Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

全反式维甲酸联合三氧化二砷双药诱导缓解治疗对初治急性早幼粒细胞白血病患者肝功能的影响

目的探讨全反式维甲酸（ATRA）联合三氧化二砷（ATO）诱导缓解治疗急性早幼粒细胞白血病（APL）期间患者肝功能的变化。方法回顾性分析80例初治APL患者临床资料,其中38例经ATRA联合ATO双药诱导,42例经ATRA或ATO单药诱导,比较两组疗效及肝损害的差异。结果双药诱导组和单药诱导组完全缓解（CR）率差异无统计学意义[94．7％（36／38）比90．5％（38／42）,P〉0．05];双药诱导组CR时间短于单药诱导组[27d（20～36d）比35d（25～49d）,P〈0．05]。双药诱导组肝功能异常的发生率高于单药诱导组[68．4％（26／38）比42．9％（18／42）,P〈0．05];中＋重度肝功能异常的发生率高于单药诱导组[39．5％（15／38）比9．5％（4／42）,P〈0．05]。双药诱导组丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）异常率以及异常AIJT和AST检测峰值均高于单药诱导组（P〈0．05）;两组开始出现肝功能异常的时间以及血清总胆红素、碱性磷酸酶、1．谷氨酰转肽酶异常率的差异无统计学意义（P〉0．05）。结论ATRA联合ATO双药诱导缓解治疗APL加重了肝脏毒性,治疗的同时需密切监测肝功能,及时行保肝治疗。     

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.     

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.     

The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis

Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00-1.17, P = 0.04), shortened the time to achieve CR (WMD: −6.51, 95% CI: −11.32 to −1.70, P = 0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14-2.66, P = 0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00-1.50, P = 0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO.     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia

BACKGROUND: From 20% to 30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) develop recurrent disease. Arsenic trioxide (ATO) is an effective agent for the salvage of patients with recurrent APL, and gemtuzumab ozogamicin (GO) has shown activity in patients with APL. METHODS: The authors investigated the efficacy of a combination of ATO, ATRA, and GO in 8 patients with APL in first recurrence (7 patients with hematologic recurrences and 1 patient with a molecular recurrence). All patients had received previous treatment with ATRA either alone or in combination with other agents. Patients received ATO 0.15 mg/kg intravenously until they achieved a bone marrow complete remission (CR). Once in CR, patients received consolidation with ATO, ATRA, and GO for 10 months. Patients then received maintenance with idarubicin, ATRA, 6-marcaptopurine, and oral methotrexate for 11 months. RESULTS: All 7 patients who had hematologic recurrences achieved CR after a median of 39 days (range, 21-56 days). After a median follow-up of >/=36 months (range, 4-55 months), 6 patients remained alive in CR, and 2 patients died in CR. Six of 8 patients remained in second CR that was longer than their first CR. All 7 evaluable patients achieved molecular remission. There were no grade 3 or 4 extramedullary toxicities. Two patients died, 1 secondary to a complication of metastatic lung adenocarcinoma, and the other of sepsis. CONCLUSIONS: The combination of ATO, ATRA, and GO was effective and may achieve durable remissions in patients with APL in first recurrence. It should be considered as an effective alternative to allogeneic or autologous transplantation.     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病50例疗效观察

 目的　观察三氧化二砷（ATO）联合全反式维甲酸（ATRA）治疗初发急性早幼粒细胞白血病（APL）的疗效。方法　98例初发APL患者分为对照组和治疗组,对照组48例,治疗组50例。对照组采用常规ATRA+DA双诱导方案治疗;治疗组采用ATRA每天25 mg／m2,ATO每天0.15 mg／kg（ATRA后第10天开始）联合治疗,直至完全缓解（CR）,CR后接受ATO和ATRA联合巩固治疗。比较两组CR率、PML-RARα融合基因转阴时间及5年无病生存率。结果　对照组和治疗组CR率分别为89.5 %（43／48）和90.0 %（45／50）,获得CR时间分别为（30.0±5.1）d和（28.1±4.4）d,两组CR率（χ2＝-0.068,P＝0.946）及获得CR时间（t＝1.757,P＝0.083）相比差异均无统计学意义。在所有获得CR的患者中,3例分别在CR后第276、385和394天复发。所有患者发病时PML-RARα融合基因均阳性,对照组和治疗组CR时分别有25.0 %（5／20）和29.4 %（5／17）转阴,巩固后分别有92.5 %（37／40）和97.6 %（41／42）转阴。对照组和治疗组5年无病生存率分别为（85.3±5.9）%和（87.6±5.6）%,差异无统计学意义（χ2＝0.232,P＝0.630）。结论　ATO联合ATRA能有效治疗初发APL患者,可以作为常规化疗方案外的另一选择。     

三氧化二砷治疗初治急性早幼粒细胞白血病疗效分析

 目的　分析以三氧化二砷（ATO）为基础的诱导和维持治疗方案治疗初发急性早幼粒细胞白血病（APL）的长期疗效。方法　回顾性分析62例初诊成年APL患者诱导缓解治疗和缓解后巩固维持治疗经过,并作5、7年随访分析。结果　诱导治疗阶段,ATO+全反式维甲酸（ATRA）双药联合化疗组与ATRA联合化疗组完全缓解（CR）率差异无统计学意义,但前者达到CR时间明显缩短。诱导治疗后PML-RARα融合基因转阴率两组分别为86.2 %、56.3 %,差异有统计学意义（P＜0.05）。巩固维持治疗阶段,ATO序贯维持组和化疗序贯维持组5年总生存（OS）率分别为（94.4±5.4）%和（45.5±10.2）%,7年OS率分别为（52.5±23.7）%和（27.3±9.3）%;两组5年无病生存（DFS）率分别为（94.7±5.5）%和（41.3±10.1）%,7年DFS率分别为（52.6±23.7）%和（27.5±9.4）%,两组差异有统计学意义（P＜0.05）。并且,ATO序贯维持组复发率（14.7 %）低于化疗序贯维持组（37.0 %）,差异有统计学意义（P＜0.05）。结论　以ATO联合ATRA、化疗的诱导化疗方案可缩短诱导化疗时间,提高PML-RARα融合基因转阴率,而且,包含ATO的序贯维持治疗明显改善APL患者的长期生存,减少复发,安全性高,患者耐受性好。     

Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML–RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome.     

Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG)

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.     

全反式维甲酸与亚砷酸联合柔红霉素对NB4细胞CD11b表达的影响

 目的　观察全反式维甲酸（ATRA）与亚砷酸（ATO）单独以及二药联合柔红霉素（DNR）诱导分化治疗过程中对NB4细胞CD11b表达的影响,及其对高白细胞血症、急性早幼粒细胞白血病（APL）分化综合征的作用。方法　采用荧光素标记的CD11b单克隆抗体,流式细胞术动态检测各组药物作用于NB4细胞24、48、72、168 h后细胞CD11b的表达状况。结果　1 μmol／L ATRA作用于NB4细胞后,CD11b表达随作用时间的延长逐渐增加,呈时间依赖性。24、48、72、168 h CD11b表达分别为（33.34±3.15）%、（55.59±5.13）%、（86.08±5.12）%、（90.69±2.69）%,在同一时间点均高于空白对照组（P＜0.01）。1 μmol／L ATO作用于NB4细胞后,随时间延长CD11b表达亦逐渐增加,但各时间点之间CD11b表达差异无统计学意义;在同一时间点CD11b表达低于ATRA组（P＜0.01）,但与空白对照组比较差异无统计学意义（P＞0.05）。1 μmol／L ATRA+1 μmol／L ATO作用于NB4细胞后,24、48 h CD11b表达分别为（16.92±1.05）%、（17.01±0.22）%,与空白对照组比较差异无统计学意义（P＞0.05）,72、168 h CD11b表达高于空白对照组（P＜0.05）,分别为（18.81±1.40）%、（25.61±4.54）%;但在同一时间点CD11b表达均低于ATRA组（P＜0.01）。1 μmol／L ATRA+1 μmol／L ATO+1 μmol／L DNR作用于NB4细胞后,在同一时间点CD11b表达低于ATRA组（P＜0.01）;与空白对照组比较差异无统计学意义（P＞0.05）。结论　ATRA联合ATO或加用DNR诱导治疗APL,可能由于避免了APL细胞诱导分化过程中CD11b表达的增高,从而在一定程度上减少了高白细胞血症、APL分化综合征的发生。     

Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.     

Outcome of therapy‐related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy

BACKGROUND:

Patients with therapy‐related acute promyelocytic leukemia (t‐APL) have been commonly exposed to topoisomerase inhibitors and may potentially benefit from induction regimens omitting anthracyclines.

METHODS:

Retrospective analysis of the outcomes of 29 patients with t‐APL who were either treated with arsenic trioxide (ATO) and all‐trans‐retinoic acid (ATRA) or with standard ATRA plus anthracycline‐based chemotherapy was performed.

RESULTS:

Prior therapy included chemotherapy alone, radiation alone, or a combination of the 2 in 19%, 33%, and 47% of patients, respectively. The combination of ATO and ATRA (n = 19) for induction resulted in a similar remission rate compared with ATRA plus chemotherapy (n = 10) (89% vs 70%; P = .35). The median overall survival for the patients treated with ATRA plus ATO was not reached compared with that for patients treated with ATRA plus chemotherapy (161 weeks; P = .79).

CONCLUSIONS:

In this cohort of t‐APL patients, outcomes with ATO and ATRA appeared to be comparable to anthracycline‐containing induction regimens. This combination may be preferable in t‐APL patients to avoid any risk of anthracycline‐induced toxicities. Cancer 2011. © 2010 American Cancer Society.     

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.     

Improved long‐term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide‐based front‐line therapy

Limited data was available for long‐term follow‐up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all‐trans‐retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)‐based front‐line therapy. The aim of this work was to retrospectively analyze the long‐term survival rate and frequency of therapy‐related myeloid neoplasia (t‐MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front‐line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non‐ATO group). The median duration of follow‐up was 7.5 years (1.0‐18.3 years). ATO group showed significant superior 10‐year estimated relapse‐free survival (RFS) up to 90.3% comparing with 65.5% in the non‐ATO group (P < 0.0001). In addition, the 10‐year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non‐ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non‐ATO group in both low‐to‐intermediate‐risk (94.2% vs 64.6%, P < 0.0001) and high‐risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3‐year RFS and OS rates in the chemotherapy‐free subgroup of the low‐to‐intermediate‐risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy‐related myeloid neoplasms (t‐MN). The estimated 5‐year cumulative incidence risk of t‐MN in the ATO and non‐ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long‐term outcome of patients treated with ATRA plus ATO‐based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.     

Treatment of acute promyelocytic leukemia in the very elderly: case report and review of the literature

Acute promyelocytic leukemia (APL) is the most curable subtype of AML yet it is not known to what extent newer therapies will succeed in the very elderly. Conventional chemotherapeutic induction regimens are usually too toxic for older patients, however, all trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may be useful therapeutic options if used judiciously. This case series describes three octogenarians with APL all treated with ATRA and achieved complete remissions. The last patient received ATO at the time of first relapse and achieved a second remission. To our knowledge, this is the first report of successful use of ATO for induction in an octogenarian with APL.     

Long-term survey of outcome in acute promyelocytic leukemia: a single center experience in 340 patients

The aims of this study are to investigate the outcome and prognostic factors influencing long-term survival on patients with acute promyelocytic leukemia (APL). A total of 340 APL patients admitted to the Department of Hematology from January 1988 to December 2009 were enrolled in this study. All patients received all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) with anthracycline-based induction therapy. After three courses of consolidation chemotherapy, 279 patients received 2 years of maintenance therapy. Survival analyses were carried out using the Kaplan-Meier method and the Cox regression model. In total, 288 achieved CR with the CR rate of 84.7%, and 50 patients died during induction therapy. Univariate analysis identified the following three risk factors for hemorrhagic mortality: fibrinogen level (<1.0 g/l) (P = 0.0007), initial peripheral WBC count(>4 × 10(9)/l) (P = 0.0001), as well as the presence of coagulopathy(P < 0.0001). With a median follow-up of 49 (6-255) months, the estimated 5-year overall survival (OS) and relapse-free survival (RFS) were (89.0 ± 2.4)% and (83.7 ± 2.6)%, respectively. Cox regression analysis of the 290 patients showed initial WBC count, years of diagnosis, and the status of PML-RARα in remission seemed to be independent prognostic indicators for OS and RFS (P = 0.03, P < 0.01 and P = 0.0001, respectively). Cytogenetics in addition to above three variables remained significant for RFS (P = 0.01). Our retrospective observations suggest that the combination of ATRA and/or ATO with anthracycline-based therapy may have useful implications in the perspective of long-term prognosis for adult APL.     

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non‐t(15;17) subtype

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated. Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French – American – British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m²/day p.o., mercaptopurine 60 mg/m²/day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m²/d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients). Results: In all patients the rates of CR, 3‐year OS and 5‐year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5‐year OS and 5‐year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively. Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.     

Improved Outcomes of All-trans-retinoic Acid and Arsenic Trioxide Plus Idarubicin as a Frontline Treatment in Adult Patients With Acute Promyelocytic Leukemia

IntroductionThe purpose of this study was to explore the outcomes of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) plus idarubicin (IDA) as a frontline treatment in adult patients with acute promyelocytic leukemia (APL).Patients and MethodsWe analyzed the outcomes of ATRA and intravenous ATO plus IDA as a frontline induction therapy in 118 patients with APL with high-risk (HR) and standard-risk (SR) disease from January 2008 to December 2017. The medical records of 118 patients with APL (HR, n = 45; SR, n = 73) who received the frontline triple combination regimen at Henan Provincial People’s Hospital and Tongji Hospital were retrospectively reviewed. Consolidation therapy comprised 6 cycles of ATO and ATRA plus IDA, and IDA was administered in 1 to 4 cycles of consolidation therapy based on the comparable clinical efficacy compared with 6 cycles and fewer side effects to myocardium without subsequent maintenance therapy.ResultsOf 118 patients, there were 3 (2.5%) early deaths and 115 (97.5%) hematologic complete remissions; 102 (88.7%) of 115 patients achieved molecular complete remission following induction therapy, and all patients were polymerase chain reaction-negative for promyelocytic leukemia-retinoic acid receptor alpha after the first cycle of consolidation therapy. The 5-year overall survival (OS) and event-free survival (EFS) were 93.0% ± 2.9% and 92.4% ± 3.0%, respectively. Early death, hematologic complete remissions, molecular complete remissions, and toxicities were comparable between the HR and SR groups. The cumulative incidence of relapse in the HR group was 4.7% (n = 2), and the cumulative incidence of relapse in the SR group was 0. The OS and EFS of the SR and HR groups were comparable (92.3% ± 4.5% vs. 92.8% ± 4.0%; X² = 0.263; P = .608; 92.3% ± 4.5% vs. 91.1% ± 4.2%, X² = 0.917; P = .338). The total dosage of IDA was approximately 181 to 258 mg, and no patient experienced cardiotoxicity. OS and EFS were not influenced by fms-related tyrosine kinase 3 internal tandem duplication mutation status (P = .405 and P = .528, respectively).ConclusionThe triple combination of ATRA and ATO plus IDA as both an induction and consolidation therapy for the HR and SR groups attained excellent outcomes, and this regimen was effective, safe, and easy, without maintenance therapy. The triple combination treatment might be a preferred frontline therapy for patients with APL, especially for those with HR or the APL fms-related tyrosine kinase 3 internal tandem duplication mutation.