Efficacy of elotuzumab for multiple myeloma deteriorates after daratumumab: a multicenter retrospective study.

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.

[Severe consciousness disturbance after cord blood transplantation for relapsed T lymphoblastic lymphoma].

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has a poor prognosis. Nelarabine has recently shown relatively good results in patients with relapsed or refractory T-ALL/LBL, but requires careful monitoring for neurological complications. A 50-year-old man with early recurrence of T-LBL after allogenic peripheral blood stem cell transplantation received nelarabine monotherapy and achieved complete remission after 1 cycle. He then received umbilical cord blood transplantation, and experienced sustained disturbance of consciousness. He later died of multiple organ failure, and autopsy suggested that nelarabine-induced leukoencephalopathy had caused the disturbance of consciousness. This case suggests that physicians should carefully monitor patients for neurological complications and consider imaging follow-up and consultation with a neurologist.

Biomarkers for predicting response to corticosteroid therapy for immune thrombocytopenic purpura.

Patients with immune thrombocytopenic purpura (ITP) often receive corticosteroids as a first-line treatment strategy. The ability to predict the therapeutic response to corticosteroids before initiating treatment would reduce the risk of adverse events, but biomarkers of this parameter have not yet been established. Here, in a single-centre, retrospective, cohort study of 127 ITP patients who received corticosteroids as first-line treatment, we compared several characteristics and test results between those patients with a favourable response to corticosteroids (responder cohort, n = 68) and those with a poor response to corticosteroids (non-responder cohort, n = 59) to identify potential biomarkers that were predictive of corticosteroid response. We extracted six factors as indicative of poor response to corticosteroid therapy for ITP: old age (≥81 years) (odds ratio [OR], 2.44; p = 0.02); low platelet count (<9 × 109 /L) (OR, 2.25; p = 0.02); high level of platelet-associated IgG (≥445 ng/107 cells) (OR, 3.95; p < 0.01), high platelet distribution width (≥ 14.0 g/dL) (OR, 2.00; p = 0.03), high lymphocyte-to-monocyte ratio (≥ 3.52) (OR, 1.40, p = 0.04), and low megakaryocyte count in bone marrow (< 85.5/µl) (OR, 1.72; p = 0.04). Thus, our present data support the fact that these six factors are useful biomarkers for predicting corticosteroid response in patients with ITP.

Benefits of plerixafor for mobilization of peripheral blood stem cells prior to autologous transplantation: a dual-center retrospective cohort study.

BACKGROUND AIMS: Before autologous stem cell transplantation (ASCT), hematopoietic stem cells must be stimulated to move from the bone marrow to the peripheral blood for harvesting. Plerixafor, a C-X-C chemokine receptor type 4 antagonist, is used to increase stem cell harvests. However, the effects of plerixafor on post-ASCT outcomes remain unclear. METHODS: In a dual-center retrospective cohort study of 43 Japanese patients who received ASCT, the authors compared transplantation outcomes in patients who underwent stem cell mobilization with granulocyte colony-stimulating factor with (n = 25) or without (n = 18) plerixafor. RESULTS: The number of days to neutrophil and platelet engraftment was significantly shorter with plerixafor than without plerixafor, as assessed by univariate (neutrophil, P = 0.004, platelet, P = 0.002), subgroup, propensity score matching and inverse probability weighting analyses. Although the cumulative incidence of fever was comparable with or without plerixafor (P = 0.31), that of sepsis was significantly lower with plerixafor than without (P < 0.01). Thus, the present data indicate that plerixafor leads to earlier neutrophil and platelet engraftment and a reduction of infectious risk. CONCLUSIONS: The authors conclude that plerixafor may be safe to use and that it reduces the risk of infection in patients with a low CD34+ cell count the day before apheresis.

[Regrowth of Isolated Local Residual Tumor Effectively Treated with Chemoradiotherapy More Than Five Years after a Resection for Pancreatic Cancer with an Involvement of the Portal Vein].

A 55-year-old man who presented with abdominal pain was diagnosed with pancreatic head cancer involving the portal vein. He underwent pylorus-preserving pancreaticoduodenectomy without a resection of the portalvein, resulting in a macroscopic residualtumor, because radicalresection was impossible owing to the severe localinvasion. Postoperative chemotherapy( GEM plus S-1)was administered. The tumor size decreased and CA19-9 values normalized. Five years after the resection, chemotherapy was stopped. The regrowth of an isolated local residual tumor without a distant metastasis was diagnosed 65 months after the resection. He underwent chemoradiotherapy(CRT)with S-1. The size of the tumor remained stable, but FDG-PET demonstrated a disappearance of high FDG uptake in the tumor and CA19-9 values normalized. We reported a case in which CRT was an effective treatment for the regrowth of localresidualtumor after resection for pancreatic cancer.

[Assessment of Functional Results after Sphincter-Preserving Surgery in Elderly Patients with Low Rectal Cancer].

The aim of this study was to evaluate postoperative dysfunction and potential problems after a sphincter-preserving operation in elderly patients with low rectal cancer. METHODS: Between 2000 and 2012, 307 consecutive patients with low rectal cancer underwent curative sphincter-preserving surgery. We evaluated postoperative anal and urinary dysfunction in 190 patients who responded to a questionnaire by mail. RESULTS: After a median follow-up of 5.7 years, there was no significant difference between the elderly and a younger group in the Wexner incontinence score. Poor anal function assessed by modified FIQL was significantly associated with the elderly. Poor urinary function assessed by the IPSS score was significantly associated with the elderly, diabetes mellitus, and autonomic nerve preservation(AN2-3). CONCLUSION: From the viewpoint of urinary function, sphincter-preserving surgery with all autonomicnerve preservation(AN4)should be considered for elderly people and patients with diabetes.

Pathogenic TNFRSF13B Variant in an Adult Japanese Patient with Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a primary B cell immunodeficiency disorder. Symptoms do not develop immediately after birth, and patients are often diagnosed in childhood and adulthood. These patients often develop autoimmune diseases and malignant tumors. We herein report a 50-year-old woman with severe hypogammaglobulinemia and recurrent respiratory tract infections who was diagnosed with CVID. Target sequencing showed a TNFRSF13B heterozygous frameshift variant. The patient had many comorbidities, probably caused by a CVID-induced immune imbalance. Physicians who treat adult patients are often unaware of CVID. CVID should be recognized as a differential diagnosis in hypogammaglobulinemia and recurrent infections.

Red blood cell distribution width is a useful biomarker to predict bleeding and thrombosis risks in patients with immune thrombocytopenic purpura.

Bleeding and thrombosis are common complications during immune thrombocytopenic purpura (ITP) treatment. There is a strong need to predict bleeding and thrombosis risks before ITP treatment to optimize therapy and appropriately manage these complications. We performed a retrospective cohort study of 120 patients with primary ITP to identify a biomarker to predict bleeding and thrombosis. We compared blood test results at diagnosis between patients with and without bleeding or thrombosis episodes. The standard deviation of red blood cell distribution width (RDW-SD) differed significantly between those with and without bleeding and between those with and without thrombosis, leading us to identify it as a variable representative of risk. RDW-SD was significantly associated with patient age and with histories of several vascular diseases. Multivariate regression analyses showed that RDW integrated several variables associated with vascular risks. RDW-SD was significantly associated with difficulty with corticosteroid discontinuation (hazard ratio [HR], 2.22, p = 0.01), incidence of bleeding (HR, 2.75, p< 0.01), incidence of thrombosis (HR, 2.67, p< 0.01) and incidence of infection (HR, 1.78, p = 0.04). The RDW-SD value at the time of ITP diagnosis is a useful biomarker to predict the risks of bleeding, thrombosis, and other complications.

COVID-19 antibody titers after tixagevimab-cilgavimab injection in patients with hematologic diseases; a single-center, prospective study.

Knowledge of the SARS-CoV-2 antibody titers induced by tixagevimab-cilgavimab in patients with hematologic diseases remains insufficient. Here, we performed a single-center, prospective study to reveal the changes in antibody titer after administration of tixagevimab-cilgavimab in 78 patients with hematologic diseases. The median peak titer was 155.4 U/mL, and the median AUC was 46556 days·U/mL. First, we compared several characteristics between patients with low titers (peak titer ≤ 155.4 U/mL) and high titers (peak titer > 155.4 U/mL). We extracted 6 factors (patient age, sex, ECOG-PS, serum albumin level, and cross-sectional area and computed tomographic number of the psoas major muscle) as candidates influencing the antibody titers. Multiple regression analysis revealed that antibody titer was closely associated with these 6 factors (contribution rate = 0.76, p = 0.02). Our data support the inability of tixagevimab-cilgavimab to induce sufficient antibody titers against SARS-CoV-2, especially in older, frailer, female patients.

Recurrence of solitary plasmacytoma in the liver 10 years after the onset of multiple bone lesions.

A 79-year-old man presented with a history of solitary plasmacytoma in the bone 10 years ago. Chemoradiotherapy was effective, and remission was maintained with intermittent treatment at relapse of the bone lesions. One year after the last treatment, a follow-up computed tomography (CT) scan revealed multiple liver masses, and a liver biopsy revealed plasmacytoma. There was no clonal plasma cell infiltration in the bone marrow, and the final diagnosis was solitary plasmacytomas of the liver. Although liver involvement is known in relapsed refractory multiple myeloma, solitary plasmacytoma in the relapsed stage confined to the liver is rare, and all previous reports have been from the initial presentation. To the best of our knowledge, this is the first recurrent case of solitary plasmacytoma of the liver.

Utilizing red blood cell distribution width (RDW) as a reliable biomarker to predict treatment effects after chimeric antigen receptor T cell therapy.

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for B cell malignancies. A certain fraction of patients, however, experience post-CAR-T relapse, and due to the difficulty of precise relapse prediction, biomarkers that can predict the strength and duration of CAR-T efficacy are needed before CAR-T infusion. Therefore, we performed a single-center cohort study including 91 diffuse large B cell lymphoma (DLBCL) patients treated with CAR-T in order to identify such a new prognostic biomarker. After confirming that each of the already reported prognostic parameters (disease status at leukapheresis, primary refractoriness, number of treatment lines, CD3+ cell counts at leukapheresis) has only limited predictive performance, we established a new composite parameter by integrating these four variables, and found that it predicts progression-free survival (PFS) after CAR-T infusion with statistical significance. Moreover, after comprehensive correlation analyses of this new composite parameter with all individual laboratory variables, we determined that the standard deviation of red blood cell distribution width (RDW-SD) at leukapheresis shows significant correlation with the composite parameter and may be a prognostic biomarker (R2 = 0.76, p = 0.02). Validation analysis indicated that a higher RDW-SD is significantly associated with poorer PFS after CAR-T cell therapy (HR, 3.46, P = 0.03). Thus, this study suggests that a single parameter, RDW-SD at leukapheresis, is a novel, useful biomarker that can be obtained early to predict therapeutic effects of CAR-T cell therapy. Post-CAR-T maintenance or re-induction therapies should be adopted for higher risk patients, who may relapse after CAR-T therapy.

Clinical Impact of Cytokine Release Syndrome on Prolonged Hematotoxicity after Chimeric Antigen Receptor T Cell Therapy: KyoTox A-Score, a Novel Prediction Model.

Prolonged hematotoxicity is the most common long-term adverse event in chimeric antigen receptor T cell therapy (CAR-T). To evaluate the impact on prolonged cytopenia of inflammatory status after CAR T infusion, we performed a single-center retrospective study and analyzed patients with B cell lymphomas after CAR-T. Among 90 patients analyzed at 90 days after infusion, the cumulative incidence was 57.5% for prolonged neutropenia, 36.7% for anemia, and 49.8% for thrombocytopenia. Patients who experienced cytokine release syndrome (CRS) had significantly higher incidence and longer duration of prolonged cytopenia. In addition, we found that among patients with grade 1 CRS, those with a longer duration of CRS-related symptoms (>5 days; grade 1b in modified CRS grading [m-CRS]) had a significantly higher incidence and longer duration of prolonged cytopenia than those whose CRS-related symptoms resolved within 5 days (grade 1a m-CRS). Multivariate analysis revealed that a higher m-CRS grade (grade 1b or 2; hazard ratio [HR], 2.42), higher peak CRP (≥10 mg/dL; HR, 1.66), longer duration of elevated CRP (≥10 days; HR, 1.83), and a decrease in serum inorganic phosphorus concentration (≥30% from baseline; HR, 1.95) were associated with significantly higher cumulative incidence of prolonged neutropenia, as well as anemia and thrombocytopenia. Using these factors, we developed a new predictive scoring model for prolonged hematotoxicity, the KyoTox a-score, which can successfully stratify the incidence and duration of cytopenia independent of the existing model, CAR-HEMATOTOX, which is based on laboratory data at lymphodepletion. Thus, this newly developed post-CAR-T inflammation-dependent score is accurate and useful for predicting prolonged hematotoxicity.

Sustained remission after cord blood transplantation for breast cancer with lung metastases and myelodysplastic syndrome.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not a standard therapy for solid cancer because of its high toxicity and insufficient evidence levels. However, the potential graft-versus-solid-tumor (GVT) effect of this therapy has been discussed. Many case reports have also described treatment effects of allo-HSCT in patients with hematologic malignancies and active solid tumors. A 38-year-old woman treated with fulvestrant and abemaciclib for recurrent breast cancer with multiple lung metastases was diagnosed with myelodysplastic syndrome (MDS) with increased blasts 2. She was classified as adverse risk by the 2017 European LeukemiaNet risk stratification and as very high risk by the Molecular International Prognostic Scoring System. Breast cancer treatment was interrupted and venetoclax and azacitidine therapy was started. Complete hematologic response was achieved after three cycles. However, multiple lung metastases from the breast cancer remained. The patient then underwent umbilical cord blood transplantation. She has maintained complete remission of MDS as of 1 year post-transplantation, without serious complications. Lung metastatic activity on FDG-PET/CT scan also completely disappeared by half a year post-transplantation, and this response has continued as of 1 year post-transplantation. This favorable treatment course suggests the existence of a GVT effect.

Significance of Omitting Day 11 Mini-Dose Methotrexate for GVHD Prophylaxis After Unrelated Bone Marrow Transplantation.

The combination of calcineurin inhibitors and short-term methotrexate has been used as a standard graft-versus-host-disease (GVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation. Mini-dose methotrexate (mini-MTX), consisting of 5 mg/m2/d on days 1, 3, 6, and 11, is occasionally selected as an alternative considering toxicity. The significance of day 11 administration remains unclear. We performed a retrospective study of 135 cases of unrelated bone marrow transplantation at our institute between 2006 and 2019 and compared the outcomes between day 11 MTX dose omitted (n = 72) and full-doses of mini-MTX (n = 63). In total cohort, the 4-year overall survival (OS) was 58.7 %, and the omitted group showed poor GVHD/relapse-free-survival (P = .01) with comparable OS (P = .11) and relapse-free survival (P = .11). Human leukocyte antigen (HLA) mismatch is a major risk factor for severe GVHD. We analyzed the impact of omitting day 11 MTX in 2 cohorts from HLA matched or mismatched donors. In both cohorts, the omitted group had a higher risk of severe acute and chronic GVHD. In conclusion, the omission of day 11 MTX was associated with a higher risk of severe GVHD. Therefore the omission of the day 11 dose is not recommended.

Extended exposure of lipopolysaccharide fraction from Porphyromonas gingivalis facilitates mononuclear cell adhesion to vascular endothelium via Toll-like receptor-2 dependent mechanism.

Certain infectious pathogens contribute to atherogenesis. Indeed, the strong relationship between periodontal pathogens, such as Porphyromonas gingivalis (P.g.) and coronary heart disease has been demonstrated. We investigated the potential role of P.g. in monocyte-endothelial interaction. Lipopolysaccharide (LPS) fraction was extracted from P.g. cultured under anaerobic conditions and compared to that obtained from an Escherichia coli (E. coli) strain (JM109). Human umbilical vein endothelial cells (HUVECs) were incubated in the presence of P.g.-LPS fraction or E. coli-LPS fraction for various periods and mononuclear cell adhesion assays were conducted under flow. The adhesion of mononuclear cells to HUVECs treated with P.g.-LPS fraction peaked after 24h of incubation, whereas those treated with E. coli-LPS fraction maximized after 4h of incubation. A fluorescent immunobinding assay revealed that P.g.-LPS fraction significantly upregulated ICAM-1 and VCAM-1 in HUVECs. Antibodies against ICAM-1 and Toll-like receptor (TLR)-2, but not TLR-4, attenuated P.g.-LPS fraction-facilitated mononuclear cell adhesion to HUVECs. In conclusion, these results suggest that chronic P.g. infection may facilitate monocyte recruitment to vascular endothelium through sustained upregulation of ICAM-1 and VCAM-1. Our findings provide new evidence that the TLR-2 pathway may contribute to atherogenesis by mediating P.g.-LPS signal transduction.