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Clinical efficacy of lower dose rituximab for chronic refractory immune thrombocytopenic purpura.

Yan LI ; Xiao-min WANG ; Min MAO ; Xiao-yan ZHANG ; Ling FU ; He-mai-jiang AI ; Lian-xing ZHANG

Chinese Journal of Hematology.2012;33(3):204-206.

OBJECTIVETo investigate the efficacy and safety as well as the effects of lower dose of rituximab on B-lymphocytes, serum immunoglobulin, and platelet glycoprotein-specific antibodies in patients with chronic refractory immune thrombocytopenic purpura (ITP).

METHODSTwenty chronic refractory ITP patients, median age 47 (20 to 60) years old, received intravenous rituximab at the dose of 100mg once weekly for 4 consecutive weeks. Laboratory studies included complete blood cell count, regular monitoring of liver and kidney functions, blood coagulation and serum concentrations of IgG, IgM and IgA. CD3(+), CD4(+), CD8(+), CD19(+), CD20(+) cell numbers were assayed by flow cytometry prior to and following rituximab. Platelet glycoprotein antibodies were detected by ELISA. The detection of indicators were compared by paired T test, with P < 0.05 as statistically significant.

RESULTSThere was significant difference of the average platelet count between prior- \[(13 ± 5) × 10(9)/L\] and post-treatment \[(124 ± 106) × 10(9)/L\] with lower dose rituximab (P < 0.01). Reaching PLT peak period was of (24 ± 7) d with median time of 18 d. The responses were of 11(55%) CR, 4 (20%) R and 5 (25%) NR, respectively, with median response duration of 8 months (5 - 23 months). There were no significant changes of peripheral blood white blood cell count, hemoglobin, serum immunoglobulin, as well as CD3(+), CD4(+), CD8(+) lymphocyte counts during prior- and post-treatment. CD19(+)/CD20(+) cells were almost depleted in all patients \[(125.65 ± 14.12) × 10(6)/L vs (50.53 ± 29.11) × 10(6)/L, P < 0.01)\]. Expectedly, three cases of positive detection of platelet antibodies were negative after 4 weeks of lower dose of rituximab; one patient experienced infusion-related reaction.

CONCLUSIONTreatment with lower dose rituximab may be an effective and safe approach in patient with chronic refractory ITP. However, the optimal therapeutic schedule, long-term efficacy and adverse events need further investigation.

Adult ; Antibodies, Monoclonal, Murine-Derived ; administration & dosage ; therapeutic use ; Humans ; Middle Aged ; Purpura, Thrombocytopenic, Idiopathic ; drug therapy ; prevention & control ; Recurrence ; Rituximab ; Treatment Outcome ; Young Adult

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A novel diagnostic measure of platelet-specific antibody in immune thrombocytopenia.

Xue-li ZHOU ; Shi YAN ; Qiang LI ; Peng LI ; Ze-ping ZHOU ; Ren-chi YANG

Chinese Journal of Hematology.2012;33(3):200-203.

OBJECTIVETo detect the platelet glycoprotein-specific antibodies in serum of thrombocytopenia patients and evaluate its diagnostic value for immune thrombocytopenia.

METHODAnti-GPIIb/IIIa, GPIb/IX and GPIa/IIa antibodies were assayed by ELISA kit (PAKUTO) in patients with thrombocytopenia.

RESULTSThe sensitivity and specificity of PAKAUTO in immune thrombocytopenia were 44.0% and 95.7%, respectively. The values of positive and negative predictions were 98.0% and 26.2%, respectively. Among those PAKAUTO positive patients, positive rates of GPIIb/IIIa, GPIa/IIa and GPIb/IX were 87%, 35% and 10%, respectively. The positive rate of patients not received immune suppressive agents (58.5%) was significantly higher than those received immune suppressive agents (26.9%) (P < 0.01). The positive rate of patients with platelet count ≤ 20 × 10(9)/L (51.6%) was significantly higher than those with platelet count > 20 × 10(9)/L (27.8%) (P < 0.01). The positive rate of patients with secondary immune thrombocytopenia (66.7%) was significantly higher than those with primary immune thrombocytopenia (41.7%) (P < 0.05).

CONCLUSIONThe highly specific method (PAKAUTO) could effectively differentiate immune or non-immune thrombocytopenia and be applied to diagnosis of immune thrombocytopenia.

Autoantibodies ; analysis ; immunology ; Enzyme-Linked Immunosorbent Assay ; methods ; Female ; Humans ; Male ; Platelet Glycoprotein GPIIb-IIIa Complex ; immunology ; Platelet Glycoprotein GPIb-IX Complex ; immunology ; Platelet Membrane Glycoproteins ; immunology ; Sensitivity and Specificity ; Thrombocytopenia ; diagnosis ; immunology

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Establishment of xenotransplated mouse model using primary multiple myeloma cells.

Chun-yan LIU ; Li ZHANG ; Na WANG ; Di WANG ; Zhe GENG ; Dan-mei XU ; Chun-rui LI ; Jian-feng ZHOU ; Liang HUANG

Chinese Journal of Hematology.2012;33(3):195-199.

OBJECTIVETo establish xenotransplated mouse model by non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with primary myeloma cells.

METHODSThe model of xenograft was established in NOD/SCID mice by tail vein injection of mononuclear cells from two end stage multiple myeloma patients, three mice were inoculated for each patient. Mice were monitored weekly for body weight. Two weeks later, the human CD45(+) cells from peripheral blood of mice were evaluated by flow cytometry (FCM). The experiment endpoint was body weight loss up to 20% or had pale, vertical hair and listlessness, then spleen and liver were studied by histologic analysis, the human CD45(+)CD38(+) cells from spleen, lymph node, peripheral blood and bone marrow were evaluated by FCM.

RESULTSBody weight of mice in group patient 1 and group patient 2 decreased seven and five weeks after inoculation respectively; the human CD45(+)CD38(+) cells appeared in the peripheral blood (26 ± 4) and (16 ± 4) days after inoculation in group patient 1 and group patient 2 respectively, and increased by time, reaching (16.2 ± 3.0)% and (31.3 ± 3.5)%, respectively at the endpoint; the spleen, liver and lymph node of both groups enlarged, the typical malignant plasma cells were observed in them. The human CD45(+)CD38(+) cells were detected in spleen, lymph node and bone marrow by FCM.

CONCLUSIONOur study successfully established a NOD/SCID mouse model xenotransplated with human primary myeloma cells.

Aged, 80 and over ; Animals ; Cell Line, Tumor ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Middle Aged ; Multiple Myeloma ; Neoplasm Transplantation

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Allogeneic peripheral blood stem cell transplantation from sibling donors for 10 patients with multiple myeloma.

Hai-feng LAN ; Zhen-gang YUAN ; Chun-yang ZHANG ; Yu-bao CHEN ; Wei-jun FU ; Hua JIANG ; Hao XI ; Jian HOU

Chinese Journal of Hematology.2012;33(3):191-194.

OBJECTIVETo evaluate the efficacy of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from sibling donors for treatment of multiple myeloma (MM).

METHODSTen patients with MM received allo-PBSCT with conditioning consisting of fludarabine plus melphalan and cyclophosphamide mostly.CsA plus mycophenolate mofetil (MMF) and short-term MTX were applied to prevent graft versus host disease (GVHD) in 8 patients, FK506 plus short-term MTX in other 2 patients.

RESULTSAll patients engrafted successfully, the median time for ANC > 0.5 × 10(9)/L was 16 (12 - 24) days, and for BPC > 20 × 10(9)/L 23 (16 - 102) days. Five patients developed acute GVHD, and only one III-IV aGVHD. Of 9 patients, 7 developed chronic GVHD. The transplant-related mortality (TRM) at 100 days was 10% (1/10), mainly from heart and renal failure and severe infection. The 1-year expected overall survival (OS), 1-year disease-free survival (DFS) and relapse rate were 67.5%, 55.56% and 11.11% respectively. Up to now, 6 patients were still alive, of them 1 patient have survived over 99 months after allo-PBSCT.

CONCLUSIONYoung MM patients having HLA-identical sibling donors well tolerated allo-PBSCT based on fludarabine to prolong their OS by reducing TRM, though further work is warranted.

Adult ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma ; surgery ; Peripheral Blood Stem Cell Transplantation ; Siblings ; Tissue Donors ; Transplantation, Homologous

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Clinical investigation of primary amyloidosis with autologous hematopoietic stem cell transplantation.

Zhi-xiang QIU ; Mang-ju WANG ; Li-hong WANG ; Yu-hua SUN ; Wei-lin XU ; Wei LIU ; Jin-ping OU ; Yu-jun DONG ; Wen-sheng WANG ; Yuan LI ; Yue YIN ; Ze-yin LIANG ; Xi-nan CEN ; Han-yun REN

Chinese Journal of Hematology.2012;33(3):187-190.

OBJECTIVETo investigate the treatment of primary amyloidosis with high-dose melphalan and autologous hematopoietic stem cell transplantation to further examine the survival, hematologic response, and improvement of amyloid-related organ dysfunction.

METHODSRetrospective analysis of 20 patients with primary amyloidosis treated with autologous hematopoietic stem cell transplantation. The status of major organ function before transplantation, mobilization programs and conditioning regimen as possible risk factors for survival were also investigated.

RESULTSOf 20 cases, 11 out of 15 evaluable cases achieved hematologic response, among them, 6 got complete remission (CR, 40%) and 5 partial remission (PR, 33%). The median onset time was 3.0 months (1.5 - 4.0 months) and 4 months (3 - 5 months), respectively after transplantation. The overall hematologic response was 73%. The 11 hematologic responders also had kidney responses. The median time to achieve kidney response was 3 months (2 - 6 months). The 3-year overall survival of the cohort of cases was 71.4%. The major causes of death were heart failure, renal dysfunction and gastrointestinal bleeding. G-CSF alone could obtain satisfactory mobilization results and most of patients well tolerated to the conditioning regimen of melphalan doses from 140 mg/m(2) to 200 mg/m(2).

CONCLUSIONTreatment of primary amyloidosis with high-dose melphalan followed by autologous peripheral blood stem cell transplantation produced high efficacy. The cardiovascular system involvement, renal dysfunction and the abnormality of coagulation function before transplantation may be the risk factors for survival.

Adult ; Aged ; Amyloidosis ; drug therapy ; mortality ; surgery ; Cardiovascular System ; physiopathology ; Female ; Gastrointestinal Hemorrhage ; physiopathology ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunoglobulin Light-chain Amyloidosis ; Kidney ; physiopathology ; Male ; Melphalan ; therapeutic use ; Middle Aged ; Retrospective Studies ; Risk Factors ; Survival Rate ; Transplantation, Autologous ; Treatment Outcome

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Analysis of plasma trough level of imatinib in Chinese CML patients.

Li ZHOU ; Fan-yi MENG ; Jie JIN ; Qing-shu ZENG ; Xin DU ; Xiao-jun HUANG ; Zhi-xiang SHEN

Chinese Journal of Hematology.2012;33(3):183-186.

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

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Study on imatinib trough concentration, efficacy and their relation in chronic myelocytic leukemia.

Jian-Sheng ZHONG ; Fan-Yi MENG ; Dan XU ; Hong-Sheng ZHOU ; Min DAI

Chinese Journal of Hematology.2012;33(3):177-182.

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

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Co-expression of CD99/MIC2 and ALK in anaplastic large-cell lymphoma tissues and its significance.

Lin ZHONG ; Qing-zhu WEI ; Xue-ping HUANG ; Tian-hai JI ; Feng LI ; Zhi-qiang WANG ; Xiang-zhao LI ; Jiang-huan LIU ; Tong ZHAO

Chinese Journal of Hematology.2012;33(3):173-176.

OBJECTIVETo investigate co-expression of CD99/MIC2 and anaplastic lymphoma kinase (ALK) protein in anaplastic large-cell lymphoma (ALCL) tissues and Karpas 299 cells and its significance.

METHODSClinical prognoses and ALK protein expressions of 25 cases of ALCL were reviewed retrospectively, the median duration of survival was analyzed for patients with ALK(+) ALCL and ALK(-) ALCL. Histological and immunohistochemical staining were applied to other 25 cases of ALCL and paraffin-embedded tissue from human anaplastic large-cell lymphoma Karpas 299 cells to detect the protein of CD99 and ALK.

RESULTSOf former 25 cases of ALCL, median duration of survival for ALK(+) patients was 59 months, whereas 20 months for ALK(-) patients. The prognosis of ALK(+) group was better than that of ALK(-) group, survival curves of these two groups showed statistically significant (P < 0.05). CD99 was positive in 18 cases (72.0%) while negative in 7 cases (28.0%) of the latter 25 ALCL, ALK was positive in 19 cases (76.0%) while negative in 6 cases (24.0%); Of 19 ALK(+) ALCL, 16 (84.2%) cases co-expressed CD99-ALK; and in 6 ALK(-) ALCL, 2(33.3%) were CD99-ALK double negative, the expression of CD99 protein strongly correlated with that of ALK protein (P < 0.05). ALK and CD99 protein expressed in Karpas 299 cells with diffuse distribution.

CONCLUSIONSCD99 highly expressed in ALCL, and showed high rate of co-expression with ALK. CD99 protein expression could be considered as a helpful diagnostic and prognostic factor of ALCL, especially for ALK(+) ALCL.

12E7 Antigen ; Adolescent ; Adult ; Aged ; Antigens, CD ; metabolism ; Cell Adhesion Molecules ; metabolism ; Cell Line, Tumor ; Female ; Humans ; Lymphoma, Large-Cell, Anaplastic ; diagnosis ; metabolism ; Male ; Middle Aged ; Prognosis ; Receptor Protein-Tyrosine Kinases ; metabolism ; Retrospective Studies ; Young Adult

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A case of p190(bcr-abl) chronic myelocytic leukemia.

Jie SHI ; Yin ZHANG ; Ping-chong LEI

Chinese Journal of Hematology.2012;33(3):172-172.

Fusion Proteins, bcr-abl ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Male ; Middle Aged

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Increased susceptibility of recombinant type 2A von Willebrand factor mutant A1500E to proteolysis by ADAMTS13.

Jing-yu ZHANG ; Jian SU ; Zhen-ni MA ; Ning-zheng DONG ; Ying-chun WANG ; Chang-geng RUAN

Chinese Journal of Hematology.2012;33(3):169-172.

OBJECTIVETo investigate the susceptibility of von Willebrand factor (VWF) type 2A mutant A1500E to proteolysis by metalloprotease ADAMTS13 and to provide the direct supports for the pathogenesis of VWF mutation A1500E responsible for von Willebrand disease (VWD) type 2A.

METHODSRecombinant wild-type VWF (WT-VWF) and A1500E mutant VWF transiently expressed on transfected HeLa cell lines. Expression media were collected and concentrated, then cleaved directly by recombinant ADAMTS13 (rADAMTS13). Compared with WT-VWF, the susceptibility of A1500E mutant VWF to proteolysis by ADAMTS13 was analyzed using SDS-agarose gel VWF multimers analysis.

RESULTSIn vitro the expression of VWF:Ag in the supernatants of WT-VWF and A1500E mutant VWF were 1.10 U/ml and 0.78 U/ml, respectively, while VWF:Ag in cells lysates of A1500E mutant VWF was 90.6% of that of WT-VWF. The SDS-agarose gel VWF multimers analysis showed that there were no differences between WT-VWF and A1500E mutant VWF. The A1500E mutant VWF could be efficiently cleaved by ADAMTS13 under static condition without denaturants such as urea and guanidine HCl. VWF multimeric analysis showed that high and intermediate molecular weight multimers dramatically decreased while low molecular weight multimers obviously increased. Conversely, WT-VWF could not be cleaved by ADAMTS13 under the same condition.

CONCLUSIONThe A1500E mutation resulted in VWF more susceptible to ADAMTS13-dependent proteolysis, which belonged to VWD type 2A group 2 mutation.

ADAM Proteins ; genetics ; metabolism ; ADAMTS13 Protein ; Genotype ; HeLa Cells ; Humans ; Hydrolysis ; Mutation ; Recombinant Proteins ; genetics ; metabolism ; von Willebrand Disease, Type 2 ; genetics ; metabolism ; von Willebrand Factor ; genetics

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