全反式维甲酸治疗急性早幼粒细胞白血病30例临床观察

全反式维甲酸治疗急性早幼粒细胞白血病３０例临床观察游慧萍，叶宝国，马旭东，林骥，游旭闽，杨素美，周艳贞福建省漳州市医院（漳州·３６３０００）我们应用全反式维甲酸治疗３０例急性早幼粒细胞白血病（ＡＰＬ），取得８６．７％的完全缓解（ＣＲ）宰，疗效较满意。...     

小剂量全反式维甲酸治疗急性早幼粒细胞白血病5例报告

小剂量全反式维甲酸治疗急性早幼粒细胞白血病５例报告孟凡义１楼方定１于力１李新梅２张伯龙１自去年以来我们应用小剂量全反式维甲酸（Ａ－ＴＲＡ）治疗急性早幼粒细胞白血病（ＡＰＬ）５例，获得满意疗效，现小结如下。材料与方法病例５例ＡＰＬ均符合ＦＡＢ诊断标准，...     

全反式维甲酸加DA方案治疗急性早幼粒细胞白血病的临床观察

全反式维甲酸加ＤＡ方案治疗急性早幼粒细胞白血病的临床观察姚广平王卫东１９９２年—１９９６年，我们应用全反式维甲酸（ＡＴＲＡ）加柔红霉素（ＤＮＲ）、阿糖胞苷（Ａｒａ－Ｃ）治疗急性早幼粒细胞白血病（ＡＰＬ）１２例，现将结果报告如下。１材料与方法１．１病例...     

维甲酸治疗急性早幼粒细胞白血病早期死亡4例报告

维甲酸治疗急性早幼粒细胞白血病早期死亡４例报告吴伟东近年来，国内外采用全反式维甲酸（ＡＴＲＡ）诱导分化治疗急性早幼粒细胞白血病（ＡＰＬ）已取得显著疗效［１］。然而ＡＴＲＡ治疗ＡＰＬ过程中的严重副作用，白细胞淤滞及维甲酸综合征而导致的早期死亡报告较少。...     

全反式维甲酸与小剂量三尖杉酯碱治疗急性早幼粒细胞白血病

急性早幼粒细胞白血病(APL)是一类预后凶险的白血病,常常在治疗中出现 DIC 而危及生命。近年来,全反式维甲酸(RA)已成为治疗 APL 的有效药物之一,并广泛应用。但全反式维甲酸与小剂量的三尖杉酯碱双重分化诱导治疗急性早幼粒细胞白血病,国内尚未报道。自1987年以来,我们在上海第二医科大学的大力支持下,采用全反式维甲酸联合小剂量三尖杉酯碱双重分化诱导治疗25例 APL,取得了满意的效果,现报告如下。     

全反式维甲酸与小剂量三尖杉酯碱治疗急性早幼粒细胞白血病

急性早幼粒细胞白血病(APL)是一类预后凶险的白血病，常常在治疗中出现DIC而危及生命。近年来，全反式维甲酸(RA)已成为治疗APL的有效药物之一，并广泛应用。但全反式维甲酸与小剂量的三尖杉酯碱双重分化诱导治疗急性早幼粒细胞白血病，国内尚未报道。自1987年以来，我们在上海第二医科大学的大力支持下，采用全反式维甲酸联合小剂量三尖杉酯碱双重分化诱导治疗25例APL，取得了满意的效果，现报告如下。     

全反式维甲酸诱导急性早幼粒细胞白血病完全缓解后继续治疗疗效观察

全反式维甲酸诱导急性早幼粒细胞白血病完全缓解后继续治疗疗效观察汪涟明，孙酬经，钱美华，黄强目前治疗急性白血病的目标在于提高完全缓解率与长期生存率。用全反式维甲酸（ＡＴＲＡ）诱导分化疗法治疗急性早幼粒细胞白血病（ＡＰＬ）已取得良好疗效，为探讨ＡＴＲＡ诱...     

全反式维甲酸治疗小儿急性早幼粒细胞性白血病12例体会

急性早幼粒细胞性白血病(APL)是急非淋白血病中较难治的一种类型,其发病急,病情重,易出血,在常规化疗中绝大多数并发弥漫性血管内凝血(DIC),是以往治疗失败的主要原因。维甲酸(RA)治疗急性早幼粒细胞性白血病有独特疗效已见报道。现将我院1990年10月～1993年4月采用全反式维甲酸治疗12例APL患儿临床体会报道如下。     

对维甲酸原发耐药的急性早幼粒细胞白血病的观察

对维甲酸原发耐药的急性早幼粒细胞白血病的观察（附５例报告）李晶金蓉珍陆益龙全反式维甲酸（ＡＴＲＡ）诱导分化治疗急性早幼粒细胞白血病（ＡＰＬ）疗效显著，完全缓解（ＣＲ）率达８５％～９０％，对ＡＴＲＡ原发耐药者少见。我们近年来，遇到５例ＡＰＬ，其中２例为...     

维甲酸治疗急性早幼粒细胞白血病高细胞期的并发症

维甲酸治疗急性早幼粒细胞白血病高细胞期的并发症沈志祥，时峰，曾晓颖，陈钰，张芬琴，李秀松目前，维甲酸已成为＂急性早幼粒细胞白血病＂首选的治疗方法［１］．在应用维甲酸后的１０天左右，大部分患者的外周血会出现一个＂高细胞期＂［２］，少数患者可出现一些严重...     

Retinoic acid-induced CD38 antigen promotes leukemia cells attachment and interferon-gamma/interleukin-1beta-dependent apoptosis of endothelial cells: implications in the etiology of retinoic acid syndrome

All-trans retinoic acid (RA) treatment of patients with acute promyelocytic leukemia (APL) induces complete remission in more than 90% of the cases. Although RA therapy is well tolerated, about 25% of APL patients develop a potentially fatal condition called retinoic acid syndrome (RAS). Molecular mechanisms underlying the development of RAS pathogenesis, especially those that result in the damage of endothelial cells remain elusive. In the present study, we found that RA treatment induces the expression of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in peripheral blast cells from APL patients. IFN-gamma and IL-1beta also exerted synergistic effect in driving human umbilical cord endothelial cells (HUVECs) and human lung microvascular endothelial cells (HLMVECs) into apoptosis. RA also upregulated the expression of CD38, an ectoenzyme responsible for the generation of the calcium messenger cyclic ADP-ribose. Importantly, RA-induced CD38 expression promoted strong attachment of leukemia cells to endothelial cells, and incubation of endothelial cells with either high concentration (100 ng/ml) of IFN-gamma alone or low concentration of IL-1beta and IFN-gamma (10 ng/ml, each) induced strong apoptotic responses as revealed by caspase-8 activation and DNA fragmentation. Our results suggest that these RA-induced events could contribute to the development of RAS pathogenesis in patients with APL.     

Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia--the occurrence of retinoic acid syndrome is a risk factor.

All-trans retinoic acid (ATRA) is now a standard agent for remission induction of acute promyelocytic leukemia (APL). Recently, extramedullary relapse, which was a rare condition in APL patients after chemotherapy alone, was reported with an increased frequency after ATRA treatment. However, it is not yet clear whether ATRA truly increases the risk of extramedullary recurrence and what are the risk factors. In this study, three of 13 patients with recurrent APL after prior treatment of ATRA were found to have extramedullary involvement, compared with none in 11 recurrent patients previously treated with chemotherapy alone (estimated relative risk 2.100, 95% confidence interval 1.341-3.289). Furthermore, in the former group of patients, the development of retinoic acid (RA) syndrome during prior induction treatment was significantly associated with extramedullary involvement at relapse (three in five patients with RA syndrome vs none in eight without the syndrome, estimated relative risk 5.000, 95% confidence interval 1.448-17.271). In conclusion, ATRA may predispose APL patients to extramedullary involvement at relapse and the occurrence of RA syndrome is a risk factor for it. Further studies are needed to confirm these findings. It also remains to be clarified whether treatment modification is necessary in patients who develop RA syndrome during ATRA treatment.     

Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells.

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells.Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.     

Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.     

Liposomal-all-trans-retinoic acid in treatment of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) characterized by the translocation t(15;17) is uniquely sensitive to the differentiation-inducing effects of all-trans-retinoic acid (ATRA). All-trans-retinoic acid therapy induces complete clinical remissions (CRs) in most of patients with APL. However, chronic daily oral administration of ATRA results in accelerated metabolism of ATRA, leading to a progressive decline in plasma drug concentrations. These lower drug levels are associated with relapses and resistance to oral ATRA in patients with APL; thus the use of ATRA as a single agent is precluded. Liposomal ATRA (Lipo-ATRA) was designed to maintain high and stable plasma concentrations and to further improve the outcome of the APL disease by overcoming the development of ATRA resistance. Liposomal ATRA was shown to circumvent accelerated drug metabolism in the liver of rats in an animal model. In a phase I clinical study, intravenous (i.v.) administration of lipo-ATRA was shown to produce a significantly better pharmacokinetic profile than oral ATRA (non-liposomal) and to maintain higher and sustained plasma drug concentrations, with a similar side effects. More importantly, lipo-ATRA as a single agent induces PCR-negative molecular remissions in a high proportion of newly diagnosed patients with APL and maintain remissions up to 15-17 months or longer. In this review, we discuss the pharmacological features of lipo-ATRA and the molecular remissions induced by lipo-ATRA in newly diagnosed patients with APL or patients previously treated with ATRA or chemotherapy, and the possible impact of lipo-ATRA on the outcome of APL.     

Inhibition of granulocytic differentiation of acute promyelocytic leukemia cells in primary culture by transforming growth factor-β

We investigated the effect of transforming growth factor-β₁ (TGFβ) on the proliferation and differentiation of cultured acute promyelocytic leukemia (APL) cells with the chromosomal t(15;17) translocation obtained from four patients to determine the role of TGFβ on growth and differentiation of APL cells.

DNA synthesis, determined by ³H-thymidine uptake, was inhibited in the presence and absence of granulocyte colony-stimulating factor (G-CSF) in a dose-dependent manner by TGFβ in APL cells obtained from three of the four cases. TGFβ and G-CSF did not significantly affect the differentiation of APL cells, but all-trans retinoic acid (RA) induced morphological and functional differentiation in all APL cells tested. G-CSF markedly enhanced RA-induced granulocytic differentiation in APL cells obtained from all four cases. In cells in which TGFβ inhibited DNA synthesis, it also inhibited RA-induced granulocytic differentiation of APL cells and, to a greater degree, granulocytic differentiation induced by RA plus G-CSF.

These results suggest that TGFβ is a negative regulator of the proliferation and differentiation of APL cells. The significance of TGFβ as an endogenous regulator in differentiation therapy with RA of APL patients is discussed.     

Establishment of a retinoic acid-resistant human acute promyelocytic leukaemia (APL) model in human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgenic severe combined immunodeficiency (SCID) mice.

To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL.     

Arsenicals in hematologic cancers

Arsenic trioxide (AT) has been the object of renewed interest as a therapeutic since studies in China in the late 1980s confirmed its efficacy in the treatment of acute promyelocytic leukemia (APL). These studies have been replicated in the West, with complete remissions achieved in 80% to 90% of patients with refractory or relapsed APL. The drug has been relatively well tolerated. The dose used for treatment of APL (0.15 mg/kg/d) is approximately 50% of the maximum-tolerated dose (MTD). Common side effects have included fatigue, rash, fluid retention, and QTc-interval prolongation on electrocardiogram. A "retinoic acid syndrome," similar in its manifestations to that noted after administration of all-trans retinoic acid (RA), has been observed in APL patients. Recent studies have included dose-ranging trials to determine pharmacokinetics and the optimum schedule of administration, and studies of possible mechanisms of action. Promising future trials include combining AT with RA in the treatment of newly diagnosed APL, and broadening the range of AT therapy to other leukemias, lymphomas, multiple myeloma and some solid tumors.