Showing papers in "The Japanese journal of clinical hematology in 2013"

Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes

Abstract: Peter L. Greenberg, Heinz Tuechler, Julie Schanz, Guillermo Sanz, Guillermo GarciaManero, Francesc Sole, John M. Bennett, David Bowen, Pierre Fenaux, Francois Dreyfus, Hagop Kantarjian, Andrea Kuendgen, Alessandro Levis, Luca Malcovati, Mario Cazzola, Jaroslav Cermak, Christa Fonatsch, Michelle M. Le Beau, Marilyn L. Slovak, Otto Krieger, Michael Luebbert, Jaroslaw Maciejewski, Silvia M.M. Magalhaes, Yasushi Miyazaki, Michael Pfeilstocker, Mikkael Sekeres, Wolfgang R. Sperr, Reinhard Stauder, Sudhir Tauro, Peter Valent, Teresa Vallespi, Arjan A. van de Loosdrecht, Ulrich Germing, and Detlef Haase

[The shortest isoform of C/EBPβ, Liver inhibitory protein (LIP), collaborates with Evi1 to induce AML in a mouse BMT model].

Abstract: Ecotropic viral integration site 1 (Evi1) is one of the master regulators in the development of acute myeloid leukemia (AML) and myelodysplastic syndrome. High expression of Evi1 is found in 10% of patients with AML and indicates a poor outcome. Several recent studies have indicated that Evi1 requires collaborative factors to induce AML. Therefore, the search for candidate factors that collaborate with Evi1 in leukemogenesis is one of the key issues in uncovering the mechanism of Evi1-related leukemia. Previously, we succeeded in making a mouse model of Evi1-related leukemia using a bone marrow transplantation (BMT) system. In the Evi1-induced leukemic cells, we identified frequent retroviral integrations near the CCAAT/enhancer-binding protein β (C/EBPβ) gene and overexpression of its protein. These findings imply that C/EBPβ is a candidate gene that collaborates with Evi1 in leukemogenesis. Cotransduction of Evi1 and the shortest isoform of C/EBPβ, liver inhibitory protein (LIP), induced AML with short latencies in a mouse BMT model. Overexpression of LIP alone also induced AML with longer latencies. However, excision of all 3 isoforms of C/EBPβ (LAP*/LAP/LIP) did not inhibit the development of Evi1-induced leukemia. Therefore, isoform-specific intervention that targets LIP is required when we consider C/EBPβ as a therapeutic target.

[Central intravenous catheter-related bacteremia due to Chryseobacterium indologenes after cord blood transplantation].

Abstract: A 3-year-old girl with acute myeloid leukemia underwent unrelated cord blood stem cell transplantation (UCBT) due to primary induction failure. Fourteen days after UCBT, she developed central venous catheter (CVC)-related bloodstream infection due to Chryseobacterium indologenes. Despite ciprofloxacin and minocycline being administered according to the results of susceptibility, a high grade fever recurred. Therefore, the CVC was removed 21 days after UCBT and symptoms related to CVC infection improved. Although C. indologenes is widely distributed in nature, it is a rare pathogen in humans. Most cases of C. indologenes bacteremia have been found in immunocompromised patients with malignancies and diabetes mellitus. C. indologenes exhibits specific characteristics, including the progression of resistance to antibiotics and the formation of a biofilm. Therefore, removal of the CVC appears to be the most reasonable treatment for CVC infection due to C. indologenes in patients undergoing hematopoietic stem cell transplantation if clinical symptoms do not improve after appropriate antibiotic therapy.

[Development of syndrome of inappropriate secretion of ADH and reversible posterior leukoencephalopathy during initial rituximab-CHOP therapy in a patient with diffuse large B-cell lymphoma].

Abstract: A 61-year-old woman presented with a right mandibular tumor and was diagnosed with DLBCL clinical stage IIIA from the biopsy results of the tumor and CT examination. An initial rituximab was administrated a week after the first CHOP treatment. During the infusion of rituximab, she exhibited disorientation, seizure, and consciousness disturbance. Hyponatremia due to SIADH and hypertension were coincidentally observed. MRI revealed T2 and FLAIR hyperintense signals involving the bilateral occipital, parietal, frontal lobes and the cerebellum that were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Her consciousness level recovered in parallel with corrections in serum sodium levels and blood pressure. Although she presented with transient cortical blindness, all neurological abnormalities disappeared 40 hours after the occurrence of seizure. She received a further 7 cycles of CHOP followed by 7 cycles of rituximab treatment with no relapse of RPLS. After irradiation for a residual abdominal tumor, she has maintained complete remission for 2 years. Although RPLS is a rare complication of rituximab-CHOP chemotherapy, it should be considered in patients with DLBCL who present with acute neurological deterioration.

Effective treatment with tranexamic acid for chronic disseminated intravascular coagulation associated with aortic dissection

Abstract: An 82-year-old female with a history of aortic dissection was admitted to our hospital for evaluation of thrombocytopenia and a bleeding tendency. Blood coagulation test data demonstrated that the patient had disseminated intravascular coagulation (DIC) secondary to aortic dissection. We initiated anti-fibrinolytic therapy with tranexamic acid. After this anti-fibrinolytic therapy, thrombocytopenia and the levels of fibrinogen and fibrinogen degradation products improved. In addition, we reviewed 7 other patients who were treated with tranexamic acid for DIC associated with aortic dissection. Anti-fibrinolytic therapy with tranexamic acid is effective for treating DIC secondary to aortic dissection.

[Outcome of patients with relapsed/refractory adult T-cell leukemia-lymphoma after salvage therapy].

Abstract: We retrospectively analyzed 81 relapsed or refractory adult T-cell leukemia-lymphoma (ATL) patients who received salvage therapy in our institution between 2000 and 2010. These patients had received chemotherapy, radiation, or hematopoietic stem cell transplantation (HSCT) as an initial treatment, and were then given chemotherapy, radiation, HSCT, or donor lymphocyte infusion (DLI) as salvage therapy. Median survival time was 3.9 months. Of 5 long-term survivors, who survived more than 2 years after the first salvage therapy, 4 patients received HSCT or DLI, and the other was given mogamulizumab as the salvage therapy. For patients with relapsed or refractory ATL, HSCT/DLI is a promising treatment for achieving long-term survival. Mogamulizumab may be the good choice for those who are ineligible for HSCT.

[Fatal zygomycosis caused by Mucor indicus after haplo-identical stem cell transplantation].

Abstract: A 62-year-old woman with acute lymphoblastic leukemia in first complete remission was treated with unrelated cord blood transplantation, but exhibited primary graft failure. She then underwent HLA-haploidentical peripheral blood stem cell transplantation from her daughter. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days, intravenous busulfan 3.2 mg/kg/day for 2 days, and thymoglobulin 1 mg/kg/day for 2 days. Voriconazole was administered to prevent fungal infections. The patient achieved prompt hematopoietic recovery. Fever was observed 21 days after the second transplant, followed by sigmoid colon perforation and a liver space occupying lesion (SOL). A filamentous fungus was detected in a percutaneous biopsy of the liver SOL. In spite of changing the antifungal drug from voriconazole to liposomal amphotericin B, the patient died on day 41. The fungus was identified as Mucor indicus, a type of zygomycete. Although Mucor indicus inhabits soil, an infectious disease is extremely rare, and breakthrough infection after voriconazole prophylaxis had not been reported until now. It is mandatory to consider preventive antifungal treatment for drug-resistant fungal infectious diseases in patients after neutrophilic recovery with a strongly immunocompromised state after a HLA-haploidentical transplant.

[Sodium-losing nephropathy caused by tacrolimus after allogeneic hematopoietic stem cell transplantation].

Abstract: A 39-year-old woman (Case 1) and a 57-year-old woman (Case 2) underwent allogeneic bone marrow transplantation for acute lymphoblastic leukemia and follicular lymphoma, respectively Both patients had received tacrolimus orally for treatment of or prophylaxis against graft-versus-host disease Seventeen months (Case 1) and 2 months (Case 2) post-transplantation, when the trough level of tacrolimus was maintained around 10 ng/ml, the serum sodium levels of Cases 1 and 2 decreased to 1235 mEq/l and 1256 mEq/l, respectively Urinary sodium excretions increased to 1868 mEq/day and 3757 mEq/day, respectively Sodium-losing nephropathy due to tacrolimus was diagnosed, and reducing the dose of tacrolimus with no other intervention resulted in resolution of the hyponatremia Although sporadic kidney transplantation cases with sodium-losing nephropathy due to tacrolimus have been reported, no prior cases with this complication after hematopoietic stem cell transplantation (HSCT) have been reported Sodium-losing nephropathy should be recognized as one of the renal toxicities of tacrolimus in HSCT as well as kidney recipients

Composite lymphoma cosisting of mantle cell lymphoma and follicular lymphoma

Abstract: Herein, we report the case of a 56-year-old man with composite lymphoma (CL) comprised of mantle cell lymphoma (MCL) and follicular lymphoma (FL). Six months after developing a right brachial tumor, he was diagnosed as having grade 3 FL with normal-size mantle zone. Simultaneously, advanced stage MCL with a diffuse growth pattern in a sigmoid colon tumor and abnormal lymphoid cells in bone marrow were observed. Thereafter, the right brachial tumor was re-examined and its mantle zone cells were immunophenotypically positive for cyclin D1 (CCND1) and cytogenetically positive for the IgH-CCND1 fusion gene. Consequently, he was diagnosed with composite lymphoma (CL) comprised of FL and MCL. As MCL and FL may form CL, the possible complication of MCL should be considered and steps taken to detect MCL.

[Successful rituximab treatment for acquired amegakaryocytic thrombocytopenic purpura complicated with Coombs-negative autoimmune hemolytic anemia].

Abstract: Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare disorder characterized by severe thrombocytopenia associated with total absence or a selective decrease in bone marrow megakaryocytes. A 67-year-old male presented with a 2-month bleeding tendency. He was referred to our hospital because of severe thrombocytopenia. Bone marrow biopsy showed complete absence of megakaryocytes without dysplasia in cells of the myeloid and erythroid lineages. AATP was diagnosed. In addition, mild normocytic normochromic anemia and reticulocytosis were also observed and haptoglobin was below the detectable level. Coombs-negative autoimmune hemolytic anemia (AIHA) was diagnosed based on the high titer of RBC-bound IgG and negative direct and indirect coombs test results. He was first treated with cyclosporine 200 mg per day and subsequently with prednisolone but only slight temporary improvement was achieved. Administration of eight doses of rituximab 375 mg/m(2) per week ameliorated both thrombocytopenia and anemia. AATP should be considered in the differential diagnosis of thrombocytopenia, and immunosuppressive therapy is a potential first-line treatment. This is the first case report of AATP accompanied by AIHA successfully treated with rituximab.

Progression of bone marrow fibrosis with reticulin and collagen hyperplasia during treatment with the thrombopoietin receptor agonist romiplostim in a patient with immune thrombocytopenia

Abstract: Romiplostim is a thrombopoietin (TPO) receptor agonist that has attracted attention as a novel drug for the treatment of refractory immune thrombocytopenia (ITP). However, bone marrow reticulin and collagen fibrosis during the long-term use of romiplostim has recently become a concern. Here, we present a patient with ITP who exhibited bone marrow fibrosis after the completion of a Japanese phase III clinical trial and long-term extension study of romiplostim. The patient was a 64-year-old woman. She was diagnosed with refractory ITP and participated in a clinical trial of romiplostim. Myeloblasts were found in her peripheral blood in Week 116 of treatment with romiplostim in the long-term extension study, and romiplostim was discontinued. In Week 118, teardrop cells appeared and she underwent a bone marrow biopsy. Results showed reticulin and collagen fiber hyperplasia and her platelet count decreased markedly to 0.4×10(4)/μl with macroscopic hematuria. Thereafter, a reduced dose of romiplostim was resumed. Approximately one year after the resumption of romiplostim, a bone marrow biopsy revealed a decrease in reticulin and collagen fibrosis. Although few patients exhibited bone marrow fibrosis with TPO and the event may be reversible, our observations indicate that careful monitoring is required for general clinical use.

Relationship between red blood cell transfusion volume and posttransfusional iron overload in hematological diseases

Abstract: We retrospectively investigated the status of transfusional iron overload at Kinki University Hospital. One hundred and sixty three patients received more than 10 red blood cell (RBC) units per year in 2009 and 2010. Myelodysplastic syndrome (37.4%) and aplastic anemia (11.0%) accounted for about 50% of the underlying diseases. At the time of receiving a total of 20 RBC units, 90.8% and 66.2% of the 65 patients evaluated had more than 500 and 1,000 ng/ml of serum ferritin, respectively. The frequency of organ dysfunction associated with iron overload was 56.9% of all the patients assessed, 37.8% of patients with serum ferritin levels of 500∼999 ng/ml, and 67.4% of patients with serum ferritin levels >1,000 ng/ml. Although the Japanese guidelines propose 40 units of RBC transfusion and/or a serum ferritin level of 1,000 ng/ml as a good point to start iron chelation therapy, our results suggest that iron overload and consequent organ dysfunction may occur earlier than this. Therefore, it may be necessary to start iron chelation therapy earlier than that suggested by the Japanese guidelines.

Follicular lymphoma complicated with myelofibrosis and macroglobulinemia at initial presentation

Abstract: A 49-year-old woman presented with pharyngeal and cervical lymph node swelling in December 2010. Biopsy of the pharynx demonstrated follicular lymphoma which secreted large volumes of immunoglobulin M (IgM) and transforming growth factor-β (TGF-β). Bone marrow aspiration yielded a dry tap, and bone marrow biopsy demonstrated myelofibrosis associated with lymphoma cells on admission. The plasma concentration of TGF-β was elevated and monoclonal IgM gammopathy was detected. After only one course of chemotherapy with CHOP plus rituximab, remission of both lymphoma and myelofibrosis was achieved. Bone marrow aspiration became possible, and TGF-β and IgM levels normalized. Thus, the myelofibrosis was reversible.

Primary myelofibrosis complicated by acquired hemophilia A and subsequent development of acute myeloid leukemia

Abstract: A 77-year-old man diagnosed with primary myelofibrosis (PMF), successfully controlled by thalidomide and prednisolone, was referred to us for massive subcutaneous bleeding involving the face, body, and all four limbs. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer, resulting in a diagnosis of acquired hemophilia A (AHA) for which he was treated with prednisolone and cyclophosphamide on admission. He developed right femoral intramuscular hemorrhage soon after immunosuppressive therapy and was treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he suffered complications of respiratory failure with increasing throat hemorrhaging. Recombinant activated factor VII (rFVIIa) was administered combined with methylprednisolone pulse therapy. Bleeding, including respiratory failure, was ameliorated with rFVIIa. Immunosuppressive rituximab therapy resolved AHA with marked efficacy. He died of Pneumocystis jiroveci pneumonitis. Autopsy showed transformation from PMF to acute myeloid leukemia.

Primary pleural of mucosa-associated lymphoid tissue lymphoma.

Abstract: A 68-year-old female presented with shortness of breath. Chest radiography showed pleural effusion in the right side only. She was suspected of having ovarian cancer because CA125 levels were increased in the pleural effusion, and she consulted our hospital. A chest CT scan showed right pleural nodular lesions. Thoracoscopic pleural resection was performed. Histologic examination of a biopsy specimen showed the diffuse infiltration of small∼medium, mature lymphocytes. These lymphocytes were found to be positive for CD20 and CD79a, but negative for CD3 by immunohistochemistry. These results were interpreted as being consistent with a diagnosis of mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). She commenced chemotherapy with R-CHOP, and the pleural effusion disappeared. MALT lymphoma arising in the pleura is very rare, with only 12 published cases, and most cases have been described in Japan. CA125 levels correlated with the stage, tumor bulk, and presence of effusion. This patient exhibited a high level of CA125 that decreased with therapy.

[Effect of bortezomib-based induction therapy on the peripheral blood stem cell harvest in multiple myeloma]

Abstract: A high dose of melphalan followed by autologous stem cell transplantation (ASCT) is considered as the standard therapy for multiple myeloma. For induction therapy, 78 patients received conventional regimens (control group) and 32 patients received bortezomib-containing regimens (bortezomib group). We retrospectively compared the yield of harvested CD34+ cells between the two groups. In order to mobilize CD34+ cells, 83% of the control group and 63% of the bortezomib group received a high dose of cyclophosphamide followed by G-CSF, and 12% of the control group received a high dose of etoposide instead of cyclophosphamide. Furthermore, 5% of the control group and 38% of the bortezomib group received G-CSF alone for CD34+ cell mobilization. Overall, the yield of CD34+ cells was higher in the control group than in the bortezomib group (7.4 vs. 5.2×10(6)/kg, P=0.004). Regarding the patients mobilized by a high dose of cyclophosphamide followed by G-CSF, the rate of achieving CD34+ cells >2.0×10(6) cells/kg was similar. Bortezomib did not significantly affect the successful collection of at least CD34+ cells > 2.0×10(6) cells/kg after mobilization with a high dose of cyclophosphamide followed by G-CSF.

[Utility of endoscopic ultrasound-guided fine needle aspiration for diagnosis of Burkitt lymphoma in two pediatric cases].

Abstract: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed as a diagnostic procedure for two pediatric patients with intra-abdominal tumors. Case 1 was an 8-year-old boy with a huge tumor in the portal-hepatic region. Case 2 was a 17-year-old girl with a history of diabetes and recurrent relapse of Burkitt lymphoma, who had a newly developing tumor in the pancreatic body. In both cases, EUS-FNA was performed as a less invasive diagnostic procedure than open biopsy or total resection of the tumor. Tumor cells were determined to be of the B cell lineage by flow cytometric and immunostaining analyses. Both cases were diagnosed as having Burkitt lymphoma based on detection of IgH/C-MYC translocation by FISH. The aspiration was successfully conducted without severe complications, and both patients were immediately given chemotherapy. EUS-FNA is a safe and minimally invasive procedure with high diagnostic value for pediatric cases with intra-abdominal tumors.

[Primary diffuse large B-cell lymphoma of the uterus complicated with hydronephrosis].

Abstract: Malignant lymphoma sometimes originates from extranodal sites; however, the uterus has rarely been reported as the site of the primary lesion. We present a patient with malignant lymphoma of the uterus complicating bilateral hydronephrosis. A 67-year-old previously healthy woman was seen at a clinic because of massive genital bleeding. She was referred to our hospital for further examination of a uterine tumor. Computed tomography scans revealed a pelvic tumor invading to the retroperitoneal region, which caused bilateral obstruction of the ureters and hydronephrosis. No lymph node swelling was detected. Magnetic resonance imaging showed a bulky uterine tumor that was homogenously low on T1-weighted imaging and isointense on T2-weighted imaging, while the endometrium was intact. A pathological examination of the biopsy specimen from the uterine cervix revealed diffuse infiltration of CD20-positive atypical large lymphoid cells, which was compatible with diffuse large B-cell lymphoma (DLBCL). Since the tumor expanded from the uterus and no other abnormal lesion was observed in imaging studies including gallium scintigraphy, a diagnosis of DLBCL of the uterus, clinical stage IE was made. The patient received six cycles of rituximab plus CHOP chemotherapy followed by involved field irradiation. She achieved complete remission and has been alive for more than two years without relapse.

[Emergence of donor-derived anti-HLA antibody and subsequent transfusion-refractory thrombocytopenia after allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor in a patient with acute myeloid leukemia].

Abstract: A 45-year-old woman with acute myelogenous leukemia developed platelet transfusion refractoriness (PTR) after the engraftment of an allogeneic peripheral blood stem cell transplantation (PBSCT) from her multiparous sister, which was attributed to HLA antibodies that could not be detected in the patient's serum before transplantation. She achieved neutrophil engraftment by day 18 and megakaryocytopoiesis and complete donor chimerism was confirmed in the bone marrow on day 21. IgG-class HLA antibodies were detected in her serum on day 24 after PBSCT; however, on day 15, no HLA antibodies were detected. The specificity of the antibodies that emerged in the patient closely resembled that of the antibodies found in the donor. The donor had probably been immunized during pregnancy by their partner's HLA-antigens expressed by the fetus. Consequently, transplanted donor-derived cells provoked HLA antibodies in the recipient early after PBSCT, and those HLA antibodies induced PTR. The presence of HLA antibodies should be examined at least in pregnant female donors whose recipients developed PTR attributable to HLA antibodies after SCT.

Retrospective analysis of eltrombopag for the treatment of refractory primary immune thrombocytopenia in Japan.

Abstract: Eltrombopag, an oral thrombopoietin receptor agonist, is a novel drug that can be used in cases with previously-treated primary immune thrombocytopenia (ITP). In this study, we retrospectively analyzed 22 Japanese ITP patients treated in four hospitals. A responder was defined as a patient achieving a platelet count between 50,000/μl and 400,000/μl, at 75% or more of on-treatment assessments. Excluding 2 patients whose treatments were interrupted at their request, 13 of 20 patients (65%) were responders. Ten of the 13 responders had been taking more than 5 mg of a steroid preparation in the form of prednisolone or its equivalent. In 7 of these patients, the steroid dose could be tapered to 5 mg or less. Disappearance or amelioration of hemorrhagic symptoms was observed in 11 of 19 patients who had these symptoms prior to treatment (9 of 10 responders, 2 of 7 non-responders), and the improvement rate was greater in responders (p=0.018). No factors were identified as being related to efficacy. Reported adverse effects were fever (1), malaise (3), headache (2), and muscle pain (1). One severe adverse event, cerebral thromboembolism, was reported in 1 patient. Although eltrombopag is a useful therapeutic agent for refractory ITP, it is necessary to evaluate its position in the overall treatment strategy for ITP after assessing long-term complications as well as therapeutic effects.

[Current national and international status of supportive therapy for the coagulopathy associated with L-asparaginase containing regimen for acute lymphoblastic leukemia].

Abstract: We investigated supportive therapy against coagulopathy associated with L-asparaginase treatment in patients with acute lymphoblastic leukemia who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), Japan Adult Leukemia Study Group (JALSG), and foreign institutes. Fresh frozen plasma (FFP) was administered as a supplement in 46% patients in the JPLSG and 86% in the JALSG. The threshold level of FFP infusion was less than 100 mg/dl plasma fibrinogen in 70% of the JALSG and 20% of the JPLSG, while in another 20% of the JPLSG, FFP was administered when the fibrinogen level was less than 50 mg/dl. The preventive use of antithrombin products (AT) was prescribed in 93% of the JPLSG and 63% of the JALSG: The threshold level of AT supplementation was less than 70% of plasma antithrombin activity, which was similar in both groups. Most foreign institutes do not routinely use FFP or AT.

Acquired coagulant factor inhibitors

Abstract: Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.