Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients.

We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000 µM min (N=111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

Bevacizumab/high-dose chemotherapy with autologous stem-cell transplant for poor-risk relapsed or refractory germ-cell tumors.

BACKGROUND: High-dose chemotherapy (HDC) using sequential cycles of carboplatin/etoposide is curative for relapsed germ-cell tumors (GCT). However, outcomes of high-risk patients in advanced relapse remain poor. We previously developed a new HDC regimen combining infusional gemcitabine with docetaxel/melphalan/carboplatin (GemDMC), with preliminary high activity in refractory GCT. Given the high vascular endothelial growth factor expression in metastatic GCT and the synergy between bevacizumab and chemotherapy, we studied concurrent bevacizumab and sequential HDC using GemDMC and ifosfamide/carboplatin/etoposide (ICE) in patients with poor-risk relapsed or refractory disease. PATIENTS AND METHODS: Eligibility criteria included intermediate/high-risk relapse (Beyer Model), serum creatinine ≤ 1.8 mg/dl and adequate pulmonary/cardiac/hepatic function. Patients received sequential HDC cycles with bevacizumab preceding GemDMC (cycle 1) and ICE (cycle 2). The trial was powered to distinguish a target 50% 2-year relapse-free survival (RFS) from an expected 25% 2-year RFS in this population. RESULTS: We enrolled 43 male patients, median age 30 (20-49) years, with absolute refractory (N = 20), refractory (N = 17) or cisplatin-sensitive (N = 6) disease, after a median 3 (1-5) prior relapses. Disease status right before HDC was unresponsive (N = 24, progressive disease 22, stable disease 2), partial response with positive markers (PRm(+)) (N = 8), PRm(-) (N = 7) or complete response (N = 4). Main toxicities were mucositis and renal. Four patients (three with baseline marginal renal function) died from HDC-related complications. Tumor markers normalized in 85% patients. Resection of residual lesions (N = 13) showed necrosis (N = 4), mature teratoma (N = 2), necrosis/teratoma (N = 3) and viable tumor (N = 4). At median follow-up of 46 (9-84) months, the RFS and overall survival rates are 55.8% and 58.1%, respectively. CONCLUSIONS: Sequential bevacizumab/GemDMC-bevacizumab/ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the results expected in this difficult to treat population. CLINICALTRIALSGOV: NCT00936936.

Vaccination guidelines after hematopoietic stem cell transplantation: practitioners' knowledge, attitudes, and gap between guidelines and clinical practice.

BACKGROUND: Hematopoietic stem cell transplant (HCT) recipients are more susceptible to infections from vaccine-preventable diseases than the general population. Despite the development of international consensus guidelines addressing immunization after HCT, studies have shown that deviations from recommended immunization practices commonly occur. METHODS: An anonymous survey aimed at determining awareness of the guidelines and attitudes toward vaccination was distributed to our HCT clinicians. In parallel, we retrospectively evaluated patients' characteristics and post-HCT vaccine administration practices from 2010 to 2013. RESULTS: The majority of survey respondents (96%) were familiar with post-HCT vaccination protocols. Seventy-four percent of respondents reported that influenza vaccines were given to >70% of their patients, and 41% stated that they prescribed live vaccines to eligible patients. However, our pharmacy database review revealed that 38% of patients received the first series of vaccinations by the recommended 6 months post HCT, and 60% received them by 1 year after HCT. Most patients who had their vaccines withheld had relapsed disease or were undergoing treatment for graft-versus-host disease. Furthermore, we identified lower immunization rates in non-English speaking individuals, African-Americans, and Hispanic patients. CONCLUSIONS: Survey respondents reported being aware of current guidelines; however, adherence to the recommendations varied, likely connected to conflicting data on vaccine effectiveness and a lack of clear recommendations in complex clinical scenarios. Similar to the general population, patient barriers also could have contributed to lower vaccination rates in some cases. To decrease the large gap between the post-HCT vaccination guidelines and clinical practice, further studies on vaccine effectiveness and specific populations are warranted.

Size and albedo of Kuiper belt object 55636 from a stellar occultation.

The Kuiper belt is a collection of small bodies (Kuiper belt objects, KBOs) that lie beyond the orbit of Neptune and which are believed to have formed contemporaneously with the planets. Their small size and great distance make them difficult to study. KBO 55636 (2002 TX(300)) is a member of the water-ice-rich Haumea KBO collisional family. The Haumea family are among the most highly reflective objects in the Solar System. Dynamical calculations indicate that the collision that created KBO 55636 occurred at least 1 Gyr ago. Here we report observations of a multi-chord stellar occultation by KBO 55636, which occurred on 9 October 2009 ut. We find that it has a mean radius of 143 +/- 5 km (assuming a circular solution). Allowing for possible elliptical shapes, we find a geometric albedo of in the V photometric band, which establishes that KBO 55636 is smaller than previously thought and that, like its parent body, it is highly reflective. The dynamical age implies either that KBO 55636 has an active resurfacing mechanism, or that fresh water-ice in the outer Solar System can persist for gigayear timescales.

Charon's radius and atmospheric constraints from observations of a stellar occultation.

The physical characteristics of Pluto and its moon, Charon, provide insight into the evolution of the outer Solar System. Although previous measurements have constrained the masses of these bodies, their radii and densities have remained uncertain. The observation of a stellar occultation by Charon in 1980 established a lower limit on its radius of 600 km (ref. 3) (later refined to 601.5 km; ref. 4) and suggested a possible atmosphere. Subsequent, mutual event modelling yielded a range of 600-650 km (ref. 5), corresponding to a density of 1.56 +/- 0.22 g cm(-3) (refs 2, 5). Here we report multiple-station observations of a stellar occultation by Charon. From these data, we find a mean radius of 606 +/- 8 km, a bulk density of 1.72 +/- 0.15 g cm(-3), and rock-mass fraction 0.63 +/- 0.05. We do not detect a significant atmosphere and place 3sigma upper limits on atmospheric number densities for candidate gases. These results seem to be consistent with collisional formation for the Pluto-Charon system in which the precursor objects may have been differentiated, and they leave open the possibility of atmospheric retention by the largest objects in the outer Solar System.

Ultrasound-guided percutaneous and transhepatic cholecystostomy: a complementary procedure to therapeutic endoscopy.

Percutaneous cholecystostomy is an expanding technique since the use of ultrasonography permits a precise puncture of the gall bladder. Cholecystitis is a classical complication of endoscopic maneuvers in the biliary tract or can be associated with obstructive jaundice. Following their results the authors conclude on the usefulness of percutaneous cholecystostomy as a complementary procedure to non-operative management of biliary diseases.