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Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all-trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow-up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen-DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event-free survival (EFS) showed an inferior trend in CD56(+) APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 10(9)/L or more, EFS and cumulative incidence of relapse in CD56(+) APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor., (© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Myeloid sarcoma (MS) is an extramedullary myeloid tumor that sometimes presents with antedating systemic leukemia, leading physicians to the misdiagnosis of lymphoma. CD25 is expressed in 13% of patients with acute myeloid leukemia (AML), and its expression is associated with FLT3-ITD mutations, an elevated serum soluble interleukin 2 receptor (sIL-2R) level and a lower survival rate. However, there are no reports concerning the relationship between MS and the CD25 expression. We herein report a case of AML accompanied by thoracic epidural MS with a high CD25 expression, the FLT3-ITD mutation and an extremely elevated serum sIL-2R level in a 59-year-old man who presented with paraplegia.

Enteropathy-associated T-cell lymphoma (EATL), an intestinal tumor of intraepithelial T lymphocytes, is a rare and highly aggressive disease. We herein describe a case of type II EATL with massive pyoid ascites in which a histological examination could not be performed despite emergency laparotomy that was successfully diagnosed using flow cytometry and the cell block technique to analyze the celomic fluid. This case suggests that EATL should be included in the differential diagnosis of pyoid ascites of unknown origin and that flow cytometry and the cell block technique of assessing celomic fluid are useful procedures for diagnosing EATL, especially in cases in which conducting a histological examination is impossible.

Objective: Vascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive therapeutic option. The aim of this study is to investigate the effects of bevacizumab for patients with POEMS syndrome., Methods: We reported six POEMS patients treated with bevacizumab and reviewed the literature., Results: The serum VEGF levels decreased immediately after bevacizumab administration in all six patients. However, four patients had entirely no clinical response, and two of them died. The remaining two showed improvement that could be explained by combined treatments. We also reviewed the literature and found 11 patients treated with bevacizumab; of these, only one was treated with bevacizumab alone. 10 had combined treatments, and four died without any response., Conclusions: Both our experience and the literature suggest ambiguous effects of bevacizumab; inhibition of VEGF alone may be insufficient because multiple cytokines are upregulated, or aberrant neo-vascularization may have already fully developed in the advanced stage of POEMS syndrome.

Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.

For patients with relapsed acute promyelocytic leukemia (APL), all-trans retinoic acid-based salvage regimens can achieve second complete remission (CR2), but the optimal post-remission strategy for APL patients after CR2 remains unclear. Hematopoietic stem cell transplantation (HSCT) during CR2 might be effective, but data on the role of HSCT for APL patients after CR2 are limited in Japan. We retrospectively analyzed outcomes for 57 relapsed APL patients who achieved CR2 in the JALSG APL97 study. Of those, six received autologous (auto)-HSCT, 21 received allogeneic (allo)-HSCT, and 30 received various regimens other than HSCT. The 5-year event-free survival (EFS) rate, overall survival (OS) rate and cumulative incidence of relapse (CIR) were 50.7%, 77.4% and 51.0% in the non-HSCT group, 41.7%, 83.3% and 58.3% in the auto-HSCT group and 71.1%, 76.2% and 9.8% in the allo-HSCT group, respectively. Both the EFS rate and CIR were significantly better in the allo-HSCT group than in other groups. Allo-HSCT appears effective in APL patients in CR2, with a low relapse rate beyond a relatively early transplantation-related mortality (19%). Among older patients (age ≥40 years), the 5-year OS was significantly better in the non-HSCT group than in the HSCT group (78.0% vs 40.5%; P = 0.04). Further prospective studies with larger patient numbers are required to confirm the impact of HSCT alone and in combination with arsenic trioxide on outcomes for patients with APL in CR2., (© 2013 Japanese Cancer Association.)

Extramedullary blast crisis of chronic myelogenous leukemia (CML) is defined as the development of extramedullary disease caused by the infiltration of blasts regardless of proliferation of blasts in the bone marrow. The onset of extramedullary blast crisis in the newly diagnosed patients is known to be extremely rare. Here, we present a case of extramedullary blast crisis of CML as an initial presentation in a 17-year-old female presenting with pain in the left femur tumor. This case was treated successfully with dasatinib and allogeneic hematopoietic stem cell transplantation, with achievement of long-term remission.

A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit(+) Lin(-) cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit(+) Lin(-) cells of lr11(-/-) mice was reduced by hypoxia much more than of lr11(+/+) animals. sLR11 induced the adhesion of U937 and c-Kit(+) Lin(-) cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1α, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1α-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1α binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behçet's disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations. Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.

Although the use of cord blood transplantation (CBT) is increasing, the optimal methods for conditioning and graft-versus-host disease (GVHD) prophylaxis remain to be established. Among previous reports, the Institute of Medical Science, University of Tokyo (IMSUT) has reported remarkably favorable results of CBT for hematologic malignancies as a single-institute experience. The aim of the present multicenter prospective study was to assess the safety and efficacy of CBT performed precisely according to IMSUT transplantation procedures. Thirty-three adult patients with hematologic malignancies, such as acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome, either lacking an HLA-identical sibling/HLA-matched unrelated donor or requiring urgent transplantation were enrolled. Conditioning consisted of total body irradiation (12 Gy), cytarabine, and cyclophosphamide. Cyclosporine A and methotrexate were used for GVHD prophylaxis. Diagnoses were acute leukemia in 26 patients, chronic myelogenous leukemia in 4, and myelodysplastic syndrome in 3; 12 patients were in first complete remission, and the others were in advanced stages at the time of CBT. Thirty-one patients achieved engraftment, and the cumulative incidence of grade II-IV acute GVHD was 45% (95% confidence interval, 28%-62%). With a median follow-up of 46.2 months in 16 surviving patients, the 1-year cumulative incidence of nonrelapse mortality was 15% (95% confidence interval, 5%-30%). Causes of nonrelapse mortality were infection (n = 4) and graft failure (n = 1). The overall and disease-free survival rates were 51% (95% CI, 34%-68%) and 42% (95% CI, 26%-59%), respectively. These results suggest that the IMSUT CBT procedures can safely provide a high disease-free survival rate in patients with high-risk hematologic malignancies., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for the characteristic symptoms such as angiomata, pleural effusion/ascites, edema, and organomegaly in the disorder. To study whether other angiogenetic factors are upregulated in POEMS syndrome, we measured serum levels of basic fibroblast growth factor and hepatocyte growth factor (HGF), as well as VEGF, in 17 patients with POEMS syndrome. All these factors were significantly upregulated in the POEMS syndrome patients. After the treatment with anti-VEGF antibody, the levels of HGF did not change, suggesting that elevation of HGF levels is not secondary to VEGF overproduction. These results suggest that different angiogenetic factors might contribute to the pathogenesis of POEMS syndrome, and this fact might contribute to the insufficient clinical effects obtained by suppression of VEGF alone.

Neurolymphomatosis (NL) is a rare clinical entity defined as peripheral nervous system infiltration by lymphoma. The diagnosis is difficult and often elusive. Whole-body diffusion-weighted magnetic resonance imaging (DW MRI) was developed to enhance the detection of vaguely delineated tumors. Here, we describe the case of a 71-year-old male with secondary NL of diffuse large B-cell lymphoma (DLBCL) that was successfully detected by whole-body DW MRI. The patient was diagnosed with DLBCL extending from the ethmoidal sinus to the nasal cavity, orbital cavity, and anterior cranial fossa. Although he was administered R-THP-COP chemotherapy and the tumor remarkably decreased in size, he developed painful paresthesia and weakness in the left upper and bilateral lower extremities during treatment. Because lymphoma cells were detected in his spinal fluid, high-dose methotrexate (MTX) and weekly intrathecal MTX and cytarabine injections were administered. Test results for lymphoma cells in the spinal fluid became negative ; however, the neurological disorders progressed. Whole-body DW MRI was performed as whole-body screening and could localize NL at the left cervical and bilateral lumbar nerve roots. Both cervical spine plain MRI and enhanced computed tomography performed around the same time could not detect the cervical lesion. Our case report suggests that whole-body DW MRI is a useful diagnostic imaging procedure, especially as whole-body screening in facilities where PET/CT is not available.

While renal comorbidity is generally defined by the serum creatinine level, the creatinine clearance rate (Ccr) is a more accurate indicator of renal function. Therefore, we retrospectively assessed how mildly reduced renal function as defined based on Ccr affects the outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Patients who underwent allogeneic HSCT at the eight institutes of the Kanto Study Group for Cell Therapy were included in this study. Based on the corrected Ccr, patients were classified into group 0 (n = 440,  ≥ 90 mL/min/1.73 m(2)), group 1 (n = 56, 60-89 mL/min/1.73 m(2)), or group 2 (n = 11, 30-59 mL/min/1.73 m(2)). Therefore, 67 patients were considered to have mild renal impairment, whereas only 2 had a serum creatinine level higher than 1.2 mg/dL. Twenty-eight patients required hemodialysis after HSCT, with 5.5, 5.4, and 9.1 % in groups 0, 1, and 2, respectively (p = 0.65). The incidence of non-relapse mortality (NRM) was higher in group 2, although these differences were not statistically significant probably due to the small sample size (23.7, 28.2, and 47.2 % at 3 years, p = 0.20). In conclusion, NRM may be associated with mildly reduced renal function before allogeneic HSCT, which cannot be detected by measurement of the serum creatinine level alone.

We recently reported that adult acute myeloid leukemia (AML) patients with granulocytic sarcoma (GS) possessed unique clinical features and poor prognosis. However, the optimal therapeutic strategy for this entity has not been established. Therefore, the aim of this study was to assess the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the management of AML with GS. We retrospectively analyzed 503 consecutive adult AML patients (median age, 44 years; range, 15-73 years) who received allo-HSCT. A total of 44 patients (8.7%) had GS before transplantation. Patients with GS achieved comparable survival to those without GS (5-year overall survival (OS), 47% vs 44%, respectively, P=0.621). In patients with GS, excellent outcomes were seen in those that underwent allo-HSCT while in complete remission, whereas nine out of ten patients with GS at the time of transplant experienced a relapse within 6 months after allo-HSCT. Local irradiation for GS prior to allo-HSCT and acute and chronic graft-versus-host disease did not affect survival significantly. Multivariate analysis identified age, disease status and the use of myeloablative conditioning as independent prognostic factors for OS. These data suggest that better control of GS prior to allo-HSCT is crucial to improve the outcome of transplantation for those with GS.

Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long-term outcome of elderly APL patients (60-70 years) with younger patients (15-59 years) treated with all-trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non-relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease-free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206., (© 2012 Japanese Cancer Association.)

Background: LR11/SorLA, a receptor interacting with CD87 on monocytes and macrophages, is highly expressed on human immature hematopoietic stem cells. However, it is unknown whether LR11 is expressed on premature leukemic cells, and whether the levels of circulating soluble LR11 (sLR11) shed from leukemic cells correlate with disease state., Methods: The expression of LR11 on leucocytes and leukemic cells was examined by flow cytometry. Serum sLR11 levels were measured by ELISA in patients with various hematological diseases, including 43 acute myeloid leukemia (AML) and 23 acute lymphoblastic leukemia (ALL) patients. Data were subjected to statistical analysis for validation of sLR11 levels and patients' clinical data., Results: LR11 is specifically expressed in monocytes, and surface levels on leukemic cells are highly induced in both AML and ALL. sLR11 levels of acute leukemia patients were significantly increased (P<0.001) (ALL, 73.5±93.5 ng/ml; AML, 26.8±29.1 ng/ml) in comparison to controls (9.2±3.3 ng/ml). Patients with AML and ALL in remission showed significantly decreased sLR11 levels to below 20 ng/ml., Conclusions: LR11 and its released soluble form are strongly elevated in acute leukemias. Remarkably, this increase in circulating sLR11 levels is ameliorated at complete remission., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6 years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow.

Objective: To systematically study abnormalities in cytokine profiles in polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, which has been increasingly recognized as a cause of demyelinating neuropathy associated with plasma cell dyscrasia and elevated serum level of vascular endothelial growth factor (VEGF)., Methods: In this case-control study, we measured serum levels of 27 cytokines in patients with POEMS syndrome using a multiplex suspension array system, and compared them with those of controls. In 10 patients, serial changes after treatment were analyzed., Results: Interleukin (IL)-12 as well as VEGF levels were markedly increased (p < 0.0001) in all the patients (n = 23). Ten kinds of other proinflammatory cytokines such as IL-6 and tumor necrosis factor-α were also significantly increased in the POEMS syndrome group, but in some patients the serum levels of such cytokines remained within the normal ranges. After treatments, the IL-12 as well as VEGF levels significantly decreased with clinical improvements (p > 0.01 and p > 0.05, respectively)., Conclusions: Our findings suggest that serum IL-12 is a biomarker of the disease activity in POEMS syndrome. The overproduction of IL-12, as well as VEGF, is likely to play an important role in the pathogenesis of the disorder, and could contribute to the peripheral nerve demyelination in POEMS syndrome.

EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2(flox/flox) mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia-like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.

Background: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with monoclonal plasma cell proliferative disorder and multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasmacytomas, is likely to be responsible for most of the characteristic symptoms. POEMS syndrome is a potentially fatal disease, and patients' quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events. There is a need for efficacious therapy to improve prognosis. This is the first update of a review first published in 2008., Objectives: To assess the effects of treatment for POEMS syndrome., Search Methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 February 2012), CENTRAL (2012, Issue 2), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012) and CINAHL Plus (January 1937 to February 2012) for all papers on POEMS syndrome, Selection Criteria: We sought all randomized and quasi-randomized controlled trials, and non-randomized controlled studies. Since we discovered no such clinical trials, we assessed and summarized all retrospective case series including five or more patients in the 'Discussion' section., Data Collection and Analysis: Two review authors independently reviewed and extracted details of all potentially relevant trials with any treatment for POEMS syndrome. We then collated and summarized information on the outcome., Main Results: We found no randomized or non-randomized prospective controlled trials of treatment for POEMS syndrome. We summarized the results of retrospective case series containing five or more patients in the 'Discussion' section., Authors' Conclusions: There are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome on which to base practice.

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography-tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270-359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib., (© 2012 Japanese Cancer Association.)

Although the tyrosine kinase inhibitor (TKI) imatinib is often used as first-line therapy for newly diagnosed chronic myelogenous leukemia (CML), some patients fail to respond, or become intolerant to imatinib. Nilotinib is a potent and selective second-generation TKI, with confirmed efficacy and tolerability in patients with imatinib-resistant or -intolerant CML. A phase I/II study was conducted in Japanese patients with imatinib-resistant or -intolerant CML or relapsed/refractory Ph+ acute lymphoblastic leukemia. Thirty-four patients were treated with nilotinib for up to 36 months. Major cytogenetic response was achieved in 15/16 patients (93.8%) with chronic-phase CML within a median of approximately 3 months. Major molecular response was achieved in 13/16 patients (81.3%). These responses were sustained at the time of the most recent evaluation in 13 patients and 11 patients, respectively. Hematologic and cytogenetic responses were also observed in patients with advanced CML. The BCR-ABL mutation associated with the most resistance to available TKIs, T315I, was observed in three patients. Common adverse events included rash, nasopharyngitis, leukopenia, neutropenia, thrombocytopenia, nausea, headache and vomiting. Most adverse events resolved following nilotinib dose interruptions/reductions. These results support the favorable long-term efficacy and tolerability of nilotinib in Japanese patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia.

Posterior reversible encephalopathy syndrome (PRES) has been reported in childhood leukemia patients increasingly frequently. However, the development of PRES in adult leukemia patients during chemotherapy is very rare. We present a case of PRES in an adult patient with acute lymphoblastic leukemia (ALL) after remission induction chemotherapy. A 28-year-old woman with ALL was administered remission induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase. After initiation of chemotherapy, the patient developed paralytic ileus and hypertension, and on day 30, she suddenly developed generalized convulsions, loss of visual acuity, and muscle weakness in the legs. Magnetic resonance imaging findings and her signs and symptoms were typical of PRES. The symptoms gradually improved following treatment with an anticonvulsant and an antihypertensive agent, and the patient underwent allogeneic bone marrow transplantation. She has completely recovered from PRES and has been asymptomatic without leukemia relapse. During remission induction chemotherapy for ALL, PRES may be caused by multiple drugs, such as L-asparaginase, vincristine, and corticosteroids, with different mechanisms of action. PRES should be recognized as an important complication, which will occur more frequently with the increased intensity of chemotherapy for adult ALL patients.

To evaluate the incidence and risk factors for secondary solid tumors in Japan after allogeneic hematopoietic SCT (allo-HSCT), 2062 patients who had received allo-HSCT between 1984 and 2005 were retrospectively analyzed. Twenty-eight patients who developed 30 solid tumors were identified a median of 5.6 years after transplantation. The risk for developing tumors was 2.16-fold higher than that of the age- and sex-adjusted general population. The cumulative incidence of solid tumors at 10 years after allo-HSCT was 2.4%. The risk was significantly higher for tumors of the skin, oral cavity and esophagus (standard incidental ratio 40.23, 35.25 and 10.73, respectively). No increase in gastric, colon or lung cancer, despite being the most prevalent neoplasm in the Japanese, was observed. In multivariate analysis, occurrence of chronic GVHD and malignant lymphoma as a primary disease was associated with a higher risk for developing solid tumors. Eighteen patients are still alive, and their 5-year probability of survival since diagnosis of solid tumors is 59.7%. Our data suggest that the incidence and risk factors of secondary solid tumors in Japanese allo-HSCT recipients are comparable to those reported in Western countries and emphasize that the early detection of solid tumors has a crucial role in improving OS.

It has recently been reported that hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg)-negative lymphoma during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation for hematologic malignancies. However, clinical data on HBV reactivation in multiple myeloma patients have not been extensively reported. This is the first reported case of HBV reactivation in an HBsAg-negative myeloma patient treated with bortezomib (BOR) as salvage therapy and not stem cell transplantation. By closely monitoring HBV-DNA and early administration of entecavir, severe hepatitis was avoided and BOR therapy was continued. We suggest the importance of close monitoring of HBV-DNA for transplant-ineligible myeloma patients treated with BOR as salvage therapy.

A 50-year-old woman with a history of aplastic anemia developed cervical lymphadenopathy and atypical lymphocytosis. Atypical cells of lymph nodes were positive for CD3 and CD30 but negative for anaplastic lymphoma kinase (ALK). Bone marrow examination showed trilineage myelodysplasia. She was diagnosed with ALK-negative anaplastic large cell lymphoma (ALCL) with leukemic transformation and myelodysplastic syndrome (MDS) which presumably developed from aplastic anemia. The lymphoma was resistant to intensive chemotherapies, ultimately leading to death. Leukemic presentation of ALK-negative ALCL as an initial manifestation is extremely rare, and the progression of the disease may be influenced by MDS through alteration of immune functions.

In order to investigate better molecular-target therapy for acute myeloid leukemia (AML), we conducted a phase I trial of a combination of gemtuzumab ozogamicin (GO) with conventional chemotherapy. Between January 2007 and December 2009, a total of 19 adult Japanese patients with relapsed or refractory CD33-positive AML (excluding acute promyelocytic leukemia) were enrolled. All registered patients received a standard dose of cytarabine (Ara-C) (100 mg/m(2) × 7 days), combined with either idarubicin (IDR) (10-12 mg/m(2) × 3 days) or daunorubicin (DNR) (50 mg/m(2) × 3-5 days), and then GO (3-5 mg/m(2) ), which was administered 1 day after the last infusion of IDR (IAG regimen) or DNR (DAG regimen). While doses of both GO and IDR and the administration period of only DNR were increased, the dose-limiting toxicity (DLT) was assessed. Among 19 patients (nine in the IAG regimen, 10 in the DAG regimen), the median age was 59 years (range 33-64), and the relapsed/refractory ratio was 13/6. In the therapy using 3 mg/m(2) GO in the IAG or DAG regimen, grade 3/4 leukopenia and neutropenia were observed in all patients, but none had grade 3/4 non-hematological toxicities, except febrile neutropenia. Three patients in the IAG regimen who were administered 5 mg/m(2) GO showed DLT. No patients had veno-occlusive disease or sinusoidal obstructive syndrome. In conclusion, 3 mg/m(2) GO combined with Ara-C and IDR or DNR can be safely administered, and phase II trials should be conducted to investigate the clinical efficacy of the combination therapy., (© 2011 Japanese Cancer Association.)

Myeloproliferative neoplasms (MPN), a group of haematopoietic stem cell (HSC) disorders, are often accompanied by myelofibrosis. We previously identified the fusion of the ETV6 gene to the LYN gene (ETV6-LYN) in idiopathic myelofibrosis with ins(12;8)(p13;q11q21). The introduction of ETV6-LYN into HSCs resulted in fatal MPN with massive myelofibrosis in mice, implicating the rearranged LYN kinase in the pathogenesis of MPN with myelofibrosis. However, the signalling molecules directly downstream from and activated by ETV6-LYN remain unknown. In this study, we demonstrated that the direct activation of STAT5 by ETV6-LYN is crucial for the development of MPN. ETV6-LYN was constitutively active as a kinase through autophosphorylation. ETV6-LYN, but not its kinase-dead mutant, supported cytokine-free proliferation of haematopoietic cells. STAT5 was activated in a JAK2-independent manner in ETV6-LYN-expressing cells. ETV6-LYN interacted with STAT5 and directly activated STAT5 both in vitro and in vivo. Of note, ETV6-LYN did not support the formation of colonies by Stat5-deficient HSCs under cytokine-free conditions and the capacity of ETV6-LYN to induce MPN with myelofibrosis was profoundly attenuated in a Stat5-null background. These findings define STAT5 as a direct target of ETV6-LYN and unveil the LYN-STAT5 axis as a novel pathway to augment proliferative signals in MPN and leukaemia., (© 2011 Blackwell Publishing Ltd.)

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare cause of demyelinating neuropathy with monoclonal plasma cell proliferation, and POEMS neuropathy is usually chronically progressive. Herein, the authors report a 34-year-old woman with POEMS syndrome presenting as acute polyneuropathy. Within 2 weeks of disease onset, she became unable to walk with electrodiagnostic features of demyelination and was initially diagnosed as having Guillan-Barré syndrome. Other systemic features (oedema and skin changes) developed later, and an elevated serum level of vascular endothelial growth factor led to the diagnosis of POEMS syndrome. She received high-dose chemotherapy with autologous peripheral blood stem cell transplantation, resulting in good recovery. The authors also reviewed patterns and speed of progression of neuropathy in the 30 patients with POEMS syndrome; 22 (73%) of them were unable to walk independently with the median period of 9.5 months from POEMS onset (range 0.5-51 months). Whereas the speed of neuropathy progression varies considerably among patients, some POEMS patients can show acute or subacute polyneuropathy. The early diagnosis and treatment could result in rapid improvement as shown in the present patient.

Recent results from the phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study have demonstrated superiority of nilotinib over imatinib for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (CML-CP). Here, we report results from the Japanese subset of patients in ENESTnd, and assess whether results in this subpopulation are consistent with the overall study population. Seventy-nine Japanese patients with CML-CP were randomized to receive nilotinib 300 mg twice daily (BID) (n = 30), nilotinib 400 mg BID (n = 24) or imatinib 400 mg once daily (QD) (n = 25). Major molecular response rates at 12 months, the primary endpoint, were at least twice as high for nilotinib 300 mg BID (57%) and nilotinib 400 mg BID (50%) compared with imatinib 400 mg QD (24%). No patient on nilotinib progressed, while one patient progressed on imatinib. Both drugs were generally well tolerated and discontinuations due to adverse events were comparable among treatment arms. The results in the subpopulation of Japanese patients from ENESTnd closely mirror the results of the overall population, and support the use of nilotinib at 300 mg BID in Japanese patients with newly diagnosed CML-CP.

We performed a retrospective analysis of patients with adult-onset chronic active Epstein-Barr virus infection (CAEBV). First, we analyzed five patients (aged 28-72) diagnosed at our hospitals with EBV-infected clonally proliferating T cells. Four patients were administered cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy, but no remarkable decrease of viral load was observed in three of the patients. The other patient died 19 days after initiation of CHOP treatment due to disease progression. Addition of high-dose cytarabine to the regimens of two of the patients was discontinued shortly after administration, due to the development of grade 4 pericardial effusion. Together, these regimens may be insufficient for treating adult-onset CAEBV. We next reviewed 23 adult-onset CAEBV patients, adding 18 previously reported patients to the five patients described in the present study. T cells were frequently infected (87%), whereas NK- and T-cell types are known to be almost equally prevalent in childhood-onset cases. The time duration from the onset of disease to initiation of treatment averaged 20 months. Reports showed that 12 patients died; seven patients died at an average of 8 months after initiation of treatment. Patients' disease courses seemed to be rapidly progressive and more aggressive than those of childhood-onset cases. More cases must be studied to clarify clinical features and establish an optimal treatment strategy.

Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication that significantly reduces a patient's quality of life. We retrospectively analysed the incidence of and risk factors for BO in allo-SCT recipients. In 2087 patients who underwent allo-SCT between January 1994 and June 2005 and survived >90 days after transplantation, 57 patients developed BO with a 5-year cumulative incidence of 2.8%. The median time interval from transplantation to BO diagnosis was 335 days (range 83-907 days). The 5-year cumulative incidence of BO was 1.62% in bone marrow transplantation (BMT) from related donors, 3.83% in peripheral blood stem cell transplantation (PBSCT) from related donors (R-PBSCT), 2.91% in BMT from unrelated donors and 2.65% in unrelated cord blood transplantation. The incidence of BO after R-PBSCT was significantly higher than that after any other type of allo-SCT (p = 0.02). R-PBSCT (p = 0.019) and preceding chronic graft-versus-host disease (GVHD) (p < 0.001) were BO-associated risk factors. Overall 5-year survival of patients with BO from the time of diagnosis was 45.4%, significantly less than those without (77.5% from day 335, p < 0.001). R-PBSCT recipients with existent chronic GVHD have a high risk of developing BO, and need extensive care and repeated pulmonary function tests.

We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among 1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.

We conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m(2) daily for 5 days) or idarubicin (12 mg/m(2) daily for 3 days) in combination with 100 mg/m(2) of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m(2) twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year disease-free survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 × 10(9)/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/ as #C000000157.

Objective: To study the utility of CT for detection of small bone lesions in POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. For patients with a solitary bone lesion, irradiation is a first-line treatment, whereas systemic chemotherapy is indicated for patients with multiple bone lesions. Therefore it is important to correctly identify the number of bone lesions., Methods: We studied the sensitivity of chest/abdomen/pelvic CT to detect bone lesions in 28 patients with POEMS syndrome. (99m)Tc-HMDP bone scintigraphy was performed in 14 patients, and the results were compared with CT., Results: CT showed multiple bone lesions in 68% of the 28 patients, and 71% of the lesions had a diameter <10 mm. In 14 patients who underwent both CT and scintigraphy, bone lesions were detected in 57% by CT and in 79% by scintigraphy, but the location and nature of the identified lesions were considerably different; CT frequently showed small lesions (diameter <10 mm) in the vertebrae and pelvis, which were not detected by scintigraphy, whereas scintigraphy could show lesions in the skull and long bones. Overall, by using both examinations, multiple bone lesions were found for 86% of patients., Conclusion: CT is particularly useful to detect small bone lesions. CT and bone scintigraphy are complementary, and therefore both should be performed for bone survey in POEMS syndrome.

Although imatinib has become the current standard treatment for chronic myeloid leukemia (CML), there is limited information regarding its efficacy and safety among Japanese patients. We therefore conducted a prospective multi-center open-label study of imatinib for Japanese patients with newly diagnosed chronic-phase CML (CP-CML). A total of 107 patients were enrolled and treated with imatinib at an initial daily dose of 400 mg. Eighty-three patients completed 3 years of study treatment. The cumulative rates of major cytogenetic response and complete cytogenetic response (CCyR) were 90.9 and 90.2% at 3 years, respectively. The safety profile was not very different from that reported in the IRIS study, although grade > or =3 neutropenia occurred relatively frequently (31.8 vs. 14.3%). Only seven patients discontinued the study due to adverse events, as did four patients due to insufficient efficacy. The 3-year probabilities of overall survival and progression-free survival were 93.2 and 91.4%, respectively. Higher average daily doses (i.e., > or =350 mg) were significantly associated not only with higher rates of achieving CCyR, but also with longer duration of CCyR. These findings confirm the clinical utility of imatinib in Japanese patients with newly diagnosed CP-CML, and suggest detrimental effect of low average daily dose on treatment results.

We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

Background: Tumor lysis syndrome (TLS) is a group of life-threatening metabolic complications that can occur after initiation of cancer chemotherapy. Onset of TLS in the middle of chemotherapy, however, has not been reported previously in patients with hematologic malignancies., Objective: We report a case of a patient who experienced TLS of super-acute onset accompanied by hypercytokinemia during chemotherapy treatment with a combination of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD)., Case Summary: A 36-year-old Japanese man (height, 182 cm; weight, 83 kg; body surface area, 2.04 m(2)) was admitted to the hospital for the treatment of malignant lymphoma (clinical stage IVB Hodgkin's lymphoma). Chemotherapy was initiated using the ABVD regimen (doxorubicin [Adriamycin] 25 mg/m(2) by 30-minute infusion, bleomycin 9 mg/m(2) by 30-minute infusion, vinblastine 6 mg/m(2) by bolus injection, and dacarbazine 375 mg/m(2) by 2-hour infusion). During the dacarbazine infusion, the patient's body temperature rose from 36.5 degrees C to 42 degrees C; he experienced a convulsion and then lost consciousness. The convulsion was not suppressed despite the use of diazepam (5 mg IV twice) and phenytoin (500 mg IV). The patient was then transferred to the intensive care unit and sedated using a continuous infusion of midazolam (10 mg/h). Levels of serum lactate dehydrogenase, aspartate aminotransferase, uric acid, blood urea nitrogen, and creatinine evaluated shortly after the ABVD regimen were outside normal limits. In addition, interleukin-6 (IL-6) concentrations were elevated to 54,220 pg/mL. Continuous hemodiafiltration was immediately performed to lower the elevated levels of IL-6. The next day, IL-6 concentrations decreased to 97 pg/mL, and the patient was weaned from ventilator support and sedation. The patient had no adverse effects after the event. According to the results of an assessment using the Naranjo adverse drug reaction probability scale (score = 3), the development of TLS in this patient was possibly related to the chemotherapy regimen., Conclusions: ABVD chemotherapy was possibly associated with the super-acute onset of TLS in this patient. In addition, hypercytokinemia occurred with TLS, which led to pyrexia, convulsion, and loss of consciousness., (Copyright 2010 Excerpta Medica Inc. All rights reserved.)