Silent Thyroiditis Associated with Ropeginterferon α-2b in a Patient with Polycythemia Vera.

Interferon is an emerging treatment option for myeloproliferative neoplasms (MPNs), especially for polycythemia vera (PV). Previous studies of interferon used therapeutically for hepatitis C have demonstrated that one of the most important adverse events associated with interferon treatment is thyroid dysfunction, and a management strategy for thyroid dysfunction has been established. However, whether or not the recommendation is also suitable for MPN settings is unclear. In this study, one PV patient developed silent thyroiditis during a phase 2 study of ropeginterferon α-2b. This case suggests that thyroid dysfunction is an important clinical issue to consider in interferon treatment for PV.

A Pancreatic Collision Tumor Comprising Mantle Cell Lymphoma and Adenocarcinoma: A Case Report and Literature Review.

A collision tumor is a rare clinical condition where two different tumors occur synchronically within a lesion. Pancreatic collision tumors with mantle cell lymphoma (MCL) are extremely rare and have only been reported in one case to date. We herein report an elderly patient with MCL and adenocarcinoma of the pancreas with Ann Arbor stage IV and Union for International Cancer Control stage IIB, respectively. The patient received palliative therapy and died 23 months after the diagnosis. Further research and case studies are required to investigate whether or not MCL-derived cyclin D1 overexpression affects the occurrence/growth of adenocarcinomas.

Molecular and clinicopathological features of granzyme B-negative extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTL) generally expresses cytotoxic molecules, including granzyme B (GZMB), T-cell-restricted intracellular antigen-1 (TIA-1), and perforin; however, the expression of these molecules varies across cases. We performed gene expression profiling and identified unique biological and clinicopathological features of GZMB-negative ENKTL. We reviewed the clinicopathological characteristics of 71 ENKTL samples. Gene expression profiling on nine ENKTLs using multiplexed, direct, and digital mRNA quantification divided ENKTLs into Groups A (n = 7) and B (n = 2) through hierarchical clustering and t-distributed stochastic neighbor embedding. Group B was characterized by downregulation of genes associated with IL6-JAK-STAT3 signaling and inflammatory responses. GZMB mRNA expression was significantly downregulated in Group B. GZMB protein expression was evaluated with immunohistochemistry in all 71 ENKTLs, and expression data of Tyr705-phosphorylated STAT3 (pSTAT3) and MYC from our previous study was utilized. T-cell receptor gamma (TRG) gene rearrangement in the selected samples was also assessed using PCR. GZMB expression was higher in pSTAT3-positive (p = 0.028) and MYC-positive (p = 0.014) ENKTLs. Eighteen percent (13/71) of all ENKTLs were negative for GZMB (defined by positivity <10 %); patients with GZMB-negative ENKTLs were often in a higher clinical stage (p = 0.016). We observed no other correlations with clinical parameters or TRG rearrangement and no significant association between GZMB expression and survival. In conclusion, GZMB expression is highly heterogeneous in ENKTLs and is associated with the activation of the JAK-STAT3 pathway and higher MYC expression. GZMB-negative ENKTLs correlate with an advanced clinical stage, suggesting the potential utility of GZMB immunohistochemistry as a biomarker of ENKTL.

[Chronic neutrophilic leukemia/chronic eosinophilic leukemia].

Chronic neutrophilic leukemia (CNL) is a clonal disorder that is characterized by increasing mature neutrophils. Colony stimulating factor 3 receptor (CSF3R) T618I mutation was frequently identified in patients with CNL and is defined as a molecular marker of the disease. Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study. In particular, ruxolitinib was more efficient for patients with CSF3R mutation. Allogeneic stem cell transplantation (Allo-SCT) may be a curative treatment for CNL. On the other hand, further studies are needed to define the optimal method of transplantation, source of donor, conditioning therapy, and timing of transplantation. Chronic eosinophilic leukemia (CEL) is a clonal disorder that is characterized by increasing eosinophils. In the World Health Organization Classification 5th edition, diagnostic criteria for CEL are renewed. Because the new criteria will be more specific for CEL than criteria in the older edition, "not otherwise specified (NOS) " is removed from the name of the disease. Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.

The chaperone protein GRP78 released from MPN cells increases the expression of lysyl oxidase in a human stromal cell line.

Impaired function of the endoplasmic stress (ER) response causes numerous pathological conditions, including tissue fibrosis. In the present study, we aimed to determine the pathological role of ER stress response systems in myeloproliferative neoplasms (MPNs). We found increased expression of the chaperone protein glucose-regulated protein (GRP) 78, a central regulator of ER stress, in megakaryocytes from primary myelofibrosis or postessential thrombocythemia myelofibrosis patients. GRP78 was overexpressed in JAK2V617F-harboring cell lines; however, inhibitors of ER stress did not affect the expression levels of GRP78. In contrast, ruxolitinib, a well-known inhibitor of JAK2V617F, clearly blocked GRP78 expression in these cells through downregulation of transcription factor 4 (ATF4). Interestingly, GRP78 was secreted from HEL and SET-2 cells into culture media. Coculture of these cells with HS-5 cells, a human bone marrow stroma-derived cell line, induced enhanced expression of lysyl oxidase (LOX), which mediates cross-linking of collagen fibers and induces tissue fibrosis, in HS-5 cells. An anti-GRP78 neutralizing antibody abrogated LOX elevation; in contrast, recombinant GRP78 protein induced LOX protein expression in HS-5 cells. Our observations suggest that the oncogenic protein JAK2V617F induces overexpression and release of GRP78, which may induce a fibrotic phenotype in surrounding bone marrow stromal cells.

Pre-exposure prophylaxis with tixagevimab/cilgavimab for coronavirus disease 2019 (COVID-19) during the Omicron BA.5 wave at a single institution in Japan.

Pre-exposure prophylaxis with tixagevimab/cilgavimab was considered a useful strategy to protect immunocompromised patients from COVID-19 based on the phase 3 PROVENT trial conducted between November 2020 and March 2021. However, after late 2021, the dominant substrains of COVID-19 changed to Omicron substrains, which showed resistance to tixagevimab/cilgavimab. Therefore, it is important to re-evaluate the real-world efficacy of tixagevimab/cilgavimab for the prevention of COVID-19 in the Omicron era. To this end, we retrospectively evaluated the efficacy and safety of tixagevimab/cilgavimab prophylaxis for COVID-19 during the Omicron BA.5 wave in Japan. A total of 240 consecutive patients with hematologic malignancies received tixagevimab/cilgavimab at our institution from October 18, 2022, to January 31, 2023. Among them, the cumulative incidence of COVID-19 at 90 days was 6.4%. A total of 10/14 (71.4%) had mild infection, and 4/14 (28.5%) had severe infection. No patient died due to COVID-19. Adverse events consisted of deep vein thrombosis in 2 patients. Our analysis indicated that pre-exposure prophylaxis with tixagevimab/cilgavimab might have clinical effectiveness in reducing the severity of COVID-19 in Japanese HM patients, even in the Omicron BA.5 surge. It also suggested that tixagevimab/cilgavimab may be associated with cardiovascular complications.

A cross-sectional survey of symptoms and daily living among patients with polycythemia vera and their treating physicians in Japan.

OBJECTIVES: This Japanese cross-sectional survey evaluated the symptoms, daily living activities, and treatment needs of patients with polycythemia vera (PV), as perceived by patients themselves and their physicians. METHODS: The study was conducted at 112 centers (March to July 2022) and included PV patients aged ≥20 years (n = 265) and their attending physicians (n = 151). The patient and physician questionnaires included 34 and 29 questions, respectively, to assess daily living, PV symptoms, treatment goals, and physician-patient communication. RESULTS: Concerning daily living (primary endpoint), work (13.2%), leisure activities (11.3%), and family life (9.6%) were most affected by PV symptoms. Patients aged <60 years more frequently reported an impact on daily living than patients aged ≥60 years. Some patients (30%) reported anxiety about their future condition. The most common symptoms were pruritus (13.6%) and fatigue (10.9%). Pruritus was ranked as the first treatment need for patients, while physicians ranked it fourth. Concerning treatment goals, physicians prioritized thrombosis/vascular event prevention, while patients prioritized delaying PV progression. Physicians were less satisfied with physician-patient communication than patients. CONCLUSIONS: Patients' daily living was largely affected by PV symptoms. There are differences in physician and patient perceptions of symptoms, daily living, and treatment needs in Japan. TRIAL REGISTRATION: UMIN Japan identifier: UMIN000047047.

Phototunable Cell Killing by Photochromic Diarylethene of Thiazoyl and Thienyl Derivatives.

We report a unique phototunable cell killing technique using diarylethene molecules as photo-isomerizing-molecular switches. These molecules were delivered to DNA in the cell nucleus due to closed-form generated by UV light, and then blue light triggered cell killing. A UV light irradiation switches the open form, having no DNA intercalation activity, to the closed form to induce intercalation in DNA. This isomer, thus prepared ready for the action, exerts photocytotoxicity upon the subsequent blue light irradiation. Molecular biological analysis clarifies that photocytotoxicity is due to DNA double-strand breaks. Since cell death is observed only when irradiated with light where both the open- and closed-ring isomers have absorption, the possible mechanism of cell death is assumed to be due to the repeated photocyclization and photocycloreversion reactions of the diarylethene molecules, which induce irreparable damage to DNA. This unique photo-controllable action in a cell system can provide the basis of a novel scheme of phototherapy.

[Hypokalemia and potassium replacement therapy in allogeneic hematopoietic stem cell transplantation].

Hypokalemia is common in allogeneic hematopoietic stem cell transplantation (allo-HCT) patients and is associated with non-relapse mortality (NRM). Therefore, it is extremely important to replace potassium adequately. We evaluated the safety and efficacy of potassium replacement therapy by retrospectively analyzing the incidence and severity of hypokalemia in 75 patients who received allo-HCT at our institution. 75% of patients developed hypokalemia during the allo-HSCT, and 44% of patients had grade 3-4 levels of hypokalemia. NRM was significantly higher in patients with grade 3-4 hypokalemia than in patients without severe hypokalemia (one-year NRM: 30% vs 7%, p=0.008). Although 75% of the patients required potassium replacement that exceeded the range of potassium chloride solutions package inserts in Japan, we did not experience any adverse events associated with hyperkalemia. Our current observations suggested that the Japanese package insert for potassium solution injection should be revised for potassium needs.

Genetic and immunohistochemical profiling of NK/T-cell lymphomas reveals prognostically relevant BCOR-MYC association.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an Epstein-Barr virus-positive, aggressive lymphoma with a heterogeneous cell of origin and variable clinical course. Several clinical prognostic indices have been proposed for ENKTL; however, there are few pathological biomarkers. This multi-institutional study sought to identify histologically assessable prognostic factors. We investigated mutation profiles by targeted next-generation sequencing (NGS) and immunohistochemical assessments of expression of MYC, Tyr705-phosphorylated (p-)STAT3, and CD30 in 71 ENKTL samples. The median age of the patients was 66 years (range, 6-100). The most frequent mutations were in STAT3 (27%), JAK3 (4%), KMT2D (19%), TP53 (13%), BCOR (10%), and DDX3X (7%). Immunohistochemistry (IHC) revealed that ENKTLs with STAT3 mutations exhibited higher expression of pSTAT3 and CD30. BCOR mutations were associated with increased MYC expression. Univariate analysis in the entire cohort showed that stage (II, III, or IV), BCOR mutations, TP53 mutations, and high MYC expression (defined as ≥40% positive neoplastic cells) were associated with reduced overall survival (OS). Multivariate modeling identified stage (II, III, or IV) and high MYC expression as independent adverse prognostic factors. In a subgroup analysis of patients treated with anthracycline (AC)-free chemotherapy and/or radiotherapy (RT) with curative intent, BCOR but not high MYC expression was an independent adverse prognostic factor. In conclusion, activating STAT3 mutations are common in ENKTLs and are associated with increased CD30 expression. MYC overexpression is, at least in part, associated with deleterious BCOR mutations, and this BCOR-MYC linkage may have prognostic significance, underscoring the potential utility of IHC for MYC in risk stratification of patients with ENKTL.

Recent progress of JAK inhibitors for hematological disorders.

JAK inhibitors are important therapeutic options for hematological disorders, especially myeloproliferative neoplasms. Ruxolitinib, the first JAK inhibitor approved for clinical use, improves splenomegaly and ameliorates constitutional symptoms in both myelofibrosis and polycythemia vera patients. Ruxolitinib is also useful for controlling hematocrit levels in polycythemia vera patients who were inadequately controlled by conventional therapies. Furthermore, pretransplantation use of ruxolitinib may improve the outcome of allo-hematopoietic stem cell transplantation in myelofibrosis. In contrast to these clinical merits, evidence of the disease-modifying action of ruxolitinib, i.e., reduction of malignant clones or improvement of bone marrow pathological findings, is limited, and many myelofibrosis patients discontinued ruxolitinib due to adverse events or disease progression. To overcome these limitations of ruxolitinib, several new types of JAK inhibitors have been developed. Among them, fedratinib was proven to provide clinical merits even in patients who were resistant or intolerant to ruxolitinib. Pacritinib and momelotinib have shown merits for myelofibrosis patients with thrombocytopenia or anemia, respectively. In addition to treatment for myeloproliferative neoplasms, recent studies have demonstrated that JAK inhibitors are novel and attractive therapeutic options for corticosteroid-refractory acute as well as chronic graft versus host disease.

Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study.

Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS ] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut-off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09-61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.

Clinical characteristics of Japanese patients with polycythemia vera: results of the JSH-MPN-R18 study.

The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of the three major criteria listed for the diagnosis of polycythemia vera (PV) in the 2017 World Health Organization Classification. However, a nationwide study has not yet been conducted in Japan since the discovery of JAK2 mutations. Therefore, the Japanese Society of Hematology (JSH) retrospectively analyzed the clinical characteristics of 596 Japanese patients with PV diagnosed between April 2005 and March 2018. Among the 473 patients with complete data on JAK2 mutations available, 446 (94.3%) and 10 (2.1%) were positive for the JAK2 V617F and JAK2 exon 12 mutations, respectively. During a median follow-up of 46 months (range: 0-179 months), 47 (7.9%) deaths occurred. The major causes of death were secondary malignancies (23.4%), acute leukemia (12.8%), non-leukemic progressive disease (10.6%) and thrombotic (6.4%) and hemorrhagic complications (6.4%). Thrombotic and hemorrhagic events occurred during the clinical course in 4.0% (n = 24) and 3.5% (n = 21) of patients, respectively. These results show that the international PV prognostic score (age, venous thrombosis and leukocytosis) is applicable to Japanese patients with PV.

Presence of bone marrow fibrosis in multiple myeloma may predict extramedullary disease.

We analyzed the incidence of bone marrow fibrosis in 91 newly diagnosed Japanese multiple myeloma (MM) patients and evaluated the impact of fibrosis on clinical characteristics and therapeutic outcomes. Thirty-four (37%) patients had greater than grade 1 bone marrow fibrosis. The presence of bone marrow fibrosis did not affect laboratory data, the percentage of plasma cells in bone marrow or cytogenetic findings. It also had no significant effect on response to initial treatment, engraftment after autologous hematopoietic stem cell transplantation or overall survival. Interestingly, the incidence of extramedullary disease at diagnosis was significantly higher in patients with bone marrow fibrosis (p = 0.006). Analysis of biological characteristics of MM cells revealed that expression of CD49e, an alpha5/beta1 integrin, was downregulated in MM cells derived from patients with bone marrow fibrosis (p = 0.026). When seven of the original 34 patients were re-evaluated for fibrosis grading after treatment, five (71%) showed a reduction in fibrosis. Our present findings suggest that the presence of bone marrow fibrosis may predict development of extramedullary disease in MM.

Efficacy and safety of ropeginterferon alfa-2b in Japanese patients with polycythemia vera: an open-label, single-arm, phase 2 study.

Ropeginterferon alfa-2b is a novel, site-selective, monopegylated recombinant human interferon alfa-2b. Safety and efficacy of ropeginterferon alfa-2b for the treatment of polycythemia vera were demonstrated in clinical studies conducted in European countries, but clinical studies in Japanese patients are lacking. This phase 2, open-label, multicenter, single-arm study investigated the safety and efficacy of ropeginterferon alfa-2b in 29 Japanese patients with polycythemia vera including young patients and patients with low thrombosis risk who are difficult to receive guideline-based standard treatments. The primary outcome of durable complete hematologic response without phlebotomy at months 9 and 12 was achieved by 8/29 (27.6%) patients. The fastest complete hematologic response was observed at week 12. A corresponding reduction in the JAK2 V617F allele burden from baseline to 52 weeks was also observed (mean ± standard deviation = - 19.2% ± 22.6%). No new safety concerns were identified in Japanese patients when compared with previous studies of ropeginterferon alfa-2b in European populations; the most common treatment-related adverse events were alopecia (55.2%), fatigue (27.6%) and influenza-like illness (27.6%). Most treatment-related adverse events were mild or moderate, with none of grade ≥ 3. Ropeginterferon alfa-2b is a safe and efficacious treatment option in Japanese patients with polycythemia vera.

Semi-automated histogram analysis of normal bone marrow using 18F-FDG PET/CT: correlation with clinical indicators.

BACKGROUND: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is increasingly applied to the diagnosis of bone marrow failure such as myeloproliferative neoplasm, aplastic anemia, and myelodysplastic syndrome, as well as malignant lymphoma and multiple myeloma. However, few studies have shown a normal FDG uptake pattern. This study aimed to establish a standard of bone marrow FDG uptake by a reproducible quantitative method with fewer steps using deep learning-based organ segmentation. METHODS: Bone marrow PET images were obtained using segmented whole-spine and pelvic bone marrow cavity CT as mask images using a commercially available imaging workstation that implemented an automatic organ segmentation algorithm based on deep learning. The correlation between clinical indicators and quantitative PET parameters, including histogram features, was evaluated. RESULTS: A total of 98 healthy adults were analyzed. The volume of bone marrow PET extracted in men was significantly higher than that in women (p < 0.0001). Univariate and multivariate regression analyses showed that mean of standardized uptake value corrected by lean body mass (SULmean) and entropy in both men and women were inversely correlated with age (all p < 0.0001), and SULmax in women were also inversely correlated with age (p = 0.011). CONCLUSION: A normal FDG uptake pattern was demonstrated by simplified FDG PET/CT bone marrow quantification.

Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study.

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.

Transdifferentiation of mantle cell lymphoma into sarcoma with limited neuromuscular differentiation after conventional chemotherapy.

We report an exceptionally rare case of mantle cell lymphoma (MCL) that transdifferentiated into sarcoma with limited neuromuscular differentiation. An 81-year-old man with t(11;14)-positive MCL was treated with rituximab and bendamustine and achieved complete remission; however, just 2 months later, the patient developed multiple systemic tumors. Pathologic studies revealed round cell sarcoma expressing synaptophysin, CD56, and myogenin without any B-cell markers. The CCND1 translocation and an identical IGL gene rearrangement were shared by both the MCL and sarcoma. Whole-exome sequencing detected 189 single nucleotide variants (SNVs) in the MCL and 205 SNVs in the sarcoma; 160 SNVs including NSD2, ATM, RB1, and TP53 mutations were shared between MCL and sarcoma cells. An additional PTPN11 mutation was specifically found in the sarcoma. These findings confirmed the shared clonal origin of MCL and sarcoma in this patient and indicated that MCL can transdifferentiate into sarcoma in rare cases.