本帖最後由 lsc0019 於 2009-6-29 23:34 編輯
作者：Becky McCall
出處：WebMD醫學新聞
June 9, 2009（德國柏林）－一項第二期臨床研究結果顯示，nilotinib（Tasigna）用於慢性骨髓性白血病（CML）慢性初期病患第一線治療的結果，比目前標準治療imatinib（Gleevec）反應好且快。
主要研究者、義大利波隆那St. Orsola-Malpighi大學醫院的Gianantonio Rosti醫師表示，這些初期研究結果是非常激勵人心的。他在第14屆歐洲血液腫瘤協會會議上報告這項發現。
Rosti醫師解釋，目前，nilotinib僅被核准作為對imatinib產生抗藥性或是無法耐受病患的第二線治療。但是長期下來，使用imatinib的病患只有70%維持完美的反應，因此其他治療是有必要的。
這項新的研究來自一項多中心試驗，由Gruppo Italiano Malattie Ematologiche dell'Adulto（GIMEMA）CML工作小組進行，研究使用每天兩次400 mg的nilotinib治療一年，作為慢性初期CML的第一線治療。
試驗前，每15天一次，為期3個月，接著每30天一次，為期9個月，監測一次血球數目與生化檢驗。在3與6個月後進行骨髓抽吸做細胞學檢驗與細胞基因學分析，於12個月後進行細胞學、細胞基因學、定量分子生物檢驗與變異分析。在試驗結束時，每6個月收集一次數據。
Nilotinib治療6個月後，完全細胞基因學反應（CCgR）為96%。在1、2、3、6、9與12個月時，達到第一次主要分子反應的比例分別為3%、21%、52%、66%、73%與85%。
這項沒有控制組介入研究的結果與imatinib的數據進行比較。為了對照，一項名為IRIS的試驗使用400 mg imatinib，研究結果顯示，在6、9與12個月時，CCgR比例分別為51%、69%與87%。然而，因為事前的抗藥性、難以治療或是耐受性不佳，四分之一接受imatinib治療的病患未能達到或是維持穩定的CCgR。
Rosti醫師強調，顯然地，使用nilotinib於CML的研究結果顯示，在快速與分子品質上的效果比imatinib更好。效果很難比imatinib好，這個藥物在使用超過一年後，CCgR的比例介於60~80%之間，但這些研究結果顯示有進一步的改善。這項研究僅收納來自18個中心的73位病患，但其初期研究結果是非常令人興奮的。
CML的特徵是一種染色體指標，稱為費城染色體。它攜帶了BCR-ABL基因，代表白血病特有的BCR-ABL蛋白。Imatinib選擇性的抑制BCR-ABL蛋白的作用，但是nilotinib相較於imatinib對腫瘤蛋白有較高的接合親合力與選擇性，且對於白血病任何時期產生imatinib抗藥性都有較好的藥效。此外，nilotinib能抑制幾近所有imatinib抗藥性的BCR-ABL突變基因。
Rosti博士解釋，此時，我們的目標是最多的病患存活且在分子層級上只有少量或沒有疾病存在的狀態。最後，我們想要部份病患能停止所有的治療。即使是新藥，也無法排除僅剩的白血病幹細胞。雖然還未知，但合併酪胺酸磷酸酶抑制劑與干擾素，可能可以治癒疾病、或至少使病患能在未治療的情況下存活4到5年的時間。
Rosti博士指出，nilotinib的耐受性佳且副作用是可以處理的。以生化觀點來看，我們會看到膽紅素增加，肝臟酵素短暫上升，部份會有高血糖的現象，但隨著持續治療，副作用會消失。有一名病患停止治療是因為胰臟澱粉酵素與脂酶上升，而非胰臟炎。第二名病患則是在nilotinib治療6個月後進展為急性轉化期。
對此結果的評論，倫敦帝國理工學院的資深研究調查員John Goldman博士向Medscape腫瘤學表示，imatinib面對的是兩個新的酪胺酸激磷酸酶抑制劑的競爭。Nilotinib是由imatinib修飾化學結構而來，它更能有效接合BCR-ABL蛋白而不需額外的物質。體外研究顯示它比imatinib更加有效，且是二至三個第二代酪胺酸磷酸酶抑制劑中的一個，我的觀點看來，它將在未來兩年取代原本的首選imatinib。Dasatinib跟nilotinib在對抗白血病上一樣有效，因此如果有病患能買得起其中一個新藥，我預期將成為治療的首選。
這項研究由GIMEMA與義大利波隆那大學贊助。Rosti博士是Novartis及Bristol-Myers Squibb藥廠的專業演講者，Goldman博士宣稱沒有相關資金上的往來。
第14屆歐洲血液腫瘤協會會議摘要1090。於2009年6月7日發表。
EHA 2009: Nilotinib Superior in Chronic Myeloid Leukemia Than Current Standard
By Becky McCall
Medscape Medical News
June 9, 2009 (Berlin, Germany) — New results from a phase?2 trial with nilotinib (Tasigna) used first-line in patients with early chronic-phase chronic myeloid leukemia (CML) showed responses that were superior and faster than those seen historically with the current standard of care, imatinib (Gleevec).
"These early results are very encouraging," said lead investigator Gianantonio Rosti, MD, from St. Orsola-Malpighi University Hospital in Bologna, Italy, who presented the findings here at the 14th Congress of the European Hematology Association.
Currently, nilotinib is approved only for second-line use in patients who have become resistant or intolerant to imatinib. But in the long term, only 70% of CML patients taking imatinib maintain a perfect response, so other therapies are needed, Dr. Rosti explained.
The new results come from a multicenter study, conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) CML working party, investigating the use of nilotinib 400?mg twice daily as a first-line treatment for early chronic-phase CML for 1 year.
Blood counts and differential and serum chemistry were assessed at baseline, every 15 days for 3 months, and then every 30 days for 9 months. A bone-marrow aspirate was taken after 3 and 6 months for cytology and cytogenetics, and after 12 months for cytology, cytogenetics, quantitative molecular biology, and mutational analysis. After the end of the study, data were collected every 6 months.
Nilotinib showed a complete cytogenetic response (CCgR) of 96% at 6 months. The achievement of the first major molecular response, after 1, 2, 3, 6, 9, and 12 months, was 3%, 21%, 52%, 66%, 73%, and 85%, respectively.
Results from this uncontrolled intervention study were compared with data for imatinib. For reference, the 400?mg imatinib group of a study known as the IRIS trial showed cumulative rates of CCgR of 51%, 69%, and 87% at 6, 12, and 60 months, respectively. However, one quarter of all imatinib-treated patients fail to acheive or maintain a stable CCgR because of upfront resistance, refractoriness, or intolerance.
"Clearly, the results with nilotinib in CML show that the response is superior to imatinib in terms of rapidity and molecular quality. It is difficult to do better than imatinib, with which we see 60% to 80% CCgR after 1 year of treatment or more, but these results show that improvement is very clear. This study only had 73 patients?.?.?. from 18 centers, but these early results are very encouraging," Dr. Rosti emphasized.
CML is characterized by a chromosomal marker called the Philadelphia chromosome. This carries the BCR-ABL gene, which codes for a specific leukemic BCR-ABL protein. Imatinib selectively inhibits the action of the BCR-ABL protein, but nilotinib has a higher binding affinity and selectivity for the oncoprotein than imatinib, and is highly effective in imatinib-resistant patients across all 3 disease phases. Furthermore, nilotinib inhibits nearly all the imatinib-resistant BCR-ABL mutants.
"At the moment, we aim to have most patients alive with minimal or no trace of the disease at a molecular level. Ultimately, we want a proportion of patients to stop treatment altogether. Even with new drugs, nothing acts in such a way as to eliminate the last leukemia stem cell. As yet it is unknown, but a combination of [tyrosine kinase inhibitor] with interferon, for example, might help cure the disease or at least enable a patient to remain without treatment for 4 or 5 years," explained Dr. Rosti.
Dr. Rosti pointed out that nilotinib is well tolerated and adverse effects are manageable. "From a biochemical point of view, we see increased bilirubin, a transitory increase in liver enzymes, and some hyperglycemia, but most side effects are short lived and nearly all patients continue treatment." One patient discontinued treatment because of an increase in the pancreatic enzymes amylase and lipase without pancreatitis. A second patient progressed to the blastic phase after 6 months on nilotinib.
Commenting on the results, John Goldman, MD, senior research investigator at Imperial College London in the United Kingdom, told to Medscape Oncology that imatinib was facing competition from 2 promising new tyrosine kinase inhibitors. "Nilotinib is a chemical modification of imatinib. It fits into the binding pocket [of the BCR-ABL protein] with less extraneous material than imatinib. In vitro studies show it is more powerful than imatinib and it is 1 of the 2 or 3 second-generation [tyrosine kinase inhibitors] that, in my view, will replace imatinib in the next couple of years as primary therapy. Dasatinib is [as] effective as nilotinib against leukemia, so for a new patient who can afford either of these new drugs, I expect they will become the treatment of choice."
The trial was funded by GIMEMA and the University of Bologna, Italy. Dr. Rosti is a professional speaker for Novartis and Bristol-Myers Squibb. Dr. Goldman disclosed no relevant financial relationships.
14th Congress of the European Hematology Association: Abstract 1090. Presented June 7, 2009. |
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