Publications by authors named "Kazuteru Ohashi"

238 Publications

Archival bone marrow smears are useful in targeted next-generation sequencing for diagnosing myeloid neoplasms.

PLoS One 2021 23;16(7):e0255257. Epub 2021 Jul 23.

Clinical Research Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Gene abnormalities, including mutations and fusions, are important determinants in the molecular diagnosis of myeloid neoplasms. The use of bone marrow (BM) smears as a source of DNA and RNA for next-generation sequencing (NGS) enables molecular diagnosis to be done with small amounts of bone marrow and is especially useful for patients without stocked cells, DNA or RNA. The present study aimed to analyze the quality of DNA and RNA derived from smear samples and the utility of NGS for diagnosing myeloid neoplasms. Targeted DNA sequencing using paired BM cells and smears yielded sequencing data of adequate quality for variant calling. The detected variants were analyzed using the bioinformatics approach to detect mutations reliably and increase sensitivity. Noise deriving from variants with extremely low variant allele frequency (VAF) was detected in smear sample data and removed by filtering. Consequently, various driver gene mutations were detected across a wide range of allele frequencies in patients with myeloid neoplasms. Moreover, targeted RNA sequencing successfully detected fusion genes using smear-derived, very low-quality RNA, even in a patient with a normal karyotype. These findings demonstrated that smear samples can be used for clinical molecular diagnosis with adequate noise-reduction methods even if the DNA and RNA quality is inferior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255257PLOS
July 2021

Cord blood index predicts engraftment and early non-relapse mortality in adult patients with single-unit cord blood transplantation.

Bone Marrow Transplant 2021 Jul 15. Epub 2021 Jul 15.

Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.

How to select optimal cord blood (CB) remains an important clinical question. We developed and validated an index of CB engraftment, the cord blood index (CBI), which uses three weighted variables representing cell doses and HLA mismatches. We modeled the neutrophil engraftment time with competing events by random survival forests for competing risks as a function of the predictors: total nucleated cells, CD34, colony-forming units for granulocytes/macrophages, and the number of HLA mismatches at the antigen and allele levels. The CBI defined three groups that had different neutrophil engraftment rates at day 30 (High, 83.7% [95% CI, 79.2-88.1%]; Intermediate, 77.0% [95% CI, 73.7-80.2%]; Low, 68.4% [95% CI, 63.6-73.2%]), platelet engraftment rates at day 60 (High, 70.4% [95% CI, 64.9-75.9%]; Intermediate, 62.3% [95% CI, 58.5-66.0%]; Low, 49.3% [95% CI, 44.2-54.5%]), and non-relapse mortality at day 100 (High, 14.1% [95% CI, 9.9-18.3%]; Intermediate, 16.4% [95% CI, 13.5-19.3%]; Low, 21.3% [95% CI, 17.1-25.5%]). This novel approach is clinically beneficial and can be adopted immediately because it uses easily obtained pre-freeze data of CB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01406-7DOI Listing
July 2021

CT classification of acute myeloid leukemia with pulmonary infiltration.

Jpn J Radiol 2021 Jun 17. Epub 2021 Jun 17.

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

Purpose: To characterize and categorize the CT findings of pulmonary leukemic infiltration (PLI) in patients with acute myeloid leukemia (AML).

Materials And Methods: Among 435 patients with AML, 20 patients with PLI were retrospectively selected, and clinical characteristics and CT findings were analyzed. PLI was categorized into four patterns according to CT findings: type A, multiple nodules and/or masses; type B, bilateral perihilar airspace opacities (GGA or consolidation) without any nodules or masses; type C, mixture of type A and B; and type D, PLI without visible abnormal lung opacity. The difference in overall survival among four CT patterns was also examined.

Results: The frequency of complex karyotypes was higher in AML patients with PLI than in whole AML patients. Percentages of patients with CT findings of type A, B, C, and D were 35%, 20%, 35%, and 10%, respectively. There was a clear difference in the localization of opacities according to the type of infiltrates, i.e., nodules/masses were mainly detected in the lower/peripheral portion. Conversely, GGA was mainly located in the upper/central portion. The median overall survival from diagnosis of PLI was 262 days (range 12-1148). The CT pattern was not significantly associated with survival (p = 0.3), with the exception of patients with type C tending to have significantly better outcomes compared to patients with type B (p = 0.05).

Conclusion: This classification can contribute in accurate non-invasive diagnosis and possibly in the estimation of prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11604-021-01151-3DOI Listing
June 2021

Successful Cord Blood Transplantation for Idiopathic CD4+ Lymphocytopenia.

Acta Haematol 2021 Jun 1:1-7. Epub 2021 Jun 1.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000516347DOI Listing
June 2021

Outcome of allogeneic hematopoietic stem cell transplantation for T-cell lymphoblastic leukemia/lymphoma: A single-center study.

Leuk Res 2021 May 18;108:106627. Epub 2021 May 18.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Although the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL) are similar, few studies have compared its outcomes for T-ALL/LBL and Ph-negative B-ALL. The clinical data of 28 patients with T-ALL, 16 with T-LBL, and 99 with Ph-negative B-ALL who underwent the first allo-HSCT from 2000 to 2019 were retrospectively analyzed. Complete remission (CR) rates at allo-HSCT were 79 %, 63 %, and 75 % for T-ALL, T-LBL, and B-ALL, respectively; the 3-year overall survival (OS) rates were 55.7 %, 56.2 %, and 58.6 %, respectively (p = 0.92). Univariate analysis revealed that disease subtypes were not significantly associated with OS (B-ALL vs. T-ALL: hazard ratio [HR]=0.89, p = 0.70; T-LBL vs. T-ALL: HR=0.87, p = 0.75), and CR at allo-HSCT was the only prognostic factor for OS (HR=0.25, p < 0.001). Multivariate analysis demonstrated that CR at allo-HSCT was the only predictor of OS (HR=0.24, p < 0.001). In all three disease subtypes, patients in CR at allo-HSCT tended to have a lower cumulative incidence of relapse than did those in non-CR (T-ALL: 13.6 % vs. 50.0 %, p = 0.10; T-LBL: 20.0 % vs. 50.0 %, p = 0.21; B-ALL: 10.0 % vs. 56.0 %, p < 0.01). Thus, the outcomes of allo-HSCT for T-ALL/LBL were comparable to those of Ph-negative B-ALL. Irrespective of the disease subtypes, achieving CR before allo-HSCT was associated with a favorable OS. Further advances in chemotherapy before allo-HSCT and defining the optimal timing of allo-HSCT would improve the prognosis of patients with T-ALL/LBL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2021.106627DOI Listing
May 2021

[Clinical features of tuberculosis among allogeneic hematopoietic stem cell transplantation recipients].

Rinsho Ketsueki 2021 ;62(4):239-244

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

The incidence of tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is 10-40 times higher than that in the general population, which ranges from 0.1% to 5.5%. However, the clinical features of TB among allo-HSCT recipients in Japan remain unknown. We retrospectively analyzed the incidence of TB and the clinical features of culture-positive TB among allo-HSCT recipients at our hospital between 2002 and 2018. Of 1,047 recipients, 5 (0.4%) developed pulmonary TB (with an incidence rate of 472 per 100,000 population) at a median of 1,730 (range: 586-2,526) days after allo-HSCT. Three patients had chronic graft-versus-host disease upon the onset of TB, which was well-controlled with tacrolimus and/or steroid. Three of five patients completed TB treatment, and the disease did not flare up after therapy completion. The incidence of TB was higher in allo-HSCT recipients than in the general population (0.01%, with an incidence rate of 12.3 per 100,000 population). Therefore, TB should be considered a late complication among allo-HSCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.62.239DOI Listing
May 2021

Changes in vaccination strategies contribute to the development of invasive pneumococcal disease in allogeneic hematopoietic stem cell transplantation recipients: a retrospective study for promoting vaccination.

Int J Hematol 2021 Aug 12;114(2):263-270. Epub 2021 Apr 12.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at high risk of developing invasive pneumococcal disease (IPD) with substantial morbidity and mortality. Pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) are the primary prevention strategy. The difference between the Japanese and international guidelines is limited except when to start PCV13. However, Japanese data regarding the incidence of IPD after allo-HSCT that include vaccination status are limited. Therefore, we aimed to study the clinical characteristics of patients with IPD following allo-HSCT, focusing on unvaccinated patients. We retrospectively reviewed allo-HSCT recipients between April 2005 and December 2018 at Komagome Hospital. Among 1,091 recipients, 11 (1008/100,000 recipients) developed 13 episodes of IPD. The median period from the first allo-HSCT to the first IPD episode was 686 days (10-3040 days). Ten patients developed IPD before vaccination, and seven of these unvaccinated patients with late-onset IPD were ineligible for vaccination based on domestic guidelines. Although appropriate treatments resulted in a good short-term prognosis, most episodes of IPD developed in unvaccinated allo-HSCT recipients. Our data support the promotion of better adherence to the current guidelines and the importance of pneumococcal vaccination even years after allo-HSCT to protect against late-onset IPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03146-2DOI Listing
August 2021

T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation.

Sci Rep 2020 12 17;10(1):22218. Epub 2020 Dec 17.

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

Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8/CMV pp65 tetramer cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson's index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2-4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-79363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747720PMC
December 2020

[Vacuolar myelopathy after allogeneic bone marrow transplantation in a patient with acute lymphoblastic leukemia].

Rinsho Ketsueki 2020 ;61(11):1625-1627

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

Vacuolar myelopathy (VM) is known to be a neurological complication in patients with acquired immunodeficiency syndrome (AIDS). In autopsy-based studies, VM was reported in approximately 20-50% of patients with AIDS. It manifests in various says, mainly presenting as a painless spastic paraparesis with a sensory ataxia. We present a rare case of VM after bone marrow transplantation (BMT) in a patient without AIDS. A 50-year-old man developed weakness in the lower legs, leg muscle atrophy, and difficulty in walking 86 days after BMT. The patient died from septic shock on day 309. The autopsy revealed intralamellar vacuolation in the spinal white matter, which was compatible with VM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.1625DOI Listing
February 2021

Prebiotics protect against acute graft-versus-host disease and preserve the gut microbiota in stem cell transplantation.

Blood Adv 2020 10;4(19):4607-4617

Hematology Division, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, management of aGVHD is important for successful transplantation. Mucosal damage and alteration of the gut microbiota after allo-HSCT are key factors in the development of aGVHD. We conducted a prospective study to evaluate the ability of prebiotics, which can alleviate mucosal damage and manipulate the gut microbiota, to mitigate posttransplantation complications, including aGVHD. Resistant starch (RS) and a commercially available prebiotics mixture, GFO, were administered to allo-HSCT recipients from pretransplantation conditioning to day 28 after allo-HSCT. Prebiotic intake mitigated mucosal injury and reduced the incidence of all aGVHD grades combined and of aGVHD grades 2 to 4. The cumulative incidence of skin aGVHD was markedly decreased by prebiotics intake. Furthermore, the gut microbial diversity was well maintained and butyrate-producing bacterial population were preserved by prebiotics intake. In addition, the posttransplantation fecal butyrate concentration was maintained or increased more frequently in the prebiotics group. These observations indicate that prebiotic intake may be an effective strategy for preventing aGVHD in allo-HSCT, thereby improving treatment outcomes and the clinical utility of stem cell transplantation approaches. This study was registered on the University Hospital Medical Information Network (UMIN) clinical trials registry (https://www.umin.ac.jp/ctr/index.htm) as #UMIN000027563.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556149PMC
October 2020

Safety of total body irradiation using intensity-modulated radiation therapy by helical tomotherapy in allogeneic hematopoietic stem cell transplantation: a prospective pilot study.

J Radiat Res 2020 Nov;61(6):969-976

Division of Radiation Oncology, Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

Total body irradiation using intensity-modulated radiation therapy total body irradiation (IMRT-TBI) by helical tomotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) allows for precise evaluation and adjustment of radiation dosage. We conducted a single-center pilot study to evaluate the safety of IMRT-TBI for allo-HSCT recipients. Patients with hematological malignancies in remission who were scheduled for allo-HSCT with TBI-based myeloablative conditioning were eligible. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were engraftment rate, overall survival, relapse rate, non-relapse mortality, and the incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively). Between July 2018 and November 2018, ten patients were recruited with a median observation duration of 571 days after allo-HSCT (range, 496-614). D80% for planning target volume (PTV) in all patients was 12.01 Gy. Average D80% values for lungs, kidneys and lenses (right/left) were 7.50, 9.03 and 4.41/4.03 Gy, respectively. Any early AEs (within 100 days of allo-HSCT) were reported in all patients. Eight patients experienced oral mucositis and gastrointestinal symptoms. One patient experienced Bearman criteria grade 3 regimen-related toxicity (kidney and liver). All cases achieved neutrophil engraftment. There was no grade III-IV aGVHD or late AE. One patient died of sinusoidal obstruction syndrome 67 days after allo-HSCT. The remaining nine patients were alive and disease-free at final follow-up. Thus, IMRT-TBI was well tolerated in terms of early AEs in adult patients who underwent allo-HSCT; this warrants further study with longer observation times to monitor late AEs and efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jrr/rraa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674702PMC
November 2020

Prognostic impact of TP53 mutation, monosomal karyotype, and prior myeloid disorder in nonremission acute myeloid leukemia at allo-HSCT.

Bone Marrow Transplant 2021 02 5;56(2):334-346. Epub 2020 Aug 5.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in nonremission acute myeloid leukemia (AML) are dismal [2-year overall survival (OS): 20-30%]. Though several risk classifications have been used, some factors are unavailable until the start of conditioning or transplantation. We analyzed prognostic gene mutations by targeted next-generation sequencing to identify predisposing factors for predicting OS at 1 month before transplantation. We enrolled 120 patients with nonremission AML who underwent first allo-HSCT between 2005 and 2018. Mutations were found in 98 patients; frequently mutated genes were FLT3-ITD, TP53, RUNX1, and WT1. TP53 mutation was detected in 21 patients and was the only predictor of poor OS. Multivariate analysis using Cox regression hazard model revealed primary AML, monosomal karyotype (MK), and TP53 mutation as independent factors for predicting poor OS. Based on these, patients were stratified into three groups. The low-risk group included patients with prior myeloid disorder without MK (n = 26). Among the rest, patients with TP53 mutation were assigned to the high-risk group (n = 19) and the rest into the intermediate-risk group (n = 75). Two-year OS in low-, intermediate-, and high-risk groups differed significantly (50.0%, 24.9%, and 0%, respectively). This suggests that the indication of allo-HSCT should be carefully judged for high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01016-9DOI Listing
February 2021

Allogeneic hematopoietic cell transplantation efficacy in patients with Philadelphia chromosome-positive acute myeloid leukemia in complete remission.

Bone Marrow Transplant 2021 01 31;56(1):232-242. Epub 2020 Jul 31.

Division of Hematology, Department of Internal Medicine, Aichi Medical University, Nagakute, Japan.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) confers a dismal prognosis when treated with chemotherapy alone. Data on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes are limited. We retrospectively analyzed 4649 AML patients who received allo-HCT and were in complete remission. Outcomes of Ph+ AML (n = 30), intermediate-risk, and poor-risk AML patients were compared. The 3-year overall survival after allo-HCT was similar in intermediate-risk (62.7%; 95% CI: 61.0-64.3%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.42); however, it differed significantly between the poor-risk (49.7%; 95% CI: 45.9-53.4%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.049). Disease-free survival in Ph+ AML patients was comparable to that in intermediate-risk patients but better than that in poor-risk patients. Relapse rates were significantly lower in Ph+ AML patients than in other groups. Non-relapse mortality (NRM) rates were similar among groups. Multivariate analysis showed that Ph+ AML was not a significant predictor of poor prognosis in terms of overall survival, disease-free survival, relapse, and NRM. Our data showed better post-transplant outcomes for Ph+ AML patients than for those with poor-risk AML. Hence, allo-HCT could be a feasible treatment option for Ph+ AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01011-0DOI Listing
January 2021

Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment-free remission.

Cancer Sci 2020 Aug 26;111(8):2923-2934. Epub 2020 Jun 26.

Department of Hematology, Nippon Medical School, Tokyo, Japan.

This study presents the final report of the multicenter, prospective tyrosine kinase inhibitor discontinuation study, D-STOP, after a 3-year follow-up of 54 patients with chronic CML who discontinued dasatinib after a sustained deep molecular response (DMR) for ≥2 years with dasatinib treatment. Estimated treatment-free remission (TFR) rates at 12 and 36 months were 63.0% [95% confidence interval (CI): 48.7-74.3] and 59.3% (95% CI: 45.0-71.0), respectively. CD3 CD56 NK, CD16 CD56 NK, and CD57 CD56 NK large granular lymphocyte (NK-LGL), CD8 CD4 cytotoxic T cell, and CD57 CD3 T-LGL cell numbers were relatively elevated throughout the 24-month consolidation only in failed patients who molecularly relapsed within 12 months. In successful patients, these subsets elevated transiently after 12 months, but returned to basal levels after 24-month consolidation. Therefore, smaller changes in NK/T, particularly the NK subset throughout consolidation, reflected higher TFR rates. TFR rates of those patients exhibiting elevation in CD3 CD56 NK >376 cells/μL, CD16 CD56 NK > 241 cells/μL, or CD57 CD56 NK-LGL >242 cells/μL during consolidation compared with others were 26.7% (8.3%-49.6%) vs 78.3% (55.4%-90.3%), HR 0.032 (0.0027-0.38; P = .0064), 31.2% (11.4%-53.6%) vs 85.0% (60.4%-94.9%), HR 0.039 (0.0031-0.48; P = .011), or 36.8% (16.5%-57.5%) vs 77.3% (53.7%-89.8%), HR 0.21 (0.065-0.69; P = .010), respectively. Therefore, silent responses of T/NK subsets to dasatinib throughout consolidation were significant for longer TFR. Elevated NK/T, particularly NK lymphocytes responsive to dasatinib, may be immunologically insufficient to maintain TFR. Their decline, subsequently replaced by altered lymphocyte population with less response to dasatinib during sustained DMR, might be immunologically significant. (D-STOP, NCT01627132).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419041PMC
August 2020

Geriatric nutritional risk index as a useful prognostic factor in second allogeneic hematopoietic stem cell transplantation.

Ann Hematol 2020 Jul 10;99(7):1655-1665. Epub 2020 Jun 10.

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

Second allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a low survival outcome and a high non-relapse mortality (NRM) rate which is a major obstacle to this treatment. We hypothesized that the status of malnourishment after first allo-HSCT as represented by the geriatric nutritional risk index (GNRI) could be used as a prognostic factor to determine the outcomes of second allo-HSCT. A total of 108 patients with a median age of 42 (range, 17-69) years, who received second allo-HSCT for disease recurrence after first allo-HSCT from our institution, were included in this study. Low GNRI had a significant impact on NRM at 2 years after second allo-HSCT: 56.9% in patients with GNRI ≤ 92 compared with 27.5% in patients with GNRI > 92 (P = 0.002). In multivariate analysis, GNRI of ≤ 92 was the only significant factor for NRM (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.15-4.56, P = 0.018). High-risk disease status at second allo-HSCT (HR 2.74, 95% CI 1.46-5.14, P = 0.002) and GNRI of ≤ 92 (HR 1.70, 95% CI 1.02-2.82, P = 0.042) were identified as significant factors for overall survival (OS). A score of 1 was assigned to each factor, and the OS rate at 2 years after second allo-HSCT decreased according to the score: 53.0% in patients with score 0, 32.3% with score 1, and 2.5% with score 2 (P < 0.001). In conclusion, GNRI could be a useful predictor for the outcomes of second allo-HSCT. A prospective study in other cohorts is warranted to validate the findings of our study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04089-0DOI Listing
July 2020

Nontuberculous mycobacterial bloodstream infections after allogeneic hematopoietic stem cell transplantation.

Int J Infect Dis 2020 Aug 29;97:131-134. Epub 2020 May 29.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Non-tuberculous mycobacteria (NTM) bacteremia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare, and limited data exist. We described the features of NTM bacteremia following allo-HSCT recipients in our hospital with a comprehensive review of the literature. Among the four cases of NTM bacteremia after allo-HSCT recipients in our hospital, two were catheter-related bloodstream infections (CRBSI), one was disseminated, and one was an unknown source of infection. Based on our report and the past literature, the incidence rate of NTM bacteremia was 0.1-1.3%. CRBSI (57%) was more common than disseminated infection (29%). Most cases with CRBSI were caused by rapidly growing mycobacteria (88%) and showed good prognoses under appropriate antimicrobial therapies. In contrast, slowly growing mycobacteria (71%) was more common than rapidly growing mycobacteria in disseminated NTM bacteremia. Although disseminated NTM bacteremia can remain stable with appropriate long-term management, three out of seven cases died of multi-organ failure. Background immunodeficiency after allo-HSCT and transplant-related comorbidities may be attributable to subsequent poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2020.05.079DOI Listing
August 2020

Bone turnover markers as an aid to monitor osteoporosis following allogeneic hematopoietic stem cell transplantation.

Ann Hematol 2020 Aug 25;99(8):1873-1882. Epub 2020 May 25.

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo, 113-0021, Japan.

Bone turnover markers (BTMs) are useful parameters for assessing fracture risk and unlike bone mineral density (BMD), can be measured at any institution. However, BTM values have not been established in patients post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the practicality of BTMs in patients who underwent allo-HSCT by measuring levels of the serum bone resorption marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), and the bone formation marker, bone-specific alkaline phosphatase (BAP), together with BMD, 1 month before and 6 months after allo-HSCT. Patients were classified into either the alendronate group (n = 14) if alendronate treatment (35 mg orally per week) was administered before allo-HSCT or within 1 month after allo-HSCT, or the control group (n = 16), in which patients did not receive alendronate treatment. Despite the high frequency of corticosteroids users in the alendronate group (71.4 vs. 18.9%; p < 0.01), the mean percentage changes in BMD at the lumbar spine (- 2.9 vs. - 3.1%; p = 0.44) and femoral neck (- 3.2 vs. - 4.1%; p = 1.00), TRACP-5b levels (- 4.8 vs. 9.9%; p = 0.45), and BAP levels (6.9 vs. 1.0%; p = 0.85) during 6 months did not differ significantly between the alendronate and control groups. Additionally, the percentage changes in BMD at the lumbar spine were negatively associated with the TRACP-5b levels 6 months after allo-HSCT (p = 0.03, r = 0.40). Our results indicate the possible effectiveness of alendronate treatment in allo-HSCT patients. BTM levels could be useful to monitor the BMD changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-04090-7DOI Listing
August 2020

The sensitivity of the -ITD detection method is an important consideration when diagnosing acute myeloid leukemia.

Leuk Res Rep 2020 19;13:100198. Epub 2020 Apr 19.

Department of Hematology, Nippon Medical School, Tokyo, Japan.

-internal tandem duplication (-ITD) is a key predictive factor for the prognosis of acute myeloid leukemia (AML). We compared the detection sensitivity of fragment analysis with that of PCR-electrophoresis using MV4-11 (-ITD) and NKM-1 (-wild type) cell lines. DNA of these cells was mixed at different ratios and subjected to PCR-electrophoresis or fragment analysis. PCR-electrophoresis was found to have an -ITD allelic ratio (AR) detection limit of 0.034-0.072. Visual inspection of the PCR-electrophoresis revealed a lower detection sensitivity than that of fragment analysis. Therefore, it is essential to conduct fragment analysis when screening for -ITD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lrr.2020.100198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184170PMC
April 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

Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34 cells under cytokine stimulation.

Cancer Sci 2020 May 14;111(5):1851-1855. Epub 2020 Apr 14.

Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.

Gene rearrangements of MLL/KMT2A or RUNX1 are the major cause of therapy-related leukemia. Moreover, MLL rearrangements are the major cause of infant leukemia, and RUNX1 rearrangements are frequently detected in cord blood. These genes are sensitive to topoisomerase II inhibitors, and various genes have been identified as potential fusion partners. However, fetal exposure to these inhibitors is rare. Therefore, we postulated that even a proliferation signal itself might induce gene rearrangements in hematopoietic stem cells. To test this hypothesis, we detected gene rearrangements in etoposide-treated or non-treated CD34 cells cultured with cytokines using inverse PCR. In the etoposide-treated cells, variable-sized rearrangement bands were detected in the RUNX1 and MLL genes at 3 hours of culture, which decreased after 7 days. However, more rearrangement bands were detected in the non-treated cells at 7 days of culture. Such gene rearrangements were also detected in peripheral blood stem cells mobilized by cytokines for transplantation. However, none of these rearranged genes encoded the leukemogenic oncogene, and the cells with rearrangements did not expand. These findings suggest that MLL and RUNX1 rearrangements, which occur with very low frequency in normal hematopoietic progenitor cells, may be induced under cytokine stimulation. Most of the cells with gene rearrangements are likely eliminated, except for leukemia-associated gene rearrangements, resulting in the low prevalence of leukemia development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226195PMC
May 2020

Influence of HLA 1-3-locus mismatch and antithymocyte globulin administration in unrelated bone marrow transplantation.

Ann Hematol 2020 May 23;99(5):1099-1110. Epub 2020 Mar 23.

Division of Hematology, Jichi Medical University Saitama Medical Center, 1-847, Amanuma-cho, Omiya-ku, Saitama-city, Saitama, 330-8503, Japan.

For patients without an HLA-matched donor, an HLA-mismatched unrelated donor (MMUD) has been considered as an alternative donor in allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a nationwide retrospective study to compare the transplant outcomes among 1-, 2-, and 3-locus (allele/antigen) mismatched unrelated donors (1MMUD n = 2044, 2MMUD n = 492, and 3MMUD n = 73) in allo-HCT and to assess the impact of antithymocyte globulin (ATG) in allo-HCT from 1-3MMUD. 2MMUD and 3MMUD were independent significant adverse factors for grade III-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR] 1.72, p < 0.001 and HR 2.48, p < 0.001), non-relapse mortality (NRM) (HR 1.47, p < 0.001 and HR 2.00, p < 0.001), and overall survival (OS) (HR 1.21, p = 0.0066 and HR 1.60, p = 0.0015). Conversely, the use of ATG was an independent favorable factor for grade III-IV acute GVHD (HR 0.43, p < 0.001), NRM (HR 0.51, p < 0.001), and OS (HR 0.74, p = 0.0012). On the other hand, HLA compatibility and the use of ATG were not associated with a risk of relapse. An interaction test between the number of HLA mismatches and the use of ATG revealed that the effect of ATG on NRM and OS in the 2MMUD group was significantly less than that in the 1MMUD group (HR 1.53, p = 0.036 and HR 2.34, p = 0.0046). This study indicated that the number of HLA mismatches and the use of ATG were significantly associated with not only GVHD, but also NRM and OS. Whereas the use of ATG could improve transplant outcomes in allo-HCT from 1MMUD, its effectiveness with 2MMUD and 3MMUD was limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-020-03995-7DOI Listing
May 2020

Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation.

Blood Adv 2020 03;4(6):1051-1061

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

Cytomegalovirus (CMV) infection is a major complication in allogeneic stem cell transplantation. The utility of CMV prophylaxis with letermovir has been reported; however, the specific applications remain unclear. In this study, we retrospectively analyzed large-scale registry data (N = 10 480) to clarify the risk factors for nonrelapse mortality (NRM) in connection with CMV reactivation. First, we identified risk factors for CMV reactivation using multivariate analysis and developed a scoring model. Although the model effectively stratified reactivation risk into 3 groups (43.7% vs 60.9% vs 71.5%; P < .001), the 3-year NRM was significantly higher in patients with CMV reactivation, even in the low (20.9% vs 13.0%, P < .001), intermediate (21.4% vs 15.6%; P < .001), and high (29.3% vs 18.0%; P < .001) reactivation risk groups. Next, survival analysis considering competing risks, time-dependent covariates, and interaction terms for exploring the heterogeneous impact of CMV reactivation on NRM in the training cohort revealed that chronic myeloid leukemia (CML) (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.05-2.96; P = .033), good performance status (PS) (HR, 1.42; 95% CI, 1.04-1.94; P = .028), HLA-matched donor (HR, 1.34; 95% CI, 1.06-1.70; P = .013), and standard-risk disease (HR, 1.28; 95% CI, 1.04-1.58; P = .022) were associated with increased NRM. In the test cohort, CMV reactivation was significantly associated with increased 3-year NRM among patients with 2 to 4 factors (22.1% vs 13.1%; P < .001) but was comparable among patients with 0 or 1 factor (23.2% vs 20.4%; P = .62). We propose that CMV prophylaxis should be determined based on reactivation risk, as well as these other factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094017PMC
March 2020

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation.

Bone Marrow Transplant 2020 07 18;55(7):1388-1398. Epub 2020 Feb 18.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients' characteristics were: median age, 61 (34-72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-0833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329632PMC
July 2020

A mathematical model for dynamics of soluble form of DNAM-1 as a biomarker for graft-versus-host disease.

PLoS One 2020 10;15(2):e0228508. Epub 2020 Feb 10.

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

DNAM-1 (CD226) is an activating immunoreceptor expressed on T cells and NK cells and involved in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously reported that a soluble form of DNAM-1 (sDNAM-1) is generated by shedding from activated T cells. Moreover, higher serum levels of sDNAM-1 in patients before allo-HSCT is a predictive biomarker for the development of aGVHD based on the retrospective univariate and multivariate analyses in allo-HSCT patients. However, it remains unclear how the serum levels of sDNAM-1 are regulated after allo-HSCT and whether they are associated with the development of aGVHD. Here, we constructed a mathematical model to assess the dynamics of sDNAM-1 after allo-HSCT by assuming that there are three types of sDNAM-1 (the first and the second were from alloreactive and non-alloreactive donor lymphocytes, respectively, and the third from recipient lymphocytes). Our mathematical model fitted well to the data set of sDNAM-1 in patients (n = 67) who had undergone allo-HSCT and suggest that the high proportion of the first type of sDNAM-1 to the total of the first and second types is associated with high risk of the development of severe aGVHD. Thus, sDNAM-1 after allo-HSCT can be a biomarker for the development of aGVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228508PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010286PMC
May 2020

[Tyrosine kinase inhibitor maintenance therapy following allogenic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia].

Rinsho Ketsueki 2020 ;61(1):11-19

Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.

There have been many reports regarding tyrosine kinase inhibitor (TKI) administration to prevent relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, there are no commonly accepted standards for the choice of TKIs. We retrospectively analyzed the clinical features of Ph+ALL patients who received TKIs after allo-HSCT at our institution. The prophylactic administration of TKIs (pro) occurred in eight patients, and six patients received preemptive TKI administration (pre). The median follow-up period after allo-HSCT was 1,427 (range, 161-2,428) days in the pro group and 773.5 (range, 156-2,243) days in the pre group. Only one patient with non-hematological complete remission before allo-HSCT relapsed among the patients in the pro group. In the pre group, four patients treated with only TKIs achieved negativity of minimal residual disease. The 2-year overall survival rate after allo-HSCT was 85.7% in the pro group and 100% in the pre group. We used lower doses of TKIs compared with previous reports and this analysis shows that the dose is safe and effective as the treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.61.11DOI Listing
February 2020

Potential prognostic impact of EBV RNA-seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort.

FEBS Open Bio 2020 03 16;10(3):455-467. Epub 2020 Feb 16.

Center for Medical Research Cooperation, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Japan.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), whose prognosis remains controversial, is diagnosed by in situ hybridization of EBV-derived EBER1/2 small RNAs. In The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) project, the EBV molecular subtype was determined through a combination of multiple next-generation sequencing methods, but not by the gold standard in situ hybridization method. This leaves unanswered questions regarding the discordance of EBV positivity detected by different approaches and the threshold of sequencing reads. Therefore, we reanalyzed the TCGA-STAD RNA sequencing (RNA-seq) dataset including 375 tumor and 32 normal samples, using our analysis pipeline. We defined a reliable threshold for EBV-derived next-generation sequencing reads by mapping them to the EBV genome with three different random arbitrary alignments. We analyzed the prognostic impact of EBV status on the histopathological subtypes of gastric cancer. EBV-positive cases identified by reanalysis comprised nearly half of the cases (49.6%) independent from infiltrating lymphocyte signatures, and showed significantly longer overall survival for adenocarcinomas of the 'not-otherwise-specified' type [P = 0.016 (log-rank test); hazard ratios (HR): 0.476; 95% CI: 0.260-0.870, P = 0.016 (Cox univariate analysis)], but shorter overall survival for the tubular adenocarcinoma type [P = 0.005 (log-rank test); HR: 3.329; 95% CI: 1.406-7.885, P = 0.006 (Cox univariate analysis)]. These results demonstrate that the EBV positivity rates were higher when determined by RNA-seq than when determined by EBER1/2 in situ hybridization. The RNA-seq-based EBV positivity demonstrated distinct results for gastric cancer prognosis depending on the histopathological subtype, suggesting its potential to be used in clinical prognoses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/2211-5463.12803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050242PMC
March 2020

Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic phase: the D-NewS Study of the Kanto CML Study Group.

Int J Hematol 2020 Mar 1;111(3):401-408. Epub 2020 Jan 1.

Department of Hematology Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8603, Japan.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naïve chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02801-zDOI Listing
March 2020
-->