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Background Dasatinib is administered at a fixed starting dosage of 100 mg once daily regardless of patient-specific factors. However, such fixed dosing may not be optimal for the treatment of Asian patients with chronic myeloid leukemia in chronic phase (CP-CML). Patients and Methods The dose-limiting toxicities (DLTs) and molecular responses (MRs) of dasatinib therapy were evaluated using clinical data obtained from 102 patients newly diagnosed with CP-CML at 17 hospitals in South Korea. Results By 36 months after the initiation of a fixed dose regimen of dasatinib 100 mg once daily as the first-line therapy, 55.9% of patients experienced at least one type of DLT. The 3 most frequent DLTs were thrombocytopenia (45.5%), pericardial or pleural effusion (30.9%), and anemia (7.3%). Patients with higher dasatinib dose adjusted for body weight (Dose/BW) had a greater rate of DLT occurrence (logit [P] = 1.58 × [Dose/BW] − 2.27, P = .03). As median Dose/BW increased from 1.23 to 2.00 mg/kg, the rate of DLT occurrence increased from 43.5% to 66.7% (P = .03). However, Dose/BW did not affect the achievement rate of major MR (60.9% to 69.6%, P = .92). Conclusion The starting dosage of dasatinib may need to be reduced (eg, 80 mg once daily or lower) for Asian patients with CP-CML, especially with lighter BW, to alleviate the risk of DLT occurrence without compromising the achievement of MR.

Neurolymphomatosis (NL) is defined as the involvement of the peripheral nervous system in lymphocytic invasion. It is a very rare form of lymphoma that may occur as an initial presentation or recurrence. It affects various peripheral nervous structures and can therefore mimic disc-related nerve root pathology or compressive mononeuropathy. NL often occurs in malignant B-cell non-Hodgkin lymphomas. Notwithstanding its aggressiveness or intractability, NL should be discriminated from other neurologic complications of lymphoma. Herein, we present a case of primary NL as the initial presentation of diffuse large B-cell lymphoma (DLBCL) of the sciatic nerve. The patient presented with weakness and pain in his left leg but had no obvious lesion explaining the neurologic deficit on initial lumbosacral and knee magnetic resonance imaging (MRI). NL of the left sciatic nerve at the greater sciatic foramen was diagnosed based on subsequent hip MRI, electrodiagnostic test, positron emission tomography/computed tomography, and nerve biopsy findings. Leg weakness slightly improved after chemotherapy and radiotherapy. We report a case wherein NL, a rare cause of leg weakness, manifested as the initial presentation of primary DLBCL involving the sciatic nerve at the greater sciatic foramen.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe, life-threatening in flammatory condition if untreated. We aimed to investigate the etiologies, outcomes, and risk factors for death in children and adults with HLH. Methods: The medical records of patients who met the HLH criteria of two regional university hospitals in Korea between January 2001 and December 2019 were retrospectively investigated. Results: Sixty patients with HLH (35 children and 25 adults) were included. The median age at diagnosis was 7.0 years (range, 0.1-83 years), and the median follow-up duration was 8.5 months (range, 0-204 months). Four patients had primary HLH, 48 patients had secondary HLH (20 infection-associated, 18 neoplasm-associated, and 10 autoimmune-associated HLH), and eight patients had HLH of unknown cause. Infection was the most common cause in children (14/35, 40.0%), whereas neoplasia was the most common cause in adults (13/25, 52.0%). Twen ty-eight patients were treated with HLH-2004/94 immunochemotherapy. The 5-year overall sur vival (OS) rate for all HLH patients was 59.9%. The 5-year OS rates for patients with primary, in fection-associated, neoplasm-associated, autoimmune-associated, and unknown cause HLH were 25.0%, 85.0%, 26.7%, 87.5%, and 62.5%, respectively. Using multivariate analysis, neoplasm-in duced HLH (p=0.001) and a platelet count

We compared efficacy and safety, according to frailty, of elderly patients with relapsed and refractory multiple myeloma (RRMM) treated with lenalidomide and dexamethasone (Rd), for whom bortezomib treatment had failed. Patients, 164 (52.9%) and 146 (47.1%), were classified as non-frail and frail using a simplified frailty scale. The overall response rates (ORR) and survival outcomes were lower in frail than in non-frail patients (ORR: 56.2% vs. 67.7%, P = 0.069; median progression free survival: 13.17 vs. 17.80 months, P = 0.033; median overall survival: 23.00 vs. 36.27 months, P = 0.002, respectively). The number of treatment emergent adverse events in grade 3 or worse was higher in frail than in non-frail patients (41.8% vs. 24.4%, P = 0.002, respectively). In frail patients, independent poor prognostic factors for survival were two or more Charlson comorbidity index (CCI) score, prior to exposure to both bortezomib and thalidomide, and achieved less than partial response In conclusion, frailty could predict clinical outcomes of Rd treatment in elderly patients with RRMM who had failed prior bortezomib. In frail patients, lower CCI in addition to less previous treatment exposure and deep response were associated with better survival.

Epstein-Barr virus (EBV) positivity in diffuse large B cell lymphoma (DLBCL) provokes a critical oncogenic mechanism to activate intracellular signaling by LMP1. LMP1 specifically mimics the role of BTK-dependent B cell receptor. Therefore, a trial considering RCHOP therapy along with ibrutinib (I-RCHOP) in combination was conducted among patients with EBV-positive DLBCL. This study was an open-label, single-arm, prospective multicenter phase II clinical trial. Patients received 560 mg of ibrutinib with RCHOP every 3 weeks until 6 cycles were completed or progression or unacceptable toxicity was observed. The primary endpoint was objective response, while secondary endpoints included toxicity, progression-free survival, and overall survival. A matched case-control analysis was completed to compare the efficacy and toxicity of I-RCHOP and RCHOP, respectively, in EBV-positive DLBCL patients. From September 2016 to August 2019, 24 patients proven to have EBV-positive DLBCL in the tissue were enrolled and received I-RCHOP. Their median age was 58 years (range, 28–84 years). The objective overall response was 66.7%, including 16 patients who achieved complete response after 6 cycles. Patients aged younger than 65 years presented a superior OR (87.5%) as compared with those older than 65 years (25.0%; p = 0.01). In a matched case-control study, I-RCHOP therapy provoked a more favorable complete response rate (87.3%) than did RCHOP (68.8%) in those younger than 65 years. Treatment-related mortality was linked most frequently with I-RCHOP therapy (four patients presented with unusual infection without Gr3/4 neutropenia) in the older age group (age ≥ 65 years). In conclusion, in this phase II trial for EBV-positive DLBCL, I-RCHOP was effective but did not show a significant improvement in response and survival in comparison with RCHOP. Also, I-RCHOP promoted serious toxicity and treatment-related death in older patients. Electronic supplementary material The online version of this article (10.1007/s00277-020-04005-6) contains supplementary material, which is available to authorized users.

Summary In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice‐daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once‐daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months’ follow‐up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR‐ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5) were achieved within 48 months by more radotinib‐treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib‐treated patients (71% and 44%, respectively). Estimated overall and progression‐free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment‐free remission may be attainable.

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr

Introduction Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. Aim We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. Methods Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). Results Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. Conclusion The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

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

Introduction Elderly patients are more prone to encounter some adverse factors when they receive chemotherapy compared to younger patients. Addition of rituximab to a reduced dose (RD) of cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy might improve patient outcomes with an improved toxicity profile when provided to elderly patients with diffuse large B-cell lymphoma. Patients and Methods A total of 53 patients aged ≥ 65 years with diffuse large B-cell lymphoma diagnosed between August 2012 and December 2014 were enrolled onto this study. RD-R-CHOP regimen consisted of rituximab at 375 mg/m2, cyclophosphamide at 600 mg/m2, doxorubicin at 30 mg/m2, and vincristine at 1 mg on day 1 of each cycle and 40 mg of prednisone on days 1 to 5. Patients received granulocyte colony-stimulating factor if they experienced grade 3/4 neutropenia or febrile neutropenia during any cycle. Results The median follow-up duration was 18 months (range, 1-44 months). Complete response and overall response rates were 64.1% and 81.1%, respectively. Three-year event-free and overall survival rates were 45.7% ± 8.4% and 62.7% ± 8.1%, respectively. Grade 3/4 neutropenia occurred in 20 patients (37.7%), while febrile neutropenia occurred in 7 patients (20.7%). Conclusion Outcomes of RD-R-CHOP chemotherapy were comparable to those of standard-dose R-CHOP or previous dose-adjusted R-CHOP chemotherapy. In the future, strategies such as tailored therapy based on geriatric assessment results are needed to determine the chemotherapeutic dosage.

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0–122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3–4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.

STUDY OBJECTIVES: While the prevalence and clinical characteristics of restless legs syndrome (RLS) are known to vary according to ethnicity, a detailed evaluation of this condition among patients with iron deficiency anemia (IDA) has not yet been reported in an Asian population. We investigated the prevalence and clinical characteristics of RLS in patients with IDA in Korea compared with age- and sex-matched patients diagnosed with idiopathic RLS. METHODS: This prospective single-center study was performed at a regional university hospital. Consecutive patients with IDA were enrolled over a 4-year period. Clinical interviews and laboratory tests were conducted at the first visit. RLS diagnosis was confirmed through face-to-face interviews. We randomly selected patients with idiopathic RLS without comorbid medical disorders from our sleep center dataset as control patients. The clinical characteristics of both groups were compared. RESULTS: We enrolled 124 patients with IDA. Fifty (40.3%) patients were diagnosed with RLS, with 82% exhibiting severe to very severe symptoms. Patients with IDA and RLS were older and reported more sleep deterioration than patients with IDA without RLS. Patients with IDA and RLS also had a more depressed mood and higher periodic limb movement index scores than patients with idiopathic RLS. CONCLUSIONS: The prevalence of RLS among patients with IDA in Korea was high, with the majority having severe to very severe symptoms. Patients with IDA and RLS had poorer sleep quality and more emotional problems than patients with IDA without RLS. Therefore, patients with IDA should be screened for RLS to prevent adverse effects on the quality of sleep and life. CITATION: Bae H, Kim KT, Heo MH, Do Y-R, Cho YW. The prevalence and clinical characteristics of restless legs syndrome in patients with iron deficiency anemia in Korea. J Clin Sleep Med. 2021;17(7):1447–1452.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their incidence is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative incidence and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative incidence of PTCLs and assess treatments and their outcomes in Asian patients. Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated. Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57.4%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n=139, 28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n=120, 24.7%), PTCL-not otherwise specified (PTCL-NOS, n=101, 20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n=34, 6.9%), and ALK-negative ALCL (n=30, 6.2%) in decreasing order of frequency. The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6–31.6) and 83.6 months (95% CI, 56.7–110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to any other. Interpretation: This multinational, multicenter study identified the relative incidence of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently in use. Funding Statement: This study was supported by a grant from the Samsung Biomedical Research Institute (GFO1150161). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This registry was approved by the Institutional Review Boards or Scientific Review Committees as required by the policies of individual institutions. Written informed consent was obtained from each patient before study enrollment.

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., Graphical Abstract

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.

Cord blood transplantation (CBT) is a valuable alternative to bone marrow transplantation in adults without readily available donors. We conducted this study to investigate the feasibility of CBT for adult patients with acute leukemia with regards to impact of different conditioning and graft-versus-host disease (GVHD) prophylaxis regimens on clinical outcomes. From 16 centers in Korea, 41 acute myeloid leukemia (AML) and 29 ALL (acute lymphoblastic leukemia) patients undergoing CBT were enrolled. For AML patients, the neutrophil engraftment was observed in 87.5% of reduced intensity conditioning (RIC) and 72.0% of myeloablative conditioning (MAC) (p = 0.242). The median RFS was 5 months and OS 7 months. Conditioning regimen did not affect relapse free survival (RFS) or overall survival (OS). GVHD prophylaxis using calcineurin inhibitors (CNI) plus methotrexate was associated with better RFS compared to CNI plus ATG (p = 0.032). For ALL patients, neutrophil engraftment was observed in 55.6% of RIC and 90.0% of MAC (p = 0.034). The median RFS was 5 months and OS 19 months. MAC regimens, especially total body irradiation (TBI)-based regimen, were associated with both longer RFS and OS compared to other conditioning regimens. In conclusion, individualized conditioning regimens will add value in terms of enhancing safety and efficacy of CBT.

There are still controversies about the use of interim positron emission tomography/computed tomography (PET/CT) in indolent non-Hodgkin lymphoma due to the variable fluorodeoxyglucose (FDG) avidity. Therefore, this study aimed to evaluate the roles of interim PET/CT in marginal zone lymphoma (MZL), a representative indolent lymphoma. We analyzed the data of 146 MZL patients. All were treated with rituximab-containing immunochemotherapy. Interim PET/CT scan was performed after 2–3 cycles of therapy, and the response was assessed using the Deauville 5-point scales (5-PS) and a semi-quantitative assessment using the SUVmax reduction rate (ΔSUVmax). Progression-free survival (PFS) was well stratified according to a visual assessment of interim PET/CT using 5-PS (p p = 0.031). The interim PET/CT response based on the 5-PS is useful for predicting PFS of patients with MZL in the post-rituximab era.

Background Although international guidelines recommend palliative care approaches for many serious illnesses, the palliative needs of patients with serious illnesses other than cancer are often unmet, mainly due to insufficient prognosis-related discussion. We investigated physicians' and the general public's respective attitudes toward prognostic disclosure for several serious illnesses. Methods We conducted a cross-sectional survey of 928 physicians, sourced from 12 hospitals and the Korean Medical Association, and 1,005 members of the general public, sourced from all 17 administrative divisions in Korea. Results For most illnesses, most physicians (adjusted proportions – end-organ failure, 99.0%; incurable genetic or neurologic disease, 98.5%; acquired immune deficiency syndrome [AIDS], 98.4%; stroke or Parkinson's disease, 96.0%; and dementia, 89.6%) and members of the general public (end-organ failure, 92.0%; incurable genetic or neurologic disease, 92.5%; AIDS, 91.5%; stroke or Parkinson's disease, 92.1%; and dementia, 86.9%) wanted to be informed if they had a terminal prognosis. For physicians and the general public, the primary factor to consider when disclosing terminal status was “the patient's right to know his/her condition” (31.0%). Yet, the general public was less likely to prefer prognostic disclosure than physicians. Particularly, when their family members were patients, more than 10% of the general public did not want patients to be informed of their terminal prognosis. For the general public, the main reason for not disclosing prognosis was “psychological burden such as anxiety and depression” (35.8%), while for the physicians it was “disclosure would have no beneficial effect” (42.4%). Conclusion Most Physicians and the general public agreed that disclosure of a terminal prognosis respects patient autonomy for several serious illnesses. The low response rate of physicians might limit the generalizability of the results., Graphical Abstract

Introduction BCR-ABL1 mutations require consideration during second-line tyrosine kinase inhibitor selection for patients with chronic myeloid leukemia (CML). The present retrospective analysis compared the frequency of BCR-ABL1 mutations in Asian and white patients in whom imatinib therapy had failed. Patients and Methods A nonstudy cohort (76 Asian patients from community clinical practices) and 2 study cohorts (29 Asian and 352 white patients from dasatinib phase II and III clinical trials) were identified. Results In the nonstudy cohort, 80 mutations were identified; the most frequent was T315I (15%), followed by phosphate-binding loop mutations E255K (11%), G250E (10%), and Y253H (10%). Asian patients had a greater proportion of T315I and phosphate-binding loop mutations compared with the white patients. The nonstudy cohort was less likely to have multiple mutations compared with either study cohort. Single mutations highly resistant to dasatinib, nilotinib, and bosutinib were more frequent in the Asian than in the white cohorts. Conclusion These results suggest that mutational analysis findings will be invaluable for choosing an appropriate second-line tyrosine kinase inhibitor in Asia.

The aim of this study was to establish a risk-stratification model integrating posttreatment metabolic response using the Deauville score and the pretreatment National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) in nodal PTCLs. We retrospectively analysed 326 patients with newly diagnosed nodal PTCLs between January 2005 and June 2016 and both baseline and posttreatment PET/CT data. The final model was validated using an independent prospective cohort of 79 patients. Posttreatment Deauville score (1/2, 3, and 4/5) and the NCCN-IPI (low, low-intermediate, high-intermediate, and high) were independently associated with progression-free survival: for the Deauville score, the hazard ratios (HRs) were 1.00 vs. 2.16 (95% CI 1.47–3.18) vs. 7.86 (5.66–10.92), P

Understanding the concept of a "good death" is crucial to end-of-life care, but our current understanding of what constitutes a good death is insufficient. Here, we investigated the components of a good death that are important to the general population, cancer patients, their families, and physicians.We conducted a stratified nationwide cross-sectional survey of cancer patients and their families from 12 hospitals, physicians from 12 hospitals and the Korean Medical Association, and the general population, investigating their attitudes toward 10 good-death components.Three components-"not be a burden to the family," "presence of family," and "resolve unfinished business"-were considered the most important components by more than 2/3 of each of the three groups, and an additional three components-"freedom from pain," "feel that life was meaningful," and "at peace with God"-were considered important by all but the physicians group. Physicians considered "feel life was meaningful," "presence of family," and "not be a burden to family" as the core components of a good death, with "freedom from pain" as an additional component. "Treatment choices' followed, "finances in order," "mentally aware," and "die at home" were found to be the least important components among all four groups.While families strongly agreed that "presence of family" and "not be a burden to family" were important to a good death, the importance of other factors differed between the groups. Health care providers should attempt to discern each patient's view of a good death.

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.

Integrated early palliative care (EPC) improves quality of life and reduces psychological distress in adult patients with cancer and caregivers, but attitudes toward EPC have been poorly studied. We aimed to investigate attitudes toward EPC in a nationwide survey of patients with cancer and caregivers. From July to October 2016, we administered nationwide questionnaires examining attitudes toward EPC in patients with cancer (n = 1001) and their families (n = 1006) from 12 Korean hospitals. When an individual considered EPC unnecessary, the reasons were collected and analyzed. Factors associated with perception of EPC were examined. A majority of patients (84.5%) and caregivers (89.5%) had positive attitudes toward EPC. The most common reasons for deeming EPC unnecessary were that EPC may be an obstacle to cancer treatment (patients: 37%; caregivers: 23%; respectively) or that they were not sure if EPC is beneficial (patients: 21%; caregivers: 24%; respectively). Financial burden as a reason was more evident in caregivers (23%) than in patients (17%). Male gender, age

Radotinib is a second‐generation BCR‐ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP‐CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP‐CML, the dose–efficacy as well as dose–safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose‐limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR‐ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12‐month follow‐up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long‐term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP‐CML.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4, and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT+RT; RT+CT) and concurrent modalities (CCRT; CCRT+CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P=0.027), prognostic index for NK/T-cell lymphoma (PINK) (P=0.026) and types of initial treatment (P=0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P=0.021) and PINK-EBV DNA (PINK-E) (P=0.002) significantly impacted on PFS; whereas ECOG performance score (P=0.008) and stage (P

Background: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. Methods: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. Results: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015–4.842; p = 0.0458). Conclusion: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.

Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months. Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction. Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.

Little is known about people’s attitudes toward death. We aimed to examine attitudes toward death and to investigate their associations with health status in various participant groups. We administered nationwide questionnaires to a total of 4,107 individuals including general Korean population, cancer patients, family caregivers, and physicians. Association of attitudes toward five aspects of dying and death—the ending of life, fearing death because it is painful, anticipating an afterlife, preparing to practice charity and being remembered—and physical, mental, social, and spiritual health status were also analyzed. Attitudes differed. Most (63.4%-76.2%) accepted that death is the ending of life, 45.6%-58.8% feared a painful death, 47.6%-55.0% anticipated an afterlife, 88.5%-93.0% expected to forgive, and 89.9%-94.1% expected to be remembered after death. The general population, cancer patients, and family caregivers had similar attitudes but had more positive attitudes than physicians on the ending of life, fearing a painful death, and anticipating an afterlife. Accepting death as the ending of life and fear of death pain were inversely associated with mental, social, spiritual, or general health status, but participants anticipating an afterlife, expecting to forgive, or expecting to be remembered showed better social, spiritual, or general health status. This nationwide study of various participant groups shows that attitudes toward dying and death were associated with mental, social, spiritual, or general health, but not physical health status. These data suggest that sensitive and skillful discussions of death and dying might contribute to peaceful end of life.

Use of recombinant tissue plasminogen activator (rt-PA) for the treatment of acute cerebral infarction secondary to aortic dissection is challenging because of a narrow time window and potential life-threatening complications. An 80-year-old woman with right middle cerebral artery infarction was treated with rt-PA. Although she had no history, symptoms, or sign of aortic dissection, carotid CT angiography revealed aortic arch dissection. Mediastinal widening, which did not show on initial chest X-ray, developed on follow-up chest X-ray. This observation indicates that physicians should monitor patient symptoms for signs of aortic dissection during thrombolysis and perform chest X-ray or carotid angiography immediately after thrombolysis even if the patient has no symptoms or signs of aortic dissection on onset of acute cerebral infarction.

Bortezomib-melphalan-prednisone (VMP) showed superior efficacy versus MP as first-line treatment for transplantation-ineligible multiple myeloma (MM). This study investigated the efficacy of VMP for Korean patients with MM. Overall, 177 MM patients received 9 cycles of VMP in this prospective, multicenter, observational study. The primary endpoint was 2-year progression-free survival (PFS). Thirty-nine (22%) patients were aged ≥ 75 years and 83 (47.4%) patients had International Staging System stage III. A median of 5 cycles were delivered. Overall response rate (ORR) was 72.9%, and complete response (CR) rate was 20.3%. With a median follow-up of 11.9 months, median PFS was 17 months. The 2-year PFS and overall survival (OS) rates were 29.2% and 80.0%, respectively. Median OS was not reached. PFS was significantly different depending on performance status (Eastern Cooperative Oncology Group < 2 vs. ≥ 2; p = 0.0002), β2-microglobulin level (< 5.5 vs. ≥ 5.5 mg/L; p = 0.0481), and cumulative dose of bortezomib (< 35.1 vs. ≥ 35.1 mg/m2; p < 0001). The common adverse events (AEs) were in line with the well-known toxicity profiles associated with VMP. In conclusion, VMP is a feasible and effective front-line treatment for transplant-ineligible older patients with MM in Korea. Continuing therapy with prompt adjustment of treatment according to AEs may be important to improve outcomes of elderly patients.

Background Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common indolent and aggressive B-cell lymphomas, respectively. Although the combination of anti-CD20 therapies rituximab (R) or obinutuzumab (G) with chemotherapy has led to improved patient (pt) outcomes, R/R disease remains a challenge, with a high unmet need. The potent and selective MDM2 antagonist idasanutlin (idasa) activates the p53 pathway, leading to anti-tumor activity. The BCL-2 inhibitor venetoclax (ven) has shown clinical activity in hematologic diseases including R/R NHL. In a Phase Ib/II study (NCT02624986), idasa could be safely combined in a doublet treatment (tx) regimen with R or G in R/R FL or DLBCL pts. Here we report the tolerability, safety and preliminary efficacy of the triplet tx regimen of idasa plus ven and G in R/R NHL pts. Methods BH39147 (NCT03135262) was an open-label, multicenter, non-randomized, Phase Ib/II study with a dose-escalation phase followed by an expansion phase. The dose-escalation phase evaluated idasa and ven combined with G in all pts (FL and DLBCL) until the maximum tolerated dose (MTD) was reached. Idasa and ven dose escalations started at 100 and 200 mg PO QD, respectively, on days 1-5 of each 28-day cycle (safety cohort); in subsequent cohorts, ven was given on days 1-10 of each cycle. G was given at a fixed dose of 1000 mg IV on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles. Pts received 6 cycles of induction tx. The primary objective of the dose-escalation phase was to determine recommended Phase II doses for idasa and ven in combination with G. Efficacy objectives included evaluating the complete response (CR) rate at the end of induction (EOI) per investigator based on PET-CT. The trial was stopped prior to initiation of the expansion phase; results are presented for the dose-escalation cohorts evaluating idasa plus ven and G. Results Of the 29 pts enrolled, 14 each had a diagnosis of FL or DLBCL at study entry, and 1 had an unknown diagnosis at study entry that was later confirmed as FL. The median age was 70 y (range, 25-82), 58.6% of pts were male, and 67.9% had an ECOG PS of 1 or 2. The majority of pts had advanced-stage disease at enrollment, with 58.6% having received ≥ 3 lines of prior anti-lymphoma therapy; 17.2% and 24.1% of pts had received 1 and 2 prior lines of tx, respectively. Median (range) tx durations during induction were 1.3 mo (0-6) for idasa, 1.5 mo (0-7) for ven and 1.5 mo (0-6) for G; post-induction median (range) tx durations (n = 4) were 3.8 mo (0-4), 3.8 mo (0-4) and 8.4 mo (0-11), respectively. The safety-evaluable population was composed of 29 pts. Grade 3/4 adverse events (AEs) occurred in 86.2% of pts, with neutropenia (79.3%), thrombocytopenia (62.1%), leukopenia (27.6%) and anemia (20.7%) as the most common. No Grade 5 AEs were reported. Serious AEs occurred in 48.3% of pts and were most commonly neutropenia (10.3%). AEs led to treatment discontinuation in 41.4% of pts, with thrombocytopenia (17.2%) and neutropenia (13.8%) being the most common. AEs related to idasa, ven and G were reported in 86.2%, 89.7% and 79.3% of pts, respectively. Dose-limiting toxicities were reported in 4 pts (13.8%): neutropenia (n = 3; 10.3%), hyperbilirubinemia (n = 1; 3.4%) and transaminitis (n = 1; 3.4%). The MTD for idasa was determined to be 150 mg in combination with 200-mg ven and G and 100 mg in combination with 400-mg ven and G. Preliminary efficacy data are shown in the table. Among all pts, 20.7% (FL, n = 5; DLBCL, n = 1) had a CR at EOI per investigator (PET-CT) based on modified Lugano 2014 criteria. Per investigator based on Lugano 2014 criteria, the CR rate at EOI (CT) was 13.8% (FL, n = 3; DLBCL, n = 1), and the complete metabolic response rate at EOI (PET-CT) was 24.1% (FL, n = 6; DLBCL, n = 1). Conclusions This study successfully showed the combinability of idasa and ven with an anti-CD20 agent. MTDs were determined for idasa and ven in combination with G in FL and DLBCL pts. No new safety signals related to any of the study drugs were identified, and the observed safety profiles were consistent with those of each individual study drug. While the combination is feasible and promising, other agents and approaches in the field make this combination less likely to proceed further. As a consequence, this trial has been discontinued following the dose-escalation/proof-of-concept phase to focus on new tx combinations. Figure Disclosures Kamdar: Roche:Research Funding.Augustson:Roche:Other: Support of parent study and funding of editorial support.Edwards:Roche:Other: Support of parent study and funding of editorial support.Hertzberg:Roche:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support;Gilead:Membership on an entity's Board of Directors or advisory committees;MSD:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria;BMS:Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees.Johnston:Roche:Other: Support of parent study and funding of editorial support.Kim:Alexion Pharmaceuticals Inc.:Honoraria, Research Funding.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding;Gilead:Consultancy.Smith:TG Therapeutics:Consultancy, Research Funding;Genentech/Roche:Consultancy, Other: Support of parent study and funding of editorial support, Research Funding;BMS:Consultancy;Karyopharm:Consultancy, Research Funding;FortySeven:Research Funding;Pharmacyclics:Research Funding;Acerta:Research Funding;Janssen:Consultancy;Celgene:Consultancy, Research Funding.Stevens:Amgen, MorphoSys:Consultancy.Monnet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Zhao:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Nouet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Marinova:Roche:Current Employment, Other: Support of parent study and funding of editorial support.

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

This trial was designed to investigate the efficacy and toxicity of bendamustine, carboplatin, and dexamethasone (BCD) for relapsed or refractory peripheral T-cell lymphomas (PTCLs), which would be expected to exhibit more promising clinical outcomes compared with bendamustine therapy alone. After treatments with BCD, eight patients exhibited a complete response (CR; 29%) and seven exhibited a partial response (PR; 25%). The overall response rate (ORR) was 54%. Five patients proceeded to ASCT and three patients finally achieved CR. The median progression-free survival (PFS) was 4.4 months (2.8-6.0, 95% CI). For a total of 85 cycles of BCD, grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 17.6, 38.8, and 16.5% of cycles, respectively. Only one patient experienced febrile neutropenia. BCD was a considerable salvage regimen for relapsed or refractory PTCLs with acceptable toxicity; AITL or ASCT eligible patients were more effective to BCD.ClinicalTrials.gov Identifier:NCT02424045.

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.

Introduction Decitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival. Patients and Methods This study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633 ) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846 ) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared. Results One hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR. Conclusion Decitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.

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

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

In real clinical settings (not clinical trials), thalidomide has been accepted as maintenance therapy to patients with multiple myeloma (MM) because of the cost of drugs, the limitations of medical insurance, etc., in our country (South Korea). The purpose of this study was to evaluate the utility of thalidomide maintenance for improving survival in transplantation-eligible patients with MM in the real clinical field. Differences in survival rates were estimated in patients treated with or without thalidomide maintenance. The 3-year progression-free survival rates (PFS) of patients with and without maintenance, respectively, were 55.4 and 37.2 % (p = 0.005). The 3-year overall survival rates (OS) were 88.0 and 84.0 % (p = 0.105). No difference in 3-year OS after relapse or progression (OS2) was observed between the two groups (50.4 and 55.3 %, p = 0.661). The 3-year PFS of patients with and without maintenance therapy who had shown less than CR after ASCT were 68.4 and 23.3 % (p

Background Everolimus, an oral mTOR inhibitor, has single-agent activity against relapsed lymphomas. Thus, we carried out a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma (PTCL) based on our phase I study results. Patients and methods Participants (n = 30) received CHOP with 5 mg everolimus per day from day 1 to 14 every 21 days for a total of six cycles. The primary end point was the overall response rate (ORR), which included complete response (CR) and partial response (PR) to this regimen. Immunohistochemistry was used to evaluate the expression of phosphatase and tensin homology (PTEN) and phosphorylated S6 kinase (pS6K) as a response. Results The objective response rate was 90% with CR (n = 17) and PR (n = 10). The CR rate was different among subtypes; angioimmunoblastic T-cell lymphoma (AITL, n = 3) had a CR whereas PTCL-not-otherwise specified and ALK-negative anaplastic large-cell lymphoma (ALCL) patients showed 63% (12/19) and 29% (2/7) of CR rate, respectively. This difference in CR rate among subtypes was associated with PTEN loss because PTEN loss was not seen in AITL but 33% of ALCL patients. The most common toxicity was hematological, with 80% of patients experiencing at least one event of grade 3/4 neutropenia, and 60% of patients had grade 3/4 thrombocytopenia. Conclusion The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.

Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has been shown to improve the rates of successful peripheral blood stem cell (PBSC) mobilization in patients with malignant lymphoma or multiple myeloma (MM) who experienced prior failure of PBSC mobilization. We evaluated the mobilization results of re-mobilization using plerixafor and G-CSF in insufficiently mobilizing patients. Forty-four patients with lymphoma (n = 29) or MM (n = 15) were included in the study. The median age was 50 (range, 24-64) years. Previous mobilization regimens were chemotherapy with G-CSF (n = 28), including cyclophosphamide with G-CSF (n = 15), and G-CSF only (n = 16). All patients with lymphoma achieved at least partial response (PR) before the mobilization, including 13 complete responses (CRs). Eleven patients with MM achieved at least PR and four patients with MM were in stable disease before mobilization. The median number of apheresis was 3 (range, 1-6). The median yield of PBSC collections was 3.41 (0.13-38.11) × 10(6) CD34(+) cells/kg. Thirty-four (77.3 %) patients had successful collections defined as at least 2 × 10(6) CD34(+) cells/kg. The rate of successful collections was not different between the two underlying diseases (79.3 % in lymphoma and 73.3 % in MM). Of the entire cohort, 38 (86.4 %) of patients went on to receive an autologous transplant. Previous long-term use of high-risk drugs (4 cycles use of alkylating agents, platinum-containing agents, or thalidomide) (HR 10.8, 95 % CI 1.1-110.0, P = 0.043) and low platelet count (100 × 10(9)/L) 1 day before the first apheresis (HR 27.9, 95 % CI 2.9-273.7, P = 0.004) were independent prognostic factors for predicting failure of PBSC re-mobilization using plerixafor and G-CSF. In conclusion, re-mobilization using plerixafor and G-CSF showed a success rate of 77.3 % in patients with lymphoma or MM who experienced prior failure of PBSC mobilization, and the majority of them underwent autologous transplant. Therefore, plerixafor-based re-mobilization was an effective method in poor mobilizers.

Introduction Dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has been administered at a fixed starting dose of 100 mg once daily for patients with chronic myeloid leukemia in chronic phase (CP-CML). However, the relationships between TKI exposure, and safety and efficacy responses suggest that such fixed dosing may not be optimal for many Asian patients. In this study, the relationships between the starting dose of dasatinib adjusted for BW (Dose/BW), and dose limiting toxicities (DLTs) and molecular responses (MRs) were evaluated to develop an initial dosing strategy of dasatinib. Methods The safety and efficacy responses of dasatinib therapy were explored from the clinical data obtained in patients newly diagnosed with CP-CML at seventeen hospitals in South Korea. The safety response was assessed as the occurrence of first DLTs by 36 months that required an interruption in dasatinib therapy. The efficacy responses were evaluated as the achievement of MR at 3 months (MR1), 6 months (MR2), 12 months (major molecular response, MMR) and 24 months (deep molecular response, MR4.5). The rates and patterns of DLT occurrence and MR achievement by 36 months were examined using a Kaplan-Meier method. A logistic regression method was used to determine the effect of the Dose/BW of dasatinib on the occurrence of first DLTs or the achievement of MRs. A chi-square test for trend was used to assess the trend of DLT occurrence and MR achievement in patient subgroups divided into quartiles (Q1 to Q4) based on Dose/BW. Results The clinical data were obtained from a total of 102 Asian patients with CP-CML whose median BW was 64.0 kg (range, 37.8 to 106.0 kg) and Dose/BW 1.60 mg/kg (1.00 to 2.80 mg/kg). Safety. The most frequent DLTs were thrombocytopenia (46%), pericardial or pleural effusion (31%) and anemia (7%); the median time of occurrence for the DLTs were 29 days (range, 7 to 417 days), 336 days (7 to 681 days) and 35 days (10 to 140 days), respectively. The rate of DLT occurred first increased rapidly by four months of starting dasatinib therapy and then steadily by 28 months until reaching approximately 56% in the Kaplan-Meier curve. Patients with higher Dose/BW had a greater risk of DLT occurrence by 36 months as determined using a logistic regression (logit [P] = 1.58 × [Dose/BW] - 2.27, p = 0.03). As Dose/BW increases from Q1 to Q4 (median Dose/BW; 1.23, 1.45, 1.65 and 2.00 mg/kg, respectively), the rate of DLTs rises from 43.5% (Q1) to 66.7% (Q4) with a statistically significant trend of increment (p = 0.03). The median dose that would produce the lowest rate of DLTs is 78.7 mg as calculated by multiplying the median Dose/BW of Q1 (1.23 mg/kg) by the median BW of patients (64.0 kg). Efficacy. The achievement rates of MMR and MR4.5 increased continuously and reached 82% and 43%, respectively, by 36 months of starting dasatinib therapy. The Dose/BW of dasatinib did not affect the rates of MR achievements based on a logistic regression analysis. Even though Dose/BW increased, the achievement rates of MR1, MR2 and MMR demonstrated neither an increasing nor a decreasing trend from Q1 to Q4. Conclusion The higher the starting Dose/BW of dasatinib, the greater is the risk of DLT occurrence without improving the potential for MR achievement. Therefore, in order to minimize the risk of DLTs without compromising MRs, a lower starting dose of dasatinib 80 mg once daily is suggested for Asian patients with CP-CML especially with lighter BW. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

Purpose Allogeneic hematopoietic stem cell transplantation (HSCT) with optimal conditioning has helped better long-term survival in acute lymphoblastic leukemia (ALL). This study investigated the efficacy and safety of reduced-intensity conditioning (RIC) with busulfan and fludarabine in adult ALL patients unfit for myeloablation. Materials and methods Records of 78 patients who underwent HSCT with RIC consisting of 3.2 mg/kg/day of busulfan for 2 or 3 days and 30 mg/m²/day of fludarabine for 5 or 6 days were analyzed. Results The median age at diagnosis was 49 years. Over a median follow-up of 22 months, 2-year estimates of relapse-free survival (RFS) and overall survival were 57.4% and 68.7%, respectively. Multivariate analysis showed a trend of improved RFS in patients with chronic graft-versus-host disease (GVHD) (hazard ratio, 0.53; 95% confidence interval, 0.26-1.08; p=0.080). The cumulative incidences of relapse and non-relapse mortality were 42.9% and 19.6%, respectively and one case of central nervous system relapse was noted. No hepatic veno-occlusive disease was reported. Grade II-IV acute GVHD and any grade chronic GVHD occurred in 21.1% and 41.7%, respectively. Conclusion RIC with busulfan and fludarabine is an effective and safe conditioning regimen for adult ALL patients unfit for myeloablation.