无化疗联合治疗可驯服最坏的白血病

亚特兰大——一项Ⅲ期试验结果显示，急性早幼粒细胞白血病(APL)的一线治疗不必包含细胞毒性化疗即可达到理想效果：全反式维甲酸(ATRA)+化疗(目前的标准治疗方案)组患者的2年无事件生存率为86.7%，而ATRA+三氧化二砷(ATO)组患者为97%，差异有显著性(P=0.03)。


Francesco Lo-Coco博士

意大利Tor Vergata 大学的Francesco Lo-Coco博士在美国血液病学会(ASH)年会上指出，这种新的无化疗方案破除了“癌症不可逆”的教条，显示出恶性肿瘤细胞可以被转化，而不一定要用化疗来将其消灭。

这项试验是首个比较ATRA+ATO与标准治疗的随机、前瞻性Ⅲ期试验。在较早的Ⅱ期试验中，ATO与其他药物的联合治疗取得了令人鼓舞的应答率。Lo-Coco博士解释称，这种联合治疗的机制在于，APL中的变异蛋白具有ATO和ATRA特异性结合位点，ATRA(一种源于中草药的物质)被认为可诱导白血病细胞分化，而ATO可通过诱导细胞凋亡等途径缓解病情。

Lo-Coco博士及其来自意大利和德国的同事招募了162例新诊断、非高危APL患者，中位年龄为45岁(范围：18~70岁)，中位白细胞计数为1.50×10⁹/L。实验组患者接受每日ATO 0.15/kg+口服ATRA 45 mg/m²治疗，直至完全缓解，然后每周给予ATO治疗5天，治疗4周暂停4周，共治疗4个疗程，给予ATRA治疗2周暂停2周，共治疗7个疗程。对照组患者接受标准ATRA+12 mg/m²伊达比星诱导治疗，序贯3个周期的以蒽环类为基础的化疗+ATRA巩固治疗，以及小剂量化疗+ATRA维持治疗。

结果显示，在可评估诱导应答的154例患者中，实验组的全部75例患者和对照组79例患者中的75例达到了完全缓解。在ATRA+化疗组患者中，发热持续超过15天以及≥3级中性粒细胞减少、血小板减少明显多于ATRA+ATO组(均P＜0.001)。在完成第3轮巩固治疗的142例可评估患者中，141例达到了分子学完全缓解。

经过中位时间31个月的随访，ATRA+ATO组患者的总生存率为98.7%，而ATRA+化疗组为91.1%(P=0.02)。不过，ATRA+ATO诱发了2例QT间期延长，其中1例需要停用ATO和退出研究。两组中APL分化综合征和肝酶水平升高的发生率相似。实验组死亡1例、复发2例，对照组死亡7例、复发4例。

ATRA+ATO治疗所取得的成功，可能会影响ATO单药在APL一线治疗中的应用。首个采用这一单药方案的研究报告称，在初治患者中取得了86%的完全缓解率(J. Clin. Oncol. 2011;29:2753-7)，然而在伊朗开展的Ⅱ期研究因未提供标准治疗而违背了医学伦理，招致了批评。不过一篇随刊述评指出，ATRA、蒽环类和阿糖胞苷治疗常常“过于昂贵，发展中国家患者难以负担” (J. Clin. Oncol. 2011;29:2743-6)。

更近期的一项中国研究显示，ATO单药治疗难治性老年患者可达到88%的完全缓解率。经过中位时间99个月的随访，10年累计复发率为10.3%，在此期间无1例患者死于ATO相关毒性(Cancer 2013;119:115-25)。

ASH主席Armand Keating博士表示，这项开创性研究为我们带来了新的方法——源于古代中医药的靶向联合治疗，其疗效堪比化疗而毒性大大减少。“这是一项令人兴奋的进展，因为它改变了我们对潜在致死性疾病治疗的思维模式。”他指出，30~40年前APL的治疗尚未因ATRA和化疗而发生变革之时，该病的死亡率为100%，绝大多数患者在1周内死亡。然后，ATRA和化疗(通常包含蒽环类)给APL带来了85%~90%的缓解率，然而在高危患者(例如老年患者)中，早期死亡和复发仍是难题。

ASH秘书长Charles Abrahms博士表示：“凭心而论，这项研究令我吃惊……APL曾经是最恶性疾病中最恶性的一种。”他们两人都认为，这项研究成果将激发人们进一步探索ATO的作用机制，不仅是在APL中，更包括多种其他疾病。

Lo-Coco博士报告称担任勃林格殷格翰的顾问和Cephalon公司[Trisenox(三氧化二砷)的生产商]的讲者。他的合著者报告称与多家药企存在利益关系。

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By: PATRICE WENDLING, Internal Medicine News Digital Network

ATLANTA – Cytotoxic chemotherapy is not needed to achieve excellent results in the first-line treatment of acute promyelocytic leukemia, a most aggressive form of acute leukemia.

A phase III trial achieved a 2-year event-free survival rate of 86.7% with all-trans retinoic acid (ATRA) and chemotherapy, the current standard, and 97% with ATRA plus arsenic trioxide (ATO), a small-molecule arsenic compound (P = .03).
 
The new chemotherapy-free regimen represents "the demolition of a dogma" by showing that cancer is not an irreversible condition and that malignant cells can be transformed rather than killed with chemotherapy, Dr. Francesco Lo-Coco said at a press briefing during the annual meeting of the American Society of Hematology.

ASH president Armand Keating said that the groundbreaking study highlights novel approaches – in this case a targeted combination with roots in ancient Chinese medicine – that can produce comparable efficacy with far less toxicity than chemotherapy.

"This, I think, is an exciting development because it is a shift in the way we think of treating potentially fatal diseases, quite remarkable," Dr. Keating said during a teleconference with reporters.

He pointed out that, 30-40 years ago, before ATRA and chemotherapy transformed the treatment of acute promyelocytic leukemia (APL), mortality was 100%, with most patients dying within a week.

ATRA and cytotoxic chemotherapy, typically containing anthracyclines, produce remission rates of 85%-90% in APL, but early death and relapse among high-risk groups such as the elderly remain problematic in the management of APL.

"I found this study amazing, frankly. ... This [disease] used to be the worst of the worst," ASH Secretary Charles Abrahms said during the teleconference.

Both men remarked that the results will spur further research to elucidate how ATO works, not just in APL but in other diseases.

The current trial is the first randomized, prospective phase III trial to compare ATRA plus ATO against the standard of care, although earlier phase II trials have reported encouraging responses to ATO in combination with other drugs.

As for how the combination works, the altered protein present in APL has specific binding sites for ATO and ATRA, explained Dr. Lo-Coco of the University of Tor Vergata, Rome. ATRA, a derivative developed from Chinese herbal medicine, is thought to induce leukemia cell differentiation, whereas ATO, well known for its activity in treating relapsed APL, produces remissions at least in part by inducing apoptosis.

Dr. Lo-Coco and his coinvestigators in Italy and Germany enrolled 162 patients with newly diagnosed, non–high-risk APL; the median age was 45 years (range 18-70) and the median white blood cell count was 1.50 × 109/L.

Patients in the experimental arm received arsenic trioxide 0.15/kg plus oral ATRA 45 mg/m2 daily until complete remission, then ATO given 5 days per week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA given 2 weeks on and 2 weeks off for a total of seven courses. Patients in the control arm received standard ATRA plus 12 mg/m2 idarubicin as induction, followed by three cycles of anthracycline-based chemotherapy plus ATRA consolidation and maintenance with low-dose chemotherapy and ATRA.

Of the 154 patients evaluable for response to induction, all 75 patients in the experimental arm and 75 of 79 in the control arm achieved complete remission, Dr. Lo-Coco reported in the plenary session.

Molecular complete remission per central review was seen in 141 of 142 evaluable patients after completing the third round of consolidation therapy.

After a median follow-up of 31 months, overall survival was 98.7% with ATRA plus ATO and 91.1% with ATRA plus chemotherapy (P = .02), he said.

Patients receiving ATRA and chemotherapy had significantly more episodes of fever lasting more than 15 days and grade 3 or higher neutropenia and thrombocytopenia than those receiving ATRA and ATO (P less than .001 for all differences).

The ATRA/ATO combination, however, induced QTc prolongation in two patients, requiring ATO discontinuation and study withdrawal for one of them, Dr. Lo-Coco reported.

Rates of APL differentiation syndrome and increased liver enzymes were similar in both groups. There was one death and two relapses in the experimental arm vs. seven deaths and four relapses in the control arm.

The success achieved with ATRA and ATO therapy is likely to raise new questions regarding use of ATO monotherapy in the first-line treatment of APL. The first study to take this approach reported a complete remission rate of 86% in treatment-naive patients (J. Clin. Oncol. 2011;29:2753-7), but the phase II study conducted in Iran prompted a backlash of criticism that it violated medical ethics by failing to provide standard treatment. An accompanying editorial, however, pointed out that treatment with ATRA, anthracyclines, and cytarabine is often "prohibitively expensive in the developing world" (J. Clin. Oncol. 2011;29:2743-6)

A more recent Chinese study pointed to benefits with single-agent ATO in the hard-to-treat elderly, with 88% of patients, aged 60 years or older, achieving a complete remission. The 10-year cumulative incidence of relapse was 10.3% after a median follow-up of 99 months, during which time no patient died of ATO-related toxicities (Cancer 2013;119:115-25).

Dr. Lo-Coco reported serving on the board of directors or advisory committees for Boehringer Ingelheim and as a speaker for Cephalon, the maker of Trisenox (arsenic trioxide). His coauthors reported relationships with several pharmaceutical firms.