Aplastic Anemia with Epstein-Barr Virus Reactivation after Anti-thymocyte Globulin Therapy.

Lymphoproliferative disorders and Epstein-Barr virus reactivation (EBV-LPDs) have various forms of onset, ranging from infectious mononucleosis-like syndrome (IM-like) to lymphoma, although whether or not IM-like progresses to lymphoma remains unclear. A 61-year-old man was diagnosed with aplastic anemia (AA). Polyclonal atypical B-lymphocytes were observed in the peripheral blood, and IM-like was diagnosed. Atypical lymphocytes disappeared, but a gastrointestinal examination revealed diffuse large B-cell lymphoma (DLBCL). Rituximab was initiated but later discontinued because of severe acute respiratory syndrome coronavirus 2 infection. Pancytopenia due to AA exacerbation recurred. The patient ultimately died of multiple organ failure due to bacterial infection.

Fetal hemoglobin level predicts lower-risk myelodysplastic syndrome.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5 years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

[Dental care behavior and related factors during the COVID-19 state of emergency in Japan].

Objectives　In response to the spread of SARS-CoV-2, a state of emergency was declared in Japan on April 7, 2020, and in the same month, Japan's Ministry of Health, Labor, and Welfare informed dentists of the need to postpone non-emergency dental care. The purpose of this study was to identify the patients who refrained from dental care during the state of emergency in April 2020, and to clarify their personal characteristics.Methods　A total of 1,335 patients who visited 28 dental clinics in Saitama in September 2020 completed survey questionnaires; of these, 1,227 valid responses were received. Among those who sought dental care under the state of emergency, those who did not visit a dental clinic comprised the "refrained group" and those who visited the dental clinics comprised the "visited group".Results　Multivariate logistic regression analysis showed that the odds ratios for the "refrained group" were 1.69 (95%Cl: 1.12-2.55) for females, 2.91 (95%Cl: 1.88-4.49) for those younger than 65 years, 1.71 (95%Cl: 1.04-2.82) for those that visited the dental clinic less than once a month, and 7.12 (95%Cl: 4.56-11.11) for those who did not have an appointment during the state of emergency.Conclusion　In conclusion, 35% of patients in this study refrained from visiting the dental clinic during the state of emergency. The related factors for refraining from dental care were being females, middle-aged (<65 years), visiting the dental clinic less than once a month, and not having an appointment during the COVID-19 state of emergency.

The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease.

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

[Treatment-free molecular remission achieved by combination therapy with imatinib and IFNα in CML with BIM deletion polymorphism relapsed after stop imatinib].

A 51-year-old man with chronic myeloid leukemia (CML) was treated with imatinib (IM). After 24 months of treatment, he achieved a complete molecular response (CMR), which he sustained for 3 years. However, 4 months after discontinuing IM treatment, the CML relapsed. The patient was treated again with IM and achieved CMR. A combination of IM and interferon-α (IFNα) was administered for the following year, and then discontinued. The patient has since sustained CMR without therapy for 24 months, to date. This patient was found to have a BCL2L11 (BIM) deletion polymorphism. CML patients with a BIM deletion polymorphism show a low response to IM, and we infer that the BIM deletion polymorphism is a negative factor for discontinuation of IM. IFNα treatment is expected to prevent relapse during immunological surveillance. Therefore, the combination of IM and IFNα might be a feasible approach for CML patients who experience difficulty with IM discontinuation.

Combining the ABL1 kinase inhibitor ponatinib and the histone deacetylase inhibitor vorinostat: a potential treatment for BCR-ABL-positive leukemia.

Resistance to imatinib (Gleevec®) in cancer cells is frequently because of acquired point mutations in the kinase domain of BCR-ABL. Ponatinib, also known as AP24534, is an oral multi-targeted tyrosine kinase inhibitor (TKI), and it has been investigated in a pivotal phase 2 clinical trial. The histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) has been evaluated for its significant clinical activity in hematological malignancies. Thus, treatments combining ABL TKIs with additional drugs may be a promising strategy in the treatment of leukemia. In the current study, we analyzed the efficacy of ponatinib and vorinostat treatment by using BCR-ABL-positive cell lines. Treatment with ponatinib for 72 h inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner. We found that ponatinib potently inhibited the growth of Ba/F3 cells ectopically expressing BCR-ABL T315I mutation. Upon BCR-ABL phosphorylation, Crk-L was decreased, and poly (ADP-ribose) polymerase (PARP) was activated in a dose-dependent manner. Combined treatment of Ba/F3 T315I mutant cells with vorinostat and ponatinib resulted in significantly increased cytotoxicity. Additionally, the intracellular signaling of ponatinib and vorinostat was examined. Caspase 3 and PARP activation increased after combination treatment with ponatinib and vorinostat. Moreover, an increase in the phosphorylation levels of γH2A.X was observed. Previously established ponatinib-resistant Ba/F3 cells were also resistant to imatinib, nilotinib, and dasatinib. We investigated the difference in the efficacy of ponatinib and vorinostat by using ponatinib-resistant Ba/F3 cells. Combined treatment of ponatinib-resistant cells with ponatinib and vorinostat caused a significant increase in cytotoxicity. Thus, combined administration of ponatinib and vorinostat may be a powerful strategy against BCR-ABL mutant cells and could enhance the cytotoxic effects of ponatinib in those BCR-ABL mutant cells.

Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation.

Imatinib, an ABL tyrosine kinase inhibitor (TKI), has shown clinical efficacy against chronic myeloid leukemia (CML). However, a substantial number of patients develop resistance to imatinib treatment due to the emergence of clones carrying mutations in the protein BCR-ABL. The phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway regulates various processes, including cell proliferation, cell survival, and antiapoptosis activity. In this study, we investigated the efficacy of NVP-BEZ235, a dual PI3K and mTOR inhibitor, using BCR-ABL-positive cell lines. Treatment with NVP-BEZ235 for 48 h inhibited cell growth and induced apoptosis. The phosphorylation of the AKT kinase, eukaryotic initiation factor 4-binding protein 1 (4E-BP1), and p70 S6 kinase were decreased after NVP-BEZ235 treatment. The combination of NVP-BEZ235 with a BCR-ABL kinase inhibitor, imatinib, or nilotinib, induced a more pronounced colony growth inhibition, whereas the combination of NVP-BEZ235 and nilotinib was more effective in inducing apoptosis and reducing the phosphorylation of AKT, 4E-BP1, and S6 kinase. NVP-BEZ235 in combination with nilotinib also inhibited tumor growth in a xenograft model and inhibited the growth of primary T315I mutant cells and ponatinib-resistant cells. Taken together, these results suggest that administration of the dual PI3K and mTOR inhibitor NVP-BEZ235 may be an effective strategy against BCR-ABL mutant cells and may enhance the cytotoxic effects of nilotinib in ABL TKI-resistant BCR-ABL mutant cells.

Non-random chromosomal deletion clustering at 20q in Waldenström macroglobulinemia.

Chromosome change at 20q11-q12, including del(20q), is sometimes reported in plasma cell dyscrasia, but most cases are found during or after chemotherapy. It is therefore still uncertain whether del(20q) is a primary change or therapy-related. We performed cytogenetic studies and fluorescent in situ hybridization (FISH) analysis using 20q12 and 20qter probes to ascertain the possible involvement of 20q in nine patients with Waldenström macroglobulinemia (WM). The FISH study demonstrated deletions of 20q12 and/or 20qter in four of nine patients (44%) with WM at diagnosis, and one of them had the del(20q) chromosome. Moreover, one patient had de novo appearance of the del(20q) chromosome with 20q12 deletion after chemotherapy, although this patient had neither the del(20q) chromosome nor 20q12 deletion at WM diagnosis. Based on the results of this study, we conclude that chromosomal breakage at 20q13 is a non-random genetic change which plays a role in the neoplastic process of WM.

Determination of donor-derived killer immunoglobulin-like receptor (KIR) by sequential genotyping in hematopoietic stem cell-transplanted patients.

Donor killer immunoglobulin-like receptor (KIR) and KIR-ligand mismatch is considered vital in clarifying the mechanism of natural killer (NK) cell alloreactivity in hematopoietic stem cell transplantation (HSCT). In practical terms, however, it may be difficult to analyze the KIR genotype of donor cells directly as all donor cells are used for the transplant rather than for research purposes. To accurately estimate donor KIR genotype, we determined recipient KIR genotyping sequentially, at a minimum of two time points, using 19 KIR-specific primers in 10 patients who underwent HSCT. Among 10 patients, four had a KIR-ligand mismatch in the graft versus host direction. Sequential KIR genotyping showed the genotype changes at the time of engraftment (donor-derived) as well as relapse (recipient-derived). Our results highlight the utility of sequential KIR genotyping to better understand ligand-ligand, KIR-KIR, or ligand-KIR mismatches. Further studies, including a functional assay of NK cells may clarify the underlying mechanism of KIR ligand-donor KIR mismatch in HSCT.

Successful prior treatment with dasatinib followed by stem cell transplantation in a patient with CML in blastic crisis with a BCR-ABL mutation.

We report a case of imatinib- and nilotinib-resistant Ph-positive chronic myeloid leukemia (CML) in blast crisis in which successful pretreatment with dasatinib with cord blood transplantation resulted in molecular remission. Before dasatinib therapy, the patient was found to have a F359V BCR-ABL mutation. He was treated with dasatinib for just 16, 19 days before allogeneic stem cell transplantation. This successful case indicates that reduction of tumor burden by second-generation tyrosine kinase inhibitors, in combination with stem cell transplantation, might be effective to treat CML, even in the advanced phase.

Speciation of arsenic trioxide penetrates into cerebrospinal fluid in patients with acute promyelocytic leukemia.

We assessed concentrations of arsenic trioxide (As(2)O(3)) and its metabolites in the plasma and cerebrospinal fluid in acute promyelocytic leukemia patients who achieved complete remission with intravenous As(2)O(3). Arsenic trioxide exists as high molecular mass proteins and low molecular mass proteins in the plasma, and metabolites seem to be able to penetrate blood-brain barrier. Methylarsonic acid (MA) in the cerebrospinal fluid is stably detected and its level was higher than that in plasma after As(2)O(3) treatment. Trivalent arsenic (AS(III)) and dimethylarsinic acid (DMA) became detectable after As(2)O(3) infusion, though the levels of arsenic metabolites in the cerebrospinal fluid was lower than plasma levels. Results suggest that a combinatory treatment of As(2)O(3) with other chemotherapeutics could be effective for APL patients with CNS involvement.

[HIV-related multiple non-Hodgkin lymphomas].

A 35-year-old man was admitted with continuous general fatigue and low grade fever. He was HIV-positive, and had gastric diffuse large B-cell lymphoma and renal T-cell anaplastic large cell lymphoma (T-ALCL). We diagnosed double lymphomas related to AIDS. The patient received anti-retroviral therapy, and started the CHOP regimen for the double lymphomas, resulting in transient improvement. However, fever again appeared during HAART and CHOP treatment, and a right inguinal subcutaneous lesion appeared. Biopsy specimen demonstrated null cell ALCL, and this patient demonstrated multiple lymphomas. This case suggested that cancer generation was promoted by low immunity, although it is known that ambivalent tumors such as non-Hodgkin lymphomas can occur frequently.