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The objective of this pilot study was to examine factors associated with the completion of advance directives (ADs) among patients with hematologic disorders in Korea. Using a descriptive design, patients with largely hematologic malignancies completed the questionnaires, including the Korean–Advance Directive (K-AD) model, which pertains to values, treatment wishes, and proxy appointment. Of 45 patients (aged 48.7 ± 10.7 years, 51.1% men), two-thirds had leukemia (40.0%) and lymphoma (26.7%). “Dying comfortably” was the most frequently selected value (n = 20). Regarding treatment wishes, hospice care was the most desired type (n = 22), whereas aggressive treatments, such as cardiopulmonary resuscitation, were less preferred (n = 3). The patient’s spouse was most frequently appointed as a proxy (n = 27). Patients who completed all the 3 components of the K-AD model (51.1%) were less depressed (t= −2.31; P= .028) and more likely to perceive the benefits of the K-AD model (t= 2.07; P= .045), compared with the noncompleters (48.9%). Further, being male (odds ratio [OR], 6.42; P= .031), having higher scores on depressive symptoms (OR, 1.28; P= .016), and perceived barriers (OR, 1.08; P= .040) were associated with lower tendency to complete the K-AD model. These findings support the need for earlier introduction of ADs in hematologic disorders, with consideration of modifiable factors such as depression or barriers to end-of-life care decisions.

This article examines the development of Korean rhyming techniques by musically analysing phonetic and grammatical structure in Korean rap. Due to major differences between Korean and English, Korean MCs had to redefine what constitutes “rhyme” in Korean rap, and the conflicting definitions of what it means to rhyme in Korean reflect diverse identities in the Korean hip hop community. Through my musical analyses, I present five types of Korean rhyming techniques: flexible word order, artificial stress accents or artificial pitch accents, rhythmic motives, multisyllabic internal rhymes and translingual rhymes. I close the article by suggesting that there is an inevitable hybridity in Korean hip hop and socioeconomic class struggles that persists in Korea.

Previous retrospective studies have revealed that a substantial portion of PV patients experience resistance to hydroxyurea (HU-R) and intolerance to HU (HU-I). Currently, the therapeutic options for both groups of patients do not differ, and most clinical trials investigating second-line therapies have enrolled patients with HU-R or HU-I without considering potential clinical distinctions between the two groups. Direct comparisons between patients with HU resistance and HU intolerance have not been conducted, and prognostic factors related to clinical outcomes, such as thrombosis, bleeding, disease progression, and survival, remain unclear for patients experiencing HU resistance or intolerance.

Background: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement.Objectives: We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse.Design: This is a prospective, multicenter study.Methods: We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR).Results: A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p= 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p= 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1(⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p= 0.015).Conclusion: Our data suggest that transcript type and BCR::ABL1transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10−3 and MR5 for ratios <10−5. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDHratios ≤10−3and MR5 for ratios <10−5. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P= .004) or 6.3 times (P= .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.govas #NCT00844298.

The purpose of this study was to evaluate the prognostic value of metabolic tumor volume (MTV) measured by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-containing immunochemotherapy. Patients with newly diagnosed DLBCL who underwent pre-treatment torso FDG-PET/CT scan taken within 10 days before treatment were included. MTV was defined as the volume of hypermetabolic tissue with a standardized uptake value (SUV) greater than a threshold value of 2.5 and calculated using volume viewer software. Association of MTV with patient characteristics and survival were compared. A total of 96 patients were evaluated. During a median follow-up period of 27.8 months, 3-year event-free survival (EFS) and overall survival was 69.5 % and 72.9 %, respectively. The Ann Arbor staging showed a limitation of prognosis because there was no difference of EFS between patients with Ann Arbor stage II and those with stage III. On the contrary, among patients with Ann Arbor stage II or III disease (n= 53), the higher MTV group showed significantly inferior EFS compared with the lower MTV group. In the current study, we identified the pre-treatment MTV measured by FDG-PET/CT as a potential predictor of survival in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), at least in Ann Arbor stage II and III disease.

To assess the usefulness of 18F-fluorodeoxyglucose PET/CT in the detection of bone marrow (BM) involvement of high-grade non-Hodgkin’s lymphoma (NHL).One hundred twenty patients with newly diagnosed diffuse large B-cell lymphoma or peripheral T-cell lymphoma between January 2007 and June 2011, who received BM trephine biopsy and 18F-FDG PET/CT before chemotherapy, were included in this retrospective study. We reviewed their 18F-FDG PET/CT images and bone marrow biopsy (BMB) results. After reviewing the images, we reviewed the medical records and radiological findings of interesting patients.There were 23 18F-FDG PET/CT scans in which the marrow was considered to be abnormal (either positive or equivocal), and 97 18F-FDG PET/CT scans were regarded as having negative FDG uptake. Of 120 patients, 100 (83.3 %) had a concordant result of BM interpretation between 18F-FDG PET/CT and BMB, and the remaining 20 patients had discordant results. Among 23 patients with either positive or equivocal 18F-FDG PET/CT scans, 1 of 12 patients with ‘positive’ 18F-FDG PET/CT had a lymphomatous involvement on BMB. In contrast, 10 of 11 patients with ‘equivocal’ BM hypermetabolism were reported as having positive involvement by BMB. Patients with abnormal 18F-FDG PET/CT had significantly higher mSUVhighestthan those with normal FDG-PET/CT.18F-FDG PET/CT and BMB are complementary techniques in assessing the presence of BM involvement in patients with high-grade NHL. The increasing availability of 18F-FDG PET/CT will raise the need for additional biopsy for FDG-avid lesions, especially in patients with negative standard BMBs. 18F-FDG PET/CT can be useful as a decision-making tool for determining whether to perform a standard BMB or targeted biopsy to the FDG-avid lesion as an initial staging procedure. A direct bone biopsy for FDGpositive bone lesions should be included in staging guidelines in future. In 18F-FDG PET/CT-negative cases, BMB is still a powerful procedure, but BMB alone is insufficient for full evaluation of BM.

The aim of this retrospective cohort study was to analyze the impact of surgery on the outcomes and qualities of life (QOL) in patients with intestinal diffuse large B-cell lymphoma (DLBCL). We assessed 345 patients with either localized or disseminated intestinal DLBCL and compared them according to treatment: surgical resection followed by chemotherapy versus chemotherapy alone. In patients with localized disease (Lugano stage I/II), surgery plus chemotherapy yielded a lower relapse rate (15.3%) than did chemotherapy alone (36.8%, P < .001). The 3-year overall survival rate was 91% in the surgery plus chemotherapy group and 62% in the chemotherapy-alone group (P < .001). The predominant pattern in the chemotherapy group was local relapse (27.6%). When rituximab was used with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), there was no improvement of the outcomes in patients treated with primary surgical resection. The QOL of patients who underwent surgery and chemotherapy was lower than chemotherapy alone, but its difference was acceptable. Multivariate analysis showed that surgical resection plus chemotherapy was an independent prognostic factor for overall survival. Surgical resection followed by chemotherapy might be an effective treatment strategy with acceptable QOL deterioration for localized intestinal DLBCL. This study was registered at www.clinicaltrials.gov as #NCT01043302.

Supplemental Digital Content is available in the text.

Kim: Il-Yang co.: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; BMS: Research Funding; Novartis: Research Funding.

BackgroundThe recent discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and undetectable molecular residual disease (UMRD) durations prior to IM discontinuation. Moreover, treatment rechallenge in patients with molecular recurrence lead a second deep molecular response, suggesting that IM discontinuation is safe. However, the issues on the definition of molecular relapse requiring treatment resumption and the occurrence of late relapse with a long-term follow-up after IM discontinuation are important. Therefore, here we analyzed the long-term follow-up results of the patients who lost UMRD after IM discontinuation

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), a potent proteasome inhibitor, is a boronic acid dipeptide that induce cancer cell death. It is an effective drug for both newly diagnosed or relapsed multiple myeloma (MM) patients and is widely used in the treatment of various kinds of lymphomas and other diseases. Peripheral nerve damage is one of the most significant nonhematologic toxicities of bortezomib. The reported incidence of bortezomib-induced peripheral neuropathy (BIPN) ranges from 25 to 75 % . When it occurs, the painful sensory neuropathy can interfere with quality of life (QOL) and with performance of activities of daily living, and it may also adversely affect clinical outcomes by forcing dose modification and/or premature treatment discontinuation. Therefore there are many efforts to improve multiple symptoms associated with BIPN. But there are no reports on amelioration of neurotoxicity which occurred in patients with treatment of bortezomib .Therefore control of this toxicity by the concomitant use of other safe candidates can make it a better option for the cancer therapy with bortezomib.

Background:In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS≤ 0.1%) and MR4.5(BCR-ABL1IS≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289).

Introduction

Introduction: Hypocellular myelodysplastic syndrome (h-MDS) comprised approximately 10-20% of total MDS cases. The difference in clinical features and prognosis between h-MDS and normo/hypercellular MDS (NH-MDS) remains uncertain and the treatment strategy of h-MDS patients has not been well-defined in epigenetic therapy era. Therefore, we conducted this study to define the prognostic factors and response to the hypomethylating agents (HMA) for Korean h-MDS patients.

Background

No relevant conflicts of interest to declare.

Lee: Amgen: Membership on an entity's Board of Directors or advisory committees.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

IntroductionChromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown.

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All-transretinoic acid (ATRA) has successfully been used in the treatment of acute promyelocytic leukemia (APL) patients, with a remission rate of greater than 90% . Despite the high cure rates, induction mortality is a still a problem in APL. One of the most common causes of death was the differentiation syndrome (DS) . The early administration of high-dose dexamethasone at the onset of the first signs or symptoms of DS is crucial, however specific biological therapies to counteract the syndrome are still not available. Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily, which is expressed in normal monocytes, various leukemias, and epithelial malignancies. PPARγ is highly induced in differentiating myeloid cells and subsequently contributes to their differentiation. Differentiation induction of APL cells is associated with increased expression of specific adhesion molecules and inflammatory cytokines, which may promote activation, migration, and adhesion of these cells. Here, we studied the effect of PPARγ agonists on the adhesion of a human leukemia cell line (HL-60) to endothelial cells. HL-60 cells were differentiated into macrophage-like cells by a PKC activator, 12-O-Tetradecanoylphorbol-13-acetate (TPA). Differentiation was determined by an increase in reactivity with the CD11b antibody. For the adhesion assay, the Matrigel transwell system was used. During the differentiation of HL-60 cells, PPARγ agonists acitvate TPA-induced CD11b expression. However, PPARγ agonists completely blocked TPA-induced ICAM-1 expression of endothelial cells,which resulted in the inhibition of adhesion of HL-60 cells to endothelial cells. These responses also were reversed by PPARγ antagonist (GW9662), indicating that PPARγ agonists inhibits the adhesion of the HL-60 cells to endothelial cells through a PPARγ dependent mechanism. These results suggest that PPARγ agonists inhibit TPA-induced adhesion signal in the between HL-60 cells and endothelial cells, and may control differentiation syndrome in APL patients.

Background: LIGHT (Homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM)/tumor necrosis factor (TNF)-related 2, HVEM-L, TNFSF14, or CD258) is a member of TNF superfamily. It is expressed as a homotrimer on activated T cells and also on immune dendritic cells, and has three receptors such as HVEM, LT-¥â receptor (LT-¥âR) and decoy receptor 3 (DcR3). So far, three receptors with distinct cellular expression patterns are described to interact with LIGHT. Follicular DCs and stromal cells bind LIGHT through LT-¥âR. We monitored the effects of LIGHT on human bone marrow-derived mesenchymal stem cells (BM-MSCs).

Kim: Alexion Pharmaceuticals: Research Funding; Celgene: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

Kim: IL-YANG Pharm.Co.Ltd: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding.

Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

Background:Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second generation tyrosine kinase inhibitors (2G TKIs) such as nilotinib and dasatinib. However, whether a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is sufficient to define failure necessitating a change of treatment is not confirmed. Radotinib (RAD) is a 2G TKI for BCR-ABL1 tyrosine kinase, which was approved by the Korea FDA for the second-line therapy, and the phase 3 study comparing the efficacy and safety of RAD 300 and 400 mg twice daily and IM 400 mg once daily in patients with newly diagnosed CP CML was performed. The aim of this study was to identify the predictive value of 3-month molecular milestone for an achievement of major molecular response (MMR) by 12 months to RAD therapy. Additionally, in the same population, predictive factors for achieving MMR by 12 months were analyzed.

Background: There is no standard therapy after the failure of hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) without only providing supportive cares including transfusion or cytokine therapies when the patient is not eligible for allogeneic hematopoietic cell transplantation. Lenalidomide is the treatment of choice in case of MDS with 5q deletion. A study of lenalidomide for non-5q deletion MDS patients showed that transfusion independency rate was 26% which was relatively acceptable and suggested that lenalidomide could be used for non-5q deletion MDS patients.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM' (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going.

Approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD) at 6-7 years of first-line imatinib (IM) therapy. Although imatinib therapy is effective in chronic myeloid leukemia (CML) patients and a substantial portion of patients achieve UMRD with prolonged IM therapy, up to 10^7 leukemic cells can still be present in the absence of detectable BCR-ABL1 in RQ-PCR assay due to the sensitivity limit of current RQ-PCR technology. The recent several reports to assess whether IM can be discontinued in CML patients have shown that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, the 12-month probability of sustained UMRD of 48 patients was 80.8% (78.4% in 37 patients with at least 12 months follow-up), a higher rate than that reported by the ‘STIM’ (Stop Imatinib) trial. To identify predictors for safer, successful IM discontinuation and to explore additional contributing factors for sustained molecular responses (MRs), this multicenter prospective Korean Imatinib Discontinuation Study (KIDS) is on-going.Patients who were treated with IM for more than 3 years and whose BCR-ABL1 was undetectable in RQ-PCR for at least 2 years were enrolled in this study. After discontinuation, molecular response was monitored using RQ-PCR assay every month up to 6 month follow-up, every 2 months up to 12 month follow-up, and every 3 months thereafter. In case of relapse, defined as loss of MMR on 2 consecutive assessments, IM therapy was re-introduced and molecular response after resumption was observed every month using RQ-PCR. Our primary objectives were to evaluate the probability of persistent UMRD at 12 month follow-up after discontinuation, and to measure the duration of persistent UMRD after discontinuation. The secondary objective was to evaluate the probability of major molecular response (MMR) loss and the time taken to lose MMR after discontinuation.Of the 100 patients who were screened for KIDS, 22 patients have failed because of positive result of RQ-PCR tested in the central laboratory (N= 15, 69%), failure to meet inclusion criteria (N=4, 18%) and informed consents withdrawal (N=3, 13%).As of data cut-off date of 10 July 2013, a total of 78 patients (42 females, 36 males) who were diagnosed between 26 Feb 1998 and 11 Dec 2009 were enrolled on KIDS, with a median age of 45 years (range, 19 – 82), the percentages of patients with low, intermediate and high Sokal risk scores were 37%, 29% and 13%, respectively with unknown Sokal risk scores in 18%. And the median time on IM therapy and the median duration of sustained UMRD were 85 months (range, 38 – 141) and 44 months (range, 23 – 114), respectively, prior to discontinuation. With a median follow-up of 14 months (range, 0.3 – 33.5), the 12-month probability of sustained MMR and UMRD were 78.5% ± 5.3% and 78.5% ± 5.1%, respectively. All patients with MMR loss were in non-transplant group, whereas none of the 21 patients in the transplant group experienced MMR loss. The probability of sustained MMR and UMRD in non-transplant group were 67.3% ± 7.7% and 68.5% ± 7.0%, respectively. Nine of 13 patients who lost MMR were resumed IM with a median time of 15 months (range, 0.1 - 22.3 months). All 9 patients, who resumed IM, re-achieved MMR at a median of 3 months (range, 1.4 - 4.7 months) after resuming IM therapy and re-achieved UMRD at a median of 7.5 months (range, 3.3 - 13.3 months). Univariate analysis of factors affecting loss of MMR showed that IM therapy duration and UMRD duration before treatment discontinuation had a higher 12-month probability of sustained MMR.Our updated data shows lower relapse rate after discontinuation compared to previous discontinuation studies. In particular, the rate of screening failure due to positive result of RQ-PCR tested in the central laboratory implied that strict PCR sensitivity criteria is important for safer, successful IM discontinuation.No relevant conflicts of interest to declare.

Off Label Use: Nilotinib for Ph+ALL-sientific and academic purpose.

We previously reported the interim analysis on the clinical outcome of nilotinib (Tasigna®, Novartis Pharma, Basel, Switzerland), when combined with multi-agent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) in adults. Herein, we reported the final results of the multicenter prospective phase2 trial of Adult Acute Lymphoblastic Leukemia Working Party, the Korean Society of Hematology. Newly diagnosed Ph+ALL patients aged 18 years old or more were eligible when they had adequate organ function. Diagnosis of Ph+ALL was performed via confirmation of the presence of Ph chromosome by conventional GTL-band technique, and/or positive molecular analysis with nested RT PCR for detection of BCR-ABL fusion transcripts. Written informed consent was obtained from all subjects. All patients received induction treatment consisting of vincristine, daunorubicin, oral or parenteral prednisolone, and nilotinib. After achieving complete remission (CR), subjects received either 5 courses of consolidation followed by 2-year maintenance with nilotinib, or allogeneic hematopoietic cell transplantation (alloHCT) depending on the donor availability, his/her tolerability, and patient's wish. Nilotinib was administered twice a day with a single dose of 400mg (800mg per day) from day8 of induction until the initiation of conditioning for alloHCT or the end of maintenance therapy. Minimal residual disease (MRD) monitoring was performed at the central lab with quantitative RT-PCR assays for peripheral blood BCR-ABL RNA using LightCycler® Technology in serial; at the time of diagnosis, at hematologic CR(HCR), and every 3 months thereafter. BCR-ABL quantification was expressed relative to the amount of glucose-6-phosphate dehydrogenase (G6PDH) mRNA. The molecular response was defined as complete (MCR, MRD-negative) if the BCR-ABL/G6PDH ratio was less than 1x10-6. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). Subjects had been followed up for 2 years after alloHCT or during maintenance therapy. Data were frozen up in June, 2013. A total of 91 subjects (male: female = 45: 46) were enrolled onto the study between January 2009 and May 2012. The median age was 47 (range 18-71) years old. Type of BCR breakpoint was minor (e1a2) in 71% of patients. The median BCR-ABL/G6PDH ratio was 6.09 (bone marrow) and 3.28 (peripheral blood) at diagnosis. During induction, all subjects required blood product transfusion, and incidence of nonhematologic adverse events (AE) over grade 3 was 17% (jaundice), 18% (ALT elevation), 13% (lipase elevation), and 2% (pancreatitis). Neither QTc prolongation over 500ms nor significant arrhythmia happened among any subject and any cycle. HCR rate was 90% and median time to HCR was 27 days (range, 13-72); most of failure was due to death in aplasia (n=8). MCR rate at HCR was 55%, Cumulative MCR rate was 84%, and median time to MCR was 1.1 months (range, 0.6-15.8). Most common cause of dropout from study was treatment-related death (n=22; during induction/consolidation vs. after alloHCT = 12 vs. 10), and HREL (n=15). Nilotinib was interrupted 75 times among 64 subjects, reduced 14 times among 12 subjects, and discontinued permanently due to hematologic relapse (HREL, n=14), AE (n=6, over gr3:3), and other cause (n=2). Fifty nine patients underwent alloHCT, 34 with myeloablative and 25 with reduced-intensity conditioning. Incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were 41% and 29%, respectively. With a median follow-up of 20.7 months of surviving subjects, estimated hematologic relapse-free survival (RFS), and overall survival (OS) rate at 2 years were 74% and 70%, respectively. Among subject achieving MCR, 2-year molecular RFS rate was 56%. When events were defined as ‘dropout due to AE, isolated molecular / extramedullary relapse, HREL, and death from any cause', median event-free survival was 12.5 months. In this prospective study, nilotinib was shown to be effective for adult Ph+ALL, and concurrent administration of nilotinib with cytotoxic drug was well-tolerable, although death in aplasia during induction was the most common cause of failure of achieving HCR. In terms of MRD, potential of nilotinib to achieve and maintain MRD negativity were satisfactory (Clinicaltrials.govNCT00844298).

For patients with aggressive lymphoma in complete remission (CR) after primary therapy, efficient detection of relapse with maintenance of performance status is important because there is the second chance for cure by salvage therapy. Contrary to initial staging workup, treatment, and its response evaluation, there is ambiguity in the field of surveillance of patients with lymphoma in CR: intervals of outpatient department (OPD) follow-up, lists of required laboratory tests, and especially routing imaging by computed tomography (CT) scan or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), have not been firmly standardized according to experts and guidelines. Despite a lack of evidence, routine imaging (RI) with CT or FDG-PET/CT has been widely adopted. The aim of the current study was to analyze the patterns and outcomes of OPD surveillance and to evaluate the role of RI and unplanned early OPD visits in patients with diffuse large B-cell lymphoma (DLBCL) in remission.Patients 1) diagnosed as DLBCL according to 2008 WHO criteria, 2) age °Ã 20 years, 3) achieved CR according to 2007 Revised Criteria after receiving R-CHOP immunochemotherapy with or without following radiotherapy or high dose therapy, and 4) had °Ã 1 OPD visit for the surveillance of relapse, were included. The institutional policy of OPD visits in patients with DLBCL in CR was as follows: OPD visit every 2 to 3 months for the first 2 years, then every 4 to 6 months for the next 3 years, and annually thereafter. History taking, physical examination, and checking complete blood cell count were performed routinely during each visit. Every single OPD visit was reviewed and classified with regard to whether or not it was planned. If an OPD visit was scheduled during the last OPD visit for purpose of surveillance of asymptomatic patients, the visit was classified as a 'planned OPD visit'. An 'unplanned early visit' was defined as any OPD visit earlier than the appointed next visit decided by the patient because of any abnormal symptom or sign. RI was defined as a CT or FDG-PET/CT scheduled by a physician at least 2 months prior to actual scanning for routine surveillance of lymphoma, i.e., without any symptom or sign of relapse. There was no specific institutional policy of RI, and three physicians (Hong J, Park J, and Lee JH) decided whether or not to perform RI during the next visit with consideration of the patient's opinion.One hundred and six patients diagnosed between May 2004 and February 2012, satisfied the inclusion criteria. During a median follow-up duration of 38.1 months, 15 patients (14.2%) experienced disease relapse. A total of 856 OPD visits (median 6, range 1-25) were analyzed from the 106 patients; 501 visits were planned OPD visits with RI, 322 visits were planned visits without RI, and 33 visits (33/856 = 3.9%) were unplanned early visits (Fig. 1). RI showed a perfect sensitivity and negative predictive value but low positive predictive value due to frequent false-positive results (Fig. 2). Six of seven patients who underwent routine CT scan and 17 of 21 patients who underwent a surveillance FDG-PET/CT received unnecessary further evaluations, even including biopsy with general anesthesia. Compared to enhanced CT scan, FDG-PET/CT showed a higher rate of false positive results [7/407 (13.7%) for CT vs. 23/165 (13.7%) for FDG-PET/CT]. Unplanned early visits of patients showed a strong association with disease relapse compared to planned OPD visits; one third of the unplanned early visits were due to disease relapse (Fig 3). Due to the small number of patients, it was impossible to determine whether RI can prolong the survival of relapsed patients with DLBCL, although there appeared to be no significant difference between the groups.Considering limited diagnostic values in addition to the risk of radiation exposure, financial cost, and anxiety of the patients, RI appears not to be an ideal strategy for surveillance in patients with DLBCL who achieved a CR in the rituximab era. Clinical symptom or sign-directed surveillance can be more useful in detecting relapse compared to RI, at least in patients with DLBCL in remission. It should be emphasized that patients should be encouraged to visit the hospital earlier if they experience any discomfort.Off Label Use: lenalidomide in newly diagnosed myeloma.

No relevant conflicts of interest to declare.

The hypomethylating agents (HMAs) 5-azacitidine (AZA) and decitabine (DAC) provided significant overall response rates (40–60%) in myelodysplastic syndrome (MDS), and improved the outcome of higher risk MDS. However, phase III trials comparing AZA or DAC to conventional treatment including best supportive care have shown discrepant results. The aim of this study is to compare the efficacy and safety between AZA and DAC in patients with MDS.We evaluated 203 patients in lower risk with significant cytopenia and higher risk MDS who received AZA and 97 patients who received DAC in Korea between January 2004 and December 2011. AZA 75mg/m2/day was given subcutaneously for 7 days every 4 weeks. DAC 20mg/m2/day was given intravenously over one hour for 5 days every 4 weeks. We compared overall response rate (complete responses, partial responses, marrow complete responses, and hematologic improvements), overall survival (OS) and adverse outcomes with the use of propensity-score matching in the overall cohort according to HMAs.Among 300 patients, propensity matching for the entire cohort created 97 matched pairs of patients. The International Prognostic Scoring System risk category was Intermediate-2/High in 40.2%. A median of 5 courses (range 1–24) were delivered in AZA and 5 courses (range 1–14) in DAC. In the overall matched cohort, there was no significant difference between AZA and DAC in overall response rate (44.2% vs. 52.1%, P=.28), OS (28 vs. 23 months; hazard ratio for AZA, 1.14; 95% confidence interval [CI], 0.75 to 1.72, P=.54) with a median follow-up duration of 29.6 months. Among the patient under 65, no significant differences were noted for OS between AZA and DAC group. Among the patient over 65, however, the patients who received DAC showed higher risk of death than those who received AZA with borderline significance (hazard ratio for AZA, 1.58; 95% CI 0.91 to 2.73, P=.10). The cumulative hazard of transformation to acute myeloid leukemia (AML) was 16.3% in AZA and 21.9% in DAC at one year, and 32.2% in AZA and 55.3% in DAC at two year. The incidence of grade 3 & 4 neutropenia was significantly higher in DAC than AZA (P=.026). Among 1151 assessable treatment courses (604 in AZA, 547 in DAC), AZA group have less likely to experience fever episodes requiring intravenous antibiotics than DAC group (8.6 vs. 15.7 episodes per 100 courses; risk ratio, 0.55; P<.001).In a cohort of patients in lower risk with significant cytopenia and higher risk MDS, AZA and DAC showed comparable efficacy in terms of overall response rate, OS and risk of transformation to AML. However, patients receiving DAC experienced more frequent grade 3 & 4 neutropenia and fever episodes than patient receiving AZA. When both AZA and DAC are available, safety profiles as well as treatment efficacy need to be considered.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.