June Won Cheong

Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by co-infusion of T cell-depleted haematopoietic stem cells and culture-expanded marrow mesenchymal stem cells from a related donor with one fully mismatched human leucocyte antigen haplotype

Summary.  A 20‐year‐old woman with high‐risk acute myelogenous leukaemia was transplanted with granulocyte colony stimulating factor (G‐CSF)‐mobilized peripheral blood CD34+ haematopoietic stem cells and bone‐marrow‐derived mesenchymal stem cells (MSC) from her human leucocyte antigen haplotype‐mismatched father after myeloablative conditioning therapy. The patient engrafted rapidly and had no acute or chronic graft‐versus‐host disease. Since transplantation, the patient has shown an enduring trilineage haematological complete response without any evidence of leukaemia relapse at 31 months. We suggest that MSC can be used effectively for genetically haploidentical haematopoietic stem cell transplantation for acute leukaemia.

Cytoplasmic Mislocalization of p27Kip1 Protein Is Associated with Constitutive Phosphorylation of Akt or Protein Kinase B and Poor Prognosis in Acute Myelogenous Leukemia

Cyclin-dependent kinase inhibitor p27Kip1 functions at the nuclear level by binding to cyclin E/cyclin-dependent kinase-2. It was shown that Akt or protein kinase B (Akt/PKB)-dependent phosphorylation of p27Kip1 led to the cytoplasmic mislocalization of p27Kip1, suggesting the potential abrogation of its activity. Here, we evaluated the localization of p27Kip1 protein in leukemic blasts in relation to Akt/PKB phosphorylation and clinical outcomes in acute myelogenous leukemia (AML). Western blot analysis of the nuclear and cytoplasmic fractions revealed a heterogenous localization pattern of p27Kip1 in AML. Cytoplasmic mislocalization of p27Kip1 was significantly associated with the constitutive serine473 Akt/PKB phosphorylation in AML cells (P < 0.05). Transfection of U937 cells with an expression construct encoding the constitutively active form of Akt/PKB resulted in a remarkable increase in the levels of cytoplasmic p27Kip1. Whereas the transfection of U937 cells with a construct encoding dominant-negative Akt/PKB resulted in a recovery of nuclear localization of p27Kip1. Both the disease-free survival and overall survival are significantly shorter in AML cases with high cytoplasmic to nuclear ratio of p27Kip1 localization compared with the cases with low cytoplasmic to nuclear ratio (P = 0.0353, P = 0.0023, respectively). Multivariate analysis indicated that the cytoplasmic to nuclear ratio of p27Kip1 localization was an independent prognostic variable for both disease-free survival and overall survival (P = 0.043, P = 0.008, respectively). These findings additionally extend our understanding of the role of p27Kip1 in AML, and buttress the case of p27Kip1 mislocalization as a prognostic indicator and Akt/PKB/p27Kip1 pathway as a ready target for antileukemia therapy.

Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome

Summary. Phosphorylation of PTEN (phosphatase and tensin homologue) affects PTEN protein stability and function. In this study, phosphorylated PTEN (pPTEN) was observed in 45 (73·8%) of 61 cases with acute myeloid leukaemia (AML). Phosphorylation of Akt and its downstream molecules [FKHR; Forkhead (Drosophila) homologue 1; and GSK‐3β; glycogen synthase kinase 3 beta] was significantly associated with pPTEN (P < 0·001). The complete remission rates were not different with respect to pPTEN, but overall survival was significantly shorter in patients with pPTEN (P < 0·05). Constitutive PTEN phosphorylation may add insight into the molecular pathogenesis of AML, and may be a new parameter for an unfavourable outcome.

Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes

The present study aimed to directly compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS). We compared the overall response rate (ORR) (complete responses, partial responses, marrow complete responses, and haematological improvements), overall survival (OS), event‐free survival (EFS), time to leukaemic transformation, and adverse outcomes between azacitidine and decitabine. To minimize the effects of treatment selection bias in this observational study, adjustments were made using the propensity‐score matching method. Among 300 patients, 203 were treated with azacitidine and 97 with decitabine. Propensity‐score matching yielded 97 patient pairs. In the propensity‐matched cohort, there were no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 22·9 months), EFS (7·7 vs. 7·0 months), and rate of leukaemic transformation (16% vs. 22% at 1 year). In patients ≥65 years of age, survival was significantly better in the azacitidine group (P = 0·017). Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes. We found that azacitidine and decitabine showed comparable efficacy. Among patients ≥65 years of age, survival was significantly better in the azacitidine group (ClinicalTrials.gov Identifier: NCT01409070).

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients

BACKGROUND This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Complete Remission Status before Autologous Stem Cell Transplantation Is an Important Prognostic Factor in Patients with Multiple Myeloma Undergoing Upfront Single Autologous Transplantation

Upfront high-dose myeloablative chemotherapy followed by a single autologous stem cell transplantation (ASCT) is the standard therapy for patients under the age of 65 years with newly diagnosed multiple myeloma (MM). Because disease status after induction chemotherapy is variable, we evaluated the prognostic effect of disease status before ASCT, especially in patients who were initially chemosensitive. We retrospectively analyzed the initially chemosensitive MM patients (> or = partial remission [PR]) enrolled in the Korean Multiple Myeloma Working Party Web-based registration system (www.myeloma.or.kr). Between November 1996 and January 2007, 197 MM patients (median age 53 years) were treated with induction chemotherapy followed by a single ASCT. All patients received peripheral blood stem cell (PBSC) support after conditioning with melphalan (Mel) alone. We considered those patients with no detectable M-protein regardless of the result of immunofixation to be in complete remission (CR) in this study. The median follow-up times were 29.2 months (range, 5.4 to 103.8 months) from the day of diagnosis and 22.4 months (range, 0.4 to 96.0 months) from the day of ASCT. Before ASCT, 63 patients (32%) were in CR and 134 (68%) were in partial remission (PR). The patients in CR had significantly longer overall survival (OS) from the day of ASCT compared with those in PR (P = .0015). Among the patients who received induction chemotherapy with vincristine, adriamycin, and dexamethasone (n = 162), the same difference in OS was seen between those in CR and those in PR before ASCT (P = .0016). CR after ASCT also predicted longer OS (P = .0135); however, patients with continued CR after ASCT had significantly higher OS after ASCT compared with patient with induced CR after ASCT who were in PR before ASCT (P = .0178). Multivariate analysis indicated that remission status pre-ASCT (CR vs PR) is a significant prognostic factor for predicting OS after ASCT (P = .012, Cox proportional hazard analysis; odds ratio = 2.83; 95% confidence interval = 1.25 to 6.37). We conclude that patients with MM who are in CR before ASCT have a better OS than those in PR before ASCT. Continued CR after ASCT may be an important prognostic factor as well. Our findings suggest that the development of more effective induction regimens, including novel antimyeloma agents to improve initial response, should be pursued to enhance clinical benefits post-ASCT.

Apicidin potentiates the imatinib-induced apoptosis of Bcr–Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades

Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide with potent antiproliferative activity against various cancer cells. We examined whether apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive human leukaemia cells. In K562 cells, the co‐administration of minimally toxic concentrations of imatinib and apicidin (imatinib/apicidin) for 48 h produced a marked increase in mitochondrial damage, processing of caspase cascades and apoptosis. Similar results were observed in leukaemic blasts obtained from patients with chronic myeloid leukaemia in blast crisis. Imatinib/apicidin co‐treatment for 48 h resulted in a near complete loss of the full‐length XIAP (X‐linked inhibitor of apoptosis) protein, with a corresponding increase in the 29‐kDa XIAP cleavage product. Both the degradation of XIAP and increased release of second mitochondria‐derived activator of caspase/direct IAP‐binding protein with low pI (Smac/DIABLO) into the cytosol were abrogated by pretreatment with the caspase‐3 inhibitor DEVD‐CHO. Imatinib/apicidin co‐treatment for 48 h produced a prominent decrease in Bcr–Abl protein levels in a caspase‐dependent manner. In summary, these data indicate that apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive leukaemia cells through the enhanced activation of the mitochondria‐dependent caspase cascades, accompanied by caspase‐dependent downregulation of Bcr–Abl and XIAP. These findings generate a rationale for further investigation of apicidin and imatinib as a potential therapeutic strategy in Bcr–Abl‐positive leukaemias.

Prognostic implications of the immunophenotype in biphenotypic acute leukemia

The present study retrospectively analyzed clinicopathological and clinical data from 43 adult patients with biphenotypic acute leukemia (BAL) from 11 Korean institutes. The incidence of BAL was 2.1% among acute leukemias. In terms of immunophenotype, 31 patients had myeloid plus B-lymphoid (M + B), 10 had myeloid plus T-lymphoid (M + T), one had myeloid plus B-lymphoid plus T-lymphoid (M + B + T), and one had B-lymphoid plus T-lymphoid (B + T). Patients with M + T phenotype had significantly lower CR rate (55.6% vs. 88.0%, P = 0.039) and lower overall survival (0% vs. 33.9% at 5 years, P = 0.028) than those with M + B phenotype. Our results suggest that immunophenotype has prognostic implications in adult patients with BAL.

Lymphopenia is an important prognostic factor in peripheral T-cell lymphoma (NOS) treated with anthracycline-containing chemotherapy

BackgroundPeripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with poor treatment outcomes. The aim of this study was to evaluate whether lymphopenia at diagnosis would have an adverse effect on survival in patients with PTCL-NOS treated with anthracycline-containing chemotherapy.MethodsA total of 118 patients with PTCL-NOS treated with anthracycline-containing chemotherapy from 4 Korean institutions were included.ResultsThirty-six patients (30.5%) had a low absolute lymphocyte count (ALC, < 1.0 × 109/L) at diagnosis. Patients with lymphopenia had shorter overall survival (OS) and progression-free survival (PFS) rates compared with patients with high ALCs (P = 0.003, P = 0.012, respectively). In multivariate analysis, high-intermediate/high-risk International Prognostic Index (IPI) scores and lymphopenia were both associated with shorter OS and PFS. Treatment-related mortality was 25.0% in the low ALC group and 4.8% in the high ALC group (P = 0.003). In patients considered high-intermediate/high-risk based on IPI scores, lymphopenia was also associated with shorter OS and PFS (P = 0.002, P = 0.001, respectively).ConclusionThis study suggests that lymphopenia could be an independent prognostic marker to predict unfavorable OS and PFS in patients with PTCL-NOS treated with anthracycline-containing chemotherapy and can be used to further stratify high-risk patients using IPI scores.

Constitutive phosphorylation of FKHR transcription factor as a prognostic variable in acute myeloid leukemia

The transcription factor FKHR, which is controlled by Akt-PKB signaling, is involved in regulating cell cycle progression and cell death. In this study, the phosphorylation of FKHR was observed in 45 (73.8%) of 61 patients with acute myeloid leukemia (AML). The phosphorylation of Akt-PKB was found to be significantly associated with phospho-FKHR (P<0.001). Patients with phospho-FKHR had a significantly shorter overall survival than those without (P<0.05). In conclusion, the constitutive phosphorylation of FKHR was observed in the majority of AML, and the detection of phospho-FKHR might provide a new tool for identifying AML patients with an unfavorable outcome.