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Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient' s death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.

DOI： 10.1272/jnms.JNMS.2023_90-105

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BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, causing widespread mortality. Many patients with COVID-19 have been treated in homes, hotels, and medium-sized hospitals where doctors were responsible for assessing the need for critical care hospitalization. This study aimed to establish a severity prediction score for critical care triage. METHOD: We analyzed the data of 368 patients with mild-to-moderate COVID-19 who had been admitted to Fussa Hospital, Japan, from April 2020 to February 2022. We defined a high-oxygen group as requiring ≥4 l/min of oxygen. Multivariable logistic regression was used to construct a risk prediction score, and the best model was selected using a stepwise selection method. RESULTS: Multivariable analysis showed that older age (≥70 years), elevated creatine kinase (≥127 U/L), C-reactive protein (≥2.19 mg/dL), and ferritin (≥632.7 ng/mL) levels were independent risk factors associated with the high-oxygen group. Each risk factor was assigned a score ranging from 0 to 4, and we referred to the final overall score as the Fussa score. Patients were classified into two groups, namely, high-risk (total risk factors, ≥2) and low-risk (total risk score, <2) groups. The high-risk group had a significantly worse prognosis (low-risk group, undefined vs. high-risk group, undefined; P< 0.0001). CONCLUSIONS: The Fussa score might help to identify patients with COVID-19 who require critical care hospitalization.

DOI： 10.7759/cureus.31210

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Sarcopenia is a prognostic factor for cancer. Because creatinine is formed from creatine phosphate in muscle tissue, urinary creatinine excretion (UCE) serves as an index of muscle volume. However, as of yet, there are no studies assessing the clinical impact of UCE or weight- adjusted urinary creatinine excretion (WA-UCE) on allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We analyzed the association between pre-transplant WA-UCE and transplant outcomes among 164 adult patients with acute myeloid leukemia in complete remission who underwent their first allo-HSCT at our center. The patients were classified into a high (n = 106) and a low WA-UCE group (n = 58) for predicting overall survival (OS) based on the receiver operating characteristics curve. On multivariate analysis, low WA-UCE was associated with poor OS, progression-free survival and a high incidence of non-relapse mortality. WA-UCE has the potential to be an objective biomarker for predicting transplant outcomes, especially the incidence of infection-related death.

DOI： 10.1080/10428194.2022.2109334

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AIM: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. METHODS: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m2 on day -7, ETP 200 mg/m2 on days -6, -5, -4, -3 and Ara-C 2 g/m2 on day -4 -3, and MEL 140 mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. RESULTS: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. CONCLUSION: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

DOI： 10.1111/ajco.13780

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Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.

DOI： 10.1007/s12185-022-03328-6

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Cyclophosphamide (CY)-induced cardiotoxicity involves rare lethal complications. We previously reported the cardiac events of 811 allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients; 12 out of 811 recipients (1.5%) developed fatal heart failure. The mortality rate was also very high (91.6%, 11/12). CY dose (200 mg/kg or more) was reported as the independent risk factor. The main disease in patients treated with 200 mg/kg or more of CY was severe aplastic anemia (AA). Therefore, we reduced the dose of CY during conditioning for AA (from 200 to 100 mg/kg), and then we analyzed the clinical features of 294 patients who received a total dose of at least 100 mg/kg of CY. We also compared the clinical features between the current study and our previous study. The proportion of patients treated with at least 200 mg/kg of CY was reduced from 4.2% to 0%. However, CY-induced heart failure occurred in four of the 294 patients (1.4%), which was similar to the finding reported in our previous study (1.5%). Two of these four patients received a post-transplant CY (PTCy) regimen (CY 100 mg/kg). All four patients were treated in the cardiac intensive care unit (C-ICU), and two patients survived. In summary, even the CY dose of 120 mg/kg or less would cause cardiotoxicity. We should also carefully monitor patients treated with PTCy, considering the possibility of CY-induced cardiotoxicity. Early diagnosis and ICU management have contributed to improved outcomes.

DOI： 10.1111/ajco.13674

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Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27-72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease.

DOI： 10.1007/s12185-021-03233-4

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Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

DOI： 10.1182/bloodadvances.2021004292

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Variants of the t (8;21) (q22;q22) involving chromosome 8, 21, and other chromosomes account for about 3% of all t (8;21) (q22;q22) in patients with acute myeloid leukemia (AML). However, the prognosis of AML with variant t (8;21) remains unknown due to the scarcity of reported cases. Herein we report a case of AML with t (6;21;8) (p23;q22;q22). Fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. This is the first report on a variant of t (8;21) involving the breakpoint 6p23. After induction chemotherapy, our patient achieved complete remission and has been stable for four years.

DOI： 10.11406/rinketsu.63.104

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Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers’ cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

DOI： 10.1007/s12328-021-01438-y

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Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers' cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

DOI： 10.1007/s12328-021-01438-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT.

DOI： 10.1002/cam4.3920

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cam4.3920

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Minimal residual disease (MRD) monitoring by quantitative real-time reverse transcription PCR (qRT-PCR) is the standard of care in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We evaluated the impact of MRD status at hematopoietic cell transplantation (HCT) on relapse, as measured by a unified protocol at a central laboratory. Only patients with Ph-positive ALL who had minor transcripts (e1a2) and who underwent allogeneic HCT in first complete remission between 2008 and 2017 were included. First, patients with negative-MRD (n = 196) and positive-MRD (n = 61) at HCT were analyzed. As expected, MRD positivity at HCT was significantly associated with an increased risk of hematological relapse (hazard ratio [HR], 2.91; 95% CI 1.67-5.08; P < 0.001) in the multivariate analysis. Next, patients with positive-MRD were divided into low-MRD (n = 39) and high-MRD (n = 22) groups. In the multivariate analysis, high-MRD at HCT was not significantly associated with an increased risk of hematological relapse compared to the low-MRD group (HR 1.10; 95% CI 0.54-2.83; P = 0.620). These results indicate that the therapeutic decisions should be made based on MRD positivity, rather than on the MRD level, at HCT.

DOI： 10.1007/s12185-021-03094-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

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.

DOI： 10.1007/s12185-021-03146-2

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Other Link： https://link.springer.com/article/10.1007/s12185-021-03146-2/fulltext.html

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Limited data exist regarding the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) among adolescent and young adult (AYA) patients with acute myeloid leukemia (AML). Here we analyzed the features and outcomes of AYA patients with AML who had achieved complete remission (CR) and those who had not (non-CR) at allo-HCT. We retrospectively analyzed 2350 AYA patients with AML who underwent allo-HCT with a myeloablative conditioning regimen and who were consecutively enrolled in the Japanese nationwide HCT registry. The difference in overall survival (OS) between younger (age 16 to 29 years) and older AYA (age 30 to 39 years) patients in CR at transplantation was not significant (70.2% versus 71.7% at 3 years; P = .62). Meanwhile, this difference trended toward a statistical significance between younger and older AYA patients in non-CR at transplantation (39.5% versus 34.3% at 3 years; P = .052). In AYA patients in CR and non-CR, the age at transplantation did not affect relapse or nonrelapse mortality (NRM). In AYA patients in CR, no difference in OS was observed between those who received total body irradiation (TBI) and those who did not (71.1% versus 70.5% at 3 years; P = .43). AYA patients who received TBI-based conditioning had a significantly lower relapse rate and higher NRM than those who underwent non-TBI-based conditioning (relapse: 19.8% versus 24.1% at 3 years [P = .047]; NRM: 14.7% versus 11.1% at 3 years [P = .021]). In contrast, among the non-CR patients, there were no differences between the TBI and non-TBI groups with respect to OS (P = .094), relapse (P = .83), and NRM (P = .27). Our data indicate that outcomes may be more favorable in younger AYA patients than in older AYA patients in non-CR at transplantation, and that outcomes of TBI-based conditioning could be comparable to those of non-TBI-based conditioning for AYA patients.

DOI： 10.1016/j.jtct.2020.12.013

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Erythropoiesis-stimulating agent (ESA) has been recognized as an effective way in the treatment of anemia due to chronic kidney disease, but we sometimes see intractable hemodialysis (HD) patients. The causes of ESA-resistant anemia in HD patients include deficiency of trace elements. We report the case of an 89-year-old male who developed pancytopenia after taking an excessive amount of zinc formulation for ESA-resistant anemia during maintenance dialysis. He was prescribed zinc acetate hydrate formulation about 6 months before his presentation. He was found to have pancytopenia 1 month before his presentation, at which point he was introduced to our hospital. We suspected a copper deficiency at the first visit and stopped zinc and added copper, and his condition subsequently improved without being handicapped. Zinc antagonizes copper, so we must take care to diagnose patients ingesting zinc supplements.

DOI： 10.4103/jrms.JRMS_25_19

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<title>Abstract</title>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.

DOI： 10.1038/s41598-020-79363-2

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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.

DOI： 10.1093/jrr/rraa078

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The aim of this study was to develop a comprehensive system for predicting non-relapse mortality after allogeneic hematopoietic cell transplantation (HCT) during first complete remission (CR) of acute myeloid leukemia (AML). After dividing 2344 eligible patients randomly into a training set and a validation set, we first identified and scored five parameters, that is, age, sex, performance status, HCT-comorbidity index (HCT-CI), and donor type, on the basis of their impact on non-relapse mortality for patients in the training set. The non-relapse mortality-J (NRM-J) index using the sum of these scores was then applied to patients in the validation set, resulting in a clear differentiation of non-relapse mortality, with expected 2-year rates of 11%, 16%, 27%, and 33%, respectively (P < 0.001). The estimated c-statistic was 0.67, which was significantly higher than that of the European Society for Blood and Marrow Transplantation score (0.60, P = 0.002) and the HCT-CI (0.57, P < 0.001). The NRM-J index showed a significant association with overall survival, but not with relapse. Our findings demonstrate that the NRM-J index is useful for predicting post-transplant non-relapse mortality for patients with AML in first CR, for whom the decision of whether to perform allogeneic HCT is critical.

DOI： 10.1038/s41409-020-01032-9

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BACKGROUND: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. METHODS: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. RESULTS: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. CONCLUSION: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.

DOI： 10.1272/jnms.JNMS.2020_87-404

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BACKGROUND: Peripheral blood stem cell (PBSC) collection places a burden on the patient and ideally should be completed in a single procedure. Consequently, a convenient predictive factor is needed for clinical use. METHODS: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9×106 CD34-positive cells/kg (range: 0.3-47.4×106 cells/kg) was collected on the first day. We defined failure as an inability to collect 2.0×106 cells/kg on the first day. Patients were classified into failure (n = 25, 34.7%) and success groups (n = 47, 65.3%), and their clinical backgrounds were analyzed. RESULTS: The success group included a significantly larger number of cases in which a differential white blood cell count of the peripheral blood on the day of PBSC collection detected promyelocytes (n = 34, 72.3% vs. failure group: n = 11, 44.0%; P＝0.008). Sixty-two patients underwent autologous PBSC transplantation with a median of 5.6×106 transplanted cells/μL (range: 1.60-47.4×106 cells/μL). Among transplanted patients, no significant differences were observed between the success and failure groups in terms of the intervals until neutrophil, platelet, and red blood cell engraftment. CONCLUSION: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.

DOI： 10.1272/jnms.JNMS.2021_88-104

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In patients with hematologic malignancies, acute kidney injury (AKI) is the most common kidney complication requiring nephrologist consultation. Although the causes of AKI are multifactorial, primary tumor infiltration is rare in patients with acute myeloblastic leukemia (AML). This makes it challenging to determine the cause of AKI and the optimal chemotherapy regimen for AML. We describe two cases of AML (French-American-British classification: M2, M4) in patients with AKI requiring hemodialysis. We successfully identified the cause of AKI as primary leukemic infiltration and started induction chemotherapy in the setting of hemodialysis. This treatment significantly improved renal function and resulted in AML remission. In this report, we describe several clinical characteristics of AKI due to primary tumor infiltration. In addition, we emphasize the importance of onconephrology, a new subspecialty concerned with the complex relationship between the kidneys and cancer.

DOI： 10.1272/jnms.JNMS.2020_87-108

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Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-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 (FLT3-ITD) and NKM-1 (FLT3-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 FLT3-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 FLT3-ITD.

DOI： 10.1016/j.lrr.2020.100198

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BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

DOI： 10.1159/000504354

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The prognostic significance of FLT3-tyrosine kinase domain (TKD) mutations remains unknown. To investigate the prognostic impact of FLT3-TKD, 676 de novo acute myeloid leukemia (AML), we retrospectively analyzed cases and conducted a review of the literature. Of the 676 de novo AML cases, 34 (5.0%) were FLT3-TKD-positive; both FLT3-TKD and FLT3-ITD were noted in only two cases (0.3%). Although no significant differences in relapse-free survival (RFS) were noted, FLT3-TKD-positive cases showed better prognoses than FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.152). For overall survival (OS), although FLT3-TKD-positive cases showed prognoses similar to those for FLT3-WT cases, their prognoses were significantly better than those of FLT3-ITD-positive cases (FLT3-TKD versus FLT3-ITD, p = 0.032). Moreover, the 5-year OS for FLT3-TKD-positive cases was 46.1%, indicating that this as an intermediate prognosis group. Although no reports from Asia have indicated a frequency of FLT3-TKD-positive cases > 10%, several reports from Europe and the United States have indicated frequencies > 10%. This suggests the possibility that FLT3-TKD-positive cases are less common in Asia than in Europe and the United States. We anticipate that in the future, the appearance of targeting agents, such as FLT3 inhibitors, will improve the prognosis of FLT3-TKD-positive AML relative to that of FLT3-WT AML.

DOI： 10.1007/s12185-019-02720-z

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INTRODUCTION: Acute myelogenous leukemia (AML) in elderly patients is associated with an increased incidence of complications and treatment-related toxicity because of the frequency of comorbid disease and age-related deterioration in organ function. Despite advances in AML treatment in recent years, elderly patients have experienced limited benefit, and their outcomes remain poor. This study aimed to perform a comprehensive gene mutation analysis in elderly AML patients and identify gene mutations that could serve as prognostic factors. METHODS: An analysis of gene mutations was performed for 281 AML patients, including 98 elderly patients aged 65 years or above. RESULTS: Compared to younger AML patients, elderly patients showed a higher frequency of the following gene mutations: TP53 (P = 0.026), PTPN11 (P = 0.006), RUNX1 (P = 0.024), TET2 (P = 0.002), and ASXL1 (P = 0.023). The complete remission rate was significantly lower in DNMT3A mutation-positive cases (4.26%, P = 0.011) and TP53 mutation-positive cases (2.13%, P = 0.031) than in negative cases. The overall survival rate was significantly poorer in cases with FLT3-ITD (P = 0.003), DNMT3A (P = 0.033), or TP53 mutation (P < 0.001). Conversely, cases with PTPN11 mutation (P = 0.014) had a significantly more favorable prognosis. In multivariate analysis, FLT3-ITD (P = 0.011) and TP53 mutation positivity (P = 0.002) were independent poor prognostic factors, as were a performance status of 3 or above (P < 0.001) and poor cytogenetic prognosis (P = 0.001). In contrast, PTPN11 mutation positivity (P = 0.023) was an independent favorable prognosis factor. CONCLUSION: Analysis of gene mutations in elderly AML patients is very important, not only for establishing prognosis, but also for introducing appropriate molecular-targeted treatments.

DOI： 10.1111/ijlh.13025

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The prognosis of atypical chronic myeloid leukemia (aCML) patients is poor, but some patients with a suitable donor can be treated with allogeneic hematopoietic stem cell transplantation (HSCT). However, many of these patients cannot be treated with HSCT due to their age. The effectiveness of decitabine was recently indicated in case reports; however, the effectiveness of azacitidine (AZA) has not yet been reported. We report the case of a aCML patient successfully treated with AZA. A 66-year-old man with no remarkable medical history was admitted to our hospital because of leukocytosis. We diagnosed his disease as aCML and administered hydroxyurea (HU) and AZA. After four courses of AZA, his blood cell values improved, and he no longer needed transfusions and was able to stop HU. He continued receiving AZA without any severe complications. This is the first report that AZA is effective for the treatment of aCML.

DOI： 10.4103/ijc.IJC_506_18

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Language：Japanese   Publisher：同愛記念病院学術雑誌部  

急性前骨髄性白血病(APL)は、全トランスレチノイン酸(ATRA)と化学療法併用で有意に生存率が改善した。しかし、アントラサイクリンによる心機能障害や感染症等が問題となる。近年、ATRAと亜ヒ酸(ATO)併用で良好な成績が報告されており、当施設でATRA+ATOの地固め療法で奏功したAPL3症例を報告する。64歳男性拡張型心筋症症例、71歳女性寛解導入療法中に心房細動及び心不全発症例、52歳男性寛解導入療法中に難治性肛門周囲感染合併例の3症例を経験した。寛解を得た後にATO+ATRAによる地固め療法を行った。地固め時の平均最小好中球数は1890/μlを示し、感染症なく輸血不要であった。Grade3以上の副作用も認めず、全例分子生物学的寛解を得た。ATRA+ATOによる地固め療法は、感染症リスクを軽減し、心機能低下症例にも比較的安全に治療効果が得られると考える。(著者抄録)

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In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)-positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication (FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation-positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut-positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival [OS], 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival [RFS] P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut-positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.

DOI： 10.1182/bloodadvances.2018020305

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BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P = 0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P = 0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P = 0.0038, P = 0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor.

DOI： 10.1002/gcc.22542

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BACKGROUND: The prophylactic administration of itraconazole (ITCZ) is effective for preventing mycotic infections during chemotherapy in patients with hematologic malignancies. However, fungal infections can occur when the ITCZ does not reach an effective concentration. METHODS: We conducted a prospective study to monitor the plasma concentration of ITCZ and hydroxyl-ITCZ (OH-ITCZ) weekly and to verify whether the day 3 plasma concentration of ITCZ could predict the subsequent acquisition of an effective plasma concentration. RESULTS: A total of 39 patients who underwent 66 courses of chemotherapy were assessed in this study. An effective plasma concentration was achieved on day 7 in 34 of 63 patients (54%) and on day 14 in 35 of 59 patients (59%). A univariate analysis revealed that age, type of chemotherapy, and the body surface area were significantly associated with a high plasma concentration of ITCZ + OH-ITCZ. A linear regression analysis extracted the body surface area and the type of chemotherapy as significant factors. An receiver operating characteristic curve analysis revealed a day 3 plasma ITCZ + OH-ITCZ concentration of >656 ng/mL led to a plasma concentration that exceeded the minimum effective level on day 7; the sensitivity and specificity were 62% and 93%, respectively. CONCLUSIONS: This study showed that the measurement of the day 3 plasma concentration could lead to a better outcome in patients receiving chemotherapy for hematologic malignancies.

DOI： 10.1097/FTD.0000000000000408

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In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P<0.0001) and in patients with intermediate cytogenetic risk (P<0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged ≤70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia.

DOI： 10.3324/haematol.2016.143073

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Objective In hematological malignancy patients, the complication of acute respiratory failure often reaches a degree of severity that necessitates mechanical ventilation. The objective of the present study was to investigate the therapeutic outcomes of mechanical ventilation in hematological malignancy patients with respiratory failure and to analyze the factors that are associated with successful treatment in order to identify the issues that should be addressed in the future. Methods The present study was a retrospective analysis of 71 hematological malignancy patients with non-cardiogenic acute respiratory failure who were treated with mechanical ventilation at Nippon Medical School Hospital between 2003 and 2014. Results Twenty-six patients (36.6%) were treated with mechanical ventilation in an intensive care unit (ICU). Non-invasive positive pressure ventilation (NPPV) was applied in 29 cases (40.8%). The rate of successful mechanical ventilation treatment with NPPV alone was 13.8%. The rate of endotracheal extubation was 17.7%. A univariate analysis revealed that the following factors were associated with the successful extubation of patients who received invasive mechanical ventilation: respiratory management in an ICU (p=0.012); remission of the hematological disease (p=0.011); female gender (p=0.048); low levels of accompanying non-respiratory organ failure (p=0.041); and the non-use of extracorporeal circulation (p=0.005). A subsequent multivariate analysis revealed that respiratory management in an ICU was the only variable associated with successful extubation (p=0.030). Conclusion The outcomes of hematological malignancy patients who receive mechanical ventilation treatment for respiratory failure are very poor. Respiratory management in an ICU environment may be useful in improving the therapeutic outcomes of such patients.

DOI： 10.2169/internalmedicine.55.5822

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Language：Japanese   Publisher：日本感染症学会東日本地方会・日本化学療法学会東日本支部  

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Language：Japanese   Publisher：関東膝を語る会  

68歳女性。左膝関節前面の運動時痛を主訴とした。膝蓋腱両側に横径約5cmの楕円形の腫瘤を触知し、左膝関節可動域に制限を認めた。X線で膝蓋骨の下方に腫瘤と一致して石灰化陰影を認め、造影MRIで膝蓋下脂肪体内にT1強調像で低信号、T2強調像で軽度高信号域と低信号域が混在する不均一な弧発性の腫瘤像を認めた。膝蓋下脂肪体に発生したpara-articular osteochondromaと診断し、腫瘍切除術を施行した。病理検査で腫瘍は軟骨帽を伴い、軟骨帽と骨組織との境界部に不完全な軟骨内骨化がみられた。異型細胞や滑膜細胞の存在はなかった。以上より、para-articular osteochondromaと確定診断した。術後4ヵ月の現在、運動時痛は消失し、関節可動域も改善した。Kujala scoreは術前46点が82点に改善し、再発を認めていない。

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Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：同愛記念病院学術雑誌部  

急性前骨髄性白血病(APL)は、全トランスレチノイン酸(ATRA)と化学療法併用で有意に生存率が改善した。しかし、アントラサイクリンによる心機能障害や感染症等が問題となる。近年、ATRAと亜ヒ酸(ATO)併用で良好な成績が報告されており、当施設でATRA+ATOの地固め療法で奏功したAPL3症例を報告する。64歳男性拡張型心筋症症例、71歳女性寛解導入療法中に心房細動及び心不全発症例、52歳男性寛解導入療法中に難治性肛門周囲感染合併例の3症例を経験した。寛解を得た後にATO+ATRAによる地固め療法を行った。地固め時の平均最小好中球数は1890/μlを示し、感染症なく輸血不要であった。Grade3以上の副作用も認めず、全例分子生物学的寛解を得た。ATRA+ATOによる地固め療法は、感染症リスクを軽減し、心機能低下症例にも比較的安全に治療効果が得られると考える。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC HEMATOLOGY  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本医科大学医学会  

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