Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report.

Sinusoidal obstruction syndrome (SOS) is a fatal complication after hematopoietic stem cell transplantation (HSCT). Only a few complications after HSCT have been reported as risk factors for SOS, including sepsis. Here, we report the case of a 35-year-old male diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent peripheral blood HSCT from a human leukocyte antigen-matched unrelated female donor in remission. Graft-versus-host disease prophylaxis contained tacrolimus, methotrexate, and low-dose anti-thymoglobulin. The patient was treated with methylprednisolone for engraftment syndrome from day 22. On day 53, he presented worsening fatigue, breathlessness, and abdominal pain in the right upper quadrant that had persisted for 4 days. Laboratory tests showed severe inflammation, liver dysfunction, and positive for Toxoplasma gondii PCR. He died on day 55. An autopsy showed SOS and disseminated toxoplasmosis. Hepatic infection with T. gondii was identified in zone 3 of the liver, which overlapped with the pathological features of SOS. In addition, the timing of the exacerbation of hepatic dysfunction coincided with the onset of systemic inflammatory symptoms and T. gondii reactivation. This rare case of toxoplasmosis is the first to suggest that hepatic infection with T. gondii is strongly associated with SOS after HSCT.

Successful treatment of proven coronavirus disease 2019-associated pulmonary aspergillosis with liposomal amphotericin B in a patient with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

Peripherally inserted central venous catheters decrease central line-associated bloodstream infections and change microbiological epidemiology in adult hematology unit: a propensity score-adjusted analysis.

Peripherally inserted central venous catheters (PICCs) have a potential advantage in preventing central line-associated bloodstream infection (CLABSI) compared with the centrally inserted ones (CICCs). However, due to a limited number of studies with insufficient statistical evaluation, the superiority of PICCs is difficult to be generalized in adult hematology unit. We conducted a single-center retrospective study and compared the risk of CLABSI between 472 CICCs and 557 PICCs inserted in adult patients with hematological disorders through conventional multivariate models and a propensity score-adjusted analysis. The overall CLABSI incidence in CICCs and PICCs was 5.11 and 3.29 per 1000 catheter days (P = 0.024). The multivariate Cox regression analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.31-0.75; P = 0.001) and Fine-Gray subdistribution analysis (HR: 0.59; 95% CI: 0.37-0.93; P = 0.023) demonstrated that PICC was independently associated with a reduced risk of CLABSI. Moreover, the stabilized inverse probability of treatment weighting analysis, which further reduced the selection bias between CICCs and PICCs, showed that PICCs significantly prevented CLABSI (HR: 0.58; 95% CI: 0.35-0.94; P = 0.029). Microbiologically, PICCs showed a significant decrease in gram-positive cocci (P = 0.001) and an increase in gram-positive bacilli (P = 0.002) because of a remarkable reduction in Staphylococci and increase in Corynebacterium species responsible for CLABSI. Our study confirmed that PICC was a superior alternative to CICC in preventing CLABSI in the adult hematology unit, while it posed a microbiological shift in local epidemiology.

Donor stem cell-derived paroxysmal nocturnal hemoglobinuria after umbilical cord blood transplantation.

Donor cell-derived hematological disorder (DCHD) is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT). The number of reports of DCHD has been increasing in the last decade, which likely reflects the growing number of HSCTs and the improved ability to identify the donor cell origin. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder arising in the context of clonal expansion of hematopoietic stem cells harboring a somatic mutation in phosphatidylinositol glycan anchor biosynthesis, class A. We report here a patient with adult T-cell leukemia/lymphoma, who developed PNH 7 years after umbilical cord blood transplantation. The patient has maintained complete remission with full-donor chimerism after HSCT. Thus, PNH was derived from stem cells of donor origin. The immature immune environment in the recipient after cord blood transplantation might have contributed to the rapid clonal expansion for neonatal stem cells in cord blood to develop typical symptomatic PNH in a short period. To the best of our knowledge, this is the first report in the literature of a case of PNH that developed in donor stem cells after HSCT.

Human herpesvirus 8-positive multicentric Castleman disease with germinotropic plasmablastic aggregates: Overlapping spectrum of human herpesvirus 8-associated lymphoproliferative disorder.

The diagnosis of human herpesvirus 8 (HHV8)-associated lymphoproliferative disorder (LPD) is challenging because of the rarity and extended spectrum of each entity. A 43-year-old, human immunodeficiency virus seropositive, Japanese man was referred to our department because of persistent fever, generalized lymphadenopathy, jaundice and anasarca. Biopsy of a left axially lymph node demonstrated relatively preserved nodal structure with multicentric Castleman disease (MCD) features. In the germinal center, there were aggregates of HHV8-infected plasmablasts that were diffusely positive for CD38, MUM1/IRF4, LCA, IgM and λ; partially positive for CD30, c-MYC, p53; and negative for CD138, CD20, PAX-5, κ, CD2, CD3 and CD5. A small number of Epstein-Barr virus encoded small RNA (EBER)-positive large cells infiltrated in the outer part of the germinal center and the mantle layer, but the cells copositive for EBER and HHV8 were not evident. We diagnosed the patient as HHV8-positive MCD with germinotropic plasmablastic aggregates, which demonstrated intermediate pathologic features between HHV8-positive MCD and germinotropic lymphoproliferative disorder. The pathogenesis of each HHV8-associated LPD differs in cellular origin, host immune status, cytoplasmic immunoglobulin expression, clonality pattern and EBV infection; however, these factors sometimes overlap and induce extended clinical and pathologic presentations.

[Human herpes virus 8-negative primary effusion lymphoma-like lymphoma recurring as a tumor adjacent to the left atrium].

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma, usually presenting as serous effusions without detectable tumor masses, and it is universally associated with the human herpesvirus 8 (HHV8). In contrast, cases of HHV8-negative effusion lymphoma have been reported and termed as HHV8-negative PEL-like lymphoma. Here, we have reported a rare case of HHV8-negative PEL-like lymphoma that developed in the left atrium tumor 4 years after the pericardial drainage. A 74-year-old female was admitted due to cardiac tamponade caused by massive pericardial effusion. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B-cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. After 4 years of the drainage, she developed syncope caused by arrhythmia. A computed tomography scan revealed a large tumor in the left atrium and multiple swollen mediastinal lymph nodes. Biopsy of one of the lymph nodes was performed, and its histology was consistent with diffuse large B-cell lymphoma. She was treated with chemotherapy, including rituximab, and complete remission was achieved again. Thus, our experience suggests that careful follow-up may be required in patients with HHV8-negative PEL-like lymphoma after complete remission has been achieved by the drainage.

[Durable remission of Langerhans cell sarcoma attained by autologous hematopoietic stem cell transplantation following surgical resection].

Langerhans cell sarcoma (LCS) is a rare neoplastic proliferation of Langerhans cells with a poor prognosis. Owing to its rarity, standard treatment for LCS has not been established to date. Here, we report a case of LCS occurring in multiple lymph nodes in the right cervix in which remission is maintained by autologous hematopoietic stem cell transplantation (auto-HSCT) after surgical resection. A 58-year-old male presented with enlarged right submandibular lymph nodes. Positron-emission tomography/computed tomography (PET/CT) revealed multiple lymphadenopathies in his right cervix. We performed a lymph node biopsy, and he was diagnosed with LCS. We selected the CHOP regimen as the first-line chemotherapy; however, rapid disease progression was observed soon after the first cycle of the therapy. The neck dissection was performed on day 16 of the CHOP therapy. As the residual tumor was suspected, we started the second-line chemotherapy with a combination of etoposide, cisplatin, ifosfamide, and gemcitabine; complete remission was confirmed by PET/CT. Subsequently, the patient was administered high-dose chemotherapy with auto-HSCT. After 2 years of auto-HSCT, complete remission has been maintained. Although there is no report of auto-HSCT for LCS, it could be an effective therapeutic tool for the disease.

[Long-term remission with mogamulizumab monotherapy in a patient with refractory adult T-cell leukemia-lymphoma].

A 73-year-old female with malaise, anorexia, and hydrodipsia was referred to our department. Peripheral blood tests revealed leukocytosis with 51% blast cells exhibiting flower-shaped nuclei. Flow-cytometry to detect tumor cells in peripheral blood indicated CD3+, CD4+, CD8-, and CD25- expression, but those in the lymph nodes expressed CD25+. Southern blots revealed clonal HTLV-1 provirus in the tumor cells, consistent with adult T-cell leukemia-lymphoma. Cytotoxic chemotherapy was ineffective, but eight cycles of mogamulizumab induced complete remission (CR). A relapse lesion appeared on the right breast but disappeared spontaneously. The patient has currently maintained CR for over five years.

HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide versus HLA-Matched Unrelated Donor Transplantation for Myelodysplastic Syndrome.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole curative therapy for myelodysplastic syndrome (MDS). In the absence of an HLA-matched sibling donor, an HLA-matched unrelated donor (MUD) is considered the leading candidate. However, in recent decades, the alternative donor pool has been extended to HLA-haploidentical donors, especially with the development of graft-versus-host disease (GVHD) prophylaxis using post-transplantation cyclophosphamide (PTCy). Comparative data for haploidentical and MUD allo-HCT in patients with MDS are scarce. We retrospectively analyzed 697 adult patients with MDS who underwent HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with PTCy (n = 136), MUD bone marrow transplantation (MUD-BMT) (n = 465), or MUD peripheral blood stem cell transplantation (MUD-PBSCT) (n = 96) as their first allo-HCT between 2014 and 2020 using Japanese registry data. Multivariable analyses demonstrated faster neutrophil engraftment (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.65 to 2.90; P < .001) and platelet engraftment (HR, 2.31; 95% CI, 1.72 to 3.10; P < 0001) in the MUD-PBSCT cohort compared with the haplo-PBSCT cohort. MUD-BMT was associated with a higher incidence of grade II-IV acute GVHD than haplo-PBSCT (HR, 1.52; 95% CI, 1.00 to 2.29; P = .048). Among patients without in vivo T cell depletion using antithymocyte globulin (ATG) (haplo-PBSCT, n = 136; MUD-BMT, n = 446; MUD-PBSCT, n = 65), MUD-PBSCT recipients experienced faster hematopoietic recovery, MUD-BMT recipients (HR, 1.54; 95% CI, 1.02 to 2.32; P = .042) or MUD-PBSCT recipients (HR, 1.83; 95% CI, 1.06 to 3.18; P = .03) had a higher incidence of grade II-IV acute GVHD, and MUD-PBSCT recipients developed chronic GVHD more frequently than haplo-PBSCT recipients (HR, 1.74; 95% CI, 1.04 to 2.89; P = .034). There were no significant differences in overall survival, disease-free survival, GVHD-free relapse-free survival, relapse, or nonrelapse mortality in the haplo-PBSCT cohort versus the MUD-BMT or MUD-PBSCT cohorts. In conclusion, despite differences in the incidences of hematopoietic engraftment and GVHD depending on graft type and ATG use in MUD transplant recipients, major transplantation outcomes were comparable between recipients of haplo-PBSCT using PTCy and recipients of MUD-BMT or MUD-PBSCT.

Peripheral blood stem cell transplantation using HLA-haploidentical donor with post-transplant cyclophosphamide versus HLA-matched sibling donor for lymphoma.

Data comparing HLA-haploidentical donors and HLA-matched sibling donors (MSDs) in peripheral blood stem cell transplantation (PBSCT) for lymphoma are scarce. We retrospectively analyzed 465 patients with lymphoma aged 16 years or older who underwent PBSCT using haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo) (n = 166) or MSDs with calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis (n = 299). Two-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) in the PTCy-haplo and MSD groups were 49.2% versus 51.9% (P = 0.64), 38.0% versus 39.9% (P = 0.97), and 27.7% versus 18.5% (P = 0.006), respectively. In multivariable analyses, PTCy-haplo recipients had slower neutrophil recovery (hazard ratio [HR], 0.62; P < 0.001) and platelet recovery (HR, 0.54; P < 0.001), lower risk of chronic GVHD (HR, 0.64; P = 0.038) and extensive chronic GVHD (HR, 0.45; P = 0.008), and better GRFS (HR, 0.66; P = 0.003) than MSD transplant recipients. OS, PFS, relapse or progression, and non-relapse mortality were similar between the groups. The difference might be mainly due to PTCy use rather than donor type; however, the results suggested that PTCy-haplo could be a possible option as an alternative to conventional MSD transplantation for lymphoma in PBSCT.

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

Salvage Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplant With Posttransplant Cyclophosphamide for Graft Failure in a Patient With Chronic Active Epstein-Barr Virus Infection.

Salvage human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide has shown promising results for graft failure in various hematological disorders. However, to our knowledge, no such findings have been reported for a case of chronic active Epstein-Barr virus infection, although graft failure is relatively common in patients with chronic active Epstein-Barr virus infection. We report a case of a 32-year-old woman with natural killer-cell type chronic active Epstein-Barr virus infection who experienced graft failure after a first allogeneic hematopoietic cell transplant from an unrelated human leukocyte antigen-matched donor.The patientreceived a second allogeneic hematopoietic cell transplant with human leukocyte antigen-haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide (cyclophosphamide, 50 mg/kg, on day 3 and day 4) following reduced-intensity conditioning as rescue therapy. Neutrophils successfully engrafted on day 19, and the patient sustained remission without severe transplant-related complication 10 months after salvage human leukocyte antigen- haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide. This report suggests that salvage human leukocyte antigen- haploidentical hematopoietic cell transplant using posttransplant cyclophosphamide may be a feasible therapeutic option for graft failure in patients with chronic active Epstein-Barr virus infection.

Clinicopathological analysis of diffuse large B-cell lymphoma lacking surface immunoglobulin light chain restriction on flow cytometry.

Although diffuse large B-cell lymphoma (DLBCL) occasionally lacks surface immunoglobulin light chain restriction (iLCR) on flow cytometry (FCM), little evidence is available for iLCR-negative DLBCL. We retrospectively compared clinicopathological features of iLCR-positive and iLCR-negative DLBCL diagnosed at our institute between April 2007 and March 2018. iLCR-positive was defined as a κ/λ ratio less than 0.5 or greater than 3 in the gated population on dual-color FCM, and iLCR-negative as other values. Of 81 DLBCL cases with available immunophenotyping by FCM, 63 iLCR-positive DLBCL (78%) and 18 iLCR-negative DLBCL (22%) cases were identified. Survival outcomes of patients with iLCR-negative DLBCL were comparable with those of patients with iLCR-positive DLBCL. Pathological analysis revealed no significant difference except for the lower expression of BCL6 in iLCR-negative DLBCL (12.5% vs 65.5%, p < 0.001), although there was a slightly higher frequency of necrosis (47.1% vs 20.7%, p = 0.058) and lower expression of CD10 (11.8% vs 35.0%, p = 0.078) in iLCR-negative DLBCL than in iLCR-positive DLBCL. The underlying mechanism remains unclear; however, low expression of germinal center markers and tumor necrosis may be associated with the loss of iLCR in DLBCL.

Extracorporeal Membrane Oxygenation with rituximab-combined chemotherapy in AIDS-associated primary cardiac lymphoma: A case report.

Although effective combination of antiretroviral medications is being developed, the incidence of non-Hodgkin lymphoma (NHL) with human immunodeficiency/acquired immunodeficiency syndrome (HIV/AIDS) still remains significantly higher than that in individuals without infection. Primary cardiac lymphoma (PCL) is an NHL that involves the heart and/or the pericardium. PCL is very rare and often causes serious complications, which can be a diagnostic challenge. To our knowledge, no study has reported the measurement of rituximab concentration under venoarterial extracorporeal membrane oxygenation (VA-ECMO). Herein, we report the case of a 54-year-old male patient with AIDS-associated primary cardiac NHL who developed right ventricular outflow tract obstruction. The patient experienced fatigue and dyspnea on exertion. Contrast-enhanced computed tomography showed a bulky tumor mass in his right atrium and ventricle, and an echocardiogram revealed severe hypokinesis of his heart and poor cardiac output. A biopsy was performed, and immunohistochemistry revealed diffuse large B-cell lymphoma. Therefore, he was treated with rituximab-combined chemotherapy under VA-ECMO. Blood levels of rituximab were measured during chemotherapy with VA-ECMO. Thereafter, he was temporarily discharged from the hospital. This clinical case suggests that VA-ECMO and rituximab-combined chemotherapy are useful in rescuing patients with severe cardiopulmonary failure due to AIDS-associated PCL.

Importance of diagnosis-to-treatment interval in newly diagnosed patients with diffuse large B-cell lymphoma.

Treatment of patients with malignancy sometimes be delayed due to various reasons. Several studies revealed that an influence of diagnosis-to-treatment interval (DTI) on outcomes differs depending on the type of malignancy. In this study, we evaluated the influence of DTI on clinical outcomes in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). A total of 199 patients were identified with a median DTI of 22 days. At 2 years, patients with short DTI (0-22 days) showed significantly poorer OS (62.7% vs 86.4%) and PFS (55.1% vs 75.9%) compared to those with long DTI (over 22 days). Although short DTI was strongly correlated with several known adverse factors, it remained to be an independent prognostic factor by multivariate analysis. In conclusion, our study confirmed the importance of DTI in patients with DLBCL. Researchers should consider DTI as one of the important prognostic factors and plan clinical trials to be able to enroll patients with aggressive disease requiring urgent treatment.