All-transretinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia

BACKGROUND: All-transretinoic acid (ATRA) and chemotherapy has improved complete remission rates and disease free survival in acute promyelocytic leukemia (APL). There is scanty data from Middle East. AIM: To determine the efficacy of ATRA and multi-agent combination chemotherapy in treatment of APL in a single Centre in Kuwait. SET-UPS AND DESIGN: Tertiary cancer centre, retrospective study. METHODS AND MATERIAL: All newly diagnosed APL patients were treated with oral ATRA 45 mg/m2 daily until complete remission (CR), intravenous daunorubicin 50 mg/m2 on days 1,3 and 5, cytosine arabinoside 100 mg/m2 12 hrly on days 1 through 10 and etoposide 100 mg/m2 on days 1 through 5. Post remission three courses of intensive consolidation chemotherapy were administered. Since October 1999, maintenance chemotherapy consisting of oral 6 mercaptopurine 9 mg/m2 daily, methotrexate 15 mg/m2 weekly and ATRA 45 mg/m2 for 2 weeks every three months was added. Complete remission rates and duration, relapse rate and toxicity were studied. RESULTS: 22 of 24 evaluable patients (91.6%) achieved CR. The median duration of remission was 13 months (range 2-55 months). Three patients (12.5%) relapsed. Two patients (8.3%) developed retinoic acid syndrome and responded to dexamethasone. Five patients (20.8%) died one each of refractory disease, during remission induction and of relapse. Two patients died while in remission. CONCLUSION: ATRA and combination chemotherapy results in high complete remission rates and low relapse rate in newly diagnosed APL. Maintenance therapy may be useful in preventing relapses.     

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.     

Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy.

PURPOSE: To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. RESULTS: Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P =.02) and incidence of microgranular M3 variant (P =.04). CONCLUSION: ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.     

全反式维甲酸联合三氧化二砷治疗初诊急性早幼粒细胞白血病的疗效及对复发率的影响分析

目的：探讨应用三氧化二砷（AS2O3）联合全反式维甲酸（ATRA）与单用ATRA对初发急性早幼粒细胞白血病（APL）诱导治疗的临床疗效及对复发率的影响。方法回顾性分析接受规律治疗的初治120例APL患者的临床资料,所有患者按治疗方法不同分为观察组和对照组,每组60例。观察组予ATRA口服联合AS2O3静脉滴注治疗,对照组仅予ATRA口服治疗,根据外周血白细胞数、肝功能以及临床症状调整药物用量,均治疗直至完全缓解（CR）。观察诱导治疗阶段CR率和早幼粒白血病基因和维甲酸受体基因融合基因（PML-RARα）转阴所需时间和不良反应,巩固化疗后3年总生存率（OS）和复发率,同时分析白细胞水平对预后的影响。结果观察组早期病死率、CR率与对照组比较差异无统计学意义（P﹥0.05）,达到CR时间少于对照组（P﹤0.05）;观察组PML-RARα转阴率和总生存率高于对照组,复发率低于对照组（P﹤0.05）;选取观察组57例患者分析白细胞水平对预后的影响,WBC≥10×109/L患者复发率、病死率、未缓解（NR）率与WBC﹤10×109/L患者比较,差异无统计学意义（P﹥0.05）,CR率与总生存率则低于WBC﹤10×109/L患者。结论 AS2O3联合ATRA治疗初发APL的疗效较好,达到CR时间缩短,预后提高,白细胞水平对APL的预后有一定影响,导致CR率与总生存率降低。     

实时定量聚合酶链反应监测慢性粒细胞白血病患者接受伊马替尼治疗期间bcr-abl融合基因拷贝数的变化

 目的　应用实时定量聚合酶链反应（RQ-PCR）技术动态监测接受伊马替尼(IM)治疗的慢性粒细胞白血病（CML）患者bcr-abl融合基因拷贝数的变化,探讨RQ-PCR技术在微小残留病（MRD）检测以及预测复发方面的应用。方法　应用RQ-PCR技术动态监测106例接受IM治疗的CML患者bcr-abl融合基因拷贝数,bcr-abl融合基因定量结果以校正比值（NQ）表示,NQ＝bcr-abl拷贝数／abl拷贝数。结果　IM治疗前患者的NQ值与其疾病进展及Ph+细胞数量均显著相关（r＝0.9824,r＝0.9346）。使用IM治疗的106例患者,62例在治疗12个月内NQ值迅速下降并长时间维持在较低水平,其中仅2例复发;8例在治疗后NQ值略有下降但随后又马上升高,其中7例在NQ值升高后的5～9个月内复发;31例治疗后NQ值未见明显下降且仍>0.1,其中11例获得过短暂的形态学缓解,随后迅速复发,7例治疗无效或疾病进展;另有5例虽然NQ值波动较大,且无规律性,但治疗后一直处于形态学缓解。结论　RQ-PCR方法准确、可靠、敏感度高,在监测CML患者的MRD、判断疗效以及预测复发等方面具有重要的临床应用价值。     

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.     

Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate.

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.     

Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has unique clinical, cytogenetic, and molecular features and is one of the most potentially curable human malignancies. The current standard treatment given to patients with newly diagnosed APL consists of all-trans retinoic acid and anthracycline-based cytotoxic chemotherapy, which is highly effective for remission induction. However, despite the potential for cure with existing treatments, approximately 20%-30% of patients relapse and require salvage therapy. Reports of the safety and efficacy of arsenic trioxide from centers in China led to a pivotal trial of this agent in the United States for patients with relapsed APL. In an initial pilot study, 11 of 12 patients experienced a complete response, and a subsequent multicenter trial confirmed the efficacy and safety of arsenic trioxide for remission induction in this patient population. Additional trials are under way to evaluate the use of this agent alone or as part of a chemotherapy regimen for consolidation and maintenance of patients with APL.     

砷剂治疗急性早幼粒细胞白血病过程中细胞形态学及遗传学变化

目的 观察四硫化四砷(TATS)治疗初治和复发急性早幼粒细胞白血病(APL)过程中细胞形态学及细胞遗传学变化,探讨其作用机制。方法 应用骨髓短期培养法、染色体荧光原位杂交(FISH)技术及形态学技术,对13例初治及7例复发APL患者进行细胞遗传学和形态学分析。结果 8例患者的骨髓APL细胞中均出现分化现象。20例患者中,19例在TATS治疗过程中t(15;17)阳性细胞呈逐渐下降,与形态学风细胞百分比的下降具有相关性(r值范围0．7298—0．9989)。19例具有t(15;17)染色体易位的患者治疗后均达血液学完全缓解(CR),16例达细胞遗传学CR,1例具有t(11;17)易位的患者未达血液学CR。结论 TATS对初治及复发APL有一定的诱导分化作用,单药TATS治疗初治及复发APL患者可达到血液学和细胞遗传学缓解。应用FISH技术监测t(15;17)阳性细胞可以客观反映APL细胞变化规律。     

An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low-dose all-trans retinoic acid

The use of arsenic trioxide (As2O3, ATO) combined with all-trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low-dose ATRA (LD-ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD-ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD-ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side-effects have been no worse with the combined ATO/LD-ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD-ATRA regimen is superior to either regimen given alone to patients with APL.     

Prospective Monitoring of Minimal Residual Disease in Acute Myeloid Leukemia with Inversion(16) by CBFβ/MYH11 RT-PCR: Implications for a Monitoring Schedule and for Treatment Decisions

Minimal residual disease in patients with acute myeloid leukemia (AML) with inversion(16) can be monitored by CBFβ/MYH11 RT-PCR. While the association between molecular remission (MR) in bone marrow (BM) and peripheral blood (PB) and long-term clinical remission (CR) seems to be established, there are insufficient data on the kinetics of CBFβ/MYH11. We have performed a prospective study in order to generate a reasonable and sufficient schedule for PCR-monitoring. 11 patients with AML and inversion (16) in complete hematological remission have been prospectively monitored by CBFβ/MYH11 RT-PCR in their BM and PB during an observation period of 7 to 67 months (median 32 months). Patients were followed during consolidation chemotherapy with repetitive cycles of high-dose Ara-C and after autologous or allogeneic stem cell transplantation in 2^nd CR or refractory AML. MR never coincided with achievement of CR but occurred between 2 and 8 months after hematological remission. All patients in continuous CR were PCR-negative after 1-8 (median 4) months. Two patients relapsed despite MR for 10 to 15 months. Molecular relapse preceded hematological relapse by 3 to 5 months. Three out of four patients who were not in MR after 8 months relapsed. Allogeneic stem cell transplantation was able to eradicate minimal residual disease in 4/4 patients. In 2 patients a temporary reconversion to PCR-positivity was reversed by reduction of immunosuppression. 1 patient did not become PCR-negative until compete withdrawal of immunosuppression. We suggest that BM and PB should be examined after the last consolidation treatment. In case of MR, PB should be examined every 1 to 2 months and BM examination should be done only in case of PCR-positivity in PB in order to confirm the molecular relapse and to identify an impending cytogenetic and/or hematological relapse. CBFβ/MYH11 RT-PCR monitoring is able to predict relapse 3 to 5 months prior to overt hematological relapse, offers a window of opportunity for preemptive therapy of molecular relapse and confers implications for immunotherapy in the setting of allografting.     

血清铁蛋白、叶酸和维生素B_(12)水平的变化在急性早幼粒细胞白血病中的意义

目的:观察急性早幼粒细胞白血病(acute promyelocytic leukemia, APL)不同疾病阶段血清铁蛋白、叶酸和维生素B12水平的动态变化.方法:研究对象为36例原发性APL患者,从治疗前至维持完全缓解3年期间,每1～3个月检测这些患者的血清铁蛋白、叶酸和维生素B12的水平.将初诊时、第1次完全缓解时、第1次完全缓解后6个月时、复发时以及第1次完全缓解维持3年时这5个时间点作为统计观察点,动态观察患者的血清铁蛋白、叶酸和维生素B_(12)水平的变化.结果:初诊时,36例APL患者中有27例(75.0%)血清铁蛋白水平升高,28例(77.8%)血清叶酸水平下降,所有36例患者的血清维生素B_(12)水平均升高.第1次完全缓解时,具有上述异常表现的患者人数较初诊时明显减少(血清铁蛋白P＜0.05,血清叶酸P＜0.01,血清维生素B_(12) P＜0.01).随着治疗的进展,患者的血清铁蛋白、叶酸和维生素B12水平逐渐趋于正常.第1次完全缓解后6个月时,大多数患者的血清铁蛋白、叶酸和维生素B_(12)水平均恢复正常.4例患者在维持完全缓解1年后疾病复发,其血清铁蛋白和维生素B_(12)水平均较复发前升高,而血清叶酸水平则较复发前降低,但差异无统计学意义(P＞0.05).15例维持完全缓解3年的患者,其血清铁蛋白、叶酸和维生素B_(12)的水平均正常.结论:APL患者病程中存在血清铁蛋白、叶酸和维生素B_(12)水平的动态变化.血清铁蛋白和维生素B_(12)水平的升高以及血清叶酸水平的降低均与APL的疾病活动状态和肿瘤负荷相关.     

Arsenic compounds as anticancer agents

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.     

Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: A retrospective analysis of JALSG‐APL97

For patients with relapsed acute promyelocytic leukemia (APL), all‐trans retinoic acid‐based salvage regimens can achieve second complete remission (CR2), but the optimal post‐remission strategy for APL patients after CR2 remains unclear. Hematopoietic stem cell transplantation (HSCT) during CR2 might be effective, but data on the role of HSCT for APL patients after CR2 are limited in Japan. We retrospectively analyzed outcomes for 57 relapsed APL patients who achieved CR2 in the JALSG APL97 study. Of those, six received autologous (auto)‐HSCT, 21 received allogeneic (allo)‐HSCT, and 30 received various regimens other than HSCT. The 5‐year event‐free survival (EFS) rate, overall survival (OS) rate and cumulative incidence of relapse (CIR) were 50.7%, 77.4% and 51.0% in the non‐HSCT group, 41.7%, 83.3% and 58.3% in the auto‐HSCT group and 71.1%, 76.2% and 9.8% in the allo‐HSCT group, respectively. Both the EFS rate and CIR were significantly better in the allo‐HSCT group than in other groups. Allo‐HSCT appears effective in APL patients in CR2, with a low relapse rate beyond a relatively early transplantation‐related mortality (19%). Among older patients (age ≥40 years), the 5‐year OS was significantly better in the non‐HSCT group than in the HSCT group (78.0% vs 40.5%; P = 0.04). Further prospective studies with larger patient numbers are required to confirm the impact of HSCT alone and in combination with arsenic trioxide on outcomes for patients with APL in CR2.     

Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies.

Arsenic trioxide has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). In clinical trials, arsenic trioxide induces complete remission in 87% of patients and molecular remission in 83% of patients. Two-year overall and relapse-free survival estimates are 63% and 49%, respectively. Treatment with arsenic trioxide may be associated with the APL differentiation syndrome, leukocytosis, and electrocardiographic abnormalities. The expanded use of arsenic trioxide in APL for postremission therapy, in conjunction with transplantation, and in patients with newly diagnosed APL is under investigation. The multiple mechanisms of action of arsenic trioxide suggest that it may have antitumor activity in malignancies other than APL and that it may be used in combination with other agents to expand its potential use. This article reviews the clinical use of arsenic trioxide to date and discusses new therapeutic strategies evolving from its diverse biologic activities.     

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.