Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen

We have studied the use of a new preparative regimen for the treatment of patients in remission of acute myeloid leukemia (AML) with autologous bone marrow transplantation. Chemotherapy consisted of busulfan 1 mg/kg every 6 hours for 4 days (total dose, 16 mg/kg) on days -7 through -4 followed by an intravenous infusion over 6 to 10 hours of etoposide 60 mg/kg on day -3. Autologous bone marrow, treated in vitro with 100 micrograms/mL of 4-hydroperoxycyclophosphamide, was infused on day 0. We have treated 58 patients up to the age of 60 years, 32 in first remission, 21 in second or third remission, and 5 with primary refractory AML unresponsive to high-dose Ara-C, but achieving remission with aggressive salvage regimens. Of the first remission patients, there has been 1 treatment related death and 5 relapses. With median follow-up of 22 months, the actuarial relapse rate is 22% +/- 9% and disease-free survival is 76% +/- 9% at 3 years. Patients with favorable French-American-British (FAB) subtypes (M3 or M4 EO) did especially well, with no relapses seen in 15 patients observed for a median of 30 months. Actuarial relapse rate at 3 years was 48% for first remission patients with less favorable FAB subtypes. Of patients in second or third remission, there were 5 treatment related deaths and 4 relapses. With median follow-up of 22 months, the actuarial relapse rate is 25% +/- 11% and disease-free survival is 56% +/- 11% at 3 years. Four of five primary refractory patients died during treatment and 1 remains in remission with short follow-up. These preliminary data are very encouraging and, if confirmed, support the use of autologous purged bone marrow transplantation using aggressive preparative regimens as one approach to improve the outcome of adults with AML.     

Hematopoietic stem cell transplantation in chronic myeloid leukemia

The expression of three sialylated mucin-associated antigens - sialosyl-Lewisa (SLEA), sialosyl-Lewisx (SLEX) and sialosyl-Tn (STN) - and their correlation with the TNM stage, histopathological growth pattern and prognosis was investigated in a series of 127 gastric carcinomas. Various classification systems (pTNM, WHO and Laurén) did not display any correlation with an expression of the sialomucin antigens under study. SLEA reactivity was strongly associated with an unfavorable outcome of the total population, whereas SLEX and STN did not exert such an impact. However, in the subgroups of pTNM stage I as well as pN0 patients, SLEA and SLEX reactivity of the tumors was associated with a worse prognosis. In the subgroup of diffuse-type cancers as defined according to Laurén's classification, the expression of all three antigens indicated a worsening of the prognosis.     

Related donor marrow transplant for chronic myeloid leukemia: patient characteristics predictive of outcome

This article presents health expectancy calculations from Bulgaria for 1976-1992. The calculations are based on mortality statistics and data from a national information system from the Expert Medical Commissions on Working Capacity about loss of working capacity. Following internationally accepted terminology, the most appropriate term for the health expectancies presented here is "occupational handicap-free life expectancy' (OHFLE). Life expectancies were calculated as partial life expectancies from ages 16 to 59. Health expectancy calculations followed Sullivan's cross-sectional method with age and sex specific prevalence data on occupational handicap. Around 1985 a three- to four-fold increase in these prevalences occurred. The distribution of occupational handicaps over sexes, age groups and severity levels, however, remained fairly constant. The results show a decrease both in partial life expectancy within the age range 16-59 and in OHFLE at the age of 16 for men. For women a more or less stable partial life expectancy and a decrease in OHFLE at the age of 16 was found around 1985. The introduction of more incentives for people who successfully registered probably caused the decrease around 1985. Major social changes may have acted as confounding factors for the fluctuations after 1985. On the other hand the findings may reflect real changes in population health due to an increasing incidence in some major disease categories. The nation-wide system for assessment and registration of health related working incapacity has proved a useful source for an attempt to calculate OHFLE. Given uncertainties about the population health underlying these changes in OHFLE, however, it is recommended that health interview and health examination surveys should be considered as alternative routes for achieving a more comprehensive picture of population health in Bulgaria.     

Autologous hematopoietic stem cell transplantation in chronic myeloid leukemia

A circuit that simulates T-type calcium-channel current characteristics of the sinoatrial (SA) node was developed from discrete electronic components and tested at physiologic membrane voltage ranges. The circuit design was based on the T-type calcium-channel current dynamics obtained from a mathematical model of the SA node membrane, which, in turn, is based on physiologic data. The design was held at a resting membrane potential and then stepped to new voltages over the entire operating range of the T-type calcium channel. The circuit was validated by comparing its transient response current with the predicted current from the mathematical model. In addition, the peak currents of the circuit were compared with plots of peak current obtained from the mathematical model and physiologic data. By showing that the electronic circuit mimics the T-type calcium-channel current dynamics found within the SA node, the results may provide a foundation for developing a novel cardiac pacemaker that is based on the ion-channel characteristics of excitable tissue.     

Relationship between cleaved L-selectin levels and the outcome of acute myeloid leukemia

High plasma levels of the shed form of L-selectin (sL-selectin) are frequently detectable in acute myeloid leukemia (AML). sL-selectin can inhibit blast cell adhesion to vascular endothelium and may thereby influence the phenotype of AML. In this study, we have investigated the relationship between sL-selectin levels and clinical presentation or disease outcome in 100 patients with AML. Fifty-eight patients were found to have sL-selectin levels >/=3.12 microgram/mL (>/=3 SD above the mean of healthy controls: "increased"). Patients with extramedullary disease such as lymphadenopathies, splenomegaly, hepatomegaly, and/or muco-cutaneous infiltration had significantly increased sL-selectin levels (P < .001). sL-selectin levels were significantly heterogeneous in the French-American-British subtypes (P = .0003). Patients with "normal" sL-selectin levels had higher probability of achieving complete remission (CR) than with "increased" levels: 81% versus 64%, respectively (P = .06). When adjusting for clinically relevant covariates predictive for CR (sex, age, Auer rods), "normal" sL-selectin levels were significantly associated with CR (odds ratio, 3.08; 95% confidence interval [CI], 1.10 to 8.58; P = .03). Moreover, patients with "increased" sL-selectin levels (>/=3.12 microgram/mL) had shorter event-free survival (EFS) (median 7.3 v 12 months, P = .008) and overall survival (median 1 v 2.05 years, P = .03) than patients with sL-selectin <3.12 microgram/mL. Multivariate statistical analysis (adjusted for age and presence of Auer rods) indicated that sL-selectin was an independent prognostic factor for EFS (hazard ratio [HR], 1.96; 95% CI, 1.21 to 3.17, P = .006) and overall survival (HR, 1.80; 95% CI, 1.09 to 2.98; P = .02). Thus, plasma sL-selectin may be a useful prognostic marker in the evaluation of AML at diagnosis.     

Treatment of chronic myeloid leukemia in relapse after umbilical cord blood transplantation

Umbilical cord blood (UCB) is increasingly used as a source of hematopoietic progenitor cells for allotransplantation. Donor-derived buffy coat cells are considered optimal treatment for leukemia relapses after transplantation of allogeneic bone marrow. Experience with relapses after UCB transplants are sparse. Here we report a girl who received an UCB transplant for chronic myeloid leukemia, relapsed after three years, failed to respond to donor buffy coat cells, but achieved a complete hematologic, cytogenetic, and molecular remission on interferon-alpha.     

Rationalizing autotransplant strategies for chronic myeloid leukemia

The molecular genetic basis of chronic myeloid leukemia (CML) is well-defined, but until recently therapeutic approaches have been largely empiric. Conventional chemotherapy and interferon offer palliation, but only bone marrow transplantation provides for cure. Because the majority of CML patients are not candidates for allogeneic transplantation, autologous strategies have emerged as an alternative. Data from murine models of CML provide insights into the mechanisms by which autotransplant might be effective in the treatment of CML. Further dissection of the molecular pathways by which the BCR/ABL protein can induce leukemia offers the promise of a more targeted, rationally-designed therapy. When used for remission maintenance therapy following autologous bone marrow transplantation, specific inhibitors of BCR/ABL should provide for long term disease-free survival.     

Autografting in chronic myeloid leukemia: an overview

Autografting could become a promising treatment for patients with chronic myeloid leukemia (CML) who cannot undergo allogeneic bone marrow transplantation or failed to respond to recombinant alpha-interferon (IFN). In this review, we analyze the results which have been published for patients transplanted in chronic phase and which suggest that autografting could prolong survival, at least in some patients. We also discuss the different methods of purging whose clinical efficacy remains to be assessed.     

Granulocytic sarcoma presented as a reactivation of chronic myeloid leukemia after allogenic marrow transplantation

The authors report the case of a chronic myeloid leukemia (CML) patient submitted to allogenic bone marrow transplantation, who had probably never entered complete remission. The disease was reactivated as a granulocytic sarcoma, next to a platinum plate installed to correct a tibia fracture 11 years earlier. Its final event was a myeloid Ph1 + blastic crisis that was unsuccessfully treated with high doses of sc interferon and citarabine.     

慢性粒细胞白血病患者血浆伊马替尼浓度检测与临床疗效分析

目的 探讨慢性粒细胞白血病(CML)患者服用伊马替尼治疗后,伊马替尼血浆浓度在个体间的差异以及与临床疗效的关系.方法 2005年7月至2008年2月开始服用伊马替尼治疗的CML患者共51例纳入研究,其中男34例,女17例,服用剂量300 mg/d 9例、400 mg/d 37例,600 mg/d5例;采用高效液相色谱法(HPLC)测定患者空腹伊马替尼血浆谷浓度;SPSS13.0软件进行统计分析.结果 伊马替尼血浆谷浓度与服用剂量有关,且个体之间差异较大,为(342～4688)ng/ml;300mg/d剂量组的伊马替尼血浆谷浓度为(1037±514)ng/ml,低于400mg/d剂量组的(2123±1016)ng/ml(t=2.34,P=0.032);300 mg/d剂量组的治疗有效率为66.67%(6/9),低于400 mg/d剂量组的89.19%(33/37)(χ2=7.14,P=0.008);在300、400mg/d剂量组中,39例治疗有效,伊马替尼血浆谷浓度高于治疗效果不理想患者,差异有统计学意义(t=2.25,P=0.037);受试者工作特征曲线(ROC曲线)结果提示伊马替尼血浆谷浓度低于1050 ng/ml者,其临床疗效可能较差,敏感度为84.6%,特异度为71.1%.结论 CML患者服用伊马替尼治疗后药物血浆浓度与服用剂量有关,不同个体间差异较大,血浆谷浓度低于1050 ng/ml提示其临床疗效可能较差.     

Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha

In 1994, the Italian and the German Chronic myeloid leukemia (CML) trials comparing interferon-alpha (IFN-alpha) with conventional chemotherapy were published. The survival advantage in favor of IFN-alpha compared with hydroxyurea (HU; 72 v 52 months) was significant in the Italian (P < .002), but not in the German trial (66 v 56 months, P < .44). We set up a collaborative study to identify the reasons for the different outcomes. There are major differences in the trial protocols concerning admission criteria, treatment strategy, and definitions. The German patients were older and more seriously sick. Fifty-two of the 327 patients in the German IFN and HU arms did not fulfil Italian admission criteria, and 41 of the 322 Italian patients did not fulfil German admission criteria. Using mutually uniform admission criteria, the median survival times of the IFN patients are 76 (Italian) and 72 (German) months (P = .56). The Italian group administered IFN combined with HU as needed, whereas the German group strictly used IFN as monotherapy with rerandomization to busulfan (BU) or HU after IFN resistance or intolerability. The differences seen between the Italian and the German trial results can be accounted for by objective differences in study design, especially the admission criteria, treatment strategy, and bias due to intention to treat analysis. The detailed analysis of the data suggests that the combination of IFN with HU as needed is more effective than either agent alone.     

Autologous transplantation for the treatment of chronic myelogenous leukemia

There is evidence that benign, Ph-negative hematopoietic progenitors persist in the marrow and blood of some patients with chronic myelogenous leukemia (CML). A number of pilot studies using purged and unpurged marrow or peripheral blood autografts have demonstrated that autologous transplantation can result in transient cytogenetic responses in CML. Although not curative, this procedure may be associated with longer-than-expected patient survival and represents an alternative treatment for patients ineligible for allogeneic transplantation and not responding to interferon-alpha therapy. Several novel approaches are being developed to improve graft purging and eliminate residual leukemia post-transplantation. Such approaches may allow for long-term restoration of Ph-negative hematopoiesis following the procedure.     

Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-alpha (IFN-alpha), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-alpha results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-alpha on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-alpha therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-alpha, whereas 22, 23, and 25 patients received IFN-alpha for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-alpha therapy administered for > or = 6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2. 1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-alpha therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight > or = 110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-alpha for less than 6 months before transplant, who were < or = 50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% +/- 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-alpha when the patient is < or = 50 years of age and has an HLA-compatible unrelated volunteer donor.