in 27, 10, and 1 patients, 2.0 x 106/kg or more CD34 cells were collected in only 12. Explorations of the mechanism of poor mobilization and adaptation of PBSC harvest policies after fludarabine treatment are therefore warranted.     

Proportion of long-term event-free survivors and lifetime of adult patients not cured after a standard acute lymphoblastic leukemia therapeutic program: adult acute lymphoblastic leukemia-94 trial

BACKGROUND: In adult acute lymphoblastic leukemia, treatment results generally are expressed in terms of overall survival or disease-free survival at 3 years. In this investigation, the authors attempted to express the results in terms of the proportion of long-term disease-free survivors and in terms of lifetime in patients who developed recurrent disease or died. METHODS: Univariate and multivariate analyses were used to assess the influence of different covariates on the 2 result criteria in 922 participants in the Adult Acute Lymphoblastic Leukemia-94 multicenter trial. RESULTS: The proportion of long-term survivors was 21.5% (95% confidence interval [95% CI], 18.1-25.4%) and was higher in women than in men. The proportion decreased with increasing age, white blood cell count, and lactate dehydrogenase level. The lowest proportion was observed in patients ages 44 years to 55 years (11.4%; 95% CI, 7-17.9%) and in patients with the t(9;22) BCR-ABL karyotype (13.4%; 95% CI, 8.8-19.8%), and the highest proportion was observed in patients with the t(4;11) MLL-AF4 karyotype (31.3%; 95% CI, 18.2-48.3%). The mean expected lifetime of patients who were not cured was 11.4 months (95% CI, 9.1-14.1 months). It was longer in men than in women and was shorter with increasing age, performance status, hemoglobin level, and white blood cell count. CONCLUSIONS: The results of this study highlighted and specified the importance of some classic prognostic factors in patients with acute lymphoblastic leukemia.     

Antifungal Stewardship in Hematology: Reflection of a Multidisciplinary Group of Experts

We have presented a practical guide developed by a working group of experts in infectious diseases and hematology to summarize the different recommendations issued by the different international groups on antifungal agents used for hematology patients. In addition, a working group of experts in the domains of nephrology, hepatology, and drug interactions have reported their different recommendations when administering antifungal agents, including dose adjustments, monitoring, and management of their side effects. This guide will enable prescribers to have a document available that will allow for better and optimal use of antifungal agents for hematology patients with consideration of the toxicity and interactions adjusted to each indication.