Pharmacokinetic modelling and development of Bayesian estimators for therapeutic drug monitoring of mycophenolate mofetil in reduced-intensity haematopoietic stem cell transplantation.

International audienceBACKGROUND: Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. OBJECTIVES: To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. PATIENTS AND METHODS: Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. RESULTS: The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data. CONCLUSION: Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy

Positive quantitative PCR detecting Fusarium solani in a case of mixed invasive fungal disease due to Mucorales and Fusarium solani.

International audienceWe present a case of invasive fungal co-infection in a young patient treated for an acute myeloid leukemia and having undergone a twice-haploid matched unrelated donor hematopoietic stem cell transplantation (HSCT) with two different donors. A mucormycosis diagnosis was made shortly after the patient's admission using imagery and specific Mucorales qPCR which was treated with liposomal amphotericin B and posaconazole. Twenty days later, a blood culture was positive for Fusarium solani, and disseminated cutaneous lesions appeared. The antifungal treatment was changed to liposomal amphotericin B and voriconazole. Thanks to a complete hematological reconstitution and despite a co-infection with two aggressive filamentous opportunistic fungi, the patient recovered. We took advantage of this clinical case to test a specific Fusarium solani qPCR, which proved to be promising when performed retrospectively on some of the patient samples

Infections disséminées à Scedosporium prolificans: à propos de 2 cas et revue de la littérature

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Digestive cryptosporidiosis mimics GVHD after Hematopoietic Stem Cell Transplantation and responds to bi-antibiotic therapy

Abstract P376

Prescription of Blood Lymphocyte Immunophenotyping in the Diagnosis of Lymphoid Neoplasms in Older Adults

Lymphoid neoplasms are a heterogeneous group of lymphoid neoplastic diseases with multiple presentations, and varying prognoses. They are especially frequent in older patients (OPs) and the atypism of this frail elderly population can make the diagnostic process even more difficult. Blood lymphocyte immunophenotyping (BLI) is essential in rapid noninvasive diagnosis orientation and guides complementary investigations. To our knowledge, BLI prescription has never been evaluated in OPs. We hypothesized that, when there is a suspicion of lymphoid neoplasm in the geriatric population, a BLI is performed in view of various clinical or biological abnormalities. This study aimed to: (1) describe the characteristics of hospitalized OPs having undergone BLI for suspected lymphoid neoplasm, (2) identify the causes leading to BLI prescription, and (3) identify the most profitable criteria for BLI prescription. This was a descriptive retrospective study on 151 OPs aged &ge;75 years who underwent BLI over a 2-year period. Regarding BLI prescriptions, eight had lymphocytosis, constituting the &ldquo;lymphocytosis group&rdquo; (LG+), while the 143 others had BLI prescribed for reasons other than lymphocytosis (LG&minus;), mainly general weakness and anemia. In the LG&minus;, we compared OPs with positive and negative BLI results. The criteria found to be profitable for BLI prescription were lymphadenopathy, splenomegaly, lymphocytosis, and thrombocytopenia. BLI identified circulating lymphoid neoplasms (positive BLI) in 21/151 OPs, mainly marginal zone lymphoma and chronic lymphocytic leukemia. In polymorbid OPs, as per our study population, the diagnostic and therapeutic complexity explained in part the sole use of indirect and minimally invasive diagnostic techniques such as BLI

False-positive Aspergillus real-time PCR assay due to a nutritional supplement in a bone marrow transplant recipient with GVH disease.

International audiencePCR screening for circulating DNA, especially when combined with antigen testing, has shown promise for the definitive diagnosis of invasive aspergillosis. False positives for Aspergillus real-time PCR assays have been described in several reports, but no sources of fungal DNA contamination could be clearly identified. We report a false-positive case for both galactomannan (GM) antigenemia and Aspergillus PCR due to nutritional supplement intake in a bone marrow transplant recipient with digestive graft-versus-host disease. Our case report also suggests that fungal DNA can pass into the serum from the intestinal tract in the same way as fungal GM. Clinicians should be aware of this possibility, so that the administration of costly, unnecessary antifungal treatments with potential adverse side-effects can be avoided

Pharmacokinetics of mycophenolic acid administered 3 times daily after hematopoietic stem cell transplantation with reduced-intensity regimen.

International audienceMycophenolate mofetil (MMF) is an immunosuppressive drug used as a prophylactic agent to prevent acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation (HSCT). After reduced-intensity conditioning (RIC) regimen, administration of MMF orally 3 times a day (tid) seems to be more beneficial than twice a day (bid). However, information regarding the pharmacokinetic (PK) parameters of mycophenolic acid (MPA), the active metabolite of MMF, administered in this regimen are very limited. We performed a prospective study in 15 patients for whom 3 sets of sampling were performed: at the beginning of the treatment, after 1 week, and after 1 month. Two consecutive 8-hour sets of sampling were performed at day 0 (D0) and D7. Plasma concentrations of MPA were quantified and areas under the curve for 8hours (AUC(0-8)), and maximal and through concentrations were calculated. The results show that AUC(0-8) increases between the beginning of treatment and the end of the first week, but remains stable thereafter. Moreover, a trend to lower AUC(0-8) was observed for the patients who experienced GVHD > or =2 compared to those patients who did not. The other PK parameters are not associated with pharmacodynamic events. A limited sampling strategy with Bayesian estimators is currently under investigation to confirm these data and the role of D7 AUC(0-8) as a potential target of therapeutic drug monitoring (TDM)

Posaconazole prophylaxis in neutropenic patients with hematological malignancies: limits in clinical practice.

International audiencePosaconazole (PSZ) is being used for prophylaxis in hematological patients who are at high risk for invasive fungal disease (IFD), but absorption limitations have been reported. Our objective was to assess both the feasibility and the efficacy of PSZ prophylaxis in clinical practice. From March 2010 to September 2010, all patients admitted to our unit for chemotherapy for acute leukemia or hematopoietic stem cell transplantation received optimized PSZ prophylaxis 200 mg four times daily with cola soda. PSZ trough concentrations (Cmin) were monitored at days 5, 7, 14, and 21. The incidence of IFDs was determined and compared to that of a historical control group. Thirty-five consecutive patients were prospectively included. PSZ prophylaxis was interrupted for 29% of them at day 14 and 51% of them at day 21. The main limitations were impracticality of oral feeding (29%) and occurrence of suspected IFDs (23%). PSZ median Cmin were 0.47, 0.40, 0.24, 0.36 μg/mL at days 5, 7, 14, and 21, respectively. Eighty percent of patient results were lower than the target Cmin of 0.5 μg/ml on day 14, the higher-risk period associated with neutropenia. Four probable breakthrough IFDs (11%) were diagnosed in 2010; no clear association between PSZ Cmin and occurrence of infection was observed. The incidence of IFDs was unchanged (historical control group: 9.7%; P = 0.72). Implementation of systematic PSZ prophylaxis did not significantly decrease the incidence of IFDs at our center. PSZ interruptions related to mucositis and too low Cmin were the main limitations to its use