Publications by authors named "Kohmei Kubo"

24 Publications

  • Page 1 of 1

Expression, mutation, and methylation of cereblon-pathway genes at pre- and post-lenalidomide treatment in multiple myeloma.

Cancer Sci 2020 Apr 12;111(4):1333-1343. Epub 2020 Mar 12.

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.
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http://dx.doi.org/10.1111/cas.14352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156787PMC
April 2020

A high CD34 cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors.

Bone Marrow Transplant 2020 09 10;55(9):1726-1735. Epub 2020 Feb 10.

Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

To elucidate the impact of infused CD34 cell doses on transplant outcome, we retrospectively analyzed 851 adult patients who received peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-matched related donors. The patients were divided into high- and low-CD34 groups at the cutoff value of 4.5 × 10/kg. Overall, the high CD34 group showed early neutrophil and platelet recovery. Stratification of disease risks demonstrated that among the patients with low-risk diseases, the high-CD34 group showed better disease-free survival (DFS) (64.9% vs. 55.5%, P = 0.0415) than did the low-CD34 group, without any increase in graft-versus-host disease (GVHD). Meanwhile, a higher CD34 cell dose had no impacts on the outcomes of patients with high-risk diseases. Multivariate analyses for the patients with low-risk diseases revealed that a high CD34 cell dose (hazard ratio [HR] 0.72, P = 0.048) and development of grade III-to-IV acute GVHD (HR 1.64, P = 0.018) were significantly associated with DFS. An excessive dose of CD34 cells (>8.0 × 10/kg) led to an increase in acute GVHD. By stratification of disease risk, a CD34 cell dose between 4.5 and 8.0 × 10/kg can be suggested for patients with low-risk diseases who undergo PBSCT from HLA-matched related donors.
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http://dx.doi.org/10.1038/s41409-020-0817-5DOI Listing
September 2020

Elotuzumab plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma: a randomized, open-label, phase 2 study in Japan.

Int J Hematol 2020 Jan 7;111(1):65-74. Epub 2019 Nov 7.

Department of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan.

Novel therapies are needed for patients with newly diagnosed multiple myeloma (NDMM). Elotuzumab plus lenalidomide and dexamethasone (ELd) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2 study in Japan evaluated ELd vs lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation. Elotuzumab infusion was accelerated to 5 mL/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 h. The primary endpoint was overall response rate (ORR) in the ELd arm. Secondary endpoints were the difference in ORR between treatments, and progression-free survival (PFS). Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld). In the ELd arm, ORR was 88% [70% confidence interval (CI) 80-93]. The estimated difference in ORR between treatments was 13% (95% CI  - 4, 30) in favor of ELd. Progression-free survival data were immature. Safety was consistent with previous findings of ELd in Japanese patients with RRMM. No infusion reactions occurred at the maximum rate of 5 mL/min, which was used in 89% of elotuzumab infusions. ELd may be an effective, well-tolerated frontline treatment for patients with NDMM ineligible for stem cell transplantation.
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http://dx.doi.org/10.1007/s12185-019-02757-0DOI Listing
January 2020

High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma: Data From the Japan Society for Hematopoietic Cell Transplantation Registry.

Biol Blood Marrow Transplant 2019 05 18;25(5):899-905. Epub 2019 Jan 18.

Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan.

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.020DOI Listing
May 2019

Efficacy and safety of obinutuzumab in patients with previously untreated follicular lymphoma: a subgroup analysis of patients enrolled in Japan in the randomized phase III GALLIUM trial.

Int J Hematol 2018 Nov 19;108(5):499-509. Epub 2018 Jul 19.

School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, Japan.

GALLIUM is a global phase III study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with obinutuzumab plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). In this single-country subgroup analysis, we explored patterns of efficacy and safety in patients enrolled in the GALLIUM study in Japan (Japanese subgroup). Patients were randomized to open-label induction treatment with G-chemo or R-chemo. Responders received maintenance monotherapy with their randomized antibody for up to 2 years. The primary endpoint was investigator-assessed PFS. Overall, 123 patients with FL were randomized in the Japanese subgroup (G-chemo, n = 65; R-chemo, n = 58). The majority of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (82.9 vs 33.1% in the global GALLIUM FL population). PFS at 3 years was 89.9% (G-chemo) vs. 74.7% (R-chemo); hazard ratio 0.42; 95% confidence interval 0.15, 1.15; P = 0.08. Higher rates of grade 3-5 adverse events (96.9 vs. 89.7%) and serious adverse events (35.4 vs. 22.4%) were observed with G-chemo vs R-chemo, respectively. Neutropenia was frequent in the Japanese subgroup (92.3% G-chemo; 79.3% R-chemo). Overall, the results in the Japanese subgroup were consistent with those in the global GALLIUM population.
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http://dx.doi.org/10.1007/s12185-018-2497-0DOI Listing
November 2018

Outcome From a Randomized Controlled Clinical Trial - Improvement of Peripheral Arterial Disease by Granulocyte Colony-Stimulating Factor-Mobilized Autologous Peripheral-Blood-Mononuclear Cell Transplantation (IMPACT).

Circ J 2018 07 7;82(8):2165-2174. Epub 2018 Jun 7.

Translational Research Informatics Center, Foundation for Biomedical Research and Innovation.

Background: The clinical usefulness of peripheral blood (PB) mononuclear cell (MNC) transplantation in patients with peripheral arterial disease (PAD), especially in those with mild-to-moderate severity, has not been fully clarified.Methods and Results:A randomized clinical trial was conducted to evaluate the efficacy and safety of granulocyte colony-stimulating factor (G-CSF)-mobilized PBMNC transplantation in patients with PAD (Fontaine stage II-IV and Rutherford category 1-5) caused by arteriosclerosis obliterans or Buerger's disease. The primary endpoint was progression-free survival (PFS). In total, 107 subjects were enrolled. At baseline, Fontaine stage was II/III in 82 patients and IV in 21, and 54 patients were on hemodialysis. A total of 50 patients had intramuscular transplantation of PBMNC combined with standard of care (SOC) (cell therapy group), and 53 received SOC only (control group). PFS tended to be improved in the cell therapy group than in the control group (P=0.07). PFS in Fontaine stage II/III subgroup was significantly better in the cell therapy group than in the control group. Cell therapy-related adverse events were transient and not serious.

Conclusions: In this first randomized, large-scale clinical trial of G-CSF-mobilized PBMNC transplantation, the cell therapy was tolerated by a variety of PAD patients. The PBMNC therapy was significantly effective for inhibiting disease progression in mild-to-moderate PAD.
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http://dx.doi.org/10.1253/circj.CJ-17-1220DOI Listing
July 2018

Clinical impact of underweight status at diagnosis on elderly patients with acute myeloid leukemia: a retrospective study of JALSG GML200.

Ann Hematol 2018 Aug 1;97(8):1481-1483. Epub 2018 Mar 1.

Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.

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http://dx.doi.org/10.1007/s00277-018-3281-1DOI Listing
August 2018

Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients.

Eur J Haematol 2018 Jan 16;100(1):27-35. Epub 2017 Oct 16.

Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan.

Objectives: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study).

Methods: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL1 ) were the post-treatment factors investigated to predict the molecular response.

Results: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL1 was the only significant landmark for predicting DMR by multivariate analysis.

Conclusions: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL1 was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.
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http://dx.doi.org/10.1111/ejh.12969DOI Listing
January 2018

Suspected Pulmonary Infection with Trichoderma longibrachiatum after Allogeneic Stem Cell Transplantation.

Intern Med 2017 15;56(2):215-219. Epub 2017 Jan 15.

Department of Hematology, Aomori Prefectural Central Hospital, Japan.

Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B.
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http://dx.doi.org/10.2169/internalmedicine.56.5316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337471PMC
March 2017

Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy.

Leuk Res 2016 12 5;51:11-18. Epub 2016 Sep 5.

Division of Haematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. Electronic address:

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874.
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http://dx.doi.org/10.1016/j.leukres.2016.09.009DOI Listing
December 2016

A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Br J Haematol 2016 Aug 12;174(4):563-70. Epub 2016 Apr 12.

Division of Medical Oncology, Haematology and Infectious Disease, Fukuoka University, Fukuoka, Japan.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.
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http://dx.doi.org/10.1111/bjh.14088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074273PMC
August 2016

Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia.

Eur J Clin Pharmacol 2016 Feb 27;72(2):185-93. Epub 2015 Oct 27.

Iwate Medical University School of Medicine, Morioka, Japan.

Purpose: Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients.

Methods: The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)CD34+cells) was calculated from each patient's dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration.

Results: Early molecular responses were not significantly associated with PK or PD (IC50 CD34+cells) parameters. However, the PK/PD parameter-time above IC50 CD34+cells-significantly correlated with BCR-ABL transcript level at 3 months (correlation coefficient (CC) = -0.292, P = 0.0375) and the reduction of BCR-ABL level at 1 or 3 months (CC = -0.404, P = 0.00328 and CC = -0.356, P = 0.0104, respectively). Patients with more than 12.6 h at time above IC50 CD34+cells achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (P = 0.013, odds ratio = 4.8 and P = 0.024, odds ratio = 4.3, respectively).

Conclusion: These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50 CD34+cells could significantly improve prognosis.
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http://dx.doi.org/10.1007/s00228-015-1968-yDOI Listing
February 2016

Comparison of micafungin and voriconazole as empirical antifungal therapies in febrile neutropenic patients with hematological disorders: a randomized controlled trial.

Eur J Haematol 2016 Jun 26;96(6):602-9. Epub 2015 Aug 26.

Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, Morioka City, Japan.

Objectives: In cases of hematological malignancy, patients with persistent fever and neutropenia receive antifungal empirical therapy to prevent and treat invasive fungal infections. The clinical efficacy and safety of micafungin and voriconazole were compared.

Methods: In this randomized, cooperative group, open-label trial, we assessed and compared the efficacy and safety of micafungin and voriconazole as an empirical antifungal therapy in febrile neutropenic patients with hematological malignancy. Patients were classified according to invasive fungal infection risk.

Results: There were no significant differences in clinical efficacy between the two treatments, evaluated based on (i) successful treatment of baseline fungal infection (no evaluation), (ii) absence of breakthrough fungal infection (P = 0.106), (iii) survival for ≥7 days after study completion (P = 0.335), (iv) premature study discontinuation due to poor efficacy (P = 0.424), and (v) resolution of fever during neutropenia (P = 0.756). Discontinuation due to drug-related adverse events (grades 3-4) occurred less frequently in the micafungin group (P = 0.005).

Conclusions: The clinical efficacy did not differ between micafungin and voriconazole. Micafungin was generally better tolerated than voriconazole when given as an empirical antifungal therapy in patients with persistent fever and neutropenia.
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http://dx.doi.org/10.1111/ejh.12641DOI Listing
June 2016

A single high-resolution HLA mismatch has a similar adverse impact on the outcome of related hematopoietic stem cell transplantation as a single low-resolution HLA mismatch.

Am J Hematol 2015 Jul;90(7):618-23

Division of Hematology, Saitama Medical Center, Saitama, Japan.

The relative importance of the resolution level of HLA typing has not been fully defined for related donor transplantation. To address this question, we retrospectively evaluated patients who underwent a first related hematopoietic stem cell transplantation (HSCT) from 2000 to 2011 from an HLA high-resolution matched (MRD, n = 2,244), high-resolution 1 locus-mismatched (HR-MMRD, n = 116), or low-resolution 1 locus-mismatched related donor (LR-MMRD, n = 396) in the graft-versus-host direction at three loci (HLA A, B, and DRB1) using the database of the Japan Society for Hematopoietic Cell Transplantation. The median age was 40 years (0-74). The median follow-up duration of surviving patients was 950 days. Although the cumulative incidences of grade III-IV acute graft-versus-host disease (GVHD) in the HR-MMRD and LR-MMRD groups were significantly higher than those in the MRD group (HR-MMRD 19.8%, LR-MMRD 20.4%, and MRD 9.5%), there was no statistically significant difference between the HR-MMRD and LR-MMRD groups (P = 0.65). Although both HR-MMRD and LR-MMRD were significantly associated with an increased risk of non-relapse mortality and a worse overall survival, there was no statistically significant difference between the HR-MMRD and LR-MMRD groups. In conclusion, LR-MM and HR-MM have a similar adverse impact on the outcome in related HSCT.
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http://dx.doi.org/10.1002/ajh.24028DOI Listing
July 2015

A prospective analysis of clinical efficacy and safety in chronic myeloid leukemia-chronic phase patients with imatinib resistance or intolerance as evaluated using European LeukemiaNet 2013 criteria.

Eur J Haematol 2015 Dec 25;95(6):558-65. Epub 2015 Mar 25.

Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan.

Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML).

Methods: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations.

Results: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent.

Conclusions: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.
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http://dx.doi.org/10.1111/ejh.12536DOI Listing
December 2015

Quantification of Epstein-Barr virus DNA is helpful for evaluation of chronic active Epstein-Barr virus infection.

Tohoku J Exp Med 2012 08;227(4):307-11

Department of Laboratory Medicine, Aomori Prefectural Central Hospital, Aomori, Japan.

Chronic active Epstein-Barr virus infection (CAEBV) presents with chronic or recurrent infectious mononucleosis-like symptoms, such as low-grade fever, liver dysfunction, lymphadenopathy, and hepatosplenomegaly. Immunological methods are useful for the diagnosis of viral infections. However, CAEBV patients do not necessarily have high titers of Epstein-Barr virus (EBV)-specific antibodies. Hosts that are immunocompromised after hematopoietic stem cell transplantations sometimes suffer from systemic EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and EBV-positive lymphoma. Patients with EBV-associated diseases are often diagnosed by analyses of bone marrow. Cytomegalovirus (CMV) can cause serious pneumonia or retinitis in immunocompromised hosts. In order to noninvasively understand the clinical status of patients with EBV-associated diseases, we conducted real-time polymerase chain reaction (PCR) methods in their peripheral blood in order to quantify EBV and CMV DNA levels, which reflect viral activity. Here, we describe a 30-year-old Japanese female patient with CAEBV. The patient had repeated fever, fatigue, and liver dysfunction. The histopathological results of liver biopsies were positive for EBV-encoded RNA-1. Acute hepatitis was associated with the EBV infection. The whole-blood EBV DNA levels were high and above 1.0 × 10⁷ copies/mL. After immunosuppressive and antiviral therapies, EBV DNA levels lowered. However, she had to receive bone marrow transplantation because of her EBV-HLH. As the number of lymphocytes increased in the post-transplantation period, EBV DNA levels gradually increased again. The simultaneous detection of CMV DNA was more sensitive than the CMV antigenemia test that is often used to diagnose CMV infections. Unfortunately, the patient died due to a fungal infection. Observing EBV DNA levels closely with real-time quantitative PCR methods is helpful for evaluating the changes in the clinical course.
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http://dx.doi.org/10.1620/tjem.227.307DOI Listing
August 2012

Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study.

Int J Hematol 2012 Jul 26;96(1):84-93. Epub 2012 May 26.

Division of Hematology and Oncology, Nagoya City West Medical Center, 1-1 Hirate-cho 1-chome, Kita-ku, Nagoya, Japan.

We conducted a multicenter prospective randomized study to compare a fixed-scheduled induction therapy with a response-oriented individualized induction therapy for elderly patients with acute myeloid leukemia (AML). Newly diagnosed AML patients, aged between 65 and 80, were randomly assigned to receive fixed or individualized induction. Both groups received daunorubicin (DNR) 40 mg/m(2) for 3 days and behenoyl cytarabine (BHAC) 200 mg/m(2) for 8 days. In the individualized group, bone marrow biopsy was done on days 8 and 10, and according to the cellularity and blast ratio, the patients received additional DNR and BHAC for two to four more days. All patients achieving complete remission (CR) were randomized a second time to determine whether they would receive ubenimex. CR was obtained in 60.1 % of the fixed group and 63.6 % of the individualized group. Predicted 4-year relapse-free survival (RFS) was 9 % for the fixed group and 18 % for the individualized group. There were no statistically significant differences in CR and RFS between the fixed and individualized groups. In the ubenimex group, prolonged RFS was observed. Notably, gender was a prognostic factor in this study, as 102 female patients had a significantly higher CR rate (72.5 vs. 54.3 %, p = 0.0048) and better OS (24 vs. 14 % at 4 years, p = 0.018), compared with 140 male patients.
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http://dx.doi.org/10.1007/s12185-012-1105-yDOI Listing
July 2012

Monitoring twenty-six chronic myeloid leukemia patients by BCR-ABL mRNA level in bone marrow:a single hospital experience.

Acta Med Okayama 2011 Oct;65(5):335-42

Department of Laboratory Medicine, Aomori Prefectural Central Hospital, Japan.

Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncogene. The Philadelphia chromosome (Ph) from a reciprocal translocation, t(9;22) (q34;q11) causes a fusion gene, BCR-ABL, that encodes a constitutively active tyrosine kinase. Treatment of CML by imatinib is effective to control the tyrosyl phosphorylation of the protein related to the cell signaling. BCR-ABL mRNA is overexpressed in the minimal residual disease (MRD), known as an early sign of relapse. Between December 2005 and June 2008, we measured BCR-ABL mRNA levels in the bone marrow (BM) from patients by quantitative real-time polymerase chain reaction (RQ-PCR) in Aomori Prefectural Central Hospital. Eighty-six samples from 26 patients were collected. Among the 26 CML patients, 11 patients (42%) were in the pretreatment group. Seven (64%) of the 11 patients achieved complete molecular response (CMR). In the post-treatment group consisting of the remaining 15 patients, 9 (60%) patients achieved CMR. The patients receiving imatinib at a dose over 300 mg per day required 13 (6-77) months [median (range)] to achieve CMR. On the other hand, the patients receiving a dose below 300 mg per day required 29.5 (11-84) months [median (range)]. When BCR-ABL mRNA was detected during the treatment course of patients with CMR, careful observation of BCR-ABL mRNA was useful for tracking the clinical course of patients. In conclusion, the BCR-ABL mRNA level was useful for monitoring the clinical course in 26 patients with CML.
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http://dx.doi.org/10.18926/AMO/47016DOI Listing
October 2011

The potential of patients' peripheral blood mononuclear cells to differentiate into dendritic cells after hematopoietic stem cell transplantation.

Life Sci 2011 Dec 20;89(25-26):946-55. Epub 2011 Oct 20.

Department of Radiological Life Sciences, Division of Medical Life Sciences, Hirosaki University Graduate School of Health Sciences, Aomori 036-8564, Japan.

Aims: Although hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological disorders, there is persistent immunosuppression in both allogeneic and autologous HSCT. Dendritic cells (DCs) play key roles in the immune system. This study investigated whether the DC progenitor cells within patients' peripheral blood after HSCT have the potential to differentiate into DCs.

Main Methods: Twenty-eight patients were included in this study, and peripheral blood samples were basically taken before starting the conditioning regimen, on the day of transplantation (day 0), and on days +14, +28, +42, +70 and +170 after transplantation. Immature DCs (iDCs) were induced from adherent mononuclear cells by using recombinant human granulocyte-macrophage colony-stimulating factor plus interleukin-4.

Key Findings: The iDCs expressed cell surface antigens such as CD40 and HLA-DR, and they had phagocytotic activity, thus showing the characteristics of iDCs. The induction of iDCs was possible from day +14 after HSCT. However, there were differences between allogeneic and autologous HSCT in the expression of CCR5 in iDCs at day +14 after transplantation. Furthermore, the up-regulation of maturation-related antigens by maturation stimuli was higher after HSCT compared with before HSCT.

Significance: We demonstrated that patients' peripheral blood mononuclear cells have the potential to differentiate into DCs beginning on day +14 after HSCT, although some differences exist between allogeneic and autologous HSCT and between before and after HSCT.
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http://dx.doi.org/10.1016/j.lfs.2011.10.005DOI Listing
December 2011

Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry.

Int J Hematol 2010 Jun 14;91(5):855-64. Epub 2010 May 14.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

We retrospectively analyzed the results of 707 adult patients who underwent myeloablative peripheral blood stem cell transplantation (PBSCT) (n = 365) and myeloablative bone marrow transplantation (BMT) (n = 342) for leukemia from HLA-identical sibling donors between 2000 and 2005 using the propensity score method. The results were obtained from the Japan Society for Hematopoietic Cell Transplantation registry. Multivariate Cox analysis showed that PBSCT was associated with lower overall survival (OS) in standard-risk patients [adjusted hazard ratio (aHR) = 1.83; 95% confidence interval (CI) 1.04-3.23; P = 0.036], but not in high-risk patients (aHR = 1.11; 95% CI 0.76-1.61; P = 0.599). Hematopoietic recovery was significantly faster after PBSCT. The risk of acquiring grade III-IV acute graft-versus-host disease (GVHD) (aHR = 2.23; P = 0.040) and extensive chronic GVHD (aHR = 1.93; P = 0.001) were significantly higher after PBSCT. PBSCT was associated with higher non-relapse mortality in standard-risk patients (aHR = 2.30; 95% CI 1.08-4.88; P = 0.030), but not in high-risk patients (aHR = 1.29; 95% CI 0.65-2.54; P = 0.468). Relapse after transplantation did not differ between PBSCT and BMT either in standard-risk group or in high-risk group (aHR = 1.17; 95% CI 0.55-2.52; P = 0.684 and aHR = 0.81; 95% CI 0.52-1.28; P = 0.370, respectively). In this retrospective analysis, OS was significantly lower after PBSCT in standard-risk patients, but not in high-risk patients. PBSCT was associated with significant risks of grade III-IV acute GVHD and extensive chronic GVHD.
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http://dx.doi.org/10.1007/s12185-010-0581-1DOI Listing
June 2010

[Long-term complete remission after single therapy with gemtuzumab ozogamicin for refractory AML in an elderly patient].

Gan To Kagaku Ryoho 2007 Nov;34(11):1881-3

Dept. of Hematology, Aomori Prefectural Central Hospital.

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, that is rapidly internalized after binding to CD33. This is followed by intracellular release of calicheamicin, which induces double-stranded DNA breaks, cell cycle arrest, and apoptosis. So GO is a more selective agent for acute myeloid leukemia (AML), because the CD33 antigen is expressed on AML, while it is not expressed on normal hematopoietic stem cells and nonhematopoietic tissues. However, some studies indicated that this agent showed resistance to refractory AML cells via various mechanisms, and that there were no potent effects. In this study, we report a 76-year-old female with recurrent AML who responded to single therapy with GO, achieving complete remission for more than 1 year after the start of administration, although additional remission induction was impossible. The response to GO can be stratified with reference to the response to conventional chemotherapy.
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November 2007

[Intracranial granulocytic sarcoma in a patient with acute myeloid leukemia].

No To Shinkei 2006 Sep;58(9):797-801

Department of Neurosurgery, Aomori Prefectural Central Hospital. 2-1-1 Higashi-tsukurimichi, Aomori 030-8553, Japan.

Granulocytic sarcoma (GS) is extramedullary tumor composed of immature leukemic cells. GS is presenting usually as a complication during the course of hematologic neoplasm, such as acute myeloblastic leukemia as well as myeloproliferative and myelodysplastic syndrome. The tumor was also called chroloma based on the green color of the tumorous mass. Central nervous system manifestations of GS are extremely rare. We report a 41-year-old man with acute leukemia type M7, who developed GS in the right occipital lobe after complete remission was achieved. Operative findings revealed the color of the hard tumor was greenish, which suggested the tumor was chroloma. Histological findings showed the tumor was GS. The majority of reported cases of GS in acute myeloid leukemia were M2 FAB classification and have chromosome translocation. Our patient was M7 FAB classification, not have specific chromosome translocation. GS occurrence in AML: M7 patient was extremely rare. This is the first case report of AML: M7 with GS in the central nervous system.
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September 2006

Prediction of chemosensitivity for patients with acute myeloid leukemia, according to expression levels of 28 genes selected by genome-wide complementary DNA microarray analysis.

Mol Cancer Ther 2002 Oct;1(12):1035-42

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

To identify genes involved in the sensitivity of acute myeloid leukemia (AML) cells to chemotherapy, we monitored gene-expression profiles of cancer cells from 76 AML patients using a cDNA microarray consisting of 23,040 genes. We identified 63 genes that were commonly overexpressed and 372 genes suppressed in AML. Because these genes represent key molecules for disclosing the molecular mechanisms of AML, they may be potential targets for drug development. We also found 28 that revealed different expression levels between good and poor responders to chemotherapy and appeared to be associated with chemosensitivity. On that basis, we developed a "Drug Response Scoring" system that was correlated well with individual sensitivity to an anticancer drug regimen. Among the 44 cases with positive drug-response scores by our definition, 40 achieved complete remission after treatment, whereas the only 3 of the 20 cases with negative scores responded well to the treatment. An ability to predict chemosensitivity should eventually lead to achievement of our goal of "personalized therapy."
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October 2002
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