Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma.

BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.

An LES Turbulent Inflow Generator using A Recycling and Rescaling Method.

The present paper describes a recycling and rescaling method for generating turbulent inflow conditions for Large Eddy Simulation. The method is first validated by simulating a turbulent boundary layer and a turbulent mixing layer. It is demonstrated that, with input specification of mean velocities and turbulence rms levels (normal stresses) only, it can produce realistic and self-consistent turbulence structures. Comparison of shear stress and integral length scale indicates the success of the method in generating turbulent 1-point and 2-point correlations not specified in the input data. With the turbulent inlet conditions generated by this method, the growth rate of the turbulent boundary/mixing layer is properly predicted. Furthermore, the method can be used for the more complex inlet boundary flow types commonly found in industrial applications, which is demonstrated by generating non-equilibrium turbulent inflow and spanwise inhomogeneous inflow. As a final illustration of the benefits brought by this approach, a droplet-laden mixing layer is simulated. The dispersion of droplets in the near-field immediately downstream of the splitter plate trailing edge where the turbulent mixing layer begins is accurately reproduced due to the realistic turbulent structures captured by the recycling/rescaling method.

A multicenter trial of myeloablative clofarabine and busulfan conditioning for relapsed or primary induction failure AML not in remission at the time of allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.

Longitudinal Spin Diffusion in a Nondegenerate Trapped

Longitudinal spin diffusion of two pseudospin domains is studied in a trapped ^{87}Rb sample above quantum degeneracy, and the effect of coherence in the domain wall on the dynamics of the system is investigated. Coherence in a domain wall leads to transverse-spin-mediated longitudinal spin diffusion that is slower than classical predictions, as well as altering the domains' oscillation frequency. The system also shows an instability in the longitudinal spin dynamics as longitudinal and transverse spin components couple, and a conversion of longitudinal spin to transverse spin is observed, resulting in an increase in the total amount of coherence in the system.

Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation.

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

Intestinal ischemia after allogeneic stem cell transplantation: a report of four cases.

Gastrointestinal ischemia after allogeneic bone marrow transplantation is a rare complication not well-described in the literature. Herein we retrospectively review charts of four patients who developed intestinal ischemia after allogeneic bone marrow transplantation at our institution. The patients were found to be predominately younger males who presented with nonspecific abdominal pain. Graft-versus-host disease was a common finding among all patients. Laboratory values suggestive of microangiopathy were present in two patients. Obesity and hypertriglyceridemia were cardiovascular risk factors found in these patients. The development of thrombotic microangiopathy and cardiovascular risk factors after allogeneic bone marrow transplantation may predispose patients to gastrointestinal ischemia and may portend a poor prognosis.

A risk-based approach to optimize autologous hematopoietic stem cell (HSC) collection with the use of plerixafor.

Autologous hematopoietic stem cell (HSC) transplant is an effective treatment for patients with hematological malignancies. Unfortunately, 15-30% of patients fail to mobilize a sufficient number of HSCs for the transplant. Plerixafor is now used as a salvage mobilization regimen, with good success. We describe here a risk-based approach for the use of plerixafor, based on the circulating CD34(+) cell count and the CD34(+) cell dose collected after 4 days of G-CSF, that identifies potential poor HSC mobilizers upfront. A total of 159 patients underwent HSC collections using this approach. Of these, 55 (35%) were identified as high risk owing to low CD34(+) cell number or low yield on day 1 of collection, and received plerixafor on the subsequent days of collection. Of the 159 patients, 151 (95%) were able to provide adequate collections with the first mobilization attempt in a median of 1.7 days using this approach. Of the eight who failed initial mobilization, 5 successfully underwent re-mobilization with plerixafor and G-CSF and 3 (1.9%) were mobilization failures. This approach helped to control the overall cost of HSC collections for our BMT program by decreasing the need for remobilization, reducing the number of collection days and avoiding the use of plerixafor in all patients.

Promising cellular therapeutics for prevention or management of graft-versus-host disease (a review).

Graft-versus-host disease (GVHD) frequently occurs following allogeneic hematopoietic stem cell transplantation. The primary treatment for GVHD involves immune suppression by glucocorticoids. If patients become refractory to steroids, they have a poor prognosis. Therefore, there is a pressing need for alternative therapies to treat GVHD. Here, we review clinical data which demonstrate that a cellular therapy using mesenchymal stromal cells (MSCs) is safe and effective for GVHD. Since MSCs derived from bone marrow present certain limitations (such as time lag for expansion to clinical dose, expansion failure in vitro, painful and invasive bone marrow MSC isolation procedures), alternative sources of MSCs for cellular therapy are being sought. Here, we review data which support the notion that MSCs derived from Wharton's jelly (WJ) may be a safe and effective cellular therapy for GVHD. Many laboratories have investigated the immune properties of these discarded MSCs with an eye towards their potential use in cellular therapy. We also review data which support the notion that the licensing of MSCs (meaning the activation of MSCs by prior exposure to cytokines such as interferon-γ) may enhance their effectiveness for treatment of GVHD. In conclusion, WJCs can be collected safely and painlessly from individuals at birth, similar to the collection of cord blood, and stored cryogenically for later clinical use. Therefore, WJCs should be tested as a second generation, off-the-shelf cell therapy for the prevention or treatment of immune disorders such as GVHD.

Late-onset intestinal perforation in the setting of posttransplantation microangiopathy: a case report.

Intestinal perforation in the setting of posttransplantation microangiopathy (TMA) is a very rare event and might be considered a terminal event of intestinal microangiopathy (i-TMA), a rather rarely recognized posttransplantation complication, as it overlaps with the more common intestinal graft-versus-host disease (GVHD). Cases of i-TMA described in literature occurred within with first 100 days posttransplantation or shortly thereafter. In this report, we describe a case of late-onset intestinal perforation that occurred in the setting of systemic microangiopathy more than a year after allogeneic transplantation. In our case, the patient poorly responded to treatment secondary to refractory mircoangiopathy.

Blastic plasmacytoid dendritic cell neoplasm should be treated with acute leukemia type induction chemotherapy and allogeneic stem cell transplantation in first remission.

Blastic plasmacytoid dendritic cell (BPDC) neoplasm is a rare but clinically aggressive tumor known to be derived from the precursors of plasmacytoid dendritic cells (CD123+) with a high frequency of cutaneous and bone marrow involvement. Though majority of the patients initially respond to multi-agent chemotherapy, most would relapse within a year. We hereby report a patient with disseminated cutaneous BPDC with marrow involvement diagnosed by typical histo-pathological and flow-cytometric findings. He was subsequently treated with leukemia type induction regimen followed by allogeneic stem cell transplantation in first complete remission. He is now 18 months posttransplantation with continued remission with full donor chimerism. We recognize that BPDC with marrow involvement behaves like acute myeloid leukemia and aggressive treatment followed by stem cell transplantation may lead to long-term remission in selected cases.

Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach.

BK virus (BKV) reactivation occurs in 50% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Standardized antiviral management of BKV infection has not been established. In order to develop a uniform guideline, a treatment algorithm for the management of symptomatic BKV replication was implemented for our allo-HSCT population. This is a retrospective analysis of patients treated according to the protocol between January 2008 and January 2009. Eighteen patients developed symptomatic BKV replication a median of 43 days after allo-HSCT. All patients had BK viruria and 12 patients had BK viremia in addition to viruria. Patients with isolated viruria were treated with intravenous (IV) low-dose cidofovir (0.5-1mg/kg IV weekly) until symptom resolution. In patients with BK viremia, therapy was continued until virological clearance was achieved in the blood. Four patients also received intravesical instillation of cidofovir per physician discretion. Thirteen of 18 (72%) patients with viruria and 8 of 12 (75%) patients with viremia responded to treatment. Three patients developed transient renal dysfunction. Low-dose cidofovir is safe and effective in allo-HSCT recipients. In absence of randomized prospective data, an institutional algorithmic protocol removes variance in practice pattern and derives data that may be used for research and improved patient care.

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.

AMD3100 given with G-CSF has been shown to mobilize CD34+ cells in non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Hodgkin's disease (HD) patients who could not collect sufficient cells for autologous transplant following other mobilization regimens. These poor mobilizers are usually excluded from company-sponsored trials, but have been included in an AMD3100 Single Patient Use protocol, referred to as a Compassionate Use Protocol (CUP). A cohort of 115 data-audited poor mobilizers in CUP was assessed, with the objective being to collect > or =2 x 10(6) CD34+ cells per kg following AMD3100 plus G-CSF mobilization. The rates of successful CD34+ cell collection were similar for patients who previously failed chemotherapy mobilization or cytokine-only mobilization: NHL -- 60.3%, MM -- 71.4% and HD -- 76.5%. Following transplant, median times to neutrophil and PLT engraftment were 11 days and 18 days, respectively. Engraftment was durable. There were no drug-related serious adverse events. Of the adverse events considered related to AMD3100, two (1.6%) were severe (one patient -- headache, one patient -- nightmares). Other AMD3100-related adverse events were mild (84.8%) or moderate (13.6%). The most common AMD3100-related adverse events were gastrointestinal reactions, injection site reactions and paresthesias. AMD3100 plus G-CSF offers a new treatment to collect CD34+ cells for autologous transplant from poor mobilizers, with a high success rate.

Atom interferometer measurement of the newtonian constant of gravity.

We measured the Newtonian constant of gravity, G, using a gravity gradiometer based on atom interferometry. The gradiometer measures the differential acceleration of two samples of laser-cooled Cs atoms. The change in gravitational field along one dimension is measured when a well-characterized Pb mass is displaced. Here, we report a value of G = 6.693 x 10(-11) cubic meters per kilogram second squared, with a standard error of the mean of +/-0.027 x 10(-11) and a systematic error of +/-0.021 x 10(-11) cubic meters per kilogram second squared. The possibility that unknown systematic errors still exist in traditional measurements makes it important to measure G with independent methods.

Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients.

The current study assessed renal function based on medical records in adult hematopoietic stem cell transplant (HSCT) recipients with proven or probable invasive fungal infection (IFI) transplanted between 1995 and 2000. We confirm that amphotericin B deoxycholate (AmB-d) is nephrotoxic in a large percentage of HSCT recipients. Due to nephrotoxicity, defined as serum creatinine (SCr) >2.5 mg/dl or a 100% increase in SCr from baseline, 88% of patients treated with AmB-d were switched to a lipid formulation of amphotericin B (LFAB). In total, 53% of patients initiated on AmB-d were switched within the first week of therapy. Significantly more patients (70.6%) treated with AmB-d experienced a 100% increase in SCr from baseline compared to patients treated with either AmBisome (44.4%) or Abelcet (41.2%). A Cox Proportional Hazards Model revealed that, compared to patients initiated on AmBisome or Abelcet, the risk of nephrotoxicity (RR=1.5 vs AmBisome; RR=1.7 vs Abelcet), dialysis (RR=2.4 vs AmBisome; RR=1.4 vs Abelcet), and death (RR=2.0 vs AmBisome; RR=1.1 vs Abelcet) were all increased for patients initiated on AmB-d. Study results suggest that renal function improves and mortality declines when an LFAB is given to HSCT patients as initial therapy rather than as second-line therapy, the current practice.

Decoherence-driven cooling of a degenerate spinor Bose gas.

We investigate the relationship between the coherence of a partially Bose-condensed spinor gas and its temperature. We observe cooling of the normal component driven by decoherence as well as the effect of temperature on decoherence rates.

Immunological and clinical effects of post-transplant G-CSF versus placebo in T-cell replete allogeneic blood transplant patients: results from a randomized double-blind study.

BACKGROUND: Immunological and clinical effects of post-transplant growth factor administration have not been well studied. This report describes the outcome and immune functions of a total of 50 HLA-matched related donor allogeneic blood stem-cell transplantation patients who received post-transplant G-CSF (10 microg/kg) or placebo. METHODS: Immune status, including number of lymphocyte subsets and their functions, and serum immunoglobulin levels and clinical status--including GvHD, rate of relapse, event-free survival, and overall survival--were determined in the patients enrolled in this study. RESULTS: Twenty-eight patients survived 1 year after transplant, and 15 patients had available results to compare immune function by randomization assignment. At 12 months post-transplant, immune parameters in G-CSF versus placebo groups showed no statistically significant differences in number of circulating lymphocyte subsets CD3, CD4, CD8, CD19 and CD56 in the two groups. There was no significant (NS) difference in immunoglobulin IgG, IgA and IgM levels, NK or LAK cell-mediated cytotoxicity levels, and mitogen-induced proliferation between post-transplant G-CSF and placebo group. In addition, the analyses of immune parameters at earlier time-points on Days 28, 100, 180, and 270 revealed that, except for LAK cytotoxicity at Day 100, there was no differences between the two groups. Fourteen of 26 patients are alive in the G-CSF arm and nine of 24 in the placebo arm. Median follow-up of surviving patients is 43 months. Four year overall and event-free survival in the G-CSF and the placebo group were 53% and 35% (NS), and 44% and 36% (NS) respectively. Bacterial or fungal infections were the cause of six of 12 deaths in the G-CSF arm (all bacterial) and of four of 15 deaths in the placebo arm (two deaths from Aspergillus) (P=0.26). Two patients relapsed in the G-CSF arm and three in the placebo arm. Four year cumulative incidences of relapse were 8% versus 13% in G-CSF versus placebo arms, respectively, (NS). Chronic GvHD developed in 14 of 19 100-day survivors after G-CSF (11 extensive stage), and in 17 of 20 (14 extensive stage) in the placebo arm. The 4-year cumulative incidence of chronic GvHD was 56% [95% confidence interval (CI) 24-88%] after G-CSF and 71% (95% CI 48-94%) after placebo; this difference was not statistically significant (log rank P=0.41). CONCLUSION: In summary, there were no significant immunological or alterations in clinical benefit of post-transplant G-CSF administration in T-replete allotransplant recipients.

Normal-superfluid interaction dynamics in a spinor bose gas.

Coherent behavior of spinor Bose-Einstein condensates is studied in the presence of a significant uncondensed (normal) component. Normal-superfluid exchange scattering leads to near-perfect local alignment between the spin fields of the two components. We observe that, through this spin locking, spin-domain formation in the condensate is vastly accelerated as the spin populations in the condensate are entrained by large-amplitude spin waves in the normal component.