肝静脉闭塞病的诊断与治疗

肝静脉闭塞病(HVOD)是造血干细胞移植常见的严重并发症,死亡率较高。其临床诊断标准已广为应用。近年来,人们也发现了一些其它的辅助诊断方法,如血清透明质酸及血清CA-125水平升高,vWF切割蛋白酶ADAMTS13活性降低等均可用于该病的诊断。Mylotarg为治疗AML的新药,但增加了HVOD的危险。组织纤溶酶原激活物在治疗HVOD中虽有一定的效果,但并不理想。去纤苷因良好的疗效而受到重视。     

Two Patients with All -trans Retinoic Acid-Resistant Acute Promyelocytic Leukemia Treated Successfully with Gemtuzumab Ozogamicin as a Single Agent

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is the target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). Therefore, GO is predicted to be a successful treatment for APL. In this article, we report on the GO treatment of 2 patients with APL, who had fully relapsed after induction therapy with all-trans retinoic acid (ATRA) following chemotherapy. Both patients had relapsed 3 times and were resistant to reinduction therapy with ATRA. GO (9 mg/m2) was administered on days 1 and 15. After GO treatment, both patients achieved complete hematologic and molecular remission. GO may be another promising agent for the treatment of ATRA-resistant relapsed APL when given as salvage chemotherapy.     

Effect of gemtuzumab ozogamicin on acute myeloid leukemia blast cells in vitro, as a single agent and combined with other cytotoxic cells

The effect of gemtuzumab ozogamicin (GO) alone, or combined with low-dose cytarabine or etoposide, on the proliferation of acute myeloid leukaemia blast cells in vitro was investigated. GO alone induced a dose-dependent inhibition of proliferation although an increase in apoptosis was only seen in a minority of patients. A correlation was found between PgP function and GO sensitivity but not between CD33 or PgP expression and GO. Combinations of GO with varying concentrations of cytarabine or etoposide were additive in inhibiting proliferation, reducing cell viability and increasing apoptosis.     

Gemtuzumab ozogamicin: promise and challenge in patients with acute myeloid leukemia

CD33 is a suitable target to guide delivery of a toxic moiety to most acute myeloid leukemia cells. Gemtuzumab ozogamicin (Mylotarg^®) is a humanized antiCD33 monoclonal antibody covalently linked to a derivative of a cytotoxic antibiotic, calicheamicin. As a single agent, gemtuzumab ozogamicin has activity (complete remission rate of 15–20%) in patients with relapsed disease. Gemtuzumab ozogamicin-based combinations are being studied as induction, maintenance and relapse regimens. The chemical hepatotoxicity often observed with gemtuzumab ozogamicin therapy is of little clinical consequence. However, hepatic veno-occlusive disease is a relatively frequent and serious toxicity for which no clear risk factors, other than stem cell transplantation, have been defined. Gemtuzumab ozogamicin-based regimens may be particularly worthy of study in patients with acute promyelocytic leukemia. Gemtuzumab ozogamicin is approved as single-agent therapy for patients over the age of 60 years in first relapse who are not considered candidates for cytotoxic therapy. The administration of gemtuzumab ozogamicin should be carried out under a level of supervision commensurate with that afforded other intensely myelosuppressive agents. Gemtuzumab ozogamicin-based combinations should not be prescribed outside the research setting until further data is available.     

Mylotarg在急性髓细胞白血病治疗中的应用

CD33在90％以上的急性髓细胞白血病患者及早期髓细胞表达,为急性髓细胞白血病的治疗提供了理想靶点。目前已用于临床试验的主要有未修饰的HuM195和与同位素偶联的HuM195以及药物偶联的Gemtuzumab Ozogamicin(GO、CMA-676、Mylotarg),其中以Mylotarg最具有应用前景。本文着重对Mylotarg的研究进展作一介绍。     

Antibody-based therapeutics in oncology

The recent clinical and commercial success of anticancer antibodies, such as rituximab (Rituxan®) and trastuzumab (Herceptin®) has created great interest in antibody-based therapeutics for hematopoietic malignancies and solid tumors. Given the likely lower toxicity for antibodies versus small molecules, the potential increase in efficacy by conjugation to radioisotopes and other cellular toxins and the ability to characterize the target with clinical laboratory diagnostics to improve the drug's clinical performance, it is anticipated that current and future antibody therapeutics will find substantial roles alone and in combination therapy strategies for the treatment of patients with cancer. It is also likely that conjugation strategies will add new radiolabeled and toxin-linked products to the market to complement the recent approvals of ibritumomab tiuxetan (Zevalin?) and gemtuzumab ozogamycin (Mylotarg®). However, although there are a large number of agents in both early and later stages of clinical development, only a handful will make it through regulatory approval and become successful products. This review considers the structure of anticancer therapeutic antibodies, the techniques used to reduce their antigenicity, factors that influence efficacy and toxicity, conjugation with isotopes and toxins and antibody target validation.     

Combination of chemotherapy and gemtuzumab ozogamicin in adult Philadelphia positive acute lymphoblastic leukemia patient harboring CD33 expression

Gemtuzumab Ozogamicin (GO) is a humanized anti-CD33 antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin-g1. It was developed at the end of the nineties as 90% of the leukemic blast population of patients with acute myeloid leukaemia (AML) express the CD33 surface antigen (Dinndorf et al. [1] Blood 1986;67:1048-53). GO is currently approved in monotherapy for the treatment of CD33+ AML patients in first relapse, showing a 26% overall response rate and a median disease-free-survival of 5.2 months for responders (Larson et al. [2] Cancer 2005;104:1442-52). CD33 antigen expression is also observed at diagnosis (in 15% of cases) (Pui et al. [3] J Clin Oncol 1998;16:3768-73) or at relapse (Guglielmi et al. [4] Leukemia 1997; 11:1501-7) of acute lymphoblastic leukaemia (ALL), representing a potential cellular target for ALL patients. Case series have already demonstrated the efficacy of GO in children with relapsed CD33+ ALL with documentation of complete remission (CR) (Balduzzi et al. [5] Leukemia 2003;17:2247-8; Cotter et al. [6] Br J Haematol 2003;122:686-91; Zwaan et al. [7] Leukemia 2003;17:468-70). In the other hand, there is no report at our knowledge of the use of GO in the setting of adult CD33+ ALL patient. Here we report the case of a 30-year-old man with a refractory CD33+ ALL who received a salvage regimen combining chemotherapy + GO and achieved a transient CR.     

抗体靶向药物Mylotarg的临床研究进展

Mylotarg(gemtuzumab ozogamicin,CMA-676)是人源化抗CD33单克隆抗体与抗肿瘤抗生素刺孢霉素偶联而成的一种新的抗体导向化疗药,是在抗肿瘤单抗药物中,第一个于2000年获批准上市的药物和单抗偶联物.本文就Mylotarg的生物学特性、结构、作用机制及在临床中的应用作一综述.