實驗性白血病聯合療法對年老體弱的患者俱有毒性 Experimental leukemia combination proves toxic for older, frail patients





About 32 percent of older, sicker patients enrolled on a leukemia clinical trial experienced serious side effects from a treatment that combined a chemotherapy and an immunotherapy drug, leading investigators to pause the trial and the U.S. Food and Drug Administration to eventually pull the combination from the current study.

Released today at the 61st American Society of Hematology (ASH) Annual Meeting, the findings serve as both triumph and warning. The randomized, two-arm trial design allowed investigators to catch the toxicity signal early, just eight months after the first patient enrolled. The trial also illustrates the tension currently facing cancer researchers, as eligibility criteria for clinical trials are loosened and as evidence mounts that immunotherapies can cause serious side effects, particularly for patients, many of them older, managing other illnesses like diabetes.

“Our findings highlight special concerns that cancer physicians must consider as we enroll vulnerable populations,” said Annette Hay, M.D., a hematologist at Queen’s University in Canada who, along with Sarit Assouline, M.D., of McGill University Jewish General Hospital, co-leads this section of the leukemia trial. “We also see the importance of vigilance and close collaborations, including with the FDA, to ensure patient safety.”

The results stem from a trial run by the SWOG Cancer Research Network, a cancer clinical trials network funded by the National Cancer Institute (NCI) through the National Institutes of Health. Hay presented them in a poster session today in Orlando, Florida at the ASH Annual Meeting, the world’s largest conference devoted to blood diseases and blood cancers like lymphoma.

The study, S1612, is a unique collaboration between the Canadian Cancer Trials Group, where Hay and Assouline are members, and SWOG, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group. All four groups are funded by NCI through their National Clinical Trials Network. S1612 launched in December 2018 to test treatments for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), a bone marrow disorder sometimes referred to as “pre-leukemia.”

Hay and the other investigators set out to minimize trial exclusions and allow older, less-fit adults to join. That’s because a majority of people who get AML and MDS are over the age of 60 when they’re diagnosed. However, these older adults have not been well-represented in trials because so many are barred from joining. To make trials more representative, and to make their results more generalizable, the American Society of Clinical Oncology and the Friends of Cancer Research called for more inclusive trial criteria in a series of articles published in 2017 in the Journal of Clinical Oncology. In 2018, the FDA and NCI both issued new enrollment guidelines for industry- and publicly-funded cancer trials, respectively, which allow patients with organ dysfunction or a past cancer diagnosis, among others, to be considered for enrollment.

There is an urgent need for new AML and MDS treatments. While the chemotherapy azacitidine is standard, few patients respond well to it. Hay and her collaborators wanted to add new drugs into the mix, including the immunotherapy nivolumab. Knowing that toxicities could result, especially in older, sicker patients, the team designed the trial to ensure maximum safety. Patients would be randomly selected to join one of three groups – patients who get azacitidine only, patients who get azacitidine and nivolumab, and patients who get azacitidine and midostaurin, a new type of targeted drug. By including a control group – patients only getting standard treatment – researchers could better spot problems with patients getting combinations.

In October 2018, after 78 patients enrolled, enrollment was suspended. At the time, researchers had found that four patients died due to side-effects from the azacitidine and nivolumab treatment, compared with one patient who died due to side effects from azacitidine only. While the number of early deaths didn’t reach statistical significance, they sent a possible toxicity signal to the study leadership. After a review of safety data, and consultation with the FDA, researchers tightened the eligibility requirements for patients who could get assigned to the azacitidine and nivolumab combination, and boosted side effect surveillance. In October 2019, the FDA removed the nivolumab combination from the trial.

In 2020, S1612 will reopen with the control group, the azacitidine and midostaurin group, and a new arm – in which patients will be treated with a combination of two chemotherapy agents – decitabine and cytarabine. In addition, the research team plans to continue to evaluate azacitidine and nivolumab in older, less fit adults, and are working to determine the appropriate population and refining the toxicity profile in order to move forward.

“There is a message here for us in cancer research,” Hay said. “As we broaden our trial eligibility criteria, we may be including patients who may not only have cancer but two, three, even five other diseases. So they may experience significant side effects from trial treatment, especially drugs that stimulate the immune system. It’s important to incorporate frailty screening tools in trial design.”


Funding for S1612 comes from the National Institutes of Health through the National Cancer Institute under grants CA180888, CA180819, CA180820, CA180821 and CA180863. Bristol Myers Squibb and Novartis Pharmaceuticals, Inc. provided nivolumab and midostaurin for the trial under their respective Cooperative Research and Development Agreement with NCI.

Along with Hay and Assouline, the S1612 study team includes Roland B. Walter, MD, PhD, of the University of Washington; Richard F. Little, MD, MPH, of the National Cancer Institute; Anna Moseley, MS, of the SWOG Statistics and Data Management Center at the Fred Hutchinson Cancer Research Center; Gail M. Sperling, MPH, CHES, of SWOG; Annie Im, MD, of University of Pittsburgh Cancer Institute; James M. Foran, MD, of Mayo Clinic, Jacksonville, Florida; Jerald Radich, MD, of Fred Hutchinson Cancer Research Center; Min Fang, MD, PhD, of Fred Hutchinson Cancer Research Center; Megan Othus, PhD, of the SWOG Statistics and Data Management Center at the Fred Hutchinson Cancer Research Center; Harry P. Erba, MD, PhD, Duke University; and Laura C. Michaelis, MD, of Medical College of Wisconsin.

SWOG Cancer Research Network is part of the National Cancer Institute’s National Clinical Trials Network and the NCI Community Oncology Research Program, and is part of the oldest and largest publicly-funded cancer research network in the nation. SWOG has nearly 12,000 members in 47 states and six foreign countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human life. Learn more at swog.org.


5000/5000Character limit: 5000參加白血病臨床試驗的大約32%的較年長,病態的患者因化學療法和免疫療法藥物的聯合治療而出現嚴重的副作用,導致研究人員暫停試驗,而美國食品藥品監督管理局最終將其從臨床試驗中撤出。目前的研究。


“我們的發現凸顯了癌症醫生在招募弱勢人群時必須考慮的特殊問題,”加拿大皇后大學血液學家安妮特·海德(Annette Hay)表示,他與麥吉爾大學猶太總醫院的薩里特·阿蘇林(Sarit Assouline)一起擔任聯合負責人本節白血病試驗。 “我們還看到了保持警惕和密切合作(包括與FDA合作)以確保患者安全的重要性。”

結果來自SWOG癌症研究網絡的一項試驗,該網絡是由美國國家癌症研究所(NCI)通過美國國立衛生研究院資助的癌症臨床試驗網絡。 Hay今天在佛羅里達州奧蘭多舉行的ASH年會上,以海報的形式介紹了它們,這是世界上規模最大的會議,專門討論血液疾病和血液癌症(如淋巴瘤)。

S1612研究是Hay和Assouline成員的加拿大癌症試驗小組與SWOG,腫瘤臨床試驗聯盟以及ECOG-ACRIN癌症研究小組之間的獨特合作。這四個小組均由NCI通過其國家臨床試驗網絡資助。 S1612於2018年12月啟動,測試急性髓細胞白血病(AML)和高危骨髓增生異常綜合症(MDS)的治療方法,該疾病有時被稱為“白血病前期”。


迫切需要新的AML和MDS治療方法。雖然化學療法阿扎胞​​苷是標準療法,但很少有患者對此反應良好。 Hay和她的合作者希望將新藥加入其中,包括免疫療法nivolumab。研究小組知道可能會產生毒性,尤其是對年紀大一些的患者而言,會產生毒性,因此設計了該試驗,以確保最大程度的安全性。將隨機選擇患者加入三組中的一組:僅接受阿扎胞苷的患者,接受阿扎胞苷和尼古拉單抗的患者以及接受阿扎胞苷和米多斯汀(一種新型靶向藥物)的患者。通過納入對照組(僅接受標準治療的患者),研究人員可以更好地發現患者接受聯合治療時出現的問題。



Hay說:“在癌症研究中這裡給我們傳達了一個信息。” “隨著我們擴大試驗資格標準,我們可能會包括不僅患有癌症而且患有兩種,三種甚至五種其他疾病的患者。 因此,他們可能會因試驗性治療而遭受重大副作用,尤其是刺激免疫系統的藥物。 在試驗設計中加入脆弱篩選工具非常重要。”

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