OBJECTIVETo evaluate the relationship between plasma trough level of imatinib and clinical outcomes in Chinese CML patients.

METHODSPlasma trough levels in 416 CML patients who received imatinib orally in six general hospitals were assessed. The correlations of imatinib plasma trough level with baseline characteristics including age, weight and BSA, and clinical response were evaluated.

RESULTS(1) Effects of age, body weight and BSA on imatinib plasma trough levels were not to be clinically significant. (2) Median imatinib plasma trough levels was 1271 (109-4329). Imatinib plasma trough level was related to dose of imatinib administration. Plasma trough levels at imatinib of dose < 400, 400 and > 400 mg were (969 ± 585), (1341 ± 595) and (1740 ± 748) µg/L (P < 0.01), respectively. (3) There was no statistic difference in imatinib plasma trough level with complete cytogenetic response [CCyR (1337 ± 571) µg/L vs no CCyR (1354 ± 689) µg/L, P = 0.255]. (4) Imatinib plasma trough level might be important for a good clinical response in some CML patients.

CONCLUSIONThere was a large interpatient variability in imatinib plasma concentration in Chinese CML patients. No correlation of imatinib plasma trough level with CCyR was observed. However, higher doses of imatinib were shown to attain greater trough plasma concentration, suggesting that imatinib plasma trough level might be important for a good clinical response in some CML patients.

Adolescent ; Adult ; Aged ; Asian Continental Ancestry Group ; Benzamides ; blood ; therapeutic use ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; Male ; Middle Aged ; Piperazines ; blood ; therapeutic use ; Pyrimidines ; blood ; therapeutic use ; Treatment Outcome ; Young Adult

OBJECTIVETo analyze the clinical efficacy of imatinib mesylate (IM) for Ph-positive or BCR-ABL positive chronic myeloid leukemia (CML) to couple the trough plasma concentrations (C mins) of IM with clinical responses and adverse events (AEs).

METHODSOne hundred and one CML patients received IM therapy, and Cmins of IM were determined in 30 patients.

RESULTS(1) Cumulative complete hematological response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and negative BCR/ABL fusion gene rates were 96.6%, 86.5%, 77.5% and 47.2%, respectively, in CML-CP patients. In accelerated and blastic phases (AP and BC) patients, CHR, MCyR, CCyR and negative BCR-ABL fusion gene rates were 58.3%, 25.0%, 25.0%, 8.3%, respectively. (2) Mean Cmins of IM was significantly higher in the CCyR at 1 year [(1472 +/- 482) microg/L] group than in the non-CCyR at 1 years group [(1067 +/- 373) microg/L] (P < 0.05), and higher in the MMR at 1 year group than in the non-MMR at 1 years group [(1624 +/- 468) microg/L vs (1137 +/- 404) microg/L, P < 0.05].

CONCLUSIONIM significantly improves cytogenetic and molecular response, event-free survival, and overall survival for patients with Ph-positive CML. The Cmins of IM exerts a significant impact on clinical response (CCyR and MMR at 1 year).

Adolescent ; Adult ; Aged ; Antineoplastic Agents ; blood ; therapeutic use ; Benzamides ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; Male ; Middle Aged ; Piperazines ; blood ; therapeutic use ; Pyrimidines ; blood ; therapeutic use ; Treatment Outcome ; Young Adult

Benzamides ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; Piperazines ; pharmacokinetics ; therapeutic use ; Pyrimidines ; pharmacokinetics ; therapeutic use

OBJECTIVETo observe the efficacy of Gleevec combined with myeloablative allogeneic stem cells transplantation(Allo-SCT) for the treatment of chronic myeloid leukemia (CML).

METHODSNine patients with CML were treated with Gleevec before and after Allo-SCT, with 5 in the chronic phase (CP), 2 in the accelerated phase (AP) and 2 in the blast-crisis phase (BP). The donors were HLA matched identical siblings (n=7) and matched unrelated donors (n=2). The conditioning regimen is BuCy2. Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for the prevention of acute GVHD.

RESULTSAll patients achieved completed hemopoietic remission (HCR) treated with pre-transplant Gleevec. The median period to gain absolute neutrophil count>0.5x10(9)/L was 12 d (8 approximately 26 d) and that for platelet count>20x10(9)/L was 20 d (8 approximately 25 d). Three cases suffered from acute GVHD and 4 from chronic GVHD. All patients achieved completed engraftment and completed molecular remission. The rate of disease free survival was 88.9% after a median follow-up of 31 m (range 7 approximately 34 m).

CONCLUSIONThe treatment of CML consisting of myeloablative Allo-SCT combined with Gleevec before and after transplantation is an effective and safe method for CML.

Adult ; Antineoplastic Agents ; therapeutic use ; Benzamides ; Combined Modality Therapy ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; therapy ; Male ; Middle Aged ; Peripheral Blood Stem Cell Transplantation ; Piperazines ; therapeutic use ; Pyrimidines ; therapeutic use ; Transplantation Conditioning ; methods ; Treatment Outcome

OBJECTIVETo compare the therapeutic effects of transcutaneous electrical point stimulation and medication on functional dyspepsia.

METHODSTwo hundred and fifty cases were randomly divided into an observation group and a control group, 125 cases in each group. The observation group was treated with transcutaneous electrical acupoint stimulation and oral administration of placebo, transcutaneous electrical stimulated at Zusanli (ST 36), Liangmen (ST 21), Taichong (LR 3) etc. The control group was treated with oral administration of Mosapride citrate dispersible tablets, Domperidone and Omeprazole and the placebo treatment of transcutaneous electrical acupoint stimulation, the stimulated position was 3-4 cm to the selected points of the observation group, the amount of the stimulation did not reach the treatment amount. The symptom score, the plasma motilin (MTL) concentration and the somatostatin (SS) concentration were observed before and after treatment of 3 courses.

RESULTSAll symptom scores after treatment were lower than that before treatment in the two groups, the scores of the upper abdominal pain, acid regurgitation, belching and abdominal distention in the observation group were significantly lower than that in the control group (P < 0.05, P < 0.01); the treatments of both two groups can increase the plasma MTL concentration and decrease the SS concentration (both P < 0.001), and the plasma MTL concentration in the observation group was significantly higher than that in the control group (P < 0.01), and the SS concentration was significantly lower than that in the control group (P < 0.05).

CONCLUSIONTranscutaneous electrical point stimulation can more reduce the symptoms of upper abdominal pain, acid regurgitation, belching and abdominal distention, etc. in the functional dyspepsia patients than medication treatment, and can increase the concentration of the plasma MTL and decrease the SS concentration, thus to improve the gastrointestinal motility.

Acupuncture Points ; Adult ; Aged ; Benzamides ; administration & dosage ; therapeutic use ; Domperidone ; administration & dosage ; therapeutic use ; Dyspepsia ; blood ; physiopathology ; therapy ; Female ; Gastrointestinal Agents ; administration & dosage ; therapeutic use ; Humans ; Male ; Middle Aged ; Morpholines ; administration & dosage ; therapeutic use ; Motilin ; blood ; Omeprazole ; administration & dosage ; therapeutic use ; Somatostatin ; blood ; Transcutaneous Electric Nerve Stimulation ; methods ; Treatment Outcome

This study was aimed to evaluate the efficacy and safety of dasatinib in BCR/ABL positive leukemia patients with primary or secondary resistance to imatinib. 27 patients with primary or secondary imatinib-resistant chronic myelogenous leukemia (CML) or Philadelphia chromosome positive acute lymphocytic leukemia (Ph(+) ALL) received 100 - 140 mg/d dasatinib orally. Their overall survival and tolerance were evaluated. The results showed that the median duration of dasatinib therapy was 8 (1-66) months in the 27 imatinib-resistant BCR/ABL positive leukemia cases, with a median follow-up of 54 (3-75) months. After the dasatinib treatment, 88.8% of all the 27 cases achieved complete hematologic response (CHR), 29.6% of them achieved major cytogenetic response (mCyR), 37% of all achieved complete cytogenetic response (CCyR) and 18.5% cases achieved major molecular response (MMR). Patients who received dasatinib in progress of disease (CML-AP, CML-BC and bone marrow relapse Ph(+) ALL) had a lower CCyR rate than those in stable disease (CML-CP and bone marrow remission Ph(+) ALL) (P = 0.0377), and 3 - 4 grade adverse events occurred more frequently in progress of disease than that in stable disease. Overall survival of the patients who achieved CCyR after dasatinib therapy was statistically longer than those who did not achieve CCyR (63 m vs 9 m, P = 0.0126). The most common grade 3 - 4 adverse events during dasatinib therapy including hematology events such as thrombocytopenia (51.8%), neutropenia (48.1%), anemia (33.3%), and non-hematologic events such as pleural effusion (18.5%), pulmonary infection (18.5%), pericardial effusion (11.1%). The 3-4 grade adverse events occurred within 12 months from dasatinib therapy, and were mainly observed in patients with progress of disease. It is concluded that dasatinib is an effective drug in imatinib-resistant BCR/ABL positive leukemia patients, the better curative effect and better tolerance has been observed in patients who received dasatinib in stable disease.
Adult ; Aged ; Benzamides ; therapeutic use ; Dasatinib ; Drug Resistance, Neoplasm ; Female ; Fusion Proteins, bcr-abl ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; Male ; Middle Aged ; Piperazines ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; blood ; drug therapy ; Protein Kinase Inhibitors ; therapeutic use ; Pyrimidines ; therapeutic use ; Thiazoles ; therapeutic use ; Treatment Outcome ; Young Adult

Imatinib, the first-line treatment in patients with advanced gastrointestinal stromal tumors (GIST), is generally well tolerated, although some patients have difficulty tolerating the standard dose of 400 mg/day. Adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug. We present two cases of advanced GIST patients in whom we managed imatinib-related toxicities through dose modifications guided by imatinib plasma level monitoring. Imatinib blood level testing may be a promising approach for fine-tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced GIST.
Aged ; Antineoplastic Agents/blood/*therapeutic use ; Benzamides/blood/*therapeutic use ; Drug Monitoring ; Exons ; Gastrointestinal Neoplasms/*drug therapy/pathology/radiography ; Gastrointestinal Stromal Tumors/*drug therapy/pathology/radiography ; Humans ; Liver Neoplasms/secondary ; Male ; Mutation ; Piperazines/blood/*therapeutic use ; Positron-Emission Tomography ; Proto-Oncogene Proteins c-kit/genetics ; Pyrimidines/blood/*therapeutic use ; Tomography, X-Ray Computed

OBJECTIVETo measure the levels of hormones in chronic myelogenous leukemia (CML) patients receiving imatinib mesylate (IM) and evaluate the effects of IM on endocrine system.

METHODS69 patients with CML while taking IM were enrolled and a total of 86 peripheral blood samples were detected. The levels of total triiodothyronine (TT3), total tetraiodothyronine (TT4), thyroid stimulating hormone (TSH), testosterone, progesterone, estradiol (E2), plasma total cortisol (PTC) at 8:00-10:00 am measured. Concentration of hormones in different groups were measured to evaluate the effects of IM on endocrine system and relationships with its administration duration, plasma concentration and clinical symptoms.

RESULTS(1) Of the 7 types of hormones, an elevation of TSH level was found in 14 patients (20.3%), a decrease of TT3 and testosterone in 8 patients (11.6%) and 8 males (18.6%), respectively. (2) A significant decline of TT3 and testosterone was observed in all patients divided by different administration duration. Negative correlation was seen between TT3 level and duration of administration (r=-0.273, P=0.010), which was also found for testosterone (r=-0.302, P=0.025). (3) There was no correlation between serum levels of the seven hormones and concentration of IM.

CONCLUSIONIM affect the levels of thyroid and sex hormones in some patients with clinical manifestations: a decrease of TT3, testosterone and testosterone, an increase of TSH, which have relationship with the duration of administration.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Benzamides ; administration & dosage ; blood ; therapeutic use ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; Male ; Middle Aged ; Piperazines ; administration & dosage ; blood ; therapeutic use ; Pyrimidines ; administration & dosage ; blood ; therapeutic use ; Thyrotropin ; blood ; Triiodothyronine ; blood ; Young Adult

OBJECTIVETo determine plasma imatinib concentration, intracellular imatinib concentration, and hOCT1 and ABCB1 mRNA expression in bone marrow cells of CML patients to further evaluate the potential usefulness of these measures as markers of imatinib efficacy and their clinical relationships.

METHODSEighty CML patients in chronic phase receiving imatinib were enrolled in this study, including 56 males and 24 females with a median age of 39.5 (6 - 76) years. Imatinib was administered at a median dose of 400 (200 - 800) mg/d orally per day with a median course of 24 (3 - 90) months. The intracellular imatinib concentrations in bone marrow cells of 28 patients were simultaneously determined. Real-time quantitative PCR with a taqman probe was used to assess hOCT1 and ABCB1 mRNA expression on bone marrow cells of 36 patients. Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry with a detectability of 2 - 10 000 µg/L. Serum α1-acid glycoprotein (AGP) was measured by immune turbidimetry on a BNProspec protein analyzer (Dade Behring, USA). All patients were divided into MMR, CCyR, PCyR or drug-resistant groups according to response.

RESULTSPlasma imatinib trough concentration of 80 patients was (1274.1 ± 559.1) (109.0 - 3400.0) µg/L. The plasma imatinib trough concentration of 59 (73.8%) patients with a dose of 400 mg/d was (1252.0 ± 569.5) (109 - 3400) µg/L, including 37 (62.7%) patients with concentrations of more than 1000 µg/L and 9 (15.2%) patients more than 800 µg/L. Plasma imatinib trough concentration in the MMR group \[(1531.9 ± 634.1) µg/L\] was significant higher than in the PCyR \[(812.8 ± 480.3) µg/L\] or drug-resistant group \[(875.2 ± 243.1) µg/L\] (P < 0.05). Plasma imatinib trough concentration in the CCyR group \[(1288.4 ± 498.2) µg/L\] was significant higher than in the PCyR group (P = 0.027). There was no significant difference between CCyR and MMR groups with regard to plasma imatinib trough concentration (P = 0.136). The intracellular imatinib concentration in bone marrow cells in the CCyR group \[12.6 (2.4 - 90.4) µg/L\] was significantly higher than drug-resistant \[6.6 (2.6 - 111.0) µg/L\] or PCyR \[2.7 (2.4 - 4.7) µg/L\] groups (P = 0.013). The hOCT1 mRNA expression on bone marrow cells in the CCyR group \[25.9(0.7 - 123.9) × 10(-5)\] was significantly higher than in drug-resistant \[7.8 (2.5 - 33.5) × 10(-5)\] or PCyR \[4.2 (1.4 - 11.9) × 10(-5)\] groups (P = 0.036). The ABCB1 mRNA expression on bone marrow cells in drug-resistant group \[136.7 (15.0 - 1604.9) × 10(-5)\] was significantly higher than in CCyR \[129.1 (12.9 - 783.3) × 10(-5)\] or PCyR \[34.4 (2.2 -108.2) × 10(-5)\] groups (P = 0.013). Plasma imatinib trough concentration was positively correlated with AGP (r = 0.446, P = 0.000) or dose (r = 0.346, P = 0.002). There were no significant correlations between plasma imatinib trough concentration and height, weight or body surface area (P > 0.05). There were no significant differences among different courses with regard to plasma imatinib trough concentration (P > 0.05).

CONCLUSIONClinical responses in CML patients were correlated with plasma and intracellular imatinib trough concentrations. Imatinib concentration was regulated by AGP and the activities of hOCT1 and ABCB1.

ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Adolescent ; Adult ; Aged ; Benzamides ; blood ; pharmacokinetics ; therapeutic use ; Bone Marrow Cells ; metabolism ; Child ; Female ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; blood ; drug therapy ; metabolism ; Male ; Middle Aged ; Organic Cation Transporter 1 ; metabolism ; Piperazines ; blood ; pharmacokinetics ; therapeutic use ; Plasma ; metabolism ; Pyrimidines ; blood ; pharmacokinetics ; therapeutic use ; Treatment Outcome ; Young Adult

This study was aimed to investigate the expression and regulation mechanism of DNA-dependent protein kinase catalylic subunit (DNA-PKcs) in chronic myeloid leukemia (CML) and its role in blast crisis of CML. Expression of DNA-PKcs mRNA was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and DNA-PKcs protein by Western blot in 62 CML patients and K562, as compared to those of 23 normal individual controls. In 26 CML patients received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) and 4 CML patients treated with imatinib, the expression of bcr-abl mRNA and DNA-PKcs protein was detected by RT-PCR and Western blot, respectively. After treatment with imatinib in mononuclear cell (MNC) of CML patients and K562 in vitro, expression of DNA-PKcs mRNA was detected by RT-PCR and DNA-PKcs protein level, tyrosine phosphorylation of bcr-abl fusion protein were detected by Western blot. The results showed that the expression of DNA-PKcs protein was significantly lower in CML and K562 than those in normal control (P<0.05). In 26 CML patients received allo-PBSCT and 4 CML patients treated with imatinib, the expression of DNA-PKcs protein was enhanced while the expression of bcr-abl mRNA decreased. After treatment of MNC of CML and K562 with imatinib in vitro, the expression of DNA-PKcs protein was enhanced while tyrosine phosphorylation of bcr-abl fusion protein decreased. It is concluded that the expression of DNA-PKcs protein is down-regulate by bcr-abl fusion gene, and the bcr-abl fusion gene down-regulate the expression of DNA-PKcs protein by post-transcriptional mechanism; the decrease of DNA-PKcs protein expression may be one of mechanisms underlying the acute transformation of CML.
Adult ; Aged ; Benzamides ; Bone Marrow Cells ; metabolism ; DNA-Activated Protein Kinase ; biosynthesis ; genetics ; Female ; Fusion Proteins, bcr-abl ; biosynthesis ; genetics ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; therapy ; Male ; Middle Aged ; Peripheral Blood Stem Cell Transplantation ; Piperazines ; therapeutic use ; Pyrimidines ; therapeutic use ; RNA, Messenger ; biosynthesis ; genetics