A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan.

PURPOSE: This phase I/II clinical study was conducted to examine the safety, tolerability, pharmacokinetics, and efficacy of 10-min dosing of bendamustine in patients with previously untreated indolent B-cell non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL) (Group 1) and patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) (Group 2). METHODS: Rituximab 375 mg/m2 was administered intravenously every 28 days to Group 1 patients on day 1 and every 21 days to Group 2 patients on day 1. Bendamustine 90 mg/m2/day was administered to the former on days 1 and 2; bendamustine 120 mg/m2/day was administered to the latter on days 2 and 3. Each regimen was delivered up to six cycles for both groups. The primary endpoints were safety and tolerability in Groups 1 and 2, respectively. RESULTS: Among 37 enrolled patients, safety was assessed in 36. In Group 1 (n = 30), 27 patients (90%) had follicular lymphoma. Adverse events (AEs) were observed in all 30 patients in Group 1. Dose-limiting toxicities were observed in two of six patients in Group 2. Common AEs included lymphocyte count decreased (86.7%, 100%). In Group 1, overall response and complete response rates were 93.1% (95% confidence interval [CI] 77.2-99.2%) and 75.9% (95% CI 56.5-89.7%), respectively. The Cmax and AUC of bendamustine tended to be higher in Group 2 than in Group 1. CONCLUSIONS: This study showed that bendamustine is safe, well-tolerated and effective for patients with previously untreated iNHL, MCL or rrDLBCL. Pharmacokinetic data were equivalent to those obtained outside of Japan. REGISTRATION NUMBERS: Registration NCT03900377; registered April 3, 2019.

Angioimmunoblastic T-cell Lymphoma Presenting as a Methotrexate-associated Lymphoproliferative Disorder with Extreme Peripheral Blood Plasmacytosis.

A 74-year-old man was admitted to our hospital because of systemic lymphadenopathy, weight loss, and a fever at night that had persisted for approximately 1 month. Blood tests revealed extreme peripheral blood plasmacytosis and hypergammaglobulinemia. A lymph node biopsy showed angioimmunoblastic T-cell lymphoma (AITL). Based on the history of methotrexate (MTX) administration, the established diagnosis was MTX-associated lymphoproliferative disorder (MTX-LPD). After MTX was discontinued, the lymphadenopathy spontaneously regressed and the plasmacytosis disappeared. He had no disease progression for three years. We found that AITL as an MTX-LPD can cause plasmacytosis, and the prognosis of this disease may not be poor.

Bendamustine Plus Rituximab as Salvage Treatment for Patients with Relapsed or Refractory Low-grade B-cell Lymphoma and Mantle Cell Lymphoma: A Single-Center Retrospective Study.

Bendamustine plus rituximab (B-R) is an effective therapy for relapsed or refractory (r/r) low-grade B-cell lymphoma (LGBCL) and mantle cell lymphoma (MCL); however, clinical data from Japanese patients treated with B-R therapy are limited. We retrospectively evaluated the efficacy and safety of B-R therapy in 42 patients who received B-R therapy at our hospital for r/r LGBCL and MCL. All patients received intravenous (IV) ritux-imab 375 mg/m2 on day 1 and IV bendamustine 90 mg/m2 on days 2 and 3 every 28 days for up to 6 cycles. The common histologic subtypes were follicular lymphoma (n = 29, 70%), marginal zone lymphoma (n = 6, 14%), and MCL (n = 5, 12%). The overall response rate was 93%, with 62% complete response and complete response unconfirmed. The median progression-free survival (PFS) was 38 months (95% confidence interval [CI], 24.6 to not reached [NR]), and the median overall survival (OS) was 80 months (95% CI, 60.7 to NR). Patients receiving a cumulative dose of bendamustine ≥ 720 mg/m2 showed a significantly longer PFS and OS. Grade 3/4 adverse events (≥ 10%) included neutropenia (55%), lymphopenia (69%), and nausea (24%). B-R therapy was effective and well tolerated, and the cumulative dose of bendamustine was associated with a favorable outcome.

Treatment outcomes of IgG4-producing marginal zone B-cell lymphoma: a retrospective case series.

IgG4-producing marginal zone B-cell lymphomas (MZLs) have been recently proposed as a subtype of MZLs. Despite the abundant literature on pathophysiological features of this type of lymphoma, only a few retrospective studies pertaining to the treatment outcomes have been reported, and its prognosis remains unclear. We retrospectively analyzed seven patients with IgG4-producing MZLs diagnosed at our institute, with specific reference to treatment and outcomes. The median age was 69.0 years (55-79), and all were males. The median follow-up period was 66.6 months (8-121). All patients had localized disease; four patients had tumors of the ocular adnexa, whereas two had retroperitoneal tumors. Five patients were treated with irradiation (30 Gy/15 fr) (n = 4) or surgery (n = 1), resulting in tumor reduction. Two patients were treated by chemotherapy or irradiation. Among them, one commenced rituximab monotherapy, which led to an inadequate reduction of the tumor. Subsequent irradiation induced complete response (CR). The other patient experienced repeated relapses during follow-up and finally achieved CR by combination chemotherapy. Treatment was well tolerated in all cases, and none of the patients showed disease progression at the last follow-up visit. Our results indicate that the standard treatments for MZLs are generally appropriate for IgG4-producing MZL.

Daratumumab therapy for relapsed or refractory multiple myeloma: a single-center retrospective study.

BACKGROUND: Significant advancements have been achieved in the quality of treatment for relapsed/refractory multiple myeloma (RRMM). Currently, daratumumab (DARA) is a highly effective drug widely used for RRMM; however, the knowledge on its efficacy and safety in Japanese patients remains limited. Accordingly, we aimed to evaluate the efficacy and safety of DARA therapy for RRMM. METHODS: We reviewed the medical records of patients who received DARA combination therapy and evaluated its efficacy and safety in our hospital. RESULTS: DARA was administered to 44 patients between October 2017 and March 2019. The median number of previous therapies was three (range 1-9). The rates of ≥ complete response and overall response were 27.3% and 61.4%, respectively. The median progression-free survival (PFS) duration was 12.3 months [95% confidence interval (CI) 5.1 to not reached (NR)] and estimated 2-year overall survival rate was 63.7% (95% CI 46.9-76.5%). In the multivariate analysis, patients with ≥ three previous lines of therapy and mass lesions showed significantly shorter PFS durations. The observed grade 3/4 adverse events (≥ 10%) included neutropenia (59.0%), thrombocytopenia (29.5%), anemia (36.4%), lymphopenia (38.6%) and febrile neutropenia (18.2%). None of the patients discontinued DARA therapy in spite of these AEs. CONCLUSION: DARA is an effective treatment option for most patients and is tolerable. However, patients with heavy treatment before DARA therapy and mass lesions are likely to show poorer outcomes. Our findings suggest the use of DARA therapy early in the course of the disease.

Differences among hemoglobin thresholds for red blood cell transfusions in patients with hematological diseases in teaching hospitals: a real world data in Japan.

A hemoglobin (Hb) threshold level of 7 g/dL has been proposed for red blood cell (RBC) transfusion in patients with chronic anemia in the Japanese guideline since 2005. However, Hb thresholds for hematological diseases in clinical practice and factors responsible for higher Hb thresholds remain unclear. Hb thresholds were collected for patients with hematological diseases from 32 Japanese teaching hospitals. Uni- and multivariate analyses were used to analyze relationships between Hb threshold level and various patient and hospital factors. In total, 4996 units of RBC were transfused to 1054 patients with hematological diseases in 2421 transfusions. Median age was 68 years. Myelodysplastic syndrome was the most frequent diagnosis. Overall median Hb threshold level was 6.9 g/dL. Multivariate linear regression analysis detected the following variables associated with Hb threshold level: hospital; cardiovascular disease; symptomatic anemia; and hematopoietic stem cell transplantation. Hospital was the most significant factor. Collectively, median Hb threshold level in clinical practice in Japan was similar to the guidelines. Higher Hb threshold level depended on the hospitals at which the transfusions were performed as well as patient condition. Educational approaches directed toward hospitals may be useful to promote transfusion guidelines.

Nationwide survey of systemic chronic active EBV infection in Japan in accordance with the new WHO classification.

Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.

[Diffuse large B-cell lymphoma relapsing with intravascular large B-cell lymphoma-like perivascular and intravascular lesions].

A 64-year-old woman was diagnosed with diffuse large B-cell lymphoma (DLBCL) in 2013. After eight courses of R-CHOP therapy followed by local irradiation of the remaining retroperitoneal soft tissue shadow, complete response was confirmed on 18F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Early in 2016, patient's serum LDH and soluble IL-2 receptor levels elevated. With suspected recurrence of DLBCL, FDG-PET/CT was performed that showed no lymphadenopathy or abnormal FDG uptake. By the end of July 2016, the patient developed fever and night sweating. Intravascular large B-cell lymphoma (IVLBCL) was suspected, and the patient underwent random skin biopsies, which revealed large atypical cells infiltrating peripheral and intravascular regions of the subcutaneous adipose tissue. Cell morphology, immunostaining, and PCR analysis of the immunoglobulin heavy chain gene suggested the recurrence of DLBCL. Despite salvage chemotherapy and autologous peripheral stem cell transplantation with high-dose chemotherapy, approximately 15 months later, DLBCL recurred and involved the lungs. The patient again received chemotherapy and achieved a second remission. Because DLBCL may recur like intravascular lymphoma, the same tests used for IVLBCL diagnosis are required in cases of suspected recurrence of DLBCL based on clinical and laboratory findings.

Efficacy and safety of autologous stem cell transplantation in patients aged ≥ 65 years with multiple myeloma in the era of novel agents.

Clinical trials evaluating the role of autologous hematopoietic stem cell transplantation (auto-HCT) in multiple myeloma have mostly included patients aged <65 years. Therefore, this study was aimed to evaluate the efficacy and safety of auto-HCT in elderly patients with multiple myeloma in the era of novel agents. We retrospectively analyzed 2056 patients with multiple myeloma, who underwent auto-HCT in 2007-2014 (287 were aged ≥65 years). We evaluated the 100-day treatment-related mortality (TRM) and overall survival (OS) in two groups; elderly patients ( ≥65 years) who underwent auto-HCT compared with younger patients ( <65 years). In the propensity score-matched-pair analysis used to adjust for possible selection bias, the incidence of 100-day TRM between patients aged <65 (0.4%; 95% confidence interval [CI]: 0.0-2.0%) and ≥65 years (1.2%; 95% CI: 0.3-3.1%) showed no statistically significant difference (p = 0.31). The probability of the 5-year OS after transplantation in those aged <65 (62.5%; 95% CI: 58.6-66.1%) and ≥65 (63.5%; 95% CI: 52.2-72.7%) years was also not significantly different (p = 0.56). This study showed that the safety and efficacy of auto-HCT in elderly patients with multiple myeloma in the era of novel agents compared with younger patients were similar.

A Host-Dependent Prognostic Model for Elderly Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.

[Successful treatment with rituximab of a patient with coincident acquired hemophilia A and thrombotic thrombocytopenic purpura].

A 66-year-old man was admitted for oral hemorrhage, purpura, and APTT prolongation. Factor VIII (FVIII) activity was decreased, due to the presence of FVIII inhibitor. He was diagnosed with acquired hemophilia A (AHA) and treated with prednisolone. Eight months later, the FVIII inhibitor titer again increased. Upon readmission, thrombocytopenia and autoimmune hemolytic anemia were found. We suspected Evans syndrome accompanied by AHA, and we treated the patient with IVIG. However, his platelet count did not increase. Speech disturbance and delirium were observed from the 12th day of hospitalization. He was subsequently diagnosed with thrombotic thrombocytopenic purpura (TTP) because ADAMTS13 inhibitor was detected, causing a decrease in ADAMTS13 activity. We initiated plasma exchange (PE) and steroid-pulse therapy. After PE for 3 days, laboratory test results and psychiatric symptoms showed dramatic improvement. However, after a 2-day period without PE, the patient's platelet count decreased markedly. Therefore, we administered rituximab to eliminate these inhibitors. His platelet count recovered rapidly, and we were able to gradually wean the patient from PE. After two additional administrations of rituximab, neither inhibitor was detected. To date, the patient has remained in complete remission for approximately 3 years.

[Successful treatment with azacitidine for myelodysplastic syndrome with large vessel vasculitis].

Paraneoplastic inflammation of the large vessels is a rare complication of myelodysplastic syndrome (MDS), and patients with MDS and systemic vasculitis have a poor prognosis. We present a 66-year-old male with MDS and large vessel vasculitis treated with azacitidine. Azacitidine administration improved his clinical symptoms, high fever and thickening of the arterial wall, and he achieved a complete bone marrow remission. However, 1 year later he showed progression of MDS. For MDS with vasculitis, intensive therapy, the same as that given to the high-risk group, should be considered and azacitidine administration may represent an efficacious treatment.

[Clopidogrel-associated thrombotic thrombocytopenic purpura].

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is a rare complication of thienopyridine treatment, especially clopidogrel. Here we report a case of clopidogrel-associated TTP. A 77-year-old male initially complained of petechiae on his legs 6 weeks after clopidogrel treatment following coronary artery stenting. He was admitted 4 weeks later with slurred speech and low-grade fever. Laboratory findings showed severe thrombocytopenia, hemolytic anemia with fragmented red cells, renal dysfunction and severe deficiency of ADAMTS13 activity with the presence of the inhibitor. Based on the clinical course and laboratory findings, he was diagnosed with TTP and underwent plasma exchange, followed by improvement of symptoms and laboratory abnormalities after 7 courses of plasma exchange. Nevertheless, the patient died of sepsis due to perforated small intestinal diverticulitis 89 days after admission. Thienopyridine-associated TTP usually occurs within 12 weeks after initiation of the therapy. Physicians should therefore be aware of this fatal complication associated with clopidogrel therapy and frequent blood tests, every 2 weeks during the first 12 weeks, is recommended for early diagnosis.

Extranodal CD20-positive peripheral T-cell lymphoma presenting with adrenal and testicular masses.

We report a case of extranodal CD20-positive peripheral T-cell lymphoma (PTCL). A 59-year-old man was admitted because of a right testicular mass in April 2006. CT scan revealed bilateral adrenal masses and he underwent right orchiectomy. The enlarged testis showed diffuse infiltration of large CD20-positive lymphocytes with slight CD3-positive cells. These cells were negative for CD10 and showed a high MIB-1 index. The pathological diagnosis was diffuse large B-cell lymphoma. He received R-CHOP, but developed brain involvement. He received whole brain radiotherapy following high-dose methotrexate, but he died of disease progression in August 2007. At autopsy, lymphoma cells were definitely positive for CD3 and negative for CD20. Monoclonal TCR gamma gene rearrangement was detected in the brain specimen without IgH rearrangement by PCR. The testicular tumor also showed the same clonal bands. Immunohistochemical re-evaluation of the testis showed CD20+, CD79a-, PAX5-, MUM1-, CD3 p+, CD5 p+, CD4-, CD8-, CD7 p+, granzyme B+, and TIA1+. Based on the clinical course and immunohistology, we finally diagnosed this case as extranodal PTCL-nos (not otherwise specified) with aberrant CD20 expression, which is extremely rare. The detection of gene rearrangement, plural immunohistochemical markers and knowledge of the possibility of CD20+ PTCL-nos are necessary for such cases.

The effect of adding rituximab to CHOP-based therapy on clinical outcomes for Japanese patients with diffuse large B-cell lymphoma: a propensity score matching analysis.

We conducted a retrospective analysis to evaluate the impact on clinical outcomes of adding rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for diffuse large B-cell lymphoma (DLBCL) patients in Japan. A propensity score method was used to compensate for the non-randomized study design. From January 2000 to December 2004, 378 patients who were newly diagnosed with DLBCL at 13 institutes were enrolled: 123 in the rituximab plus CHOP-based chemotherapy (R+) group, and 255 in the CHOP-based chemotherapy only (R-) group. The complete response rate was significantly higher in the R+ group than in the R- group (77.7 vs. 69.4%, P < 0.001). The progression-free survival (PFS) at 2 years was 62.4% in the R+ group and 57.0% in the R- group. The 2-year overall survival (OS) was 76.9% for the R+ group and 70.5% for the R- group. A multivariate analysis revealed that the addition of rituximab was a strong independent prognostic factor for PFS (hazard ratio 0.64, 95% CI 0.43-0.96, P = 0.031). A subgroup analysis revealed that R+ particularly benefited younger patients (hazard ratio 0.25, 95% CI 0.08-0.75, P = 0.013). IPI also showed significant impact for PFS (hazard ratio 1.82, 95% CI 1.55-2.14 for one score increase, P < 0.001) as well as OS (hazard ratio 2.10, 95% CI 1.71-2.57, P < 0.001). In summary, the addition of rituximab to CHOP-based chemotherapy results in better outcomes for Japanese DLBCL patients, particularly younger patients.

[Successful rituximab treatment in a patient with refractory hairy cell leukemia-Japanese variant and suffering from acute respiratory distress].

A 69-year-old man was referred to our hospital because of thrombocytopenia and was diagnosed as having hairy cell leukemia-Japanese variant (HCL-Jv) in December 2000. In June 2002, he was treated with pentostatin for progression of thrombocytopenia, but his response was incomplete. In addition, the number of hairy cells (HCs) in his peripheral blood (PB) began gradually to increase. He received treatment with interferon-alpha and cladribine, but he failed to respond completely to these treatments. The HCs in his PB decreased after splenic irradiation in July, 2004. However, he was admitted with acute respiratory distress in November. His white blood cell count was 123.1 X 10(9)/L with 91% HCs. Radiography and computed tomography of his chest revealed ground-glass opacity in both lungs. A bone marrow (BM) aspirate indicated increased cellularity with an 84% HC infiltration level. Based on these findings, we diagnosed pulmonary infiltration by HCs. Rituximab was administered weekly at a dose of 375 mg/m2, and he also received low-dose melphalan in a supportive role. After 8 courses of rituximab therapy, the HCs disappeared in his PB and BM, and his pulmonary infiltrates subsided. These results suggest that rituximab may be a very effective treatment for refractory HCL-Jv.

Antilung cancer effect of WT1-specific cytotoxic T lymphocytes.

We and other groups have recently reported that CTLs that specifically recognize a peptide derived from WT1 lyse leukemia cells in a HLA class I-restricted manner. Because WT1 is expressed in various solid tumors as well as in leukemic cells, we investigated whether WT1-specific CTLs can also inhibit the growth of lung cancer by examining their cytotoxic activity against lung cancer cell lines in vitro and their inhibitory effect on the growth of human lung cancer cells engrafted into nude mice. The WT1 transcript was detected in most of the lung cancer cell lines examined. A WT1-specific, HLA-A24-restricted CTL clone (designated TAK-1) exhibited cytotoxicity against lung cancer cell lines bearing HLA-A24 but did not lyse cells lacking this HLA. This suggests that the target antigen for TAK-1 on HLA-A24-positive lung cancer cells is the naturally processed WT1 peptide. Adoptive transfer of TAK-1 into nude mice that had been engrafted with a HLA-A24-positive lung cancer cell line resulted in inhibition of cancer cell growth and prolonged survival. These findings strongly suggest that WT1 is a universal tumor-associated antigen and that WT1-targeting immunotherapy offers a potentially effective treatment option for lung cancer as well as leukemia.

Successful treatment of progressive NK cell lymphoma with allogeneic peripheral stem cell transplantation followed by early cyclosporine tapering and donor leukocyte infusions.

We describe a patient with progressive natural killer (NK) cell lymphoma who was treated successfully with allogeneic peripheral blood stem cell transplantation (allo-PBSCT) followed by early cyclosporine (CsA) tapering and donor leukocyte infusion (DLI). Because the disease showed early resistance to conventional chemoradiotherapy, we performed high-dose chemotherapy followed by allo-PBSCT. After achieving hematologic engraftment, the patient underwent early tapering of CsA and DLI in an attempt to induce a graft-versus-lymphoma effect. Although the disease was in a progressive state at the time of transplantation, complete remission was obtained after allo-PBSCT. As of this report, the patient has been well for more than 2 years.