Pre-engraftment syndrome (PES) is a unique complication of cord blood transplantation (CBT) whose risk factors and impact on transplant outcomes remain controversial. Using a nationwide database in Japan, we analyzed a total of 3734 patients who underwent single-unit CBT. PES occurred in 18.3% of patients, and risk factors for PES included a higher hematopoietic cell transplantation-specific comorbidity index, first transplantation, myeloablative conditioning (MAC), lower total nucleated cell (TNC) dose, and graft-versus-host disease (GVHD) prophylaxis regimens excluding tacrolimus with methotrexate. Patients who developed PES had significantly higher incidences of grade II-IV acute GVHD (53.1% vs. 31.3%, p < 0.001) and chronic GVHD (27.2% vs. 21.7%, p = 0.002) compared to those without PES. Landmark analysis with multivariable adjustment revealed that PES was independently associated with increased non-relapse mortality (NRM, hazard ratio [HR] 1.46; 95% CI 1.22-1.75; p < 0.001), reduced relapse incidence (HR 0.78; 95% CI 0.63-0.96; p = 0.020), and a trend toward inferior overall survival (OS, HR 1.13; 95% CI 0.98-1.30; p = 0.088). Moreover, patients who experienced both PES and acute GVHD had the highest 2-year NRM (31.7%; 95% CI 26.0%-37.6%) and the lowest 2-year OS (55.9%; 95% CI 50.0%-62.4%), compared with those who experienced either PES (NRM 20.7%; OS 65.0%) or acute GVHD (NRM 19.5%; OS 62.8%) (p < 0.001), highlighting the combined effects of these complications. This study, the largest to date on PES, demonstrates its clinical significance as an early complication with lasting effects on transplant outcomes.

Mixed-phenotype acute leukemia (MPAL) is an uncommon hematological malignancy, and cases exhibiting trilineage differentiation are extraordinarily rare. Here, we report the case of a 63-year-old male patient who presented with severe dyspnea secondary to a massive anterior mediastinal mass and pleural effusion, in the absence of detectable abnormal cells in the peripheral blood. Immunophenotypic analysis of pleural fluid and tumor biopsy revealed an unprecedented trilineage phenotype with concurrent expression of T-lymphoid (cytoplasmic CD3+ and CD7+), B-lymphoid (CD19+ and CD22+), myeloid (cytoplasmic MPO+ and CD33+) markers, along with stem cell (CD34+ and HLA-DR+), and lymphoblastic (TdT+) markers. B-lineage commitment was further confirmed by immunoglobulin heavy chain gene rearrangement. These findings established a diagnosis of T/B/myeloid triphenotypic MPAL presenting as an aleukemic disease with minimal bone marrow infiltration (<1%). Initial treatment with acute myeloid leukemia-directed induction therapy (daunorubicin plus cytarabine) proved refractory. However, the hyperCVAD regimen, which is an acute lymphoblastic leukemia (ALL)-directed approach, achieved a complete metabolic response. Subsequent consolidation with cord blood transplantation resulted in durable remission lasting 2 years before a late relapse, which occurred in the mediastinal region. This is the first reported case of non-leukemic, triphenotypic MPAL presenting as a primary mediastinal tumor, highlighting the diagnostic complexity and therapeutic challenges associated with this rare malignancy. Based on our experience, intensive ALL-directed chemotherapy followed by allogeneic stem cell transplantation may offer an effective therapeutic strategy for this exceptionally rare clinical entity.

Spontaneous regression or a long-term lack of obvious progression is often observed in patients with low-tumor-burden (LTB) follicular lymphoma (FL). However, conventional prognostic risk models are unable to precisely identify the patients who will not require any antilymphoma treatment for a long term, especially at diagnosis. In this study, we identified genes whose expression levels were associated with the clinical outcome of LTB FL and verified their prognostic value using immunohistochemistry. Because the tumor microenvironment may influence FL pathogenesis, we used digital expression profiling to quantify the expression of 730 immune-related genes extracted from tumor tissue specimens collected from 55 untreated patients with LTB FL. Five genes were identified as potential transcriptomic predictive markers. Among these, FCGR2B , an inhibitory FC gamma receptor, was immunohistochemically stainable and identified as a reliable immunohistochemical prognostic marker mainly expressed in tumor cells but not in the surrounding reactive cells. Our findings could help identify patients with LTB FL who do not require any antilymphoma treatment for the long term.

A man in his 60s on methotrexate for rheumatoid arthritis developed a fever and lymph node swelling, suggesting a lymphoproliferative disorder. Methotrexate was discontinued; however, the patient was admitted for acute kidney injury (AKI) and thrombocytopenia. Blood tests showed high levels of inflammatory markers, positive plasma Epstein-Barr virus (EBV) DNA, and CD10-positive abnormal T cells, indicating T-cell neoplasm. CHOP chemotherapy with continuous hemodiafiltration improved the patient's condition. A lymph node biopsy confirmed the diagnosis of angioimmunoblastic T-cell lymphoma (AITL). To our knowledge, this is the first reported case of methotrexate-associated AITL complicated by AKI with a successful treatment course.

Nodal Epstein-Barr virus-positive T/NK-cell lymphoma (EB-nTNKL) is an extremely rare disease characterized by an aggressive clinical course and poor prognosis, for which treatment strategies have not yet been established. We herein report a young man with EB-nTNKL. Although initial chemotherapies, including L-asparaginase, failed to produce a good response, subsequent myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) resulted in favorable disease control and a long-term disease-free survival. The prompt performance of alloHSCT using an available donor source at that time, regardless of whether or not the initial chemotherapy was effective, could be critical to saving patients with this otherwise fatal disease.

A 21-year-old man was diagnosed with myeloid/natural killer precursor leukemia (MNKPL) with bone marrow infiltration of blasts of cyCD3+, CD7+, CD33+, CD34dim, CD56+/-, HLA-DR+, cyMPO+, and TdT- immunophenotypes. Although hyper-CVAD therapy was unsuccessful, induction treatment with idarubicin and cytarabine resulted in complete remission (CR). The patient subsequently underwent cord blood transplantation with a myeloablative conditioning regimen, which resulted in durable CR and complete donor chimerism. He had been in good health without relapse for over nine months since transplantation. Timely allogeneic hematopoietic stem cell transplantation using an available donor source may be a promising treatment strategy for MNKPL.

Luspatercept has shown durable clinical efficacy for the treatment of anemia in transfusion-dependent patients with lower-risk myelodysplastic syndromes (LR-MDS). We report the results of a prespecified primary analysis of a phase 2 trial of luspatercept in non-transfusion-dependent (NTD) Japanese patients with anemia due to LR-MDS. Luspatercept (starting dose 1.0 mg/kg) was administered subcutaneously once every 3 weeks. The primary endpoint was the proportion of patients who achieved hematological improvement-erythroid (HI-E) response (≥ 1.5 g/dL increase in hemoglobin level for 8 weeks) without transfusions within the first 24 weeks of treatment. At the primary analysis data cutoff, 21 patients had been enrolled/treated; 17 and 10 patients had completed 24 and 48 weeks of treatment, respectively. HI-E response occurred within 24 weeks in 10 patients (47.6%; 95% confidence interval, 25.7-70.2; P < 0.0001), which was significantly higher than the predefined threshold (10%). By week 48, HI-E response occurred in 12 patients (57.1%) and 17 patients (81.0%) remained NTD. Luspatercept was well tolerated. Three patients (14.3%) had grade 3-4 treatment-related treatment-emergent adverse events. Luspatercept resulted in statistically and clinically significant improvements in hemoglobin levels, and may help delay the need for transfusions in NTD patients with LR-MDS.

Follicular lymphoma (FL) may undergo histological transformation (HT) into a more aggressive lymphoma. Although rituximab for B-cell non-Hodgkin lymphomas (B-NHL) has greatly improved the overall survival (OS) of patients with transformed FL (tFL), relapse after anthracycline-based chemoimmunotherapy has a poor prognosis. CD19-targeting chimeric antigen receptor-modified T-cell (CAR-T) therapy is a promising treatment for relapsed or refractory (r/r) large B-cell lymphoma (LBCL), including tFL. However, lymphopenia and reduced T-cell fitness caused by bendamustine exposure for treatment of underlying FL may impair the feasibility and reduce the efficacy of CAR-T therapy. Herein, we report the case of a 44-year-old woman with tFL who relapsed following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received CAR-T therapy. The patient could not initially undergo CAR-T therapy due to lymphopenia caused by bendamustine exposure, but CAR-T therapy became feasible following allo-HSCT. Although CAR-T therapy using T cells harvested from an allo-HSCT recipient may theoretically cause alloreactivity, the patient did not experience graft versus host disease (GVHD) or serious complications specific to CAR-T therapy, such as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), and she has remained in complete response (CR) for >18 months. CAR-T therapy following allo-HSCT for patients with r/r tFL may be a safe and effective treatment option. Allo-HSCT may enhance the efficacy of CAR-T therapy.

BACKGROUND: De novo chronic myeloid leukemia in blastic phase (CML-BP) showing lymphoid immunophenotype mimics Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Although upfront allogeneic hematopoietic cell transplantation (HCT) is considered in both diseases, it is not yet clear whether the transplant outcomes are also similar. METHODS: Using a registry database, the transplant outcomes between de novo CML-BP and Ph-positive ALL in negative-minimal residual disease (MRD), positive MRD, and nonremission cohorts were compared, respectively. All of the included patients had received tyrosine kinase inhibitor therapy before HCT and underwent HCT between 2002 and 2021. Regarding Ph-positive ALL, patients with p210 transcripts were excluded because there was concern that this group might include patients with de novo CML-BP. RESULTS: Although most of the outcomes were comparable, in patients with positive MRD at HCT, de novo CML-BP was significantly associated with superior disease-free survival (DFS) (hazard ratio [HR] 0.6, p = .0032), overall survival (HR 0.66, p = .027), and a lower risk of relapse (HR 0.48, p = .0051). In subgroup analyses, BCR::ABL1 mutation status had a significant interaction with the disease (p for interaction = .0027). De novo CML-BP seemed to be associated with superior disease-free survival in a BCR::ABL1 mutation-positive cohort, whereas this association was not observed in a mutation-negative cohort. CONCLUSIONS: Considering previous reports that showed inferior outcomes for de novo CML-BP compared to Ph-positive ALL, the data suggested that allogeneic HCT could overcome the poor prognosis of de novo CML-BP. These findings highlight the importance of distinguishing de novo CML-BP from Ph-positive ALL.

Although rearrangement of the MYC oncogene (MYC-R) is frequently observed in aggressive B-cell lymphomas, it is extremely rare in T-cell malignancies. A 64-year-old man who had been under observation for several years because of asymptomatic pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALToma) was admitted to our hospital because of poor general condition and hypotension. Blood tests revealed thrombocytopenia and elevated serum lactate dehydrogenase levels, whereas computed tomography revealed systemic lymphadenopathy and splenomegaly. An inguinal lymph node biopsy precipitated a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Shortly after admission, the patient experienced spontaneous intestinal perforation and hemorrhage caused by multiple intestinal infiltrations of the AITL. Although chemotherapy was administered, the patient died several weeks after admission. A 46,XY,t(8;14)(q24;q11.2) karyotype was identified, and fluorescence in situ hybridization analyses showed split signals for the MYC and T-cell receptor (TCR) alpha genes, by which a TCR::MYC translocation was confirmed. Pathological autopsy analysis revealed systemic infiltration of the AITL and no MALToma lesions. Only a few cases of mature T-cell lymphoma harboring MYC-R have been reported in the literature thus far. To the best of our knowledge, this is the first reported case of AITL with TCR::MYC rearrangement. This condition could be associated with refractoriness to chemotherapy and aggressive clinical course with systemic infiltration that included the intestine.

Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

BACKGROUND: Splenectomy is indicated in cases of autoimmune hemolytic anemia (AIHA), which are refractory to medical management. In post-splenectomy, there exists a theoretical risk of AIHA recurrence, especially if an accessory spleen undergoes compensatory hypertrophy. In this context, we present a unique case of recurrent AIHA managed through laparoscopic excision of the accessory spleen (LEAS). CASE PRESENTATION: A 60-year-old male underwent laparoscopic splenectomy (LS) for AIHA refractory to standard medical therapies. Following the surgery, there was a marked improvement in hemolytic anemia symptoms, and oral steroid therapy was terminated 7 months post-LS. Nonetheless, a year after the LS, the patient exhibited a marked decline in hemoglobin levels, dropping to a concerning 5.8 g/dl, necessitating the reintroduction of oral steroids. A subsequent contrast-enhanced computed tomography (CT) scan unveiled an enlarged accessory spleen. The patient then underwent LEAS, during which the accessory spleen, obscured within adipose tissue, proved challenging to visualize laparoscopically. This obstacle was surmounted utilizing intraoperative ultrasonography (US), enabling successful excision of the accessory spleen. The post-surgical period progressed without complications, and the steroid dosage was reduced to one-twelfth of its initial preoperative quantity. CONCLUSIONS: Recurrent AIHA can be instigated by post-splenectomy compensatory hypertrophy of the accessory spleen. Ensuring comprehensive splenic tissue excision is crucial in AIHA management to obviate recurrent stemming from hypertrophic remnants. In scenarios of AIHA recurrence tied to an enlarged accessory spleen, LEAS stands as a viable and effective therapeutic modality.

Monitoring of hepatitis B virus (HBV)-DNA and HBV-DNA-guided preemptive therapy using nucleos(t)ide analogs (NAs) are recommended to prevent the development of hepatitis due to HBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with resolved HBV infection. However, little is known about the appropriate duration of NA treatment and the effect of NA cessation on the recurrence of HBV reactivation. This study aimed to clarify the consequences of NA cessation in allo-HSCT recipients with resolved HBV infection who experienced HBV reactivation following transplantation. We retrospectively reviewed the clinical records of recipients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative, anti-HBc-positive) before allo-HSCT who had been diagnosed with HBV reactivation (HBsAg-positive and/or HBV-DNA detectable) after allo-HSCT between January 2010 and December 2020. A total of 72 patients from 16 institutions were registered (median age, 60 years; age range, 27 to 73 years; 42 males and 30 females). The day of initial HBV reactivation ranged from day 10 to day 3034 after allo-HSCT (median, 513 days). Anti-HBs were lost in >80% of the patients at the time of HBV reactivation. All 72 patients received preemptive NAs, and no fatal HBV reactivation-related hepatitis was observed. HBV-DNA without hepatitis was continuously detected in 5 patients during the follow-up period. Administration of NAs was discontinued in 24 of 72 patients (33%) by physician decision. Second HBV reactivation occurred in 11 of the 24 patients (46%) in whom administration of NAs was discontinued. The duration of NA treatment did not differ significantly between patients with or without second HBV reactivation. The frequency of further HBV reactivation tended to be lower in patients with an anti-HBs titer of >10 mIU/mL at the time of NA cessation. Multiple reactivations of HBV after NA cessation was common in patients with HBV reactivation who underwent allo-HSCT despite the long duration of NAs. Careful monitoring of HBV-DNA is important even after the discontinuation of NAs in the case with HBV reactivation after allo-HSCT, because multiple reactivations could occur. Active immunization by HB vaccine might be effective for suppressing further HBV reactivation after cessation of NAs.

A 41-year-old woman with right shoulder pain was found to have multiple tumors with osteolysis and M-proteinemia. Abnormal plasma cells (CD38+, CD138+, Igλ≫κ) were detected in 1.4% of bone marrow nucleated cells, and G-banding analysis revealed a 46,XX,t (8;14), (q24;q32) karyotype in 4 of 20 cells analyzed. A biopsy specimen from an extramedullary lesion had a packed proliferation of aberrant plasmacytoid cells with positive IgH::MYC fusion signals on fluorescence in situ hybridization. The patient was diagnosed with symptomatic multiple myeloma and treated with the BLd regimen, which significantly reduced M protein levels. Extramedullary lesions were initially reduced, but increased again after four cycles. The lesions disappeared with subsequent EPOCH chemotherapy and radiation, and complete remission was confirmed. The patient was then treated with high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Complete remission was maintained for over one year with lenalidomide maintenance therapy. A solitary IgH::MYC chromosomal translocation is extremely rare in multiple myeloma and may be associated with high tumor proliferative capacity, multiple extramedullary lesions, and poor prognosis. Combined therapeutic modalities with novel and conventional chemotherapy and radiation might be a promising treatment strategy for patients with this type of multiple myeloma.

Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.

BACKGROUND: Aplastic anemia patients who are refractory to immunosuppressive therapy or with very low neutrophil counts require allogeneic hematopoietic stem cell transplantation (HSCT). Umbilical cord blood transplantation (UCBT) has been a treatment option when an HLA-matched donor is not available, and HSCT from a related haploidentical donor using post-transplant cyclophosphamide (PTCY) for GVHD prophylaxis (PTCY-haplo) recently became another important approach. OBJECTIVE: We aimed to compare the outcomes of PTCY-haplo and UCBT in adult patients with aplastic anemia in order to identify more effective and safer approaches for alternative donor transplantation. STUDY DESIGN: Data in a nationwide registry were retrospectively analyzed to assess the outcomes of aplastic anemia patients aged ≥16 years who received PTCY-haplo or UCBT as first HSCT between 2016 and 2020. The primary endpoint was 1-year overall survival (OS) after HSCT. Secondary endpoints included 1-year failure-free survival (FFS), neutrophil and platelet engraftment, and acute and chronic GVHD. RESULTS: Eighty-three patients who received PTCY-haplo (n = 24) and UCBT (n = 59) were eligible. One-year OS rates were 78.5% (95%CI, 55.7 - 90.5) in the PTCY-haplo group and 77.5% (95%CI, 64.5 - 86.3, P=0.895) in the UCBT group. One-year FFS rates were 78.7% (95%CI, 56.1 - 90.6) in the PTCY-haplo group and 62.2% (95%CI, 48.5 - 73.3, P=0.212) in the UCBT group. Among patients <40 years, the PTCY-haplo group had a significantly higher FFS rate; 92.9% (95%CI, 59.1 - 99.0) vs. 63.9% (95%CI, 43.2 - 78.7, P=0.047). Neutrophil and platelet engraftment rates were significantly higher in the PTCY-haplo group than in the UCBT group; 95.8% (95%CI, 73.9 - 99.4) vs. 78.0% (95%CI, 65.1 - 86.6, P<0.001) and 83.3% (95%CI, 61.5 - 93.4) vs. 72.9% (95%CI, 59.6 - 82.4, P=0.025). No significant difference was observed in the cumulative incidence of grade II-IV acute GVHD and chronic GVHD between the two groups. CONCLUSIONS: Aplastic anemia patients achieved significantly higher neutrophil and platelet engraftment rates with PTCY-haplo than with UCBT. OS and the incidence of acute and chronic GVHD were similar between the two groups. In patients <40 years, the FFS rate was higher in the PTCY-haplo group. Therefore, PTCY-haplo is promising for alternative donor transplantation in adult patients with aplastic anemia.

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) against anti-HLA-A, -B, -C, and -DRB1 in HLA-mismatched hematopoietic stem cell transplantation (HSCT) is associated with graft failure. DSAs against HLA-A, -B, -C, and -DRB1 with a mean fluorescence intensity (MFI) of greater than > 1,000 was shown to increase the risk of graft failure in single-unit umbilical cord blood transplantation (UCBT). Nevertheless, the impact of DSAs against HLA-DP or -DQ on transplantation outcomes is not fully understood. In this report, we present a case of UCBT in a patient with myelodysplastic syndrome who was positive for DSAs against HLA-DP with MFI of 1,263 before UCBT but successfully achieved neutrophil engraftment. If HLA-DP or -DQ is mismatched in UCBT, evaluating DSAs against HLA-DP or -DQ is crucial to avoid graft failure. However, the criteria for DSAs against HLA-A, -B, -C, and -DRB1 may not be directly applicable to those against HLA-DP or -DQ.

BACKGROUND: Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. METHODS: To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). RESULTS: With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12 months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80 ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). CONCLUSION: We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

Mitochondria play essential and specific roles during erythroid differentiation. Recently, FAM210B, encoding a mitochondrial inner membrane protein, has been identified as a novel target of GATA-1, as well as an erythropoietin-inducible gene. While FAM210B protein is involved in regulate mitochondrial metabolism and heme biosynthesis, its detailed function remains unknown. Here, we generated both knockout and knockdown of endogenous FAM210B in human induced pluripotent stem-derived erythroid progenitor (HiDEP) cells using CRISPR/Cas9 methodology. Intriguingly, erythroid differentiation was more pronounced in the FAM210B-depleted cells, and this resulted in increased frequency of orthochromatic erythroblasts and decreased frequencies of basophilic/polychromatic erythroblasts. Comprehensive metabolite analysis and functional analysis indicated that oxygen consumption rates and the NAD (NAD+)/NADH ratio were significantly decreased, while lactate production was significantly increased in FAM210B deletion HiDEP cells, indicating involvement of FAM210B in mitochondrial energy metabolism in erythroblasts. Finally, we purified FAM210B-interacting protein from K562 cells that stably expressed His/biotin-tagged FAM210B. Mass spectrometry analysis of the His/biotin-purified material indicated interactions with multiple subunits of mitochondrial ATP synthases, such as subunit alpha (ATP5A) and beta (ATP5B). Our results suggested that FAM210B contributes prominently to erythroid differentiation by regulating mitochondrial energy metabolism. Our results provide insights into the pathophysiology of dysregulated hematopoiesis.

Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic mutations in splicing factor 3b subunit 1 (SF3B1), which is involved in the RNA splicing machinery, are frequently found in MDS-RS, the detailed mechanism contributing to RS formation is unknown. To explore the mechanism, we established human umbilical cord blood-derived erythroid progenitor-2 (HUDEP-2) cells stably expressing SF3B1K700E. SF3B1K700E expressing cells showed higher proportion of RS than the control cells along with erythroid differentiation, indicating the direct contribution of mutant SF3B1 expression in erythroblasts to RS formation. In SF3B1K700E expressing cells, ABCB7 and ALAS2, known causative genes for congenital sideroblastic anemia, were downregulated. Additionally, mis-splicing of ABCB7 was observed in SF3B1K700E expressing cells. ABCB7-knockdown HUDEP-2 cells revealed an increased frequency of RS formation along with erythroid differentiation, demonstrating the direct molecular link between ABCB7 defects and RS formation. ALAS2 protein levels were obviously decreased in ABCB7-knockdown cells, indicating decreased ALAS2 translation owing to impaired Fe-S cluster export by ABCB7 defects. Finally, RNA-seq analysis of MDS clinical samples demonstrated decreased expression of ABCB7 by the SF3B1 mutation. Our findings contribute to the elucidation of the complex mechanisms of RS formation in MDS-RS.

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) has a favorable prognosis in general; however, some cases are resistant to chemotherapy, which leads to a poor clinical outcome. We herein report the case of a 32-year-old male with aggressive ALK+ ALCL who presented with hemorrhage from a large tumor in the duodenum and multiple tumors in the lungs, mediastinum, and peritoneal cavity. Although induction chemotherapy resulted in a marked reduction of the tumor lesions, premature progression with massive pulmonary infiltration and central nervous system invasion occurred immediately after the completion of chemotherapy. The patient was then promptly treated with brentuximab vedotin (BV) and high-dose methotrexate, which resulted in complete remission. Subsequently, he successfully underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor and has been healthy and did not relapse for more than 3 years after transplantation without any additional therapy. Allo-HSCT may be a promising treatment option for ALK+ ALCL due to its graft-versus-lymphoma effect. In addition, molecular targeting agents, such as BV, may be promising as a bridging therapy before allo-HSCT to achieve disease remission.

X-linked sideroblastic anemia (XLSA), the most common form of congenital sideroblastic anemia, is caused by a germline mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. In XLSA, defective heme biosynthesis leads to ring sideroblast formation because of excess mitochondrial iron accumulation. In this study, we introduced ALAS2 missense mutations on human umbilical cord blood-derived erythroblasts; hereafter, we refer to them as XLSA clones. XLSA clones that differentiated into mature erythroblasts showed an increased frequency of ring sideroblast formation with impaired hemoglobin biosynthesis. The expression profiling revealed significant enrichment of genes involved in ferroptosis, which is a form of regulated cell death induced by iron accumulation and lipid peroxidation. Notably, treatment with erastin, a ferroptosis inducer, caused a higher proportion of cell death in XLSA clones. XLSA clones exhibited significantly higher levels of intracellular lipid peroxides and enhanced expression of BACH1, a regulator of iron metabolism and potential accelerator of ferroptosis. In XLSA clones, BACH1 repressed genes involved in iron metabolism and glutathione synthesis. Collectively, defective heme biosynthesis in XLSA clones could confer enhanced BACH1 expression, leading to increased susceptibility to ferroptosis. The results of our study provide important information for the development of novel therapeutic targets for XLSA.

Chronic myeloid leukemia (CML) is triggered by t(9;22)(q34;q11.2) translocation, leading to the formation of the BCR-ABL1 fusion gene. Although the development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of CML, the disease could often relapse, presumably because leukemic stem cell fraction of CML (CML-LSC) may reside in specific niches, and also acquire an ability to resist the cytotoxic agents. Recently a study indicated that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1, also known as SERPINE1) would cause detachment of CML-LSCs from their niche by inducing maturation of membrane-type matrix metalloprotease-1 (MT1-MMP), leading to increased susceptibility of CML-LSCs against TKIs. However, the direct antitumor effect of PAI-1 inhibition in CML remains unclear. Because PAI-1 mRNA expression was lower in CML cell line (K562) than bone marrow mononuclear cells derived from CML patients, we established K562 cell clones stably expressing exogenous PAI-1 (K562/PAI-1). We found that TM5614 treatment significantly suppressed cell proliferation and induced apoptosis in K562/PAI-1 cells, accompanied by increased activity of Furin protease, which is a known target of PAI-1. Besides processing mature MT1-MMP, Furin is in charge of cleaving the NOTCH receptor to form a heterodimer before exporting it to the cell surface membrane. In K562/PAI-1 cells, TM5614 treatment increased NOTCH1 intracellular domain (NICD) protein expression as well as NOTCH1 target of HEY1 mRNA levels. Finally, forced expression of either Furin or NICD in K562/PAI-1 cells significantly inhibited cell proliferation and induced apoptosis. Collectively, PAI-1 inhibition may have an antitumor effect by modulating the Furin/NICD pathway.

Adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders (EBV-T/NK-LPDs) often progress rapidly, and require allogeneic stem cell transplantation early in the course of treatment. Unrelated cord blood transplantation (UCBT) is a readily available option for patients without HLA-matched donors. We retrospectively analyzed the outcomes of 12 UCBT in adult patients with chronic active EBV infection (CAEBV, n = 8), EBV-positive hemophagocytic lymphohistiocytosis following primary EBV infection (n = 2), hydroa vacciniforme-like lymphoproliferative disorder (n = 1), and systemic EBV-positive T-cell lymphoma of childhood (STCLC, n = 1). The median age at transplantation was 31.5 years (range 19-58). At the median follow-up time for survivors, which was 6.3 years (range 0.3-11.3), 3-year overall survival (OS) rates in all patients and 8 CAEBV patients were 68.2% (95% CI 28.6-88.9) and 83.3% (95% CI 27.3-97.5), respectively. Graft failure occurred in 4 of 8 CAEBV patients, requiring a second UCBT to achieve neutrophil engraftment. The cumulative incidence of grade II-IV acute GVHD was 33.3% (95% CI 9.1-60.4%). The EBV-DNA load became undetectable or very low after UCBT in all cases. UCBT may be a promising treatment option for adult-onset EBV-T/NK-LPDs.

Peritoneal lymphomatosis (PL) is a rare presentation of malignant lymphoma cases, many of which are diagnosed as diffuse large B-cell lymphoma (DLBCL) and characterized by aggressive clinical courses. We herein report a 63-year-old woman presenting with the rapid development of abdominal distention due to bulky peritoneal tumors. The pathological evaluation of a needle biopsy sample, combined with flow cytometry, yielded the diagnosis of DLBCL. Prompt chemotherapeutic intervention resulted in favorable disease control and sustained complete remission. It is necessary to diagnose cases of DLBCL presenting as PL early to ensure prompt treatment and prevent mortality.

Hepatitis C virus (HCV) infection has an adverse impact on outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). It is recommended that HSCT candidates infected with HCV receive the treatment prior to transplantation. Although the recent approval of direct-acting antivirals (DAAs) has led to great advances in the treatment of HCV infection, little information is available on the efficacy and safety of DAA therapy in patients receiving allogeneic HSCT. Herein, we report the clinical course of an umbilical cord blood (UCB) recipient treated with DAAs for HCV infection. The patient achieved HCV RNA negativity with glecaprevir and pibrentasvir after consolidation therapy for acute myeloid leukemia (AML), and underwent transplantation before confirming sustained virological response (SVR) at 12 weeks. The HCV viral load became detectable on day +28 after transplantation and second HCV treatment with sofosbuvir, velpatasvir, and ribavirin was required. It is important to confirm SVR prior to transplantation, but it is often difficult. If early transplantation is required, close monitoring of HCV RNA after transplantation is needed. Further investigation is required to clarify the optimal management of HCV infection for allogeneic HSCT recipients in the DAA era.

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.

Bladder tamponade due to hemorrhagic cystitis caused by BK virus in immunocompetent patients is familiar to urologists. BK virus is an important cause of nephropathy and graft loss in kidney transplant recipients. Although urothelial carcinoma of the bladder in kidney transplant recipients with persistent BK viruria is known, BK virus-associated urothelial carcinoma (BKVUC) in peripheral blood stem cell transplantation recipients is not as well known. A 54-year-old man with acute lymphoblastic leukemia was treated in the Department of Hematology of our hospital. After recurrence 25 months later, he received chemotherapy for half a year and underwent peripheral blood stem cell transplantation. He achieved temporarily complete remission, but he developed hematuria with BK virus-positive result 1 month after peripheral blood stem cell transplantation. One month later, he developed bladder tamponade-diagnosed hemorrhagic cystitis due to BK virus in our Urological Department. We performed transurethral coagulation to manage hemorrhage and removed a bleeding lesion in the bladder wall. Pathological examination of the removed bladder wall revealed pT1 stage BKVUC. We found that bladder tamponade could have led to reactivation of BK virus in this immunocompetent patient. This could be the first report of BKVUC of the bladder found in a peripheral blood stem cell transplantation recipient with close urological follow-up for 24 months. Adequate removal of bleeding lesions from the bladder mucosa with appropriate timing during hemorrhagic cystitis due to BKVUC could be essential to achieve good outcomes.

Acquired factor X deficiency (AFXD) is a very rare coagulation disorder. A 40-year-old man with no comorbidities suffering from a fever, malaise, and severe hemorrhagic symptoms, including massive hematuria, was emergently admitted. His platelet count was normal, but his prothrombin time and activated partial thromboplastin time were markedly prolonged, which was thought to be due to autoantibody against a coagulation factor in the common pathway. Despite severe massive hematuria resulting in transient renal failure, he was successfully treated with urgent immunosuppressive therapy. Computed tomography revealed bronchopneumonia, which improved with antibiotic administration. AFXD without evidence of amyloidosis was subsequently diagnosed.

Methotrexate (MTX)-associated classical Hodgkin lymphoma (CHL) is unlikely to regress following discontinuation of MTX, and its treatment usually requires chemotherapy. Standard chemotherapy for CHL is the ABVD regimen, which contains pneumotoxic bleomycin. This can be problematic in MTX-CHL patients suffering from an autoimmune disease (AID), such as rheumatoid arthritis (RA), as they frequently have pulmonary complications. However, brentuximab vedotin (BV)-containing chemotherapy without bleomycin (A + AVD regimen) was recently reported to show favorable efficacy for CHL, and could therefore be beneficial in MTX-CHL. We treated three cases of MTX-CHL using the A + AVD regimen. All were female and had received MTX for more than 15 years. Underlying AIDs in these patients were RA in two patients, and overlap syndrome with systemic lupus erythematosus and dermatomyositis in one patient. The A + AVD regimen resulted in a complete response in all patients. Peripheral neuropathy developed in two patients, necessitating reduction of the BV dose. All three patients experienced hematological toxicity necessitating dose reduction; however, no severe adverse effects, including infection or pulmonary complication, were documented. RA was well-controlled without additional immunosuppressants. The A + AVD regimen is a promising chemotherapy for MTX-CHL with favorable efficacy and tolerable toxicity profiles.

Fusariosis is a critical infectious complication that can develop in immunocompromised hosts, mainly under conditions of prolonged neutropenia, and is often disseminated and associated with a high mortality rate. Disseminated fusariosis developing during the course of hematopoietic stem cell transplantation (HSCT) is a critical condition, and there have been few reports of successful treatment of cases complicated with fusariosis before HSCT. Here, we present a case of acute myeloid leukemia (AML) with the development of fungal endophthalmitis during chemotherapy. Vitrectomy was performed and Fusarium solani infection was confirmed by vitreal culture. The infection was also disseminated to the lung, triceps, and spleen. The splenic lesions disappeared with the administration of antifungal agents, and residual lesions in the lung and triceps were surgically resected. After two courses of consolidation chemotherapy, the patient received cord blood transplantation (CBT) twice because of graft failure in the first transplantation. Antifungal agents were administered continuously during chemotherapy and transplantation. Although Fusarium sinusitis developed after neutrophil engraftment, it was well controlled by surgical resection. Thereafter, the patient has been well without recurrence of fusariosis for more than 2 years since transplantation. A combination of continuous administration of antifungal agents and vigorous surgical intervention may be important for management of disseminated fusariosis in the setting of HSCT.

A 37-year-old man was admitted to our department following the detection of bulky tumors in his bilateral adrenal glands. A biopsy resulted in the diagnosis of extranodal NK/T cell lymphoma, nasal type (ENKL). After debulking by chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHCT) was performed. Relapses in the liver and adrenal glands were identified 2 months post alloHCT, for which temporary administration of l-asparaginase resulted in complete metabolic response. However, multiple relapses in the central nervous system and lethal lymphomatous meningitis successively developed. Primary adrenal ENKL could tend to present as bulky lesion and follow an aggressive clinical course.

Umbilical cord blood transplantation (UCBT) is a possible option for patients with aplastic anemia (AA) without a related or unrelated HLA-matched donor, particularly if immunosuppressive therapy (IST) has failed or transplantation is urgently needed. However, a higher rate of graft failure after UCBT remains a major problem, and the optimal conditioning regimen for stable engraftment after UCBT has not been established. Here we investigated 6 adult patients with AA who underwent UCBT using a reduced-intensity conditioning (RIC) regimen comprising fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and 4 Gy of total body irradiation (Flu/CY/TBI4Gy) without antithymocyte globulin (ATG). Five patients underwent UCBT after IST failure, and 1 patient underwent UCBT as a first-line treatment due to a fulminant clinical finding of a neutrophil count of 0, despite granulocyte colony-stimulating factor administration. Regarding graft-versus-host disease (GVHD) prophylaxis, 2 patients received tacrolimus plus short-term methotrexate and 4 patients received tacrolimus plus mycophenolate mofetil, and all patients achieved sustained engraftment of both neutrophils and platelets, at a median of 17.5 days (range, 14 to 37 days) and 38.5 days (range, 31 to 86 days), respectively, with complete donor chimerism confirmed in all patients at a median of 14 days (range, 14 to 32 days). Three patients developed grade II acute GVHD (aGVHD), but grade III/IV aGVHD was not observed, whereas 4 patients developed chronic GVHD involving only skin. At the time of this report, all 6 patients were alive without the need for blood transfusion, at a median follow-up of 16 months (range, 12 to 131 months). Although further study is needed, our findings suggest that conditioning with Flu/CY/TBI4Gy without ATG might allow stable engraftment in UCBT for adults with AA.

Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is essential for cell proliferation and differentiation. Heterozygous germline GATA2 mutations induce GATA-2 deficiency syndrome, characterized by monocytopenia, a predisposition to myelodysplasia and acute myeloid leukemia, and a profoundly reduced dendritic cell (DC) population, which is associated with increased susceptibility to viral infections. Because patients with GATA-2 deficiency syndrome could retain a wild-type copy of GATA-2, boosting residual wild-type GATA-2 activity may represent a novel therapeutic strategy for the disease. Here, we sought to establish a screening system to identify GATA-2 activators using human U937 monocytic cells as a potential model of the DC progenitor. Enforced GATA-2 expression in U937 cells induces CD205 expression, a marker of DC differentiation, indicating U937 cells as a surrogate of human primary DC progenitors. Transient luciferase reporter assays in U937 cells reveals a high promoter activity of the -0.5 kb GATA-2 hematopoietic-specific promoter (1S promoter) fused with two tandemly connected GATA-2 +9.9 kb intronic enhancers. We thus established U937-derived cell lines stably expressing tandem +9.9 kb/-0.5 kb 1S-luciferase. Importantly, forced GATA-1 expression, a repressor for GATA-2 expression, in the stable clones caused significant decreases in the luciferase activities. In conclusion, our system represents a potential tool for identifying novel regulators of GATA-2, thereby contributing to the development of novel therapeutic approaches.