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A 27-year-old woman with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia received induction therapy with dasatinib and prednisolone. From the time of diagnosis, oocyte storage was planned in accordance with the patient's wishes. After progesterone administration for suppression of menstruation, and blood cell recovery, ovarian stimulation was performed and a sufficient number of eggs was collected. The patient was considered at high risk for ovarian stimulation syndrome (OHSS) and received cabergoline and letrozole. However, ovarian enlargement and ascites were observed on ultrasonography 2 days after egg collection, and a diagnosis of moderate OHSS was made. Circulatory management was performed and low-molecular-weight heparin was administered. Dasatinib was discontinued due to the appearance of pleural effusion. Fluid retention improved after menstruation resumed, and the patient was able to continue consolidation with dasatinib and cord blood transplantation. Although tyrosine kinase inhibitors are expected to simplify planning of oocyte storage, the risk of complicating OHSS should be noted.

Ravulizumab is the first long-acting complement inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH) treatment. We evaluated patient preference for ravulizumab or eculizumab among Japanese adults with PNH. The ALXN1210-PNH-301 (NCT02946463) and ALXN1210-PNH-302 (NCT03056040) studies included 23 Japanese adults who are enrolled in complement inhibitor treatment-naive and eculizumab (≥6 months) treatment. Patient preference was assessed using the PNH-specific patient preference questionnaire (PNH-PPQ©). Most patients preferred ravulizumab (19/23, 82.6%), none preferred eculizumab, and four (17.4%) reported no preference (χ 2 test, p<0.005). The preference for ravulizumab was driven by its lower infusion frequency (every 8 weeks) compared with eculizumab (every 2 weeks). The included Japanese patients with PNH preferred ravulizumab because of its reduced infusion frequency, which increases activity planning ability, treatment convenience, and overall quality of life, as compared with eculizumab. These data provide useful insight into patient perspectives and may aid decision-making for PNH treatment.

A 73-year-old woman was hospitalized with sudden chest pain and hematemesis. Chest computed tomography and upper gastrointestinal endoscopy revealed an idiopathic submucosal hematoma from the cervical esophagus to the esophagogastric mucosal junction. Idiopathic esophageal submucosal hematoma is often prone to a bleeding tendency of an underlying disorder. The patient had a history of essential thrombocythemia (ET) and was taking aspirin. She successfully recovered after aspirin discontinuation and conservative treatment; however, died of cardiopulmonary arrest in the ward on day 9 of hospitalization. The autopsy revealed that the cause of death was pulmonary thromboembolism. This is the first report of ET with submucosal hematoma of the esophagus. The possibility of an esophageal submucosal hematoma should be considered when patients with ET complain of chest pain since ET and treatment with aspirin are considered risk factors for bleeding. Additionally, close attention should be focused on the risk of developing thrombosis if a patient with myeloproliferative neoplasm is required to discontinue antithrombotic therapy due to a bleeding event.

Desquamative esophagitis (DE) is a rare benign condition characterized by sheet-like shedding of esophageal squamous epithelial tissue. Although cases of drug-induced DE, such as those induced by direct oral anticoagulants, have been reported, cases of DE complicated with hematopoietic stem cell transplantation (HSCT) are rare. We herein report the case of a 52-year-old woman with FLT3-ITD mutation-positive acute myeloid leukemia who presented with DE immediately after HSCT. Allogeneic peripheral blood HSCT with FBM (fludarabine 180 mg/m 2 , busulfan 12.8 mg/m 2 , and melphalan 80 mg/m 2 ) was performed during the first remission. Tacrolimus plus short-term methotrexate was planned for graft-versus-host disease prevention. Common Terminology Criteria for Adverse Events grade 3 equivalent vomiting was observed during treatment with the conditioning regimen. On day 5 after HSCT, a white band of 10 cm in length and 1 cm in width was discharged from the oral cavity during vomiting. Upper gastrointestinal endoscopy revealed mucosal detachment in the entire esophagus and the diagnosis of DE was made. DE improved on providing conservative treatment. We concluded that the mechanical pressure that developed on the esophagus due to frequent vomiting contributed to the mucosal detachment owing to regimen-related toxicity. Even in the FBM regimen, which is widely used as a conditioning regimen, caution is required to prevent DE.

A 71-year-old woman presented to a clinic with the chief complaint of facial edema and dyspnea; chest radiography showed mediastinal mass shadow and right pleural effusion. Computed tomography guided biopsy of the mediastinal mass had been performed by her previous doctor, and she was diagnosed with diffuse large B-cell lymphoma. She was referred to our hospital for chemotherapy. Electrocardiography performed before initiating chemotherapy showed sinus arrest for about 4 s, and Holter electrocardiography showed sinus arrest for up to about 7.4 s, which was repeatedly observed 6 times, indicating sick sinus syndrome (SSS). The mediastinal mass completely excluded the superior vena cava, and considering the risk of infection, an extracorporeal pacemaker was not inserted. We believed that the tumor effect was the cause of sinus arrest; hence, chemotherapy initiation was prioritized. R-CHOP therapy preceding vincristine and prednisolone was started, and sinus arrest was not observed after initial treatment. SSS may have been caused by carotid hypersensitivity syndrome that involved the exclusion of carotid artery pressure receptors by the tumor or the direct stimulation of the vagus nerve by microtumor infiltration.

Paroxysmal nocturnal hemoglobinuria (PNH) causes clonal expansion of hematopoietic stem cells with abnormal GPI-anchor biosynthesis. The major pathological condition of PNH is that the erythrocytes lacking the complement regulatory factors CD55 and CD59, which are GPI-anchored proteins, lead to intravascular hemolysis through complement activation. Clonal expansion has been assumed to be involved in an immunological attack on hematopoietic stem cells, and the bone marrow failure associated therewith modifies the pathology to varying degrees. The introduction of eculizumab made complement control possible; however, the problems associated with it became apparent as the treatment progressed. Additionally, the PNH Reference Guide was significantly revised in 2016, partly because PNH was designated as a Japanese medical subsidy. With the revised edition of 2020, minor revisions have been added to reflect further advances in treatment and understanding of the disease, while mainly dealing with the clinical introduction of eculizumab derivative, ravulizumab, which uses recycling antibody technology. This review outlines the points of the 2020 revision, including the important points of the previous revision.

A 72-year-old man with ileocecal lymphadenopathy was found to have Epstein-Barr virus-positive diffuse large B-cell lymphoma using open biopsy, and an ileostoma was created. R-CHOP-like chemotherapy was initiated, but his malnutrition did not improve. After 3 cycles of chemotherapy, a 2-m-long Cestoda was removed from the stoma and was identified as Diphyllobothrium nihonkaiense using mitochondria cytochrome c oxidase subunit 1 targeted polymerase chain reaction analysis. Although D. nihonkaiense infections are asymptomatic, the ileostomy was thought to have exacerbated the malabsorption in this patient. Parasitic infections are rare; however, they should be added to the differential diagnosis of malnutrition of unknown cause during chemotherapy for hematological malignancies.

A 81-year-old female was diagnosed with symptomatic multiple myeloma (MM; IgG κ type, D&S: IIB, ISS: 2) in August 2017. Although treatment with lenalidomide and dexamethasone was started, she developed deep venous thrombosis in the lower extremities as a complication; therefore, the treatment was changed to DBd. In February 2018, she required hospitalization due to general weakness and altered consciousness. Her IgG level and κ/λ ratio were elevated at 4,156 mg/dl and 605.56, respectively, revealing that MM was treatment-resistant. A protein-cell dissociation (cell blood count, 0/µl; protein, 100.6 mg/dl) was detected in the cerebrospinal fluid, whereas the ammonia level in serum was high (172 µg/dl). T2-weighted magnetic resonance imaging showed a broad range of high-density area in deep cerebral white matter suggesting leukoencephalopathy, whereas the cerebrospinal fluid was negative for JC virus. No pathological conditions causing secondary hyperammonemia were found. Although the involvement of drug-induced leukoencephalopathy in altered consciousness could not be ruled out since the chromosome with the normal karyotype at the first visit had a complex chromosomal abnormality, an originally minor clone of MM cells with a chromosomal abnormality might have contributed to the ammonia production resulting in altered consciousness.

Pregnancy with paroxysmal nocturnal hemoglobinuria (PNH) poses a high risk of thrombosis, maternal death, miscarriage, and premature infants. Eculizumab lowers complications for pregnancy with PNH. A proposed protocol for the management of pregnancy in women with PNH by The National Research Group on Idiopathic Bone Marrow Failure Syndrome (the Japanese Guideline) recommends patients to start eculizumab at an early stage of pregnancy if they have not been treated with eculizumab or continue eculizumab during pregnancy. A 31-year-old female with PNH who was transfusion-independent but had occasional hemolysis was treated with eculizumab after a missed abortion and soon conceived. During pregnancy, the patient had neither hemolysis nor thrombosis and gave birth to a healthy child without using heparin. Heparin was initiated soon after delivery and continued for six weeks because of the known high postpartum risk of thrombosis. No postpartum complications were observed. PNH is a rare disease with fewer cases of pregnancy reported. Hence, it is essential to accumulate cases of PNH with pregnancy to establish the validity of the Japanese Guideline.

A 73-year-old woman diagnosed with symptomatic multiple myeloma (MM; IgG-κ type, D&S: IIIA, ISS: 2) was administered bortezomib plus dexamethasone (BD) therapy. Post BD therapy, although autologous hematopoietic stem cell transplantation and thalidomide, lenalidomide, and melphalan/prednisolone/thalidomide (MPT) therapies were also performed, the patient remained unresponsive. However, the disease relapsed, and she eventually developed pantalgia. Therefore, the patient was admitted to our hospital and was administered pomalidomide and dexamethasone (Pd) therapy. The serum amylase (AMY) and urine AMY levels were 6,329 and 6,098 IU/l, respectively, which were salivary gland-type amylase (S-AMY). Notably, the markedly high levels immediately decreased after the first course of the Pd therapy; additionally, the pantalgia also disappeared. The S-AMY level in the supernatant from cultured bone marrow mononuclear cells was higher than that observed in a normal control. In addition, AMY was high when MM previously relapsed, suggesting the presence of AMY-producing MM. Although AMY-producing MM was first reported by Hata et al. in 1988, few cases have been reported in the new-drug era. In conclusion, AMY-producing MM frequently, including in our case (as the patient was refractory to treatment), is difficult to treat. However, our patient positively responded to the novel next-generation drugs such as pomalidomide and carfilzomib.

Primary myelofibrosis (PMF) is commonly associated with anemia. IMiD ® immunomodulatory drugs including thalidomide and lenalidomide have been shown to be effective in improving anemia associated with PMF. However, because of adverse events, their use has been restricted. Herein we report the case of a 67-year-old male patient with transfusion-dependent PMF treated with the immunomodulatory drug pomalidomide in a clinical trial. Significant improvements in anemia and thrombocytopenia were observed with pomalidomide, and the patient recovered from transfusion dependence for 8 months. Although phase 3 trial failed to show the superiority of pomalidomide over placebo, pomalidomide may have some benefit in selected patients with transfusion-dependent PMF.

Myelodysplastic syndrome (MDS) is a group of clonal disorders affecting hematopoietic stem cells. Thus, the only potential curative therapy is hematopoietic stem cell transplantation (HSCT). Indeed, for high-risk patients with MDS, who have a higher anticipated risk of leukemic transformation and shorter survival, HSCT is the first choice for eligible patients. DNA hypomethylating agents, the only agents proved to prolong survival, are used in non-HSCT-eligible high-risk patients with MDS. In contrast, due to high transplant-related mortality rate, treatment strategies other than HSCT are mainly applied for the low-risk group with expected long-term survival. Lately, treatment options, including the progress of supportive therapy, for low-risk patients with MDS have increased. The availability of the treatment options that enhance QOL and prolong survival is the need of the present time. This review will discuss the outline of such treatment strategies, especially for low-risk patients with MDS.

The subject was an 83-year-old female; she had a history of Propionibacterium acnes-related sarcoidosis at the age of 79 years. At diagnosis, she was treated with clarithromycin and achieved remission. Four years later, during a routine physical check-up, she presented with pulmonary opacities and swelling of multiple lymph nodes. A definitive diagnosis of lymphoma could not be made by inguinal lymph node biopsy. The patient's general condition was good, and we observed her clinical course. Oh the 56th day of her illness, she died suddenly. Autopsy revealed diffuse large B-cell lymphoma (DLBCL). Sarcoidosis-lymphoma syndrome (SLS) was diagnosed after sampling hyalinized nodules from both lungs. The cause of death was organizing pneumonia around an epithelioid granuloma and cor pulmonale. Organization markedly increased around the DLBCL. These findings might be associated with cor pulmonale. Although SLS often appears during chronic active sarcoidosis, sudden death is rare and there are few reports on SLS in Japan. We report this case along with a review of the literature.

Pulmonary artery hypertension (PAH) has been reported to be a severe adverse event associated with dasatinib therapy. Among the 76 chronic myeloid patients who were treated with dasatinib at our hospital, six patients showed high estimated pulmonary arterial systolic pressure, as observed by echocardiography. PAH was confirmed using right heart catheterization in three (3.9%) patients with increased mean pulmonary artery pressure (mPAP). In one patient, although mPAP was higher than the normal range, it did not fulfill the criteria of pulmonary hypertension. After the discontinuation of dasatinib, BNP and dyspnea were improved in five patients. Therefore, it should be noted that dasatinib can cause PAH at higher rates than those reported previously, and if PAH is confirmed or suspected during dasatinib therapy, then dasatinib should be immediately discontinued.

Cardiac amyloid light-chain amyloidosis (AL amyloidosis) is a rare disease with a very poor prognosis, associated with plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance and multiple myeloma. Though bortezomib-containing regimens have achieved high hematologic response rates, there are still few reports describing the outcomes of Japanese patients. Six patients with severe cardiac AL amyloidosis were treated with bortezomib-containing regimens. Involved free light chain (iFLC) decreased immediately in most of these cases. However, the condition of heart failure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) worsened in the early phase of this treatment and then improved several months later. At 29 months, the median duration of follow-up (2-47months), all patients remain alive except one who died of sudden cardiac arrest. Bortezomib-containing regimens are considered to be among the effective treatments for severe cardiac AL amyloidosis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder that presents with hemolytic anemia, thrombosis, and bone marrow failure. Stressors such as infection and pregnancy have been known to exacerbate hemolysis in PNH patients. Surgery can also trigger prominent complement activation and is an important risk factor for hemolysis. Furthermore, the postoperative thrombosis risk is high. Eculizumab, which is a humanized monoclonal antibody against C5, suppresses hemolysis and prevents thrombosis, and thus improves quality of life for PNH patients. However, few reports have focused on eculizumab-treated PNH patients undergoing surgery. We report a 79-year-old PNH patient receiving eculizumab treatment who underwent three consecutive orthopedic surgeries requiring general anesthesia. Perioperative management was carried out routinely, as in non-PNH patients, and no postoperative complications developed. Surgery was formerly considered to be a high risk event for PNH patients, but this case raises the possibility that even elderly PNH patients may undergo surgery safely when maintained on eculizumab treatment.

We report an 81-year-old woman with multiple myeloma who developed acute cardiac injury after receiving bortezomib. The patient received weekly intravenous bortezomib. She developed shortness of breath and bilateral pedal edema on day 19. Electrocardiography showed no ST-T changes but the cardio-thoracic ratio was increased, the ejection fraction was decreased, the ventricular septum showed hypokinesis and mitral regurgitation was noted. We stopped bortezomib and started acute congestive heart failure treatment. ST-T changes were detected after the patient's condition improved. There was no evidence of coronary stenosis on CT angiography. Acute cardiac injury is rare during bortezomib administration, but patients should be monitored carefully during treatment.

A 36-year-old woman with a left lung tumor was referred to our hospital since a pathological diagnosis had not been obtained at a previous medical institution. We carried out CT-guided percutaneous lung biopsy with an 18-gauge needle and obtained four samples. Immunological staining revealed the specimens to be CD30- and PAX5-positive, with large dysplastic lymphocytes negative for Bob-1 and Oct-2 with a background of small lymphocytes and eosinophils. Primary pulmonary Hodgkin lymphoma (PPHL) was diagnosed. Although PPHL is very rare, it should be included in the differential diagnosis of lung tumors and immunological staining with CD15 and CD30 is recommended. Furthermore, carefully planned CT-guided lung biopsy is useful for diagnosing PPHL.

A 78-year-old man with liver cirrhosis was admitted to our hospital because of persistent diarrhea and abdominal pain. Colonoscopy revealed erosions and submucosal tumors in portions of the sigmoid colon and rectum, which were diagnosed as mantle cell lymphoma with biopsy. After chemotherapy consisting of vincristine and prednisone, he developed Aeromonas hydrophila septicemia, resulting in septic shock and necrotizing fasciitis despite prescribing antimicrobial agents to which this organism was susceptible. Whenever we intend to treat patients with hematological malignancies and an underlying chronic liver disease, we must keep this bacterium in mind.

A 48-year-old man presented with consciousness disturbance with vasogenic edema in the occipital lobe on brain CT. The diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS) was made. His hypertension was refractory to treatment, and his neurological disabilities and CT abnormalities, along with renal dysfunction, became worse. Hemodialysis and strict management of blood pressure resolved the neurological findings and the lesions on brain CT. However, one week later, consciousness disturbance and brain CT abnormalities recurred. At that time, hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and renal dysfunction became apparent. We therefore diagnosed thrombotic thrombocytopenic purpura (TTP). Plasma exchange and vincristine administration improved not only the clinical findings of TTP, but also consciousness disturbance and brain CT abnormalities. We concluded that latent TTP had caused RPLS in this patient.

Bortezomib is a proteasome inhibitor that can be effective in the treatment of refractory and relapsed multiple myeloma. Recently, severe pulmonary complications associated with bortezomib therapy have been reported in Japan. Because bortezomib has not yet been approved for general use in Japan and is imported by attending physicians on the request of patients, The Japanese Society of Hematology and The Japanese Society of Clinical Hematology sent urgent questionnaires to the councilors of both societies in order to explore the situation and details of pulmonary complications associated with bortezomib therapy. Clinical details were available for 46 patients who had been treated with personally imported bortezomib in Japan. Seven patients (15.2%), including 3 who died from respiratory failure, showed complications definitely or probably caused by bortezomib. Of the 7 patients, 6 had a prior history of stem cell transplantation (SCT), whereas only 14 of 39 patients without lung injury had received SCT treatment (p = 0.033 by Fischer's exact test). Multivariate analysis revealed that the concomitant use of corticosteroids might reduce the risk of lung injury (p = 0.024; odds ratio = 0.055) and that a previous SCT might increase the risk (p = 0.042; odds ratio = 13.140). We summarized these data from questionnaires for a limited Japanese cohort and therefore do not know the precise incidence of lung injury linked to fatal progression. Thus, future verification concerning these matters is warranted after the approval of bortezomib for use in Japan. Clinicians should be aware of the possibility of severe pulmonary complications associated with bortezomib therapy. Note that this report has the same contents as the article appeared in the International Journal of Hematology (vol. 84, p406-412, 2006) by permission of both the editorials of the Japanese Society of Hematology and the Japanese Society of Clinical Hematology, and should be considered as the Japanese translation of the article.

A 27-year-old man was admitted to our hospital with the complaint of general fatigue. He had cervical and mediastinal lymphadenopathy. Laboratory examination revealed anemia, hypergammaglobulinemia, and increased levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). A chest radiograph showed opacities in both lung fields. Pathological findings from thoracoscopic mediastinal lymph node and lung biopsies were compatible with multicentric Castleman's disease (MCD), plasma cell type with pulmonary involvement. Chemotherapy combined with radiation therapy resulted in no improvement of his lymphadenopathy and inflammatory symptoms. Eight mg/kg humanized anti-human IL-6 receptor antibody (tocilitumab) was thus administered biweekly. Soon after initiating the tocilitumab treatment, the patient's general fatigue disappeared, and anemia, CRP, ESR, hypergammaglobulinemia and lymphadenopathy all improved remarkably. Further treatment with tocilitumab for two years resulted in maintenance of this good response without any severe adverse events, but the pulmonary findings showed no obvious improvement. Tocilitumab therapy was effective in this MCD patient, however its influence on concurrent lung disease needs to be investigated further.

It has been previously demonstrated that aging, a history of malignancy or surgery, and exposure to bovine thrombin may be related to the presence of factor V inhibitor. However, dermatomyositis (DM) and autoimmune thrombocytopenic purpura (ATP) have rarely been associated with factor V inhibitor. Here we report a patient with factor V inhibitor accompanied by DM and ATP. In January 2000, a 77-year-old woman with DM was hospitalized because of susceptibility to bleeding. At the onset of DM, she had suffered from gastric leiomyosarcoma, and had undergone gastrectomy and splenectomy without the use of bovine thrombin. Thereafter, she had been treated with prednisolone until October 1999. On admission, prolongation of both APTT and PT was seen. Her factor V activity had fallen to 6%, and factor V inhibitor was positive at 8.9 Bethesda units. Moreover her platelet count had dropped to 1.0 x 10(9)/l. A bone marrow aspirate showed a cellular marrow with megakaryocytic hyperplasia, and the patient's PA-IgG level was elevated at 389 ng/10(7) cells. These findings suggested that ATP was also present. Additionally, the patient showed a positive result for Coombs test and consumption of complement. After a further course of steroid therapy, the patient's condition was markedly improved. This is a very rare case that showed factor V inhibitor and ATP simultaneously. Furthermore, the patient's clinical course suggests the relationship between the presence of factor V inhibitor and the reactivation of her collagen disease activity.