Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.

BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.

Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer. METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, phase 2-3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 [SOX] or oral capecitabine 1000 mg/m2 [CAPOX], twice daily on days 1-14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing. FINDINGS: Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7-14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44-14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97-9·40) in the placebo plus chemotherapy group (hazard ratio [HR] 0·68; 98·51% CI 0·51-0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1-29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67-20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18-19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75-1·08; p=0·26). The most common treatment-related grade 3-4 adverse events were neutrophil count decreased (71 [20%] of 359 patients in the nivolumab plus chemotherapy group vs 57 [16%] of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 [9%] vs 33 [9%]). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 [5%] vs ten [3%]). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease). INTERPRETATION: Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients. FUNDING: Ono Pharmaceutical and Bristol-Myers Squibb.

A prognostic index for extranodal marginal-zone lymphoma based on the mucosa-associated lymphoid tissue International Prognostic Index and serum ß2-microglobulin levels.

The mucosa-associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum ß2-microglobulin level in the context of MALT-IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to ß2-microglobulin level, MALT-IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high ß2-microglobulin levels had significantly worse progression-free survival (PFS) and overall survival (OS) outcomes. A high ß2-microglobulin level was independently associated with poor PFS and OS. ß2-microglobulin levels further stratified patients in the MALT-IPI intermediate-risk group in terms of PFS and OS. A new prognostic index based on the MALT-IPI and the ß2-microglobulin level, MALT-IPI-B, was proposed. The MALT-IPI-B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT-IPI-B enabled the identification of patients with poor survival outcomes who were classified into the intermediate-risk group by the MALT-IPI. In conclusion, this new ß2-microglobulin-based prognostic index may have the specific advantage of identifying high-risk patients who may require systemic treatment.

Erratum: Correction of Affiliations in the Article "Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study".

This corrects the article on p. e393 in vol. 35, PMID: 33258329.

A Randomized Controlled Trial of Epidermal Growth Factor Ointment for Treating Epidermal Growth Factor Receptor Inhibitor-Induced Skin Toxicities.

BACKGROUND: The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor-related skin adverse events (ERSEs). MATERIALS AND METHODS: This placebo-controlled, double-blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily. RESULTS: Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex-16 after treatment were significantly different among arms (mean ± SD: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and - 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm. CONCLUSION: EGF ointment is effective for managing ERSEs. It can also improve patients' QoL compared with placebo. Clinical trial identification number. NCT02284139 IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor-related skin adverse events.

Long-term follow-up of abbreviated R-CHOP chemoimmunotherapy for completely resected limited-stage diffuse large B cell lymphoma (CISL 12-09).

The standard of treatment for completely resected limited-stage diffuse large B cell lymphoma (DLBCL) in patients without residual lesions has not yet been established. Previously, we designed a phase II trial to evaluate the safety and efficacy of three cycles of abbreviated R-CHOP in patients with completely resected limited-stage DLBCL and reported favorable survival outcomes. We present the long-term follow-up results to taking into account the importance of delayed relapse in patients with limited-stage DLBCL. With a median follow-up duration of 62.7 months (range, 60.2-75.5 months), the 5-year OS and DFS rates were both 95.0% (95% confidence interval, 85.59-104.11%). Only one patient experienced disease progression which was confirmed at 12.3 months, and one patient with primary intestinal DLBCL developed non-small cell lung cancer 6 years after treatment. The long-term results of our data support the use of three cycles of abbreviated R-CHOP for patients with completely resected limited-stage DLBCL. The study was reviewed and approved by the review boards of the participating institutes and registered at ClinicalTrials.gov , number NCT01279902, in August 3, 2010.

Correction to: Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

An additional affiliation for the first author was not indicated. Hyewon Lee is also affiliated with: Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea.

A phase II study of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) for patients with refractory or relapsed Hodgkin's lymphoma.

We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m2 on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m2 on day 5, and i.v. oxaliplatin 130 mg/m2 on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.

Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study.

BACKGROUND: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea. METHODS: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016. RESULTS: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively (P = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively. CONCLUSION: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.

The effects of erythropoiesis-stimulating agents on the management of chemotherapy-induced anemia and tumor growth in diffuse large B-cell lymphoma patients.

Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (EPO) and darbepoetin, may alleviate anemia in diffuse large B-cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy-related anemia in DLBCL patients. We examined EPOR expression in germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab-mediated complement-dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels <10.0 g/dl after a maximum of three R-CHOP cycles and received ≥4 doses of fixed-dose darbepoetin (360 µg) once every 3 weeks. EPOR mRNA was detected in all GCB-DLBCL cell lines, but little/none was detected in ABC-DLBCL cell lines. GCB-DLBCL and ABC-DLBCL cell proliferation was unaffected by EPO or darbepoetin. Rituximab-mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dl; the overall mean change in hemoglobin was 1.59 ± 1.3 g/dl (16 weeks). Forty-eight percent of enrolled patients achieved a hematopoietic response. Our study shows that ESAs do not affect the growth of DLBCL cells or rituximab-mediated CDC under the experimental conditions that we used, and the appropriate use of ESAs may be effective and safe for DLBCL patients with anemia after R-CHOP.

Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma.

BACKGROUND: The upregulated expression of the JAK/STAT pathway promotes tumor growth in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBCL). Based on the hypothesis that JAK2 is a therapeutic target, we performed a prospective pilot study using ruxolitinib. METHODS: Relapsed or refractory patients with HL or PMBCL were eligible for this study, and JAK2 amplification was assessed by fluorescence in situ hybridization. Ruxolitinib was administered orally at a dose of 20 mg twice daily for a 28-day cycle. Treatment was continued for up to 16 cycles or until progressive disease or intolerability. The primary objective was to assess the overall disease control rate comprising complete response (CR), partial response (PR), or stable disease (SD). RESULTS: We analyzed 13 HL patients and six PMBCL patients. All responders (one CR, five PR, and one SD) had HL whereas all cases of PMBCL progressed after first or second cycle. The disease control rate for HL was 54% (7/13) with median response duration of 5.6 months. JAK2 amplification was present in six of nine patients tested (four HL, two PMBCL), and three of these HL patients showed PR (n = 2) or SD (n = 1). None of the three HL patients shown to not have JAK2 amplification responded to ruxolitinib. Most treatment-related adverse events were grade 1 or 2 and manageable. CONCLUSIONS: Ruxolitinib has single-agent activity against HL but does not act against PMBCL with or without JAK2 amplification. TRIAL REGISTRATION: The study population was patients who had relapsed or refractory HL or PMBCL, and patients were registered for our pilot study after providing written informed consent between November 2013 and November 2015 (CilinicalTrials.gov: NCT01965119).

Multicenter retrospective analysis of the clinicopathologic features of monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 World Health Organization classifications. To further elucidate the clinicopathologic features of this new disease, we carried out a retrospective, multicenter analysis of 42 patients with MEITL. The median age of the patients was 59 years (range, 20-84 years), and 27 patients (64 %) were male. Thirty-two patients (76 %) were Ann-Arbor stages I-II and 28 (67 %) were Lugano stages I-II1&2. The most frequent site of involvement was the jejunum (N = 21). Most cases expressed CD8 (79 %) and CD56 (95 %) and did not express CD30 (5 %) or EBER (0 %). The median progression-free survival was 6.9 months (95 % CI 4.3-9.6); the median OS was 14.8 months (2.4-27.2). Thirty-two patients (76 %) underwent surgery and 37 (88 %) received chemotherapy. A complete response (CR) rate was 38 %. Sixteen patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 24 cases, most frequently in the primary site (N = 23). Four cases showed central nervous system relapse. Age over 55 years, poor performance scale, advanced Lugano stage (IIE-IV), not achieving CR, and not receiving ASCT were associated with inferior OS. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem essential. As CHOP might be insufficient for achieving CR, more efficient combinations should be investigated. Additionally, considering the frequent local failure and CNS relapse, novel therapeutic approaches are required to improve survival.

Treating synchronous bilateral ocular adnexal marginal zone lymphoma: the consortium for improving survival of lymphoma study.

Both-side synchronous involvement has been reported to account for 7-24% of ocular adnexal marginal zone lymphoma (OAML). We conducted a retrospective analysis to identify the clinical features and treatment outcomes of synchronous bilateral OAML (SB-OAML) by treatment modality. We analyzed patients with a histologic diagnosis of SB-OAML, excluding metachronous bilateral involved OAML. We enrolled a total of 95 patients for this analysis, 36 males and 59 females; the median patient age was 42 years (range 16-77 years). Eleven (11.6%) patients had been treated with chemotherapy or chemo-immunotherapy (eight R-CVP, two CVP, and one R-CHOP). The median number of treatments was 6 (range 6-8); there were 9 complete responses (CRs; 81.8%) and 2 partial responses (PRs; 18.2%). Nearly all patients (88.4%) received radiotherapy in both eyes, and the median radiation dose was 27 Gy (range 20-40 Gy) to each eye; 68 CRs (80.9%) and 14 PRs (16.7%) were achieved. Ten-year progression-free survival (PFS) and overall survival (OS) rates were 79.8 and 91.1%, respectively. Radiotherapy continued to be an independent prognostic marker, with the hazard of progression (P = 0.036). Eleven patients (13.1%) had surgery for cataract treatment during follow-up, and patients who received low-dose radiation (< 30.3 Gy) experienced fewer cataract operations. SB-OAML was predominantly observed in young females, and they had good response and prognosis regardless of treatment modalities. Low-dose radiotherapy to both eyes showed a tendency of longer PFS than did chemotherapy and could decrease cataract operations.

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a multicenter retrospective analysis.

Bendamustine plus rituximab (BR) showed efficacy and safety in indolent lymphomas and mantle cell lymphoma. However, there were limited experiences of real-world practice of BR in diffuse large B cell lymphoma (DLBCL). In this study, we report the Korean experiences with BR in relapsed or refractory DLBCL who are not eligible for intensive chemotherapy and autologous stem cell transplantation. This is an observational, multicenter, retrospective analysis. Between December 2011 and December 2015, a total of 58 patients with relapsed or refractory DLBCL were treated with BR in 11 tertiary hospitals in Korea. Patients received an intravenous (IV) infusion of rituximab at a dose of 375 mg/m2 on day 1. On days 2 and 3, patients received an IV infusion of bendamustine at doses of 120 or 90 mg/m2. Median age was 69 (range 18-86), 74.1% had stage III or IV disease, and 67.2% showed high-intermediate or high International Prognostic Index scores at diagnosis. In an intention-to-treat analysis, 18 patients (31.0%) showed a complete response and 14 (24.1%) showed a partial response, resulting in an overall response rate of 55.1%. The median duration of the response was 3.7 months (range 1.0-47.2 months). The median progression-free survival was 3.9 months (95% confidence interval [CI], 2.4-5.4 months), and the median overall survival was 6.7 months (95% CI, 4.7-8.7 months). The most common grade 3/4 adverse event was neutropenia (n = 40; 68.9%). Febrile neutropenia was observed in 11 patients (18.9%). Grade 3/4 thrombocytopenia was observed in 34 patients (58.6%). Our study confirmed the high efficacy and acceptable toxicity profile of BR in relapsed or refractory DLBCL patients. However, we need to closely observe the higher tendency of grade 3/4 hematological toxicities in Korean patients.

Cancer Pain Management Education Rectifies Patients' Misconceptions of Cancer Pain, Reduces Pain, and Improves Quality of Life.

Objectives: More than half of the patients have reported improper management of breakthrough cancer pain. Empirical evidence is lacking concerning the effectiveness of cancer pain education on breakthrough pain control. This study aimed to examine the effects of individual pain education on pain control, use of short-acting analgesics for breakthrough pain, quality of life outcomes, and rectification of patients' misconceptions regarding cancer pain. Design: A quasi-experimental design was used. In total, 176 (102 inpatients and 74 outpatients) and 163 (93 inpatients and 70 outpatients) cancer patients completed questionnaires on pain intensity, quality of life, use of short-acting medication for breakthrough pain, and misconceptions about cancer pain and opioid use before and immediately and/or seven days after individual pain education. Results: The mean age of the participants was 60.9 years (±11.2), and 56.3% were male. The most common cancers were lung cancer (17.0%), colon cancer (15.9%), and breast cancer (12.5%). The subjects' reasons for attrition were conditional deterioration, death, or voluntary withdrawal (N = 13, 7.4%). Following the education, there was a significant reduction in overall pain intensity over 24 hours (P < 0.001). The outpatients showed more use of short-acting analgesics for breakthrough pain. Sleep quality change was most significantly associated with intervention; other quality of life aspects (e.g., general feelings and life enjoyment) also improved. Pain education also significantly reduced misconceptions regarding cancer pain management. Conclusions: The present educational intervention was effective in encouraging short-acting analgesic use for breakthrough pain, improving quality of life outcomes, and rectifying patients' misconceptions about analgesic use.

Antiemetic Corticosteroid Rotation from Dexamethasone to Methylprednisolone to Prevent Dexamethasone-Induced Hiccup in Cancer Patients Treated with Chemotherapy: A Randomized, Single-Blind, Crossover Phase III Trial.

BACKGROUND: To assess whether the rotation of dexamethasone to methylprednisolone decreases the intensity of dexamethasone-induced hiccup (DIH) in cancer patients treated with chemotherapy. MATERIALS AND METHODS: Adult patients who experienced DIH within 3 days after the administration of dexamethasone as an antiemetic were screened. Eligible patients were randomly assigned to receive dexamethasone (n = 33) or methylprednisolone (n = 32) as an antiemetic (randomization phase). In the next cycle of chemotherapy, the dexamethasone group received methylprednisolone and vice versa in the methylprednisolone group (crossover phase). The primary endpoint was the difference in hiccup intensity as measured using the numeric rating scale (NRS) between two groups. RESULTS: No female patients were enrolled, although the study did not exclude them. At the randomization phase, hiccup frequency was 28/33 (84.8%) in the dexamethasone group versus 20/32 (62.5%) in the methylprednisolone group (p = .04). Intensity of hiccup was significantly higher in the dexamethasone group than that in the methylprednisolone group (mean NRS, 3.5 vs. 1.4, p < .001). At the crossover phase, hiccup intensity was further decreased after the rotation of dexamethasone to methylprednisolone in the dexamethasone group (mean NRS, 3.5 to 0.9, p < .001), while it was increased by rotating methylprednisolone to dexamethasone in the methylprednisolone group (mean NRS, 1.4 to 3.3, p = .025). There were no differences in emesis intensity between the two groups at either the randomization or crossover phases. Clinicaltrials.gov identifier: NCT01974024. CONCLUSION: Dexamethasone-induced hiccup is a male-predominant phenomenon that can be ameliorated by rotating dexamethasone to methylprednisolone without compromising the antiemetic efficacy. IMPLICATIONS FOR PRACTICE: In this randomized, multicenter, phase III trial, hiccup intensity was significantly lower when the antiemetic corticosteroid was rotated from dexamethasone to methylprednisolone without a change in emesis intensity than that when dexamethasone was maintained. At the crossover phase, hiccup intensity was increased again if dexamethasone was readministered instead of methylprednisolone. The present study demonstrated that dexamethasone-induced hiccup can be improved by rotating from dexamethasone to methylprednisolone without compromising its antiemetic efficacy.

Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

After introducing a rituximab-containing chemoimmunotherapy (R-CHOP) for diffuse large B cell lymphoma (DLBCL), a partial response (PR) which is regarded as treatment failure is still observed. To investigate the prognostic factors for the DLBCL patients with a PR to R-CHOP, we retrospectively evaluated 758 newly diagnosed DLBCL patients. After R-CHOP, 88 (11.6%) achieved a PR. Three-year progression-free and overall survival rates measured from the date of PR achievement (PFS2 and OS2) were 57.4 and 67.8%, respectively. The secondary International Prognostic Index (IPI2) scores after R-CHOP were low (0-1) in 68.2% and high (2-3) in 31.8% of the patients. The Deauville scores from 18-fluorodeoxyglucose positron emission tomography after R-CHOP showed low (2-3) in 58.0% and high (4) in 42.0% of the patients. High IPI2 and high Deauville scores were associated with worse PFS2 (P < 0.001 and P = 0.009) and OS2 (P = 0.013 and P = 0.067). The high-risk group defined by the IPI2 and Deauville scores, whose scores were both high, showed significantly lower 3-year PFS2 (P < 0.001) and OS2 (P = 0.006) rates compared with those of the other groups. In multivariate analyses, the IPI score of ≥ 3 at diagnosis and bone marrow involvement at diagnosis were independent prognostic factors. In addition, high IPI2-Deauville score after R-CHOP was significantly associated with poor PFS2 (P = 0.009) and demonstrated a trend toward inferior OS2. In conclusion, DLBCL patients who partially responded to R-CHOP are still a heterogeneous group, for which IPI2 and Deauville scores should be evaluated for prediction of prognosis.

Peripheral T cell lymphomas in elderly patients: a retrospective analysis from the Hematology Association of South East Korea (HASEK).

Limited data are available on the clinical features and the outcomes of elderly patients with peripheral T cell lymphomas (PTCLs). We identified PTCL patients of age 60 years or older from the records of the Hematology Association of South East Korea between 2001 and 2014. The median age of the patients (70.4 % male) was 71 years (range 60-88 years). The majority (80.2 %) had stage III/IV disease, and 61.7 % of patients had Charlson comorbidity index (CCI) score 0. Out of 74 patients treated with chemotherapy, 62 were administered anthracycline-based combination chemotherapy (CHOP: 47 patients, CHOEP: 15 patients), and 12 received non-anthracycline-based combination chemotherapy (IMEP: 8 patients, and CVP: 4 patients). The overall response rate for the 74 patients treated with chemotherapy was 70.2 % (CR 37.8 % and PR 32.4 %). With a median follow-up of 23.8 (range 0.5-156) months, the estimated 5-year progression-free survival (PFS) and overall survival (OS) were 16.6 and 45.9 %, respectively. There were no significant differences in PFS and OS between patients treated with anthracycline-based and non-anthracycline-based combination chemotherapy. In the univariate analysis, increased age, elevated serum lactate dehydrogenase, Eastern Cooperative Oncology Group performance status >1, higher CCI, high or high-intermediate IPI, and PIT groups 3-4 were associated with shorter OS. Our findings may provide valuable information on the management and outcomes of elderly patients with PTCL in clinical practice.

Transdermal granisetron versus palonosetron for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: a multicenter, randomized, open-label, cross-over, active-controlled, and phase IV study.

BACKGROUND: Palonosetron is the second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT3RA) that has shown better efficacy than the first-generation 5-HT3RA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC). Granisetron transdermal delivery system (GTDS), a novel transdermal formulation, was developed to deliver granisetron continuously over 7 days. This study compared the efficacy and tolerability of the GTDS to palonosetron for the control of CINV following MEC. MATERIAL AND METHOD: A total of 196 patients were randomized to GP or PG group. In this multicenter, randomized, open-label, cross-over, active-controlled, Phase IV study, GP group was assigned to receive transdermal granisetron (one GTDS patch, 7 days) in the first chemotherapy cycle, palonosetron (iv 0.25 mg/day, 1 days) in the second chemotherapy cycle before receiving MEC, and PG group was assigned to receive palonosetron in the first cycle and GTDS in the second cycle. Primary endpoint was the percentage of chemotherapy cycles achieving complete response (CR; defined as no emetic episodes and no rescue medication use) during the acute phase (0-24 h in post-chemotherapy; non-inferiority comparison with palonosetron). RESULTS: Total 333 cycles (165 in GTDS and 168 in palonosetron) were included in the per protocol analysis. The GTDS cycles showed non-inferiority to palonosetron cycles during the acute phase: CR was achieved by 124 (75.2 %) patients in the GTDS cycles and 134 (79.8 %) patients in the palonosetron cycles (treatment difference, -4.6 %; 95 % confidence interval, -13.6-4.4). There was no significant difference in CR rate during acute phase after the end of the first and second chemotherapy cycle between GP and PG group (p = 0.405, p = 0.074). Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), GTDS cycle were higher than those of palonosetron cycle in GP group (FLI-E score; median 1549.5 in GTDS cycle, median 1670.0 in palonosetron cycle). Both treatments were well tolerated and safe. CONCLUSION: Transdermal granisetron is a good alternative therapeutic option to palonosetron for preventing CINV after MEC.

Phase II trial of epidermal growth factor ointment for patients with Erlotinib-related skin effects.

PURPOSE: The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs). METHODS: This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤ grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks. RESULTS: Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2%) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37%). CONCLUSIONS: Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs. CLINICAL TRIAL REGISTRATION NO: ClinicalTrials.gov identifier: NCT01593995.