Publications by authors named "Kinuko Mitani"

121 Publications

Essential thrombocythaemia with aggressive megakaryocytosis after myelofibrotic transformation.

Hematology 2021 Dec;26(1):594-600

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan.

Background: Among myeloproliferative neoplasms, it is often difficult to distinguish essential thrombocythaemia (ET) from prefibrotic-stage primary myelofibrosis (PMF) with thrombocytosis given their overlapping clinicopathological phenotypes.

Case Presentation: We encountered a 45-year-old male who was initially diagnosed with ET and eventually became transformed to secondary myelofibrosis 20 years later. Two distinct types of aberrant megakaryocytes were observed at diagnosis: one type characteristic of ET and the other type characteristic of PMF. With a proliferation in the bone marrow, aberrant megakaryocytes were infiltrated into the extramedullary organs and were even present in the thrombus were observed at autopsy. As a result of next-generation sequencing, the significant increase of variant allele frequency (VAF) of V617F and S34Y mutations was observed in the bone marrow cells at the final stage.

Conclusions: This patient could be recognized as an atypical case of aggressive megakaryocytosis transformed from ET.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/16078454.2021.1965714DOI Listing
December 2021

A case report of secondary neurolymphomatosis showing selective nerve infiltration and massive lumbar plexus enlargement.

BMC Neurol 2021 Jul 27;21(1):296. Epub 2021 Jul 27.

Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, 321-0293, Japan.

Background: Neurolymphomatosis (NL) is a rare manifestation of malignant lymphoma that shows selective infiltration to the peripheral nervous system primarily or secondarily. We report a patient with secondary NL caused by germinal center B-cell (GCB)-type diffuse large B-cell lymphoma (DLBCL) who showed selective infiltration of the lumbar plexus to the spinal cord and massive nerve enlargement resulting in severe pain.

Case Presentation: A 72-year-old female exhibited asymmetric motor and sensory impairments and pain in the lower limbs that progressed for five months. Magnetic resonance imaging (MRI) showed an enlarged lumbar plexus, which continued to the cauda equina via the L3 and L4 spinal nerves. Her symptoms gradually worsened. Ten months after the onset of symptoms, the enlarged cauda equina filled the spinal canal space, and the spinal cord was swollen. A cauda equina biopsy was performed, and she was diagnosed with GCB-type DLBCL with CD10 positivity. The primary tumor was found in a mammary cyst. The autopsy study did not show apparent infiltration, except in the nervous system.

Conclusions: Although there are many neurologic phenotypes of malignant lymphoma, the association between the cytological characteristics of lymphoma and the neurological phenotypes is still unclear. Several reports of CD10-positive secondary NL are available, whereas peripheral or central nervous tissue origin lymphoma cases are mostly negative for CD10. CD10 staining may be useful for distinguishing primary NL from secondary NL. NL often has a strong organotropism for peripheral nervous tissue, which makes early diagnosis challenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-021-02330-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314556PMC
July 2021

Allo-anti-M: Detection peaks around 2 years of age, but may be attenuated by red blood cell transfusion.

Transfusion 2021 Sep 21;61(9):2718-2726. Epub 2021 Jul 21.

Japan Society of Blood Transfusion and Cell Therapy, Tokyo, Japan.

Background: Anti-M is frequently observed as a naturally occurring antibody of little clinical significance. Naturally occurring anti-M is often found in children although the specific triggers of production, persistence, and evanescence of anti-M have yet to be elucidated.

Methods: In a retrospective, multicenter, nationwide cohort survey conducted from 2001 to 2015, alloantibody screening was performed before and after transfusion in 18,944 recipients younger than 20 years. Recipients were categorized into six cohorts based on their age at transfusion; within and among these cohorts, allo-anti-M was analyzed in regard to its production, persistence, and evanescence.

Results: In 44 patients, anti-M detected before and/or after transfusion was an age-related phenomenon, with a median age of 2 years and an interquartile range of 1-3 years; anti-M was most frequently detected in a cohort of children 1 to <5 years (0.77%, 31 of 4035). At least five patients were presumed to have concurrent infections. Among 1575 adolescents/young adults (15 to <20 years), no anti-M was detected. Of 29 patients with anti-M prior to transfusion, the antibody fell to undetectable levels in 17 recipients (89.5%, of whom at least 13 received only M-negative red cells) after anywhere from 5 days to 5.8 years; anti-M persisted in 2, and was not tested in 10. Only 15 recipients (0.08%) produced new anti-M after transfusion.

Conclusion: Naturally occurring anti-M is a phenomenon of younger ages, predominantly between 1 and 3 years. After transfusion, it often falls to undetectable levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16594DOI Listing
September 2021

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Nat Commun 2021 05 14;12(1):2833. Epub 2021 May 14.

Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23097-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121838PMC
May 2021

Clonal hematopoiesis in adult pure red cell aplasia.

Sci Rep 2021 01 26;11(1):2253. Epub 2021 Jan 26.

Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-81890-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838416PMC
January 2021

Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.

Int J Hematol 2021 Jun 5;113(6):936-940. Epub 2021 Jan 5.

Department of Hematology and Oncology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.

Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-03074-7DOI Listing
June 2021

Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.

Br J Haematol 2021 01 5;192(1):190-199. Epub 2020 Nov 5.

Division of Transfusion Medicine, Kanazawa University Hospital, Kanazawa, Japan.

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 10 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821109PMC
January 2021

The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells.

Nat Commun 2020 09 17;11(1):4681. Epub 2020 Sep 17.

Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, #C-504, 145, Gwanggyo-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16229, Republic of Korea.

Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/β-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18491-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499193PMC
September 2020

Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.

Ann Hematol 2020 May 4;99(5):1063-1072. Epub 2020 Apr 4.

Higashi Nagoya National Hospital, Nagoya, Japan.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-03988-6DOI Listing
May 2020

[Effective treatment of POEMS syndrome accompanied by plasmacytoma with lenalidomide, dexamethasone, and local irradiation].

Rinsho Ketsueki 2020 ;61(3):262-267

Department of Hematology and Oncology, Dokkyo Medical University Hospital.

A 70-year-old woman experienced pain in both gastrocnemius muscles, numbness in the toes, and muscle weakness in both the legs that lasted for two months. After getting admitted to our hospital, the muscle weakness extended to both her arms, and nerve conduction studies revealed decreased nerve conduction velocity, which was more prominent in the elbow and the axilla than in the wrist. A magnetic resonance imaging revealed a tumor in the right femoral neck, which was histologically diagnosed as plasmacytoma. Laboratory findings revealed IgA lambda type M protein and an elevated VEGF level of 2,320 pg/ml; edema was present in both the legs. After a diagnosis of POEMS syndrome, lenalidomide and dexamethasone treatment were initiated simultaneously, along with irradiation. The treatment improved polyneuropathy, along with a decrease in the VEGF level. Increased vascular permeability due to elevated VEGF led to the development of neuropathy of POEMS syndrome, and treatment against proliferating monoclonal plasma cells is effective. In the present case, we believe that a prompt control of the plasmacytoma with novel therapeutic agents for myeloma with irradiation resulted in the improvement of the neurological symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.262DOI Listing
May 2020

Serum ferritin levels at diagnosis predict prognosis in patients with low blast count myelodysplastic syndromes.

Int J Hematol 2019 Nov 29;110(5):533-542. Epub 2019 Jul 29.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Serum ferritin, a marker of systemic iron status, is considered a prognostic factor for patients with myelodysplastic syndromes (MDS), despite the lack of supporting evidence. We investigated the association between serum ferritin levels at diagnosis and the prognoses of Japanese MDS patients with bone marrow blasts < 5% and peripheral blood blasts < 2%. Three hundred and ninety patients with cytopenia were registered prospectively in the multicenter database, among whom 107 patients with MDS (72 males and 35 females, with a median age of 70 years) met the eligibility criteria. The median serum ferritin level at diagnosis was 204 ng/mL; we divided the cohort into low (n = 56) and high (n = 51) ferritin groups using a cutoff of 210 ng/mL. Kaplan-Meier analyses revealed that the 3-year overall survival (OS) of the high ferritin group was significantly shorter than that of the low ferritin group (66% and 79%, respectively). The cumulative incidences of leukemic progression were similar between the groups. On multivariate analysis, age, blast percentage, cytogenetic abnormalities, and serum ferritin levels at diagnosis were independently associated with OS in our patients. Thus, modest elevations of ferritin levels at diagnosis may influence the prognoses of patients with MDS who have low blast counts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02710-1DOI Listing
November 2019

[Ⅰ.Myelodysplastic Syndromes].

Gan To Kagaku Ryoho 2019 May;46(5):862-867

Dept. of Hematology and Oncology, Dokkyo Medical University.

View Article and Find Full Text PDF

Download full-text PDF

Source
May 2019

[Acquired hemophilia A requiring plasma exchange and mechanical ventilation].

Rinsho Ketsueki 2019 ;60(3):191-196

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine.

A 56-year-old man who sustained a right waist injury 1 month ago, reported to our department complaining of pain in the right waist and femur for 1 day. In a computed tomography examination, hematoma of the right iliopsoas muscle was revealed, and arterial embolization was immediately performed but was not effective. Laboratory findings showed hemoglobin levels as 5.4 g/dl, platelet of 20.2×10/µl, prothrombine time of 13.1 s, partial thromboplastin time (APTT) of 81.1 s, and a convex upward curve of the APTT cross-mixing test. The activity of the coagulation factor VIII was <1.0%, but its amount was 120%, and the level of factor VIII inhibitor was 130 Bethesda Unit/ml. Disseminated intravascular coagulation was not noted. Under the diagnosis of acquired hemophilia A, treatment with prednisolone and recombinant activated factor VII was initiated. However, APTT remained prolonged, and intubation and mechanical ventilation were required because of right hemothorax. After steroid pulse therapy and plasma exchange, APTT returned to its normal range, and the inhibitor disappeared. Thus, we finally succeeded in extubation. This case indicated that intensive care may be necessary in the early phase treatment for acquired hemophilia A.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.60.191DOI Listing
August 2019

RUNX1-EVI1 induces dysplastic hematopoiesis and acute leukemia of the megakaryocytic lineage in mice.

Leuk Res 2018 11 26;74:14-20. Epub 2018 Sep 26.

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Tochigi, Japan. Electronic address:

The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1-expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2018.09.015DOI Listing
November 2018

Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan.

Haematologica 2018 11 5;103(11):1835-1842. Epub 2018 Jul 5.

Department of Hematology and Oncology, Japanese Red Cross Narita Hospital.

The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response ( ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4-78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 48.6%, respectively; =0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.194894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278957PMC
November 2018

Interobserver concordance of assessments of dysplasia and blast counts for the diagnosis of patients with cytopenia: From the Japanese central review study.

Leuk Res 2018 11 7;74:137-143. Epub 2018 Jun 7.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The diagnosis of myelodysplastic syndromes (MDS) is based on morphology and cytogenetics. However, limited information is currently available on the interobserver concordance of the assessment of dysplastic lineages (<10% or ≥10% in bone marrow (BM)). The revised International Prognostic Scoring System (IPSS-R) described a new threshold (2%) for BM blasts. However, the interobserver concordance of the categories (0-≤2% and >2-<5%) has limited data. The purpose of the present study was to investigate the assessment of dysplastic lineages and IPSS-R reproducibility. Our study was divided into two Steps. In each Step, the microscopic examinations were performed separately by two morphologists. Regarding the category of BM blasts ≤2% and >2-<5%, interobserver agreement was more than 'moderate' in all pairs (kappa test: 0.43-0.90). Regarding dysgranulopoiesis (dysG) and dyserythropoiesis (dysE) in BM, interobserver agreement was more than 'moderate' in all pairs (kappa test, dysG: 0.45-0.96, dysE: 0.45-0.81). Regarding the category of dysmegakaryopoiesis (dysMgk) in BM, interobserver agreement was more than moderate in 4 out of 5 pairs (kappa test: 0.58-1.00), and was fair for one pair (kappa test: 0.37). We consider that high interobserver concordance may be possible for the BM blast cell count (≤2% or >2-<5%) and dysplasia (<10% or ≥10%) of each lineage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2018.06.003DOI Listing
November 2018

Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan.

Int J Hematol 2018 Aug 30;108(2):176-183. Epub 2018 Apr 30.

Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.

The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR, BCR-ABL1 ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1 ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR increased over time. The rates of MR in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7-36.8%)] and 44.6% [90% CI (34.7-54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-018-2459-6DOI Listing
August 2018

Validation of the revised International Prognostic Scoring System in patients with myelodysplastic syndrome in Japan: results from a prospective multicenter registry.

Int J Hematol 2017 Sep 11;106(3):375-384. Epub 2017 May 11.

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes has been conducting prospective registration, central review, and follow-up study for patients with aplastic anemia and myelodysplastic syndrome (MDS) since 2006. Using this database, we retrospectively analyzed the prognosis of patients with MDS. As of May 2016, 351 cases were registered in this database, 186 of which were eligible for the present study. Kaplan-Meier analysis showed that overall survival (OS) curves of the five risk categories stipulated by the revised international prognostic scoring system (IPSS-R) were reasonably separated. 2-year OS rates for the very low-, low-, intermediate-, high-, and very high-risk categories were 95, 89, 79, 35, and 12%, respectively. In the same categories, incidence of leukemic transformation at 2 years was 0, 10, 8, 56, and 40%, respectively. Multivariate analysis revealed that male sex, low platelet counts, increased blast percentage (>2%), and high-risk karyotype abnormalities were independent risk factors for poor OS. Based on these data, we classified Japanese MDS patients who were classified as intermediate-risk in IPSS-R, into the lower risk MDS category, highlighting the need for careful assessment of treatments within low- and high-risk treatment protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-017-2250-0DOI Listing
September 2017

ALK-negative anaplastic large cell lymphoma with loss of CD30 expression during treatment with brentuximab vedotin.

Rinsho Ketsueki 2016 05;57(5):634-7

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine.

A 59-year-old woman with anaplastic large cell lymphoma (ALCL), ALK-negative, was treated with brentuximab vedotin (BV) against relapse after 6 regimens of systemic chemotherapy and radiation. Despite achieving an initial response, skin lesions worsened after 11 courses. A skin biopsy after the development of resistance to BV confirmed loss of CD30 expression by the tumor cells, suggesting a possible cause of resistance. This case shows that down-regulation of CD30 does occur during BV treatment, resulting in resistance to this drug. Because of this possibility, in the future, expression of CD30 should be carefully monitored with extended use of BV against ALCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.57.634DOI Listing
May 2016

Prognostic significance of Wilms tumor 1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes.

Cancer Biomark 2016 Mar;17(1):21-32

Japanese Association of Medical Sciences, Tokyo, Japan.

Background: This present study was designed to follow up 82 patients among 115 MDS patients registered in study ODK-0801 for 5 years, to analyze the relationship between the WT1 mRNA expression level and prognosis.

Objective: This study aimed to investigate the clinical utility of WT1 mRNA expression levels.

Methods: After study ODK-0801, we investigated the conditions of the same patients once a year, including any clinical and laboratory findings supporting the diagnosis, and treatment among the living patients.

Results: When we assessed the survival time of 82 MDS patients by WT1 mRNA expression level, there were significant differences between the < 500 and ≥ 104 copies/μ g RNA groups and between the 500-104 and ≥ 104 copies/μ g RNA groups for BM levels (p < 0.01). Examination of the time of freedom from acute myeloid eukemia (AML) transformation indicated that a high WT1 mRNA expression level (> 104 copies/μ g RNA) was a strong prognostic factor for a short time to AML transformation.

Conclusion: The results indicate that the tumorigenesis of MDS is likely to originate at the stem cell level, suggesting that the WT1 mRNA level measurement in the BM is an effective prognostic marker in patients with MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/CBM-160612DOI Listing
March 2016

[Systemic organ invasion accompanied by immunophenotypic change observed in extraosseous plasmacytoma].

Rinsho Ketsueki 2016 Jan;57(1):56-9

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine.

We report a 57-year-old man who was diagnosed based on morphological findings as having extraosseous plasmacytoma of the left lower eyelid. Tumor cells were positive not only for CD38 and CD138, but also for CD19 and surface immunoglobulin lambda chain. He obtained a complete remission with irradiation and VAD therapy, but the disease relapsed one year later in the testis and popliteal fossa. Because tumor cells appeared to be blastoid, CHOP therapy was administered, and the patient achieved a temporary remission. Cytoplasmic lambda chain-positive and CD19-negative tumors eventually recurred at multiple sites including the central nervous system but not in the bone marrow. Treatment with the BD regimen and lenalidomide failed, and he died four years after the initial diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.57.56DOI Listing
January 2016

Chronic myelogenous leukemia in chronic phase transforming into acute leukemia under treatment with dasatinib 4 months after diagnosis.

Int J Hematol 2016 Mar 12;103(3):348-53. Epub 2015 Dec 12.

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-Gun, Tochigi, 321-0293, Japan.

We report a 64-year-old woman morphologically diagnosed with chronic myelogenous leukemia in the chronic phase. Despite having achieved a complete hematological response following treatment with dasatinib, she developed lymphoblastic crisis 4 months later. Blastic cells were in a CD45-negative and SSC-low fraction, and positive for CD10, CD19, CD34, and HLA-DR expression and rearrangement in the immunoglobulin heavy chain gene. Chemotherapy using the HyperCVAD/MA regimen led to a complete cytogenetic response, and after cord blood transplantation, she obtained a complete molecular remission. However, the crisis recurred 6 months later. Another salvage therapy using L-AdVP regimen followed by nilotinib led to a complete molecular remission. Retrospective analyses using flow cytometry and polymerase chain reaction revealed a minimal blastic crisis clone present in the initial marrow in chronic phase. This case is informative as it suggests that sudden blastic crisis may occur from an undetectable blastic clone present at initial diagnosis and that leukemic stem cells may survive cytotoxic chemotherapy that eliminates most of the blastic cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-015-1909-7DOI Listing
March 2016

A randomized controlled trial comparing darbepoetin alfa doses in red blood cell transfusion-dependent patients with low- or intermediate-1 risk myelodysplastic syndromes.

Int J Hematol 2015 Oct 1;102(4):401-12. Epub 2015 Sep 1.

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, 880, Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.

Darbepoetin alfa (DA) is a standard treatment for anemia in lower-risk MDS. However, to date there has been no comparative study to investigate the initial dosage. We, thus, conducted a randomized controlled trial to elucidate the optimal initial dosage of DA. International Prognostic Scoring System low or intermediate-1 risk MDS patients with hemoglobin levels ≤9.0 g/dL, serum erythropoietin levels ≤500 mIU/mL, and red blood cell transfusion dependency were enrolled. Patients were randomized to receive DA either at 60, 120, or 240 μg/week for 16 weeks followed by continuous administration with dose adjustment up to 48 weeks. Of 17, 18, and 15 patients in the 60, 120, and 240 μg DA groups included in the efficacy analysis, 64.7, 44.4, and 66.7 %, respectively, achieved the primary endpoint (major or minor erythroid response), while 17.6, 16.7, and 33.3 % achieved major erythroid responses in the initial 16-week period. No clinically significant safety concerns were identified. DA reduced the transfusion requirements effectively and safely in transfusion-dependent, lower-risk MDS patients. Given the highest achievement rate of the major erythroid response in the 240 μg group and the absence of dose-dependent adverse events, 240 μg weekly is the optimal initial dosage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-015-1862-5DOI Listing
October 2015

Prognostic significance of pleural or pericardial effusion and the implication of optimal treatment in primary mediastinal large B-cell lymphoma: a multicenter retrospective study in Japan.

Haematologica 2014 Dec 12;99(12):1817-25. Epub 2014 Sep 12.

Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital; Department of Internal Medicine and Laboratory Medicine, National Hospital Organization Suzuka National Hospital, Japan.

The prognosis of patients with primary mediastinal large B-cell lymphoma has improved over recent years. However, the optimal treatment strategy including the role of radiotherapy remains unknown. We retrospectively analyzed the clinical outcomes of 345 patients with newly diagnosed primary mediastinal large B-cell lymphoma in Japan. With a median follow up of 48 months, the overall survival at four years for patients treated with R-CHOP (n=187), CHOP (n=44), DA-EPOCH-R (n=9), 2(nd)- or 3(rd)-generation regimens, and chemotherapy followed by autologous stem cell transplantation were 90%, 67%, 100%, 91% and 92%, respectively. Focusing on patients treated with R-CHOP, a higher International Prognostic Index score and the presence of pleural or pericardial effusion were identified as adverse prognostic factors for overall survival in patients treated with R-CHOP without consolidative radiotherapy (IPI: hazard ratio 4.23, 95% confidence interval 1.48-12.13, P=0.007; effusion: hazard ratio 4.93, 95% confidence interval 1.37-17.69, P=0.015). Combined with the International Prognostic Index score and the presence of pleural or pericardial effusion for the stratification of patients treated with R-CHOP without radiotherapy, patients with lower International Prognostic Index score and the absence of effusion comprised approximately one-half of these patients and could be identified as curable patients (95% overall survival at 4 years). The DA-EPOCH-R regimen might overcome the effect of these adverse prognostic factors. Our simple indicators of International Prognostic Index score and the presence of pleural or pericardial effusion could stratify patients with primary mediastinal large B-cell lymphoma and help guide selection of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2014.111203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258760PMC
December 2014

Expressional changes of genes and miRNA in common megakaryocyte-erythroid progenitors from lower-risk myelodysplastic syndrome.

Int J Hematol 2014 Oct 24;100(4):361-9. Epub 2014 Jul 24.

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.

Myelodysplastic syndrome (MDS) is a stem cell tumor characterized by dysplastic features and ineffective hematopoiesis in the early phase and leukemic progression in the late phase. Speculating that differences in the expression of genes and microRNA (miRNA) in control and MDS-derived erythroid progenitors may cause ineffective erythropoiesis, we sorted common megakaryocyte-erythroid progenitors (MEPs) in bone marrow cells from three lower-risk MDS patients, and compared expression levels of genes and miRNA with those from controls. In apoptosis-related pathways, the expression of some pro-apoptotic genes, such as cell death-inducing DFFA-like effector A, caspase 5, and Fas ligand, was elevated in MDS-derived MEPs, while those of anti-apoptotic CD40 and tumor necrosis factor were lower. In hematopoiesis-regulating pathways, RUNX1 and ETV6 genes showed reduced expression. Expression profiling revealed that three and 35 miRNAs were significantly up- and down-regulated in MDS-derived MEPs. MIR9 exhibited robust expression in MEPs and CD71+GlyA+ erythroid cells derived from one of the three patients. Interestingly, overexpression of MIR9 inhibited the accumulation of hemoglobin in UT-7/GM cells. Some of these alterations in gene and miRNA expression may contribute to the pathogenesis of ineffective hematopoiesis in lower-risk MDS and provide molecular markers for sub-classification and making a prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-014-1639-2DOI Listing
October 2014

Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib.

Biomark Res 2014 Mar 20;2(1). Epub 2014 Mar 20.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 010-8543 Akita, Japan.

Background: Nilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP).

Results: We analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2-4, 29%; grades 3-4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2-208.0).

Conclusions: Nilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms.

Trial Registration: clinicaltrials.gov: UMIN000002201.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/2050-7771-2-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994575PMC
March 2014

[Inv(16)-type acute myeloid leukemia with repeated skin infiltration without bone marrow relapse before and after allogeneic hematopoietic stem cell transplantation].

Rinsho Ketsueki 2013 Dec;54(12):2203-6

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine.

We report a 40-year-old woman diagnosed as having acute myeloid leukemia with CBFB-MYH11. Before and after stem cell transplantation in the phase of molecular remission of the marrow, CBFB-MYH11-positive cells were detected by RT-PCR analysis in skin lesions. The former was pathologically diagnosed as leukemic infiltration, while the latter was considered to be graft-versus-host disease. We can speculate that a low level of leukemic stem cells not detectable by RT-PCR analysis remained in the bone marrow, at least prior to transplantation. This case may suggest interesting biological features of inv(16)-type acute myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2013

[Detection of BCR-ABL1 chimeric gene-positive neutrophils in a patient with mixed phenotype acute leukemia].

Rinsho Ketsueki 2013 Nov;54(11):2074-8

Department of Hematology and Oncology, Dokkyo Medical University School of Medicine.

We experienced two patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1 according to the WHO classification 2008. The type of BCR/ABL1 was major in both patients, and the chimeric gene was also detected in neutrophils from peripheral blood by the fluorescence in situ hybridization technique. Patient 1 was a 59-year-old Japanese woman, and patient 2 a 45-year-old Japanese man. They had both developed leukemia suddenly. Their leukemic blasts expressed B cell and myeloid cell antigens, but concomitantly in patient 1 (biphenotypic) and separately in patient 2 (biclonal). Percentages of BCR-ABL1-positive neutrophils were 98% and 89%, respectively. Both patients received an imatinib (600 mg/day)-combined Hyper-CVAD regimen as induction therapy, followed by treatment with dasatinib (140 mg/day). MEC therapy was also applied between these two treatments in patient 2. At present, patient 1 has obtained complete molecular remission quantitatively and qualitatively, and patient 2 only quantitatively. Considering their acute onsets with no prior history of chronic myelocytic leukemia (CML), they were both diagnosed as having acute leukemia with Ph1, but not blastic crisis of CML. In this tyrosine kinase inhibitor era, it has become more difficult to differentiate these two types of Ph1-positive leukemia development.
View Article and Find Full Text PDF

Download full-text PDF

Source
November 2013
-->