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.     

FLAG方案治疗小儿复发难治性急性白血病临床研究

目的探讨FLAG方案（氟达拉滨,阿糖胞苷,粒细胞集落刺激因子）治疗小儿复发难治性急性白血病的疗效。方法采用FLAG方案[氟达拉滨30mg／（m^2·d）X5＋阿糖胞苷2g／（m^2·d）×5d＋粒细胞集落刺激因子5μg/（kg·d）]治疗21例2—13岁的小儿复发难治性急性白血病,其中急性非淋巴细胞性白血病（AML）15例,急性淋巴细胞性白血病（ALL）6例。首次复发（R1）后首选FLAG方案者8例,次选10例,原发难治2例,第三次缓解（CR3）后FLAG巩固治疗1例。结果21例患儿中1例作为缓解后巩固治疗,1例因化疗后感染死亡而无法评估FLAG应用后缓解率;其他19例可评估患儿中9例（47％）获完全缓解（CR）,3例（16％）部分缓解（PR）,7例（37％）无效（NR）,总有效率63％。其中AMLCR率57％,ALL为20％;R1后首选FLAG方案者CR率为57％,次选为20％。应用FLAG后患儿中性粒细胞〉0．5×10^9／L的中位时间为21（12～36）天,血小板〉20×10^9/L的中位时间为19．4（13～30）天。21例患儿中18例合并感染（86％）,除1例死亡外其余均得到有效控制,治疗相关死亡率为4．76％。FLAG治疗后7例患儿进行了造血干细胞移植治疗,目前2例无病存活,分别已移植后无病生存14个月和56个月,其他4例死于移植相关并发症,1例死于移植后复发。另外14例非移植患儿中1例因FLAG相关感染死亡,7例因NR而放弃治疗或合并感染死亡,FLAG治疗有效的6例患儿中2例放弃治疗,4例复发死亡。本组患儿FLAG治疗后中位生存时间5个月。结论FLAG方案治疗小儿复发难治性白血病疗效肯定,毒副作用可以耐受;AML选择FLAG的疗效优于ALL;复发后首选FLAG治疗效果好于次选者。     

Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.     

Salvage therapy for refractory or relapsed acute lymphocytic leukemia

The overall prognosis for patients with relapsed or refractory adult ALL remains poor. Further insight into the biology of ALL is required, and novel therapeutic agents are needed to counter mechanisms of resistance. A palliative approach to the management of multiply relapsed or refractory ALL should be supplanted by enrollment into clinic trials to promote drug discovery. Monitoring of minimal residual disease may allow an earlier intervention before overt clinical relapse and improve outcome; prospective studies are needed. Attainment of a second or later CR should be followed by allogeneic BMT when feasible owing to the paucity of long-term survivors with salvage chemotherapy alone.     

Mito-FLAG方案治疗难治/复发急性髓细胞白血病的临床观察

目的:研究Mito-FLAG方案(米托蒽醌、氟达拉滨、阿糖胞苷和粒细胞集落刺激因子联合应用)治疗难治/复发急性髓细胞白血病的疗效和不良反应。方法:Mito10mg/dd1(1例15mg/d,d1;另有1例5mg/d,d1-5);Flu30mg·m-2·d-1静脉滴注30min,d1-5;Ara-C1.5g·m-2·d-1静脉滴注4h,d1-5;G-CSF300μg·kg-1·d-1从d0开始一直应用到白细胞恢复至20.0×109/L。治疗9例(11例次)难治/复发AML。结果:9例患者完全缓解率44.4%,其中7例难治AML的完全缓解率为57%,所有病例总有效率达66.7%,无效3例,其中早期死亡1例。毒副作用为骨髓抑制、消化道症状、轻度黄疸和静脉炎等。结论:Mito-FLAG方案治疗难治复发AML有较好的疗效,且毒副作用可以耐受,可用于治疗对其他化疗方案无效的难治/复发AML,并为患者赢得了进行造血干细胞移植的时机。     

Gemtuzumab ozogamicin (Mylotarg) in children with refractory or relapsed acute myeloid leukemia

BACKGROUND: Gemtuzumab ozogamicin (GO) is an immunoconjugate consisting of the CD33 antibody and calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. PATIENTS AND METHOD: We report 12 children with multiple relapsed or refractory AML receiving GO as compassionate use. 11 children had initially been treated according to the AML-BFM 93 or 98 protocol, 1 girl received relapse treatment (liposomal daunorubicin/FLAG) due to secondary AML. After relapse, 10 children received an intensive relapse therapy (AML-BFM 97 or international AML-Relapse Study 2001/01). 2 of them had been transplanted in first or second CR before GO therapy. RESULTS: 5 of 12 children responded to treatment with blast reduction to below 5%, but no child achieved CR after GO. Time until reoccurrence of blasts in almost all children with GO response was 3-8 months. In 5 children stem cell transplantation (SCT) was performed after GO therapy. 4 of them suffered from further progression of AML, 1 boy is in second remission with a follow-up of 8 months. 2 children had severe side effects. An anaphylactic reaction with severe hypotension was managed by catecholamine support and intensive care. In 1 girl, who relapsed after SCT in first remission, a veno-occlusive disease of the liver occurred, but could be treated successfully with defibrotide. CONCLUSION: GO therapy can induce blast reduction in children who have no further conventional treatment options. Frequency and severity of adverse events are limited, and therapy seems to be feasible for children with a sufficient general condition. Controlled studies are necessary to learn more about efficacy and side effects, especially implications for further therapy.     

MEAD方案治疗难治复发性成年人急性淋巴细胞白血病

目的 观察MEAD化疗方案治疗难治复发性成年人急性淋巴细胞白血病(ALL)的疗效和安全性.方法 对2006年6月至2009年6月收治的22例成年人难治复发性ALL患者,采用MEAD方案化疗,米托蒽醌6 mg/d静脉滴注,第1天至第3天;阿糖胞苷100 mg/d静脉滴注,第1天至第5天;依托泊苷100mg/d静脉滴注,第1天至第5天;地塞米松10mg/d静脉滴注,第1天至第8天.结果 成年人难治复发性ALL完全缓解率31.8%.部分缓解率22.7%,总有效率54.5%;两次MEAD方案化疗后,累积完全缓解率为50.0%,部分缓解率40.9%.主要不良反应为不同程度的骨髓抑制,重要脏器毒性反应轻微.结论 MEAD化疗方案对难治复发性成年人ALL有较好的疗效.患者不良反应轻微.     

MEAD方案治疗难治复发性成年人急性淋巴细胞白血病

目的 观察MEAD化疗方案治疗难治复发性成年人急性淋巴细胞白血病(ALL)的疗效和安全性.方法 对2006年6月至2009年6月收治的22例成年人难治复发性ALL患者,采用MEAD方案化疗,米托蒽醌6 mg/d静脉滴注,第1天至第3天;阿糖胞苷100 mg/d静脉滴注,第1天至第5天;依托泊苷100mg/d静脉滴注,第1天至第5天;地塞米松10mg/d静脉滴注,第1天至第8天.结果 成年人难治复发性ALL完全缓解率31.8%.部分缓解率22.7%,总有效率54.5%;两次MEAD方案化疗后,累积完全缓解率为50.0%,部分缓解率40.9%.主要不良反应为不同程度的骨髓抑制,重要脏器毒性反应轻微.结论 MEAD化疗方案对难治复发性成年人ALL有较好的疗效.患者不良反应轻微.     

MEAD方案治疗难治复发性成年人急性淋巴细胞白血病

 目的　观察MEAD化疗方案治疗难治复发性成年人急性淋巴细胞白血病（ALL）的疗效和安全性。方法　对 2006年6月至2009年6月收治的22例成年人难治复发性ALL患者,采用MEAD方案化疗,米托蒽醌6 mg／d静脉滴注,第1天至第3天;阿糖胞苷100 mg／d静脉滴注,第1天至第5天;依托泊苷100 mg／d静脉滴注,第1天至第5天;地塞米松10 mg／d静脉滴注,第1天至第8天。结果　成年人难治复发性ALL完全缓解率31.8 %,部分缓解率22.7 %,总有效率 54.5 %;两次MEAD方案化疗后,累积完全缓解率为50.0 %,部分缓解率40.9 %。主要不良反应为不同程度的骨髓抑制,重要脏器毒性反应轻微。结论　MEAD化疗方案对难治复发性成年人ALL有较好的疗效。患者不良反应轻微。     

Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide

Purpose To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg. Methods Inorganic arsenic (As^III and As^V) and the major metabolites monomethylarsonic acid (MAA^V) and dimethylarsinic acid (DMAA^V) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS. Results The plasma concentrations of As^III and As^V on day 1 reached the similar Cmax (12.4 ± 8.4 and 10.2 ± 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC_0–∞ of As^V was about twice that of As^III. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA^V and DMAA^V concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day1 and remained at about 60% of daily dose during week 1–4. Conclusions This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood. This study was partly supported by a Grant-in-aid for Cancer Research (no. 9–2) of the Ministry of Health and Welfare.     

Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene)

Clinical trials for treatment of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) using all-trans-retinoic acid (ATRA) have shown satisfactory therapeutic responses, although efficacies were limited. Recently, many synthetic retinoids have been developed and among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARalpha- and RARbeta-specific retinoid expected to overcome ATRA resistance. The present study examined the inhibitory effects of Am80 on HTLV-I-infected T-cell lines and ATL cells. Am80 had negligible growth inhibition of peripheral blood mononuclear cells but marked growth inhibition of both HTLV-I-infected T-cell lines and ATL cells. Am80 arrested cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. It inhibited also the phosphorylation of IkappaBalpha and NF-kappaB-DNA binding, in conjunction with reduction of expression of proteins involved in the G1/S cell cycle transition and apoptosis. Am80 also inhibited the expression of JunD, resulting in suppression of AP-1-DNA binding. Furthermore, severe combined immunodeficient mice with tumors induced by subcutaneous inoculation of HTLV-I-infected T cells, responded to Am80 treatment with partial regression of tumors and no side-effects. These findings demonstrate that Am80 is a potential inhibitor of NF-kappaB and AP-1, and is a potentially useful therapeutic agent against ATL.     

Molecular mechanisms of retinoid action in acute promyelocytic leukemia (Review)

Acute promyelocytic leukemia (APL) is, at present, the first and only example of leukemia which can be induced into remission with a single cyto-differentiating agent. This is due to the fact that APL is exquisitely sensitive to the differentiating action of all-trans retinoic acid (ATRA). Thus, the APL model offers a unique opportunity to study the cyto-differentiating action of ATRA and synthetic retinoids in a clinically relevant setting. This review article summarizes the work relating to the molecular mechanisms underlying the action of retinoic acid and retinoids in APL cells, and focuses on: a) genes which are expressed and regulated by ATRA; b) synthetic retinoids as cyto-differentiating agents; c) rational combinations between retinoids and cytokines or other cyto-differentiating agents; d) cellular paradigms of retinoic acid resistance. It is our aim to give an updated, about nonexhaustive, account of some of the most recent development regarding the pharmacological action of retinoic acid and its derivatives in APL cells.     

Mitoxantrone and high-dose etoposide for patients with relapsed or refractory acute leukemia.

Among 35 patients with relapsed or refractory acute myelogenous leukemia (AML) who received salvage chemotherapy, 28 were treated with mitoxantrone (7.5 mg/m2/d intravenously [IV] over 1 hour for 5 days) and etoposide (VP-16) (2 g/m2 over 4 days either as a daily infusion or as two daily doses). Seven patients received mitoxantrone (6 mg/m2/d for 5 days) and VP-16 (1500 mg/m2 over 3 days). The median duration of the initial complete remission (CR) was 6 months and 83% of the patients had initial CR that lasted 12 months or less. Forty-six percent of the patients were undergoing a second or subsequent salvage attempt. Eight patients (23%) achieved CR; seven of these CR were obtained after one course of therapy. Twelve patients (33%) died and 15 patients (42%) had disease that was resistant to treatment. Patients undergoing a first salvage attempt had a higher incidence rate of CR than those undergoing a second or subsequent salvage attempt (37% versus 6%; P = 0.03). CR rates were also higher in patients with a favorable (translocation 8;21 or 15;17) or diploid karyotype compared with other patients (32% versus 8%; P = 0.10). The median survival time was 2 months for all patients and 8 months for patients achieving CR. Mucositis occurred in 74% of the patients and was severe in 32%. Diarrhea and rash occurred in less than 33% of the patients. Fever was noticed in all but 1 of the patients and documented infections occurred in 65% of the patients. Six patients had pancytopenia or thrombocytopenia that lasted more than 42 days from the initiation of treatment. Although mitoxantrone and high-dose VP-16 is an effective antileukemic regimen, it is associated with a high incidence of mucositis. Strategies that are used to limit mucosal damage may improve the tolerance of this combination.     

FLAG与MEA方案治疗复发、难治成年人急性髓系白血病的临床观察

 【摘要】　目的　观察FLAG与MEA方案治疗复发、难治成年人急性髓细胞白血病（AML）的疗效及不良反应。方法　回顾性分析51例复发、难治成年AML（M3除外）患者的临床资料,按化疗方案分为FLAG组（23例）、MEA组（28例）,观察两组的疗效及不良反应。结果　FLAG组完全缓解（CR）7例（30.4 %）,部分缓解（PR）4例（17.4 %）,有效率为47.8 %（11／23）;MEA组CR 10例（35.7 %）,PR 6例（21.4 %）,有效率为57.1 %（16／28）,两组有效率比较差异无统计学意义（χ2＝0.443,P＞0.05）。两组均出现IV度骨髓抑制,继发感染率、出血发生率差异无统计学意义[95.7 %（22／23）比89.3 %（25／28）,82.6 %（19／23）比85.7 ％（24／28）,均P＞0.05]。两组心脏毒性比较差异有统计学意义（χ2＝4.554,P＝0.042）。结论　FLAG方案治疗复发、难治成年人AML的疗效与MEA方案疗效相近,心脏毒性低,不良反应可耐受,可作为复发、难治AML的一线治疗方案。     

Retraction: Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene)

This article has been retracted at the request of Editor‐in‐Chief & Author. The following article from Cancer Science: Tetsuro Nakazato, Taeko Okudaira, Chie Ishikawa, Shinji Nakama, Shigeki Sawada, Mariko Tomita, Jun‐nosuke Uchihara, Naoya Taira, Masato Masuda, Yuetsu Tanaka, Kazuiku Ohshiro, Nobuyuki Takasu, Naoki Mori. Anti‐adult T‐cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene), Cancer Science 2008; 99 : 2286–2294, (doi: 10.1111/j.1349‐7006.2008.00917.x ), published online on 1 September 2008 on Wiley Interscience ( http://www.interscience.wiley.com ), now Wiley Online Library ( http://onlinelibrary.wiley.com/ ), has been retracted by agreement between the authors, the journal Editor‐in‐Chief, Yusuke Nakamura, and Blackwell Publishing Asia Pty Ltd. All authors wish to retract this paper due to inappropriate image utilization in three of the figures within the article. Yusuke Nakamura
Editor‐in‐Chief
Cancer Science     

Phase I clinical investigation of benzisoquinolinedione (amonafide) in adults with refractory or relapsed acute leukemia

After Phase I studies of benzisoquinolinedione (amonafide) in solid tumors identified myelosuppression as the dose-limiting toxicity, we conducted a Phase I study in patients with relapsed or refractory acute leukemia to define the optimal dose. Amonafide was given i.v. over 2-4 h daily for 5 days. The starting dose was 600 mg/m2/day with subsequent escalation to 750, 900, 1100, 1400, and 1800 mg/m2/day. Thirty-eight courses were administered to 24 patients, of whom 12 participated in concomitant pharmacological studies. Nausea and vomiting, transient orange discoloration of the skin, and tinnitus occurred at all dose levels. The latter symptom, along with lightheadedness and flushing, was related to infusion duration; this was increased to 4 h with doses greater than or equal to 900 mg/m2. The dose-limiting toxicities were mucositis and painful skin erythema which occurred in all 4 patients treated with 1800 mg/m2. No remissions occurred. Clearing of peripheral blood blasts occurred in 67% of patients treated with 1100 mg/m2 and in all patients treated with greater than or equal to 1100 mg/m2/day. A decrease in marrow leukemic infiltrate (% blasts x % cellularity) to less than 10% occurred in 15 and 50% of patients treated at these levels, respectively. There were 10 deaths (42%), which were unrelated to dosage. The harmonic mean terminal plasma half-life was 4.6 h (range, 2.5-35.5 h). Three patients had long drug half-lives of 9.7, 16.4, and 35.5 h and each had initial bilirubin levels greater than 1.0 mg/dl. The average urinary excretion of amonafide over 5 days was 3.5% of the total dose. This establishes 1100-1400 mg/m2/day for 5 days as the maximally tolerated dose of amonafide for studies in acute leukemia.     

Treatment of primary refractory or relapsed acute lymphoblastic leukemia (ALL) in children.

Thirty-one intensively pretreated children with ALL in first bone marrow relapse or refractory to initial therapy were treated with a combination of intermediate-dose Ara-C and idarubicin (IDA). Twenty-four patients (77%) achieved complete remission (CR), 8 patients relapsed early and 2 were removed from the study. Fourteen (45% of the original 31 patients) underwent bone marrow transplant (BMT) and 7 of them (22%) are still in continuous CR (CCR) with a median follow-up of 18 months. These results confirm that it is possible to achieve CR even in ALL children who failed on an initial intensive regimen. Newer modalities of post-remission therapy, especially for children lacking an HLA donor, should be considered.     

CLAG方案治疗复发难治急性髓系白血病的疗效观察

目的:评价CLAG方案（2-CdA+Ara-C+G-CSF）治疗复发难治急性髓系白血病的疗效及安全性。方法:回顾性分析我中心2015年6月至2016年8月应用CLAG方案治疗的12例复发难治急性髓系白血病患者。结果:12例患者均系复发难治急性髓系白血病,根据NCCN急性髓系白血病指南（2017年第1版）细胞遗传学及分子生物学标记,进行危险度分级,其中预后良好组3例,预后中等组5例,预后不良组4例。所有患者均给予1疗程CLAG方案化疗,其中8例（72.7%）达到完全缓解（CR）,2例（18.2%）达到部分缓解（PR）,总有效率（OR）90.9%。所有患者均出现Ⅲ-Ⅳ级血液学毒性,主要毒副反应为粒细胞缺乏及血小板减少所导致的感染和出血,其中肺部感染8例（72.7%）,侵袭性真菌病5例（45.5%）,革兰阴性杆菌败血症2例（18.2%）。6例患者（54.5%）发生Ⅲ-Ⅳ级出血,1例因弥漫性肺泡出血早期死亡。化疗所致恶心呕吐、肝肾毒性、口腔黏膜炎等非血液学毒性均为Ⅰ-Ⅱ级。结论:CLAG方案治疗复发难治性急性髓系白血病有效率较高。化疗所致骨髓抑制较重,但合并感染、出血可控制,非血液学毒性轻微,安全性较好,可作为复发难治急性髓系白血病挽救性治疗的首选方案。