Rinsho Ketsueki
Online ISSN : 1882-0824
Print ISSN : 0485-1439
ISSN-L : 0485-1439
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Volume 57, Issue 6
Displaying 1-18 of 18 articles from this issue
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The 77th Annual Meeting of the Japanese Society of Hematology
Symposium 3
  • Current issues concerning drug development for pediatric hematologic malignancies
    Masahiro SEKIMIZU
    2016 Volume 57 Issue 6 Pages 693-700
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.693
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    Cure rates for pediatric hematologic malignancies (HM) have improved dramatically due to the intensive use of conventional chemotherapy and hematopoietic stem cell transplantation. However, many children still die of their disease or treatment-related toxicities. Even in patients experiencing an apparent cure, there can be significant acute and late complications of treatment. Further improvements of therapy will likely depend on the development of new therapeutic strategies. Immune-based therapy, for example monoclonal antibody-based and adoptive T-cell therapies, offers an attractive alternative that has emerged as a potent treatment strategy. Drug repositioning of molecular target drugs is now receiving remarkable attention, especially that based on recent genome wide studies. However, there are many obstacles to overcome in developing these novel drugs for pediatric patients. Pediatric drug development is difficult in itself because many of these agents are not profitable, largely due to their being too few patients, preclinical models are limited, there are too few formulations for children, special ethical considerations must be addressed when treating children and so on. Obstacles to the development of new drugs are a characteristic feature of pediatric HM. Furthermore, the approach to developing drugs for pharmaceutical approval is quite different from that to developing new therapies using approved drugs and is not well-known among investigators. Although many challenges remain in pediatric hematologic anticancer drug development, none are insurmountable.
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  • Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies
    Yozo NAKAZAWA
    2016 Volume 57 Issue 6 Pages 701-708
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.701
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    Chimeric antigen receptor (CAR) is the generic name for synthetic T cell receptors redirected to tumor-associated antigens. Most CARs consist of an ectodomain (scFv or ligand), a hinge region, a transmembrane domain, and signaling endodomains derived from one or two co-stimulatory molecules (CD28, 4-1BB, etc) and from a CD3-ζ chain. CD19-targeted CAR T cell therapy has achieved major success in the treatment of B cell malignancies. CD19 CAR-T cells elicited complete remission in 70-90% of adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). CD19 CAR T cell therapy from allogeneic donors including third party donors is a potential option for B-cell malignancies. CAR T cell therapies for myeloma, acute myeloid leukemia, and T-cell leukemia are still under development. Our group is currently preparing a phase I study of CD19 CAR T cell therapy in pediatric and young adult patients with ALL using a non-viral gene transfer method, the piggyBac-transposon system.
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  • A bispecific antibody mimicking factor VIII in hemophilia A therapy
    Keiji NOGAMI
    2016 Volume 57 Issue 6 Pages 709-714
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.709
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    Serious issues in current hemostatic treatment of hemophilia A are the requirement for frequent intravenous administrations of factor (F) VIII, FVIII inhibitor development, and hemostatic treatment for patients with this inhibitor. For the purpose of overcoming these challenges, the FVIIIa-substituting bispecific antibody against FIXa/FX (ACE910, INN emicizumab) was produced. Emicizumab demonstrated marked hemostatic effects on both ongoing and spontaneous joint bleeding in the acquired hemophilia A primate model. The clinical phase 1 study designed to assess the pharmacokinetics, pharmacodynamics and safety of emicizumab has been initiated. Severe emicizumab-related adverse events were minimal. The t1/2 was approximately 30 days, and bleeding events were significantly decreased by weekly subcutaneous administration in severe hemophilia A patients, independently of the presence of the inhibitor. Currently, the phase 1/2 extension study is ongoing. We anticipate that emicizumab will show the benefits of prophylactic efficacy with subcutaneous administration at a much lower frequency.
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Symposium 9
  • Significance of TET2 mutations in myeloid and lymphoid neoplasms
    Shigeru CHIBA
    2016 Volume 57 Issue 6 Pages 715-722
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.715
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    The TET2 gene is an epigenetic regulator. Loss-of-function mutations of TET2 are found in a variety of blood cancers in both myeloid and lymphoid lineages. Meanwhile, clonal blood cells carrying leukemia-driver mutations have been detected in significant proportions of different cohorts without blood cancers. Amongst these driver mutations, those in the TET2 gene are second/third most frequent. The presence of such clonal blood cells predicts elevated risk for developing various blood cancers. These results indicate that acquisition of TET2 mutations in blood cells does not per se cause cancers; however, TET2 mutations are likely to be acquired at the common myeloid/lymphoid progenitor levels. Such hematopoietic stem/progenitor cells may wait for second hit mutations for the development of multiple blood cancers, and play a role as pre-leukemia/pre-lymphoma cells. Combinations of TET2 and disease-specific gene mutations have been demonstrated in individual blood cancers. Correspondingly, mice into which such combinatorial gene abnormalities have been introduced will recapitulate the respective blood cancers.
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  • Clonal evolution in myelodysplastic syndromes
    Kenichi YOSHIDA
    2016 Volume 57 Issue 6 Pages 723-729
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.723
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    During the past ten years, genome-wide analysis of genetic alterations in myelodysplastic syndromes (MDS) has improved our understanding of their pathogenesis. Especially, single nucleotide polymorphism array karyotyping and next-generation sequencing technologies (NGS) have unveiled frequent genetic changes in novel functional pathways, including DNA methylation, RNA splicing and cohesin complex formation, in MDS. Moreover, NGS shed light on the clonal evolution which occurs during the development and progression of MDS, pre-cancerous lesions of MDS, and the effects of germline mutations in MDS.
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  • Genetic predisposition to pediatric myeloid malignancies
    Hideki MURAMATSU
    2016 Volume 57 Issue 6 Pages 730-735
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.730
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    Various genetic disorders are known to be associated with cancer predisposition. For example, children with Down syndrome are predisposed to developing acute myeloid leukemia, and those with RASopathies, such as Noonan syndrome, are predisposed to juvenile myelomonocytic leukemia. To date, more than 250 diseases or syndromes have been reported to be associated with the development of pediatric cancers. Recently, the advent of the massive parallel sequencing technique revealed several germline mutations, including RUNX1, CEBPA, GATA2, SRP72, ETV6, and DDX41, which are associated with familial myeloid malignancies. A significant number of children with myeloid malignancies may harbor pathognomonic germline variants. It is strongly recommended that precise diagnosis, genetic counseling, familial screening, and follow-up programs be provided for patients with such a predisposition to cancer. To identify genetic disorders associated with predispositions to pediatric myeloid malignancies, the development of an efficient screening system with the massive parallel sequencer for germline and somatic mutations, which would also be useful for familial genetic studies and prediction of tumor progression, is needed.
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Case Reports
  • Early diagnosis and successful treatment of disseminated toxoplasmosis after cord blood transplantation
    Taro KURIHARA, Masahiko SUMI, Hiroko KAIUME, Wataru TAKEDA, Takehiko K ...
    2016 Volume 57 Issue 6 Pages 736-741
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.736
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    A 66-year-old woman with refractory angioimmunoblastic T-cell lymphoma underwent cord blood transplantation. Prior to transplantation, a serological test for Toxoplasma gondii-specific IgG antibodies was positive. On day 96, she exhibited fever and dry cough. Chest CT showed diffuse centrilobular ground glass opacities in both lungs. The reactivation of T. gondii was identified by the presence of parasite DNA in peripheral blood and bronchoalveolar lavage fluid. Moreover, brain MRI revealed a space occupying lesion in the right occipital lobe. Therefore, disseminated toxoplasmosis was diagnosed. She received pyrimethamine and sulfadiazine from day 99. The lung and brain lesions both showed improvement but the PCR assay for T. gondii DNA in peripheral blood was positive on day 133. On day 146, she developed blurred vision and reduced visual acuity, and a tentative diagnosis of toxoplasmic retinochoroiditis was made based on ophthalmic examination results. As agranulocytosis developed on day 158, we decided to discontinue pyrimethamine and sulfadiazine and the treatment was thus switched to atovaquone. Moreover, we added spiramycin to atovaquone therapy from day 174, and her ocular condition gradually improved. In general, the prognosis of disseminated toxoplasmosis after hematopoietic stem cell transplantation (HSCT) is extremely poor. However, early diagnosis and treatment may contribute to improvement of the fundamentally dismal prognosis of disseminated toxoplasmosis after HSCT.
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  • Successful non-myeloablative allogenic bone marrow transplantation in a child with severe congenital neutropenia complicated by chronic pulmonary infection
    Nanako NINO, Aiko KOZAKI, Daiichiro HASEGAWA, Go UEDA, Hironobu TAKAHA ...
    2016 Volume 57 Issue 6 Pages 742-747
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.742
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    We herein describe a 2-year-old boy with severe congenital neutropenia (SCN) who was successfully treated with reduced-intensity bone marrow transplantation (HSCT). He had suffered recurrent episodes of bacterial pneumonia from 12 months of age, and was found to have severe neutropenia with white blood cell counts below 100/μl. The patient harbored a heterozygous missense mutation in ELANE exon 4 (p.Gln134Pro, NM_001972.2: c.401A>C). This was a novel mutation. Due to intractable pneumonia and severe persistent neutropenia, reduced-intensity HSCT was performed from an HLA-matched sibling donor. The preparative regimen consisted of melphalan, fludarabine, and 4 Gy of total body irradiation. Hematopoietic engraftment was rapidly obtained, i.e., by day +14, and complete donor chimerism was subsequently achieved. The lung complications observed pre-transplantation markedly improved after neutrophil recovery, i.e., by day +60. We concluded that HSCT is a useful treatment for SCN patients, especially for those at high risk of leukemic transformation. Fludarabine-based reduced-intensity HSCT may represent a safe and effective therapeutic option for patients with SCN who need HSCT even if they have intractable infectious complications.
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  • Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants
    Shunsuke KIMURA, Daisuke HASEGAWA, Yuri YOSHIMOTO, Shinsuke HIRABAYASH ...
    2016 Volume 57 Issue 6 Pages 748-753
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.748
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    Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.
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  • Spontaneous splenic rupture in a patient with light-chain deposition disease undergoing autologous peripheral blood stem cell transplantation
    Shojiro HAJI, Junichi KIYASU, Yoshimichi TACHIKAWA, Jiro TOYONAGA, Mot ...
    2016 Volume 57 Issue 6 Pages 754-759
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.754
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    Light-chain deposition disease (LCDD) is a rare plasma cell neoplasm that secretes an abnormal immunoglobulin light chain, which is deposited in tissues, leading to organ dysfunction. Spontaneous splenic rupture is a rare and life-threatening complication of treatment with granulocyte colony-stimulating factor (G-CSF). Herein, we describe spontaneous splenic rupture after the administration of lenograstim to a patient with LCDD undergoing autologous stem cell transplantation (ASCT). The patient was successfully treated by transcatheter embolization of the splenic artery, and long-term stringent complete remission was attained. Plasma cell neoplasms, including multiple myeloma with amyloidosis, are among the most commonly reported conditions associated with spontaneous splenic rupture in patients undergoing ASCT. This finding suggests that, in addition to the effect of G-CSF on the spleen, a combination of factors, including tissue vulnerability induced by the infiltration of abnormal immunoglobulins, may be involved in the pathogenesis of spontaneous splenic rupture. Notably, splenomegaly is not always evident in these patients. Surgical treatment may not be an option, because of severe myelosuppression, and thus less invasive treatment using transcatheter embolization may be feasible.
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  • Successful high-dose dexamethasone treatment of acquired pure red cell aplasia following ABO major mismatched allogeneic hematopoietic stem cell transplantation
    Yuki HIROSHIMA, Yousuke SHIONO, Ikuko SUZUKI, Masakazu YAMAMOTO, Yuich ...
    2016 Volume 57 Issue 6 Pages 760-764
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.760
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    A 46-year-old man was diagnosed with acute myelomonocytic leukemia involving inv(16)(p13.1q22) in August 2007. He received a human leukocyte antigen-identical, ABO major-mismatched (donor: A, recipient: O) bone marrow transplantation from an unrelated donor in June 2009. Cyclosporin A (CsA) and short-course methotrexate were used for graft versus host disease prophylaxis. Although granulocyte and platelet engraftment were achieved, the patient exhibited persistent anemia and was dependent on red blood cell (RBC) transfusions. Bone marrow aspiration on day 63 revealed the near absence of erythroid precursors, a finding consistent with pure red cell aplasia. No CBFβ-MYH11 transcripts were detected. The recipient's anti-A IgM antibody titer was 1:64, and his anti-A IgG antibody titer was 1:1024. The discontinuation of CsA, and the initiation of rituximab and donor lymphocyte infusions were all ineffective against his anemia. He was treated with high-dose dexamethasone (DEXA) (40 mg/day DEXA, days 657-660, days 757-760; 20 mg/day DEXA, days 764-767, days 772-775) in April 2010. A follow-up examination performed at 7 months after the high-dose DEXA treatment showed the patient's anti-A antibody titer to have dropped to an undetectable level. His hemoglobin levels also returned to normal (Hb: 13.4 g/dl), and he no longer required RBC transfusions.
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  • Severe stomatitis and ileocecal perforation developed after all-trans retinoic acid monotherapy in an HLA-B51-positive patient with acute promyelocytic leukemia
    Kenji KIMURA, Masahiro TAKEUCHI, Nagisa HASEGAWA, Emi TOGASAKI, Ryoh S ...
    2016 Volume 57 Issue 6 Pages 765-770
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.765
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    A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51.
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Short Reports
  • Repeated rituximab-induced serum sickness with anaphylaxis
    Atsushi ISODA, Tetsuya ISHIKAWA, Naru SATO, Yuri MIYAZAWA, Morio MATSU ...
    2016 Volume 57 Issue 6 Pages 771-773
    Published: 2016
    Released on J-STAGE: July 06, 2016
    DOIhttps://doi.org/10.11406/rinketsu.57.771
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    We describe a patient who developed repeated rituximab-induced serum sickness (RISS) followed by anaphylaxis soon after the third administration of rituximab at relapse. A 65-year-old woman with Sjögren's syndrome and relapsed mucosal associated lymphoma tissue (MALT) lymphoma of the lung underwent rituximab monotherapy (375 mg/m2/week). Several days after the second exposure to rituximab, she developed a rash, fever, and arthralgia. These symptoms showed relief, but a severe anaphylactic reaction occurred when she was treated with rituximab for the third time. Although a rare complication in patients with lymphoma, clinicians should be aware of RISS symptoms and avoid repeatedly administering rituximab to such patients.
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