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  • Overshoot of FVIII activity in patients with acquired hemophilia A who achieve complete remission
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-14
    Yoshiyuki Ogawa, Kunio Yanagisawa, Chiaki Naito, Hideki Uchiumi, Takuma Ishizaki, Hiroaki Shimizu, Fumito Gohda, Masahiro Ieko, Akitada Ichinose, Hiroshi Handa

    Abstract Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activity (median 2.1%; range < 1.0–8.9%) due to FVIII inhibition (median 14.7 BU/mL; range 2.0–234.0) and all achieved CR within a median of 39 (range 19–173) days. Overshoot occurred in 11 (64.7%) patients and maximal FVIII activity reached > 200% in six of them. The median duration from CR to overshoot was 13 (range 0–154) days. The FVIII overshoot was transient (72.7%) or persistent (27.3%). Venous thromboembolism developed as a complication of overshoot in one patient due to iliac vein compression by a massive hematoma. Overshoot of FVIII activity after CR occurs more frequently than previously expected in patients with AHA.

    更新日期:2020-01-14
  • Insignificance of surveillance imaging in patients with diffuse large B-cell lymphoma who achieved first complete remission: a retrospective cohort study
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-14
    Takanori Fukuta, Noriko Nishimura, Yuko Shirouchi, Norihito Inoue, Hideki Uryu, Yoshiharu Kusano, Yuko Mishima, Masahiro Yokoyama, Naoko Tsuyama, Kengo Takeuchi, Yasuhito Terui

    The aim of this study was to evaluate the value of scheduled imaging for patients who achieved first complete remission after CHOP-like chemotherapy plus rituximab. In this retrospective cohort study, we included 759 patients newly diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) at the Cancer Institute, Japanese Foundation for Cancer Research. Relapsed patients were divided into two groups based on method of diagnosis: clinical symptoms (symptom group, n = 57) or scheduled imaging (imaging group, n = 27). Our primary goal was to compare overall survival and relapse-free survival between the two groups. No significant difference in outcomes was found between the symptom and imaging groups. Median overall survival [7.5 years; 95% confidence interval (CI) 4.0–9.7 vs. 9.1 years; 95% CI 2.7 to not reached; P = 0.747), and median relapse-free survival (1.8 years; 95% CI 1.4–2.5 vs. 2.4 years; 95% CI 1.2–4.4; P = 0.108). Surveillance imaging in patients with DLBCL who achieved first complete remission did not demonstrate an advantage in terms of overall survival or relapse-free survival.

    更新日期:2020-01-14
  • Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-14
    Maryam Rassoulzadegan, Fereydoun Ala, Mohammad Jazebi, Mohammad Said Enayat, Shadi Tabibian, Mahmood Shams, Mehran Bahraini, Akbar Dorgalaleh

    Type 2 von Willebrand disease (VWD) is the most common congenital bleeding disorder, with variable bleeding tendency and a complex laboratory phenotype. In the current study, we report the clinical and molecular profile of a large number of Iranian patients with type 2 VWD. All exons, intron–exon boundaries, and untranslated regions were sequenced by Sanger sequencing for direct mutation detection. All identified mutations were confirmed in family members and by relevant bioinformatics studies. A total of 136 patients with type 2 VWD were diagnosed, including 42 (30.9%), 32 (23.6%), 38 (27.9%), and 24 (17.6%) patients with type 2A, type 2B, type 2M, and type 2N, respectively. Epistaxis (49%), gum bleeding (30.2%), ecchymosis (23.2%), and menorrhagia (16.3%) were the most common clinical presentations, while miscarriage (2.3%) and umbilical cord bleeding (0.8%) were the rarest. Thirty mutations were identified within the VWF gene, nine (30%) being novel, with p.Arg1379Cys (n = 20), p.Val1316Met (n = 13), p.Arg1597Trp (n = 13), p.Arg1374Cys (n = 10), p.Ser1506Leu (n = 10), and p.Arg1308Cys (n = 9) the most common. Type 2 VWD is a hemorrhagic disorder with variable bleeding tendency and a heterogeneous molecular basis in patients in Iran.

    更新日期:2020-01-14
  • Immunophenotypic analysis of cerebrospinal fluid reveals concurrent development of ATL in the CNS of a HAM/TSP patient
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-13
    Reina Takeda, Tomohiro Ishigaki, Nobuhiro Ohno, Kazuaki Yokoyama, Toyotaka Kawamata, Tomofusa Fukuyama, Natsumi Araya, Yoshihisa Yamano, Kaoru Uchimaru, Arinobu Tojo

    Abstract Both adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by HTLV-1, but concurrent development has been rarely reported. We present the case of a 55-year-old female who developed cranial nerve symptoms after a 20-year history of HAM/TSP. Although multiple white matter lesions were observed on brain magnetic resonance imaging, no abnormalities were seen on a systemic computed tomography scan. Quantitative flow-cytometric analysis of cell populations in the cerebrospinal fluid (CSF) revealed that most of the infiltrating cells were not inflammatory cells, but HTLV-1-infected CD4+ CADM-1+ T-cells completely lacking CD7 expression. As stepwise downregulation of CD7 is correlated with disease progression from HTLV-1 carrier to aggressive ATL, the CSF cells were classified as aggressive ATL; these cells exhibited a more progressed phenotype than those in peripheral blood (PB). HAM/TSP disease activity was estimated to be low. From these and other examinations, we made a diagnosis of acute-type ATL, which unusually developed in the central nervous system at initial onset prior to systemic progression. In ATL cases with a challenging diagnosis, immunophenotypic characterization of CSF and PB is valuable for differential diagnosis and understanding disease status.

    更新日期:2020-01-13
  • Hemophagocytic relapsed intramedullary plasmacytoma
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-03
    Tarek H. Mouhieddine, Bart Barlogie, Julie Teruya-Feldstein

    Abstract We report a case of a relapsed hemophagocytic intramedullary plasmacytoma, previously non-phagocytic, in conjunction with development of a new clone with different cytogenetic abnormalities forming a solitary plasmacytoma.

    更新日期:2020-01-04
  • Coagulation and fibrinolytic features in AL amyloidosis with abnormal bleeding and usefulness of tranexamic acid
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-03
    Masahisa Arahata, Hiroyuki Takamatsu, Eriko Morishita, Yasuko Kadohira, Shinya Yamada, Akitada Ichinose, Hidesaku Asakura

    Abnormal bleeding is sometimes observed in patients with immunoglobulin light chain (AL) amyloidosis. Although several theories have been proposed regarding the pathological causes of the bleeding tendency in AL amyloidosis, many lacked sufficient evidence and full consensus. We conducted a retrospective survey at a single institution to assess bleeding manifestations, methods for evaluating hematological abnormalities, and treatments for bleeding in patients with systemic AL amyloidosis over the past 13 years. The participants were 10 men and 14 women, aged 39–84 years (mean 65 years). The prevalence of bleeding was 29%. Prolonged prothrombin time (PT), elevated plasmin–α2-antiplasmin complex, and factor X deficiency were distinctive to the bleeding group. Two case studies showed that tranexamic acid was effective for treating this hematological condition. However, two patients with normal PT and activated partial thromboplastin time (APTT) also had a bleeding manifestation. The rates of administration of coagulation and fibrinolytic tests were relatively low in the non-bleeding group. Therefore, a close investigation concerning coagulation and fibrinolysis should be performed in every patient with AL amyloidosis regardless of the PT/APTT values. A more careful, comprehensive, and large-scale study is required to reinforce these findings.

    更新日期:2020-01-04
  • Cord blood infusion-accelerated hematopoietic recovery after combined immunosuppressive therapy with fludarabine and rabbit ATG in severe aplastic anemia
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-03
    Jieling Jiang, Yu Cai, Liping Wan, Jun Yang, Chun Wang

    Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine A (CsA) is currently the standard treatment for patients with severe aplastic anemia (SAA) who have no suitable donor or are ineligible for allogeneic stem cell transplantation. However, the delayed hematopoietic recovery, which accounts for most early deaths, remains a key problem. Thus, we designed an IST protocol with fludarabine, rabbit ATG, and CsA followed by unrelated cord blood (UCB) infusion to study whether hematopoiesis could be accelerated. Nineteen patients were enrolled in this study. The median neutrophil recovery time was 22 days and the treatment-related mortality within 3 months was 5.3%. The median platelet recovery time was 180 days. Six patients had transient or sustained UCB engraftment and the median platelet recovery time of these patients was significantly shorter than those who had no UCB engraftment (46 days vs 206 days, p = 0.006). The cumulative incidence of response rate at 12 months was up to 88.7% with CR rate of 72.2%. The overall survival at 2 years and 5 years was 94.7% and 78.9%, respectively. These results suggest that UCB infusion may play an important role in accelerating hematopoietic recovery in this protocol.

    更新日期:2020-01-04
  • High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-02
    Ken Takase, Hirokazu Nagai, Moe Kadono, Takanori Yoshioka, Nobuyuki Yoshio, Yukio Hirabayashi, Takuo Ito, Morio Sawamura, Akihiro Yokoyama, Shinichiro Yoshida, Ikuyo Tsutsumi, Maki Otsuka, Youko Suehiro, Michihiro Hidaka, Isao Yoshida, Hisayuki Yokoyama, Hitoshi Inoue, Hiroatsu Iida, Maki Nakayama, Terutoshi Hishita, Hiromi Iwasaki, Akiko Kada, Akiko M. Saito, Yoshiaki Kuroda

    There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18–80 years with platelet counts of < 20 × 109/l, or < 50 × 109/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7–77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.

    更新日期:2020-01-04
  • Correction to: Analysis of glutathione S -transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-11-26
    Seitaro Terakura, Makoto Onizuka, Mariko Fukumoto, Yachiyo Kuwatsuka, Akio Kohno, Yukiyasu Ozawa, Koichi Miyamura, Yuichiro Inagaki, Masashi Sawa, Yoshiko Atsuta, Ritsuro Suzuki, Tomoki Naoe, Yoshihisa Morishita, Makoto Murata

    In the original article of Terakura et al., the COI disclosure were missing.

    更新日期:2020-01-04
  • Advances in gene therapy for hemophilia: basis, current status, and future perspectives
    Int. J. Hematol. (IF 2.251) Pub Date : 2018-08-06
    Tsukasa Ohmori

    Abstract Hemophilia is a congenital hemorrhagic disease caused by genetic abnormalities in coagulation factor VIII or factor IX. Current conventional therapy to prevent bleeding requires frequent intravenous injections of coagulation factor concentrates from early childhood. Accordingly, gene therapy for hemophilia remains an exciting future prospect for patients and their families, due to its potential to cure the disease through a one-time treatment. After a series of successes in basic research, recent clinical trials have demonstrated clear efficacy of gene therapy for hemophilia using adeno-associated virus (AAV) vectors. Although this is likely to alter the paradigm of hemophilia care in the near future, it will be important to overcome immune responses against AAV. Gene therapy for hemophilia cannot be given to patients with anti-AAV capsid-neutralizing antibodies, and cellular immunity with CD8+ T cells should be controlled for sustained expression. Furthermore, long-term therapeutic effects should be closely observed because of the failure of the AAV vector genome to replicate during cell division. This review focuses on the basis of gene therapy, current successes of clinical trials, and the future direction of hemophilia gene therapy.

    更新日期:2020-01-04
  • Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity
    Int. J. Hematol. (IF 2.251) Pub Date : 2018-10-22
    Takehisa Kitazawa, Midori Shima

    Hemophilia A is a congenital disorder caused by deficiency or malfunction of coagulation factor (F) VIII. While exogenously provided FVIII effectively reduces bleeding complications in many hemophilia A patients, multiple efforts are underway to develop new drugs to meet the needs that conventional FVIII agents do not. We have been long engaged in creating and clinically developing a humanized anti-FIXa/FX asymmetric bispecific IgG antibody with a FVIIIa-cofactor activity. Since this project was born from a creative and unique idea, our group recognized from the first that it would face many difficulties in the course of research including establishment of industrial manufacturability of an asymmetric bispecific IgG antibody. The group actually faced various challenges, but addressed all of them during about 10 years of research, and successfully created the potent humanized bispecific antibody, emicizumab. Emicizumab has showed clinical benefits in the human trials among which the first one was started in 2012, and has been currently approved in US, EU, Japan, and some other countries. It is now expected to improve the quality of life of patients and their families. In this article, we review the course of the research and clinical development of emicizumab, and describe its molecular characteristics.

    更新日期:2020-01-04
  • Donor single nucleotide polymorphism in ACAT1 affects the incidence of graft-versus-host disease after bone marrow transplantation
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-26
    Sonoko Kamoshita, Makoto Murata, Daisuke Koyama, Jakrawadee Julamanee, Shingo Okuno, Erina Takagi, Kotaro Miyao, Tatsunori Goto, Yukiyasu Ozawa, Koichi Miyamura, Seitaro Terakura, Tetsuya Nishida, Hitoshi Kiyoi

    Abstract Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesteryl esters. A recent in vivo study reported that inhibiting ACAT1 enzyme activity upregulates the membrane cholesterol levels of T cells, enhancing their cytotoxic function. In the present study, we investigated whether the presence of the ACAT1 single nucleotide polymorphism rs11545566 in transplant donors affected the risk of graft-versus-host disease (GVHD) in 116 adult patients who underwent bone marrow transplantation from human leukocyte antigen-identical sibling donors, and who received GVHD prophylaxis with short-term methotrexate and cyclosporine. The frequencies of the AA, AG, and GG genotypes in the donors were 31%, 45%, and 24%, respectively. The cumulative incidences of grade II–IV acute GVHD on day 100 in patients whose donors had AA vs. non-AA genotypes were 6% and 18%, respectively, and those of extensive chronic GVHD at 2 years were 7% and 32%, respectively. Multivariate analyses demonstrated that donor rs11545566 non-AA genotypes showed a trend toward a higher incidence of grade II–IV acute GVHD (P = 0.079), and were significantly associated with a higher incidence of extensive chronic GVHD (P = 0.021). These results suggest that donor ACAT1 rs11545566 genotype may be predictive of GVHD.

    更新日期:2020-01-04
  • Genetic analysis of a compound heterozygous patient with congenital factor X deficiency and regular replacement therapy with a prothrombin complex concentrate
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-30
    Tomoki Togashi, Satomi Nagaya, Masayuki Nagasawa, Makiko Meguro-Horike, Keiji Nogami, Yuta Imai, Kana Kuzasa, Akiko Sekiya, Shin-ichi Horike, Hidesaku Asakura, Eriko Morishita

    Congenital factor X (FX) deficiency is a rare bleeding disorder with an incidence of one in one million. The proband, a 2-year-old girl, exhibited easy bruising and a history of umbilical cord bleeding at birth. Prothrombin time (> 40 s) and activated partial thromboplastin time (65.0 s) were prolonged. Marked declines in FX activity (< 1%) and FX antigen levels (5%) were also observed. Genetic analysis of the proband identified two types of single-base substitutions, c.353G>A (p.Gly118Asp) and c.1303G>A (p.Gly435Ser), indicating compound heterozygous congenital FX deficiency. Genetic analysis of family members revealed that her father and older sister (5-year-old) were also heterozygous for p.Gly118Asp, and that her mother was heterozygous for p.Gly435Ser. To improve the bleeding tendency, the proband received regular replacement of 500 units of PPSB-HT, a prothrombin complex concentrate (PCC). Following continued regular replacement of 500 units of PPSB-HT once per week, the proband has exhibited no bleeding tendencies and no new bruises have been observed. There are no previous report of the use of PPSB-HT for regular FX replacement. Regular replacement therapy with PPSB-HT may be an effective method for preventative control of bleeding tendencies in FX deficiency.

    更新日期:2020-01-04
  • Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia
    Int. J. Hematol. (IF 2.251) Pub Date : 2018-10-09
    Pratima Chowdary

    Novel approaches to the treatment of haemophilia are needed due to the limitations of the current standard of care, factor replacement therapy. Aspirations include lessening the treatment burden and effectively preventing joint damage. Treating haemophilia by restoring thrombin generation may be an effective approach. A promising target for restoring thrombin generation is tissue factor pathway inhibitor (TFPI), a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor-induced coagulation via factor Xa-dependent feedback inhibition of the tissue factor–factor VIIa complex. Inhibition of TFPI reverts the coagulation process to a more primitive state evolutionarily, whilst regulation by other natural inhibitors is preserved. An aptamer and three monoclonal antibodies directed against TFPI have been investigated in clinical trials. As well as improving thrombin generation in the range associated with mild haemophilia, anti-TFPI therapies have the advantage of subcutaneous administration. However, the therapeutic window needs to be defined along with the potential for complications due to the novel mechanism of action. This review provides an overview of TFPI, its role in normal coagulation, the rationale for TFPI inhibition, and a summary of anti-TFPI therapies, previously or currently in development.

    更新日期:2020-01-04
  • Analysis of glutathione S -transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-25
    Seitaro Terakura, Makoto Onizuka, Mariko Fukumoto, Yachiyo Kuwatsuka, Akio Kohno, Yukiyasu Ozawa, Koichi Miyamura, Yuichiro Inagaki, Masashi Sawa, Yoshiko Atsuta, Ritsuro Suzuki, Tomoki Naoe, Yoshihisa Morishita, Makoto Murata

    Abstract Sporadic incidence of veno-occlusive disease (VOD) continues to occur, despite achievement of recommended busulfan (BU) concentrations after real-time BU dose adjustment. To explore the potential influence of glutathione S-transferase (GST) and cytochrome P450 (CYP) genotypes on plasma BU concentration, subsequent VOD, and transplant outcome, we assessed the polymorphisms of multiple GST and CYP genes. Fifty-five patients were included (median age 38 years; range 21–67). Of these, 49 received dose-adjusted BU/CY therapy. Twenty-six patients received transplants from human leukocyte antigen-identical siblings, 26 from unrelated donors. The GSTA1*A/*A genotype was significantly associated with lower BU first-dose area under curve (AUC1st). We found that patients with higher AUC1st showed a significantly higher serum total bilirubin during the first month after transplantation, but this was not necessarily associated with subsequent development of VOD. We further analyzed a possible association of GST and CYP polymorphisms and VOD development, and found none of the polymorphisms investigated was associated with VOD incidence. Regarding transplant outcomes, GSTM1-positive patients showed lower relapse rates and better overall survival in multivariate analyses. These results suggest that a GSTM1-positive genotype in patients receiving BU/CY conditioning protects against relapse of hematological malignancies after allogeneic hematopoietic stem cell transplantation.

    更新日期:2020-01-04
  • Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-11-22
    Kazuko Kudo, Miho Maeda, Nobuhiro Suzuki, Hirokazu Kanegane, Shouichi Ohga, Eiichi Ishii, Yoko Shioda, Toshihiko Imamura, Shinsaku Imashuku, Yukiko Tsunematsu, Mikiya Endo, Akira Shimada, Yuuki Koga, Yoshiko Hashii, Maiko Noguchi, Masami Inoue, Ken Tabuchi, Akira Morimoto, The Histiocytosis study group of the Japanese Society of Pediatric Hematology/Oncology

    The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9–5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

    更新日期:2020-01-04
  • Impact of low-dose anti-thymocyte globulin on immune reconstitution after allogeneic hematopoietic cell transplantation
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-22
    Ayumu Ito, Shigehisa Kitano, Kinuko Tajima, Youngji Kim, Takashi Tanaka, Yoshihiro Inamoto, Sung-Won Kim, Noboru Yamamoto, Takahiro Fukuda, Shinichiro Okamoto

    Abstract How low-dose anti-thymocyte globulin (ATG) for prophylaxis of graft-versus-host disease (GVHD) influences immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HCT) remains incompletely understood. We prospectively enrolled 41 consecutive adult patients and conducted cytometry-based immunophenotyping for 12 months after allo-HCT. Rabbit ATG (Thymoglobulin) was administered at a median total dose of 1.75 mg/kg in 16 of the 41 patients. Compared with patients who did not receive ATG, those who did had a significantly smaller number of naïve T cells (especially CD4+ ) within three months after allo-HCT. No significant difference was observed between the two groups in the reconstitution of other T cells (effector, memory, Th1, Th2, Th17, Treg, and Tfh), B cells (transitional, naïve, memory, and plasmablast), NK cells (regulatory and cytolytic), or dendritic cells (myeloid and plasmacytoid). Patients with fewer CD4+ naïve T cells than the median count (7.60 cells/µL) at two months after allo-HCT developed chronic GVHD less frequently than those with CD4+ naïve T cells above the median count (2-year cumulative incidences were 0.31 and 0.53, respectively; p = 0.133). This pilot study suggests low-dose Thymoglobulin suppresses the recovery of naïve T cells after allo-HCT, which may contribute to a lower incidence of chronic GVHD.

    更新日期:2020-01-04
  • Nilotinib treatment induced large granular lymphocyte expansion and maintenance of longitudinal remission in a Philadelphia chromosome-positive acute lymphoblastic leukemia
    Int. J. Hematol. (IF 2.251) Pub Date : 2020-01-01
    Masao Hagihara, Jian Hua, Morihiro Inoue, Tomoyuki Uchida, Shiro Ide, Shin Ohara, Tomoiku Takaku

    It is well known that the second-generation tyrosine kinase inhibitor dasatinib evokes an immunological reaction as an off-target effect and induces large granular lymphocytes (LGLs) expansion in 30% of patients. However, LGLs expansion in nilotinib-treated patients is rare. We report the case of a 65-year-old patient with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) who showed LGLs expansion during nilotinib treatment. The patient achieved complete remission (CR) after multi-agent chemotherapy combined with dasatinib treatment. However, ALL relapsed in the central nervous system and bone marrow when treatment was interrupted due to interstitial pneumonia. Nilotinib treatment was subsequently started and the patient achieved second CR. Marked peripheral blood lymphocytosis emerged after the start of nilotinib treatment. CD8 + CD57 + cytotoxic T cells were predominantly expanded and showed strong cytocidal activity against K562 Ph-positive leukemia cells. These results suggest that similar to dasatinib, nilotinib can induce LGLs expansion, possibly contributing to long-term remission in patients with Ph-ALL.

    更新日期:2020-01-04
  • 更新日期:2019-11-01
  • 2019 Updated diagnostic criteria and disease severity classification for TAFRO syndrome.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Yasufumi Masaki,Hiroshi Kawabata,Kazue Takai,Norifumi Tsukamoto,Shino Fujimoto,Yasuhito Ishigaki,Nozomu Kurose,Katsuhiro Miura,Shigeo Nakamura,Sadao Aoki,

    更新日期:2019-11-01
  • Correction to: Analysis of glutathione S-transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Seitaro Terakura,Makoto Onizuka,Mariko Fukumoto,Yachiyo Kuwatsuka,Akio Kohno,Yukiyasu Ozawa,Koichi Miyamura,Yuichiro Inagaki,Masashi Sawa,Yoshiko Atsuta,Ritsuro Suzuki,Tomoki Naoe,Yoshihisa Morishita,Makoto Murata,

    In the original article of Terakura et al., the COI disclosure were missing.

    更新日期:2019-11-01
  • Analysis of glutathione S-transferase and cytochrome P450 gene polymorphism in recipients of dose-adjusted busulfan-cyclophosphamide conditioning.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-27
    Seitaro Terakura,Makoto Onizuka,Mariko Fukumoto,Yachiyo Kuwatsuka,Akio Kohno,Yukiyasu Ozawa,Koichi Miyamura,Yuichiro Inagaki,Masashi Sawa,Yoshiko Atsuta,Ritsuro Suzuki,Tomoki Naoe,Yoshihisa Morishita,Makoto Murata,

    Sporadic incidence of veno-occlusive disease (VOD) continues to occur, despite achievement of recommended busulfan (BU) concentrations after real-time BU dose adjustment. To explore the potential influence of glutathione S-transferase (GST) and cytochrome P450 (CYP) genotypes on plasma BU concentration, subsequent VOD, and transplant outcome, we assessed the polymorphisms of multiple GST and CYP genes. Fifty-five patients were included (median age 38 years; range 21-67). Of these, 49 received dose-adjusted BU/CY therapy. Twenty-six patients received transplants from human leukocyte antigen-identical siblings, 26 from unrelated donors. The GSTA1*A/*A genotype was significantly associated with lower BU first-dose area under curve (AUC1st). We found that patients with higher AUC1st showed a significantly higher serum total bilirubin during the first month after transplantation, but this was not necessarily associated with subsequent development of VOD. We further analyzed a possible association of GST and CYP polymorphisms and VOD development, and found none of the polymorphisms investigated was associated with VOD incidence. Regarding transplant outcomes, GSTM1-positive patients showed lower relapse rates and better overall survival in multivariate analyses. These results suggest that a GSTM1-positive genotype in patients receiving BU/CY conditioning protects against relapse of hematological malignancies after allogeneic hematopoietic stem cell transplantation.

    更新日期:2019-11-01
  • An overview of cytidine deaminases.
    Int. J. Hematol. (IF 2.251) Pub Date : 2006-05-25
    Naveenan Navaratnam,Rizwan Sarwar

    Enzymes that deaminate cytidine to uridine play an important role in a variety of pathways from bacteria to man. Ancestral members of this family were able to deaminate cytidine only in a mononucleotide or nucleoside context. Recently, a family of enzymes has been discovered with the ability to deaminate cytidines on RNA or DNA. The first member of this new family is APOBEC1, which deaminates apolipoprotein B messenger RNA to generate a premature stop codon. APOBEC1 has the conserved active site motif found in Escherichia coli cytidine deaminase. In addition, APOBEC1 has a unique motif containing 2 phenylalanine residues and an insert of 4 amino acid residues across the active site motif. This motif is present in APOBEC family members including activation-induced cytidine deaminase (AID), APOBEC2, and APOBEC3A through APOBEC3G. AID is essential for initiating class-switch recombination, somatic hypermutation, and gene conversion. The APOBEC3 family is unique to primates. APOBEC3G is able to protect cells from human immunodeficiency virus and other viral infections. This function is not unique to APOBEC3G; other APOBEC3 family members also have this ability. Overexpression of enzymes in this family can cause cancer, suggesting that the genes for the APOBEC family of proteins are proto-oncogenes. Recent advances in the understanding of the mechanism of action of this family are summarized in this review.

    更新日期:2019-11-01
  • Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Kazuko Kudo,Miho Maeda,Nobuhiro Suzuki,Hirokazu Kanegane,Shouichi Ohga,Eiichi Ishii,Yoko Shioda,Toshihiko Imamura,Shinsaku Imashuku,Yukiko Tsunematsu,Mikiya Endo,Akira Shimada,Yuuki Koga,Yoshiko Hashii,Maiko Noguchi,Masami Inoue,Ken Tabuchi,Akira Morimoto,

    The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

    更新日期:2019-11-01
  • Inotuzumab ozogamicin versus standard of care in Asian patients with relapsed/refractory acute lymphoblastic leukemia.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-28
    Naohito Fujishima,Toshiki Uchida,Yasushi Onishi,Chul Won Jung,Yeow Tee Goh,Kiyoshi Ando,Ming Chung Wang,Chiho Ono,Miyako Matsumizu,M Luisa Paccagnella,Barbara Sleight,Erik Vandendries,Yosuke Fujii,Masayuki Hino

    Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population.Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.

    更新日期:2019-11-01
  • Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-23
    Orly Leiva,Seng Kah Ng,Shinobu Matsuura,Vipul Chitalia,Hector Lucero,Alison Findlay,Craig Turner,Wolfgang Jarolimek,Katya Ravid

    Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that usually portends a poor prognosis with limited therapeutic options available. Currently, only allogeneic stem cell transplantation is curative in those who are candidates, while administration of the JAK1/2 inhibitor ruxolitinib carries a risk of worsening cytopenia. The limited therapeutic options available highlight the need for the development of novel treatments for PMF. Lysyl oxidase (LOX), an enzyme vital for collagen cross-linking and extracellular matrix stiffening, has been found to be upregulated in PMF. Herein, we evaluate two novel LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, in two animal models of PMF (GATA1low and JAK2V617F-mutated mice). Specifically, PXS-LOX_1 or vehicle was given to 15- to 16-week-old GATA1low mice via intraperitoneal injection at a dose of 15 mg/kg four times a week for 9 weeks. PXS-LOX_1 was found to significantly decrease the bone marrow fibrotic burden and megakaryocyte number compared to vehicle in both male and female GATA1low mice. Given these results, PXS-LOX_1 was then tested in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 30 mg/kg four times a week for 8 weeks. Again, we observed a significant decrease in bone marrow fibrotic burden. PXS-LOX_2, a LOX inhibitor with improved oral bioavailability, was next evaluated in 15- to 17-week-old JAK2V617F-mutated mice at a dose of 5 mg/kg p.o. four times a week for 8 weeks. This inhibitor also resulted in a significant decrease in bone marrow fibrosis, albeit with a more pronounced amelioration in female mice. Taking these results together, PXS-LOX_1 and PXS-LOX_2 appear to be promising new candidates for the treatment of fibrosis in PMF.

    更新日期:2019-11-01
  • Successful outcome with reduced-intensity condition regimen followed by allogeneic hematopoietic stem cell transplantation for relapsed or refractory anaplastic large-cell lymphoma.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-18
    Reiji Fukano,Tetsuya Mori,Naoto Fujita,Ryoji Kobayashi,Tetsuo Mitsui,Koji Kato,Ritsuro Suzuki,Junji Suzumiya,Takahiro Fukuda,Motohiro Shindo,Nobuo Maseki,Tatsu Shimoyama,Keiko Okada,Masami Inoue,Jiro Inagaki,Yoshiko Hashii,Atsushi Sato,Ken Tabuchi

    We report a retrospective analysis of 38 patients (age ≤ 30 years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72 months (range, 35-96 months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15 years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

    更新日期:2019-11-01
  • Idiopathic anaphylaxis and systemic mastocytosis.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-14
    Ivo M B Francischetti,Irina Maric

    更新日期:2019-11-01
  • Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-12
    Mai Nanya,Kimiko Yurugi,Itaru Kato,Hidefumi Hiramatsu,Hiroshi Kawabata,Tadakazu Kondo,Tomoki Iemura,Rie Hishida,Erika Shibutani,Keiko Matsui,Yoko Nakagawa,Norimi Niwa,Yasunari Kasai,Joseph M Roig,Yasuyuki Arai,Yasuo Miura,Akifumi Takaori-Kondo,Taira Maekawa,Hideyo Hirai

    Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

    更新日期:2019-11-01
  • TERT and JAK2 polymorphisms define genetic predisposition to myeloproliferative neoplasms in Japanese patients.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-02
    Masafumi Matsuguma,Toshiaki Yujiri,Kaoru Yamamoto,Yasuko Kajimura,Yoshihiro Tokunaga,Mayumi Tanaka,Yoshinori Tanaka,Yukinori Nakamura,Yukio Tanizawa

    Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are often characterized by specific somatic mutations in any of the three genes: JAK2, CALR, or MPL. A single nucleotide polymorphism (SNP), rs2736100, in the reverse transcriptase gene (TERT) and a germline JAK2 46/1 haplotype have been associated with MPNs in North American and European patients. We examined 201 Japanese MPN patients, including 52 with PV, 131 with ET, and 18 with PMF, as well as 366 control individuals for TERT rs2736100 and JAK2 rs10974944, a tagging SNP of the 46/1 haplotype. Furthermore, correlations between the JAK2 V617F allele burden at diagnosis and TERT rs2736100 or JAK2 rs10974944 were evaluated using a digital PCR assay for accurate quantitation. The JAK2 46/1 haplotype, but not the TERT rs2736100 SNP, was correlated to the JAK2 V617F mutant allele burden in JAK2 V617F-positive MPN patients. In conclusion, we demonstrated that both TERT rs2736100_C and JAK2 46/1 haplotype are predisposing factors for MPNs in Japanese patients. While TERT rs2736100_C tended to have a more general, non-specific effect on all MPNs, the JAK2 46/1 haplotype was essentially predisposed to the JAK2 V617F-positive MPNs.

    更新日期:2019-11-01
  • Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-29
    Jinchul Kim,Jisun Park,Yeonsook Moon,Suk Jin Choi,Joo Han Lim,Moon Hee Lee,Jinhyun Cho

    As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24 months after entering TFR phase was 55% [95% confidence interval (CI) 0.51-0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24 months after stopping TKI.

    更新日期:2019-11-01
  • Phase I study of graft-versus-host disease prophylaxis including bortezomib for allogeneic hematopoietic cell transplantation from unrelated donors with one or two HLA loci mismatches in Japanese patients.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-29
    Takahiko Nakane,Hiroshi Okamura,Yumi Tagaito,Shiro Koh,Takuro Yoshimura,Yosuke Makuuchi,Satoru Nanno,Mika Nakamae,Asao Hirose,Yasuhiro Nakashima,Hideo Koh,Masayuki Hino,Hirohisa Nakamae

    This phase I study was designed for graft-versus-host disease (GVHD) prophylaxis including bortezomib in allogeneic hematopoietic cell transplantation (allo-HCT) from human leukocyte antigen (HLA)-mismatched unrelated donors in Japanese patients. Patients were administered bortezomib on days 1, 4, and 7, with short-term methotrexate and tacrolimus. Three bortezomib dose levels were prepared (1.0, 1.3, and 1.5 mg/m2). A dose of 1.3 mg/m2 was planned for administration to the initial six patients, and was adjusted if dose-limiting toxicity developed. Five of six patients enrolled for the initial dose had bone marrow donors. Two cases had single-antigen and single-allele mismatches; four had single-antigen mismatch at the A, B, C, and/or DRB1 loci in the GVH direction. All patients achieved neutrophil engraftment and complete donor chimerism. Three patients developed grade II acute GVHD, and none developed grade III-IV GVHD or any dose-limiting toxicity attributable to bortezomib by day 100. Two patients developed late-onset acute GVHD, and two developed chronic GVHD, but all cases were manageable. All patients were alive without relapse after a median follow-up period of 52 months. The optimal dose of bortezomib was determined to be 1.3 mg/m2. Prophylaxis against GVHD using a regimen including bortezomib thus seems feasible for HLA-mismatched unrelated allo-HCT.

    更新日期:2019-11-01
  • Supportive care for hemostatic complications associated with pediatric leukemia: a national survey in Japan.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-29
    Shinya Osone,Keitaro Fukushima,Michihiro Yano,Mariko Kakazu,Hirozumi Sano,Yoko Kato,Yuichi Shinkoda,Kunihiro Shinoda,Naoko Mori,Souichi Adachi

    Optimal supportive care for disseminated intravascular coagulation (DIC) and hemostatic complications by asparaginase is indispensable for the successful treatment of pediatric leukemia. However, the situation regarding this type of care in Japan is unclear. We conducted a questionnaire-based survey at 155 institutions treating childhood leukemia in Japan. The questionnaire asked about the supportive care provided by each institution to acute leukemia patients with DIC and asparaginase-induced hemostatic alterations. Ninety-eight institutions responded. The most common diagnostic criteria for DIC were those established by the Japanese Ministry of Health and Welfare. Regardless of the etiology underlying DIC, recombinant human thrombomodulin and synthetic protease inhibitors were used as anticoagulation therapy by around 70% and 40% of institutions, respectively. Additionally, 92%, 93%, and 73% of institutions measured plasma antithrombin, fibrinogen, and D-dimer/fibrin degradation products, respectively, more than twice per week during induction therapy for acute lymphoblastic leukemia. Survey responses indicate that 95% and 24% of the institutions used antithrombin replacement and fresh-frozen plasma, respectively. Supportive care for DIC and/or asparaginase-induced hemostatic alterations at Japanese pediatric centers was intensive and differs markedly from protocols in other countries. The efficacy of supportive care should be evaluated prospectively in the setting of pediatric leukemia.

    更新日期:2019-11-01
  • Promyelocyte-like blasts in B-lymphoblastic leukemia of a 67-year-old male patient.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-27
    Yu Ma,Qing Leng,Yue Zhao,Endi Wang

    更新日期:2019-11-01
  • Evaluation of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in Japanese healthy donors: a prospective study.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-23
    Keijiro Sato,Ken Ishiyama,Go Aoki,Hiroyuki Maruyama,Noriaki Tsuji,Mikoto Tanabe,Yoshitaka Zaimoku,Hidehiro Sato,Hirohito Yamazaki,Masaki Yamaguchi,Akiyoshi Takami,Shinji Nakao

    A "biosimilar" is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.

    更新日期:2019-11-01
  • Cessation of nilotinib in patients with chronic myelogenous leukemia who have maintained deep molecular responses for 2 years: a multicenter phase 2 trial, stop nilotinib (NILSt).
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-21
    Koji Nagafuji,Itaru Matsumura,Takayuki Shimose,Tatsuya Kawaguchi,Junya Kuroda,Hirohisa Nakamae,Toshihiro Miyamoto,Norimitsu Kadowaki,Jun Ishikawa,Yutaka Imamura,Hirohito Yamazaki,Koichi Akashi,Yuzuru Kanakura

    The aim of this multicenter phase 2 trial, Stop Nilotinib (NILSt), was to examine the safety and efficacy of discontinuation of nilotinib in patients with chronic phase (CP)-chronic myelogenous leukemia (CML). Patients with CP-CML who had achieved molecular response (MR4.5) after initiation of imatinib or nilotinib therapy received consolidation therapy with nilotinib 300-400 mg twice daily for up to 24 months. Patients who maintained MR4.5 at 24 months of consolidation therapy proceeded to discontinuation of nilotinib. The study enrolled 149 patients; 112 patients proceeded to consolidation therapy with nilotinib; 90 patients maintained MR4.5 with consolidation therapy, and 87 proceeded to discontinuation of nilotinib. The treatment-free remission (TFR) (MR4.5) rate at both 1 and 3 years after discontinuation of nilotinib was the same, at 60.9% (90% CI 51.6-69.7). Among 34 patients with molecular relapse, nilotinib was resumed in 33 patients; all of them attained MR4.5. There was no significant association between molecular relapse and age, sex, Sokal score, previous interferon-α exposure, duration of tyrosine kinase inhibitors treatment, or trough concentration of nilotinib. With nilotinib, it might be possible to avoid prognostic factors for TFR that exist with imatinib discontinuation. Cessation of nilotinib after two years of consolidation was safe and feasible.Trial registration UMIN000007141.

    更新日期:2019-11-01
  • Cryoglobulinemic vasculitis with interruption of ibrutinib therapy for chronic lymphocytic leukemia (CLL).
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-09
    Nicholas Wright,Ensi Voshtina,Gemlyn George,Arun Singavi,Joshua Field

    Chronic lymphocytic leukemia (CLL) can trigger autoimmune phenomena, with immune thrombocytopenia (ITP) the most common presentation. Upon cessation of CLL therapy, including ibrutinib, autoimmune flares can occur. In a 68-year-old man with CLL, ibrutinib was held for 2 weeks prior to elective shoulder surgery. Eleven days after stopping therapy, he presented with a purpuric rash on his right hip, buttock, and lower extremities. He experienced two episodes of seizure activity while hospitalized. MRI brain demonstrated patchy areas of altered signal involving deep white matter and sub-cortical white matter structures concerning for cerebral vasculitis. Although there was no evidence of hemolysis, serum cold agglutinin titer was elevated at > 1:512 and cryoglobulin levels were positive at 36%. He was diagnosed with type I cryoglobulinemia and treated with rituximab, plasmapheresis, methylprednisolone, and ibrutinib was restarted. This regimen resolved his symptoms. A rare complication of CLL is the production of cryoglobulins, which can present at initial diagnosis or in relapsed disease. Our case demonstrates that the cessation of ibrutinib therapy, even for a short time, can precipitate complications. To our knowledge, we report the first case of a patient with well-controlled CLL who rapidly developed cryoglobulinemic vasculitis after stopping ibrutinib therapy.

    更新日期:2019-11-01
  • Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-09-02
    Takeshi Takahashi,Kensuke Usuki,Kosei Matsue,Hitoshi Ohno,Toru Sakura,Ryota Imanaka,Masato Murakami,Shoichi Ohwada,Taiga Takagi,Sakura Sakajiri

    FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective FLT3 inhibitor in Japanese patients (median age 65 years) with FLT3-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2-70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451-480 ms and 481-500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with FLT3-ITD R/R AML.

    更新日期:2019-11-01
  • Safety and pharmacokinetics of quizartinib in Japanese patients with relapsed or refractory acute myeloid leukemia in a phase 1 study.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-07-31
    Kensuke Usuki,Hiroshi Handa,Ilseung Choi,Takahiro Yamauchi,Hiroatsu Iida,Tomoko Hata,Shoichi Ohwada,Noriko Okudaira,Kota Nakamura,Sakura Sakajiri

    Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.Trial registration ClinicalTrials.gov identifier NCT02675478.

    更新日期:2019-11-01
  • Successful treatment with 2-chlorodeoxyadenosine of refractory pediatric Langerhans cell histiocytosis with initial involvement of the gastrointestinal tract.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-07-28
    Azusa Mayumi,Toshihiko Imamura,Kenichi Sakamoto,Takeshi Ota,Shinya Osone,Ikuya Usami,Hajime Hosoi

    Gastrointestinal (GI) tract involvement in Langerhans cell histiocytosis (LCH) is extremely rare. Langerhans cell histiocytosis with GI tract involvement (GI-LCH) is frequently associated with multi-system disease, and usually presents with severe systemic symptoms, such as protein-losing enteropathy (PLE). Although the GI tract is not included among the organs at risk, the prognosis of GI-LCH is poor, and no effective chemotherapeutic regimen has been identified. Here, we report an infant case of primary refractory GI-LCH with PLE that showed marked improvement in response to 2-chlorodeoxyadenosine (2-CdA) therapy with no severe adverse events, even under conditions of deteriorating general health. The present findings indicate that 2-CdA may be effective for refractory GI-LCH with PLE. Further studies are warranted to determine the optimal therapeutic strategies for GI-LCH with PLE.

    更新日期:2019-11-01
  • Progress in elucidation of molecular pathophysiology of myeloproliferative neoplasms and its application to therapeutic decisions.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Ruochen Jia,Robert Kralovics

    Myeloproliferative neoplasms (MPNs) are hematological diseases that are driven by somatic mutations in hematopoietic stem and progenitor cells. These mutations include JAK2, CALR and MPL mutations as the main disease drivers, mutations driving clonal expansion, and mutations that contribute to progression of chronic MPNs to myelodysplasia and acute leukemia. JAK-STAT pathway has played a central role in the disease pathogenesis of MPNs. Mutant JAK2, CALR or MPL constitutively activates JAK-STAT pathway independent of the cytokine regulation. Symptomatic management is the primary goal of MPN therapy in ET and low-risk PV patients. JAK2 inhibitors and interferon-α are the established therapies in MF and high-risk PV patients.

    更新日期:2019-11-01
  • Evaluation of clinical severity in patients with type 2N von Willebrand disease using microchip-based flow-chamber system.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Yuto Nakajima,Keiji Nogami,Koji Yada,Takeshi Kawamura,Kenichi Ogiwara,Shoko Furukawa,Naruto Shimonishi,Masahiro Takeyama,Midori Shima

    Type 2N von Willebrand disease (VWD) is characterized by impaired factor VIII (FVIII) binding to von Willebrand factor (VWF). Type 2N VWD patients generally exhibit mild bleeding tendency, but some exhibit a more severe hemorrhagic pattern. An assay for assessing hemostatic potential and predict clinical severity could significantly improve clinical management in these patients. We examined the relationship between bleeding score (BS) and the potential for thrombus formation in whole blood from type 2N VWD patients with various BS using rotational thromboelastometry (ROTEM) and microchip flow-chamber system (T-TAS®). Collagen-coated PL-chips, or thromboplastin- and collagen-coated AR-chips, were utilized in the T-TAS to assess platelet thrombus formation at high shear flow, or fibrin-rich platelet thrombus formation at low shear flow, respectively. Neither ROTEM nor the T-TAS using PL-chips reflected the BS. The AR-chip parameters in the T-TAS, however, were highly sensitive to different BS levels among these patients, despite similar FVIII/VWF-related measurements including FVIII/VWF binding. Additionally, the results with AR-chip assay were restored to normal after infusions of FVIII/VWF concentrates in the most severe patients. The data indicate that T-TAS using AR-chips may be a useful assay for predicting clinical severity and assessing therapeutic efficiency in type 2N VWD patients.

    更新日期:2019-11-01
  • A megakaryocyte in a peripheral blood smear.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-07
    Tokiko Nakai,Yasuyuki Okamoto

    更新日期:2019-11-01
  • High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Sung-Won Kim,Yoshitaka Asakura,Kinuko Tajima,Toshiki Iwai,Hirofumi Taji,Takaaki Chou,Yasuo Morishima,Junji Suzumiya,Hisashi Sakamaki,Ritsuro Suzuki,Takahiro Fukuda

    To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.

    更新日期:2019-11-01
  • The impact of overweight on renal toxicity in patients treated with dexamethasone, high-dose cytarabine, and cisplatin.
    Int. J. Hematol. (IF 2.251) Pub Date : null
    Kento Umino,Kaoru Hatano,Shin-Ichi Ochi,Harunobu Genda,Takashi Ikeda,Shin-Ichiro Kawaguchi,Yumiko Toda,Shoko Ito,Takashi Nagayama,Kiyomi Mashima,Daisuke Minakata,Hirofumi Nakano,Ryoko Yamasaki,Kaoru Morita,Chihiro Yamamoto,Masahiro Ashizawa,Kazuya Sato,Iekuni Oh,Shin-Ichiro Fujiwara,Ken Ohmine,Kazuo Muroi,Yoshinobu Kanda

    The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is used as salvage chemotherapy for relapsed or refractory lymphoma. It includes the administration of cisplatin in a single dose of 100 mg/m2, and renal toxicity is a common adverse event. In this study, we retrospectively analyzed the risk factors for renal toxicity (≥ grade 2) in 74 patients who received DHAP as salvage chemotherapy. Regarding maximal renal toxicities, 38 (51.4%), 6 (8.1%), and 1 (1.4%) patients had grade 2, 3, and 4 toxicities, respectively. Multivariate analyses revealed that overweight (body mass index ≥ 25) was an independent predictive factor for renal toxicity of ≥ grade 2 (odds ratio [OR] 4.08, P = 0.032). A subgroup analysis for patients with diffuse large B cell lymphoma treated with DHAP as second-line therapy (n = 44) confirmed that overweight was an independent risk factor (OR 5.28, P = 0.049). In conclusion, we demonstrated that overweight was an independent risk factor for renal toxicity of ≥ grade 2 in patients who received DHAP. Further clinical studies will be needed to identify a method to decrease renal toxicities after the administration of cisplatin.

    更新日期:2019-11-01
  • Intestinal thrombotic microangiopathy: a distinct entity in the spectrum of graft-versus-host disease.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-10-06
    Eleni Gavriilaki,Ioanna Sakellari,Ioanna Karafoulidou,Nikoleta Pasteli,Ioannis Batsis,Despina Mallouri,Andriana Lazaridou,Michalis Iskas,Anna Vardi,Apostolia Papalexandri,Aliki Tsompanakou,Styliani Papaemmanouil,Anastasios Ilias,Achilles Anagnostopoulos

    Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) with multisystem involvement. Cases of TMA in the intestinal vasculature (intestinal TMA/iTMA) have been reported. We hypothesized that iTMA is a distinct entity from TA-TMA. To test this hypothesis, we prospectively recruited allo-HCT recipients with an indication for endoscopy. Among 20 patients, histological features of iTMA, including loss of glands, total denudation of mucosa, apoptosis and detachment of endothelial cells, mucosal hemorrhage, intraluminal fibrin and microthrombi were found in six. Only 2/6 were classified as GVHD/TA-TMA, while the other 4 as GVHD/no TA-TMA. Gastro-intestinal symptoms were similar between the patients with or without iTMA. With a median follow-up of 11.1 (2.1-67.5) months, 1-year overall survival was 22.2% for iTMA, 55% for GVHD and 60% for TA-TMA. On multivariate analysis, independent unfavorable predictors of OS were iTMA (p = 0.048), HLA mismatched donors (p = 0.008) and gastro-intestinal bleeding (p = 0.021). In conclusion, iTMA emerges as a novel distinct entity in patients with GVHD and/or TA-TMA. Distinct histological features may be useful in differential diagnosis of these severe HCT complications. The higher mortality rates of iTMA than TA-TMA highlight the need for further investigation of this condition.

    更新日期:2019-11-01
  • Patterns of onset and outcome of cryptogenic organizing pneumonia after allogeneic hematopoietic stem cell transplantation.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-04-12
    Yoshitaka Adachi,Kazutaka Ozeki,Shun Ukai,Ken Sagou,Nobuaki Fukushima,Akio Kohno

    Cryptogenic organizing pneumonia (COP) after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by frequent recurrence. Few studies have examined onset and recurrence patterns of COP after HSCT. We investigated the clinical features of COP after HSCT in a single-center retrospective study including 165 consecutive patients who underwent allogeneic HSCT. Eighteen patients (11%) developed COP after HSCT. Hypoxemia and pleural effusion at the onset of COP were significantly associated with umbilical cord blood transplantation (P = 0.002 and P = 0.002, respectively). Recurrence of COP was observed in six patients and significantly associated with the presence of chronic graft-versus-host disease (cGVHD; P = 0.013) and stem cell sources other than umbilical cord blood (P = 0.038). Four patients with COP died of pulmonary failure after recurrence of COP. No patients who underwent umbilical cord blood transplantation experienced recurrence of COP. These findings suggest that the clinical features at the onset of COP may depend on stem cell sources. Moreover, both stem cell source and the absence or presence of cGVHD may affect COP recurrence, indicating the need to develop treatment strategies against COP according to stem cell source and risk of cGVHD.

    更新日期:2019-11-01
  • Evaluation of the safety and efficacy of daratumumab outside of clinical trials.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-04-10
    Hiroki Kobayashi,Takafumi Tsushima,Toshiki Terao,Yoshiaki Abe,Daisuke Miura,Kentaro Narita,Akihiro Kitadate,Masami Takeuchi,Kosei Matsue

    Daratumumab-based therapy has been shown to have significant clinical efficacy in phase 3 trials of patients with relapse or refractory multiple myeloma. Outside of clinical trials, however, clinical data on daratumumab remain limited. We reviewed medical records of patients who received daratumumab combination therapy at our institute (median age 74 years; median lines of prior therapy 4). The overall response rate was 69.4%, and 36.7% of patients achieved complete response (CR) or better. The proportion of patients who attained CR or better was significantly higher among patients with < 4 prior therapies than those with ≥ 4 (56.5% vs 19.2%, P = 0.009). Estimated median progression-free survival (PFS) was 12.4 months (95% confidence interval 8.6-not reached). The median PFS was significantly worse in patients who were refractory to bortezomib and lenalidomide and had received ≥ 4 lines of prior therapy. Twelve of 49 patients attained negative minimal residual disease. Common adverse events included hematological toxicities including neutropenia and lymphopenia; however, the rate of febrile neutropenia was low (3.8%). Infusion-related reactions occurred in 32.1% of patients, but were grade 1 or 2. Daratumumab combination therapies therefore appear to be effective and safe as salvage regimens in clinical practice, especially when used in the early phase.

    更新日期:2019-11-01
  • Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with hepatitis-associated aplastic anemia.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-04-10
    Takehiko Mori,Yasushi Onishi,Yukiyasu Ozawa,Chiaki Kato,Tatsuyuki Kai,Yoshinobu Kanda,Mineo Kurokawa,Masatsugu Tanaka,Takashi Ashida,Yasushi Sawayama,Takahiro Fukuda,Tatsuo Ichinohe,Yoshiko Atsuta,Hirohito Yamazaki

    Outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) for hepatitis-associated aplastic anemia have not been fully evaluated. In the present study, the outcomes of 37 adult patients with hepatitis-associated aplastic anemia who underwent allogeneic HSCT were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. The median age of the patients was 24 years (range, 16-61). The median period between diagnosis of hepatitis-associated aplastic anemia and HSCT was 6.0 months (range, 0.5-430.8). Stem cell sources were bone marrow (N = 19) or peripheral blood stem cells (N = 5) from an HLA-identical sibling or bone marrow (N = 11) and cord blood (N = 2) from an unrelated donor. The majority of conditioning regimens were fludarabine-based or high-dose cyclophosphamide-based. In all but 2 cases of early death, neutrophil engraftment was achieved. At the time of analysis, 32 patients were alive, with a median follow-up of 54.1 months. Five-year overall and failure-free survival rates were 86.0% (95% CI, 69.4-93.9%) and 75.0% (95% CI, 57.4-86.2%), respectively. Despite the heterogeneity in transplant procedures in a small number of patients, these results suggest that allogeneic HSCT is safe for use in hepatitis-associated aplastic anemia with a low rate of transplant-related mortality.

    更新日期:2019-11-01
  • Hemostatic assessment of combined anticoagulant therapy using warfarin and prothrombin complex concentrates in a case of severe protein C deficiency.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-04-10
    Kenichi Ogiwara,Keiji Nogami,Kuniyoshi Mizumachi,Takashi Nakagawa,Nozomi Noda,Shouichi Ohga,Midori Shima

    Patients with severe congenital protein (P)C deficiency require long-term anticoagulant management. Recombinant PC concentrates for prophylactic use are not available in Japan; prothrombin complex concentrates (PCC), containing factors (F)II, VII, IX, X, and PC (PPSB-HT®), have been used 'off-label' in a few patients. We investigated the combined use of prophylactic PCC and Warfarin (VKA; PT-INR 2.0-2.5) in a severely PC-deficient patient in whom VKA alone did not prevent recurrent purpura. Plasma VKA-dependent factor levels and global PC function (Thrombopath®) were assessed. Plasma activity levels of FII/FVII/FIX/FX post-infusion of PCC (6.3 unit/kg) increased 35/27/27/35 (initial level) to 59/60/38/83 IU/dl, respectively. FVII:C and FIX:C rapidly returned to baseline levels 12-24 h post-infusion, but FII:C and FX:C returned more slowly. PC antigen (< 5%) increased to ~ 15%, followed by return to baseline levels 24 h post-infusion. Global PC function was very low (%PiCi 24%), but improved post-PCC infusion. This potential was slightly detectable even at an undetectable PC level. At day 3, high levels of D-dimer and FDP were observed without thrombotic event, but these improved post-infusion. Although PCC restored VKA-dependent coagulation factors, PC contained in PCC significantly improved global anticoagulation, and was clinically beneficial in this severely deficient patient.

    更新日期:2019-11-01
  • Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-04-10
    Taiki Ando,Shin Fujisawa,Haruka Teshigawara,Eriko Ogusa,Yoshimi Ishii,Kazuho Miyashita,Kenji Motohashi,Takuya Miyazaki,Takayoshi Tachibana,Maki Hagihara,Kenji Matsumoto,Masatsugu Tanaka,Chizuko Hashimoto,Hideyuki Koharazawa,Katsumichi Fujimaki,Jun Taguchi,Hiroyuki Fujita,Heiwa Kanamori,Etsuko Yamazaki,Hideaki Nakajima,

    We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

    更新日期:2019-11-01
  • Comparison of valproate and levetiracetam for the prevention of busulfan-induced seizures in hematopoietic stem cell transplantation.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-03-28
    Toshihisa Nakashima,Takashi Tanaka,Keiichi Koido,Yukiko Nishibuchi,Hironobu Hashimoto,Ayumu Ito,Yoshihiro Inamoto,Saiko Kurosawa,Sung-Won Kim,Takahiro Fukuda,Hiroyuki Terakado

    Anticonvulsant administration is the standard of care for prevention of busulfan-induced seizures (BIS) in hematopoietic stem cell transplantation (HSCT). While valproate interacts with other drugs, including carbapenem antibiotics, levetiracetam has no known clinically significant interactions. Only a few reports have discussed the use of levetiracetam for the prevention of BIS in HSCT recipients. This retrospective study aimed to evaluate the efficacy and safety of valproate and levetiracetam for BIS prophylaxis in adult HSCT recipients. We identified patients who received valproate or levetiracetam to prevent BIS at the National Cancer Center Hospital from December 2015 to November 2017. Ninety-one patients were analyzed (valproate group 45; levetiracetam group 46). No BIS occurred in either group. The pattern of anticonvulsant-related adverse events was similar in both groups, except for a higher incidence of rash in the valproate group. Carbapenem antibiotics were more frequently used in the levetiracetam group than in the valproate group. In conclusion, valproate and levetiracetam are effective and safe for the prophylaxis of BIS. Levetiracetam may be more useful in patients colonized with extended-spectrum beta-lactamase-producing bacteria due to its lack of any clinically significant drug-drug interactions.

    更新日期:2019-11-01
  • A multicenter phase I study of inebilizumab, a humanized anti-CD19 monoclonal antibody, in Japanese patients with relapsed or refractory B-cell lymphoma and multiple myeloma.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-03-28
    Ken Ohmachi,Michinori Ogura,Youko Suehiro,Kiyoshi Ando,Toshiki Uchida,Ilseung Choi,Yoshiaki Ogawa,Miki Kobayashi,Koichi Fukino,Yuki Yokoi,Jun Okamura

    This multicenter, phase I, open-label dose escalation study evaluated safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of inebilizumab in Japanese patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or multiple myeloma (MM) who were ineligible for hematopoietic stem cell transplantation. Patients received inebilizumab 2, 4, or 8 mg/kg intravenously on days 1 and 8 of the first 28-day cycle, and once every 28 days thereafter, with a 12 mg/kg cohort added. Twenty patients (11 FL, six DLBCL, two CLL, and one MM) received inebilizumab at four dose levels (2 mg/kg cohort, n = 3; 4 mg/kg cohort, n = 7; 8 mg/kg cohort, n = 4; 12 mg/kg cohort, n = 6). Three patients experienced dose-limiting toxicities: grade 4 neutropenia/grade 3 leukopenia (n = 1, 12 mg/kg) and grade 3 infusion reaction (n = 1 each, 4 mg/kg and 12 mg/kg); the maximum tolerated dose was 8 mg/kg. Four (three FL and one DLBCL) patients achieved complete response; eight (six FL and two DLBCL) achieved partial response. Overall response rate was 60%. Over the dose ranges evaluated, the pharmacokinetic profile of inebilizumab in Japanese patients was generally dose proportional. This phase I study showed acceptable toxicity and preliminary and promising efficacy of inebilizumab in patients with relapsed/refractory FL and DLBCL.

    更新日期:2019-11-01
  • Effects of low-dose combined oral contraceptives and protein S K196E mutation on anticoagulation factors: a prospective observational study.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-03-21
    Takekazu Miyoshi,Hisato Oku,Saiko Asahara,Akira Okamoto,Koichi Kokame,Michikazu Nakai,Kunihiro Nishimura,Fumiyuki Otsuka,Aya Higashiyama,Jun Yoshimatsu,Toshiyuki Miyata

    The association between low-dose combined oral contraceptives (COCs) and anticoagulation factors in Japanese women has been rarely studied. A total of 394 Japanese women with a new beginning cycle of COC use were enrolled, of whom 335 women visited the clinic within 4 weeks after starting the first cycle of COC. Visits occurred in the active phase (272 women) and the placebo phase (63 women). Free protein S (PS) antigen and activity levels and antithrombin activity levels decreased significantly in both the active and placebo phase groups. Protein C (PC) activity levels increased significantly in both groups. Larger reductions in free PS antigen and activity levels occurred with COC comprising either 30 µg ethinylestradiol/desogestrel or 20 µg ethinylestradiol/drospirenone than that comprising 35 µg ethinylestradiol/norethisterone. In four women with the Japanese-specific PS K196E mutation, mean PS activity was 65% before COC use and 57% during COC use, indicating further decrease with COC use. In conclusion, decreased antigen and activity levels of PS and antithrombin and increased activity levels of PC were observed even during the first cycle of low-dose COC use. The effects on PS and PC activities were also observed in the hormone-free interval.

    更新日期:2019-11-01
  • Short-term clinical outcomes after HLA 1-locus mismatched uPBSCT are similar to that after HLA-matched uPBSCT and uBMT.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-03-17
    Shigeo Fuji,Koichi Miyamura,Yoshinobu Kanda,Takahiro Fukuda,Takeshi Kobayashi,Yukiyasu Ozawa,Koji Iwato,Naoyuki Uchida,Tetsuya Eto,Takashi Ashida,Takehiko Mori,Masashi Sawa,Tatsuo Ichinohe,Yoshiko Atsuta,Junya Kanda,

    In Japan, use of unrelated peripheral blood stem cell transplantation (uPBSCT) from HLA-mismatched unrelated donors has recently been approved. We compared outcomes between HLA-matched and 1-locus mismatched uPBSCT, as well as the impact of HLA disparity in uPBSCT and in unrelated bone marrow transplantation (uBMT). In total, 5862 uBMT recipients and 234 uPBSCT recipients were included. In terms of HLA allele disparity, 185 uPBSCT patients (79.1%) had no HLA mismatch, and 49 (20.9%) had 1-locus mismatch; in comparison, 3585 uBMT patients (61.2%) had no HLA mismatch, and 2277 (38.8%) had 1-locus mismatch. The impact of 1-locus mismatch as compared with match in uPBSCT was not significantly higher than in uBMT [hazard ratio (HR) = 1.02 and 1.27 for grade III-IV acute graft-versus-host disease, HR = 0.98 and 1.14 for non-relapse mortality, and HR = 0.87 and 1.06 for overall survival, respectively]. In conclusion, the impact of single-locus mismatch on short-term outcomes was comparable in uPBSCT and uBMT. Larger studies with longer follow-up are needed to assess long-term outcomes.

    更新日期:2019-11-01
  • Follicular lymphoma suggested to transform into EBV-negative plasmablastic lymphoma.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-03-13
    Toshiki Yamada,Takeshi Hara,Naoe Goto,Hitoshi Iwata,Hisashi Tsurumi

    Follicular lymphoma (FL) is an indolent lymphoma that often transforms into a high-grade lymphoma, mostly diffuse large B-cell lymphoma. A case of FL suggested to transform into plasmablastic lymphoma is presented. A 59-year-old man was admitted to our hospital because of right lower abdominal pain and vomiting. Computed tomography showed a mass in the ileocecum. Colonoscopy showed a mass with an ulcer in the ascending colon, and surgery was performed. Immunohistochemical staining of the biopsied mass showed infiltrated lymphocytes that were positive for CD38, CD45, CD138, and λ chain, and negative for CD4, CD5, CD8, CD10, CD20, CD56, and κ chain. Flow cytometric analysis of the ascites showed similar results. FISH analyses performed using lymph node biopsy specimens, ascite fluid and pleural effusion fluid identified the presence of an IGH/BCL2 translocation. FL was suggested to transform into PBL. Although the patient received three courses of R-CHOP chemotherapy and salvage chemotherapy, the patient died because of lymphoma progression less than 6 months after the diagnosis of PBL. Transformation of FL to PBL is highly unusual. The lack of a standard treatment for PBL results in the poor outcome of this entity. Novel therapeutic approaches are needed.

    更新日期:2019-11-01
  • Dasatinib for chronic myelogenous leukemia improves skin symptoms of systemic sclerosis.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-02-23
    Kosuke Arai,Kota Yoshifuji,Yotaro Motomura,Saeko Sonokawa,Sayaka Suzuki,Takashi Kumagai

    A 64-year-old man was diagnosed with limited cutaneous systemic sclerosis 5 years prior to this report. His sclerotic skin symptoms did not respond to oral low-dose prednisone (5-10 mg/day). Five years after the diagnosis, the patient presented with leukocytosis 3.8 × 109/L in a routine blood test, and was finally diagnosed with chronic-phase chronic myelogenous leukemia (CML). The leukemia responded optimally to initial dasatinib, and a complete cytogenetic response was achieved after 6 months of therapy. His skin symptoms dramatically improved in parallel with dasatinib therapy, as indicated by a decrease in the modified Rodnan skin score, from 12 points at diagnosis to 2 after 9 months. It has been reported that imatinib, a first-generation tyrosine kinase inhibitor, improves skin sclerosis in some patients with systemic sclerosis. To the best of our knowledge, this is the first report of simultaneous improvement of CML and limited cutaneous systemic sclerosis in response to dasatinib. Further study of the mechanism of action of dasatinib is crucial.

    更新日期:2019-11-01
  • Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-02-02
    Yusuke Yamashita,Akinori Nishikawa,Yoshifumi Iwahashi,Masakazu Fujimoto,Izumi Sasaki,Hiroyuki Mishima,Akira Kinoshita,Hiroaki Hemmi,Nobuo Kanazawa,Kouichi Ohshima,Ken-Ichi Imadome,Shin-Ichi Murata,Koh-Ichiro Yoshiura,Tsuneyasu Kaisho,Takashi Sonoki,Shinobu Tamura

    Aggressive natural killer cell leukemia (ANKL) is a rare neoplasm characterized by the systemic infiltration of Epstein-Barr virus (EBV)-associated NK cells, and rapidly progressive clinical course. We report the case of a 45-year-old man with intellectual disability who developed ANKL, and describe the identification of a novel genetic mutation of coiled-coil domain-containing 22 (CCDC22). He presented with persistent fever, severe pancytopenia, and hepatosplenomegary. Following bone marrow aspiration, numerous hemophagocytes were identified. High EBV viral load was detected in NK cells fractionation by qPCR. The initial diagnosis was EBV-related hemophagocytic lymphohistiocytosis (EBV-HLH). A combination of immunosuppressive drugs and chemotherapy was administered, but was unsuccessful in controlling the disease. Therefore, he was treated with HLA-matched related allogeneic hematopoietic stem cell transplantation. However, his condition deteriorated within 30 days, resulting in fatal outcome. Autopsy revealed many EBV-infected NK cells infiltrating major organs, consistent with ANKL. Furthermore, whole-exome sequencing identified a novel missense mutation of the CCDC22 gene (c.112G>A, p.V38M), responsible for X-linked intellectual disability (XLID). CCDC22 has been shown to play a role in NF-κB activation. Our case suggests that CCDC22 mutation might be implicated in pathogenesis of EBV-HLH and NK-cell neoplasms as well as XLID via possibly affecting NF-κB signaling.

    更新日期:2019-11-01
  • A case of double-refractory multiple myeloma with both the IgH-MMSET fusion protein and the congenital abnormality t(11;22).
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-01-27
    Rikio Suzuki,Takayuki Warita,Yoshihiko Nakamura,Yuka Kitamura,Yasuyuki Aoyama,Yoshiaki Ogawa,Hiroshi Kawada,Kiyoshi Ando

    A 67-year-old female was referred to our hospital with a sternal fracture in March 2008. She received a diagnosis of multiple myeloma (MM) BJP-κ type (ISS stage III). G-banding karyotype revealed 46, XX, t(11;22)(q23.3;q11.2) (Hubacek, Gene 592:193-9, 2016), which was later confirmed to be congenital. After repeated rounds of chemotherapy with bortezomib and lenalidomide, she obtained a very good partial response in August 2014, and she was followed up with no treatment. However, she relapsed in February 2016. At that time, fluorescence in situ hybridization identified del(13q) and t(4;14)(p16;q32), which are associated with a poor prognosis. Furthermore, PCR analysis showed that the chromosome 11 breakpoint was at the APOA5/APOA4 locus at 11q23.3, which is associated with malignancy, and that the chromosome 22 breakpoint was at the SEPT5 intron 1 locus, which also plays a role in leukemogenesis through formation of a fusion gene with MLL. Although she was treated with three further lines of therapy, she died from disease progression in August 2017. Synergism between t(11;22) and t(4;14) may have induced the double-refractory phenotype to proteasome inhibitor and lenalidomide, at least during the chemorefractory phase. We present a biological analysis of this case and a review of the literature.

    更新日期:2019-11-01
  • Clinicopathological features of TAFRO syndrome complicated by acquired hemophilia A and development of cardiopulmonary arrest that were successfully treated with VA-ECMO and tocilizumab.
    Int. J. Hematol. (IF 2.251) Pub Date : 2019-01-27
    Kei Suzuki,Takeshi Matsumoto,Yoshiaki Iwashita,Ken Ishikura,Masaki Fujioka,Hideo Wada,Naoyuki Katayama,Hiroshi Imai

    TAFRO syndrome and acquired hemophilia A (AHA) are rare, life-threatening diseases; however, the relationship between these two diseases is unknown. A 25-year-old man was transferred to our hospital because of bleeding tendency accompanied by multiple organ failure with generalized edema, massive pleural effusion, and ascites. He was diagnosed with AHA. Bypass therapy for hemostasis and cyclophosphamide with prednisolone to eradicate possible inhibitors were provided. However, he suffered from cardiopulmonary arrest. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated as rescue therapy. His hemodynamic status stabilized and he was weaned from VA-ECMO in 1 week. We confirmed normal FVIII activity and disappearance of the inhibitor, and bypass therapy was discontinued. However, generalized edema with massive ascites, pleural effusion, and renal insufficiency persisted. Bone marrow biopsy showed reticulin fibrosis. These symptoms fulfilled the diagnostic criteria of TAFRO syndrome. He received tocilizumab (TCZ) and steroid was tapered off. After four cycles of TCZ, symptoms of TAFRO syndrome gradually improved. To the best of our knowledge, this is the first report of TAFRO syndrome accompanied by AHA with rescue by VA-ECMO. Additionally, AHA and TAFRO syndrome were well controlled by TCZ.

    更新日期:2019-11-01
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