Late relapse of acute promyelocytic leukemia treated with all-<Emphasis Type="Italic">trans</Emphasis> retinoic acid and chemotherapy: report of two cases

Two patients with acute promyelocytic leukemia (APL) relapsed at 111 and 84 months after achievement of complete remission (CR) induced by a combination of all-trans retinoic acid and chemotherapy. In both patients molecular remission, obtained after consolidation, had been confirmed at 60 months from CR achievement. At relapse, morphological, immunophenotypic, cytogenetic, and molecular analyses showed findings identical to those at diagnosis. Hematological and molecular remission was induced with the identical treatment applied at diagnosis. We conclude that, although infrequently, patients with APL treated with modern combination therapy can experience very late relapse and can be rescued with treatment similar to that administered at diagnosis.Grant from COFIN (MIUR, Rome, Italy), Regione Campania (Italy), CNR (Rome, Italy), AIL (Rome, Italy)     

Current issues in the management of acute promyelocytic leukemia

trans retinoic acid (ATRA), both PML-dependent apoptotic mechanisms and myeloid-specific gene expression programs are reactivated. In the clinic, the combination of anthracycline-based chemotherapy plus ATRA cures approximately 80% of APL patients, and a high percentage of relapsed patients can achieve second remissions with arsenic trioxide. With the publication of results from the European APL 93 trial, the ‘standard-of-care’ for induction treatment of APL now includes ATRA plus concurrent anthracycline-based chemotherapy. The amount and type of consolidation therapy necessary for an individual APL patient remains somewhat of an open question, but at present should include at least two cycles of chemotherapy. Based on recent trials that demonstrate a benefit of maintenance ATRA ( ± low-dose chemotherapy), all APL patients should probably receive some type of maintenance therapy. While the above approach currently cures the majority of APL patients, future improvements in the treatment of this disease will require risk-adapted protocols that incorporate real-time molecular monitoring and appropriate introduction of novel therapeutic agents. Received: 19 August 1999 / Accepted: 9 November 1999     

急性早幼粒细胞白血病合并弥散性血管内凝血(附30例报告)

回顾性分析30例APL并发DIC患者的治疗过程,显示颅内出血为其主要致命性并发症。D-D是高可信度检测指标;APTT易受多种因素影响,如果一项延长,超过正常对照2.5倍以上,高度提示肝素过量。亚临床型DIC应给予小剂量肝素持续静滴;对进展期DIC应同时输注血液制品;确有纤溶亢进时应给予抗纤溶治疗。     

Characteristics of fibrinolytic disorders in acute promyelocytic leukemia

ABSTRACT

Objectives: Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL.

Methods: Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated.

Results: Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin–ɑ₂ antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients’ plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values.

Conclusions: In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.     

急性早幼粒细胞白血病患者早期死亡原因探讨

目的 :探讨急性早幼粒细胞白血病 (APL)患者早期死亡原因。方法 :分析 12例早期死亡患者的临床资料。结果 :12例患者中 ,8例外周血白细胞大于 4 0× 10 9/L ,全部患者均检获t(15 ;17)及PML/RARα 基因 ,8例PML/RARα 基因为S型 ;9例死于DIC ,3例死亡与纤溶有关。结论 :具有高细胞负荷 ,FAB亚型为M3 b ,PML/RARα 基因为S型 ,未经ATRA诱导分化即开始联合化疗的APL易于早期死亡 ;并与DIC的发生和纤溶亢进有关。     

全反式维甲酸治疗急性早幼粒细胞性白血病致Sweet综合征--病例报告及文献复习

目的:提高对全反式维甲酸(ATRA)治疗急性早幼粒细胞性白血病(APL)少见副作用的认识。方法:报告1例ATRA治疗APL致Sweet综合征的病例及治疗过程,并对相关文献进行复习总结。结果:ATRA治疗APL可以导致Sweet's综合征,采用糖皮质激素治疗有效。结论:Sweet综合征是维甲酸的少见副作用,临床上应提高对该综合征的早期诊断。     

All-trans retinoic acid in acute promyelocytic leukemia: Preliminary results in Cuba

Summary Seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Five (71.4%) achieved complete remission (CR). Most side effects were transient and well tolerated. Hyperleukocytosis was the major adverse effect. These observations confirm the efficacy of ATRA for inducing CR in APL.     

单倍型相合骨髓移植治疗伴髓外侵犯的难治复发变异型急性早幼粒细胞白血病获长期生存1例并文献复习

目的:探讨单倍型相合骨髓移植治疗伴有髓外侵犯的难治性变异型急性早幼粒细胞白血病的疗效。方法:采用母亲供髓的单倍型相合移植治疗1例伴髓外侵犯的难治复发变异型急性早幼粒细胞白血病,预处理方案为CyTBI加Ara-c,GVHD预防采用联合免疫抑制剂和供者应用G-CSF的方法,联合免疫抑制剂包括环胞素A、短程氨甲碟呤、霉酚酸酯、CD 25单抗和抗胸腺细胞球蛋白的应用。结果:移植后+1个月造血重建,植入成功,免疫功能逐渐恢复,定期随访,PML/RARα融合基因持续(-),现已无病生存76个月。结论:单倍型相合骨髓是治愈高危难治复发急性早幼粒白血病的有效措施,为患者提供了长期生存的机会。     

The global problem of early deaths in acute promyelocytic leukemia: A strategy to decrease induction mortality in the most curable leukemia

Acute promyelocytic leukemia (APL) is a hyper-acute illness and presents with profound cytopenias in most patients and disseminated intravascular coagulation (DIC). Excellent treatment options are now available with drugs such as all-trans retinoic acid (ATRA), arsenic trioxide (ATO), anthracyclines and cytarabine. The outcome in APL has improved tremendously in the last 50 years due to better understanding of the disease, development of effective targeted agents and improvement in supportive care. Carefully selected groups of patients treated in large multi-center trials on a protocol and in experienced centers have shown survival rates in excess of 85%. However population data and other studies show that approximately 30% of patients die during induction. This is an Institutional, national and global problem and remains a pressing and frustrating challenge in APL.While most APL experts are aware of the high rate of early deaths (ED), such awareness is not typically present among general hematologists and oncologists. Our area of focus over the last 7 years has been the reduction of ED in both academic and community centers; as a result we have acquired substantial experience in APL induction. Two centers have implemented population-wide prospective trials; Brazil and Georgia/South Carolina, USA with improvement in the ED rate. Both centers used standardized guidelines along with consultative support and sharing of expertise which proved effective and helped to decrease ED.Induction mortality in APL is 30% or greater. We believe ED is largely preventable and population-wide survival can be improved. An effective strategy is to utilize a set of simplified treatment guidelines coupled with support from a group of experts during induction. Treating oncologists in both academic and community hospitals should receive aggressive education about ED and be encouraged to seek advice from a core group of established APL experts. This model could be implemented nationally to improve population-wide survival in this most curable leukemia.     

三氧化二砷联合化疗治疗急性早幼粒细胞白血病的疗效观察

目的:观察三氧化二砷(As2O3)联合化疗治疗急性早幼粒细胞白血病(APL)的疗效.方法:46例初治APL患者均采用As2O3诱导治疗,完全缓解(CR)后用DA或MA方案巩固1个疗程,以后As2O3与化疗交替治疗,每3月1次,连续治疗3年.再继以甲氧蝶呤片与巯嘌呤片维持治疗1年.结果:46例患者有38例(82.6％)达到CR,34例坚持治疗者持续缓解,缓解时间17～119个月,中位缓解时间67个月;4例CR2患者缓解时间43～ 71个月,中位缓解时间54个月.38例患者仍处于CR,生存时间131～ 18个月,中位生存时间65个月.结论:APL患者CR后,采取每年4个周期的巩固和维持方案序贯治疗,减少了化疗及As2O3的疗程,避免了长期连续用药所致的耐药,减少了药物的副作用,复发率很低.     

Microgranular promyelocytic leukemia: a multiparameter examination

Six cases of microgranular variant acute promyelocytic leukemia (M3v) were studied by use of a multiparameter approach including morphology, cytochemistry, flow cytochemistry, flow cytometry, cytogenetics, and gene rearrangement. Three of six cases demonstrated both myeloid and monocytoid associated surface markers by flow cytometry. One of six cases had strong alpha-naphthyl-butyrate esterase (alpha-NBE) activity in addition to myeloperoxidase activity. There was no correlation between percentage of positive monocytoid surface markers and intensity of cytoplasmic alpha-NBE activity. Four of six cases also had a T-cell-associated surface antigen. Further studies indicated that the T-cell markers appeared to be on the promyelocytes and that the T-B receptor gene was not rearranged. Similarly, cytogenetics studies indicated only one clonal abnormality t(15q+; 17q-). Whether these cases represent true "lineage infidelity" remains to be answered. Future important studies are needed on normal hematopoietic progenitor cells at early stages of development and childhood to study lineage-specific characteristics and to determine whether co-expression normally exists during early development.     

初发急性早幼粒细胞性白血病老年患者诊治全过程1例报告及文献复习

目的报导初发APL老年患者对ATRA联合ATO加化疗的疗效并结合文献讨论。方法采集病史,书写病程演进,作辅助检查,进行PML—RARu,融合基因检测和随访。记录治疗方案、并发症、药物不良反应及处理经过。结果本例AML—RARa融合基因阳性。采用ATRA联合ATO加化疗方案。经诱导、巩固和维持等3阶段治疗,住院5m,巩固治疗结束后,获MR。全程治疗32m完成。并发症主要是肺部感染,处理要及时,支持治疗要重视。药物治疗的计量应掌握在成人的2／3-3／4。结论老年APL患者能够耐受ATRA联合ATO加化疗并取得良好的疗效。     

Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia

Genetic diagnosis is currently considered the most reliable method to accurately identify patients with acute promyelocytic leukemia (APL) requiring tailored therapy including all-trans retinoic acid (ATRA). We investigated the clinical effectiveness of immunofluorescence techniques with the anti-PML monoclonal antibody PG-M3 for rapid and accurate diagnosis of APL. PML immunofluorescence staining was analyzed in 164 patients with acute myeloblastic leukemia (AML), including APL (110 patients) and non-APL subtypes (54 patients). All 54 patients with an AML phenotype, in whom tests for t(15;17) or its fusion gene PML/RAR were negative, showed a speckled (macrogranular) nuclear pattern. Of the 110 genetically diagnosed APL patients, 108 showed a microgranular pattern that confirmed PG-M3 positivity. The remaining two patients were not evaluable for PG-M3 reactivity because of scarcity of cells. No patient with APL showed a normal pattern. The high sensitivity and specificity of immunolabeling using PG-M3 monoclonal antibody show that it is a highly efficient and reliable tool to identify PML/RAR-positive patients with APL and that it should be standardized as a first-line diagnostic procedure. In addition, it is technically simple, fast, and cheap, only requiring small tissue samples and non-sophisticated equipment.     

Palliative gastrectomy and chemotherapy for stage IV gastric cancer

Purpose To investigate the value of palliative gastrectomy and chemotherapy in a large series of patients with stage IV gastric cancer. Methods A total of 389 patients were identified in survival analysis. Among which, 183 cases received palliative gastrectomy (PG) and 206 cases received unresectable operation, 184 cases received palliative chemotherapy (PC) and 205 cases did not receive chemotherapy. The survival advantages of patients, based on treatments modality, were also analyzed in patients with liver metastasis, peritoneal dissemination and lymph node metastasis. Results The 1-year, 3-year, 5-year survival rate of those patients who were treated with PG + PC were 85.7% (96/112), 32.1% (36/112), and 8.9% (10/112), which were far better than those who were not. For those patients with liver metastasis, peritoneal dissemination, and/or N3 lymph node metastasis, survival advantages were also present if treated with this multimodality approach. Conclusion The survival time and palliative duration were significantly longer in patients after PG than after non-resection operations. Postoperative chemotherapy prolonged the survival time of patients after palliative surgery. PG combined with adjuvant chemotherapy may improve survival in patients with stage IV gastric cancer, even with liver metastasis, peritoneal dissemination, and lymph node metastasis.     

胃癌腹腔化疗进展

胃癌是最常见的消化道恶性肿瘤,胃癌手术切除后转移和复发率高。腹腔内化疗作为进展期胃癌的辅助治疗手段已逐渐应用于临床,且因其独特的药代动力学特征而有肯定的疗效。此文从腹腔化疗的药代动力学及临床应用方面概述胃癌腹腔化疗的新进展。     

Meta-analysis of all-trans retinoic acid-linked arsenic trioxide treatment for acute promyelocytic leukemia

Objectives

To explore the combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO, As₂O₃) on acute promyelocytic leukemia (APL).

Methods

A meta-analysis of six studies was performed. Among 415 included cases, 165 cases were in the ATRA + ATO group, 129 cases in the ATRA-alone group, and 121 cases in the ATO-alone group. The complete remission (CR) rate and incidences of three groups were compared, respectively, between the therapies of ATRA + ATO with ATRA-alone, ATRA + ATO with ATO-alone, and ATRA with ATO.

Results

The assessment results showed that ATRA + ATO therapy significantly improved the CR rate and decreased the incidences of cutaneous reaction compared with ATRA-alone (P < 0.05). However, incidence of liver injury was higher in the ATRA + ATO and ATO-alone groups than that in ATRA-alone group (P < 0.05). Difference in the complications between ATRA + ATO therapy and ATO-alone was not significant (P > 0.05).

Conclusions

In conclusion, we suggest low-dose ATRA and ATO combination therapy may be more effective for the treatment of APL.     

Surgical resection of advanced gastric cancer following trastuzumab/oxaliplatin/capecitabine combination therapy

Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates. To improve long-term outcomes, perioperative chemotherapies are combined with surgery. Human epidermal growth factor receptor 2 (HER2) overexpression had been noted in gastric cancer; therefore, trastuzumab has been used occasionally in this setting. A 63-year-old male Chinese patient, who was diagnosed with adenocarcinoma in the gastric antrum, as well as lymph node metastases along the left gastric and hepatic artery, and left adrenal area, was admitted to our hospital. HER2 expression was positive, and cluster amplification was detected in a fluorescence in situ hybridization assay. The patient received three cycles of a neoadjuvant trastuzumab/oxaliplatin /capecitabine regimen. He subsequently underwent distal gastrectomy, D2+ lymphadenectomy, left adrenalectomy, cholecystectomy and Billroth II anastomosis. Treatment was continued with another five postoperative cycles of the same medication and trastuzumab application for 1 year. No recurrence has been observed 18 mo after the operation. Trastuzumab as perioperative and adjuvant medication, in combination with oxaliplatin and capecitabine for a HER2-overexpressing advanced gastric adenocarcinoma, led to recurrence-free survival of at least 18 mo after surgery.     

Clustered incidence of acute promyelocytic leukemia during gefitinib treatment for non-small-cell lung cancer: experience at a single institution

Although gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been shown a significant activity for recurrent non-small-cell lung cancer (NSCLC), its long-term adverse effect with its continuous usage has hitherto not been clearly elucidated. Subjects were 108 consecutive NSCLC cases who were treated with gefitinib between November 2001 and December 2004 at our single institution. A crude incidence rate ratio was calculated by ratio of crude incidence rate in our subject to population-based incident rate of all leukemia (ICD: C91-95) in the same region. The 95% confidence intervals (CIs) were calculated based upon a Poisson distribution. Three cases of acute promyelocytic leukemia (APL) occurred during gefitinib treatment, and these patients' past treatment histories are presented herein. No other malignancy was identified. All of the cases were diagnosed at the stage of mild-to-moderate cytopenia, especially thrombocytopenia, without disseminated intravascular coagulation. All presented a normal karyotype with positive PML-RARalpha in RT-PCR, indicating submicroscopic translocation. They responded well to APL treatments, including all-trans-retinoic acid. The crude incident rate ratio was 639.9 (95% confidence interval: 131.6-1,878.9, P < 0.0001) when the APL incidence in this cohort was compared to all leukemia cases in the general population in the same district in Japan. Thus we had three cases of secondary APL patients within the gefitinib-treated NSCLC cohort. Although we cannot exclude an effect of past exposure of other cytotoxic agents and radiotherapy as a cause of APL, APL inducibility of gefitinib should be clarified in the further study.