Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group.

First results of a randomized trial (APL91 trial) and other randomized or non-randomized studies have shown that ATRA followed by chemotherapy significantly increased event-free survival (EFS) and survival, and decreased the incidence of relapse by comparison to chemotherapy alone in newly diagnosed APL. We present here long-term follow-up of the APL91 trial. In this trial, 101 patients had been randomized between ATRA followed by three courses of daunorubicin-AraC chemotherapy (ATRA group) and the same chemotherapy alone (chemotherapy group). Results were reanalyzed 73 months after closing of patient entry. Updated results of APL 91 trial found a Kaplan-Meier estimate of EFS and relapse rate at 4 years of 63% and 31% in the ATRA group, as compared to 17% and 78% in the chemotherapy group (P= 10(-4) and relative risk 2.95, P= 10(-4) and relative risk 3.68, respectively). Kaplan-Meier survival at 4 years was 76% in the ATRA group and 49% in the chemotherapy group (P= 0.026, relative risk 2.7). In the chemotherapy group, seven of the 27 relapses occurred after 18 months, but no relapse was seen after 43 months. In the ATRA group, four of the 17 relapses occurred after 18 months, including two late relapses (at 58 and 74 months). In the chemotherapy group, 23 of the 25 patients who relapsed achieved a second CR with ATRA, and the Kaplan-Meier estimate of second relapse was 40% at 30 months. In the ATRA group, the 10 patients who relapsed and were retreated with ATRA achieved a second CR. In conclusion, long-term results of APL91 trial confirm the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL, and that ATRA should be incorporated in the front-line treatment of APL.     

Successful treatment after acute promyelocytic leukemia (APL) syndrome of relapsed API with arsenic trioxide

A 52-year-old female was diagnosed with relapsed APL in 2000. After obtaining informed consent, we administered 10 mg/day of arsenic trioxide intravenously. The complications were vomiting, increased transaminase and ATRA syndrome which included high fever, retention of body fluid, pleural effusion, pericardial effusion and respiratory failure from day 16. Administration of steroid and low dose chemotherapy (DNR 60 mg x day 1-2, BH-AC 250 mg x day 1-2) with arsenic was effective for APL syndrome, and complete remission (CR) was obtained at day 35 and PML-RAR mRNA became negative. After obtaining CR, consolidation chemotherapy was conducted and the patient was maintained the CR for more than 18 months. Although arsenic trioxide may be effective for relapsed APL, sufficient caution is needed because of the possibility of various complications.     

Epidemiology of acute promyelocytic leukemia in Italy. APL Collaborating Group.

This retrospective epidemiologic study on 256 cases of Acute Promyelocytic Leukemia (APL) observed in 20 Italian hematology centers between 1980 and 1988 demonstrated that APL is different from the other acute non-lymphocytic leukemias (ANLL). The male/female ratio was 0.9; median age at diagnosis was 40 years (with 80% of patients between 15 and 54 years of age). The minimal annual incidence of APL in Italy per 1,000,000 inhabitants was estimated to be 0.6; an increased incidence was observed in spring and in autumn. The overall median survival duration of APL patients was 12.6 months. From an epidemiological point of view APL is a distinctive subtype of ANLL.     

急性早幼粒细胞白血病化疗后继发骨髓增生异常综合征一例并文献复习

目的分析急性早幼粒细胞白血病(APL)经治疗缓解后继发骨髓增生异常综合征(MDS)患者的临床特点,以提高对APL继发MDS的认识。方法回顾性分析江苏省苏北人民医院2013年9月收治的1例APL患者经治疗缓解后于2018年10月继发MDS的诊断及治疗经过,并复习相关文献。结果该患者初诊时确诊为APL,经标准治疗获得缓解。5年后因全血细胞减少再次就诊,经过骨髓相关检查,确诊MDS并再次行化疗治疗。结论APL治疗缓解后存在发生继发性MDS这一远期并发症可能,化疗结束后应定期、长期正规随访,改善患者预后。     

Chromosome abnormalities in acute promyelocytic leukemia (APL).

Sixteen patients, 15 adults and one child, with APL have been studied cytogenetically; 14 of these had an abnormal karyotype (87%). Eleven of these consistently showed a t(15;17)(q26;q22) structural anomaly, one patient showed a 47,+8 karyotype, one a rearrangement of chromosomes No. 15 and No. 17, apparently different from that in the other patients, and one a No. 17 deletion without a demonstrable translocation. as an additional chromosome change trisomy No. 8 was found in 5 cases and monosomy No. 7 in two. The t)15;17)(q26;q22) structural anomaly is highly characteristic of APL, is found in APL of children and adults, but it is apparently not associated with a clinically different form of APL.     

Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience.

We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.     

Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group.

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.     

HLA class I in acute promyelocytic leukemia (APL): possible correlation with clinical outcome.

The majority of patients with acute promyelocytic leukemia (APL) possess either a bcr1 or a bcr3 type fusion between PML and RARalpha genes. The junction sequences may possibly be a target for immune response and influence susceptibility to the disease. In this case, HLA class I allele frequencies would be different between bcr1 and bcr3 patients. To test this hypothesis, we typed 102 APL patients for HLA-A, -B and -Cw alleles. The A*1, A*30, B*51, B*41, Cw*0602, and Cw*1701 alleles showed a different distribution between bcr1 and bcr3 patients, but in no case was this statistically significant after correction for the number of comparisons or was confirmed in an independent panel. Moreover, no difference was detected between bcr1 and bcr3 when HLA alleles were grouped according to their peptide binding specificities. Comparing HLA frequencies, clinical features at diagnosis and clinical outcome of the 64 patients homogeneously treated with all-trans retinoic acid and idarubicin (AIDA protocol) we observed a statistically significant association between HLA-B*13 and risk of relapse by univariate and multivariate regression analysis. Should this finding be confirmed in larger future studies, this observation would be of outmost importance in identifying patients at high risk of relapse in which more aggressive consolidation therapies should be used.     

ATRA and anthracycline-based chemotherapy in the treatment of childhood acute promyelocytic leukemia (APL): A 10-year experience in Tunisia

Reports on childhood APL from developing countries are scarce. We treated 65 APL with two consecutive trials combining ATRA and chemotherapy. Twenty (30.7%) were aged less than 20 years including 11 girls and 9 boys, with a median age of 12 years. Fever at presentation (P = 0.002) and variant APL (P = 0.044) were more frequent in children, while there were no significant difference between children and adults for WBC count, Sanz’s score distribution and additional cytogenetic abnormalities. The CR rate was 95% (19/20) in children and 80% (36/45) in adults (P = 0.13). Differentiation syndrome (DS) was less often observed in children (1/20) than in adults (13/45) (P = 0.031). Two children relapsed and died during salvage therapy, and 2 died in CR from infection and from cardiac failure attributed to anthracyclines, while other children remained alive in CR. With a median follow-up of 4 years, 4-year EFS was 75% in children and 71.1% in adults (P = 0.57), while 4-year OS was 75% in children vs. 73.3% in adults (P = 0.72). Our results suggest that, even in the absence of optimal socio-economic condition, ATRA combined with anthracycline-based chemotherapy gives adequate results in childhood APL, as in adults.     

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.     

Therapy-related acute promyelocytic leukemia.

PURPOSE: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries. PATIENTS AND METHODS: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients. RESULTS: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years. CONCLUSION: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.     

维甲酸与急性早幼粒细胞白血病(APL)

维甲酸(retinoic acid, RA)为维生素A的衍生物,它在生长控制、上皮分化、胚胎发育等方面发挥主要功能.维甲酸受体RARs(retinoic acid receptors )及RXRs(retinoid X receptors)是类似于类固醇激素受体和甲状腺素受体的一类核受体,它是一种依赖于激素活化的转录因子,能以RAR/RXR异二聚体的形式结合在目的基因的启动子上,抑制或活化转录过程,该过程受激素控制.染色体的易位促使早幼粒白血病(promyelocytic leukemia, PML)基因和RARα的编码基因相结合,表达PML/RARα融合蛋白并最终导致急性早幼粒细胞白血病(APL)的发生.维甲酸处理后,APL细胞在体内或体外表现发生了极大的改变(APL细胞停止了恶性分裂,经历了类似HL60细胞和F9细胞的终端分化).同时,APL也对三氧化二砷(As2O3)非常敏感,维甲酸和As2O3都可以直接作用于PML/RARα融合蛋白.正因为如此,APL细胞成为了分化治疗及癌基因靶向治疗的首例.本文重点综述了APL发生的机制及维甲酸治疗APL的进展.     

Outpatient management of acute promyelocytic leukemia after consolidation chemotherapy.

The feasibility and safety of outpatient management of acute promyelocytic leukemia (APL) during the aplastic phase after intensive consolidation chemotherapy, the incidence and types of complications requiring readmission to hospital, and the number of hospital days spared by this policy have been prospectively evaluated. After chemotherapy administration, patients were evaluated on an ambulatory basis. In the event of any complication they referred to the Emergency Unit (EU) of our Department dedicated to outpatients with hematologic diseases. Forty patients with APL observed over a 4 year period were eligible for intensive chemotherapy. After the achievement of complete remission they received a total of 104 consolidation courses and in 98 instances they were followed on an ambulatory basis. There were 41 cases (42%) of rehospitalization for fever (40 cases) or severe anemia (one case). Only one patient died due to a brain hemorrhage. Streptococcus viridans was the organism most frequently isolated from blood. Empiric once-a-day antibacterial therapy with ceftriaxone and amikacin was effective in 87% of the cases and made possible early discharge in 28% of the cases to continue the antibiotic therapy on an outpatient setting. Patients were managed out of the hospital for 76% of the post-consolidation neutropenia period. Thanks to the availability of an EU specifically dedicated to outpatients with hematologic diseases, out-hospital management of APL patients after consolidation therapy appeared to be safe, well accepted, potentially cost-saving, and contributed to saving the risk of developing severe nosocomial infections.     

Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial.

Treatment combining ATRA and chemotherapy (CT) has improved the outcome of APL patients, by comparison with CT alone. ATRA syndrome is a life-threatening complication of ATRA treatment whose prophylaxis remains somewhat controversial. In APL93 trial, newly diagnosed APL patients CT) and ATRA with early addition of CT, on day 3 of ATRA treatment (ATRA + CT). The incidence of ATRA syndrome in the ATRA --> CT arm was 18% (22/122) as compared to 9.2% (17/184) in the ATRA + CT arm (P = 0.035). In the ATRA --> CT arm, three (2.5%) patients died from ATRA syndrome, as compared to one (0.5%) in the ATRA + CT group. Early addition of chemotherapy to ATRA in newly diagnosed APL with low WBC counts significantly reduced the incidence of ATRA syndrome.     

Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia.

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.