Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

Real-world efficacy of DA-EPOCH-R/HD-MTX regimen in CD5-positive diffuse large B cell lymphoma: a single-institute analysis.

CD5-positive diffuse large B cell lymphoma (CD5+ DLBCL) is a high-risk lymphoma type. Recently, the PEARL5 (a Phase II trial of DA-EPOCH and Rituximab with HD-MTX therapy for newly diagnosed DLBCL with CD5 expression) study demonstrated the efficacy of the DA-EPOCH-R (cyclophosphamide, etoposide, doxorubicin, vincristine, prednisone, and rituximab)/HD-MTX (high-dose methotrexate) regimen for CD5+ DLBCL. In this report, we revealed the impact of the DA-EPOCH-R/HD-MTX regimen on the clinical course of CD5+ DLBCL in the real-world. We retrospectively compared CD5+ and CD5- DLBCL patients diagnosed from January 2017 to December 2020 and analyzed their clinicopathological characteristics, treatment, and prognosis. There was no difference in age, sex, clinical stage, and cell of origin; however, the CD5-positive group had higher lactate dehydrogenase levels and a worse performance status than the CD5-negative group (p=0.00121 and p=0.0378, respectively). International prognostic index (IPI) was worse in the CD5-positive group than in the CD5-negative group (p=0.0498), but NCCN-IPI (National Comprehensive Cancer Network-IPI) was no different between the two groups. The CD5-positive group was more frequently treated with the DA-EPOCH-R/HD-MTX regimen than the CD5-negative group (p =0.001857). Complete remission rate and 1-year overall survival did not differ between the CD5-positive and -negative groups (90.0% vs 81.4%, p=0.853; 81.8% vs 76.9%, p=0.433). We conclude that the DA-EPOCH-R/HD-MTX regimen is effective for CD5+ DLBCL in this single institute analysis.

Tumor long-axis diameter and SUVmax predict long-term responders in 90Y-ibritumomab tiuxetan monotherapy.

90Y-ibritumomab tiuxetan (90Y-IT) is widely used, but the factors responsible for its optimal treatment effects are unknown. We enrolled 34 patients with relapsed indolent lymphoma treated with 90Y-IT monotherapy at Gunma University Hospital between 2003 and 2014 in the present study. Clinical data including computed tomography and 18-Fluoro-deoxyglucose positron emission tomography were retrospectively analyzed. The overall response rate and complete response rate were 91% and 82%, respectively. The median progression-free survival (PFS) and overall survival were 32 months and not reached, respectively. In univariate analysis, tumor long-axis diameter ≤ 2.5 cm, maximum standardized uptake value (SUVmax) ≤ 6.5, localized disease, normal levels of serum soluble interleukin-2 receptor, and the number of involved nodal sites ≤ 3 immediately prior to 90Y-IT were associated with median PFS greater than 6 years. However, in multivariate analysis, only tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5 affected PFS [hazard ratio (HR) 0.130, P = 0.0021 and HR 0.283, P = 0.0311, respectively]. Patients with only one prior regimen needed less granulocyte colony-stimulating factor and platelet transfusion. Thus, 90Y-IT treatment should be considered for patients with indolent lymphoma in first relapse who have tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5.

Prognostic impact of trisomy 21 in follicular lymphoma.

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.

[Congenital factor V and factor VIII deficiency discovered in an elderly patient with abnormal bleeding after trauma].

Congenital combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) (F5F8D) is a rare autosomal recessive bleeding disorder caused by mutations in lectin mannose-binding type 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2) encoding chaperone molecules involved in the intracellular transport of FV and FVIII. Here, we report a case of F5F8D in an elderly patient diagnosed with hematoma after a right thigh injury. A 71-year-old male had a history of abnormal bleeding after tooth extraction and cholecystectomy. The patient injured his right thigh with a kitchen knife; he was urgently hospitalized to a referral hospital 8 days later due to the occurrence of hematoma at the same site. Owing to prolongation of the coagulation time (PT 16.1 s, 1.72; APTT, 66.1 s), he received hemostatic treatment with fresh-frozen plasma. He was then referred to our hospital for examination of PT and APTT prolongation. FV and FVIII activities were moderately decreased to about 15%, and no inhibitor was detected. Whole-exome sequencing identified a previously reported homozygous nonsense mutation in LMAN1, revealing F5F8D in the proband. In this case, FFP infusion alone was not sufficient for increasing coagulation factor activities. Definitive diagnosis of F5F8D provides him with the treatment option with FVIII concentrates.

Clinical management and outcomes of completely resected stage I follicular lymphoma.

Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used 18F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a "watch-and-wait" (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow-up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies.

Clinical experience of bendamustine for adult Langerhans cell sarcoma.

A 40-year-old man was diagnosed with Langerhans cell histiocytosis (LCH) in October 2010. His LCH was refractory to conventional chemotherapy, and thus worsened to Langerhans cell sarcoma (LCS) in May 2011. Although we repeated combination chemotherapies, new infiltration of the liver and bone marrow, as well as primary lesions of the bone, lymph nodes, and skin, appeared. These intensive chemotherapies caused candida liver abscesses, invasive aspergillosis, disseminated varicella zoster virus infection and bacterial sepsis. We administered bendamustine for chemotherapy, which resulted in a partial response (PR) with no severe adverse events. Because of pancytopenia caused by secondary myelodysplastic syndrome, we stopped the bendamustine chemotherapy after two courses. PR was maintained for 4 months. We plan to perform allogeneic hematopoietic stem cell transplantation from a sibling donor after a conditioning regimen. Optimal therapy for adult LCH, which is a rare and treatment-resistant disease, has yet to be established. Bendamustine is a potential chemotherapeutic agent for standard treatment of LCS.

Prognostic importance of the soluble form of IL-2 receptorα (sIL-2Rα) and its relationship with surface expression of IL-2Rα (CD25) of lymphoma cells in diffuse large B-cell lymphoma treated with CHOP-like regimen with or without rituximab: a retrospective analysis of 338 cases.

We evaluated the prognostic significance of the serum level of the soluble form of interleukin-2 receptorα (sIL-2Rα) and investigated its association with CD25 expression on tumor cells in diffuse large B-cell lymphoma (DLBCL). Three hundred and thirty-eight adult patients with newly diagnosed DLBCL were eligible for this retrospective study. 32.2% of patients were treated with CHOP-like regimen and 67.8% with R-CHOP-like regimen. CD25 expression on the surface of tumor cells was evaluated in 143 cases and its relationship with sIL-2Rα level was also investigated. Both overall survival (OS) and progression-free survival (PFS) were poorer in patients with higher sIL-2Rα, in both R-CHOP and CHOP groups. sIL-2Rα > 1,000 U/mL and performance status (PS) ≥ 2 were independently associated with poorer OS, and sIL-2Rα > 1,000 U/mL, age > 60 years, and ≥ 2 extranodal sites were independently associated with poorer PFS in the R-CHOP group. The sIL-2Rα level was higher in the CD25-positive group than in the CD25-negative group in stage 3 or 4 disease (p = 0.010). Multiple linear regression analysis showed CD25 expression to be independently correlated with sIL-2Rα levels. High sIL-2Rα is an important risk factor for survival in DLBCL treated with not only CHOP-like, but also R-CHOP-like regimens, regardless of the tumor's expression of CD25.

[Retrospective survey on the clinical features of non-Hodgkin lymphomas in Gunma Prefecture, Japan].

We retrospectively investigated pathological types, clinical backgrounds, treatments and prognoses in 726 adult patients with newly diagnosed malignant lymphoma in Gunma Prefecture. They consisted of 679 patients with non-Hodgkin lymphoma (B-cell type, 603; T- and NK-cell type, 76) of which 376 patients had diffuse large B-cell lymphoma (DLBCL) and 47 patients with Hodgkin lymphoma. When comparing the prognosis of DLBCL between patients receiving rituximab (R-CHOP group; n=212) and not using rituximab (CHOP group; n=126), both 3-year overall survival (73.5% vs 61.7%, p=0.010) and 3-year progression-free survival (65.1% vs 45.8%, p<0.001) were statistically better in the R-CHOP group compared to the CHOP group. Our results suggest that more than half of patients were DLBCL and the rituximab-containing regimen results in an improved prognosis for DLBCL patients.

Circulating plasmacytoid dendritic cells in patients with primary and Helicobacter pylori-associated immune thrombocytopenia.

OBJECTIVES: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the production of autoreactive antibodies against platelet antigens. Although dysfunction of multiple aspects of cellular immunity is considered to be important in the pathogenesis of ITP, it has not been clarified which cell types play a principal role. METHODS: We enrolled 46 untreated patients with chronic ITP and 47 healthy adult volunteers, and investigated by flow cytometry the percentage and absolute number of cells in their peripheral blood that participate in the regulation of cellular immunity. These included plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), natural killer (NK) cells, natural killer T (NKT) cells, regulatory T (Treg) cells, and Th17 cells. RESULTS: We found a significant reduction in the absolute number of pDCs, but not of mDCs, in patients with ITP when compared with healthy controls (P < 0.001). Reduced numbers of circulating pDCs were observed in both Helicobacter pylori (H. pylori)-positive and Helicobacter pylori (H. pylori)-negative patients with ITP. In contrast, there were no significant differences in the numbers of circulating Treg cells, Th17 cells, NK cells, or NKT cells. Interestingly, we observed increases in the number of pDCs after H. pylori eradication by antibiotics in responders but not in non-responders, while pDCs and mDCs decreased markedly after prednisolone therapy in both responders and non-responders. In patients without treatment, low pDC numbers persisted during the observational period. CONCLUSIONS: We demonstrated that the number of circulating pDCs is low in patients with primary and H. pylori-associated ITP and that it changes depending on treatment modality. Further investigation is warranted with regard to the role of pDCs in the immunopathogenesis of ITP.

Differences in the JAK2 and MPL mutation status in the cell lineages of the bcr/abl-negative chronic myeloproliferative neoplasm subtypes.

OBJECTIVE: While the somatic mutation of Janus Kinase 2 (JAK2) and the thrombopoietin receptor (c-MPL) gene are thought to affect the pathogenesis of bcr/abl negative chronic myeloproliferative neoplasm (MPN), the relationship between the mutation and the clinical features remain obscure. METHODS: The mutation status of these genes in granulocytes, platelets, T-cells, and erythroid colonies (BFU-E) was obtained from 115 MPN patients, and then the clinical features of the MPN subtypes were compared. RESULTS: The JAK2-V617F mutation was observed in three lineages of granulocytes, platelets, and BFU-E in almost all polycythemia vera (PV) and primary myelofibrosis (PMF) patients. In contrast, 68% of essential thrombocythemia (ET) patients have the JAK2-V617F mutation in at least one of the lineages, of which 70% of these patients have the JAK2-V617F mutation in three lineages; the remaining ET patients with the JAK2-V617F mutation only exhibited the mutation in one or two lineages. Further, the ET patients that exhibited the JAK2-V617F mutation in three lineages had higher WBC and granulocyte counts as compared to the ET patients that did not have the JAK2-V617F mutation or only had the mutation in one or two lineages. Concerning the MPL gene, two ET patients had the MPL-W515L gene mutation in their platelets, although the lineage of the JAK2-V617F mutation involved differed from case to case. CONCLUSION: The progenitor cells that are involved with the JAK2-V617F mutation in MPNs are different in each subtype and this difference may also affect the clinical features of MPNs.

Successful treatment with reduced-intensity stem cell transplantation for secondary myelofibrosis following polycythemia vera.

Ten years after being diagnosed with polycythemia vera, a 55-year-old woman required frequent blood transfusion due to secondary myelofibrosis. She underwent reduced-intensity stem cell transplantation (RIST) from an HLA-identical sibling donor. Since mixed chimerae were identified in the peripheral blood at day 35, cyclosporine was withdrawn. At day 73, she developed acute graft-versus-host disease of the liver, while simultaneous resolution of splenomegaly occurred and complete donor chimerism in the peripheral blood was achieved. Frequent red blood cell transfusion was required until day 300 after transplantation. Thus, RIST for an older patient with secondary myelofibrosis was successful without severe treatment-related morbidity. This case suggests that RIST could be an effective treatment modality for secondary myelofibrosis.

Low burden of a JAK2-V617F mutated clone in monoclonal haematopoiesis in a Japanese woman with Budd-Chiari syndrome.

Approximately one-half of the cases of Budd-Chiari syndrome (BCS) are caused by bcr/abl negative chronic myeloproliferative disorders (CMPDs). Furthermore, a mutation in the Janus kinase protein (JAK2-V617F) is detected in half of the patients with BCS. However, whether the JAK2 mutation is the primary event leading to CMPDs and BCS is controversial. We present a report concerning a young woman who suffered from BCS prior to the onset of CMPDs. Analysis of X-chromosome inactivation patterns in this patient, using the human androgen receptor gene demonstrated monoclonal haematopoiesis in her granulocytes. In contrast, she had a low burden of a JAK2-V617F mutation positive clone among granulocyte populations. These results suggest that the JAK2-V617F mutation occurs after the onset of monoclonal haematopoiesis; thus the V617F mutation of JAK2 may not be the primary event in the induction of BCS.

JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets.

There have been conflicting reports over the JAK2-V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2-V617F status, not only in granulocytes but also in platelets. The JAK2-V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2-V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2-V617F expression. The remaining 44 patients showed negative JAK2-V617F expression on granulocytes, but positive JAK2-V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2-V617F status (both-positive, platelets-only positive and both-negative), the both-positive and platelets-only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2-V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2-V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.