Severe Liver Dysfunction after Donor Lymphocyte Infusion for Relapsed Multiple Myeloma.

Donor lymphocyte infusion (DLI) is performed to augment an anti-tumor immune response or ensure donor stem cells remain engrafted following allogeneic stem cell transplantation but may induce graft-versus-host disease (GVHD) involving skin, intestine, and liver. Although hepatic involvement of GVHD can manifest as mild to severe hepatitis, few reports have mentioned acute severe liver dysfunction with encephalopathy. We experienced a case of acute severe liver dysfunction with semicoma after DLI in a patient with relapsed multiple myeloma following allogeneic stem cell transplantation, in whom chronic viral hepatitis B had been suppressed by antiviral treatment. The patient recovered after high-dose glucocorticoid administration based on an assessment of hepatic GVHD. Clinicians should be aware of the possibility of this catastrophic hepatic complication after DLI in hematologic disorders.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Efficacy, Safety, and Pharmacokinetics of Beroctocog Alfa in Patients Previously Treated for Hemophilia A.

PURPOSE: Beroctocog alfa is a second generation recombinant factor VIII manufactured by removing the B-domain from factor VIII. This prospective clinical trial was conducted to evaluate the efficacy, safety, and pharmacokinetics of beroctocog alfa in patients of ages ≥12 years previously treated for severe hemophilia A. MATERIALS AND METHODS: Seventy subjects received beroctocog alfa as an on-demand treatment for acute hemorrhage. RESULTS: The final hemostatic effect was excellent in 35 subjects (50%) and good in 26 subjects (37.1%). The drug showed an overall efficacy rate of 87.1%. The majority of acute hemorrhages was treated by administering the study drug once (86.2%) or twice (10.0%), and the mean dose administered per single infusion was 28.55±6.53 IU/kg. Ten subjects underwent 12 surgical procedures, and hemostatic efficacy was excellent in seven cases (58.3%) and good in five cases (41.7%), showing a 100% efficacy rate. A total of 52 of 88 subjects (59.0%) experienced 168 adverse events. There were 18 serious adverse events (10.7%) in 11 subjects, and two (mild dyspnea and facial edema) in one subject were related to the study drug. Only one subject formed a de novo factor VIII inhibitor, for an occurrence rate of 1.4% (one-sided 95% upper confidence limit: 3.85%). The final elimination half-life was 13.3 h and 12.6 h at baseline and 6 months after administration, respectively. CONCLUSION: Our results suggest that beroctocog alfa is safe and efficacious as either an on-demand treatment for acute hemorrhage or a surgical prophylaxis in patients with hemophilia A.

HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy.

Allopurinol, a widely used urate-lowering agent, is a leading cause of severe cutaneous adverse reactions (SCARs), especially in patients with HLA-B*58:01. Despite its routine use for the prevention of tumor lysis-related hyperuricemia prior to chemotherapy, the risk of allopurinol-induced hypersensitivity has not been investigated in patients with hematologic malignancies. This retrospective cohort study was conducted to investigate the incidence and risk factors of allopurinol-induced hypersensitivity in patients at least 18 years of age with hematologic malignancies. We reviewed 463 patients who had ever taken allopurinol for the prevention of hyperuricemia prior to chemotherapy and had undergone serologic HLA typing as a pre-transplant evaluation from January 2000 to May 2010. Thirteen (2.8%) patients experienced maculopapular eruptions (MPE) and none experienced SCARs. Among subtypes of underlying hematologic malignancies, percentage of chronic myeloid leukemia was significantly higher in the allopurinol hypersensitivity group compared with the tolerant group (23.1% (3/13) vs. 5.9% (26/440), P = 0.044). According to HLA subtypes, the incidence of allopurinol-induced MPE was 4.0% in HLA-B58 (+) patients (2/50) and 2.7% in HLA-B58 (-) patients (11/403) but this difference was statistically insignificant. In contrast to HLA-B58, the frequencies of DR9 and DR14 were significantly higher in the allopurinol-induced MPE group compared with the allopurinol tolerant group (38.5% (5/13) vs. 13.6% (53/443), P = 0.019, and 38.5% (5/13) vs. 15.6% (41/440), P = 0.038, respectively). In conclusion, HLA-DR9 and DR14, but not HLA-B58, are associated with hypersensitivity reaction by allopurinol when administered in patients with hematologic malignancy prior to chemotherapy.

Multicenter study evaluating the impact of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in myelodysplastic syndromes.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is currently the only curative treatment modality for myelodysplastic syndromes (MDS). The treatment paradigm for MDS has changed in recent years with the introduction of hypomethylating agents (HMAs). The present retrospective multicenter study was designed to assess the effects of pre-transplant HMA on transplant outcome and determine which patients would benefit most from this therapy. A total of 109 patients who received alloSCT at one of five institutions between 2007 and 2010 were enrolled in this study regardless of pre-transplant HMA therapy. 81 of the 109 patients enrolled were treated with HMA prior to alloSCT. 28 patients received alloSCT without HMA bridging. The distributions of WHO classification groups and IPSS scores were similar between the two groups (P = 0.752 and P = 0.265, respectively). Pre-transplant HMA did not affect OS (P = 0.244), and there were no differences in response to HMA therapy within the HMA-treated group. The cumulative incidence of NRM was not significantly different between the two groups (P = 0.500). However, for patients with a high blast count (>5 % of bone marrow at the time of diagnosis), pre-transplant HMA therapy had a NRM benefit (83.3 vs. 48.6 %, P = 0.014).

ABCB1 C3435T genetic polymorphism on population pharmacokinetics of methotrexate after hematopoietic stem cell transplantation in Korean patients: a prospective analysis.

BACKGROUND: Methotrexate (MTX) is often used to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, MTX has great pharmacokinetic variability and its use can result in fatal complications and/or infections after HSCT. OBJECTIVES: The purposes of this study were to build a population pharmacokinetic model of MTX treatment in Korean patients who have undergone HSCT and to identify covariates, including genetic polymorphisms, that affect the pharmacokinetic properties of MTX. METHODS: Clinical characteristics and MTX concentration data for 20 post-HSCT patients were collected. For each patient, ABCB1, ABCC2, ATIC, GGH, MTHFR, and TYMS genotyping was performed. Population pharmacokinetic analysis was performed using the NONMEM program. Analysis of MTX pharmacokinetic properties was accomplished using a 2-compartment pharmacokinetic model that incorporated first-order conditional estimation methods with interaction. The effects of a variety of demographic and genetic factors on MTX disposition were investigated. RESULTS: The study population consisted of 12 men (60%) and 8 women (40%). Median age and body weight were 28 years (range, 18-49 years) and 55.6 kg (range, 44.8-80.8 kg), respectively. Within the study population, the estimated mean MTX clearance (CL) was 7.08 L/h, whereas the mean central compartment volume (V(1)) of MTX distribution was 19.4 L. MTX CL was significantly affected by glomerular filtration rate (GFR), penicillin use, and the ABCB1 3435 genotype. Interindividual variabilities for CL and V(1) were 21.6% and 73.3%. A 10-mL/min GFR increase was associated with a 32% increase in mean MTX CL, whereas penicillin use was associated with a decrease in MTX CL of 61%. MTX CL was significantly greater (by ∼21%) in patients with the ABCB1 3435 CC and CT genotype than in those with the ABCB1 3435 TT genotype (P < 0.001). CONCLUSIONS: There was great interindividual variation in MTX pharmacokinetic properties in patients who had undergone HSCT. GFR, concurrent penicillin use, and the presence of the ABCB1 3435 C

Patient counseling program to improve the compliance to imatinib in chronic myeloid leukemia patients.

To achieve successful therapeutic outcomes in chronic myeloid leukemia (CML), continuous and adequate imatinib (Gleevec(®), Glivec(®), Novartis Pharmaceuticals, Basel, Switzerland) dosing is essential. Here, we report a patient counseling program ("Care club", "Happy club" in Korea) performed to improve patient compliance with imatinib. From January 2006 to December 2008, patients diagnosed with chronic phase CML and taking imatinb were eligible for this retrospective study. A total of 114 patients from 4 centers in Korea were recruited at a 50:50 ratio for Happy club group versus non-Happy club group at each center. During 36-month follow-up, persistency (the number of days of imatinib prescribed versus 1 year) was higher in the Happy club group (98.2 ± 0.03%) than in the non-Happy club group (79.3 ± 0.16%, P = 0.001), whereas dose compliance (miligrams of imatinib that were actually taken versus miligrams that should have been taken) was not different between two groups; 96.5 ± 0.6% and 96.6 ± 0.7% in the Happy club and non-Happy club (P = 0.958). Overall compliance (the product of persistency and dose compliance) improved in the Happy club group (93.0 ± 2.3%) compared with the non-Happy club group (76.2 ± 7.4%, P = 0.001). The patient counseling program was efficient especially in patients who needed high-dose imatinib (>400 mg/day), and overall compliance was 87.8 ± 6.0% in the Happy club group versus 65.5 ± 16.1% in the non-Happy club group (P = 0.017). In conclusion, the patient counseling program was effective in persisting imatinib medication, resulting in the improvement of overall compliance.

Gene expression profile during chondrogenesis in human bone marrow derived mesenchymal stem cells using a cDNA microarray.

Mesenchymal stem cells (MSCs) have the capacity to proliferate and differentiate into multiple connective tissue lineages, which include cartilage, bone, and fat. Cartilage differentiation and chondrocyte maturation are required for normal skeletal development, but the intracellular pathways regulating this process remain largely unclear. This study was designed to identify novel genes that might help clarify the molecular mechanisms of chondrogenesis. Chondrogenesis was induced by culturing human bone marrow (BM) derived MSCs in micromass pellets in the presence of defined medium for 3, 7, 14 or 21 days. Several genes regulated during chondrogenesis were then identified by reverse transcriptase-polymerase chain reaction (RT-PCR). Using an ABI microarray system, we determined the differential gene expression profiles of differentiated chondrocytes and BM-MSCs. Normalization of this data resulted in the identification of 1,486 differentially expressed genes. To verify gene expression profiles determined by microarray analysis, the expression levels of 10 genes with high fold changes were confirmed by RT-PCR. Gene expression patterns of 9 genes (Hrad6B, annexinA2, BMP-7, contactin-1, peroxiredoxin-1, heat shock transcription factor-2, synaptotagmin IV, serotonin receptor-7, Axl) in RT-PCR were similar to the microarray gene expression patterns. These findings provide novel information concerning genes involved in the chondrogenesis of human BM-MSCs.

Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia.

To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378 ±â€Š725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group with  <1000: 80.6% vs. 19.4%;  ≥ 1000: 94.6% vs. 5.4%; p = 0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group with  <1000: 3.2% vs. 96.8%;  ≥ 1000: 21.4% vs. 78.6%; p = 0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level of  ≥ 1000 compared with those with a level of <1000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (<1000 ng/mL).

Triptolide-induced suppression of phospholipase D expression inhibits proliferation of MDA-MB-231 breast cancer cells.

In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD- mediated physiology. We examined one such here, denoted Triptolide, which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-mM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.

Non-myeloablative allogeneic stem cell transplantation for metastatic renal cell carcinoma.

Between 1999 and 2004, 11 patients with metastatic renal cell carcinoma (RCC) underwent non-myeloablative stem cell transplantation (NST) with conditioning using fludarabine-based regimens in two institutions of Korea. Among 11 patients, only one patient showed partial response (response rate: 9%), three showed stable disease, and six progressive disease. Three patients developed acute graft-versus-host disease (GVHD), and among them, one developed grade III acute GVHD which caused early death at day 60 after transplantation, and this patient showed partial response at day 30. Six patients developed chronic GVHD, three limited, and three extensive GVHD, respectively. Survival after one yr was 18% in transplanted patients. Median overall survival for entire cohort was 4.3 months. Eight patients died from progressive disease and three (27%) from treatment-related mortality. Only one patient survived 51.2 months after NST with slowly progressive disease. This patient received donor lymphocyte infusion three times after NST and achieved complete donor chimerism. NST does not lead to durable response and prolonged overall survival in the majority of patients with RCC in our series.

DNA copy number alterations and expression of relevant genes in mouse thymic lymphomas induced by gamma-irradiation and N-methyl-N-nitrosourea.

The genetic mechanism for the development and progression of a lymphoma is unclear. This study investigated the alterations in the DNA copy number and the expression profiles of the genes located in the altered regions in mouse thymic lymphomas that were induced by two mutagens, gamma-irradiation and N-methyl-N-nitrosourea (MNU). Microarray-based comparative genomic hybridization was used to precisely delineate the boundaries of the altered region. The copy number gains of chromosomes 4 and 5 were observed only in the radiation-induced lymphomas, and gains of chromosomes 10 and 14 were observed only in the MNU-induced lymphomas. Regional copy number losses in chromosomes 11, 16, and 19 appeared frequently in the radiation-induced lymphomas. The cancer-related genes Pten, Ikaros/Znfn1a1, Ercc4, and Top3b were located in the minimal deletion regions. In particular, the expression levels of the Pten, Top3b, and Ikaros genes were downregulated in both lymphoma groups, but the expression level of Ercc4 was downregulated only in the MNU group. This study also examined the expression levels of Sparc, Cxcl1, and Myc (synonym: c-Myc), which are located in the copy number gained chromosomes. Sparc was upregulated specifically in the radiation group, and Cxcl1 in the MNU group. c-Myc was upregulated in both groups. There was limited correlation between the DNA copy number profiles and the expression of the cancer-related genes in mouse lymphomagenesis. The chromosome aberrations and novel expression profiles of the cancer-related genes within the altered regions may provide important clues to the genetic mechanism for the development of lymphoma.

Outcomes of Hickman catheter salvage in febrile neutropenic cancer patients with Staphylococcus aureus bacteremia.

OBJECTIVE: To evaluate the outcome of attempted Hickman catheter salvage in neutropenic cancer patients with Staphylococcus aureus bacteremia who were not using antibiotic lock therapy. DESIGN: Retrospective cohort study. SETTING: A university-affiliated, tertiary-care hospital with 1,500 beds for adult patients. PATIENTS: All neutropenic cancer patients who had a Hickman catheter and S. aureus bacteremia (32 episodes in 29 patients) between January 1998 and March 2002. METHODS: Salvage attempts were defined as cases where the Hickman catheter was not removed until we obtained the results of follow-up blood cultures performed 48 to 72 hours after starting treatment with antistaphylococcal antibiotics. Salvage was considered to be successful if the Hickman catheter was still in place 3 months later without recurrent bacteremia or death. RESULTS: Catheter salvage was attempted in 24 (75%) of the 32 episodes. Of the salvage attempts, the success rate was 50% (12 of 24). Salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures, and in 65% (11 of 17) of those with negative follow-up blood cultures (P = .07). If the analysis is confined to cases with no external signs of catheter infection, salvage attempts were successful in 14% (1 of 7) of the episodes with positive follow-up blood cultures and in 80% (8 of 10) of those with negative follow-up blood cultures (P = .02). CONCLUSION: In neutropenic cancer patients with S. aureus bacteremia, attempted catheter salvage without antibiotic lock therapy was successful in 50% of the cases.

A study on 289 consecutive Korean patients with acute leukaemias revealed fluorescence in situ hybridization detects the MLL translocation without cytogenetic evidence both initially and during follow-up.

Translocations involving the MLL gene on the chromosome 11 (11q23) are frequently observed in acute leukaemia. The detection of this genetic change has a unique significance as a result of its implication of poor prognosis. To reveal the utility of fluorescence in situ hybridization (FISH) in detecting the MLL translocation, we analysed 289 consecutive Korean patients (children and adults) with acute leukaemias using both conventional cytogenetic analysis (CC) and FISH, placing an emphasis on the result discrepancies. Twenty-two of 289 patients (7.6%) had the 11q23/MLL translocation. In nine of 22 patients (41%), only FISH detected the translocation. In eight of these 22 patients, a total of 19 follow-up examinations were performed, of which FISH detected a significant level of leukaemic cells harbouring the MLL translocation in five patients (26%) without cytogenetic evidence. In addition to the MLL translocation, FISH detected submicroscopic amplification, partial deletion of the MLL gene and trisomy 11 in 12 patients without cytogenetic evidence. In summary, up to 41% of the MLL translocations at initial work-up and 26% during follow-up were detected by FISH without cytogenetic evidence. Thus, we recommend that MLL FISH should be performed in the diagnosis and monitoring of acute leukaemias in combination with CC.