A nationwide real-world study for evaluation of effectiveness and safety of T-DM1 in patients with HER2-positive metastatic breast cancer in Korea (KCSG BR19-15).

Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia (n = 107, 13.2%), neutropenia (n = 23, 2.8%), anemia (n = 21, 2.6%), and elevated liver enzyme (n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.

Clinical importance of Bcl-6-positive non-deep-site involvement in non-HIV-related primary central nervous system diffuse large B-cell lymphoma.

In several studies of primary central nervous system lymphoma (PCNSL), deep-site involvement of the brain, as well as age and performance status (PS), were found to be independent prognostic factors. In immunocompetent patients, most primary central nervous system lymphomas (PCNSL) are diffuse large B-cell lymphomas (DLBCL), and recent studies have shown that Bcl-6 would be a favorable prognostic biomarker in PCNS-DLBCL. The objective of this study is to evaluate the clinical importance of the central nervous system (CNS) involvement pattern combined with Bcl-6 expression in PCNS-DLBCL patients. This study included 65 immunocompetent patients with PCNS-DLBCL who underwent treatment with high-dose methotrexate with whole-brain radiotherapy. Immunochemistry was performed for the Bcl-6 and Ki-67 antigens. Forty-four patients were male and 21 patients were female, with median age of 59 years. During the median follow-up period of 26 months, progression-free survival (PFS) was 25% and overall survival (OS) was 31%. Of 65 cases that could be subclassified, 31 patients were Bcl-6 positive and 34 patients were negative. Deep-site involvement of the brain was observed in 31 patients. The Bcl-6-positive group and the group having non-deep-site involvement of the brain were associated with favorable progression-free survival (PFS) (P < 0.001; P < 0.001) and overall survival (OS) (P = 0.001; P < 0.001). Results of univariate analysis showed that age above 60 years, Eastern Cooperative Oncology Group (ECOG) PS above 2, elevated lactate dehydrogenase (LDH) state, complete response (CR), and Bcl-6-positive and deep-site involvement were prognostic factors associated with PFS and OS. Results of multivariate analysis revealed that age above 60 years, ECOG above 2, elevated LDH state, Bcl-6 positivity, and deep-site involvement were independent prognostic factors for prediction of outcome. According to the combined prognostic value of Bcl-6 expression and the deep-site involvement pattern, the subgroup having Bcl-6-positive non-deep-site involvement of the brain showed more favorable PFS and OS than the other subgroups (P < 0.001, P < 0.001), whereas differences of survival among the other three subgroups were not significant (P = 0.054, P = 0.056). Bcl-6 positivity was found to be an independent prognostic factor for survival. Bcl-6 expression was associated with higher PFS and OS in patients having non-deep-site involvement. However, this was counteracted in the group of patients having deep-site involvement of the brain.

Clinical impact of bulky mass in the patient with primary extranodal diffuse large B cell lymphoma treated with R-CHOP therapy.

Although numerous studies about primary extranodal diffuse large B cell lymphoma (DLBCL) were reported sporadically, the literature of clinical value of immunophenotype and bulky diameter in rituximab era is limited. Ninety-six patients with primary extranodal DLBCL receiving R-CHOP therapy were analyzed to evaluate whether immunophenotype and size of bulky disease are significantly important. The International Prognostic Index was still an important prognostic factor for progression-free survival (PFS) and overall survival (OS; p = 0.003, p = 0.027). Difference of survival between germinal center (GC) type and non-GC type was not different (PFS: p = 0.192; OS: p = 0.197). In two separated groups according to extranodal maximum tumor diameter (EN-MTD) 7.5 cm as cutoff value for survival, the group of EN-MTD > or =7.5 cm had lower PFS and OS than <7.5 cm (PFS: p = 0.001; OS: p = 0.008). In four divided subgroups according to EN-MTD combined with immunophenotype, the subgroup of non-GC type with EN-MTD > or = 7.5 cm had lower PFS and OS compared with the other subgroups (PFS: p < 0.001; OS: p = 0.008). Multivariate analysis revealed that non-GC with EN-MTD > or = 7.5 cm was an independent prognostic parameter (PFS: HR = 5.407, 95%CI = 2.378-12.294, p < 0.001; OS: HR = 4.136, 95%CI = 1.721-9.941, p = 0.002). Bulky primary extranodal DLBCL would be associated with unfavorable outcome especially in non-GC type.

Clinical value of absolute lymphocyte counts before bortezomib-dexamethasone therapy in relapsed multiple myeloma patients.

A high absolute lymphocyte count (ALC) at diagnosis is known as a surrogate marker of favorable prognosis in newly diagnosed multiple myeloma (MM). Recent studies showed tumor sensitization and enhanced cytotoxicity of bortezomib. We hypothesized that a high ALC before bortezomib treatment would contribute to tumor sensitization and activated cytotoxicity of bortezomib in relapsed MM. Ninety-seven relapsed MM patients who underwent bortezomib-dexamethasone (Vel-Dex) therapy were analyzed. Median follow-up duration was 21 months and median age was 61 years. Complete response (CR) and very good partial response (VGPR) after 2 cycles of Vel-Dex therapy were higher in the high-ALC group (>or=1.1 x 10(9)/l) (CR + VGPR 50.0% in the high-ALC group vs. 10.4% in the low-ALC group, p = 0.001), and stable disease (SD) rate was lower in the high-ALC group (SD 11.8% in the high-ALC group vs. 44.8% in the low-ALC group, p < 0.001). In the univariate analysis, the low-ALC group before therapy was associated with shorter progression-free survival (PFS) [hazard ratio (HR), 2.780; 95% confidence interval (95% CI) 1.703-4.536, p < 0.001]. Multivariate analysis revealed that a low ALC represented an independent predictive factor for PFS (HR 1.937, 95% CI 1.168-3.212, p = 0.010). A low ALC just before Vel-Dex therapy was associated with a poor prognosis in relapsed MM.

Is the early cyclosporine A level predictive of the outcome of immunosuppressive therapy in severe aplastic anemia?

Immunosuppressive therapy (IST) has provided an alternative treatment option for cure of aplastic anemia patients who cannot receive bone marrow transplantation. Although there have been many recent studies on the efficacy of antithymoglobulin (ATG) combined with cyclosporine A (CsA), there is no data on the correlation between the variability of CsA levels and the response to IST. Therefore, we retrospectively assessed the factors associated with IST efficacy in patients with acquired severe aplastic anemia (SAA). Sixty-six patients were treated with ATG combined with CsA for 6 months. In the response group, the CsA levels were increased rapidly to more than 200 ng/mL within the first 2 wk after starting the IST. However, the non-response group had a pattern of slower increase of the CsA levels. The CsA levels, during the first and second week of treatment with IST, were significantly different in the responders and non-responders. The factors predictive of response to IST and survival were analyzed. The univariate analysis showed that a younger age at the initiation of IST, a high absolute neutrophil count prior to starting IST, a short interval between the diagnosis and initiation of IST, and high CsA levels during the first and second week of IST treatment were positively associated with the response rate and overall survival. The multivariate analysis showed that these four factors were independent factors associated with a longer patient survival. A high response rate was associated with a short interval between diagnosis and initiation of IST as well as high CsA levels during the first and second week of IST. Therefore, early intensification of CsA levels might improve patient outcome.

Influence of lactate dehydrogenase and cyclosporine A level on the incidence of acute graft-versus-host disease after allogeneic stem cell transplantation.

Previous reports have suggested that a high serum cyclosporine A (CsA) level could result in a lower incidence of acute-graft-versus-host disease (aGVHD). An elevated serum lactate dehydrogenase (LDH) level has been reported to be an adverse predictor of outcome in stem cell transplantation (SCT) for acute myeloid leukemia. In this study, we retrospectively analyzed the records of 24 patients who received allogeneic SCT from an HLA-matched sibling donor for acute and chronic myelogenous leukemia. Univariate analysis showed that two factors (the serum CsA level at the third week after SCT and the LDH level at the third week after SCT) were significantly associated with the incidence of aGVHD among several variables (age, sex, stem cell source, cell dose, C-reactive protein, absolute lymphocyte count, conditioning regimens, and time to engraftment). A higher serum level of CsA and lower serum LDH level at the third week after SCT were associated with a lower incidence of aGVHD (P=0.015, 0.030). In multivariate analysis, the serum CsA level (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.022-0.652, P=0.0014) and serum LDH level (HR, 6.59; 95% CI, 1.197-36.316, P=0.030) at the third week after SCT were found to be independent factors that were significantly associated with the development of aGVHD. We conclude that a high CsA level and low LDH level might predict a low cumulative incidence of aGVHD after allogeneic transplantation from a matched sibling donor.

Retrospective evaluation of the efficacy and safety of rivaroxaban in patients with cancer-associated venous thromboembolism: A single-center study.

ABSTRCT: The purpose of this study was to evaluate the efficacy and safety of rivaroxaban for the treatment of cancer-associated venous thromboembolism (VTE).We performed a retrospective chart review of cancer patients with a pulmonary embolism, deep vein thrombosis, or both. Our analysis included all patients who received rivaroxaban from March 2013 to June 2016 at the Hemato-Oncology Division at the Pusan National University Hospital in Korea.Preliminary results identified 123 patients with a history of cancer that were treated with rivaroxaban. The average duration of rivaroxaban therapy was 95.25 days. While 35 patients had resolved VTE after the initiation of rivaroxaban, only one patient had it recur on rivaroxaban treatment. Major bleeding was observed in 6 (4.9%) patients and minor bleeding in 12 (9.8%) patients. The majority of bleeding events occurred spontaneously and most incidences of bleeding could be treated conservatively. Recurrence and major bleeding events on rivaroxaban were relatively low despite the fact that many patients had metastatic disease. Among 52 patient deaths (42.3%), none were due to VTE or bleeding complications; the cause of death in the majority of cases was cancer progression.Rivaroxaban is effective and safe for the treatment of cancer-associated VTE.

Successful treatment by chemotherapy of pineal parenchymal tumor with intermediate differentiation: a case report.

A 37-year-old male presented with a mass measuring 2.5 cm in size in the midbrain and obstructive hydrocephalus, which had manifested as a headache and dizziness. Magnetic resonance (MR) imaging of the brain showed intermediate enhancement on T1-weighted MR imaging and a high intensity of enhancement on T2-weighted MR. Neurosurgeons performed an occipital craniotomy with partial removal of the tumor and the postoperative diagnosis was a pineal parenchymal tumor with intermediate differentiation. He had undergone irradiation with 54 Gy of radiation on 27 fractions for removal of the remaining tumor approximately one month after surgery. However, in follow-up imaging performed four months after radiotherapy, a remnant mass in the superoposterior aspect of the midbrain was found to have extended to the hypothalamus and the third ventricle. He was treated with six cycles of procarbazine, lomustine, vincristine chemotherapy. At five months since the completion of chemotherapy, the brain MR imaging showed no evidence of any remaining tumor and he no longer displayed any of his initial symptoms.

Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes.

PURPOSE: The role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes. METHODS: Thirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m(2) of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes). RESULTS: The median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred. CONCLUSION: These results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.

The risk factors for herpes zoster in bortezomib treatment in patients with multiple myeloma.

BACKGROUND: Bortezomib has significant activity in treating multiple myeloma (MM). The risk of herpes zoster (HZ) has been reported to increase significantly with bortezomib treatment, but the predisposing factors for HZ are not clear. This study is a retrospective analysis of the relevant risk factors for HZ in Korean MM patients treated with bortezomib. METHODS: Sixty-six patients with refractory or relapsed MM who underwent chemotherapy with bortezomib were included in the study. Prophylactic antiviral drugs were not used for treatment. The following parameters were reviewed: age, gender, stage and type of MM, extent of previous treatment, history of HZ, duration from the time of diagnosis to the time of bortezomib treatment initiation, and absolute lymphocyte counts (ALC) at the time of bortezomib treatment initiation. RESULTS: The incidence of HZ was 16.7%. There were no intergroup differences between the HZ-positive and the HZ-negative groups with regard to a history of HZ, number of previous treatments, and exposure to steroids before bortezomib treatment. The median duration from the time of MM diagnosis to the time of bortezomib treatment initiation in the HZ-positive group was significantly shorter than that in the HZ-negative group. The median ALC at the time of bortezomib initiation in the HZ-positive group was significantly lower than that in the HZ-negative group. CONCLUSION: Bortezomib itself might act as a risk factor for HZ by inhibiting cell-mediated immunity, and patients with low ALC at the time of bortezomib treatment initiation were at greater risk of HZ during bortezomib treatment.

Elevation of serum ferritin is associated with the outcome of patients with newly diagnosed multiple myeloma.

BACKGROUND/AIMS: Serum ferritin is a marker of acute phase reactions and iron storage. In addition, hematologic malignancies are associated with elevated serum ferritin levels. Other studies have suggested that ferritin is a surrogate for advanced disease and has an impact on relapse, because elevated serum ferritin predicts overall survival (OS) and relapse-free survival following autologous stem cell transplantation for lymphomas. METHODS: We studied 89 consecutive patients with newly diagnosed multiple myeloma to determine the value of serum ferritin in comparison with known prognostic factors. RESULTS: The OS in the elevated serum ferritin group (>or=300 ng/mL) was shorter than that in the normal serum ferritin group (<300 ng/mL, p<0.001) after a median follow-up of 25 months. In univariate analysis, elevated ferritin was correlated with poor survival in the patients (relative risk [RR], 2.588; 95% confidence interval [CI], 1.536 to 4.358; p<0.001). Furthermore, multivariate analysis showed that elevated serum ferritin was an independent predictor of mortality in patients with multiple myeloma (RR, 2.594; 95% CI, 1.403 to 4.797; p=0.002). CONCLUSIONS: The serum ferritin can a prognostic parameter of survival as well as disease activity in patients with multiple myeloma.

Mean cell volume can be an early predictor for the cytogenetic response of chronic myeloid leukemia patients treated with imatinib?

Imatinib-induced macrocytic anemia was known to result from c-kit inhibition in chronic myeloid leukemia (CML). However, recent studies showed that the prevalence of anemia is increased with high trough imatinib level and increased doses of imatinib influence decreased proliferation of burst forming units-erythroids (BFU-Es). The aim of this study was to evaluate the continuously increased mean cell volume (MCV) level's correlation with cytogenetic response and the favorable outcome in early chronic phase (CP)-CML patients. Clinical importance of MCV level was evaluated to correlate with cytogenetic response and compared with Sokal score, a known excellent prognostic parameter of cytogenetic response (CCR) in 84 early CP-CML patients. The patients with early and continuously increased MCV level irrespective of anemia achieved higher CCR after 12 months of imatinib therapy than patients with non-CCR (p=0.011). When the value was compared with low Sokal score, elevated MCV was independent predictor of CCR (RR=12.925, p=0.002 vs. RR=35.445, p<0.001). Furthermore, the patients with early and continuously increased MCV level had a higher probability of maintaining CCR than non-increased level (p=0.019). Increased MCV level was surrogate marker of achievement and durability to CCR for early CP-CML patients in the present study.

Prognostic significance of the Bcl-2 negative germinal centre in patients with diffuse large B cell lymphoma treated with R-CHOP.

The classification of germinal centre (GC) and non-GC is an important prognostic immunophenotype for patients with diffuse large B cell lymphoma (DLBCL) following anthracycline-based chemotherapy. The expression of the anti-apoptotic protein, Bcl-2, has been associated with an unfavourable prognosis in patients with DLBCL. Immunohistochemistry was performed using antibodies against CD10, Bcl-6, MUM-1 and Bcl-2. To establish the combined prognosis of the immunophenotype and Bcl-2 overexpression, patients were separated into four subgroups based on their gene expression profile: the Bcl-2 positive GC subgroup, Bcl-2 negative GC subgroup, Bcl-2 positive non-GC subgroup, and the Bcl-2 negative non-GC subgroup. The clinical characteristics and survival outcomes of the four patient subgroups were compared. Ninety-six patients with de novo DLBCL received R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisone) therapy. The baseline characteristics of the patient subgroups were similar. The Bcl-2 negative GC subgroup had a favourable progression-free and overall survival (OS) compared with the other three subgroups (p = 0.042, 0.043). Multivariate analysis confirmed that the Bcl-2 negative GC group was independently associated with progression-free survival and OS. The results of this study showed that the Bcl-2 negative GC patients had the most favourable prognosis among patients with DLBCL that received R-CHOP.

Pulmonary nodular lymphoid hyperplasia associated with Sjögren's syndrome.

Pulmonary nodular lymphoid hyperplasia (NLH) is a term first suggested by Kradin and Mark to describe one or more pulmonary nodules or localized lung infiltrates consisting of reactive lymphoid proliferation. To date, there have been only a few cases of pulmonary NLH reported associated with autoimmune disorders. There is no case of NLH associated with Sjögren's syndrome from Korea in the medical literature. A 56-year-old woman was referred to our hospital with cough productive of sputum and chest tightness. The Computed tomography scans of the chest revealed multiple and well-defined peribronchiolar nodular opacities. A video assisted thoracoscopic surgery (VATS) biopsy was performed and the nodular opacity in the lung parenchyma was pathologically confirmed as NLH. Through meticulous review of patient's record, we found that she had been suffering from dry eye and dry mouth. The symptoms suggested Sjögren's syndrome, which was confirmed by specific laboratory tests including the Schirmer test, anti-nuclear antibody and anti-Ro/La antibody. The patient is followed regularly and has no further progression of symptoms.