Chikako Ohwada

Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program

Chronic graft‐versus‐host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR‐BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post‐transplant was 45·8% and 28·2%, respectively. On multivariate analysis, seven variables predicting chronic GVHD were identified: recipient age over 20 years, donor age over 30 years, primary diagnosis of chronic myeloid leukaemia, human leucocyte antigen (HLA)‐A or ‐B mismatch, total body irradiation‐containing regimen, platelet count not having reached 50 × 109/l by day 100, and prior acute GVHD. Among 2609 patients with haematological malignancy, overall survival was significantly higher in patients with limited chronic GVHD but lower in patients with extensive chronic GVHD compared with those without chronic GVHD. The cumulative incidence of relapse among patients with limited or extensive chronic GVHD was significantly lower than that among patients without chronic GVHD. Our results suggest that limited chronic GVHD provides a survival benefit to patients with haematological malignancies by reducing the risk of relapse without increasing the risk of death from chronic GVHD.

CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44‐expressing population from a Dex‐sensitive MM cell line, RPMI8226, in which the CD44‐high population had a significantly higher potential to resist Dex than did the CD44‐low population. Furthermore, we demonstrate that CD44 engagement by an anti‐CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex‐induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti‐CD44 mAb led to phosphorylation and degradation of IκB‐α, thus preventing its Dex‐induced up‐regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Restrictive usage of monoclonal immunoglobulin λ light chain germline in POEMS syndrome

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially lambda-restricted. Here we determined complete nucleotide sequences of monoclonal immunoglobulin lambda light chain (IGL) variable regions in 11 patients with POEMS syndrome. The V-region of the Ig lambda gene of all 11 patients was restricted to the V lambda 1 subfamily. Searching for homologies with IGL germlines revealed that 2 germlines, IGLV1-44*01 (9/11) and IGLV1-40*01 (2/10), were identified, with an average homology of 91.1%. The IGLJ3*02 gene was used in 11 of 11 re-arrangements with an average homology of 92.2%. These data suggest that the highly restricted use of IGL V lambda 1 germlines plays an important role in the pathogenesis of POEMS syndrome.

Reactivation of Hepatitis B Virus in Hematopoietic Stem Cell Transplant Recipients in Japan: Efficacy of Nucleos(t)ide Analogues for Prevention and Treatment

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.

Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells

New strategies are needed to overcome the resistance of multiple myeloma (MM) to dexamethasone (Dex). Several recent in vitro studies demonstrated the antitumor effect of nitrogen‐containing amino‐bisphosphonates (N‐BPs) in various tumor cell lines. Inhibition of the prenylation of small G proteins is assumed to be one of the principal mechanisms by which N‐BPs exert their effects. There have been few reports on N‐BP treatment of MM cells that are resistant to Dex. Additionally, it is not known how small G proteins are altered in N‐BP‐treated MM cells. In this study, we evaluated the effect of the most potent N‐BP, zoledronate (ZOL), on a Dex‐resistant human MM cell subline (Dex‐R) that we established from the well‐documented RPMI8226 cell line. ZOL reduced the viability and induced apoptosis of Dex‐R cells. Some of the ZOL‐treated RPMI8226 cells and ZOL‐treated Dex‐R cells were elongated; however, elongated cells were not seen among the Dex‐treated RPMI8226 cells. Furthermore, we found that portions of the small G proteins, Rho and Rap1A, were unprenylated in the ZOL‐treated MM cells. Geranylgeraniol reduced the above‐mentioned ZOL‐induced effects. These findings suggest that ZOL may be beneficial for the treatment of Dex‐resistant MM by suppressing the processing of RhoA and Rap1A.

Identification of a novel TEL–Lyn fusion gene in primary myelofibrosis

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by an excessive production of blood cells by hematopoietic precursors and are often accompanied by myelofibrosis. The V617F somatic mutation in the Janus kinase 2 gene (JAK2) has recently been found in the majority of patients with polycythemia vera, in 60–70% of patients with essential thrombocythemia and in approximately 50% of patients with primary myelofibrosis (PMF). The expression of JAK2 V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow (BM) transplant model. In addition, a gain-of-function c-MPL W515 mutation was described in nearly 10% of patients with JAK2 V617F-negative PMF. However, the mechanism responsible for MPN and for the formation of myelofibrosis in patients without the JAK2 or c-MPL mutation is still unclear. The TEL gene is a member of the ets family transcription factor located on the 12p13 chromosome. It is well known that TEL forms fusion genes with more than 20 partner genes in hematological and even nonhematological malignancies. A major group of TEL fusion partners includes protein tyrosine kinases (PTK) and transcriptional factors such as RUNX1 (AML1) in childhood leukemia. The former group includes fusions of TEL to ABL, ARG, JAK2, NTRK3, FGFR3, PDGFR-a and Syk kinase, which have been found in MPN and other hematological malignancies. The most precisely defined mechanism of transformation by TEL–PTK fusion products is through a constitutive kinase activation by oligomerization of TEL–PTK mediated by the PNT domain of TEL in TEL–PTK chimeras. Lyn kinase is a specific member of the src family of kinases and is an important component in cytokine signal transduction in a variety of cells; it is also reported to have a key role in the growth and apoptotic regulation of hematopoietic cells. Donato et al. reported that Lyn kinase is highly expressed and activated in imatinib-resistant K562 cells and in samples from chronic myeloid leukemia patients who progressed to a blastic crisis or to an accelerated phase during imatinib treatment. In addition, Lyn is constitutively activated in acute myeloid leukemia and in BCR-ABL-positive acute lymphoblastic leukemia. However, there has been no report of the src family tyrosine kinase gene fusing to TEL and a possible association with MPN. In this study, we identified a novel TEL–Lyn fusion gene in PMF bearing the chromosomal abnormality ins (12;8)(p13;q11q21), and analyzed its mitogenic and clonogenic capacity. A 21-year-old man developed a huge abdominal mass, pain and high fever and was admitted to a hospital in November 2004. His physical examination revealed a huge splenomegaly reaching to his pelvic cavity. Laboratory findings disclosed

Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes

This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, −2–30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival.

Second cord blood transplantation (CBT) with reduced-intensity conditioning for graft failure after the first CBT for AML.

Second cord blood transplantation (CBT) with reduced-intensity conditioning for graft failure after the first CBT for AML

Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy

OBJECTIVE Bortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy. METHODS Threshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma. RESULTS In total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability, P<0.001; decreased depolarizing threshold electrotonus 90-100ms, P=0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment. CONCLUSIONS Bortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na(+)-K(+)-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria. SIGNIFICANCE Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.