Combined chemotherapy for acute promyelocytic leukemia: a meta-analysis

Background: This study evaluates the efficacy of combined chemotherapy for the management of acute promyelocytic leukemia (APL).

Method: Literature search was carried out in several electronic databases. Meta-analyses were performed to achieve weighted effect sizes of overall survival (OS), disease-free survival (DFS), complete remission (CR) rate, and relapse rate. Metaregression analyses were performed to evaluate the factors affecting CR and relapse rates.

Results: Data from 37 studies (7566 patients) were used for meta-analysis. Median follow-up was 49.24 [95% confidence interval (CI): 41.33, 57.16] months. Five-year OS and DFS were 86.41 [83.97, 88.85] % and 75.42 [67.44, 83.40] %, respectively (pooled effect size [95% CI]). Following induction therapy, 89.77 [87.04, 92.50] % patients achieved CR in 38.25[37.84, 38.65] days and 6.34 [5.98, 6.70] % of the patients died during induction. Induction with all-trans retinoic acid (ATRA), arsenic trioxide (ATO), and daunorubicin (DNR) combination was associated with the highest rate of CR (96.16 [89.92, 92.40] %), followed by ATRA-DNR (94.29 [93.15, 95.43] %), ATRA-DNR-cytarabine (92.04 [88.38, 95.71] %), and ATRA-idarubicin (91.16 [89.92, 92.40] %). Overall relapse rate in the study population was 14.42 [11.97, 16.86] %. Baseline leukocyte count was inversely related to the CR rate.

Conclusion: Combined chemotherapy for APL is associated with 90% CR, 14.4% relapse rate, 86% 5-year OS, and 75% 5-year DFS. Induction with ATRA-DNR-ATO is found better than other combinations with respect to CR and relapse rates. Initial leukocyte count may affect prognosis.     

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。     

急性早幼粒细胞白血病早期死亡原因分析

目的:探讨急性早幼粒细胞白血病(APL)早期死亡的原因,分析其潜在危险因素。方法:回顾性分析60例初诊APL患者在确诊后30 d内早期死亡的病例(10例)和非早期死亡病例(50例)的临床特征。结果:10例(16.7%)早期死亡,原因分别为颅内出血(5例)、重度肺部感染(3例)、白细胞淤滞症和维甲酸综合征各1例。预后分层属于高危组患者(即WBC≥10×109/L)中,早期死亡组所占比例较非早期死亡组高(70%vs 30%,P0.05)。早期死亡组凝血酶原时间(PT)均值和CD56阳性表达者比例也高于非早期死亡组(P0.01)。2组之间年龄、性别、初诊时血红蛋白水平、骨髓早幼粒细胞百分比、活化的部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原、尿酸、肌酐的差异并不明显(P0.05)。早期死亡组乳酸脱氢酶(LDH)水平及WBC高于非早期死亡组,血小板计数(PLT)低于非早期死亡组,差异均无统计学意义(均P0.05)。结论:出血、感染、白细胞淤滞症和维甲酸综合征是APL早期死亡的主要原因。高危的预后分层、明显延长的PT或CD56的阳性表达均可能是初诊APL患者早期死亡的潜在危险因素。     

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。     

Long-term survival in an acute promyelocytic leukemia patient with recurrent granulocytic sarcomas: A case report

Rationale:Granulocytic sarcoma (GS) is an extramedullary myeloid tumor composed of immature cells of the granulocytic series. It rarely occurs in acute promyelocytic leukemia (APL). No case of long-term survival in an APL patient with recurrent GS has been reported.Patient concerns:A 54-year-old female patient was diagnosed with APL in 1995 and has been in complete remission (CR) of bone marrow morphology for 24 years; however, recurrent GS occurred successively in ovary, breast, spine, body of sternum, lymph nodes, soft tissues from 2004 to 2019.Diagnoses:The immunohistochemistry confirmed the diagnosis of GS, and fluorescence in situ hybridization (FISH) revealed its origin from APL.Interventions:She received surgery, and had an excellent response to all-trans retinoic acid (ATRA), DA (daunorubicin combined with cytarabine) regimens, and arsenic trioxide (ATO).Outcomes:The patient achieved CR in March 2020 after radiotherapy followed by ATO and ATRA. So far, she is still in follow-up.Lessons:It is rare that recurrent GS at multiple sites is involved in APL patient with bone marrow morphology in CR. It is interesting to observe a long-term excellent response to ATRA, chemotherapy and ATO. Although multiple recurrence of GS in patients with APL is rare, the data in this case highlight the need for individualized treatment when such conditions occur.     

Acute promyelocytic leukemia with myelofibrosis: A case report and literature review

Rationale:Acute promyelocytic leukemia (APL) with myelofibrosis (MF) is rare, and only 14 cases have been reported in the literature to date.Patient concerns:A 42-year-old woman was admitted to the hospital with easy bruising and excessive bleeding. With the remission of the primary disease during treatment, the degree of fibrosis did not decrease, but worsened progressively.Diagnosis:The woman was diagnosed with acute promyelocytic leukemia with secondary myelofibrosis.Interventions:All-trans retinoic acid (ATRA) was discontinued after 6 months of complete remission of APL. Arsenic trioxide (ATO) was discontinued because of supraventricular tachycardia 9 months after complete remission of APL.Outcomes:After withdrawal of ATRA for 2 months, the degree of fibrosis was significantly alleviated, and after withdrawal of ATRA for 8 months and ATO for 5 months, bone marrow biopsy showed no reticular fiber deposition.Lessons:In this case report and review of an additional 14 cases of APL with MF, we highlighted the importance of the degree of MF to be evaluated by bone marrow biopsy at the time of bone marrow aspiration when APL is suspected. If MF is present, the type of MF should be determined in a timely manner, and appropriate intervention measures should be taken accordingly.     

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.     

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.     

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.