Real-world data of AML in Japan: results of JALSG clinical observational study-11 (JALSG-CS-11).

This report covers acute myeloid leukemia (AML) results from a multicenter, prospective observational study of AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia in Japan. From August 2011 to January 2016, 3728 AML patients were registered. Among them, 42% were younger than 65, and the male-to-female ratio was 1.57:1. With a median follow-up time of 1807 days (95% confidence interval [CI]: 1732-1844 days), the estimated 5-year overall survival (OS) rate in AML patients (n = 3707) was 31.1% (95% CI: 29.5-32.8%). Trial-enrolled patients had a 1.7-fold higher OS rate than non-enrolled patients (5-year OS, 58.9% [95% CI: 54.5-63.1%] vs 35.5% [33.3-37.8%], p < 0.0001). Women had a higher OS rate than men (5-year OS, 34% [95% CI; 31.4-36.7%] vs 27.7% [25.7-29.7%], p < 0.0001). The OS rate was lower in patients aged 40 and older than those under 40, and even lower in those over 65 (5-year OS for ages < 40, 40-64, 65-74, ≥ 75: 74.5% [95% CI; 69.3-79.0%] vs 47.5% [44.4-50.6%] vs 19.3% [16.8-22.0%] vs 7.3% [5.5-9.4%], respectively). This is the first paper to present large-scale data on survival and clinical characteristics in Japanese AML patients.

Real-world data of MDS and CMML in Japan: results of JALSG clinical observational study-11 (JALSG-CS-11).

We conducted a multicenter, prospective observational study of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) in Japan. From August 2011 to January 2016, we enrolled 6568 patients. Herein, we report the results for MDS (n = 2747) and CMML (n = 182). The percentage of patients aged 65 years or older was 79.5% for MDS and 79.7% for CMML. The estimated overall survival (OS) rate and cumulative incidence of AML evolution at 5 years were 32.3% (95% confidence interval: 30.2-34.5%) and 25.7% (23.9-27.6%) for MDS, and 15.0% (8.9-22.7%) and 39.4% (31.1-47.6%) for CMML. Both diseases were more common in men. The most common treatment for MDS was azacitidine, which was used in 45.4% of higher-risk and 12.7% of lower-risk MDS patients. The 5-year OS rate after treatment with azacitidine was 12.1% (9.5-15.1%) for of higher-risk MDS patients and 33.9% (25.6-42.4%) for lower-risk patients. The second most common treatment was erythropoiesis-stimulating agents, given to just 20% of lower-risk patients. This is the first paper presenting large-scale, Japanese data on survival and clinical characteristics in patients with MDS and CMML.

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.

Prognostic factors for the development of lower respiratory tract infection after influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients: A Kanto Study Group for Cell Therapy multicenter analysis.

OBJECTIVES: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. METHODS: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. RESULTS: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. CONCLUSION: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.

The clinical impact of absolute lymphocyte count in peripheral blood among patients with methotrexate - associated lymphoproliferative disorders.

Regressive lymphoproliferative disorders (R-LPD) after methotrexate (MTX) withdrawal are one of the specific features of methotrexate - associated lymphoproliferative disorders (MTX-LPD). Although the impact of the absolute lymphocyte count (ALC) on the pathogenesis of R-LPD has been recently emphasized, understanding relapse/regrowth events (RRE) and differences among LPD subtypes is necessary. In this study, we confirmed ALC recovery in the regressive group (R-G; R-LPD without RRE) and relapse/regrowth group (R/R-G; R-LPD with RRE). The increase in ALC lasted at least 2 years in R-G, whereas it decreased within 3 years in R/R-G, supporting the better overall survival (OS) in R-G, as previously reported. In addition, our study suggested that an ALC of 1000/µL at the time of development of LPD is a significant predictor for treatment-free survival (TFS). Furthermore, an ALC of 1000/µL at 6 months after MTX withdrawal was found to be a significant indicator of TFS and OS for R-G and R/R-G. The ALC decreased gradually before LPD development in R/R-G, whereas it decreased 6 months before LPD development in R-G, confirming the important role of ALC in the pathogenesis of MTX-LPD such as regressive events and RRE. In addition to ALC, other predictive factors, such as serum C-reactive protein and soluble interleukin-2 receptors, may be helpful in the management of MTX-LPD, including the decision making for an additional chemotherapy for regressive LPD after MTX withdrawal.

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11.

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.

[Human parvovirus B19-induced hemophagocytic lymphohistiocytosis and myocarditis in an adult patient with hereditary spherocytosis].

Human parvovirus B19 (HPV-B19) causes hemophagocytic lymphohistiocytosis (HLH). Here we describe a 35-year-old female with hereditary spherocytosis (HS) who developed HLH due to HPV-B19 infection. Upon admission, she had high fever and diarrhea. Laboratory findings included severe pancytopenia and elevated serum triglyceride and ferritin levels. Moreover, high HPV-B19 levels in the peripheral blood and increased reactive lymphocytosis in the bone marrow led to a diagnosis of HLH due to HPV-B19 infection. With supportive therapy and a blood transfusion, HLH symptoms, including fever and myelosuppression, improved in 1 week. However, symptoms of heart failure (HF) suddenly developed, and an echocardiography revealed diffuse systolic dysfunction, suggesting viral myocarditis due to HPV-B19 infection. Conservative management with diuretics gradually improved HF symptoms over a period of 2 weeks. HPV-B19 infection in adult patients with HS rarely results in severe HLH, but conservative therapy may improve the symptoms. Nonetheless, a careful follow-up is required after HLH improves because viral myocarditis can develop, as was seen in our patient.

The aggressive clinical courses of Hodgkin lymphoma primarily diagnosed as methotrexate-induced non-specific lymphoproliferative disorder in patients with rheumatoid arthritis.

Recently, attention has been focused on methotrexate-induced lymphoproliferative disease (MTX-LPD), and atypical phenotypes are occasionally documented. We encountered two patients with rheumatoid arthritis (RA) who were diagnosed with non-specific LPD (LPD-nos). Biopsy samples were not obtained during the initial examination when the LPD development was discovered, and the patients achieved a complete response after MTX cessation (case 1) or steroid pulse therapy (case 2). However, the tumors flared up 1.5 years later, and LPD-nos was determined following biopsies of the lymph node (LN, case 1) and liver (case 2). Prednisolone was subsequently administered instead of chemotherapy; however, multiple masses, including in the spine (case 1), and severe icterus with liver dysfunction (case 2) were exacerbated within a few months. Although the re-biopsy of LN proved the presence of HL and radiation followed by aggressive chemotherapy rescued the patient (case 1), the superficially accessible biopsy site was not found, and autopsy finally revealed HL (case 2). In both cases, the underlying pathogenesis along with the B symptoms and laboratory abnormalities suggested MTX-LPD, HL in particular. Therefore, even if the pathological diagnosis does not confirm the specific LPD subtype, the administration of aggressive chemotherapy should be considered if the LPD activity flares severely.

Successful early romiplostim use in a case of severe immune thrombocytopenia with critical carotid arterial injury.

Thrombopoietin receptor (TPO-R) agonists have been shown to be effective in refractory chronic immune thrombocytopenia (ITP); however, their efficacy in patients under critical care is not known. We report the case of a female patient with a newly diagnosed ITP who experienced severe bleeding from an external wound. The patient was administered the standard treatments for ITP, which are high-dose intravenous immunoglobulin (IVIg) and corticosteroids. However, following failure of these treatments, we administered romiplostim on day 6 after the onset of ITP. On day 6 after the initiation of romiplostim, there was improvement in platelet count and bleeding tendency. We were subsequently able to perform a splenectomy successfully. The efficacy of TPO-R agonists in ITP has been reported in several situations, including before surgery in an ITP patient; however, the use of TPO-R for arterial bleeding with shock has not been reported. To our knowledge, the present article is a rare case report of the use of a TPO-R agonist in a patient with critical artery injury. Our data suggest that the early use of romiplostim is effective in emergency cases of newly diagnosed ITP with life-threatening bleeding, which is refractory to standard treatment.

[Cardiac and breast diffuse large B-cell lymphoma with pericardial effusion and AV-block].

Primary cardiac lymphoma is extremely rare and is associated with a poor prognosis. In most cases, cardiac involvement occurs as a late symptom and the diagnosis is thus delayed. We herein report a 35-year-old woman with cardiac diffuse large B-cell lymphoma (DLBCL) with breast infiltration. The patient was admitted to our hospital based on an initial presentation with dyspnea on exertion, chest pain, and a hard mass of the left breast. Echocardiography revealed a mass in the right atrium wall and interatrial septum, and massive pericardial effusion. ECG showed atrioventoricular block. We promptly performed a needle biopsy of the breast mass, which showed CD5-positive DLBCL, non-GCB type. The serum HIV reaction was negative. We thus diagnosed this patient as having cardiac and breast CD5-positive DLBCL, stage IVA, based on the massive pericardial effusion. The patient's prognosis was apparently poor. Therefore, she received 3 cycles of R-CHOP chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT), resulting in a complete response. In general, cardiac lymphoma is associated with high mortality and has a poor prognosis. This case demonstrates that rapid and appropriate diagnosis, and immediate intensive chemotherapy followed by PBSCT might be necessary for the treatment of extranodal lymphoma indicative of a poor prognosis.

TM-233, a novel analog of 1'-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities.

Although the introduction of bortezomib and immunomodulatory drugs has led to improved outcomes in patients with multiple myeloma, the disease remains incurable. In an effort to identify more potent and well-tolerated agents for myeloma, we have previously reported that 1'-acetoxychavicol acetate (ACA), a natural condiment from South-East Asia, induces apoptotic cell death of myeloma cells in vitro and in vivo through inhibition of NF-κB-related functions. Searching for more potent NF-κB inhibitors, we developed several ACA analogs based on quantitative structure-activity relationship analysis. TM-233, one of these ACA analogs, inhibited cellular proliferation and induced cell death in various myeloma cell lines with a lower IC50 than ACA. Treatment with TM-233 inhibited constitutive activation of JAK2 and STAT3, and then downregulated the expression of anti-apoptotic Mcl-1 protein, but not Bcl-2 and Bcl-xL proteins. In addition, TM-233 rapidly decreased the nuclear expression of NF-κB and also decreased the accumulation of cytosolic NF-κB. We also examined the effects of TM-233 on bortezomib-resistant myeloma cells that we recently established, KMS-11/BTZ and OPM-2/BTZ. TM-233, but not bortezomib, inhibited cellular proliferation and induced cell death in KMS-11/BTZ and OPM-2/BTZ cells. Interestingly, the combination of TM-233 and bortezomib significantly induced cell death in these bortezomib-resistant myeloma cells through inhibition of NF-κB activity. These results indicate that TM-233 could overcome bortezomib resistance in myeloma cells mediated through different mechanisms, possibly inhibiting the JAK/STAT pathway. In conclusion, TM-233 might be a more potent NF-κB inhibitor than ACA, and could overcome bortezomib resistance in myeloma cells.

Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis.

Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.