Prolonged shedding of viable SARS-CoV-2 in immunocompromised patients with haematological malignancies: A prospective study.

Prolonged SARS-CoV-2 infection in immunocompromised individuals has been scattered, but the details remain unclear. We conducted a prospective study with 26 COVID-19 patients with haematological malignancies to determine viral shedding kinetics and characteristics. We obtained nasopharyngeal swabs from the patients 21-28 days post-onset for a PCR test and performed virus isolation from the PCR-positive samples. A viable virus was detected in five patients (19.2%), all of whom had malignant lymphoma. Those patients had significantly lower CD4+ T-cell counts than the PCR-negative patients. A comparison of previous chemotherapy showed that anti-CD20 antibodies and bendamustine may be risk factors for prolonged viral shedding.

Event-free survival at 36 months is a suitable endpoint for diffuse large B-cell lymphoma patients treated with immunochemotherapy: real-world evidence from the North Japan Hematology Study Group.

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

[Hb Hirosaki hemoglobinopathy initially suspected due to low oxygen saturation levels and abnormally low HbA1c levels].

More than 1,200 hemoglobin variants are identified worldwide, and approximately 200 variants are detected in one of 3,000 Japanese people. Most of these patients are asymptomatic; however, some patients had hemolytic anemia or cyanosis. Herein, we report a case of a 49-year-old woman with prolonged fatigability after experiencing symptoms of common cold and intermittent brown urine. Her clinical data showed mild hemolysis, a disparity between SpO2 (93%) and pO2 (85.2 mmHg), and abnormally low HbA1c levels (3.7%). These findings lead to the diagnosis of unstable hemoglobin variant, Hb Hirosaki. A simple series of tests using pulse oximetry, an arterial blood gas analysis, measurement of HbA1c levels, or identifying the HPLC chromatogram of HbA1c can be the factors associated with the diagnosis of hemoglobinopathy.

Disseminated fusariosis emerged from prolonged local genital infection after cord blood transplantation.

Disseminated fusariosis (DF) is a rare life threatening fungal infection in immunocompromised hosts. We herein report a case of a fatal DF mimicking varicella zoster virus (VZV) infection that was emerged from a localized genital infection during cord blood transplantation (CBT) in a patient with severe aplastic anemia (SAA). The patient developed an ulcer following small painful vesicles mimics herpes simplex virus infection (HSV) on the glans penis before CBT, but a Fusarium species was identified. Despite administration of voriconazole, liposomal amphotericin B and granulocyte transfusion, the lesion was extended to extensive skin looked like VZV infection and the patients died after CBT. Massive fusarium infiltration was detected in multiple organs at autopsy. A genetic analysis of the mold identified Fusarium solani after his death. It should be noted that in patients with fusarium infection, localized and disseminated lesions of fusarium infection sometimes mimic HSV and VZV infections, which hampers an early diagnosis.

[Clinical efficacy of high-dose cepharanthine for idiopathic thrombocytopenic purpura: retrospective multicenter analysis].

Cepharanthine (CEP), an alkaloid drug that has a cell membrane stabilizing effect and an immunomodulating effect, has been reported to improve symptoms and signs of chronic immune thrombocytopenia (ITP). In this study, we retrospectively assessed the clinical efficacy and adverse events of high-dose CEP for 47 patients with ITP. The response rate (elevation of platelet count>5×10(4)/µl) was 44%, and CEP treatment was judged useful in clinical aspects by their attending doctors in 77% of the cases. Next, we made a comparative analysis between patients who were administered CEP as a single agent (22 patients) and those administered CEP in combination therapy with prednisolone (PSL) (20 patients). There was a marked increase in platelet count in both groups compared to the count before CEP treatment (P<0.01), and no significant difference was seen between the two groups. High-dose CEP was well tolerated, and in some patients single-agent CEP therapy resulted in a significant elevation of platelets, allowing a reduced dosage of PSL.

[Successful treatment with reduced-intensity cord blood transplantation for acute myeloid leukemia with complete tetraploidy (92, XXXX)].

A 56-year-old female was diagnosed with acute myeloid leukemia (FAB: AML-M1). G-banding karyotype of her bone marrow showed complete tetraploidy (92, XXXX [24/24]). Although she achieved complete remission (CR) after induction therapy and maintained CR during consolidation therapy, relapse occurred only 2 months after discharge. When the relapse occurred, bone marrow karyotypic analysis showed complete tetraploidy again. The patient received reduced-intensity cord blood transplantation (RI-CBT), which induced CR for the second time. The patient is currently alive 24 months after transplantation and there have not been any signs of recurrence to date. There have been a few reports of AML with near-tetraploidy, but cases of AML with complete tetraploidy are extremely rare. Tetraploid AML has been reported to have a poor prognosis and there have been very few cases maintaining CR over the long term after chemotherapy alone. This is the first case of complete tetraploid AML successfully treated by RI-CBT. The clinical course of this case suggests that hematopoietic stem cell transplantation during the first CR phase should be considered a treatment option for tetraploid AML.

Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients.

Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m(2)), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low-dose total body irradiation (TBI; 4 Gy) (Flu-BU2-TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty-eight patients (58%) were high-risk patients (median age: 56 years). The overall survival rate at 2 years of the high-risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard-risk patients (P = 0.68). The relapse rates at 2 years in the standard-risk and high-risk patients were 16 and 28%, respectively, and day 100 treatment-related mortality rates were 0 and 6%, respectively. The Flu-BU2-TBI regimen for high-risk patients showed therapeutic effects equivalent to those for standard-risk patients and favorable outcomes compared with those of other previous RIC regimens.

[Intravascular large B-cell lymphoma with massive pulmonary lesions].

A 61-year-old man was admitted to our hospital with dyspnea on effort. Neither computed tomography scan nor chest X-ray film detected any specific findings that could explain hypoxemia. Since (67)Ga scintigraphy showed abnormal uptake in the bilateral lungs, transbronchial lung biopsy (TBLB) was performed. The TBLB specimen was diagnosed as intravascular large B-cell lymphoma (IVLBCL). There was no involvement of any other organ considered typical of IVLBCL. In cases showing clinical findings such as hypoxia despite mild pulmonary radiographic changes, a definitive diagnosis should be made using methods such as TBLB with consideration given to the possibility of IVLBCL.

Regimen-related mucosal injury of the gut increased the incidence of CMV disease after allogeneic bone marrow transplantation.

Cytomegalovirus (CMV) infection is 1 of the major causes of morbidity in patients undergoing allogeneic stem cell transplantation (allo-SCT). The incidences of CMV antigenemia and CMV disease in 43 patients who received allogeneic bone marrow transplantation (BMT) using a reduced-intensity conditioning (RIC) regimen, which mainly consisted of fludarabine (Flu), busulfan (Bu), and total body irradiation (TBI), were compared with those in 68 patients who received a myeloablative conditioning (MAC) regimen, and risk factors for CMV antigenemia and CMV disease were identified. Before engraftment, grade 3-4 mucosal injury because of the conditioning regimen was significantly decreased in RIC patients (stomatitis: P = .02; diarrhea: P < .01). Rate of engraftment, incidences of acute graft-versus-host disease (aGVHD), and rate of corticosteroid administration were not different in RIC patients and MAC patients. Although the incidences of CMV antigenemia were not significantly different in RIC patients and MAC patients (64.1% versus 57.8%, log rank, P = .59), the incidence of CMV disease was significantly decreased in RIC patients (5.4% versus 20.3%, log rank, P = .04). CMV seropositivity in the patients (P < .01) and corticosteroid administration (P < .01) were revealed by multivariate analysis to be significant risk factors for CMV antigenemia. Grade II-IV aGVHD (P = .02) and grade 3-4 diarrhea before engraftment (P = .04) were revealed to be risk factors for CMV disease. The present study is the first study to show that severe diarrhea before engraftment is a significant risk factor for CMV disease. In summary, risk of CMV disease was significantly decreased in patients without severe mucosal injury of the gut because of the conditioning regimen before engraftment.

Ro52 functionally interacts with IgG1 and regulates its quality control via the ERAD system.

The 52-kDa form of SSA/Ro protein (Ro52) is one of autoantigens associated with autoimmune disorders such as systemic lupus erythematosus and Sjögren's syndrome. Anti-SSA/Ro antibodies, the biological function of which remains unknown, are frequently found in the serum of these patients. Recent functional genomic approaches have shown that Ro52/TRIM21 is one of the TRIM family proteins with a RING-finger domain which is closely associated with E3 ubiquitin ligase activity. We found by using yeast-two hybrid screening that Ro52 has an E3 activity in vitro and interacts with human IgG1 heavy chain. We also found that IgG1 heavy chain was modified with polyubiquitination by Ro52 and degraded through the ubiquitin-proteasome system in mammalian cells. Our results also showed that Ro52 interacts with the molecular chaperone p97/VCP, which is thought to function in the endoplasmic reticulum associated degradation (ERAD) system. It is likely that Ro52 plays a role in proteasomal degradation of unfolded IgG1, which is retrogradely transferred from the endoplasmic reticulum to the cytosol. Taken together, our findings suggest that Ro52 plays a significant role in quality control of IgG1 through the ERAD system.

[Pyogenic spondylitis following unrelated hematopoietic stem cell transplantation].

Pyogenic spondylitis is regarded as a rare infectious disease. The incidence of this disease has been increasing recently due to an increase in the ratio of elderly people in the population as well as an increase in immunocompromised hosts complicated by cancer, diabetes mellitus and liver cirrhosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is now performed widely as a curative treatment for various malignant hematological diseases. However, allogeneic HSCT causes chronic immunocompromise. There is no case report describing infectious spondylitis after HSCT. Here we describe a case of infectious spondylitis after HSCT and discuss risk factors and treatment. The patient was a 56-year-old female with AML-M1 who underwent allogeneic HSCT in our hospital. She developed back pain and fever about 150 days after HSCT and became unable to walk due to the severity of back pain. MRI T1 images showed a low intensity area, T2 images showed a high intensity area and Gd-DTPA-enhanced images showed a high intensity area at the S1-2 disk space. Clinical findings and MRI findings suggested pyogenic spondylitis. Back pain improved gradually after conservative treatment with meropenem (MEPM) for two weeks. After 4 weeks of MEPM administration, she had fully recovered and there has not been any recurrence of back pain to date. In conclusion, pyogenic spondylitis should be considered in the differential diagnoses for HSCT recipients with severe back pain.

Endoscopic biliary drainage for choledocholithiasis in a patient with aplastic anemia before hematological engraftment after allogeneic transplantation.

A 30-year-old man was diagnosed with severe aplastic anemia in 1997. He received mPSL pulse therapy and was treated with ATG and cyclosporine, resulting in remission and exacerbation; however, his pancytopenia gradually progressed and transfusions were required. He was referred to our hospital for further treatment by allogeneic bone marrow transplantation (allo-BMT). Before allo-BMT, he suffered febrile neutropenia. His white blood cell count was <100/microl despite daily administration of G-CSF. Although we detected asymptomatic stones in his gallbladder (GB) and common bile duct (CBD) by a screening test before allo-BMT, we decided to remove the stones after BMT because of his severe neutropenia. He underwent allo-BMT from an HLA-matched unrelated donor after conditioning with a reduced-intensity regimen. On day 9 after BMT, he developed acute obstructive suppurative cholangitis. Germ-free care was transiently stopped and endoscopic biliary drainage (EBD) was performed for the stones in the common bile duct. Engraftment of WBC was confirmed on day 24, and the stones were removed using endoscopic sphincterotomy on day 57 after confirmation of platelet recovery. We could perform EBD safely before hematological engraftment. A strategy for the management of asymptomatic stones of the GB and CBD has not yet been established. The possibility of removing stones before BMT should therefore be considered. Consideration should also be given to the possibility of improving acute obstructive suppurative cholangitis by EBD and antibiotics before hematological engraftment in such cases when stones cannot be removed before BMT.

Iron deficiency anemia successfully treated by Helicobacter pylori eradication in a patient with idiopathic thrombocytopenic purpura.

A 53-year-old woman had demonstrated idiopathic thrombocytopenic purpura (ITP) and iron deficiency anemia (IDA) since 1978. Although she was treated with prednisolone for ITP and oral iron compounds for IDA, neither ITP nor IDA showed any improvement. Since her (13)C-urea breath test was positive, Helicobacter pylori (H. pylori) eradication therapy was performed in 2001. The therapy was effective for IDA but not for ITP. Analysis of cases such as this will be useful for clarifying the mechanisms underlying the development of ITP and IDA associated with H. pylori.

A role for IL-34 in osteolytic disease of multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell-derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell-derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

HB vaccination in the prevention of viral reactivation in allogeneic hematopoietic stem cell transplantation recipients with previous HBV infection.

Hepatitis B virus (HBV)-reverse seroconversion (RS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a frequent late-onset complication in recipients with previous HBV infection. We followed 38 allo-HSCT recipients with previous HBV infection, and conducted posttransplant HB vaccine intervention in 13 recipients. First, we followed the recipients without any intervention (historic control) until 2003; hence, we commenced HB vaccination. Out of the patients who underwent transplantation after 2003, 13 recipients were immunized by a standard three-dose regimen after immunosuppressant cessation (vaccine group), whereas 12 recipients were observed without any intervention (nonvaccine group). Eight of the 13 historic control group recipients and 3 of the 12 nonvaccine group recipients, but none of the 13 vaccine group recipients, suffered HBV-RS. Cumulative risks of HBV-RS at 3 years post-HSCT in the historic control, nonvaccine and vaccine groups were 41%, 39%, and 0% respectively (P=.022). We therefore conclude that intervention with HB vaccines is significantly effective in preventing post-HSCT HBV-RS.

A retrospective analysis of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia/lymphoma (ATL): clinical impact of graft-versus-leukemia/lymphoma effect.

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

Excellent outcome of allogeneic hematopoietic stem cell transplantation using a conditioning regimen with medium-dose VP-16, cyclophosphamide and total-body irradiation for adult patients with acute lymphoblastic leukemia.

We retrospectively evaluated the outcomes of 37 adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) conditioned with medium-dose VP-16 (VP, 30 mg/kg), cyclophosphamide (CY, 120 mg/kg), and fractionated total-body irradiation (TBI, 12 Gy) (medium-dose VP/CY/TBI). The median age of the patients was 26 years. Thirteen patients underwent transplantation from HLA-matched related donors (MRD), 18 patients underwent transplantation from HLA-matched unrelated donors (MUD), and 6 patients underwent transplantation from HLA-mismatched donors (MMD). Thirty-two patients received bone marrow and 4 patients received peripheral blood stem cells. Ten patients were Philadelphia chromosome-positive (Ph(+)) and 35 patients were in complete remission (CR) at transplantation. All of the patients achieved engraftment, and grade 3 organ toxicity before engraftment occurred in 27 patients. Grade II-III acute graft-versus-host disease (GVHD) and chronic GVHD (cGVHD) occurred in 15 and 18 patients, respectively. No patient developed grade IV acute GVHD (aGVHD) or died of GVHD. At median follow-up of 35.1 months, 32 patients were alive and all Ph(+) patients were alive. Three patients died of relapse and 2 died of transplant-related mortality (TRM). The actuarial 3-year overall survival (OS) rate, relapse rate, and TRM rate were 89.2%, 8.1%, and 5.4%, respectively. Non-CR at transplantation, MRD, and no aGVHD were significant adverse prognostic factors for survival. Medium-dose VP/CY/TBI for adult ALL patients was associated with lower relapse rate and no increase in toxicity, resulting in better survival.

Administration of micafungin as prophylactic antifungal therapy in patients undergoing allogeneic stem cell transplantation.

Invasive fungal infection is one of the major causes of death in neutropenic patients undergoing allogeneic stem cell transplantation (SCT). Although prophylactic antifungal therapy with fluconazole (FLCZ) has become the standard care for these patients, there remains a need for more effective and cost-beneficial alternative drugs. We conducted a prospective study to evaluate the usefulness of the administration of micafungin (MCFG) as a prophylactic antifungal therapy for patients undergoing allogeneic SCT. The results were compared with previous data for patients who had received FLCZ. A total of 44 patients who underwent allogeneic SCT were enrolled in the study. Data from 29 patients who received allogeneic SCT using prophylactic FLCZ before this study were used as historical control data. Underlying diseases included acute leukemia (n = 16), non-Hodgkin's lymphoma (n = 11), myelodysplastic syndrome (n = 6), and others (n = 11) in the MCFG group and acute leukemia (n = 18), chronic myelogenous leukemia (n = 6), and others (n = 5) in the FLCZ group. The median durations of administration of MCFG and FLCZ were 36 and 34 days, respectively. Prophylactic success, defined as the absence of proven, probable, and possible invasive fungal infection (IFI) until the end of prophylactic therapy was achieved in 36 (87.8%) of the 41 evaluated patients in the MCFG group and in 65.5% of the patients in the FLCZ group (P = 0.038). No patients in the MCFG group showed proven or probable IFI, whereas proven or probable IFI was observed in three patients in the FLCZ group. Four patients in the MCFG group required dose escalation due to febrile neutropenia. Although one patient in the MCFG group required the discontinuation of MCFG due to allergic skin eruption (grade 2), none of the other patients in either group required dose reduction due to adverse effects. Although the study design was not a prospective randomized trial, our results indicate that the administration of MCFG at a daily dose of 100 mg is promising for prophylactic antifungal therapy in patients undergoing allogeneic SCT.

Durable remission of Sézary syndrome after unrelated bone marrow transplantation by reduced-intensity conditioning.

A 22-year-old Japanese man was diagnosed with Sézary syndrome with large cell transformation. His skin lesions persisted after treatment with 7 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), psoralen and ultraviolet light A, and total skin electron beam irradiation. He subsequently underwent allogeneic bone marrow transplantation by reduced-intensity conditioning from a human leukocyte antigen-identical unrelated donor. He developed grade II of acute graft-versus-host disease and extensive-type chronic graft-versus-host disease. He has no signs of disease 36 months after the transplantation. The prognosis of patients with advanced stage of mycosis fungoides or Sézary syndrome is very poor. Allogeneic hematopoietic stem cell transplantation, especially by reduced-intensity conditioning, is expected to become a curative treatment option, and graft-versus-tumor effect might play a critical role for sustained remission.

[Loss of CD20 expression following rituximab-combined chemotherapy in CD20-positive and CyclinD1-positive multiple myeloma].

Several studies have confirmed that CD20 is expressed in about 20% of multiple myeloma (MM) cases. This is closely related to a chromosomal translocation between chromosome 11 and chromosome 14, which results in the expression of CyclinD1. The use of rituximab (RIT) in the treatment of CD20-positive MM has been reported, however its effectiveness is still not well established. We encountered a case of CD20-positive/CyclinD1-positive MM; interestingly, CD20 expression could not be detected in MM cells following RIT-combined chemotherapy, while it gradually recovered when RIT therapy was discontinued. This is the first report in which the transition of CD20 expression was accurately analyzed by flow cytometry and immunohistochemical staining before, during and after RIT treatment. Consequently, this case provides insight regarding the mechanism through which CD20 expression is lost following RIT therapy for CD20-positive lymphoid neoplasm, as well as the efficacy of RIT in CD20-positive MM.