科学家最新完成的研究显示，两种正处于试验阶段的新药能够抑制人体对抗癌药物伊马替尼出现的抗药性，从而弥补伊马替尼药性的不足。科学家希望将它们同伊马替尼配合使用，用于配合治疗慢性骨髓白血病。
伊马替尼（Imatinib）也称为格列卫（Gleevec）。过去几年里，由于伊马替尼进入临床使用，一度被视为不治之症的慢性骨髓白血病已列入了可治疗疾病的名单之列。然而，随着时间的推移人们发现，在服用伊马替尼的患者中，有17％的人在5年后会出现抗药性，继而旧病复发。
美国休斯顿医学博士安德森癌症中心的血液和肿瘤学家哈古普•坎塔加恩说，在上世纪90年代，医生认为患有慢性骨髓白血病的患者只能再活3年到5年，但现在，将新药同伊马替尼结合使用，大多数慢性骨髓白血病患者则有可能享受正常的生活。此外，他补充说，如果将药物进行某些改良，它们有望治愈多数患者的疾病。
据悉，新药dasatinib和nilotinib与伊马替尼一样，作用对象都是人体内被称为Bcr-Abl的异常蛋白质，这种异常蛋白质可通过切断细胞复制控制机能而导致白血病。研究发现，当编译Bcr-Abl蛋白质的基因发生变异后，伊马替尼就无法同变化了的蛋白质结合，但是上述两种新药却仍能紧紧地附着在蛋白质上。
坎塔加恩研究小组对两种新药进行了人体试验，有180名慢性骨髓白血病病人和23名与白血病相关病人参与试验，他们都已对伊马替尼产生了抗药性。在试验的9个月中，这些患者或者服用了2个月的nilotinib，或者服用了2个月的dasatinib。结果显示，这两种药物对白血病处于尚未扩散期的病人收效最好，在40名这样的患者中，经过服用dasatinib，有37名患者的血细胞检测已恢复到正常状态。但是，对于那些癌细胞已经扩散了的患者，两种药物的治疗效果均不理想。
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
