[Effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia].

OBJECTIVE: To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML). METHODS: Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase. Allo-HSCT from HLA identical siblings was performed for 35 patients, of whom 11 received bone marrow transplantation (BMT) and 24 peripheral blood stem cell transplantation (PBSCT). Conditioning regimens was TBI (total-body irradiation) + CY (CTX) protocol in 8 patients and BU/CY protocol in 27 patients. The average follow-up was 48 months (range 7 - 108 months). RESULTS: 34 (97.1%) patients were successfully engrafted. Among them, 21 patients (60.0%) had three years disease-free (DFS) survival. The overall 5-year survival (OS) was 57.1%. Two patients (5.7%) relapsed. Transplant-related mortality occurred in 12 patients. Hemorrhagic cystitis (HC) occurred in 5 patients and HVOD was observed in 1 patient. Acute graft-versus-host disease (aGVHD) occurred in 18 patients (51.4%), among them 7 patients (20.0%) were of grade III-IV. Chronic GVHD was in 17 patients (48.5%). There was no significant difference in 3-years DFS between BMT group and PBSCT group (54.5% vs. 62.5%, P > 0.05). The 3-year disease-free survival (DFS) was 42.9% in TBI/CY group and 55.6% in BU/CY group (P > 0.05). In univariate prognostic analysis model, the DFS at 3 years is 75% and 47.4% for < or =30 years patients and >30 years patients, respectively, P < 0.05. The 3-year DFS of patients with first chronic phase is higher than patients with advanced diseases (61.3% vs. 40%, P < 0. 05). The 3-year DFS in patients of grade I - II GVHD was higher than that in patients of grade III-IV GVHD (81.8% vs. 14.3%, P < 0.05). CONCLUSION: The patients who had transplantation done within 1 year after diagnosis during their first chronic phase of disease and who had low-grade GVHD have better prognosis. Those patients who had III-IV acute GVHD are prone to incorporate severe infection, which was a worse prognostic factor of allo-HSCT for chronic myelogenous leukemia.

[Preliminary report of fludarabine, mitoxantrone and dexamethasone in treating refractory or relapsed multiple myeloma].

BACKGROUND & OBJECTIVE: Multiple myeloma has low complete remission rate and high recurrence rate. Recurrence or relapse of the disease is almost inevitable for most of the patients after several cycles of combined chemotherapy. This study was designed to compare efficacy of fludarabine-based regimen (fludarabine, mitoxantrone and dexamethasone) with that of pirarubicin, vincristine and dexamethasone (VAD) on refractory or relapsed multiple myeloma, and analyze their toxicities. METHODS: Twenty-two patients who had received VAD regimen were taken as a historical control group. A total of 11 patients received FND regimen. The differences between FND group and VAD group were observed and compared. The following indexes were assessed before, during, and after treatment: the partial remission (PR) rate, total response rate, time to achieve PR, the number of patients and time of serum M-component drop to more than 50% of the pre-treatment value, the ratio of myeloma cells in bone marrow drop to less than 5% or more than 80% of pre-treatment level, and the hemoglobin level increase to more than 20 g/Lû the white blood cell and platelet count of the peripheral blood, serum calcium, creatinine, beta2-microglobin and glutamic-oxaloacetic transaminase (GPT) level, adverse events were also analyzed. RESULTS: The PR rate was significantly higher in FND group than in VAD group (45.5% vs. 22.7%, P<0.05). The median time to achieve PR was significantly longer in FND group than in VAD group (76 days vs. 68 days, P<0.05). The occurrence rates of M-component decrease and hemoglobin elevation were significantly higher in FND group than in VAD group [45.5% vs. 22.7%, and 54.5% vs. 18.2%, P<0.05]. There were no significant differences in serum calcium, creatinine and GPT level pre- and post-treatment between the 2 groups. The level of serum beta2-microglobin after treatment was significantly lower than that before treatment in FND group [(1 042.8+/-72.3) microg/L vs. (2 350.2+/-184.0) microg/L, P<0.05]. The nadir white blood cell count was significantly lower in FND group than in VAD group [(0.9+/-0.46)x10(9)/L vs. (2.09+/-0.6)x10(9)/L, P<0.05], and the occurrence rates of fever and cough was significantly higher in FND group than in VAD group (36.4% vs. 4.5%, 45.5% vs. 9.0%, P<0.05). CONCLUSIONS: Compare with VAD regimen, FND regimen may enhance the PR rate of refractory or relapsed multiple myeloma patients, but it takes longer time to achieve PR, and shows obvious bone marrow inhibition, with no significant renal or hepatic toxicity. FND regimen is effective and safe in treating refractory or relapsed multiple myeloma.

[The relation between Bence Jones protein gene polymorphism and function of renal tubular-epithelial cell in multiple myeloma].

OBJECTIVE: Bence Jones protein (BJP) plays an important role in multiple myeloma (MM) renal lesion, we try to study the relation between the characteristics of BJP variable gene and the function of renal tubular-epithelial cell (TEC). METHODS: MM patients whose function of TEC was abnormal at diagnosis constituted a group damage and patients whose function of TEC was normal for a long period a group normal. We also collected MM patients and divided them into a group BJPkappa and a group BJPlambda. Total RNAs were isolated from the mononuclear cells of bone marrow and reverse transcription was carried out with an oligo dT18 primer; these cDNAs were then amplified with PCR, cloned and sequenced, the comparison and analysis of the sequences were made according to current ESBC/Gen Bank sequence directories. RESULTS: 3/5 cases of BJPlambda use V3-4 gene in the group damage, the replacement R mutation ratio of CDRS in the group damage (7.57 +/- 3.40) was higher than that in the group normal (4.25 +/- 1.90) and higher than that of FWRS in the group damage (3.29 +/- 1.25); R mutation ratio of CDRS region in the group BJPlambda (6.64 +/- 2.38) was higher than that in the group BJPkappa (4.10 +/- 2.13) and higher than that of FWRS in the group BJPlambda (2.91 +/- 0.94), R mutation ratio of CDRS both in the group BJPkappa or BJPlambda was higher than that of FWRS respectively. CONCLUSIONS: The higher ratio of renal lesion in some MM patients and BJPlambda patients is correlated with the high ratio of their variable gene R mutation which result in changing organization and physicochemical activity of BJP. BJP translated by some subtype genes may incline to injure the function of TEC.

[Efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on chronic myeloid leukemia in blast phase].

BACKGROUND & OBJECTIVE: Chronic myeloid leukemia (CML) in blast phase is refractory with a poor prognosis. This study was to evaluate efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on CML in blast phase. METHODS: Nineteen patients with CML in blast phase (imatinib treatment group) received induction of cytarabine-based standard chemotherapy for 2 cycles, and 400 mg/d of imatinib mesylate for 4 weeks. Patients with no remission received 600 mg/d of imatinib mesylate for another 8 weeks. Treatment of 600 mg/d of imatinib mesylate was maintained if it showed effects after 8 weeks, otherwise it would be stopped. Twenty-two patients with CML in blast phase (historical control group) received inducement of cytarabine-based chemotherapy for 2 cycles, and other regimens of consolidation or continuous induction. RESULTS: Sixteen patients of imatinib treatment group achieved no hematologic remission after induction. After treated with imatinib mesylate, 6 of 16 (38%) achieved hematologic complete remission (CHR), and major cytogenetic response; 2 of 16(13%) achieved hematologic partial remission (PHR); 1 of 16 (6%) returned to chronic phase with minor cytogenetic response. Total hematologic response rate of imatinib treatment group was 57%; 1-year survival rate was 38% (6/16). Eighteen patients of historical control group achieved no hematologic remission after inducement. After treated with other regimens, 2 (11%) achieved CHR, and 1 (6%) achieved PHR. Total hematologic response rate of historical control group was 17%; 1-year survival rate was 6%(1/18), significantly lower than that of imatinib treatment group (P< 0.05). CONCLUSIONS: Imatinib mesylate may have anti-leukemic activity, and prolong survival time of patients with CML in blast phase. But problems of tumor relapse, and drug resistance are still present.

[Expression of CD117 antigen on multiple myeloma and its significance].

BACKGROUND & OBJECTIVE: Leukocyte differentiation antigen CD117 is one of the targets that tyrosine kinase selective inhibitors work on. Whether CD117 is expressed on the cell surface, and the expression level are highly correlated with tyrosine kinase selective inhibitors. This study was designed to investigate the expression of CD117 on multiple myeloma (MM) cells, which may provide a theoretical evidence for the use of tyrosine kinase selective inhibitors in MM,meanwhile,the importance of CD117 expression on MM cells was estimated. METHODS: CD117, CD56, and CD54 were measured by three-color flow cytometry with CD45/SSC gating strategy. RESULTS: Of 48 patients with MM, 17 (35.5%) had positive CD117 expression on myeloma cells, 39 (81.2%) had positive CD56 expression, and 48 (100.0%) had positive CD54 expression. CD117 expression on myeloma cells was lower than CD56, and CD54. CD117 positive expression was positive correlated with the percentage of myeloma cells in bone marrow. CD117 positive in IgG type of MM was 64%, higher than other types such as light chain or IgA. CD117 positivity showed no significant difference in different stages (P >0.05), and in patients haven't been pretreated, or relapsed after pretreated (P >0.01). In MM patients haven't been pretreated, the reaction rate of VAD chemotherapy in CD117 positive cases was 71.4%, and showed no significant difference (P >0.05) compared with the reaction rate of 66.7% in CD117 negative cases. CONCLUSION: CD117 can be regard as the related tumor antigen of MM, and may be a valuable marker in the use of tyrosine kinase selective inhibitors, which inhibit the signal conduct to the target.

[Effects of combination therapy with all-trans retinoic acid and arsenic trioxide on acute promyelocytic leukemia].

BACKGROUND & OBJECTIVE: The mechanism of effect of arsenic trioxide on promyelocytic leukemia is different from that of all-trans retinoic acid. Arsenic trioxide exerts its action by accelerating cell apoptosis, while all-trans retinoic acid by inducing cell differentiation. However, both drugs can inhibit the transcription of tissue factor (TF) mRNA in acute promyelocytic leukemia, and decrease TF level and coagulative activity to normalize coagulopathy. The objective of the study was to observe whether combination of the two drugs could improve efficacy or in contrary accentuate adverse reactions. METHODS: Two groups of patients with acute promyelocytic leukemia were included. Twenty-two patients (17 untreated cases and 5 relapsed cases) from January 2000 to October 2001 in group I were treated only with oral retinoic acid [25 mg/(m(2)x d) in two divided doses] for less than 50 days. Nineteen cases (15 untreated cases and 4 relapsed cases) from November 2001 to June 2003) in Group II were treated with combination of arsenic trioxide and all-trans retinoic acid. 0.1% AS2O3 10 ml in 500 ml 5% glucose solution was given intravenously for 4 to 6 hours per day for 28 days. The dosage of retinoic acid in group II was the same as that in group I. RESULTS: Nineteen of 22 cases in retinoic acid-treated group (group I)(16 untreated cases and 3 relapsed cases) achieved complete remission (CR). The CR rate was 86.4%. Seventeen of 19 cases in combination therapy group (group II)(15 untreated cases and 2 relapsed cases) achieved CR. The CR rate was 89.5%. The death rates were 13.6% (3/22, 1 untreated case, 2 relapsed cases) in group I and 10.5% (2/19, 2 relapsed cases) in group II, respectively. The median time to CR was 23 days in group I and 26 days in group II, and the median time to normalization of coagulopathy was 7 days in group I and 4 days in group II. Significant differences were found between the two groups. No significant adverse reaction was observed in both groups. CONCLUSION: The CR rate and death rate were not different between the two groups. The combination therapy with AS2O3 and all-trans retinoic acid can shorten the time to CR and normalization of coagulopathy.

[Comparison of two conditioning regimens in treatment of leukemia by allogeneic hematopoietic stem cell transplantation].

BACKGROUND & OBJECTIVE: The conditioning regimens are the critical factors in the allogeneic hematopoietic stem cell transplantation. This study was conducted to compare the effectiveness and side-effects of two conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Twenty-one cases received busulfan(BU) 16 mg/kg plus cyclophosphamide(CY) 120 mg/kg,the other 23 cases received total body irradiation(TBI) 7.5-8.5 Gy plus CY 120 mg/kg regimen. RESULTS: The 3-year disease-free survivals (DFS) were 61.5% in BU/CY group and 64.7% in TBI/CY group, respectively (P >0.05). The relapse rates were 23.8% and 26%, respectively, without significant difference (P >0.05). The incidence of liver damage in the BU/CY group was higher (80.9%) than that in the TBI/CY group (54.3%) (P< 0.05), while no case developed hepatic veno-occlusive disease. Stomatitis and gastrointestinal toxicity were significantly lower in the BU/CY group (33.3% and 42.9%) compared with TBI/CY group (78.2% and 78.2%), respectively (P< 0.05). Bladder toxicity (23.8% and 26%) and pulmonary toxicity(14.3% and 13%) were similar in the two groups(P >0.05), while one patient in TBI/CY group developed grade IV pulmonary toxicity, which is lethal. No case was found to have cardiac, renal, or central nervous system grade I toxicity. CONCLUSION: The two groups have equal effectiveness, BU/CY regimen is relatively easy to administer and well tolerated with low extramedullary toxicity.

[Influence of thalidomide on bone marrow microenvironment in refractory and relapsed multiple myeloma].

BACKGROUND & OBJECTIVE: More and more studies indicated that microenvironment plays a major role in growth, survival, and drug resistance of myeloma cells. Thalidomide is one of agents targeting the bone marrow microenvironment. This study was conducted to investigate the mechanism of thalidomide by observation of influence of thalidomide on bone marrow microenvironment in refractory and relapsed multiple myeloma. METHODS: The expression of ICAM-1 and VCAM-1 of bone marrow stromal cell (BMSC) membrane of refractory and relapsed multiple myeloma was measured using flow cytometry. The expression of IL-1beta(m)RNA, IL-6mRNA, and TNF-alpha(m)RNA in myeloma BMSC was measured by semiquantitative RT-PCR. The serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor(bFGF) were measured by ELISA. RESULTS: The average values of fluorescence of ICAM-1 and VCAM-1 on the myeloma BMSC membrane were 13.28+/-4.26 and 10.35+/-2.47, respectively; while the average values of fluorescence after treatment effectively with thalidomide were both lower (4.29+/-0.98 and 3.54+/-0.62) (P< 0.01, P< 0.05). The ratios of IL-1beta(m)RNA, IL-6(m)RNA, and TNF-alpha mRNA to beta-actin of the myeloma BMSC were 1.83+/-0.64, 24.52+/-11.46, and 3.42+/-1.83, respectively; while the ratios after treatment effectively with thalidomide were all lower (0.58+/-0.11, 13.47+/-14.31, and 1.25+/-0.76)(P< 0.05,P< 0.05,P< 0.01). There was no significant difference between the values of ICAM-1 and VCAM-1 or among the ratios of IL-1beta(m)RNA, IL-6(m)RNA, and TNF-amRNA to beta-actin of the myeloma BMSC before and after treatment ineffectively with thalidomide (all P >0.05). The serum levels of VEGF and bFGF of the patients were (150.26+/-19.33) ng/L and (23.78+/-13.63) ng/L, respectively. The serum levels of VEGF and bFGF were higher after treatment (effectively and ineffectively) than those before treatment (P< 0.002, P< 0.005). CONCLUSION: Thalidomide can not only inhibit angiogenesis, but also abrogate the adhesion of multiple myeloma cells to bone marrow stromal cells.

[In vitro inhibition and mechanism of multiple myeloma cells growth by thalidomide].

To investigate the influence of the thalidomide on the growth of multiple myeloma cells from untreated, relapsed or refractory patients and summarize its mechanisms, thalidomide influence on colony growth of untreated, relapsed or refractory multiple myeloma cells cultured by semisolid methylcellulose was observed. The level of interleukin-6 (IL-6) autosecreted by myeloma cells was tested by IL-6-dependent cell line when myeloma cells were treated with thalidomide at 200 microgram/ml, and in the same concentration of thalidomide the expression of IL-6 receptor were tested by flow cytometry. Results showed that colony growths of myeloma cell from untreated and relapsed or refractory patients were all colonies were inhibited when treated by thalidomide up to 75 microgram/ml or 100 microgram/ml concentration. The inhibition was concentration-dependent, higher concentration cause more inhibition. After treatment with thalidomide at 200 microgram/ml, the concentrations of IL-6 secreted by myeloma cells were (148.5 +/- 96.7) microgram/ml, and the levels of IL-6 receptor expressed on the cell surface were 16.7% and 20.2% in untreated and relapsed or refractory patients, respectively, and those were significantly lower than those levels in the cells before exposure to thalidomide. It was concluded that thalidomide can inhibit growth of both relapsed or refractory cells and untreated myeloma cells in vitro. Therefore, it can be used to treat untreated multiple myeloma patients. Inhibiting tumor cells secreting level of IL-6 and reducing the expression of IL-6 receptor on myeloma cell surface is one of the mechanisms for thalidomide to remedy multiple myeloma patients