Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in an observational study: The JALSG-CS11-MDS-SCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndrome (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were ≤ 70 years old at the time of registration for a prospective observational study to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT, and 26 underwent allo-SCT without BRT as the initial treatment. Multivariate analysis identified BRT as an independent factor influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, P = 0.005; CCT vs. without BRT, HR 3.82, P = 0.003). In multivariate analysis, BRT was independently associated with progression-free survival (AZA vs. without BRT: HR, 2.23; P = 0.041; CCT vs. without BRT: HR, 2.94; P = 0.010). Transplant-eligible patients with MDS-EB should undergo allo-SCT when clinically acceptable, and upfront allo-SCT without BRT may be superior to AZA or CCT.

CD37 expression in follicular lymphoma.

CD37 is a tetraspanin protein expressed in various B-cell lymphomas that mediates tumor survival signaling. Follicular lymphoma (FL) is a representative B-cell neoplasm composed of germinal center B cells. In recent years, CD37 has been focused on as a therapeutic target for B-cell lymphoma. The purpose of this study was to characterize CD37 expression in FL patients to identify risk factors associated with various prognostic factors. We retrospectively reviewed 167 cases of FL and evaluated the immunohistochemical expression of CD37 and its statistical association with clinicopathological features. Immunohistochemically, CD37 was observed in the cytoplasm and/or membrane of neoplastic cells, mainly in neoplastic follicles to various extents. One hundred cases (100/167, 60.0%) were categorized as CD37-positive, and 67 cases were CD37-negative. In cases with high Follicular Lymphoma International Prognostic Index (FLIPI), CD37-negative cases had a poor overall survival compared with CD37-positive cases (P = 0.047), although no significant differences were observed in other clinicopathologic factors, including histological grade, BCL2-IGH translocation, and immunohistochemical phenotype. Therefore, CD37 protein may play a role in tumor progression and may serve as a therapeutic target. However, further studies are needed to explore its significance.

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.

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.

Diagnosis of a difficult to differentiate case of early-onset hyperviscosity syndrome caused by IgM type multiple myeloma: a case report.

Hyperviscosity syndrome (HVS) can cause multiple organ damage if not treated immediately. IgM multiple myeloma (IgM MM) is a very rare form of myeloma with clinical features such as elevated serum IgM, and anemia, that resemble Waldenström macroglobulinemia (WM). Distinguishing between these two diseases is important, but can be a challenging problem. It is well known that MyD88 mutations and t(11;14) translocations are useful for differential diagnosis. We diagnosed HVS in a 29-year-old male with IgM MM. He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy. His clinical course was monitored by serum IgM levels, and bone marrow myeloma cell counts by multiparameter flow cytometry analysis. After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.

Deep learning shows the capability of high-level computer-aided diagnosis in malignant lymphoma.

A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma.

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.

Phase I study of graft-versus-host disease prophylaxis including bortezomib for allogeneic hematopoietic cell transplantation from unrelated donors with one or two HLA loci mismatches in Japanese patients.

This phase I study was designed for graft-versus-host disease (GVHD) prophylaxis including bortezomib in allogeneic hematopoietic cell transplantation (allo-HCT) from human leukocyte antigen (HLA)-mismatched unrelated donors in Japanese patients. Patients were administered bortezomib on days 1, 4, and 7, with short-term methotrexate and tacrolimus. Three bortezomib dose levels were prepared (1.0, 1.3, and 1.5 mg/m2). A dose of 1.3 mg/m2 was planned for administration to the initial six patients, and was adjusted if dose-limiting toxicity developed. Five of six patients enrolled for the initial dose had bone marrow donors. Two cases had single-antigen and single-allele mismatches; four had single-antigen mismatch at the A, B, C, and/or DRB1 loci in the GVH direction. All patients achieved neutrophil engraftment and complete donor chimerism. Three patients developed grade II acute GVHD, and none developed grade III-IV GVHD or any dose-limiting toxicity attributable to bortezomib by day 100. Two patients developed late-onset acute GVHD, and two developed chronic GVHD, but all cases were manageable. All patients were alive without relapse after a median follow-up period of 52 months. The optimal dose of bortezomib was determined to be 1.3 mg/m2. Prophylaxis against GVHD using a regimen including bortezomib thus seems feasible for HLA-mismatched unrelated allo-HCT.

Hodgkin-like adult T-cell leukemia/lymphoma that developed during the follow-up of HTLV-1 associated myelopathy/tropical spastic paraparesis.

Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare variant of ATLL, which represents the early neoplastic phase of ATLL that follows an indolent clinical course compared with typical ATLL. Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder characterized by the paralysis of lower limbs and urinary disturbance. Although these diseases are caused by HTLV-1 infection, there are no reports describing the coexistence of Hodgkin-like ATLL and HAM/TSP. Here, we report the first case of Hodgkin-like ATLL complicated by HAM/TSP. The patient was a 56-year-old man with right inguinal lymphadenopathy who had been using the neurology outpatient service for 13 years after being diagnosed with HAM/TSP. He was unable to receive intensive chemotherapy or allogeneic stem cell transplantation due to a poor performance status, but his condition was stable for approximately two years.

[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.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia.

OBJECTIVE: We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large-scale data on Japanese patients with essential thrombocythemia (ET). METHOD: We conducted a study in 352 patients with ET to validate previous prognostic models and search for new prognostic factors. RESULTS: The International Prognostic Score for essential thrombocythemia (IPSET), the conventional risk classification and the International Prognostic Score for thrombosis in essential thrombocythemia (IPSET-T) were confirmed to be reproducible in Japanese patients. However, no significant difference was observed between the low-risk and intermediate-risk categories according to the revised IPSET-T, which does not allow direct comparison of the four risk groups. We reevaluated the risk using a modified revised IPSET-T, which was derived from the revised IPSET-T by scoring the factors as follows: one point for age > 60 years, two points for past history of thrombosis, two points for JAK2 gene mutation-positive; total points of 0 = very low risk, 1 =  low risk, 2 =  intermediate risk, 3 and above = high risk, with significantly different thrombosis-free survival. CONCLUSION: The modified revised IPSET-T has been useful for 4-group stratification to predict a population that requires therapeutic intervention, irrespective of the treatment regimens.

[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.

Drug interactions and safety profiles with concomitant use of caspofungin and calcineurin inhibitors in allogeneic haematopoietic cell transplantation.

AIM: Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients. METHODS: We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors. RESULTS: Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6-672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8-74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy. CONCLUSIONS: Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients.