- Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels. [JOURNAL ARTICLE]
- Br J Haematol 2016 Jun 28.
Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0 × 10(9) /l, haemoglobin level >100 g/l and platelet count of <100·0 × 10(9) /l in the absence of morphological and karyotypic abnormalities in the bone marrow. Glycosylphosphatidylinositol-anchored protein-deficient blood cells [paroxysmal nocturnal haemoglobinuria (PNH)-type cells] were detected in 7 of the 25 (28%) patients and elevated plasma thrombopoietin (TPO, also termed THPO) levels (>320 pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPO(high) patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPO(low) patients and four of 11 TPO(high) patients. The 3-year failure-free survival rate of the CsA-treated TPO(high) patients (100%) was significantly higher than that of the untreated TPO(high) patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.
- Health-Related Quality of Life and Burden of Fatigue in Patients with Primary Immune Thrombocytopenia by Phase of Disease. [JOURNAL ARTICLE]
- Am J Hematol 2016 Jun 28.
The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI, -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI, -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI, -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI, -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI, -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. This article is protected by copyright. All rights reserved.
- Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide. [REVIEW, JOURNAL ARTICLE]
- Clin Pharmacokinet 2016 Jun 28.
Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration-time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3-4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug-drug interactions.
- A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study. [JOURNAL ARTICLE]
- J Neurooncol 2016 Jun 27.
Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.
- Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma. [JOURNAL ARTICLE]
- Cancer Sci 2016 Jun 27.
B-cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti-BAFF monoclonal antibody. This phase 1, multicenter, open-label, nonrandomized, dose-escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous (IV) tabalumab 100 mg (Cohort 1, n=4) or IV tabalumab 300 mg (Cohort 2, n=12) in combination with oral dexamethasone 20 mg/day and IV or subcutaneous (SC) bortezomib 1.3 mg/m(2) . All patients had treatment-emergent adverse events (TEAEs) possibly related to study treatment; the most common TEAEs were thrombocytopenia (81.3%), lymphopenia (43.8%), and increased alanine aminotransferase (43.8%). Two (20.0%) dose-limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (< 33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered IV vs SC. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these 3 agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438). This article is protected by copyright. All rights reserved.
- Blastic plasmacytoid dendritic cell neoplasm: A case report and literature review. [JOURNAL ARTICLE]
- Exp Ther Med 2016 Jul; 12(1):319-322.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor, which frequently presents as cutaneous lesions and subsequently progresses to bone marrow (BM) involvement and leukemic dissemination. BPDCN is a rare entity that belongs in the same class as acute myeloid leukemia-associated precursor neoplasms, according to the 2008 World Health Organization classification. The present study reported the case of a 26-year-old female who presented with evident thrombocytopenia, leukocytosis and anemia, but without skin lesions. The results of peripheral blood, BM smear and BM biopsy examinations detected numerous blastic or abnormal cells. In addition, flow cytometric analysis of BM demonstrated the presence of plasmacytoid dendritic cell-neoplastic precursor cells (CD4+, CD56+, CD123+, CD304+ and human leukocyte antigen-DR+ phenotype).
- [Efficiency and adverse effects of the effective therapy applying etoposide + cisplatin and its subsequent maintenance therapy with different durations in patients with small cell lung cancer]. [English Abstract, Journal Article]
- Zhonghua Zhong Liu Za Zhi 2016 Jun 23; 38(6):454-9.
To explore the efficiency and adverse effects of the effective EP (etoposide + cisplatin) therapy and its subsequent maintenance therapy with different durations in patients with small cell lung cancer (SCLC).Clinical data of 104 SCLC patients diagnosed and treated at the Jilin Province Cancer Hospital between September 2010 and December 2013 were retrospectively analyzed.Among them, 35 patients were subsequently treated with a 4-week maintenance therapy following the original therapeutic regimen after the effective EP therapy (4-week maintenance therapy group), 35 patients were treated with a subsequent 6-week maintenance therapy (6-week maintenance therapy group), and 34 patients were treated without maintenance therapy (control group).52 patients were in limited stage, and 52 patients were in extensive stage. The progression-free survival (PFS), overall survival (OS) and adverse effects in the 4-week maintenance therapy group, 6-week maintenance therapy group and control group were analyzed.The median PFS in the control group, 4-week maintenance therapy group and 6-week maintenance therapy group was 4.0, 3.5, and 4.0 months, respectively, and the median OS was 9.0, 10.0 and 12.0 months, respectively, showing no significant difference among the groups (P>0.05 for all). The median PFS was prolonged by 2 months as compared with the control group after the 4-week maintenance therapy in the patients with complete remission in first-line chemotherapy (P=0.041), while the median OS was not improved (P=0.131). Neither the median PFS nor median OS showed statistically significant difference between each two groups in the patients with partial remission in first-line chemotherapy (P>0.05 for all). In the limited stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 5.0, 6.5, and 4.0 months, respectively, and median OS was 11.0, 13.5, and 13.0 months, respectively, the differences showed no statistical significance (P>0.05 for all). In the extensive stage, the median PFS in the control group, 4-week maintenance therapy group, and 6-week maintenance therapy group was 3.0, 3.0, and 3.5 months, respectively, showing significant differences (P=0.015); the median OS was 6.5, 8.0, and 8.0 months, respectively, presenting no statistically significant differences (P=0.096). In addition, the PFS in the 6-week maintenance therapy group was significantly improved as compared with that in the control group (P=0.016). Compared with the control group, the incidence rates of nausea (grade 3-4), vomiting, hypodynamia, leukopenia, neutropenia, and thrombocytopenia in the 4-week maintenance therapy group and 6-week maintenance therapy group were increased significantly (P<0.05 for all), however, the side effects were tolerable.Prolonging the treatment cycle of EP therapy can improve the PFS in SCLC patients in first-line CR chemotherapy and extensive stage.
- Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. [JOURNAL ARTICLE]
- Lancet Oncol 2016 Jun 23.
Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population.In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients.Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related.Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy.F Hoffmann-La Roche Ltd.
- Chest radiographic manifestations of scrub typhus. [JOURNAL ARTICLE]
- J Postgrad Med 2016 Jun 24.
Respiratory system involvement in scrub typhus is seen in 20-72% of patients. In endemic areas, good understanding and familiarity with the various radiologic findings of scrub typhus are essential in identifying pulmonary complications.Patients admitted to a tertiary care center with scrub typhus between October 2012 and September 2013 and had a chest X ray done were included in the analysis. Details and radiographic findings were noted and factors associated with abnormal X-rays were analyzed.The study cohort contained 398 patients. Common presenting complaints included fever (100%), generalized myalgia (83%), headache (65%), dyspnea (54%), cough (24.3%), and altered sensorium (14%). Almost half of the patients (49.4%) had normal chest radiographs. Common radiological pulmonary abnormalities included pleural effusion (14.6%), acute respiratory distress syndrome (14%), airspace opacity (10.5%), reticulonodular opacities (10.3%), peribronchial thickening (5.8%), and pulmonary edema (2%). Cardiomegaly was noted in 3.5% of patients. Breathlessness, presence of an eschar, platelet counts of <20,000 cells/cumm, and total serum bilirubin >2 mg/dL had the highest odds of having an abnormal chest radiograph. Patients with an abnormal chest X-ray had a higher requirement of noninvasive ventilation (odds ratio [OR]: 13.98; 95% confidence interval CI: 5.89-33.16), invasive ventilation (OR: 18.07; 95% CI: 6.42-50.88), inotropes (OR: 8.76; 95% CI: 4.35-17.62), higher involvement of other organ systems, longer duration of hospital stay (3.18 3 vs. 7.27 5.58 days; P < 0.001), and higher mortality (OR: 4.63; 95% CI: 1.54-13.85).Almost half of the patients with scrub typhus have abnormal chest radiographs. Chest radiography should be included as part of basic evaluation at presentation in patients with scrub typhus, especially in those with breathlessness, eschar, jaundice, and severe thrombocytopenia.
- JAK2V617F mutation in immune thrombocytopenia. [LETTER]
- Thromb Res 2016 Jun 17.:149-151.