科學(xué)家最新完成的研究顯示，兩種正處于試驗(yàn)階段的新藥能夠抑制人體對(duì)抗癌藥物伊馬替尼出現(xiàn)的抗藥性,，從而彌補(bǔ)伊馬替尼藥性的不足,?？茖W(xué)家希望將它們同伊馬替尼配合使用，用于配合治療慢性骨髓白血病,。
伊馬替尼（Imatinib）也稱為格列衛(wèi)（Gleevec）,。過去幾年里，由于伊馬替尼進(jìn)入臨床使用,，一度被視為不治之癥的慢性骨髓白血病已列入了可治療疾病的名單之列,。然而,，隨著時(shí)間的推移人們發(fā)現(xiàn)，在服用伊馬替尼的患者中,，有17％的人在5年后會(huì)出現(xiàn)抗藥性,，繼而舊病復(fù)發(fā)。
美國(guó)休斯頓醫(yī)學(xué)博士安德森癌癥中心的血液和腫瘤學(xué)家哈古普•坎塔加恩說,，在上世紀(jì)90年代,，醫(yī)生認(rèn)為患有慢性骨髓白血病的患者只能再活3年到5年，但現(xiàn)在,，將新藥同伊馬替尼結(jié)合使用,，大多數(shù)慢性骨髓白血病患者則有可能享受正常的生活。此外,，他補(bǔ)充說,，如果將藥物進(jìn)行某些改良，它們有望治愈多數(shù)患者的疾病,。
據(jù)悉,，新藥dasatinib和nilotinib與伊馬替尼一樣，作用對(duì)象都是人體內(nèi)被稱為Bcr-Abl的異常蛋白質(zhì),，這種異常蛋白質(zhì)可通過切斷細(xì)胞復(fù)制控制機(jī)能而導(dǎo)致白血病,。研究發(fā)現(xiàn)，當(dāng)編譯Bcr-Abl蛋白質(zhì)的基因發(fā)生變異后,，伊馬替尼就無法同變化了的蛋白質(zhì)結(jié)合,，但是上述兩種新藥卻仍能緊緊地附著在蛋白質(zhì)上。
坎塔加恩研究小組對(duì)兩種新藥進(jìn)行了人體試驗(yàn),，有180名慢性骨髓白血病病人和23名與白血病相關(guān)病人參與試驗(yàn),，他們都已對(duì)伊馬替尼產(chǎn)生了抗藥性。在試驗(yàn)的9個(gè)月中,，這些患者或者服用了2個(gè)月的nilotinib,，或者服用了2個(gè)月的dasatinib。結(jié)果顯示,，這兩種藥物對(duì)白血病處于尚未擴(kuò)散期的病人收效最好,，在40名這樣的患者中，經(jīng)過服用dasatinib,，有37名患者的血細(xì)胞檢測(cè)已恢復(fù)到正常狀態(tài),。但是，對(duì)于那些癌細(xì)胞已經(jīng)擴(kuò)散了的患者,，兩種藥物的治療效果均不理想,。
Two new drugs overcome the resistance that can develop to the first-line-therapy imatinib (Gleevec, Novartis) in chronic myeloid leukemia (CML), and results from phase 1 clinical trials reported in the June 15 issue of the New England Journal of Medicine show that both are clinically effective in this patient population. "They provide immediate hope for patients in whom CML cells have developed resistance to imatinib," comments Brian Druker, MD, from the Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute, Portland, in an accompanying editorial.
One of the new drugs — dasatinib (Sprycel, Bristol-Myers Squibb) — is awaiting Food and Drug Administration (FDA) approval for this indication, with an announcement expected on June 28, while the other — nilotinib (Novartis) — is in phase 2 clinical trials.
"Imatinib has revolutionized the treatment of CML," Dr. Druker told Medscape. "Previously, 5-year survival rates would be no more than 50%, while now they are close to 90%." But while most of the responses are stable, resistance to treatment can develop after an initial response. At 5 years, approximately 17% patients develop some form of resistance and another 5% or so discontinue because of toxicity, Dr. Druker noted; it is this 21% or so of patients that need the new therapies.
"The good news for patients with CML is that the long-term prospects for control of the disease are excellent," Dr. Druker commented.
New Drugs Are More Potent Inhibitors
Imatinib is an ABL tyrosine kinase inhibitor and strikes at the root of the problem in CML, the unregulated production of this enzyme resulting from a genetic defect (the fusion gene BCR-ABL), which allows proliferation of white blood cells. Mutations of this gene lead to much (about 50% to 70%) of the resistance that develops to imatinib, although there are also other mechanisms involved, as yet not understood, Dr. Druker said. Both of the new drugs are more potent ABL inhibitors than imatinib, and they inhibit all tested mutations (except T315I), the editorial notes. All 3 drugs are taken orally.
The dasatinib trial was conducted in 84 CML patients who were resistant to or could not tolerate imatinib and was headed by Charles Sawyers, MD, from the Jonsson Comprehensive Cancer Center, University of California, Los Angeles. Dasatinib produced a complete hematologic response in 37 of 40 patients with chronic-phase CML and major hematological responses in 31 of 44 other patients, of whom 11 had accelerated-phase CML, 23 with myeloid blast crisis and 10 with lymphoid blast crisis or pH-positive acute lymphoblastic leukemia (ALL). These responses were maintained in 95% of the chronic-phase CML patients at a median follow-up of more than 12 months and in 83% of the other group at a median of 5 months.
The researchers note that in addition to showing activity in patients with a broad range of BCR-ABL mutations, dasatinib showed activity in patients who received little or no cytogenetic benefit from imatinib, which raises the possibility that the new drug may benefit other patients with CML who have a suboptimal response to imatinib, even if they do not exhibit frank hematologic resistance.
The major adverse effect of dasatinib was reversible myelosuppression, and nonmalignant pleural effusions developed in 15 of 84 patients, often in the absence of edema. However, the common imatinib-related side effect of periorbital edema was less frequent, and other side effects associated with imatinib such as muscle cramps and nausea were rarely observed, the researchers comment. "An important finding is that patients who could not tolerate imatinib and were treated with dasatinib did not have a recurrence of the nonhematological toxic effects (eg, liver-function abnormalities and rash) that were associated with imatinib," they add.
Further clinical data have accrued with dasatinib since this study and were discussed at a special session during the 42nd meeting of the American Society of Clinical Oncology, which featured members of the FDA's Oncology Drug Advisory Committee. Five phase 2 studies have been conducted between December 2004 and February 2005, and results confirm the findings from phase 1, Neil Shah, MD, PhD, from the University of California, San Francisco, told the meeting. "There was a complete hematologic response of 90% overall and a 6-month survival rate of 95%." The only significant adverse effect was pleural and pericardial effusion, but this was managed effectively, he added.
The nilotinib trial was conducted in 119 patients with imatinib-resistant CML or ALL. First author Hagop Kantarjian, MD, from the University of Texas MD Anderson Cancer Center, Houston, and colleagues report that 11 of 12 patients with chronic-phase CML had a complete hematologic response. Of 33 patients with the blastic phase of the disease, 13 had a hematologic response and 9 had a cytogenetic response, while of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response. The researchers suggest that nilotinib has a limited efficacy in patients with pH-positive ALL, as responses were seen in only 2 of 13 of these patients.
Common adverse effects with nilotinib were myelosuppression, which was dose related and dose limiting; transient clinically insignificant elevations of indirect bilirubin levels; and mild to moderate rashes. The researchers note that they did not observe fluid retention, edema, or weight gain, the common toxic side effects seen with imatinib, nor did they observe any pleural effusions (as seen with dasatinib). However, they comment that the side effects of nilotinib may be dose limiting in 10% of patients. They recommend that phase 2 trials use a lower dose of 400 mg twice daily, which appears to have similar efficacy but a better safety profile than 600 mg twice daily.
Responses "Impressive and Durable"
In these phase 1 trials, response rates in patients with chronic-phase CML with both new drugs were "impressive and have thus far been durable, but responses in accelerated-phase and blast-phase disease were lower, and relapses have been common," the editorial comments. "For this reason, other strategies are required for advanced phases of CML and for patients with the T315I ABL mutation."
This mutation was found in 2 of 119 patients in the nilotinib trial and 3 of 84 patients in the dasatinib trial, and none of these patients responded to treatment. "This may be an underestimate, however, as there was an element of selection — patients who were known to have this mutation would not have been enrolled in these trials," Dr. Druker comments. "This remains an unmet medical need."
The new drugs may also be useful at earlier stages of the disease, Dr. Druker says. In most patients treated with imatinib, CML is well controlled but not eradicated. It may be that the greater potency of the new drugs in inhibiting the kinase enzyme will lead to a bigger drop in white blood cells, and this better response may lead to better outcomes. This will have to be tested in head-to-head comparisons against imatinib in newly diagnosed patients, to see whether there is a greater drive to remission and a lower risk of a relapse. Such trials are already planned, and once the 2 new drugs are marketed, they will also be compared with one another, Dr. Druker says. There will also be trials to investigate combinations and sequential use of these agents, he says, predicting that it will take another 5 to 10 years to establish the best treatment approach and the optimal use of these drugs.
In the editorial, Dr. Druker asks why 2 large pharmaceutical companies would be interested in a disease that affects fewer than 5000 patients a year in the US and in which drug resistance is relatively uncommon. One reason is that imatinib had gross sales of $2.1 billion in 2004, and while not all of these sales are for CML, it does show that CML therapy is an attractive market, he comments.
N Engl J Med. 2006;354:2542-2551, 2531-2541, 2594-2596
