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。     

Treatment advances have not improved the early death rate in acute promyelocytic leukemia

Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.     

老年急性早幼粒细胞白血病的临床及预后

目的探讨老年急性早幼粒细胞白血病（APL）与年轻APL患者的临床表现、对治疗反应性及长期生存情况,明确老年患者在现有砷剂联合维甲酸及化疗的治疗模式下的有效性和安全性。方法收集北京大学人民医院血液病研究所的247例APL病例,其中老年组21例、年轻组226例,统计临床资料并分析缓解率、复发率、死亡率、存活时间。结果（1）老年APL在性别、白细胞、血红蛋白、血小板、弥散性血管内凝血（DIC）、中枢神经系统白血病（CNSL）及免疫表型上与年轻患者未见明显差异。（2）老年组完全缓解（CR）率、诱导期死亡率稍优于年轻组（100.0%vs 95.1%,0.0%vs 4.4%）,但差异均无统计学意义（P＝0.301,P＝0.325）;复发率及CR期死亡率稍高于年轻组（19.0%vs 16.3%,4.8% vs 1.9%）,差异亦无统计学意义（P＝0.744,P＝0.095）。（3）4年、6年和7年总存活率及无事件存活率与年轻组比较均无显著差异（P＞0.05）。结论老年APL与年轻APL在临床特点、对治疗的反应性及长期生存上无明显差异,现有治疗模式对老年患者安全、有效。     

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     

All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.     

Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome

BACKGROUND: Even after the introduction of all-trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL). METHODS: To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG). RESULTS: Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 x 10(9)/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5-yr event-free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease-free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage. CONCLUSIONS: These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high-risk features may benefit from more aggressive supportive care.     

Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience

Arsenic trioxide (As(2)O(3)) has been found effective in the treatment in the treatment of acute promyelocytic leukemia (APML). Most studies with As(2)O(3) involve patients with APML who have relapsed following standard therapy. Between January 1998 and July 2000, 14 patients were recruited for an ongoing trial of As(2)O(3) in the treatment of newly diagnosed APML. Arsenic trioxide was administered at a dose of 10 mg/day until complete remission (CR) was achieved. Afterward, a consolidation course and a maintenance schedule consisting of As(2)O(3) as a single agent were administered over 6 months. There were 3 early deaths related to intra-cerebral hemorrhage: two on day 3 and one on day 4. Of the 11 evaluable patients, one died on day 21 secondary to uncontrolled sepsis, while the remaining 10 (91%) have attained CR. The average time to CR was 52.3 days (range: 34-70 days). One patient developed an isolated central nervous system (CNS) relapse and subsequently went into a second CR following therapy with triple intrathecal chemotherapy, cranial irradiation, and an additional 4-week course of systemic As(2)O(3). This patient, as well as the remaining nine, has continued to remain in CR at a median follow up of 15 months (range: 2-33 months). Eight out of 10 patients achieved molecular remission at variable periods during their consolidation and maintenance schedules. One patient developed an ATRA syndrome and was administered daunorubicin (40 mg/day) for 2 days. The side effects with this therapy were minimal and did not require cessation of therapy in any patient. There was no significant hepatic toxicity. In our experience, arsenic trioxide is effective in inducing and maintaining remission in patients with APML with minimal side effects. The optimal regimen and total dose required need to be defined.     

Granulocyte colony-stimulating factor and its receptor in acute promyelocytic leukemia

Expression of granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) and in vitro proliferative response to G-CSF were investigated by quantitative immunofluorescence and [³H] thymidine uptake, respectively, in a series of acute myeloid leukemias (AML). The results indicated that G-CSFR was detected at high levels in acute promyelocytic leukemia (APL) cells, in comparison with other types of AML. Moreover, APL cells were also seen to predominantly proliferate in response to G-CSF. Based on these observations, we administered recombinant human G-CSF to a patient with APL in the third relapse that was resistant to both cytotoxic agents and all trans retinoic acid, in an attempt to sensitize the leukemic cells to cell-cycle-dependent agents. Complete remission was achieved. The finding that APL cells are exquisitely responsive to G-CSF supports the view that G-CSF is useful for augmentation of their vulnerability to cell-cycle specific agents. Am. J. Hematol. 58:31–35, 1998. © 1998 Wiley-Liss, Inc.     

Presenting features and treatment outcome of acute promyelocytic leukemia arising after multiple sclerosis

We report the clinical features and treatment outcome of 33 patients with multiple sclerosis who developed acute promyelocytic leukemia. Thirty patients were previously exposed to mitoxantrone. The median latency period between treatment initiation and acute promyelocytic leukemia diagnosis was 32 months. The PML-RARA bcr1 iso-form was identified in 87% of cases. Twenty-nine (90%) patients achieved hematologic remission after all-trans retinoic acid and chemotherapy (n = 31) or arsenic trioxide and all-trans retinoic acid. Consolidation included modified chemotherapy or arsenic trioxide. At a median follow up of 26 months, 23 patients are in complete remission, 4 relapsed and one developed secondary leukemia. The 5-year cumulative incidence of relapse and overall survival were 23% and 68%, respectively. Although treatment heterogeneity and suboptimal post-remission therapy must be taken into account, overall results and development of secondary leukemia in one patient suggest that effective and less toxic agents like arsenic trioxide warrants further investigation in this context.     

Hemophagocytic syndrome associated with retinoic acid syndrome in acute promyelocytic leukemia

A 56-year-old woman with an acute promyelocytic leukemia (APL) developed a severe all-trans-retinoic (ATRA) syndrome on day 17 of treatment. Shortly after, she presented a picture of pancytopenia, hepatosplenomegaly, increased triglycerides, ferritin, and liver enzymes. A bone marrow biopsy showed abundant macrophages and no evidence of leukemia. Tests for secondary hemophagocytic syndrome (HPS) were negative. A diagnosis of HPS was made. Treatment with dexamethasone and high-dose immunoglobulins was unsuccessful. Consolidation chemotherapy with idarubicin and ATRA rapidly reversed the HPS. The HPS in this patient could be related to the release of macrophage-stimulating cytokines by APL cells during ATRA syndrome.     

Immunological definition of acute promyelocytic leukemia (FAB M3): a study of 39 cases

Acute promyelocytic leukemia (FAB-M3) is a distinct entity among acute non-lymphoid leukemias (ANLL) with peculiar morphological, biological, clinical and prognostic features. An atypical form of M3 (M3v) could be confused with other FAB ANLL and therefore the diagnosis of this variant requires ultrastructural analysis and/or cytogenetic study and/or selective gene rearrangement studies. The immunological phenotype of blast cells in 39 APL patients was studied at diagnosis. The diagnosis of M3 FAB type was ascertained in 32 and the diagnosis of M3v in 7 cases. Using a large series of monoclonal antibodies (mAb), the APL blast cells were B and T cell antigens-negative, HLA-DR constantly negative, CD13- and/or CD33-positive, CD9-positive. Among ANLL this phenotype seems to be closely related to APL both in M3 type and M3v subtype. Because the diagnosis of APL (M3 or M3v) is important in order to establish the specific therapeutic approach, the discriminant capacity of the immunological typing to identify M3 and mainly M3v (hypogranular) could be determinant for a "quick" diagnosis.     

Rapid improvement of coagulopathy by all-trans retinoic acid in acute promyelocytic leukemia

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), cross-linked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-α2-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (A TIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells. © 1994 Wiley-Liss, Inc.     

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。     

急性早幼粒细胞白血病分化综合征临床特征及对预后的影响研究

目的探讨急性早幼粒细胞白血病(APL)分化综合征(DS)的临床特征和影响预后的因素。方法收集中山大学附属第一医院2003—2010年收治的97例APL患者,采用维甲酸或维甲酸联合三氧化二砷(ATO)双诱导治疗,初诊者诱导分化治疗后WBC≥5×109/L联合化疗,完全缓解后采用ATO联合常规化疗巩固治疗方案。结果27例(27.83%)并发DS,出现DS中位时间为诱导分化治疗第6(2～24)天,其中24例(88.89%)发生在第1、2周。27例DS均给予地塞米松治疗,其中12例暂时停用诱导分化剂患者DS症状均缓解,15例继续使用者2例(7.41%)病情恶化死亡。中位随访37个月,DS组与未并发DS组患者无病生存(LFS)差异无统计学意义(P=0.269)。分析与DS发生的相关因素表明DS更多见于初诊WBC>10×109/L患者(χ2=4.994)。结论初诊WBC>10×109/L患者易并发DS,DS主要发生在诱导分化治疗前2周,DS对长期预后无影响。     

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.     

急性早幼粒细胞白血病患者诱导治疗中出现分化综合征的多因素分析

目的：分析初诊的急性早幼粒细胞白血病（APL）患者在接受全反式维A酸（ATRA）诱导治疗期间出现分化综合征（DS）影响因素。方法收集2005至2014年间海军总医院血液科初诊APL并接受ATRA联合三氧化二砷（ATO）酸或蒽环类药物诱导治疗的84例患者。根据Frankel描述诊断其中35例出现DS。按照潜在危险因素收集数据,对影响DS发生、发展的危险因素进行单因素分析及logistic多因素回归分析。结果 logistic多因素回归分析显示,患者初诊时白细胞计数及早幼粒细胞白血病-维A酸受体α（PML-RARa）基因分型是影响DS发生的独立危险因素（P＜0.05）。进一步对不同组间外周血白细胞计数及PML-RARa基因分型行χ2检验分析,以排除多因素间相互影响因素,结果显示患者初诊时外周血白细胞及PML-RARa基因分型,两组间差异分析存在统计学意义（P＜0.05）。并对PML-RARa基因分型的长（L）亚型及短（S）亚型行χ^2检验分析,结果显示L亚型早幼粒细胞白血病-α纸A酸变体（PML-RARa）基因对DS的发生有统计学意义（P＜0.05）。结论初诊时外周血白细胞计数较高的患者及PML-RARa基因为L亚型的患者在初期接受维A酸联合诱导化疗时更易出现DS。