[COVID-19 development during the treatment of paroxysmal nocturnal hemoglobinuria].

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder in which an activated complement causes intravascular hemolysis of erythrocytes that do not have complement regulators. It is critical to monitor the rapid progression of hemolysis caused by infection and thrombosis. As far as we can tell, this is the first report of 5 COVID-19 patients with PNH in Japan. Three patients were being treated with ravulizumab, one with eculizumab, and one with crovalimab. All five cases had received two or more COVID-19 vaccinations. COVID-19 was classified as mild in four cases and moderate in one. None of the cases required the use of oxygen, and none became severe. All of them experienced breakthrough hemolysis, and two required red blood cell transfusions. In any case, no thrombotic complications were observed.

[Transformation of follicular lymphoma to classical Hodgkin lymphoma during observation].

A 44-year-old female was diagnosed with follicular lymphoma (FL), grade 3A stage III, by right cervical lymph node biopsy at the age of 43 years. The patient chose to not receive the treatment despite the high tumor burden. The patient came back after 18 months with respiratory distress and had systemic infiltration and pleural effusion. Positron emission tomography (PET)/computed tomography (CT) showed fluorine-18 deoxyglucose accumulation with maximum standardized uptake value ranging from 10 to 18 in bone marrow, liver, spleen, lung, and systemic lymph nodes (cervical, supraclavicular, infraclavicular, axillary, mediastinal, hilar, para-aortic, iliac, and inguinal). Left inguinal lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (CHL), which was thought to be an FL transformation or a composite condition. The patient was treated with A + AVD and achieved lymph node shrinkage as well as improvement of tumor fever and pleural effusion. Interim PET/CT showed improvement in most parts after two courses; however, it revealed some new or progressive lesions in the bone marrow and left cervical lymph nodes. Left cervical lymph node biopsy revealed nodular sclerosis CHL. The patient was treated with ESHAP, which resulted in stable disease; following this, the patient was treated with nivolumab, which was highly effective. FL transformation to CHL is rare, and this is the first report of such transformation without treatment.

[The efficacy of alemtuzumab for pure red cell aplasia associated with autoimmune polyendocrine syndrome type 1].

We present a case of a 41-year-old woman who was diagnosed with autoimmune polyendocrine syndrome type 1 (APS-1) at the age of 2. She developed severe anemia and was diagnosed with pure red cell aplasia (PRCA) and T-cell large granular lymphocyte leukemia at the age of 34. The pathogenesis of APS-1 is based on the presence of an inactive mutation in the autoimmune regulator gene on thymic medullary epithelial cells. It is thought that the autoimmune T cells generated by impaired negative selection in the thymus induce PRCA. The patient was treated with immunosuppressive therapy (ciclosporin, antithymocyte globulin, prednisolone, and cyclophosphamide) for a long time by her previous doctor. After a long period of remission and exacerbation, she became dependent on blood transfusion approximately at the age of 40 and was transferred to our hospital. At our hospital, alemtuzumab treatment resulted in the disappearance of large granular lymphocytes and improvement of anemia. We report this case as a valuable demonstration of the efficacy of alemtuzumab for treating PRCA associated with APS-1.

[Successful treatment of large granular lymphocytic leukemia accompanied by refractory anemia with alemtuzumab].

A 39-year-old man with anemia presented at our hospital in November 2011. Peripheral blood analysis revealed lymphocytosis with a large granular lymphocyte (LGL) count of 2,272/µl, with CD3+, CD4-, CD8+, CD56-, TCR-αß+; Southern blotting analysis revealed clonal TCR Cß 1 gene rearrangement, leading to the diagnosis of T-LGL leukemia. In June 2012, the patient was administered with cyclophosphamide as an initial treatment because he developed transfusion-dependent anemia. His anemia improved, and the treatment was discontinued in March 2013. However, anemia recurred in March 2014. The administration of cyclophosphamide was resumed; however, it was subsequently replaced with cyclosporine because of the risk of secondary cancer due to the long-term use of cyclophosphamide. However, his anemia did not improve. Further, the patient was administered with prednisone, methotrexate, and pentostatin; however, the transfusion-dependent state persisted with the cumulative transfusion of 186 RBC units until March 2016. After CD52 expression on the surface of LGL cells was confirmed, treatment with alemtuzumab, which is a monoclonal antibody against CD52, was initiated in April 2016 and the dose was gradually increased from 3 mg to 30 mg thrice per week. The patient's anemia began to improve 1 week after initiating alemtuzumab treatment, and he became transfusion-independent in the second week. Although alemtuzumab treatment was discontinued at the fifth week on the basis of a positive test result for CMV antigenemia, the result consequently became negative after ganciclovir treatment. To date, the patient's hemoglobin level has been maintained at approximately 12 g/dl without any treatment. Herein we reported the case of a patient having LGL leukemia with refractory anemia that was successfully treated using alemtuzumab.

Efficacy of pomalidomide in a multiple myeloma patient requiring hemodialysis.

A 67-year-old male patient developed multiple myeloma with acute renal failure caused by myeloma kidney. Although a very good partial response was achieved with bortezomib with dexamethasone (BD) therapy under temporary dialysis, relapse occurred 3 years later. Thalidomide was added to the BD therapy but was discontinued because of drug-induced eczema. Subsequently, bone lesions and chromosomal abnormalities appeared. Because renal failure progressed with increased serum free light chain levels, maintenance hemodialysis was introduced. Administration of lenalidomide showed no effect due to intolerance. BD therapy was re-started, but diffuse ground-glass opacity with pleural effusion was observed in both lungs, leading to the discontinuation of this treatment. Subsequently, pomalidomide with low-dose dexamethasone (PD) therapy was begun under hemodialysis. Seven cycles of PD therapy maintained disease stability. However, a dosage adjustment was needed because of pancytopenia. Maintaining the therapeutic effect apparently required a pomalidomide dose of 4 mg/day in this case. These findings suggest that pomalidomide is useful in relapsed or refractory advanced myeloma, with careful dose reductions and supportive care, even for patients with renal failure requiring hemodialysis.

Prevalence of chromosome 8p11.2 translocations and correlation with myeloid and lymphoid neoplasms associated with FGFR1 abnormalities in a consecutive cohort from nine institutions in Japan.

Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities (MLN-FGFR1 abnormalities) are rare hematologic malignancies associated with chromosome 8p11.2 abnormalities. Translocations of 8p11.2 were detected in 10 of 17,039 (0.06%) unique patient cytogenetic studies performed at nine institutions in Japan. No inversions or insertions of 8p11.2 were detected. Among the 10 patients with 8p11.2 translocations, three patients were diagnosed with MLN-FGFR1 abnormalities, which were confirmed by FISH analysis. Peripheral blood eosinophilia was observed in all three patients, and all progressed to AML or T-lymphoblastic lymphoma/leukemia. The prevalence of 8p11.2 translocations in clinical practice and the proportion of MLN-FGFR1 abnormalities in patients with 8p11.2 translocations in Japan were consistent with those in previous reports from Western countries.

Effective azacitidine treatment for myelodysplastic syndrome transformed from essential thrombocythemia.

A 68-year-old woman with essential thrombocythemia had been treated with hydroxycarbamide and aspirin for 13 years. She exhibited the rapid progression of anemia, and a bone marrow examination showed dysplasia of the erythroid cells, myeloid cells, and megakaryocytes. Karyotype analysis indicated complex abnormalities including der (5;21)(p10;q10). She was diagnosed with myelodysplastic syndrome (MDS), refractory anemia with excess blasts-1 (RAEB-1). Lenalidomide was started, but no improvement in anemia was recorded. Lenalidomide was discontinued due to eosinophilia, basophilia, and a skin rash. Azacitidine was administered. The patient became transfusion independent, and a complete cytogenetic response was achieved with three courses of azacitidine. However, disease progression to acute myeloid leukemia (AML) was observed after an additional two courses of azacitidine, which was resistant to induction chemotherapy. The patient died five months later from AML transformation. Azacitidine may be effective in MDS transformed from essential thrombocythemia, and also in lenalidomide-resistant MDS with the deletion of 5q.

Is higher lymphocyte count a potential strategy for preventing chronic kidney disease in patients receiving long-term dasatinib treatment?

BACKGROUND: Dasatinib, which is used to treat treating chronic myeloid leukemia, induces increases in blood lymphocytes during the treatment. In addition, neutrophil-lymphocyte count ratio (NLR) is associated with the related to development of chronic kidney disease (CKD). However, it has not been reported whether development of CKD during long-term dasatinib treatment is related to lymphocyte count or NLR. This study aimed to reveal the relationship between CKD and lymphocyte count or NLR during long-term dasatinib treatment. METHODS: A retrospective study was conducted in patients treated with dasatinib for 6 months or longer. Risk factors for CKD development were explored using multivariate analysis. Changes in maximal lymphocyte count and NLR over time were examined separately. RESULTS: A total of 33 patients in CKD group (n = 8) and No CKD group (n = 25) who received dasatinib were enrolled. In univariate analysis, significant differences between the groups were observed in maximal lymphocyte count, lymphocytosis, age, and estimated glomerular filtration rate at baseline. As the factor independently associated with the development of CKD, maximal lymphocyte count (odds ratio 0.999, 95% confidence interval: 0.999-1.000, p = 0.033) was identified. In this analysis, age had borderline significance (odds ratio 1.073, 95% CI: 0.999-1.153, p = 0.054)]. After 6 months of dasatinib therapy, lymphocyte count was significantly lower in CKD group [median (range), 2184 (878‒3444)/µL] than in the No CKD group [3501 (966‒7888)/µL] (p = 0.020). However, no significant difference in lymphocyte count was observed between the groups at the last follow-up. During the study period, the median NLR in the No CKD group fluctuated between 1.11 and 1.42, and median NLR in CKD group was increased from 1.13 to 2.24 between after 6 months of dasatinib therapy and the last follow-up. CONCLUSIONS: The development of CKD during dasatinib therapy was associated with lower maximal lymphocyte counts. In contrast, the higher levels of lymphocytes induced during dasatinib treatment may prevent CKD progression.

[Clinical analysis of autologous stem cell transplantation for nine cases of cardiac amyloidosis].

Long-term survival remains poor for patients with cardiac amyloidosis. High-dose melphalan (MEL) with stem cell transplantation (HDM/SCT) is an effective treatment for AL amyloidosis, but patients with cardiac involvement are ineligible because of high therapy-related mortality. Here we report detailed HDM/SCT outcomes of 9 patients with cardiac failure. Their median age was 56 years (range, 45∼66). After a median follow-up of 15 months (range 9∼32), three died of multiorgan failure within the early phase after HDM/SCT, and the other six including poor risk patients are alive at present. Their symptoms of cardiac decompensation have improved. Decreases in interventricular septum thickness were confirmed in 4 patients 6∼12 months after HDM/SCT by echocardiography. One-year overall survival rate was 67%, longer than previously reported rates. HDM/SCT may lead to improvements in quality of life and extended survival in cardiac amyloidosis patients. Meanwhile, the median dosage of MEL in our procedure was 103 mg/m(2) (range 68∼180), less than the recommended dose, and patients were maintained on miscellaneous therapies. Further studies are required to clarify an effective MEL dose and to refine selection criteria for patients undergoing HDM/SCT.

[Increased level of KL-6 in a BJP-λ-type multiple myeloma patient with poor prognosis].

A 63-year-old female with BJP-multiple myeloma (Durie-Salmon stage III B, International Staging System III) showed an increased level of KL-6, a sialylated carbohydrate antigen that is a MUC1 molecule expressed in type II pneumocytes and reflects activity of interstitial pneumonia. At the time of diagnosis, KL-6 was as high as 22,030 U/ml; however, surfactant protein D (SP-D) was normal, and stroma-related pneumonia was not indicated on CT images. Expression of KL-6 in multiple myeloma cells was detected by immunostaining and the patient was diagnosed with KL-6-positive multiple myeloma. Usually, MUC1 is encoded by chromosome 1q21, but the karyotypic analysis of the patient's bone marrow cells lacked chromosome 1. KL-6 increased as the disease progressed. The patient did not respond to chemotherapy, including bortezomib, showed an increase of pleural effusion, and died. For this patient, multiple myeloma with high KL-6 was refractory to chemotherapy, suggesting that new treatment strategies, including transplantation of hematopoietic stem cells, are required.

Disappearance of monosomy 7 in a patient with aplastic anemia after eltrombopag treatment.

We present the case of a patient with aplastic anemia (AA) who was treated with eltrombopag. To the best of our knowledge, this is the first report of the disappearance of monosomy 7 after eltrombopag treatment. The patient was a 77-year-old woman with intraoral hematoma and purpura who was diagnosed with very severe AA with a normal karyotype. After combination therapy with rabbit antithymocyte globulin, cyclosporin, and granulocyte-colony-stimulating factor (G-CSF), pancytopenia transiently improved. When pancytopenia worsened again, the patient was administered darbepoetin alfa for renal anemia and danazol. Bone marrow examination showed 2.5% blasts with the karyotype 45,XX,-7[17]/46,XX[3], and 87.0% of marrow cells had monosomy 7, as determined by 7q31 interphase fluorescence in situ hybridization (FISH) analysis. Pancytopenia was considered owing to the evolution of myelodysplastic syndrome, and we stopped G-CSF and darbepoetin treatment. As she refused treatment with a hypomethylating agent, considering her age, eltrombopag was started against refractory pancytopenia after obtaining informed consent. She showed an improvement in pancytopenia and became transfusion independent. After 1 year of eltrombopag treatment, bone marrow examination revealed 0.7% blasts with the karyotype 46,XX[20] and without monosomy 7 clone by FISH analysis. After a further 1 year of eltrombopag treatment with dose tapering, she has achieved a complete response. This case suggested that eltrombopag treatment is not necessarily contraindicated in patients with monosomy 7.

Romiplostim is effective for eltrombopag-refractory aplastic anemia: results of a retrospective study.

Eltrombopag (EPAG) and romiplostim (ROM), thrombopoietin receptor-agonists with demonstrated efficacy against aplastic anemia (AA) in prospective controlled studies, were authorized in Japan for use in adults with aplastic anemia in 2017 and 2019, respectively. So far, no data are available on the potential contribution of switching from ROM to EPAG or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles of ten patients, who failed to respond to the maximum dose of EPAG and then switched to ROM, were evaluated. All ten patients received a maximum dose of ROM (20 µg/kg/week). At a median follow-up of twelve months, seven of ten patients (70%) had achieved either neutrophil, erythroid, or platelet response, including one complete response. No patients showed platelet count fluctuations that were reported during ROM treatment for immune thrombocytopenia. In univariate analysis of the relationship between efficacy and demographics, the response had a correlation with neither factors. None of the patients stopped the ROM treatment because of adverse events. Although a larger number of patients and a longer follow-up period are needed to confirm our findings, our results show the efficacy of ROM in patients with EPAG-refractory AA.

Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis.

Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a patient with FPD/AML possessing a nonsense mutation R174X in the RUNX1 gene. Consistent with the clinical characteristics of the disease, FPD iPSC-derived hematopoietic progenitor cells were significantly impaired in undergoing megakaryocytic differentiation and subsequent maturation, as determined by colony-forming cell assay and surface marker analysis. Notably, when we corrected the RUNX1 mutation using transcription activator-like effector nucleases in conjunction with a donor plasmid containing normal RUNX1 cDNA sequences, megakaryopoiesis and subsequent maturation were restored in FPD iPSC-derived hematopoietic cells. These findings clearly indicate that the RUNX1 mutation is robustly associated with thrombocytopenia in patients with FPD/AML, and transcription activator-like effector nuclease-mediated gene correction in iPSCs generated from patient-derived cells could provide a promising clinical application for treatment of the disease.

Recurrent CDC25C mutations drive malignant transformation in FPD/AML.

Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.