Dong Hwan Dennis Kim

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

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.

Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy

BACKGROUND Imatinib could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients. Methods, materials and patients: The current study investigated the impact of four vascular endothelial growth factor type A (VEGFA) and three vascular endothelial growth factor receptor type 2 (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following imatinib therapy. VEGFA genotypes such as -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) loci and VEGFR2 genotypes (rs1531289, rs1870377 and rs2305948) were analyzed using matrix-assisted laser desorption/ionization time-of-flight-based method. RESULTS In single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289/rs1870377), between treatment failure and VEGFR2 genotype (rs1870377) and between progression to advanced disease and VEGFA genotypes (rs699947/rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR and treatment failure to imatinib. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure and of VEGFA genotype (rs699947) with progression to advanced disease. CONCLUSION The VEGFR2 gene polymorphism correlates with cytogenetic response, treatment failure following imatinib therapy for CML, while VEGFA genotype correlates with progression to advanced disease.

Retrospective multicenter study on the development of peripheral lymphocytosis following second-line dasatinib therapy for chronic myeloid leukemia.

The current retrospective study investigated the incidence of lymphocytosis following second‐line dasatinib therapy in chronic myeloid leukemia (CML) and analyzed the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Fifty CML patients who failed imatinib treatment and received dasatinib were included from nine centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. After a median of 17 months of dasatinib therapy, 23 patients (46%) developed lymphocytosis (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The group presenting lymphocytosis showed a higher complete cytogenetic response (CCyR; 78.3 vs. 29.6%, P = 0.001) and major molecular response (MMR; 52.2 vs. 14.8%, P = 0.005), in comparison to the group without presenting lymphocytosis. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (P = 0.002) or MMR (P = 0.003). Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Am. J. Hematol. 86:346–350, 2011.

Monosomal karyotype in acute myeloid leukemia predicts adverse treatment outcome and associates with high functional multidrug resistance activity.

Monosomal karyotype (MK) reflects highly unfavorable prognosis in patients with acute myeloid leukemia (AML). This study aimed to study the association of AML‐MK with multidrug resistance (MDR) functional activity. A total of 369 AML patients (excluding APL) between 1995 and 2008 at a single center were included retrospectively. Functional MDR activity was evaluated with rhodamine‐123 efflux activity with/without verapamil inhibition. MK was noted in 23 patients, only among whom classified into unfavorable cytogenetic risk group. Unfavorable cytogenetic subgroup with MK showed shorter OS (8.7 ± 5.9% vs. 23.5 ± 7.5% at 3 years, P = 0.030), EFS (8.7 ± 5.9% vs. 19.0 ± 6.9% at 3 years, P = 0.029), and a lower CR rate (34.8% vs. 65.7%, P = 0.031) compared with unfavorable subgroup without MK. Functional MDR activity was significantly higher in the unfavorable cytogenetic group with MK compared to all other cytogenetic risk groups taken as a whole (P = 0.026) and showed a trend toward statistical significance when compared with the unfavorable cytogenetic risk group without MK (P = 0.06). AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS, and the presence of MK appeared to be associated with higher MDR functional activity of leukemic blasts. Am. J. Hematol., 2012.

Genome-wide high density single-nucleotide polymorphism array-based karyotyping improves detection of clonal aberrations including der(9) deletion, but does not predict treatment outcomes after imatinib therapy in chronic myeloid leukemia.

The current study investigated molecular cytogenetic characteristics of chronic myeloid leukemia (CML) using genome-wide, single nucleotide polymorphism arrays (SNP-A) capable of detecting cryptic submicroscopic genomic aberrations. Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was performed in 118 patients having CML, chronic phase. Thirty-nine clonal aberrations (CAs) were identified (35 losses, two gains, two copy neutral loss of heterozygosity) that were not detected by metaphase cytogenetics in 25 patients (21%). The 9q34 deletions were found in 10% of cases, while 22q11.2 deletions were observed in 12% of cases. Seven patients (6%) harbored both 5′-ABL and 3′-BCR deletions adjacent to the t(9;22) breakpoint. Copy number gains were identified at 8p and 9p, and losses at 2q, 7q, 8q, 9q, 11q, 13q, 16p, and 22q. When we compared the treatment outcome of imatinib therapy between patients with and without CAs identified by SNP-A, treatment failure and progression to advanced disease were not significantly different (p > 0.05). In addition, according to the presence of deletions of 9q34 and/or 22q11.2 identified by SNP-A, the treatment outcome did not show any significant differences (p > 0.05). Our data suggests that SNP-A analysis is a useful tool for detection of clonal aberrations including deletions adjacent to the t(9;22) breakpoint in the CML cancer genome. However, clonal aberrations detected by SNP-A could not improve a prognostic stratification in CML patients with chronic phase.

Comprehensive evaluation of time-to-response parameter as a predictor of treatment failure following imatinib therapy in chronic phase chronic myeloid leukemia: Which parameter at which time-point does matter?†

Early recognition of high‐risk patient is important to improve long‐term outcomes following imatinib therapy for chronic myeloid leukemia (CML). Some controversy surrounds the question, which of short‐term response parameters at which time‐point, including complete cytogenetic response (CCyR) or major molecular response (MMR) at 6 or 12 months, is the best predictor for treatment outcomes. In this comprehensive analysis, we adopted landmark analysis method, time‐dependent Coxs proportional hazard model, and receiver‐operating characteristics (ROC) method to analyze time‐to‐response parameter as predictor of long‐term outcomes in 187 chronic phase (CP) CML patients. Regardless of the methods of analysis, earlier achievement of short‐term response such as CCyR or MMR could predict the higher probability of achieving better interim outcome (such as treatment failure or loss of response [LOR]). Similar to the findings from other studies, our ROC analysis provided cutoff time points for MMR (18–36 months) and CCyR (6–12 months) that were the best predictors for LOR or treatment failure, which can be an indirect evidence supporting the ELN recommendation. The patient who achieves short‐term response rapidly will have a lower risk of losing response or failing after imatinib therapy in CML patients. Am. J. Hematol., 2010.

Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category.

The purpose of this study was to evaluate the detection rate of chromosomal rearrangements in leukemia using single nucleotide polymorphism array (SNP‐A) in combination with metaphase cytogenetics (MC), with the aim of proposing a practical approach for clinical karyotyping applications of SNP‐A. The Genome‐Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA) was applied in 469 patients with a variety of hematologic malignancies. Combined use of SNP‐A with MC improved the detection rate in comparison with MC alone: acute myeloid leukemia (AML) with normal karyotype (NK), 32% versus 0%; core binding factor (CBF)‐AML 40% versus 29%; myelodysplastic syndrome (MDS), 54% versus 39%; chronic myeloid leukemia (CML), 24% versus 3%; and acute lymphoblastic leukemia (ALL), 88% versus 63%. Different patterns of abnormalities (especially the type, size, and location) were noted in the leukemia subtypes. Copy neutral loss of heterozygosity lesions was detected in 23% of AML‐NK, 3% of CBF‐AML, 25% of MDS, 2% of CML, and 20% of ALL. SNP‐A also provided information on cryptic deletions and a variety of aneuploidies in ALL, while the benefit was minimal in CML. In conclusion, different patterns of abnormal lesions were presented according to the disease category, thus requiring a different approach of adopting SNP‐A‐based karyotyping among different leukemia subtypes.

Feasibility of second hematopoietic stem cell transplantation using reduced-intensity conditioning with fludarabine and melphalan after a failed autologous hematopoietic stem cell transplantation

This study was performed to determine the feasibility of second hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning (RIC) with fludarabine and melphalan in patients with relapsed hematologic malignancies after a prior autologous HSCT. Twelve patients (multiple myeloma [n = 7], non-Hodgkin lymphoma [n = 3], and acute myeloid leukemia [n = 2] received allogeneic HSCT using RIC with fludarabine (25 mg/m(2) for 5 days) and melphalan (140 mg/m(2) for 1 day) after a failed autologous HSCT. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine plus a minidose of methotrexate. All patients achieved a neutrophil and platelet engraftment in a median 13.5 days and 17.5 days, respectively. The transplant-related mortality was 2 patients (16.7%). Grade II-IV acute GVHD and chronic extensive GVHD were noted in 4 (33.3%) and 1 patient (11.1%), respectively. Over a median follow-up duration of 376 days, 5 patients were alive without evidence of disease. The estimated nonrelapse mortality at 1 year was 28.4%. The estimated overall survival rate at 1 year was 58.3%, and the estimated event-free survival rate at 1 year was 41.7%. Allogeneic HSCT using RIC with fludarabine and melphalan appears to be feasible for a second HSCT in patients with relapsed hematologic malignancies after a failed autologous HSCT.

A genome-wide single-nucleotide polymorphism-array can improve the prognostic stratification of the core binding factor acute myeloid leukemia.

Core binding factor (CBF) AML with the D816 C‐KIT gene mutation demonstrate inferior treatment outcomes. However, the remaining cases without the D816 C‐KIT mutation imply a requirement of more sophisticated dissection of the patients according to their prognosis. In this study, we analyzed the prognostic value of a single nucleotide polymorphism array (SNP‐A) based karyotyping combined with metaphase cytogenetics (MC) to facilitate further stratification of CBF AML patients. A total of 98 CBF AML patients were included and genome‐wide Human SNP 6.0 Arrays (Affymetrix) were performed using marrow samples taken at diagnosis. Overall, 40 abnormal lesions were identified in 25 patients (26%). Survival of the patients with the abnormal lesion(s) detected by SNP‐A and/or MC was worse than those without lesions in terms of the 2‐year overall survival (OS; 57.5% vs. 76.4%, P = 0.028), event‐free (EFS; 45.7% vs. 66.2%, P = 0.072), and leukemia‐free survival (LFS; 49.0% vs. 77.4%, P = 0.015), specially in the subgroup with inv(16)/t(16;16) (40.9% vs. 80.2% OS, P = 0.040) and in the subgroup without the D816 C‐KIT mutation (61.6% vs. 82.7% OS, P = 0.038). Multivariate analysis confirmed the prognostic impact of the abnormal SNP‐A and/or MC lesion on EFS (HR 2.011, P = 0.047), and LFS (HR 3.231, P = 0.005) in the overall CBF AML. This study suggests that the combined use of SNP‐A with MC in the CBF AML can provide important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without the D816 C‐KIT mutation. Am. J. Hematol., 2012.

Detection of new mutations in patients (pts) with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib.

6516 Background: BCR-ABL transcript levels have been reported to be a predictor of response outcomes, including the detection of new mutations, in pts with imatinib resistance. In this posthoc anal...