We describe a 69-year-old woman with bilateral adrenal hemorrhage complicated with antiphospholipid syndrome (APS). She was hospitalized with nausea and vomiting in September 2003. Laboratory data ...demonstrated hyponatremia, hypoglycemia and prolongation of activated partial thromboplastin time (aPTT). Abdominal computed tomography showed bilateral adrenal enlargement. In October 2003, she demonstrated altered mental status with progressive hyponatremia, a high level of ACTH, and a low level of serum cortisol. She also showed thrombocytopenia, anti-cardiolipin IgG antibody, anti-β2GPI antibody, and lupus anticoagulants. After four months, anti-cardiolipin IgG antibody was still positive. Based on these findings, she was diagnosed as having APS complicated with adrenal insufficiency due to hemorrhagic infarction. After treatment with corticosteroid, a low dose of aspirin and normal saline infusion, her condition quickly improved. Platelet counts and aPTT were also normalized. To our knowledge, this is the second Japanese case of APS complicated with bilateral adrenal hemorrhage. APS should be considered an important underlying cause of adrenal insufficiency.
The INO-VATE study demonstrated efficacy and safety of inotuzumab ozogamicin versus standard care in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Here, we report the ...frequency of, and potential risk factors for, hepatotoxicity in patients in this trial and after treatment and subsequent haemopoietic stem-cell transplantation (HSCT).
In this open-label, phase 3, multicentre, international study, adults with relapsed or refractory, CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative B-cell acute lymphoblastic leukaemia who were due to receive first or second salvage treatment were randomly assigned (1:1) via an interactive voice response system to receive inotuzumab ozogamicin (starting dose 1·8 mg/m
per cycle 0·8 mg/m
on day 1; 0·5 mg/m
on days 8 and 15 of a 21-28 day cycle for ≤6 cycles) or standard care (either fludarabine plus cytarabine plus granulocyte colony-stimulating factor, mitoxantrone plus cytarabine, or high-dose cytarabine). Stratification factors at randomisation were duration of first remission (<12 months vs ≥12 months), salvage treatment phase (first vs second), and age (<55 years vs ≥55 years). We present data up to March 8, 2016. At this cutoff date, all patients had been discontinued from treatment but 54 patients were continuing in long-term follow-up. Long-term follow-up has now been completed, with the final patient's last visit on Jan 4, 2017. This prespecified safety analysis describes investigator-assessed treatment-emergent hepatotoxicity, including sinusoidal obstruction syndrome (also known as veno-occlusive disease) in patients during study treatment or thereafter (without follow-up HSCT) and after study treatment and subsequent HSCT, for all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01564784.
Between Aug 27, 2012, and and the data cutoff of March 8, 2016, 326 patients were randomly assigned to receive inotuzumab ozogamicin (n=164) or standard care (n=162). 164 patients in the inotuzumab ozogamicin group and 143 in the standard care group received at least one dose of study treatment and were included in the safety population. At data cutoff, median duration of treatment (induction) was 8·9 weeks (IQR 4·1-13·1) in the inotuzumab ozogamicin group and 0·9 weeks (0·9-1·1) in the standard care group. Treatment-emergent hepatotoxicities (of all grades) were more frequent in the inotuzumab ozogamicin group (83 51% of 164 patients) than in the standard care group (49 34% of 143 patients). The frequency of sinusoidal obstruction syndrome-comprising events occurring during treatment (or follow-up without HSCT) and after treatment and subsequent HSCT-was higher in the inotuzumab ozogamicin group (22 13%; 18 82% of which were grade 3 or worse) than in the standard care group (one <1%). During study therapy or follow-up without HSCT, five (3%) patients in the inotuzumab ozogamicin group developed sinusoidal obstruction syndrome compared with no patients in the standard care group. Of the 77 patients who received inotuzumab ozogamicin and proceeded to HSCT, 17 (22%) had sinusoidal obstruction syndrome; five events after follow-up HSCT were fatal. Of 32 patients who received standard care and proceeded to HSCT, one (3%) had (non-fatal) sinusoidal obstruction syndrome that was ongoing at the time of death due to septic shock. In multivariate analysis, conditioning with two alkylating agents (p=0·015 vs one alkylating agent) and last available pre-HSCT bilirubin concentration of greater than or equal to the upper limit of normal (ULN; p=0·009 vs <ULN) were associated with increased risk of sinusoidal obstruction syndrome in patients who received inotuzumab ozogamicin. The estimated hazard ratio for overall survival in patients with follow-up HSCT (inotuzumab ozogamicin vs standard care) was 1·227 (97·5% CI 0·656-2·292; one-sided stratified log-rank p=0·77); at 24 months, the estimated probability of survival was 38·9% (95% CI 27·6-50·0) in the inotuzumab ozogamicin group versus 28·7% (11·2-49·1) in the standard care group.
Treatment with inotuzumab ozogamicin is associated with increased hepatotoxicity, especially after follow-up HSCT, compared with standard care.
Pfizer.
•A nationwide epidemiologic study for acquired PRCA identified 1055 patients, an incidence rate of 1.06 patients per million per year.•The median age was 73 years old with female predominance ...(1.5:1), and 69% of the PRCA was idiopathic.
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Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by anemia with reticulocytopenia and a marked reduction in erythroid precursors. Given its rarity, the true incidence is largely unknown, and epidemiological data representing the general population, with a description of the full spectrum of etiologies, are scarce. An epidemiological study on PRCA in Japan conducted 30 years ago estimated the annual incidence as 0.3 per million. To update the data and investigate the incidence and demographics of PRCA, we conducted a nationwide epidemiological study using the Japanese Society of Hematology (JSH) Hematologic Disease Registry, a hematologic disease registration database managed by the JSH and the Diagnosis Procedure Combination (DPC) study data available at a website of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. A total of 1055 patients with newly diagnosed acquired PRCA were identified between 2012 and 2019, and the average annual incidence was calculated at 1.06 (95% confidence interval CI, 0.83-1.28) per million. The median age was 73 (range, 18-99) years. The female-to-male ratio was 1.5:1, and the female predominance was most prominent in the child-bearing age group. Sixty-nine percent of acquired PRCA was idiopathic. The incidence of PRCA was approximately 20% of that of aplastic anemia (AA) during the same period. Approximately 0.98 patients per million per year (95% CI, 0.89-1.07) required hospitalization for the treatment of PRCA. These results are expected to contribute to the discussion of resource allocation for PRCA in the aging population in many countries, including Japan.
We examined the expression profiles of doxorubicin-resistant K562 cells by serial analysis of gene expression (SAGE) to identify novel and/or partially characterized genes that might be related to ...drug resistance in human leukemia. SAGE complementary DNA (cDNA) libraries were constructed from K562 and doxorubicin-resistant K562 (K562/ADM) cells, and concatamer sequences were analyzed with SAGE 2000 software. We used 9792 tags in the identification of 1076 different transcripts, 296 of which were similarly expressed in K562 and K562/ADM cells. There were 343 genes more actively expressed in K562/ADM than in parental K562 cells and 437 genes expressed less often in K562/ADM cells. K562/ADM cells showed increased expression of well-known genes, including the genes for spectrin beta, eukaryotic translation initiation factor 1A (EIF1A), RAD23 homolog B, laminin receptor 1, and polyA-, RAN-, and PAI-1 messenger RNA-binding proteins. K562/ADM cells showed decreased expression of the genes for fatty acid desaturase 1 (FADS1), hemoglobin epsilon 1, N-myristoyltransferase 1, hemoglobin alpha 2, NADH dehydrogenase Fe-S protein 6, heat shock 90-kDa protein, and karyopherin beta 1. Quantitative reverse transcription-polymerase chain reaction analysis confirmed the increased expression of EIF1A and the decreased expression of FADS1 in K562/ADM cells. Prior to this investigation, such differences in the expression of these genes in doxorubicin-resistant leukemia cells were unknown. Although we do not provide any evidence in the present report for the potential roles of these genes in drug resistance, SAGE may provide a perspective into our understanding of drug resistance in human leukemia that is different from that provided by cDNA microarray analysis.
Primary immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia caused by IgG anti-platelet autoantibodies and represents an organ-specific autoimmune disorder. Although the ...glycoprotein (GP)IIb/IIIa and GPIb/IX have been shown to be targets for autoantibodies, the antigen specificity of autoantibodies is not fully elucidated. To identify the characteristics of IgG B-cell receptor (BCR) repertoires in ITP, we took advantage of adaptor-ligation PCR and high-throughput DNA sequencing methods for analyzing the clone-based repertoires of IgG-expressing peripheral blood B cells. A total of 2,009,943 in-frame and 315,469 unique reads for IGH (immunoglobulin heavy) were obtained from twenty blood samples. Comparison of the IGHV repertoires between patients and controls revealed an increased usage of IGHV4-28 in ITP patients. One hundred eighty-six distinct IGHV4-28-carrying sequences were identified in ITP patients and the majority of these clones used an IGHJ4 segment. The IGHV4-28/IGHJ4-carrying B-cell clones were found in all ITP patients. Oligoclonal expansions of IGHV4-28/IGHJ4-carrying B cells were accompanied by multiple related clones with single amino substitution in the CDR3 region suggesting somatic hypermutation. Taken together, the expansion of IGHV4-28/IGHJ4-carrying IgG-expressing B cells in ITP may be the result of certain antigenic pressure and may provide a clue for the immune pathophysiology of ITP.
A 53-year-old woman presented at our hospital due to nasal bleeding and petechiae with profound thrombocytopenia (0.4×109/L). Her platelet count returned to the normal range immediately following a ...platelet transfusion. In this case, tea brewed from Taxus yunnanensis was the only suspected agent ingested prior to the onset of thrombocytopenia while all other etiologies for thrombocytopenia were excluded. A re-exposure test to Taxus yunnanensis resulted in the recurrence of acute thrombocytopenia. The association of thrombocytopenia with substances other than drugs has so far only been rarely described and to the best of our knowledge, this is the first reported case of thrombocytopenia caused by Taxus yunnanensis.
Quizartinib is a potent, oral, second‐generation, selective type II FMS‐like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase ...3 (QuANTUM‐First) study in patients with FLT3‐internal tandem duplication (ITD)‐positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose‐escalation method in each study, including 3 patients who were FLT3‐ITD positive. No dose‐limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib‐related, treatment‐emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM‐First study.
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Background.
Idiopathic PRCA and secondary PRCA not responding to the treatment of the underlying diseases are generally treated by immunosuppressive therapy. Because of the rarity of this disease, ...there are few reports regarding the long-term outcome following immunosuppression. We previously conducted the nationwide study for chronic PRCA in Japan that had been diagnosed between 1990 and 2006 across 109 institutions, and collected the data on a total of 185 patients (PRCA2004/2006 study). This study revealed that poor response to induction therapy and relapse of anemia were associated with death. There was no significant difference in survival between idiopathic and secondary PRCA in the PRCA2004/2006 study cohort.
Objective.
In order to identify the adverse risk factors for survival in acquired PRCA following immunosuppression in a prospective way, we have conducted another nationwide cohort study for acquired PRCA in adults (PRCA2016 study). The primary endpoint is the overall survival (OS) and the secondary endpoints include efficacy of immunosuppression, causes of treatment failure and survival times with iron-chelation therapy.
Methods.
This is designed as a prospective longitudinal observational study. Between 2006 and 2014, 554 PRCA patients were registered in the hematological disorder registry managed by the Japanese Society of Hematology. We sent the first questionnaires to the physicians asking for collaboration with this study and the responses showed the potential size of cohort was 181 patients (Fig. 1). We then sent the second questionnaires to collect data regarding underlying disease, laboratory findings including CBC and leukocyte differentials, results of bone marrow examination, immunological and cytogenetics, efficacy of immunosuppression, iron-chelation therapy in refractory cases and outcome. The review boards of participating institutions and the ethical committee of the JSH approved this study and informed consent was obtained from the patients.
Results.
As of June 16, 2018, 103 patients were registered in this study. Fifty-two patients were classified as having idiopathic PRCA and 51 patients as having secondary PRCA, including 16 thymoma- and 5 large granular lymphocyte (LGL) leukemia-associated PRCA. Seventy-one patients were treated with immunosuppressive agents. The response rates of cyclosporine, predonisolone, cyclophosphamide, azathioprine and combination with more than one immunosuppressants were 84% (43/51), 89% (8/9), 100% (2/2), 0% (0/1), 60% (9/15), respectively (Fig. 2). The Kaplan-Meyer estimates of the survival revealed that the estimated median survival time in idiopathic PRCA was 6,430 days and that in secondary PRCA has not yet been reached (Fig. 3). Survival time was not significantly different between the two subtypes of PRCA. Twenty-two deaths were reported and the major causes of death were infection and heart failure.
Discussion/Conclusion.
The most common subtypes of chronic PRCA in Japan were idiopathic, thymoma-associated and LGL leukemia-associated PRCA and this result was consistent with our observation in the PRCA2004/2006 study. Cyclosporine and prednisolone were frequently chosen for the induction therapy resulting in favorable responses. Preferential use of these two agents might reflect the physician's concern about the toxicity of the cytotoxic drugs. The median survival time of idiopathic PRCA was quite similar to the results in the previous cohort study. No significant difference in survival between idiopathic and secondary PRCA has been confirmed by the present study. These two cohort studies clearly indicate that novel diagnostic and predictive biomarkers should be developed to segregate the good and poor responders to immunosuppressive therapy in PRCA.
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Nakao:Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Yonemura:Alexion Pharma: Honoraria, Research Funding. Matsuda:GlaxoSmithKline K.K.: Honoraria; Novartis Pharma K. K.: Honoraria; Chugai Pharmaceutical Co, Ltd.: Honoraria; Kyowa Hakko Kirin Co, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Celgene Corporation: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Sanofi K.K.: Honoraria; Beckman Coulter K.K.: Honoraria. Kurokawa:Otsuka Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; MSD: Honoraria, Research Funding; Pfizer: Research Funding; Eizai: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding; Teijin Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Takeda Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Arai:Novartis: Research Funding. Mitani:Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Bristol-Myesr Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Chugai: Research Funding; Astellas: Research Funding; Sumitomo Dainippon: Research Funding; Novartis: Research Funding; Toyama Chemical: Research Funding.
We compared the expression profiles of highly purified human CD34+ cells and erythroid progenitor cells by micro-serial analysis of gene expression (microSAGE). Human CD34+ cells were purified from ...granulocyte colony-stimulating factor-mobilized blood stem cells, and erythroid progenitors were obtained by cultivating these cells in the presence of stem cell factor, interleukin 3, and erythropoietin. Our 10,202 SAGE tags allowed us to identify 1354 different transcripts appearing more than once. Erythroid progenitor cells showed increased expression of LRBA, EEF1A1, HSPCA, PILRB, RANBP1, NACA, and SMURF. Overexpression of HSPCA was confirmed by real-time polymerase chain reaction analysis. MicroSAGE revealed an unexpected preferential expression of several genes in erythroid progenitor cells in addition to the known functional genes, including hemoglobins. Our results provide reference data for future studies of gene expression in various hematopoietic disorders, including myelodysplastic syndrome and leukemia.
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