[B-cell acute lymphoblastic leukemia with glycophorin A expression].

This study reports a case of a 49-year-old woman having B-cell acute lymphoblastic leukemia with glycophorin A, a representative erythroid marker, expression. According to the WHO criteria for mixed phenotype acute leukemia (MPAL), erythroid lineage is not defined, and to the best of our knowledge, only one other case with erythroid/B-cell biphenotypic acute leukemia has been reported previously. To establish the disease entity and clarify the pathophysiology of erythroid/lymphoid MPAL, additional cases need to be analyzed.

Sequential therapy of four cycles of bortezomib, melphalan, and prednisolone followed by continuous lenalidomide and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma.

The combinations of melphalan, bortezomib, and prednisolone (VMP) and of lenalidomide and dexamethasone (Rd) are standard treatment strategies for transplant-ineligible newly diagnosed multiple myeloma (NDMM). To make the most of these two strategies, we investigated the efficacy and feasibility of first-line treatment with 4 cycles of VMP followed by continuous Rd therapy in a multi-institutional phase 2 study in Japanese patients with transplant-ineligible NDMM. Thirty-six patients of median age 74 years old with NDMM initially received 35-day cycles of VMP: oral melphalan (6 mg/m2) and prednisolone (60 mg/m2) on days 1 to 4 and bortezomib (1.3 mg/m2) on days 1, 8, 15, and 22. After 4 cycles of VMP, treatment was switched to 28-day cycles of Rd, which was continued until disease progression or emergence of an unacceptable adverse event (AE) in 33 patients, while one patient who achieved CR after VMP continued VMP at the physician's discretion. The overall response rates after VMP and after Rd were 66.7% and 86.1%, including CR rates of 5.6% and 36.1%, respectively. In a median follow-up period of 34.3 months, the progression-free survival and overall survival rates at 3 years were 43.2% and 81.3%, respectively. Grade 3-4 hematological AEs included neutropenia (39% with VMP and 24% with Rd) and thrombocytopenia (11% with VMP and 3% with Rd). There was no death due to an AE. In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registered as UMIN000034815.

Identification of IGHCδ-BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B-cell lymphoma/leukemia.

In B-cell malignancies, genes implicated in B-cell differentiation, germinal center formation, apoptosis, and cell cycle regulation are juxtaposed to immunoglobulin loci through chromosomal translocations. In this study, we identified the BTB and CNC homology 2 (BACH2) gene as a novel translocation partner of the immunoglobulin heavy chain (IGH) locus in a patient with IGH-MYC-positive, highly aggressive B-cell lymphoma/leukemia carrying der(14)t(8;14) and del(6)(q15). Fluorescence in situ hybridization analysis using an IGH/MYC probe detected an IGH-MYC fusion signal on der(14) and IGH signal on del(6). Genome copy number analysis showed a deletion in the 6q15-25 region and a centromeric breakpoint within the BACH2 gene. cDNA bubble polymerase chain reaction using BACH2 primers revealed that the first exon of Cδ was fused to the 5'-untranslated region of BACH2 exon 2. The Cδ-BACH2 fusion transcript consisted of exon 1 of Cδ and exons 2 to 9 of BACH2, encompassing the entire BACH2 coding region, and the BACH2 was highly expressed in this patient. These results indicate that Cδ-BACH2 fusion may cause constitutive activation of BACH2. Although additional screening of 47 samples of B-cell non-Hodgkin's lymphoma (B-NHL) patients and 29 cell lines derived from B-cell malignancies by double-color fluorescence in situ hybridization analysis detected a split signal with deletion of centromeric region of BACH2 only in a patient with follicular lymphoma, BACH2 was highly expressed in lymphoma cells of the patient and B-NHL cell lines with IGH-MYC translocation. These findings suggest that BACH2 plays a critical role in B-cell lymphomagenesis, especially related to IGH-MYC translocation in some way.

Successful treatment of paraneoplastic pemphigus and bronchiolitis obliterans associated with follicular lymphoma with obinutuzumab and bendamustine.

We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.

A case of pancreatic walled-off necrosis successfully treated with endoscopic ultrasonography-guided drainage using Hot AXIOS System in a patient with severe hemophilia A.

BACKGROUND: Hemophilia A causes a bleeding tendency due to the congenital absence of coagulation factor VIII or the production of antibodies against it. It is challenging to perform invasive procedures in patients with hemophilia A. Walled-off necrosis (WON) is a serious complication of acute pancreatitis. Recently, a new metallic stent has been used to drain WON. CLINICAL COURSE: We treated a 32-year-old man who developed WON due to acute pancreatitis and has severe congenital hemophilia A. Since conservative treatment was ineffective, he underwent endoscopic ultrasonography (EUS)-guided transgastric WON drainage using a new metallic stent Hot AXIOS System. The procedure was successful without any severe hemorrhagic complications. Before and after the procedure, his clotting factors were strictly monitored by a hemophilia specialist. CONCLUSION: EUS-guided pancreatic cyst drainage can be an effective option for WON in patients with severe congenital hemophilia, under adequate management.

Cyclosporine A for chemotherapy-resistant subcutaneous panniculitis-like T cell lymphoma with hemophagocytic syndrome.

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL.

Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma.

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers.

Risk factors for infection in haematology patients treated with rituximab.

OBJECTIVES: Although rituximab therapy is not considered to be closely associated with infection, there have been reports of serious infections in patients treated with rituximab. We performed a statistical retrospective analysis to clarify the risk factors for infection in patients receiving rituximab therapy. METHODS: A retrospective study of data from clinical records was performed that targeted haematology patients treated at our university hospital between April 2003 and October 2006. We selected 63 patients with CD20-positive lymphoma whose peripheral blood immunoglobulin levels had been measured within 6 months before and after rituximab therapy. Logistic regression analysis was used to investigate the risk factors for serious infection in these patients. RESULTS: The three risk factors identified were: 1) reduction in IgM after administration of rituximab [odds ratio (OR) = 1.032, confidence interval (CI) = 1.007-1.057; P = 0.009], 2) duration of rituximab therapy [OR = 0.962, CI = 0.932-0.994; P = 0.021] and 3) G-CSF administration [OR = 4.825, CI = 1.411-16.495; P = 0.012]. CONCLUSIONS: Rituximab therapy may be associated with infection, indicating the need for sequential monitoring of IgM levels and identification of the optimal interval between rituximab cycles.

Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents.

OBJECTIVE: Clostridium difficile is a major cause of diarrhea in hospitalized patients. Although pseudomembranes are crucial evidence for diagnosis of C. difficile-associated diarrhea (CDAD), some cases do not show any pseudomembranes. The aim of this study was to verify the hypothesis that pseudomembranes are not generated in immunosuppressed patients because of the absence of immunoreactions. MATERIAL AND METHODS: We investigated the endoscopic findings of patients with ulcerative colitis (UC) or who had received hematopoietic stem cell transplantation, and who presented with C. difficile toxin A and had undergone colonoscopy between April 2002 and July 2007 at our institutes. Results. In 4 patients the diagnosis was UC and C. difficile infection, and in another 4 patients the diagnosis was CDAD after hematopoietic stem cell transplantation. None of these cases showed pseudomembranes. Shallow ulcers were found in all four cases with UC. Only non-specific findings were obtained for the CDAD patients after hematopoietic stem cell transplantation. CONCLUSIONS: Pseudomembranes, the typical evidence for CDAD, were not detected in any patients using immunosuppressive agents. Additional bacterial examination is therefore essential when UC becomes exacerbated and when patients present with diarrhea after hematopoietic stem cell transplantation, even in the absence of pseudomembranes.

Length of vancomycin administration for treatment of clostridium difficile-associated diarrhea may depend on presentation of colonic ulcer.

BACKGROUND/AIMS: Clostridium difficile-associated diarrhea (CDAD) is a notorious iatrogenic infection with typical endoscopic features consisting of pseudomembranes (PMs). Concomitant colonic ulcers are sometimes endoscopically detected. We hypothesized that length of vancomycin (VCM) administration for treatment depends on presentation of colonic ulcer. METHODOLOGY: We investigated retrospectively endoscopic findings and total number of days of vancomycin administration for patients who showed evidence of C. difficile toxin A or PMs at our hospitals. We excluded CDAD cases with inflammatory bowel disease. RESULTS: Sixteen patients were diagnosed as having CDAD. All patients receiving endoscopic examination presented PMs. Two cases had PMs in the transverse and small intestine. The patients with ulcers needed 5-28 days of administration of VCM, while all those without ulcers except one were cured within seven days. CONCLUSIONS: Our results suggest that ulcer may be a factor of poor prognosis, and we recommend endoscopic examination for all patients with CDAD for identification of poor prognostic groups.

Prediction of delayed platelet engraftment after autologous stem cell transplantation for B-cell non-Hodgkin lymphoma.

Delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment after autologous peripheral blood stem cell transplantation (auto-PBSCT). To identify risk factors for DPE and to develop a simple and clinically applicable system for predicting the time required for platelet recovery, we conducted a multi-institutional retrospective study in 144 patients with B-cell non-Hodgkin lymphoma who underwent auto-PBSCT. In a median observation period of 930 days (range: 25-5272 days), 139 patients successfully achieved platelet engraftment (≥50.0 × 109/L). The median duration for platelet engraftment was 19 days, and 130 patients had platelet engraftment within 40 days after auto-PBSCT; however, the other 14 patients failed to achieve platelet engraftment within 60 days. These 14 patients with DPE required a significantly greater number of apheresis procedures and had a lower pre-apheresis absolute lymphocyte count (PA-ALC) compared to those without DPE. Importantly, multivariate analysis revealed that the number of transplanted CD34+ cells (≤2.0 × 106/kg), number of required apheresis procedures (≥3 days), and PA-ALC (≤1.0 × 109/L) were independently associated with a longer time for platelet engraftment after auto-PBSCT. By incorporating these three independent factors as variables, we generated a new scoring system for prediction of the time and probability for platelet engraftment after auto-PBSCT.

Combined rituximab, bendamustine, and dexamethasone chemotherapy for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma: a multicenter phase II study.

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.

Left main crossover stenting in a patient with severe thrombocytopenia due to aplastic anemia.

A 76-year-old man with aplastic anemia presented with recurrent acute myocardial infarction (AMI) with heart failure. After the initial appearance of AMI approximately 2 months earlier, he had received conservative treatment/transfusion alone because of severe thrombocytopenia and anemia (platelet 11 × 103/µL, hemoglobin 6.4 g/dL). Refractory heart failure persisted despite repeated conservative treatment/transfusion for the second AMI, and therefore, we performed transradial coronary angiography and left main crossover stenting with a bare metal stent. His critical condition markedly improved; however, soon after discharge, he complicated with subdural hematoma. He has since been free of cardiovascular/hemorrhagic events for 7 months without antiplatelet/anticoagulant therapy.

Favorable Event Free-Survival of High-Dose Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Higher Risk Diffuse Large B-Cell Lymphoma in First Complete Remission.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been applied to patients with diffuse large Bcell lymphoma (DLBCL); it is well established that ASCT shows significant survival benefits for chemosensitive relapse. However, half of relapsed patients are resistant to salvage chemotherapy, indicating that they are not suitable for ASCT. We retrospectively analyzed the clinical records of 47 patients with DLBCL classified as high or high-intermediate (higher) risk, according to the International Prognostic Index, who underwent upfront ASCT in first complete remission (CR1). Compared with 10 patients with similar characteristics who did not receive ASCT, event free survival at 5-year was significantly superior in ASCT group. Toxicity of ASCT was acceptable and therapy-related death was not observed. We therefore propose that upfront ASCT for higher risk DLBCL in CR1 might provide survival benefit, probably because the high-dose therapy removes minimally resided tumor.

Acute lymphoblastic leukemia with eosinophilia lacking peripheral blood leukemic cell: a rare entity.

We describe a 57-year-old woman who was diagnosed as precursor B-cell acute lymphoblastic leukemia with marked eosinophilia (ALL-eo). She presented with low grade fever and eosinophilia (absolute count 16.5 × 10(9)/l). Most of eosinophils had hypogranular cytoplasm. Immature cells were absent in her peripheral blood. Since her platelet count was low, bone marrow examination was carried out. 57.2 % of nucleated cells were blastic cells positive for CD10, 19, and 20. Chromosomal analysis revealed a karyotype of 46,XX,t(5;14)(q31;q32). Despite induction chemotherapy, her disease progressed and she died of sepsis a month later. ALL-eo is extremely rare and the diagnosis might be delayed unless leukemic cells are seen in peripheral blood. Therefore, bone marrow should be examined as soon as possible in cases with eosinophilia not only for the differential diagnosis of eosinophilic disorders but also not to overlook ALL-eo.

Inversion of chromosome 7q22 and q36 as a sole abnormality presenting in myelodysplastic syndrome: a case report.

INTRODUCTION: Deletions of chromosome 7 are often detected in myelodysplastic syndrome. The most commonly deleted segments are clustered at band 7q22. A critical gene is therefore suggested to be located in this region. We report a patient with myelodysplastic syndrome whose marrow cells carried an inversion of 7q22 and q36 as a sole karyotypic abnormality. How this extremely rare chromosomal aberration contributes to the pathogenesis of myelodysplastic syndrome should be clarified by accumulating clinical data of such cases. CASE PRESENTATION: A 74-year-old Japanese man presented with pancytopenia incidentally detected by routine medical check-up. His complete blood cell counts revealed that his white blood cells had decreased to 2100/mm3, neutrophils 940/mm3, red blood cells 320×104/mm3, hemoglobin 11.1g/dL, hematocrit 33.1%, and platelets 12.6×104/mm3. Bone marrow examination showed normal cellularity with nucleated cells of 9.4×104/mm3. The proportion of blasts was 4%. A morphological examination showed only basophilic stippling of erythroblasts which was seen as dysplasia. According to World Health Organization classification, the diagnosis was myelodysplastic syndrome-u. Karyotypic analysis showed 46,XY,inv(7)(q22q36) in all of 20 metaphases examined. Additional analysis revealed the karyotype of his lymphocytes was 46,XY. He is asymptomatic and cytopenia has slowly progressed. CONCLUSIONS: To the best of our knowledge, this karyotype from a clinical sample of de novo malignancies has never been documented although the identical karyotype from secondary myelodysplastic syndrome was reported. Despite the extremely low frequency, inversion of 7q22 appears to play a crucial role for myelodysplastic syndrome in this patient.