Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE).

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.

Prognostic significance of focal lesions and diffuse infiltration on MRI for multiple myeloma: a meta-analysis.

OBJECTIVES: MRI of bone marrow of the axial skeleton is recommended for evaluation of multiple myeloma. The impact of bone marrow involvement pattern on MRI for determining progression-free survival (PFS) and overall survival (OS) is not yet clear. METHODS: We performed a meta-analysis of research on the prognostic significance of MRI patterns for OS and PFS using a random effects model. Databases searched without language restriction were MEDLINE, EMBASE, and the Cochrane Library (January 1976 to April 2014). Manual searches were also conducted. RESULTS: Of 10,953 citations identified in the original search, 10 cohort studies for a total of 2015 patients met the inclusion criteria. Nine of the 10 included studies are from three research groups. Pooled hazard ratios were 1.80 (95 % confidence interval [CI] 1.32-2.46; P < 0.001) for OS and 2.30 (95 % CI 1.65-3.20; P < 0.001) for PFS for focal lesions on MRI; and 1.70 (95 % CI 1.30-2.21; P < 0.001) for OS and 1.74 (95 % CI 1.07-2.85; P = 0.03) for PFS for diffuse infiltration on MRI. No significant heterogeneity was observed among studies. CONCLUSIONS: This meta-analysis demonstrated an association between focal lesions and diffuse infiltration and poor prognosis in this population. KEY POINTS: • MRI findings of multiple myeloma include normal, focal, variegated and diffuse infiltration • Focal lesions and diffuse infiltration on MRI were poor prognostic factors • Bone marrow involvement pattern on MRI can help physicians assess prognosis.

Prognostic value of the inverse platelet to lymphocyte ratio (iPLR) in patients with multiple myeloma who were treated up front with a novel agent-containing regimen.

Recently, reactive thrombosis or platelet to lymphocyte ratio has been reported as a strong predictor of poor prognosis in various types of cancer. However, a study investigating the relationship between platelet counts and thrombopoietic cytokines suggested that low platelet could be important in multiple myeloma (MM), which means platelet count decreased in advanced International Staging System (ISS) stage. Therefore, we developed inverse platelet to lymphocyte ratio (iPLR) and assessed the prognostic value of iPLR in patients with MM. We retrospectively analyzed 283 patients who were treated up front with a novel agent-containing regimen. Patients were classified into three groups based on hazard ratio (HR) according to iPLR: low iPLR (group 1), middle iPLR (group 2), and high iPLR (group 3). Over a median follow-up of 34.8 months, staging by iPLR group had predictive value for progression-free survival (PFS) and overall survival (OS). In addition, staging by iPLR group was a reliable method to predict for survival in patients who presented with renal failure (eGFR<60 mL/min/1.73 m2) and in elderly patients. Multivariate analyses demonstrated that staging by iPLR group was associated with PFS and OS in patients with MM. In conclusion, this study suggested that iPLR is a simple and reliable inflammatory prognostic factor in the era of novel agents.

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors.

Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).

Effectiveness of pegfilgrastim prophylaxis in preventing febrile neutropenia during R-FC chemoimmunotherapy for chronic lymphocytic leukemia: A multicenter prospective phase II study.

Background: A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL. Patients and methods: A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort. Results: Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42-0.79, P = 0.032). Conclusion: Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.

Intensified First Cycle of Rituximab Plus Eight Cycles of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone with Rituximab Chemotherapy for Advanced-Stage or Bulky Diffuse Large B-Cell Lymphoma: A Multicenter Phase II Consortium for Improving Survival of Lymphoma (CISL) Study.

PURPOSE: This phase II, open-label, multicenter study aimed to investigate the efficacy and safety of a rituximab intensification for the 1st cycle with every 21-day of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP-21) among patients with previously untreated advanced-stage or bulky diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Ninety-two patients with stage III/IV or bulky DLBCL from 21 institutions were administered 8 cycles of R-CHOP-21 with an additional one dose of rituximab intensification on day 0 of the 1st cycle (RR-CHOP). The primary endpoint was a complete response (CR) rate after 3 cycles of chemotherapy. RESULTS: Among the 92 DLBCL patients assessed herein, the response rate after 3 cycles of chemotherapy was 88.0% (38.0% CR+50.0% partial response [PR]). After the completion of 8 cycles of chemotherapy, the overall response rate was observed for 68.4% (58.7% CR+9.8% PR). The 3-year progression-free survival rate was 64.0%, and the 3-year overall survival rate was 70.4%. Febrile neutropenia was one of the most frequent grade 3 adverse events (40.0%) and 5 treatment-related deaths occurred. Compared with the clinical outcomes of patients who received R-CHOP chemotherapy as a historical control, the interim CR rate was higher in male patients with RR-CHOP (20.5% vs. 48.8%, p=0.016). CONCLUSION: Rituximab intensification on days 0 to the 1st cycle of the standard 8 cycles R-CHOP-21 for advanced DLBCL yielded favorable response rates after the 3 cycles of chemotherapy and acceptable toxicities, especially for male patients. ClinicalTrials.gov ID: NCT01054781.

Radioimmunotherapy with 131 I-rituximab for patients with relapsed or refractory follicular or mantle cell lymphoma.

AIM: This study aimed to evaluate the safety and efficacy of 131 I-rituximab in patients with relapsed or refractory follicular or mantle cell lymphoma. METHODS: Twenty-four patients with relapsed or refractory follicular or mantle cell lymphoma were administered unlabeled rituximab (70 mg) immediately before receiving a therapeutic dose of 131 I-rituximab. Contrast-enhanced 18F-fluorodeoxyglucose positron emission tomography/computed tomography was used a month later to assess tumor response. RESULTS: This study enrolled 24 patients between June 2012 and 2022. Depending on how they responded to radioimmunotherapy (RIT), 131 I-rituximab was administered one to five times. Of the 24 patients, 9 achieved complete response after RIT and 8 achieved partial response. The median progression-free and overall survival was 5.9 and 37.9 months, respectively. During the follow-up period of 64.2 months, three patients were diagnosed with a secondary malignancy. Among treatment-related adverse events, hematologic toxicities were common, and grade 3-4 thrombocytopenia and neutropenia were reported in 66.6% of cases. CONCLUSION: 131 I-rituximab has an effective and favorable safety profile in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma. This suggests that RIT may also be considered a treatment option for patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma.

Anti-leukemic effect of 2-pyrone derivatives via MAPK and PI3 kinase pathways.

Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 × 10(-6) M to 5 × 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea.

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.

Salvage therapy with gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for B-cell non-Hodgkin's lymphoma: a consortium for improving survival of lymphoma (CISL) trial.

BACKGROUND: We investigated response rates to and toxicities of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Patients with recurrent or refractory diffuse large B-cell lymphoma or mantle cell lymphoma (DLBCL) were eligible for enrollment in this study. Treatment consisted of gemcitabine 1,000 mg/m(2) intravenously (i.v.) on Days 1 and 8, ifosfamide 2,000 mg/m(2) i.v. on Day 1, dexamethasone 40 mg orally on Days 1-4, and oxaliplatin 130 mg/m(2) i.v. on Day 2, every 21 days. The primary goal of treatment was to establish a response rate after three cycles. Afterwards, patients could proceed to high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) or receive up to six treatment cycles. RESULTS: Twenty-seven eligible patients were evaluated for toxicity and response. The median age of the patients was 54 years (range, 18-75 years), and most had DLBCL. After three cycles, there were four CR (15%) and 10 PR (37%) for an overall response rate (RR) of 52%. Among a total of 88 GIDOX cycles, grade 3 and 4 neutropenia occurred in 33% and 16% of the cycles, respectively. Likewise, grade 3 and 4 thrombocytopenia occurred in 14% and 16% of the cycles, respectively. Two patients (2%) experienced febrile neutropenia, while seven patients (26%) proceeded to HDC-ASCT. CONCLUSIONS: GIDOX is an active salvage regimen for aggressive B-cell NHL and can be tolerated by patients with acceptable toxicity.

Bortezomib, thalidomide, dexamethasone induction therapy followed by melphalan, prednisolone, thalidomide consolidation therapy as a first line of treatment for patients with multiple myeloma who are non-transplant candidates: results of the Korean Multiple Myeloma Working Party (KMMWP).

Bortezomib (VELCADE), thalidomide and dexamethasone (VTD), as well as melphalan, prednisolone, and thalidomide (MPT) therapy, are highly effective in patients with multiple myeloma. We evaluated the responses and survival times of 35 patients treated with VTD followed by MPT. All patients were newly diagnosed and non-transplantation candidates. Patients received six cycles of VTD, which were followed by eight cycles of MPT. Approximately 97% of patients exhibited early responses to therapy, as early as the second cycle of VTD. Thirty percent of the responses were high quality, which was defined as a complete response (CR), a near-CR or a very good partial response. High-risk patients were defined as patients with any of the following aberrations: del(13), t(4;14), or del(17p). The remaining patients were defined as standard risk. Eleven high-risk patients showed 100% response rates, including 91% high-quality responses. In contrast, 13 standard-risk patients exhibited 92% response rates, including 61% high-quality responses. The overall 2-year survival rates were 60% in high-risk patients and 85% in standard-risk patients, which was not significantly different. As a first-line therapy, VTD followed by MPT has the potential to provide high-quality responses with durable remission among elderly and high-risk patients (clinicaltrials.gov identifier: NCT00320476).

Clinical features and prognostic factors of patients with "peripheral T cell lymphoma, unspecified".

The purpose of this retrospective study was to investigate clinical features and treatment outcomes in patients with peripheral T cell lymphoma-unspecified (PTCL-U). Eighty-four patients who were diagnosed with PTCL-U between February 1995 and December 2005 were included in the study. Around 70% of the patients presented with stage III-IV disease; 24% were categorized as high or high-intermediate risk according to the International Prognostic Index (IPI) scoring system, and 45% were classified as groups 3 or 4 using the Prognostic Index for PTCL-U (PIT). Extranodal involvement was found in 51 of 85 patients (60%). Most of the initial chemotherapy regimens were anthracycline-based (75%). The overall response rates for patients treated with initial chemotherapy and salvage chemotherapy were 63.1% (52.6% of complete response (CR), 10.5% of partial response (PR)) and 35% (9% of CR, 26%of PR), respectively. The median progression-free survival and overall survival of all patients were 17.1 months (95% CI, 0.0-40.5) and 35.5 months (95% CI, 1.2-69.8), respectively. Poor performance status, the presence of B symptoms, IPI scores >or=3 and PIT class >or=2 were predictive prognostic factors for survival.

[The clinical usefulness of focally enhanced gastritis in Korean patients with Crohn's disease].

BACKGROUND/AIMS: Focally enhanced gastritis (FEG) has been suggested as a specific diagnostic marker for patients with Crohn's disease (CD). However, the usefulness of FEG for distinguishing CD from ulcerative colitis (UC) is uncertain and the incidence or prevalence of FEG for inflammatory bowel disease (IBD) patients in Korea has not been defined yet. In this study, we investigated the frequency of FEG and other gastric histological abnormalities in Korean patients with CD and UC. METHODS: We evaluated 37 patients with known CD, 43 patients with UC and 41 non-IBD control group; all underwent upper gastrointestinal endoscopy followed by biopsy from the antrum and the body. The pathology of the gastric biopsy specimens and the presence of Helicobacter pylori (H. pylori) were evaluated. FEG was characterized by a focal perifoveolar or periglandular inflammatory cell infiltrates. RESULTS: H. pylori positive gastritis was found in 10 of 37 (27.0%) of CD patients, in 16 of 43 (37.2%) of UC patients, and in 22 of 41 (53.7%) of non-IBD control group (p=0.054). In H. pylori-negative patients, FEG was found in 8 of 27 patients (29.6%) of CD patients, 6 of 27 (22.2%) patients with UC, and 2 of 9 (10.5%) of non-IBD control group (p=0.324). CONCLUSIONS: In H. pylori-negative patients, there was no statistically significant difference in the occurrence of FEG among CD, UC and control groups in Korea.

[Comparison of Helicobacter pylori eradication rate in patients with non-ulcer dyspepsia and peptic ulcer diseases according to proton pump inhibitors].

BACKGROUND/AIMS: Conflicting results have been reported whether patients with non-ulcer dyspepsia (NUD) respond differently to Helicobacter pylori (H. pylori) eradication treatment compared with patients with peptic ulcer diseases (PUD). The aim of this study was to evaluate any difference in H. pylori eradication rates between patients with NUD and PUD according to each proton pump inhibitor (PPI). METHODS: From September, 2004 to April, 2007, we retrospectively reviewed 2,297 patients with NUD (1,050 patients) or PUD (1,247 patients) infected with H. pylori. All patients received a standard 1 week triple therapy comprising of one of the five PPIs (pantoprazole, esomeprazole, omeprazole, lansoprazole, rabeprazole), clarithromycin and amoxicillin. The follow-up H. pylori test was performed 4 weeks after the completion of therapy. RESULTS: There was no significant difference in the eradication rates between the two groups. In comparison of eradication rates according to PPI, omeprazole- based triple therapy group showed higher eradication rate than other groups in patients with NUD, but not in patients with PUD. CONCLUSIONS: This study failed to show any difference in H. pylori eradication rate between patients with NUD and PUD. There is no convincing evidence that the eradication rate may be affected by different PPI.

[Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea].

BACKGROUND/AIMS: Antibiotic resistance and poor compliance are the main causes of Helicobacter pylori (H. pylori) eradication failure. Proton pump inhibitor (PPI)-based triple therapy is the most preferred regimen in clinical practice. However, a critical fall in the H. pylori eradication rate has been observed in the recent years. A novel 10 day-sequential therapy consists of five days of dual therapy followed by five days of triple therapy regimen has recently been described. We aimed to evaluate whether 10 day-sequential therapy eradicated H. pylori infection better than the PPI-based triple therapy in Korea. METHODS: 158 patients with proven H. pylori infection were randomized to receive either 10 day-sequential therapy (20 mg of omeprazole, 1.0 g of amoxicillin, each administered twice daily for the first 5 days, followed by 20 mg of omeprazole, 500 mg of clarithromycin, 500 mg of metronidazole, each administered twice daily for the remaining 5 days) or PPI-based triple therapy (20 mg of omeprazole, 1.0 g of amoxicillin, 500 mg of clarithromycin, each administered twice daily for 1 week). Outcome of eradication therapy was assessed 8 weeks after the cessation of treatment. RESULTS: Eradication rates of 10 day-sequential therapy and PPI-based triple therapy were 77.9% (60/77) and 71.6% (58/81) by intention to treat analysis, respectively (p=0.361). By per protocol analysis, eradication rates of 10 day-sequential therapy and triple therapy were 85.7% (60/70) and 76.6% (58/76), respectively (p=0.150). There were no significant differences in adverse event rates and treatment compliance between two groups. CONCLUSIONS: The 10 day-sequential therapy regimen failed to achieve significantly higher eradication rates than PPI-based triple therapy.

Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia.

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.

Comparative analyses of nilotinib versus high-dose imatinib versus sustained standard-dose imatinib in patients with chronic phase chronic myeloid leukemia following suboptimal molecular response to first-line imatinib.

The aim of this study was to investigate the efficacy of nilotinib (NIL) versus high-dose imatinib (IM) versus sustained standard-dose IM for patients with chronic myeloid leukemia (CML) with suboptimal molecular response to first-line IM therapy. Patients with CML who achieved complete cytogenetic response (CCyR) but not major molecular response (MMR) after 18-24 months on first-line IM therapy were enrolled and divided into three treatment cohorts: NIL 800 mg/day (Cohort 1, n = 28) and IM 800 mg/day (Cohort 2, n = 28) in the RE-NICE study, and sustained IM 400 mg/day (Cohort 3, n = 52) in clinical practice. The primary efficacy variable of cumulative rate of MMR by 12 months was not different among the three cohorts. However, the cumulative incidence of MMR by 36 months was significantly higher in Cohort 1 than Cohort 3 (83.1% vs. 57.1%, P = 0.021), but there were no significant differences in Cohort 1 vs. 2 (P = 0.195) and Cohort 2 vs. 3 (P = 0.297). Different profile for adverse events was observed between NIL and high-dose IM therapy. In conclusion, our data suggested that switching to NIL may provide more effective long-term response than sustaining standard-dose IM for patients with suboptimal molecular response to first-line IM.

Nongastric marginal zone B-cell lymphoma: a prognostic model from a retrospective multicenter study.

The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL. Two-hundred and five patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression-free survival (PFS), and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI. According to our multivariate analysis, nodal MZL, ECOG performance > or = 2, and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low-risk group, score 1 as an intermediate risk group, and score 2 as a high-risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P=0.0007) evidenced a more discriminated pattern than IPI (P=NS) or FLIPI (P=0.0044). MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.

Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas: a phase II study.

PURPOSE: The present study was conducted to evaluate the safety and efficacy of alemtuzumab plus CHOP chemotherapy for patients with peripheral T-cell lymphomas (PTCLs). PATIENTS AND METHODS: Twenty patients with newly diagnosed PTCLs were enrolled. The treatment consisted of classical CHOP plus alemtuzumab (10 mg i.v. on day 1 and 20 mg i.v. on day 2 in the first cycle, then 30 mg i.v. on day 1 in the subsequent cycles) based on 3-week intervals. RESULTS: Thirteen complete responses (65.0%) and three partial responses (15.0%) were confirmed, giving an overall response rate of 80.0%. The estimated event-free survival at 1 year was 43.3%. The most severe hematologic adverse event was neutropenia, which occurred with a grade-4 intensity in 18 patients (90.0%). Also, febrile neutropenia was observed in 11 patients (55.0%). Five patients (25%) experienced cytomegalovirus (CMV) reactivation, while three patients developed CMV diseases, such as pneumonitis or retinitis. There were two treatment-related deaths. Based on the high incidence of the adverse infectious and hematologic events, the current study was closed after 20 of the planned 43 patients had been enrolled. CONCLUSION: The alemtuzumab plus CHOP chemotherapy seemed to produce active antitumor activity in terms of the complete response rates in patients with PTCLs. However, since high infectious and hematologic toxicities were observed, careful monitoring and early treatment are needed to prevent treatment-related mortality.

The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test.

BACKGROUND & AIMS: Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis. METHODS: Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events. RESULTS: In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001). CONCLUSIONS: The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.