Hawk Kim

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)

Comparison between Matched Related and Alternative Donors of Allogeneic Hematopoietic Stem Cells Transplanted into Adult Patients with Acquired Aplastic Anemia: Multivariate and Propensity Score-Matched Analysis

We retrospectively compared the outcomes of 225 patients with adult acquired aplastic anemia (AA) who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) from matched related donors (MRDs), and those treated by alloHSCT from alternative donors (ADs). Univariate and multivariate analyses of factors associated with survival were performed. Multivariate analysis showed that age at alloHSCT of ≤ 31 years, MRD, successful engraftment, absence of acute graft-versus-host disease (aGVHD), and platelet engraftment at ≤ 21 days, were independent predictors of longer survival. In addition, time to aGVHD and cumulative nonrelapse mortality (NRM) were better in MRD than in AD recipients. Using propensity score matching (PSM), we performed a case-control study comparing 25 patients in each group who underwent alloHSCT from MRDs and ADs. Pretransplantation clinical factors were well balanced in either group. Median survival time was similar, and no statistically significant difference in transplantation outcomes was apparent when MRD and AD recipients were compared. In conclusion, our results suggest that alloHSCT from an AD should be considered earlier in adult patients with AA who do not have an MRD.

Allogeneic Hematopoietic Stem Cell Transplant for Adults over 40 Years Old with Acquired Aplastic Anemia

Although younger age is associated with favorable prognosis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aplastic anemia (AA), other pretransplantation factors may be more important than age. We retrospectively analyzed the impact of older age on transplantation outcomes and survival in a total of 225 adult patients with AA who underwent allo-HSCT: 57 patients >40 years old (older patient group [OPG]) and 168 patients ≤40 years old (younger patient group [YPG]). Age at allo-HSCT ≤40 years, time from diagnosis to allo-HSCT ≤6 months, and matched related donor (MRD) were favorable prognostic factors in all study patients. Risk analysis of survival in the OPG showed that age >50 years was the only poor prognostic factor. Survival did not differ significantly between the YPG and patients <50 years old in the OPG. In conclusion, patients between the ages of 41 and 50 years with severe AA and MRDs should undergo allo-HSCT as early as possible to optimize survival.

Incidences and Prognostic Impact of c-KIT, WT1, CEBPA, and CBL Mutations, and Mutations Associated With Epigenetic Modification in Core Binding Factor Acute Myeloid Leukemia: A Multicenter Study in a Korean Population

Background To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. Methods Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. Results The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (≤5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number of t(8;21) patients were analyzed, WT1 mutation status did not affect prognosis significantly. Relapse or death during follow-up occurred more frequently in t(8;21) patients carrying c-KIT mutations than in those without the mutation, although the difference was significant only in a specific patient subgroup with no WT1 mutations (P=0.014). Conclusions The incidences of mutations in epigenetic genes are very low in CBF AML; however, c-KIT and WT1 mutations occur more frequently than others. The poor prognostic impact of c-KIT mutation in t(8;21) AML patients only applies in a specific patient subgroup without WT1 mutations. The prognostic impact of WT1 mutation in CBF AML is not evident and further investigation is required.

A Phase II Study of Ifosfamide, Methotrexate, Etoposide, and Prednisolone for Previously Untreated Stage I/II Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Multicenter Trial of the Korean Cancer Study Group

BACKGROUND Combination chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) was active as first-line and second-line treatment for extranodal natural killer/T-cell lymphoma (NTCL). METHODS Forty-four patients with chemo-naïve stage I/II NTCL were enrolled in a prospective, multicenter, phase II study and received six cycles of IMEP (ifosfamide 1.5 g/m(2) on days 1-3; methotrextate 30 mg/m(2) on days 3 and 10; etoposide 100 mg/m(2) on days 1-3; and prednisolone 60 mg/m(2) per day on days 1-5) followed by involved field radiotherapy (IFRT). RESULTS Overall response rates were 73% (complete remission [CR] in 11 of 41 evaluable patients [27%]) after IMEP chemotherapy and 78% (CR 18 of 27 evaluable patients [67%]) after IMEP followed by IFRT. Neutropenia and thrombocytopenia were documented in 33 patients (75%) and 7 patients (16%), respectively. Only 8 patients (18%) experienced febrile neutropenia. Three-year progression-free survival (PFS) and overall survival (OS) were 66% and 56%, respectively. High Ki-67 (≥70%) and Ann Arbor stage II independently reduced PFS (p = .004) and OS (p = .001), respectively. CONCLUSION Due to the high rate of progression during IMEP chemotherapy, IFRT needs to be introduced earlier. Moreover, active chemotherapy including an l-asparaginase-based regimen should be use to reduce systemic treatment failure in stage I/II NTCL.

Efficacy and safety of deferasirox estimated by serum ferritin and labile plasma iron levels in patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia with transfusional iron overload

Patients receiving red blood cell (RBC) transfusions are at risk of iron overload, which can cause significant organ damage and is an important cause of morbidity and mortality.

Prospective, multicenter, phase II study on reducing the dosage of idarubicin and FLAG for patients younger than 65 years with resistant acute myeloid leukemia: a comparison with a higher dosage trial.

We previously assessed continuous infusion (CI) of fludarabine and cytarabine plus idarubicin (CI-FLAG1) for patients under 65 years of age with resistant acute myeloid leukemia. Induction chemotherapy consisted of idarubicin (IDA) plus fludarabine and cytarabine (ARAC) as a 24-hour CI. In response to induction, 31.6% of patients achieved complete remission (CR) and in 68.4% the treatment failed. We concluded that CI-FLAG1 carried a high risk of toxicity and reduced CI-FLAG doses were recommended. Therefore, we revised the protocol (CI-FLAG2) by reducing the dose of IDA and ARAC. In total, 38 and 68 patients were enrolled into CI-FLAG1 and CI-FLAG2, respectively. When comparing outcomes between CI-FLAG1 and CI-FLAG2, there were no differences in terms of the CR rate (p = 0.306) and the overall response rate (ORR; p = 0.206). The treatment failure patterns were different between CI-FLAG1 and CI-FLAG2. The median overall survival showed only a trend towards longer survival in CI-FLAG2 (p = 0.074). Among intermediate-risk patients, there were high response rates favoring CI-FLAG2 in terms of the CR rate (p = 0.108), the ORR (p = 0.031), and overall survival (p = 0.033). This represented a relatively improved response rate compared to our previous study. There was decreased aplasia with dose reductions at the expense of increased resistance. A reduced dose of CI-FLAG might be most beneficial for intermediate-risk groups.

Track following controller for optical disk drives based on adaptive output regulation

Abstract This paper presents an adaptive output regulator. It is an add-on type output regulator with frequency adaptation algorithm. A frequency adaptation algorithm based on internal model principle is used to identify frequency of sinusoidal disturbance. It is shown that the proposed method is stable for frequency within a connected compact set. Its stability is proven under the assumption that the frequency of disturbance varies slowly in time. The performance of the proposed method is verified with simulation and experiment results. There is a good agreement between simulation and experiment results.

Comparable Allogeneic Hematopoietic Cell Transplantation Outcome of a Haplo-Identical Family Donor with an Alternative Donor in Adult Aplastic Anemia.

We performed a study on allogeneic hematopoietic cell transplantation (alloHCT) from an HLA-haplo-identical familial donor (haploFD) using a busulfan-fludarabine-antithymocyte globulin conditioning regimen for severe aplastic anemia (sAA) and hypoplastic myelodysplastic syndrome. For the comparison between a haploFD and an alternative donor (AD; matched unrelated or partially matched donor) for sAA in adults, we collected haploFD data retrospectively and prospectively. Forty-eight AD cases were selected for the comparison with 16 haploFD cases. All transplantation outcomes except for extensive chronic graft versus host disease (GvHD) were similar. The frequencies of hepatic sinusoidal obstruction syndrome (p = 1.000), acute GvHD (p = 0.769), grade 3/4 acute GvHD (p = 0.258), chronic GvHD (p = 0.173), extensive chronic GvHD (p = 0.099), primary neutrophil engraftment failure (p = 1.000), secondary graft failure (p = 1.000) and platelet engraftment failure (p = 0.505) were similar. Time to neutrophil engraftment was faster in haploFD (p = 0.003), while the cumulative incidence of platelet engraftment was similar (p = 0.505). Overall survival was also similar between AD and haploFD (p = 0.730). In conclusion, alloHCT from haploFD in sAA was comparable with alloHCT from AD, but extensive chronic GvHD seemed frequent in haploFD. Therefore alloHCT from haploFD could be an alternative approach for alloHCT from AD in adult sAA.

A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome‐positive chronic myeloid leukemia in chronic phase: ENESTKorea

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 MR4.5 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 MR4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR4, and MR4.5 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.