Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study

Arsenic trioxide (As2O3) effectively induces remissions in relapsed acute promyelocytic leukaemia (APL), but the safety of its long-term administration is unknown. The anthracycline idarubicin is highly active alone or in combination chemotherapy for the treatment of APL. To minimize arsenic exposure and based on the high sensitivity of APL cells to anthracyclines, we conducted a prospective study to evaluate induction with As2O3 followed by consolidation with idarubicin in the treatment of APL in relapse. Eight patients were treated with As2O3 at a daily dose of 10 mg until remission, followed by three monthly courses of idarubicin, at 6 mg/m(2)/day for 5 days in the first course and 6 mg/m(2)/day for 2 days in the subsequent two courses. All patients achieved morphological but not molecular remission after As2O3 treatment. During As2O3 therapy, an increase in white cell count peaking at a median of 17 days occurred in all the cases. Serial flow cytometric analysis of apoptosis, with mitochondrial APO2.7 antigen expression and the sub-G1 cell fraction on DNA histogram as markers, showed induction of apoptosis of APL cells in vivo. With both qualitative and real-time quantitative polymerase chain reaction, all patients were shown to attain molecular remission after subsequent idarubicin treatment. With a median follow up of 13 months, seven of eight patients have remained in complete clinical remission, with six patients in molecular remission as well. One patient who was in third remission became PCR-positive after being transiently negative. One patient died from an intracranial extramedullary relapse after achieving marrow molecular remission. We conclude that As2O3 induction followed by idarubicin consolidation is an effective therapy for APL in relapse. This regimen avoids the possible long-term toxicities of As2O3 and mutagenicity of combination chemotherapy, a strategy that might be suitable for this potentially curable leukaemia.     

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.     

Treatment of Acute Promyelocytic Leukemia with Single Agent Arsenic Trioxide: Experience from a Tertiary Care Center in India

APML is a highly curable hematological malignancy which is treated with differentiation agents and chemotherapy. The morbidity caused by chemotherapy in the treatment of APML is a great cause of concern. We treated 12 patients with newly diagnosed APML with single agent arsenic trioxide between 2010 and 2014 irrespective of risk stratification. Out of 12 patient 2 patients died during induction. All the ten patients who completed induction, completed their consolidation and maintenance without any delays. One out of these ten patients relapsed 10 months after treatment. The remaining nine patients (80 %) are in molecular remission and are under regular follow up. The toxicity with arsenic was negligible and was very well tolerated. Hence arsenic trioxide as single agent can be offered as a standard alternative regimen to ATRA based chemotherapy in patients with economic constraints.     

Molecular remission without blood product support using all-trans retinoic acid (ATRA) induction and combined arsenic trioxide/ATRA consolidation in a Jehovah's Witness with de novo acute promyelocytic leukaemia

Arsenic trioxide has recently been used in the treatment of both relapsed and de novo acute promyelocytic leukaemia (APML). Molecular remissions have been attained using arsenic trioxide with minimal associated haematological toxicity, making protocols utilizing this drug an attractive option for Jehovah's Witnesses with APML. A 62-year-old female Jehovah's Witness with de novo APML was treated with all-trans retinoic acid induction followed by combined arsenic trioxide/ATRA consolidation, and achieved molecular remission with minimal haematological toxicity and no blood product support.     

Successful treatment of relapsed and refractory acute promyelocytic leukemia with arsenic trioxide (As2O3)

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.     

Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia

Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses.     

Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide

The optimal treatment of acute promyelocytic leukaemia (APL) recurring from relapses successfully treated using arsenic trioxide (As2O3) is undefined. Three APL patients relapsing from As2O3-induced remission were studied. Re-treatment with As2O3 failed in one patient in third relapse, and resulted in morphological but not molecular remission in another patient. Combination therapy with As2O3 and all-trans retinoic acid (ATRA), however, resulted in morphological and molecular remission in all three cases, with a follow-up time ranging from 6 to 16 months. Our results suggest a synergistic therapeutic effect between As2O3 and ATRA in APL in advanced relapse.     

Oral administration of arsenic trioxide induced molecular remission in relapsed acute promyelocytic leukemia

I report on a 21-year-old man with acute promyelocytic leukemia (APL) which relapsed after a therapeutic regimen consisting of tretinoin, daunorubicin, enocitabine, mitoxantrone, and cytarabine. The patient also had severe mental retardation caused by a congenital central nervous system malformation. Administration of arsenic trioxide (As2O3) is indicated for patients with APL, however, daily intravenous infusion of As2O3 presented problems because of the patient's violent resistance to venous access. Accordingly, 10mg of an oral solution of As2O3 was given once daily for 70 days. No adverse events were observed with the exception of transient hyperleukocytosis and fever. The patient achieved molecular remission 103 days after the start of oral As2O3, and remains in remission after an additional 2 courses of oral As2O3 as consolidation chemotherapy. Oral As2O3 may be useful in the treatment of relapsed APL as an alternative to intravenous As2O3.     

Arsenic and all-trans retinoic acid as induction therapy before autograft in a case of relapsed resistant secondary acute promyelocytic leukemia.

Arsenic trioxide has recently been reported to be successful in the treatment of promyelocytic leukemia. Several concerns about the use of this toxic agent are currently reducing its potential clinical use even in severely ill patients. In this report we describe the results achieved by As2O3 with all-trans retinoic acid in a patient suffering from secondary, relapsed, resistant promyelocytic leukemia. Several complications, including sepsis and an extensive area of skin necrosis, did not allow us to treat the patient further with chemotherapy. With As2O3 and ATRA therapy, the patient obtained a complete molecular remission without any significant toxicity and, subsequently, it was possible to perform a bone marrow autograft in a state of complete remission.     

Mitoxantrone and cytosine arabinoside as treatment for acute myeloblastic leukemia in older patients

The majority of patients with acute myeloid leukemia (AML) are elderly, and their response to chemotherapy is poorer than that of younger patients. The combination of mitoxantrone (MTN) and cytosine arabinoside (Ara-C) is a possible alternative to an anthracycline/Ara-C combination for the treatment of AML in these patients. Of 52 older patients (> 59 years) referred over a 3.5-year period, 33 patients (age range 60–78 years, median 67 years) received MTN and Ara-C as therapy for newly diagnosed AML. MTN was administered at a dose of 12 mg/m²/day, intravenously, for 3 days (23 patients), or 10 mg/m²/day for 5 days (10 patients), and Ara-C at a dose of 100 mg/m² twice daily, intravenously, for 7 days. Complete remission (CR) was achieved in 16/33 patients (48%). The median remission duration was 6 months (range 1–37 months). The median survival was 14 months for those who achieved CR compared with 9 months for those with resistant disease. Two patients remain in first CR after 13 and 37 months, but three patients died whilst receiving consolidation therapy. In selected elderly patients with AML, the combination of MTN and Ara-C provides an acceptable alternative to an anthracycline/ Ara-C regimen, with a higher CR rate than historical controls. However, the CR rate and remission duration remain low compared with those of younger patients, supporting the need to investigate new approaches to treatment in this population.     

Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation

BACKGROUND AND OBJECTIVES: Arsenic trioxide (ATO) has been reported to be a safe and effective treatment for relapsed acute promyelocytic leukemia (APL). The aim of this study was to evaluate the efficacy and toxicity as well as the eligibility to stem cell transplantation (SCT) in a series of 7 patients with relapsing APL, managed with ATO. DESIGN AND METHODS: Seven patients with relapsing APL while on maintenance treatment with all-trans-retinoic acid (ATRA) or who were ATRA refractory-received ATO at a dose of 10 mg daily by 2-hour intravenous infusion until complete remission (CR). After consolidation chemotherapy, patients were programmed to receive autologous or allogeneic stem cell transplantation (SCT) according to donor availability. The median age of the patients was 55 (21-71) years: 2 patients presented with concomitant extramedullary relapse. RESULTS: Six patients (86%) achieved CR after a median of 35 ATO doses (20-49) with negligible toxicity; one patient died from pneumonia. After consolidation with a four-day course of cytarabine at 1 g/m2 and mitoxantrone 6 mg/m2, two patients underwent allogeneic SCT, two received PML/RARa negative autologous peripheral blood stem cells collected after consolidation plus granulocyte colony-stimulating factor, one failed mobilization and received a second consolidation course. One elderly patient refused further treatment and relapsed 6 months later. After a median follow-up of 15 months from CR2 achievement, 5 patients are alive in continuous CR. INTERPRETATION AND CONCLUSIONS: The high CR rate and the mild toxicity confirm that ATO represents a valid alternative to salvage chemotherapy for patients relapsing while on ATRA treatment or who are ATRA-refractory. Allogeneic or autologous SCT after ATO-induced CR is feasible in the majority of patients.     

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。     

Arsenic trioxide and ascorbic acid: synergy with potential implications for the treatment of acute myeloid leukaemia?

Arsenic trioxide (As2O3) induces remission in a high proportion of patients with acute promyelocytic leukaemia (APL) via induction of apoptosis. Preliminary reports suggest that the apoptotic effect of As2O3 is not specific for APL but can also be observed in non-APL acute myeloid leukaemia (AML) cells, although these are less sensitive than APL cells. Ascorbic acid has recently been demonstrated to enhance the apoptotic effect of As2O3. We have therefore evaluated combined As2O3/ascorbic acid treatment in various clinical samples of AML. Our results indicate a significant synergistic effect of As2O3 and ascorbic acid, suggesting a possible future role of As2O3/ascorbic acid combination therapy in patients with AML.     

Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity

Arsenic trioxide, as a single agent, has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). There is limited long-term outcome data with single-agent As2O3 in the management of newly diagnosed cases of APL. Between January 1998 to December 2004, 72 newly diagnosed cases of APL were treated with a regimen of single-agent As2O3 at our center. Complete hematologic remission was achieved in 86.1%. At a median follow-up of 25 months (range: 8-92 months), the 3-year Kaplan-Meier estimate of EFS, DFS, and OS was 74.87% +/- 5.6%, 87.21% +/- 4.93%, and 86.11% +/- 4.08%, respectively. Patients presenting with a white blood cell (WBC) count lower than 5 x 10(9)/L and a platelet count higher than 20 x 10(9)/L at diagnosis (n = 22 [30.6%]) have an excellent prognosis with this regimen (EFS, OS, and DFS of 100%). The toxicity profile, in the majority, was mild and reversible. After remission induction, this regimen was administered on an outpatient basis. Single-agent As2O3, as used in this series, in the management of newly diagnosed cases of APL, is associated with responses comparable with conventional chemotherapy regimens. Additionally, this regimen has minimal toxicity and can be administered on an outpatient basis after remission induction.     

Successful bone marrow transplantation with a matched unrelated donor in an acute promyelocytic leukemia patient after reinduction therapy with arsenic trioxide

A 44-year-old man with relapsed acute promyelocytic leukemia (APL), refractory to all-trans-retinoic acid (ATRA), daunorubicin, and cytosine arabinoside, was treated with arsenic trioxide (ATO). ATO was given intravenously at a dose of 0.15 mg/kg/day for 20 days, and the patient achieved complete remission. No serious adverse events related to ATO infusion were observed. He received ATO for 10 days as consolidation therapy and subsequently underwent HLA-matched unrelated donor stem cell transplantation. He remains in molecular remission 10 months after transplant. This case suggests that ATO could be a useful therapy prior to allogeneic stem cell transplantation in relapsed APL.