Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.

BACKGROUND: With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment. METHODS: In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts. RESULTS: The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies. CONCLUSION: Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.

Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.

The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.

Hypocholesterolemia in patients with polycythemia vera.

Polycythemia vera (PV) is characterized by low serum total cholesterol despite its association with vascular events such as myocardial and cerebral infarction. Serum cholesterol level has not been used as a diagnostic criterion for PV since the 2008 revision of the WHO classification. Therefore, we revisited the relationship between serum lipid profile, including total cholesterol level, and erythrocytosis. The medical records of 34 erythrocytosis patients (hemoglobin : men, > 18.5 g/dL ; women, > 16.5 g/dL) collected between August 2005 and December 2011 were reviewed for age, gender, and lipid profiles. The diagnoses of PV and non-PV erythrocytosis were confirmed and the in vitro efflux of cholesterol into plasma in whole blood examined. The serum levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-Ch), and apolipoproteins A1 and B were lower in PV than in non-PV patients. The in vitro release of cholesterol into the plasma was greater in PV patients than in non-PV and non-polycythemic subjects. Serum total cholesterol, LDL-Ch, and apolipoproteins A1 and B levels are lower in patients with PV than in those with non-PV erythrocytosis. The hypocholesterolemia associated with PV may be attributable to the sequestration of circulating cholesterol into the increased number of erythrocytes.

Relationship between clotting activity and phosphatidylserine expression on erythrocyte membranes in polycythemia vera patients with the JAK2 V617F mutation.

INTRODUCTION: Polycythemia vera (PV) accompanies the clinical course of thrombosis. Phosphatidylserine (PS) expression on the plasma membrane has been known to be one of place where the coagulation system activates. We studied the relationship between clotting factor activity and PS expression on the erythrocyte membrane in patients with erythrocytosis. METHODS: The coagulation test and PS expression in 23 patients with erythrocytosis were measured. PS expression was determined indirectly by measuring annexin V binding to erythrocytes using fluorescence activated cell sorter analysis (FACS). RESULTS: The activity of clotting factors (II, V, VII, VIII, von Willebrand factor, IX, X) was significantly lower in PV than in the mutation-negative erythrocytosis. There was a significant correlation between reduced activity of clotting factors such as V, X, and IX and increased PS expression of the erythrocyte membrane. CONCLUSION: Increased expression of PS on the erythrocyte membrane may reduce the activities of clotting factors in PV patients with JAK2 V617F mutation.

[Low-titer cold agglutinin disease following Salmonella gastroenteritis].

We encountered a patient with cold agglutinin disease (CAD) that worsened after Salmonella gastroenteritis. A 52-year-old male complained pain in the left fingers with cyanosis and was admitted in a local hospital. After treatment for ischemia, he demonstrated diarrhea with fever. Because of progressive anemia, he was referred to our hospital. Salmonella gastroenteritis was diagnosed based on the results of microbiological examination. Severe hemolysis was noted at admission, and Coombs test was positive (IgG-, C3d+). Cold agglutinin titer was elevated (x256). There were no findings of malignancy or infection demonstrating CA. A diagnosis of CAD with Salmonella gastroenteritis was made. Because spherocytosis was noted during admission, we measured the mean channel fluorescence (MCF) of eosin-5-maleimide (EMA) in erythrocytes from patients. MCF of EMA of the patient's erythrocytes was similar to that of normal subjects. Therefore, we concluded that coexisting hereditary spherocytosis was unlikely. We also examined the in vitro hemolytic effect of Salmonella infection on his blood and on blood from normal subjects. Treatment with Salmonella enteritidis isolated from this patient was found to induce hemolysis in the patient's blood, but not in blood from a normal subject. Moreover, treatment with Salmonella increased the titer of cold agglutinin in vitro. These data suggested that Salmonella infection might worsen hemolysis in CAD.

Idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia accompanied with cutaneous involvement and renal dysfunction.

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hypergammaglobulinemia has been proposed as a new disease entity resembling the plasma cell type of multicentric Castleman's disease. Here, we report a case of IPL accompanied by renal failure and skin involvement. A 35-year-old man was admitted for advanced renal failure, anemia, systemic lymphadenopathy and skin rashes. Laboratory examinations indicated polyclonal hypergammaglobulinemia and elevated serum interleukin-6 (IL-6). Biopsy of a cervical lymph node revealed follicular hyperplasia with normal germinal centers, sheets of polyclonal proliferating plasma cells and the absence of marked proliferation of blood vessels in the interfollicular area. Lesions of the kidney and skin also had pathological characteristics of IPL. Following a diagnosis of IPL, corticosteroid therapy successfully improved the anemia and hypergammaglobulinemia, and serum IL-6 levels decreased to a normal range. This case may give suggestions about diagnosing and preventing the progression of complications from this disease entity.

Glutest Neo Super--a new handheld blood glucose meter-corrects for the effects of the hematocrit values in both hematocrit-adjusted samples and samples obtained from anemic patients.

BACKGROUND: Handheld blood glucose (BG) meters are convenient tools that are widely used to measure the BG levels. However, the hematocrit (Hct) value has been identified as a confounding factor for accurate BG measurement. Some BG meters are equipped with an Hct-correcting feature, whose effectiveness has been tested previously. Nevertheless, the measurements yielded by many BG meters are confounded by the Hct values. Recently, a new BG meter equipped with an Hct-correcting feature has been developed; however, its effectiveness has not yet been confirmed. STUDY DESIGN: Venous blood samples were collected from two healthy volunteers, and the Hct values in the samples were adjusted to approximately 0%, 10%, 20%, 30%, 40%, 50%, and 60%. Further, venous blood samples were collected from 10 anemic patients (Hct <40%). The whole BG (WBG) levels in the samples were measured using two devices-the new BG meter (Glutest Neo Super [Sanwa Kagaku Kenkyusho Co. Ltd., Nagoya, Japan]) and a standard BG meter (OneTouch Ultra [Life Scan Inc., Milpitas, CA]). For reference, plasma glucose (PG) levels were measured using a machine at our hospital laboratory (GA08 [A&T Co., Kanagawa, Japan]). The bias in the measurements was calculated as follows: bias = ([WBG - PG]/PG) x 100. Further, the correlation between the Hct values and the bias was assessed by performing linear regression analysis. RESULTS: In both the Hct-adjusted samples and the samples obtained from anemic patients, the WBG levels measured using Glutest Neo Super were minimally affected by the Hct values, while those measured using OneTouch Ultra were affected by the Hct values to a statistically significant extent. CONCLUSIONS: The Hct-correcting feature of the new BG meter Glutest Neo Super was effective. The use of this new device for BG measurements may lead to more appropriate treatment selection.

[Successful radiotherapy for the thoracic cord infiltration of adult T-cell leukemia/lymphoma].

A-51-year-old woman with a sixteen-year history of mixed connective tissue disease was admitted to the Kitasato University Hospital because of hypogastric pain in September 1999. Colonofiberscopy and computed tomography in the abdomen demonstrated thickening of the intestinal wall with a hemorrhagic ulcer in the terminal ileum. The histopathologic findings of the lesion revealed diffuse infiltration of atypical T-lymphocytes. The titers of anti-HTLV-I antibody and serum soluble IL-2 receptor were elevated. The diagnosis of adult T-cell leukemia/lymphoma (ATLL) infiltrating the terminal ileum was made. Combination chemotherapy including VEPA-M was undertaken, and resulted in a partial response. ATLL became refractory about June 2000. Flaccid paralysis, dysesthesia in the left lower limb and bladder-bowel disturbance emerged in a few days, July 2000. T2-weighed MRCT images demonstrated that a lesion with a high intensity signal was present in the spinal cord around Th 7. Flower-like cells were detected in the cerebrospinal fluid. Infiltration of ATLL into the thoracic cord was diagnosed. Administration of intrathecal methotrexate and prednisolone, systemic dexamethasone and local irradiation of 30 Gy improved the paralysis and the abnormal MRCT findings. Rehabilitation restored the patient's ability to walk.

[Granulocytic sarcoma of the colon in chronic myelomonocytic leukemia].

A 59-year-old man with a six-month history of chronic myelomonocytic leukemia (CMML) was admitted to the Kitasato University Hospital because of melena in September 2000. Colonofiberscopy and barium enema demonstrated an ulcerated tumorous lesion in the transverse colon. The histopathologic findings of the ulcer bed revealed diffuse infiltration of granulocytes at each stage of differentiation. The diagnosis of granulocytic sarcoma (GS) was made. Surgical resection was not indicated, because thrombocytopenia was hardly improved enough to allow surgery despite repetitive transfusion of platelet concentrates. CMML developed to refractory anemia with excess of blast in transformation in February 2001. Two courses of low dose cytarabine plus aclarubicin were ineffective on the GS in spite of a decrease in the peripheral blood blasts. Progression to acute myeloid leukemia eventually broke out, in July 2001. The patient died of leukemia complicated with pneumonia and intestinal obstruction. At present, nine cases of GS in the colon have been reported. However, these cases did not include CMML. This is the first report describing GS in the colon associated with CMML.