Seung-Shin Lee

OCT-1, ABCB1, and ABCG2 Expression in Imatinib-Resistant Chronic Myeloid Leukemia Treated with Dasatinib or Nilotinib.

This study explored drug transporter expression levels and their impact on clinical response to imatinib and second-generation tyrosine kinase inhibitors (TKIs) in imatinib- resistant chronic myeloid leukemia (CML). Imatinib-resistant chronic phase CML patients treated with dasatinib (n=10) and nilotinib (n=12) were enrolled. The mRNA expression of the OCT-1, ABCG2, and ABCB1 genes was quantified by using paired bone marrow samples obtained before administering imatinib and at the point of detecting imatinib resistance (just before starting second-generation TKIs). The expression levels of OCT-1 and ABCG2 were lower in follow-up than in imatinib-naïve samples. ABCB1 revealed highly variable expression levels before and after imatinib treatment. In addition, median ABCB1 expression in follow-up samples was lower in patients achieving complete cytogenetic response or major molecular response during imatinib treatment than in failed patients. Higher ABCG2 expression in imatinib-exposed samples showed a negative impact on optimal response to dasatinib. Patients with higher ABCG2 expression in imatinib-exposed samples also had shorter progression- free survival with dasatinib treatment. However, no significant correlation was found between these drug transporter expression levels in imatinib-naïve or imatinib- exposed samples and responses to nilotinib. In imatinib-resistant CML, OCT-1 and ABCG2 mRNA expression decreased after imatinib treatment. Patients with higher ABCG2 expression in imatinib-exposed samples showed poor treatment outcome with dasatinib. On the other hand, a higher expression level of ABCB1 in imatinib-exposed samples did not affect second-generation TKI responses but was correlated with poor imatinib responses.

The Impact of Hyperglycemia on Risk of Severe Infections during Early Period of Induction Therapy in Patients with Newly Diagnosed Multiple Myeloma

The association between hyperglycemia and infections during induction chemotherapy has been reported in a number of hematologic disorders. This retrospective study evaluated the incidence of hyperglycemia during induction therapy in 155 patients with newly diagnosed multiple myeloma (MM) and its effect on serious infections during the first 60 days of induction. A total of 20 (12.9%) patients developed overt hyperglycemia (≥200 mg/dL) during induction therapy. Serious infections occurred in 28 (18.1%) of 155 patients and infection-related mortality within 2 months after treatment was 0.6% (1 patient). In a univariate analysis, overt hyperglycemia, poor performance status (≥2), International Staging System III, lymphopenia (<500/μL), and elevated serum creatinine (≥2 mg/dL) were found to be associated with serious infections. In multivariate analysis, only overt hyperglycemia (HR 7.846, 95% CI 2.512–24.503, P < 0.001) and poor performance status (HR 5.801, 95% CI 1.974–17.050, P = 0.001) remained significant. In conclusion, this study demonstrated an association between hyperglycemia and serious infections during induction therapy in patients with MM.

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation

Background/Aims BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Methods Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Results Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Conclusions Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.

Application of bone marrow samples for discrimination of acute promyelocytic leukemia from other types of acute leukemia using the routine automated hematology analyzer

Unreported parameters produced by automated blood cell counter, particularly large unstained cells (LUC) and delta neutrophil index (DNI), indicated the presence of immature and possibly abnormal cell populations in white blood cell population. The purpose of this study was to investigate the laboratory performance for discrimination of acute promyelocytic leukemia (APL) cells from other types of leukemia cells and clinical value of LUC and DNI parameters in bone marrow (BM) samples of patients with acute leukemia.

Poor prognostic significance of Mycobacterium tuberculosis infection during bortezomib-containing chemotherapy in patients with multiple myeloma.

Background Bortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the hosts defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen. Methods We retrospectively investigated the incidence of Mycobacterium tuberculosis in 115 patients with MM who were given a bortezomib-containing regimen and studied the disease prognosis. Results All patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2-230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (P<0.05) and significantly shorter overall survival times amongst tuberculosis vs. non-tuberculosis patients (P=0.017). Conclusion Tuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.

Clinical Outcome of Bortezomib Retreatment in Patients with Relapsed or Refractory Multiple Myeloma

This retrospective study investigated the clinical efficacy and safety of bortezomib retreatment in patients with relapsed or refractory multiple myeloma (MM). A total of 30 patients who relapsed or progressed after ≥6 months since the last dose of their previous bortezomib therapy were included in this study. During the median 6 cycles (range: 2–12) of bortezomib retreatment, 10 (33.3%), 2 (6.7%), and 6 (20.0%) patients achieved complete response, very good partial response, and partial response, respectively. Grade 3 or 4 neutropenia (47.0%), thrombocytopenia (43.0%), anemia (10.0%), and peripheral sensory neuropathy (3.0%) were observed. The median time to progression, progression-free survival, and overall survival were 5.8 months (95% CI: 2.6–9.0), 5.5 months (95% CI: 4.2–6.8), and 13.4 months (95% CI: 6.1–20.7), respectively. Patients who received bortezomib retreatment ≥12 months from initial last therapy had a 1-year OS rate of 65.8% (95% CI: 43.5–88.1) while patients receiving retreatment after 6–12 months interval had a 1-year OS rate of 41.7% (95% CI: 13.9–69.5) (P = 0.038). In conclusion, this study demonstrates that retreatment with bortezomib is an effective strategy for patients with MM who relapsed at a long interval after initial bortezomib therapy.

STAT3 expression is associated with poor survival in non-elderly adult patients with newly diagnosed multiple myeloma

Background Signal transducer and activator of transcription 3 (STAT3) is not only a key signaling molecule in the regulation of growth but is also involved in malignant transformation. We investigated the prognostic significance of STAT3 expression in 94 non-elderly adult patients (aged 38 to 65 yr) with newly diagnosed multiple myeloma (MM). Methods Tumor cell-specific phosphotyrosine-STAT3 (PY-STAT3) expression at the time of diagnosis was evaluated with dual immunohistochemical (IHC) staining for PY-STAT3 and CD138. Results PY-STAT3 positivity was detected in 10 patients (10.6%), including three who showed strong expression. PY-STAT3-positive patients had higher serum C-reactive protein and calcium levels at diagnosis than did PY-STAT3-negative patients. PY-STAT3 positivity had predictive value for poor progression-free survival (PFS; P=0.001) and overall survival (OS; P=0.003). Among the 60 patients who received frontline autologous stem cell transplantation, PY-STAT3-positive patients had poorer PFS than did PY-STAT3-negative patients (4.2 vs. 19.2 mo, respectively; P=0.013). Multivariate analysis identified PY-STAT3 expression as an independent prognostic factor for PFS (relative risk [RR]=2.706, P=0.014) and OS (RR=3.091, P=0.044). Conclusion These data show that PY-STAT3 positivity, as determined using dual IHC, is a marker of poor prognosis in non-elderly adult patients with MM.

Assessment of a new genomic classification system in acute myeloid leukemia with a normal karyotype

This study was performed to assess if a recently recommended genomic classification is predictive in patients with normal-karyotype (NK) acute myeloid leukemia (AML). A total of 393 patients were included. Analysis of genetic mutations was performed using targeted resequencing with an Illumina Hiseq 2000. We identified driver mutations across 40 genes, with one or more driver mutations identified in 95.7% of patients. The molecular subclassification was as follows: 34.6% patients (n = 136) with AML with the NPM1 mutation, 10.7% (n = 42) with AML with mutated chromatin or RNA-splicing genes or both, 1.5% (n = 6) with AML with TP53 mutations, 13.5% (n = 53) with AML with biallelic CEBPA mutations, 2.0% (n = 8) with AML with IDH2-R172 mutations and no other class-defining lesion, 29.5% (n = 116) with AML with driver mutations but no detected class-defining lesion, 4.3% (n = 17) with AML with no detected driver mutation, and 3.8% (n = 15) patients with AML who met the criteria for ≥2 genomic subgroups. The 5-year overall survival and relapse rate of subgroup in AML with mutated chromatin, RNA-splicing genes, or both was 11.6% (95% CI = 1.4–21.8%) and 71.4% (95% CI = 45.7–86.5%), respectively. This study suggests that the recently recommended genomic classification is an appropriate and replicable categorization system in the NK AML population. The subgroup of AML with mutated chromatin, RNA-splicing genes, or both showed extremely poor survival in NK-AML; thus, a novel approach is needed to improve their prognosis.

Next-generation sequencing–based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse

Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF0.2%-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF0.2%-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P = .003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.

5-Hydroxymethylcytosine correlates with epigenetic regulatory mutations, but may not have prognostic value in predicting survival in normal karyotype acute myeloid leukemia

Stem cells display remarkably high levels of 5-hydroxymethylcytosine (5hmC). Both TET2 and IDH1/2 mutations can impair the production of 5hmC, thus decreasing 5hmC levels. TET2 or IDH1/2 mutations are commonly observed in acute myeloid leukemia (AML). However, the implications of 5hmC on survival in normal karyotype AML patients have not been fully evaluated. The 5hmC levels were analyzed in 375 patients using ELISA. The levels of 5hmC in DNA samples were converted to a log scale for the analysis and correlations with TET2 and/or IDH1/2 mutations were evaluated. The median 5hmC level was 0.065% (range 0.001–0.999). Mutation rates were 13.1% for TET2mut, 6.7% for IDH1mut, and 13.9% for IDH2mut. The prevalence of TET2 and/or IDH1/2 was 33.1% (124/375). TET2 and IDH1/2 mutated patients had significantly lower levels of log(5hmC) compared with patients without TET2 or IDH1/2 mutations (p<0.001). With a median follow-up of 55.5 months (range, 0.7–179.8), there was no significant difference in overall survival, event-free survival, and relapse risk according to TET2mut or IDH1/2mut (all, p>0.05). To identify its prognostic value, we sub-classified the levels of 5hmC into tertiles for 5hmC values. However, there was no significant association between the categories of 5hmC levels and survival or relapse risk (all p>0.05). Patients with TET2 or IDH1/2 mutations had lower levels of 5hmC. The 5hmC levels may not be predictive of survival in patients with normal karyotype AML.