[Plasmablastic lymphoma presenting clinical symptoms similar to plasmablastic myeloma].

A 75-year-old man developed multiple head masses as well as a compression fracture. His blood test revealed elevated immunoglobulin G (IgG) protein levels, and immunofixation electrophoresis revealed the presence of monoclonal IgGκ. Furthermore, positron emission tomography/computed tomography revealed multiple bone lesions, although bone marrow examination revealed only 1.2% of plasma cells. Biopsy of a head mass led to the diagnosis of plasmablastic lymphoma (PBL), an aggressive B-cell lymphoma with plasma cell phenotypes but no B-cell antigen expression. Because the tumor cells have plasmablastic morphologies, it is difficult to distinguish PBL from plasmablastic myeloma, which is a subtype of multiple myeloma. Both diseases have similar immunophenotypes and clinical courses. In this case, PBL was finally diagnosed based on Epstein-Barr virus positivity, and the patient made a complete recovery after treatment with DA-EPOCH.

Outcomes of ixazomib/lenalidomide/dexamethasone for multiple myeloma: A multicenter retrospective analysis.

OBJECTIVES: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM). METHODS: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database. RESULT: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type. CONCLUSION: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM.

Clinical efficacy of mogamulizumab for relapsed/refractory aggressive adult T-cell leukemia/lymphoma: A retrospective analysis.

OBJECTIVES: Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. METHODS: We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. RESULTS: The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. CONCLUSIONS: In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naïve essential thrombocythemia patients in a real-world setting.

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab.

BACKGROUND: There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab. METHODS: We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed. RESULTS: The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515). CONCLUSION: The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

[Successful treatment with brentuximab vedotin maintenance therapy after autologous stem cell transplantation in high-risk Hodgkin lymphoma].

A 56-year-old woman was diagnosed with classical Hodgkin lymphoma in December 2012. She achieved complete remission (CR) with six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In March 2015, she experienced a relapse marked by high fever, respiratory discomfort, and pain in the left thigh owing to tumor involvement of the femur. She was treated with one cycle of brentuximab vedotin (BV), followed by irradiation of the left femoral lesion. She achieved partial remission (PR) but developed recurrence after the third cycle of BV. She achieved PR again with two cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen; therefore, autologous stem cell transplantation (ASCT) was performed. Because the dosing interval used for BV therapy was longer than that in the recommended schedule, we could not definitively attribute her recurrence to BV resistance. Moreover, she maintained a good performance status after recurrence during subsequent cycles of BV therapy. Because of attaining PR after ASCT, she subsequently received a total of 12 BV cycles for consolidation. She achieved CR 3 months after ASCT and has remained in CR until 29 months. For patients who show relapse after initial BV therapy, retreatment with BV should be carefully considered. Patients who show relapse after achieving at least PR with initial BV therapy are potential candidates for post-ASCT BV maintenance therapy to reduce their tumor burden.

Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience.

Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.

Rapid improvement of hyperammonemic encephalopathy by bortezomib treatment in IgD-type multiple myeloma.

A 74-year-old man visited our hospital with complaints of anorexia, weight loss, and impaired activities of daily living. He presented mild consciousness disturbance at the first visit, but specific causes were identified. The IgD level was>2,000 mg/dl and bone marrow biopsy was performed after aspiration failed due to excessive density. He was diagnosed with IgD/λ multiple myeloma (MM). He lapsed into a coma with an extremely high ammonia level of 484 µg/dl on day 8 after admission. His diagnosis was established as hyperammonemic encephalopathy (HE). He was treated with dexamethasone (Dex) pulse therapy and continuous hemodiafiltration. Minor improvement of hyperammonemia was achieved. Combination therapy with bortezomib and Dex was commenced. His ammonia level rapidly decreased and his mental state improved. HE accompanied by MM is rare and further studies are needed to clarify outcomes in response to treatment using the novel agent Bor. Although HE is potentially fatal, we found Bor to be rapidly effective against HE.

Second primary malignancies among patients with myeloma-related-diseases in the KMF database.

The incidence of second primary malignancies (SPMs) in Japanese patients with myeloma or myeloma-related diseases was studied by using the Kansai Myeloma Forum (KMF) database registered from November 2012 to March 2015. We studied 1,571 cases. Hematologic malignancies were documented in 10 patients, and solid tumors in 36 during this period. The cumulative 5-year incidence was estimated to be 1.0% for hematological malignancies and 3.7% for solid tumors. In the patients with smoldering myeloma or MGUS without treatment, solid tumors but not hematologic malignancies developed, though the cumulative incidence of each malignancy did not differ significantly from that in patients receiving treatment. Although statistical analysis showed that treatment with melphalan, bortezomib, lenalidomide, or thalidomide had no effect on the occurrence of hematological malignancies, lenalidomide administration was more frequent in the patients with solid tumors. To evaluate the SPMs in myeloma or myeloma-related diseases more accurately, accumulation of a larger number of patients and longer observation are needed.

[Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder in a Patient with Acute Lymphocytic Leukemia].

A 27-year-old woman with acute lymphocytic leukemia, who underwent allogeneic hematopoietic stem cell transplantation, complained of nausea and blurred vision 288 days after the transplantation. Intracranial tumors were identified on brain MRI. She received whole brain radiation after open biopsy, but she died. The tumors had characteristics of diffuse large B cell lymphoma, and she was finally diagnosed with primary central nervous system post-transplant lymphoproliferative disorder. This disease is rare and has a poor outcome. Therefore, accumulation of cases and establishment of treatments for this condition are urgently needed.

Does the hematopoietic cell transplantation specific comorbidity index (HCT-CI) predict transplantation outcomes? A prospective multicenter validation study of the Kanto Study Group for Cell Therapy.

Recent advances in allogeneic hematopoietic stem cell transplantation have led to increasing use of this modality in older patients who tend to have been more heavily pretreated and have more comorbidities. Thus, the evaluation of comorbidity is of increasing importance to more precisely assess the benefits and risks of the transplantation procedure. Researchers from Seattle developed the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which was associated with the risk of mortality in several retrospective studies. However, its clinical utility has not been extensively documented in prospective studies. The aim of the present study was to evaluate the utility of the HCT-CI prospectively in a multicenter setting. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years were 59% and 20%, respectively (n = 243). We found that the HCT-CI in its original scale failed to predict OS and NRM in this set of patients. Thus, we applied a flexible HCT-CI risk scoring system (restratifying scores from 0 to 3 to indicate low risk, and scores of 4 or higher as high-risk). The flexible HCT-CI was found to predict 2-year NRM and OS better than the original HCT-CI (NRM: P = .01, OS: P = .003). In subgroup analysis, we evaluated the usefulness of the original HCT-CI for patients excluding those who received cord blood transplantation (n = 186). Both 2-year OS and 2-year NRM were not significantly different according to the original HCT-CI (P = .304, P = .996), but with the flexible HCT-CI, there were significant differences in 2-year OS and 2-year NRM (P = .005 and P = .005, respectively). Multivariate analysis identified age >50, performance status (PS) <90, donor type (HLA-mismatched/unrelated donor), and the flexible HCT-CI ≥4 as significant predictors for worse OS at 2 years. However, the flexible HCT-CI did not remain a significant predictor for NRM at 2 years in multivariate analysis, whereas age, PS, and donor type did. The HCT-CI did not consistently predict both NRM and OS, but it still can be a useful tool in combination with other factors, such as PS and age. Furthermore, the HCT-CI, although potentially useful for capturing pretransplantation comorbidity and risk assessment, may need further validation before its adoption for routine clinical use.

[Are the Japanese guidelines for the management of hepatitis B virus reactivation being properly implemented ?].

Hepatitis B virus(HBV)reactivation has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapies. The Japanese Guidelines for HBV reactivation were published in 2009. Despite the publication of these guidelines, there have been some reports of fulminant hepatitis B. Therefore, it was suggested that the guidelines were not yet been widely implemented. We investigated whether the guidelines had been implemented in our hospital. After the evaluation, it was determined that 89%of HBV cases were screened for the HBV surface antigen(HBs-Ag). Additionally, the screening for HBV surface antibody(HBs-Ab)and HBV core antibody(HBc-Ab)should be performed in cases negative for HBs-Ag, which was performed in only 17% of HBs-Ag-negative cases. It was concluded that the guidelines had not been implemented in our hospital. Therefore, we conducted educational activities to promote the implementation of the guidelines. Screening tests were performed in all 270 HBV cases between January and June 2013. Two antigen-positive carriers were identified. The rate of HBs-Ag-negative and/or HBc antibody -positive cases was 20.3%. Of these, 76.4%were tested using a DNA quantitative test, but DNA quantification did not increase in any case. HBV reactivation is expected to increase due to the development of new drugs and the use of diverse regimens. All physicians who perform immunotherapy and chemotherapy should immediately participate in educational activities.

[Retrospective analysis of Charlson comorbidity index (CCI)].

Owing to the advance of supportive care and the development of molecular targeted therapies, the elderlies or patients who have comorbidities have been treated more than before. The assessment of the comorbidity is indispensable to select the appropriate treatment or the control of following therapy. Some indices to determine them have been developed in western countries but not in Japan. The index which is used most is the Charlson comorbidity index (CCI). This index has never been evaluated in Japan. So we investigated the utility of the index for Japanese population. We surveyed retrospectively 498 patients aged 65 or more patients with colon cancer, breast cancer, lung cancer that have been treated in our hospital during 2002-2007. According to CCI, patients are classified into three groups and verified 1-year and 3-year survival rate. 1-year survival rate was 76.9% in groups of 0 points, 83.5% in groups of1 -5 points, 75.0% in the group of six or more points respectively (p=0.19). 3-year survival rate were 59.0%, 63.1%, 75.0%, respectively (p=0.46). Multivariate analysis identified age (≥ 50), Sex (man), stage (III and IV) as significant predictors for worse OS at 3-year. However, there was no significant difference in CCI. There are some items which frequency is zero, so the items of CCI may not match to Japanese population. Presence of existing disease is an important factor for the cancer therapy, and it should be evaluated accurately. It is urgently necessary to develop an evaluation method and establish the scale.

Venetoclax Combined with Azacytidine Can Be a First-line Treatment Option for Elderly Blastic Plasmacytoid Dendritic Cell Neoplasm.

An 84-year-old Japanese man was diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN). We administered combination therapy using venetoclax and azacytidine. We observed neutropenia (Grade 4), thrombocytopenia (Grade 2), and stomatitis (Grade 3). After six cycles of treatment, the BPDCN abnormal cells in the bone marrow specimen almost disappeared, and atypical cells were not detected in a skin biopsy. We propose venetoclax combined with azacytidine as a useful treatment approach in elderly patients, although clinicians should be mindful that therapeutic modifications may be essential to minimize and/or avoid adverse events.

Real-world data on induction therapy in patients with transplant-ineligible newly diagnosed multiple myeloma: retrospective analysis of 598 cases from Kansai Myeloma Forum.

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.

Impact of cytogenetic abnormalities in symptomatic multiple myeloma; a Japanese real-world analysis from Kansai Myeloma Forum.

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis.

[Marked improvement of anemia during treatment with deferasirox in patients with primary myelofibrosis and acute myeloid leukemia with myelodysplasia-related changes].

We report two patients who achieved a marked improvement of hematopoiesis with the use of deferasirox (DSX) for transfusional iron overload. Case 1 is an 81-year-old male who was diagnosed with primary myelofibrosis in July, 2007. He required regular red blood cell (RBC) transfusion of 4 units/month when he was started on DSX treatment in June, 2009. Four months after the treatment, he became transfusion independent, and has maintained hemoglobin levels of around 13 g/dl until today. Case 2 is a 70-year-old female with acute myeloid leukemia with myelodysplasia-related changes. She had been on RBC transfusion of 4 units/month when she was started on DSX treatment in January, 2010. Two months after the treatment, she became transfusion-independent, and 5 months after treatment, blast cells completely disappeared in the peripheral blood, together with normalization of white blood cell and neutrophil counts. Achieving durable transfusion-independency and normalization of white blood cell count and differential with a single use of DSX is a very rare event. Prospective accumulation of more patients and research to understand the mechanism underlying these effects are clearly warranted.

[Treatment of patients with COVID-19 on Hemodialysis: Efficacy of Remdesivir]. / Tratamiento de pacientes con COVID-19 en Hemodiálisis: Eficacia de Remdesivir.

BACKGROUND: There is no standard therapy for hemodialysis (HD) patients with COVID-19. Data on remdesivir in HD patients with COVID-19 are scarce. METHODS: We retrospectively analyzed 25 HD patients with COVID-19 treated with remdesivir. RESULTS: The median age of the patients was 78 years (range, 45-92 years) and was predominantly male (84%). A total of 44% of the patients had mild disease, 36% had moderate-1, and 20% had moderate-2. The most common symptoms were fever (76%) and coughing (44%). The most common comorbidity was renal failure (100%), followed by hypertension (60%) and cardiac disease (44%). The most frequent biomarker was elevated creatinine (100%), followed by C-reactive protein (80%), lymphopenia (76%), and D-dimer (68%). C-reactive protein levels decreased significantly before and after remdesivir administration (p < 0.001). Two patients showed deterioration, but none died. All patients recovered from COVID-19 and no adverse effects of treatment with remdesivir were observed. CONCLUSION: Our study suggests the safe use of remdesivir in HD patients with COVID-19.

Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis.

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd). Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database. Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia. Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered.

[Epidural abscess in the spine extended from pulmonary zygomycosis during consolidation chemotherapy for acute lymphoblastic leukemia].

A 37-year-old woman with acute lymphoblastic leukemia developed fever and pneumonia during persistent neutropenia after consolidation chemotherapy. Pneumonia was rapidly followed by the formation of abscess in adjacent subcutaneous tissues, muscles and bones. She subsequently developed sudden onset of paraplegia and loss of all sensation below Th4. Epidural abscess was detected by MRI. Emergency drainage was performed, but the patient died 4 days after the operation. Rhizopus oryzae grew from culture of the epidural abscess. Since the incidence of zygomycosis appears to have increased over the recent years, clinicians should be aware of the possibility of zygomycosis in case of any infection that is resistant to antibiotics.