Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.

OBJECTIVES: Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life. METHODS: We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016. RESULTS: Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE. CONCLUSION: To our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice.

Is R-CHOP Therapy a Lymphoma Growth Factor?

This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 × 109/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.

Lethal toxicity after administration of azacytidine: implication of the cytidine deaminase-deficiency syndrome.

Azacytidine, an antimetabolite with an original epigenetic mechanism of action, increases survival in patients diagnosed with high-risk myelodysplasic syndromes or acute myeloid leukemia with less than 30% medullar blasts. Azacytidine is a pyrimidine derivative that undergoes metabolic detoxification driven by cytidine deaminase (CDA), a liver enzyme whose gene is prone to genetic polymorphism, leading to erratic activity among patients. Clinical reports have shown that patients with the poor metabolizer (PM) phenotype are likely to experience early severe or lethal toxicities when treated with nucleosidic analogs such as gemcitabine or cytarabine. No clinical data have been available thus far on the relationships between CDA PM status and toxicities in azacytidine-treated patients. Here, we measured CDA activity in a case of severe toxicities with fatal outcome in a patient undergoing standard azacytidine treatment. Results showed that the patient was PM (i.e. residual activity reduced by 63%), thus suggesting that an impaired detoxification step could have given rise to the lethal toxicities observed. This case report calls for further prospective studies investigating the exact role that CDA status plays in the clinical outcome of patients treated with azacytidine.

Physicochemical properties and cellular toxicity of (poly)aminoalkoxysilanes-functionalized ZnO quantum dots.

Luminescent ZnO nanocrystals were synthesized by basic hydrolysis of Zn(OAc)(2) in the presence of oleic acid and then functionalized with (poly)aminotrimethoxysilanes in the presence of tetramethylammonium hydroxide to render the QDs water-dispersible. The highest photoluminescence quantum yield (17%) was achieved using N(1)-(2-aminoethyl)-N(2)-[3-(trimethoxysilyl)propyl]-1,2-ethanediamine as surface ligand. Transmission electron microscopy and powder x-ray diffraction showed highly crystalline materials with a ZnO nanoparticle diameter of about 4 nm. The cytotoxicity of the different siloxane-capped ZnO QDs towards growing Escherichia coli bacterial cells was evaluated in MOPS-minimal medium. Although concentrations of 5 mM in QDs caused a complete growth arrest in E. coli, siloxane-capped ZnO QDs appeared weakly toxic at lower doses (0.5 or 1 mM). The concentration of bioavailable Zn (2+) ions leaked from ZnO QDs was evaluated using the biosensor bacteria Cupriavidus metallidurans AE1433. The results obtained clearly demonstrate that concentrations of bioavailable Zn(2+) are too low to explain the inhibitory effects of the ZnO QDs against bacteria cells at 1 mM and that the siloxane shell prevents ZnO QDs from dissolution contrary to uncapped ZnO nanoparticles. Because of their low cytotoxicity, good biocompatibility, low cost and large number of functional amine end groups, which makes them easy to tailor for end-user purposes, siloxane-capped ZnO QDs offer a high potential as fluorescent probes and as biosensors.

High-resolution melting analysis of sequence variations in the cytidine deaminase gene (CDA) in patients with cancer treated with gemcitabine.

Gemcitabine (2',2'-difluorodeoxycytidine) is a major antimetabolite cytotoxic drug with a wide spectrum of activity against solid tumors. Hepatic elimination of gemcitabine depends on a catabolic pathway through a deamination step driven by the enzyme cytidine deaminase (CDA). Severe hematologic toxicity to gemcitabine was reported in patients harboring genetic polymorphisms in CDA gene. High-resolution melting (HRM) analysis of polymerase chain reaction amplicon emerges today as a powerful technique for both genotyping and gene scanning strategies. In this study, 46 DNA samples from gemcitabine-treated patients were subjected to HRM analysis on a LightCycler 480 platform. Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme. Genotyping of three well-described single nucleotide polymorphisms in coding region (c.79A>C, c.208G>A and c.435C>T) was successfully achieved by HRM analysis of small polymerase chain reaction fragments, whereas unknown single nucleotide polymorphisms were searched by a gene scanning strategy with longer amplicons (up to 622 bp). The gene scanning strategy allowed us to find a new intronic mutation c.246+37G>A in a female patient displaying marked CDA deficiency and who had an extreme toxic reaction with a fatal outcome to gemcitabine treatment. Our work demonstrates that HRM-based methods, owing to their simplicity, reliability, and speed, are useful tools for diagnosis of CDA deficiency and could be of interest for personalized medicine.

Pulmonary hypertension in patients with myeloproliferative neoplasms: A large cohort of 183 patients.

BACKGROUND: Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE). METHODS: One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH. RESULTS: Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development. CONCLUSION: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population.

A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation.

Autologous hematopoietic stem cell transplantation is the standard treatment for multiple myeloma and relapsed or refractory lymphomas. After autologous hematopoietic stem cell transplantation, hematologic reconstitution and infectious complications are the two most critical issues. Although many patients develop infectious complications after therapeutic intensification, it remains impossible to predict infection for each individual. The goal of this work was to determine and identify a predictive transcriptomic signature of systemic inflammatory response syndrome and/or sepsis in patients receiving autologous hematopoietic stem cell transplantation. High-throughput transcriptomic and bioinformatics analysis were performed to analyze gene expression modulation in peripheral blood mononuclear cells in 21 patients undergoing autologous hematopoietic stem cell transplantation for hematological malignancies (lymphoma or multiple myeloma). Transcriptomic analysis of peripheral blood mononuclear cells samples collected just after conditioning regimen identified an 11-gene signature (CHAT, CNN3, ANKRD42, LOC100505725, EDAR, GPAT2, ENST00000390425, MTRM8, C6orf192, LOC10289230, and XLOC-005643) that was able to early predict (at least 2-7 days before its occurrence) the development of systemic inflammatory response syndrome or sepsis. The possibility of systemic inflammatory response syndrome or sepsis occurrence early prediction (2-7 days before occurrence) opens up new therapeutic strategies based on preemptive antibiotic and/or antifungal prophylaxis adapted to the specific risk profile of each patient.

Common strategy for adult and pediatric medulloblastoma: a multicenter series of 253 adults.

PURPOSE: To assess prognostic factors for adults with medulloblastoma in a multicenter, retrospective study. METHODS AND MATERIALS: Data were collected by file review or mail inquiry for 253 adults treated between 1975 to 2004. Radiologists or surgeons assessed disease characteristics, such as volume and extension. Patients were classified as having either high- or standard-risk disease. Prognostic factors were analyzed. RESULTS: Median patient age was 29 years. Median follow-up was 7 years. Radiotherapy was delivered in 246 patients and radiochemotherapy in 142. Seventy-four patients relapsed. Respective 5- and 10-year overall survival rates were 72% and 55%. Univariate analysis showed that survival significantly correlated with metastasis, postsurgical performance status, brainstem involvement, involvement of the floor of the fourth ventricle (V4), and radiation dose to the spine and to the posterior cerebral fossa (PCF). By multivariate analysis, brainstem, V4 involvement, and dose to the PCF were negative prognostic factors. In the standard-risk subgroup there was no overall survival difference between patients treated with axial doses of >or=34 Gy and patients treated with craniospinal doses <34 Gy plus chemotherapy. CONCLUSION: We report the largest series of medulloblastoma in adults. Prognostic factors were similar to those observed in children. Results suggest that patients with standard-risk disease could be treated with radiochemotherapy, reducing doses to the craniospinal area, maintaining at least 50 Gy to the PCF. The role of chemotherapy for this group is still unclear. A randomized study should be performed to confirm these results, but because frequency is very low, such a study would be difficult.

Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy.

Fluoropyrimidine drugs such as 5-fluorouracil (5-FU) and capecitabine are a mainstay in the treatment of numerous solid tumors, including colorectal cancers, alone or as part of combination therapies. Cytotoxic drugs such as 5-FU and oral capecitabine display narrow therapeutic indexes combined with high interpatient pharmacokinetic variability. As a result, severe toxicities often limit or delay the administration of successive, optimal chemotherapeutic courses, leading to unfavorable clinical outcome in patients with cancer. Catabolism and deactivation of fluoropyrimidine drugs depend on a single and exclusive enzymatic step driven by dihydropyrimidine dehydrogenase (DPD). Dihydropyrimidine dehydrogenase is prone to marked circadian rhythms, drug-drug interactions, and genetic polymorphisms; influence of its erratic activity on 5-FU pharmacokinetics and toxicity profile has been extensively investigated, and it is now well known that DPD deficiency leads to severe toxicities with 5-FU or possibly capecitabine exposure. With the ever-increasing number of patients with cancer likely to be treated with fluoropyrimidines, predicting and preventing the occurrence of such toxicities is now a major issue in clinical oncology. Early determination of DPD status in patients with cancer would allow identification of those at risk and help in subsequent dose adjustment or selection of other treatment modalities. Numerous methods, either genotypic or phenotypic, have been proposed to achieve this goal. This review covers a wide range of techniques available to establish DPD status in patients with cancer.

Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency.

This report here is the case of a 52-year-old male patient who suffered from extremely severe haematological toxicities (G4 neutropenia, G4 thrombocytopenia) while undergoing Xelox (Xeloda + Oxaliplatin) treatment for his multifocal hepatocarcinoma. Despite appropriate supportive treatment, his condition quickly deteriorated and led to death. It was hypothesized that dihydropyrimidine deshydrogenase (DPD) gene polymorphism could be, at least in part, responsible for this fatal outcome. To test this hypothesis, both phenotypic and genotypic studies were undertaken, and fully confirmed the DPD-deficient status of this patient. Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population. Interestingly, the canonical IVS14+1G>A single nucleotide polymorphism, usually associated with the most severe toxicities reported with 5-fluorouracil (5-FU), was not found in this patient, but further investigations showed instead a heterozygosity for the 1896C>T mutation located in the exon 14 of the DPYD gene. Taken together, the data strongly suggest for the first time that a toxic-death case after capecitabine-containing protocol could be, at least in part, linked with a DPD-deficiency syndrome. The case reported here warrants therefore systematic detection of patients at risk, including when oral capecitabine is scheduled.

Mixed Streptococcus pneumoniae and Streptococcus pyogenes meningitis in an immunocompromised adult patient: a case report.

INTRODUCTION: Community-acquired meningitis is a monomicrobial infection caused by either viruses or bacteria in the vast majority of patients. We report here one exceptional case of a patient with mixed bacterial meningitis due to Streptococcus pneumoniae and Streptococcus pyogenes. CASE PRESENTATION: We report the case of a 68-year-old immunocompromised Caucasian man suffering from otitis and then meningitis caused by Streptococcus pneumoniae and Streptococcus pyogenes. Bacteria were undistinguishable by direct microscopic examination of the cerebrospinal fluid. He responded well to treatment with cefotaxime and dexamethasone, with no sequelae observed at the 4-month follow-up. CONCLUSIONS: This first reported case of mixed S. pneumoniae and S. pyogenes meningitis illustrates the life-threatening consequences of barotrauma in immunocompromised patients suffering from otorhinolaryngeal infections.

Eradication of T315I mutation in chronic myeloid leukemia without third-generation tyrosine kinase inhibitor: a case report.

We report the case of a patient bearing a T315I-mutant chronic myeloid leukemia resistant to nilotinib, successfully treated with omacetaxine and then with dasatinib. After 9 months of nilotinib, the patient achieved a major molecular response but relapsed 3 months later due to the T315I mutation. Because third-generation tyrosine kinase inhibitor was not available and the patient refused bone marrow transplantation, he received two cycles of omacetaxine. This treatment had been stopped after two cycles because of clinical intolerance, but a major molecular response and total disappearance of the T315I clone was obtained. Treatment with dasatinib was then started and after 34-month follow-up the patient is still in major molecular response, thus suggesting that eradication of the T315I mutation could be achieved without third-generation tyrosine kinase inhibitors.

Yin and yang of cytidine deaminase roles in clinical response to azacitidine in the elderly: a pharmacogenetics tale.

Azacitidine is a mainstay for treating hematological disorders. Azacitidine is metabolized by cytidine deaminase, coded by a highly polymorphic gene. Here, we present two elderly patients with opposite clinical outcomes after azacitidine treatment. First, an acute myeloid leukemia patient showed life-threatening toxicities, but outstanding complete remission, after a single round of azacitidine. Further investigations showed that this patient was cytidine deaminase 79A>C (rs2072671) homozygous with a marked deficient phenotype. Next, a chronic myelomonocytic leukemia patient displayed complete lack of response despite several cycles of azacitidine. This patient had a rapid-deaminator phenotype linked to the -31delC deletion (rs3215400). These polymorphisms lead to opposite clinical outcomes in patients with myelodysplastic syndromes treated with azacitidine, thus suggesting that determining cytidine deaminase status could help to forecast clinical outcome.

Optimize administration protocol of capecitabine plus docetaxel combination in metastatic breast cancer patients.

Combining several cytotoxics is the current mainstay for treating breast cancer patients. The combination between capecitabine and docetaxel was found to be more efficient than capecitabine or docetaxel when both were used as single agents. However, the administration protocol for this combination has been empirically chosen from single-agent trials. Based on already available population analysis, we propose here to optimize the administration protocol of this association so as to enhance efficacy while limiting treatment-related toxicity. Efficacy parameters evaluated from population analysis using a disturbed tumor growth model and safety characteristics from the available databases evidenced that: 1) Docetaxel is more efficient than capecitabine at the start of the treatment, but becomes less efficient next because of acquisition of resistance; 2) Over a long period of time, capecitabine is better tolerated than docetaxel. These characteristics allowed the following recommendations for an optimized modality of combination: 1) The treatment has to be started at the maximum tolerated dose for docetaxel; this dose should be individualized right from the start of the second cycle of treatment; 2) In parallel, capecitabine has to be started at a dose lower than its maximum tolerated dose. 3) When docetaxel becomes less efficient than capecitabine because of resistance, docetaxel dose has to be reduced but not discontinued. 4) If adverse events show during the treatment, it is recommended to reduce docetaxel, rather than capecitabine dosage. Combining modeling and statistical analysis of clinical data permit to optimize combination treatments. This procedure could be extended to others treatments involving combination of several cytotoxics.