Two New Drugs Appear to Overcome Imatinib Resistance in CML

ATLANTA—Although imatinib produces complete remissions in the vast majority of patients with chronic myelogenous leukemia (CML), resistance develops at a rate of approximately 4% a year, and some patients remain intolerant to imatinib. As reported here at the ASH Annual Meeting, though, two new drugs for CML appear to overcome resistance to imatinib and may even offer an alternative to it if future studies continue to show promise. The two drugs are dasatinib, developed by Bristol-Myers Squibb, and AMN-107, developed by Novartis. Dasatinib is an oral tyrosine kinase inhibitor that is 300 to 1,000 times more potent than imatinib at BCR-ABL inhibition in vitro. Dasatinib overcomes resistance conferred by activation of Src family kinases. AMN-107, an oral signal transduction inhibitor, is 20 to 50 times more potent than imatinib at BCR-ABL inhibition. “Approximately 16% of patients with CML treated with imatinib will relapse by four and a half years,” said imatinib pioneer Brian J. Druker, MD, the JELD-WEN Chair of Leukemia Research at Oregon Health & Science University. “We've learned that most relapses in CML are due to mutations in BCR-ABL that are imatinib resistant. “These two new agents are showing significant promise in overcoming resistance to imatinib. They may eventually replace imatinib or be used in combination with imatinib to prevent resistance. Prospective studies will define their eventual role.” Phase I studies at the University of Texas M. D. Anderson Cancer Center and UCLA found that 93% of patients in chronic-phase CML treated with dasatinib had complete hematologic responses (i.e., their blood counts returned to normal) and 35% of these patients had a complete cytogenetic response (CCyR). Eighty-one percent of those with advanced CML responded, and 25% had CCyRs. Responses were durable in chronic-phase patients, but relapses were seen in the more advanced phase of the disease. The drug was well tolerated. Phase II START-C Trial of Dasatinib Results of a Phase II study program called START-C (CA180013) reported at the ASH meeting showed that dasatinib produced significant hematologic and cytogenetic responses in imatinib-resistant and imatinib-intolerant CML patients in chronic phase.Figure: Andreas Hochhaus, MD, reported that dasatinib is efficacious in imatinib-resistant and imatinib-intolerant patients with all BCR-ABL mutations except T315I.“Dasatinib is efficacious in imatinib-resistant and imatinib-intolerant patients with all BCR-ABL mutations except T315I,” explained the investigator who presented the results, Andreas Hochhaus, MD, Professor of Internal Medicine at Medical Clinic of Mannheim at the University of Mannheim in Germany. “No relapses have been seen in patients with cytogenetic responses.” The Phase II program included four parallel Phase II studies with a total of 445 chronic-phase CML patients with resistance (127 patients) or intolerance (59 patients) to imatinib. The studies were done in 20 countries and 75 institutions, and the results reported at the meeting were based on 186 patients followed for six months. The median time to diagnosis of CML was 63.8 months. All patients received prior imatinib, 86% received prior hydroxyurea or anagralide, and 70% received prior interferon-alpha. After six months of treatment with dasatinib at 70 mg b.i.d., 90% of patients achieved a hematologic response to dasatinib, and 45% had a major cytogenetic response; 33% had a complete cytogenetic response, and 12% had a partial cytogenetic response (PCyR). A major cytogenetic response was seen in 73% of imatinib-intolerant patients (56% CCyR, 17% PCyR); and 31% of imatinib-resistant patients achieved a major cytogenetic response (22% CCyr, 9% PCyR). Tolerability Acceptable Tolerability was acceptable, Dr. Hochhaus reported. Grade 2 and 4 hematologic toxicities were anemia (18% of patients), leucopenia (23%), thrombocytopenia (46%), and neutropenia (45%). Most hematologic toxicities occurred during the second month of treatment. The myelosuppression seen with dasatinib is transient and not severe, he said—“It is part of the activity of dasatinib, and not part of the toxicity.” Less than 2% of patients treated with dasatinib had Grade 3 or 4 nonhematologic toxicity, and almost no cross-resistance to imatinib was observed. “There were fewer nonhematologic adverse events with dasatinib compared with what we've seen with imatinib,” Dr. Hochhaus commented. Fifty-two percent of patients required dose adjustments for side effects, 78% had dose interruptions, and 3% had dose escalations. At six months, the progression-free survival rate was 95%, and 100% in imatinib-intolerant patients. A total of 160 patients are still on dasatinib; 26 patients discontinued, six of them due to intolerance. Dasatinib in Advanced Disease Phase II studies in advanced disease showed that major hematologic responses occurred in 31% of patients in myeloid-blast crisis, and 29% had a major cytogenetic response. Of the 99 patients in accelerated-phase CML who were resistant to imatinib, 59% had a major hematologic response, and 31% had a major cytogenetic response. Dr. Hochhaus said that significant improvements have been seen in all phases of CML with dasatinib. Commenting on the importance of dasatinib, Michael Hallek, MD, Director of the Internal Medicine Clinic at the University of Köln in Germany, said, “I am very impressed that our concept introduced in 1996 suggesting that Src kinases are involved in the pathogenesis of CML is now confirmed by clinical results showing that a Src kinase inhibitor, dasatinib, overcomes treatment resistance to imatinib.”Figure: Michael Hallek, MD: “I am very impressed that our concept introduced in 1996 suggesting that Src kinases are involved in the pathogenesis of CML is now confirmed by clinical results showing that a Src kinase inhibitor, dasatinib, overcomes treatment resistance to imatinib.”AMN-107 In a Phase I study reported by long-time CML researcher Hagop Kantarjian, MD, Professor and Chairman of the Leukemia Department at the University of Texas M. D. Anderson Cancer Center, use of AMN-107 produced high hematologic and cytogenetic response rates in all phases of CML and in acute lymphoblastic leukemia (ALL). AMN-107 was rationally designed to overcome resistance to imatinib, Dr. Kantarjian explained. “We saw encouraging response rates across chronic, accelerated, and blastic phases of CML in patients with imatinib resistance due to BCR-ABL mutations. The drug was well tolerated, and Phase II studies are now ongoing.” The Phase I study identified 400 mg b.i.d. as the dose to carry forward in subsequent trials. The study included 106 patients with Philadelphia-positive (Ph+) CML and 13 patients with Ph+ ALL. Of the CML patients, 17 were chronic phase, 56 were accelerated phase, and 24 were blastic phase (24 myeloid and 9 lymphoid). Patients were recruited from three centers—two in the United States and one in Germany—over a period of one year. All patients had failed to respond to imatinib, and 53% had BCR-ABL mutations. The median duration of CML was 5.5 years. Adverse events included skin rash, temporary increases in bilirubin, transient increases in lipases, thrombocytopenia in 20%, and neutropenia in 13%. Of the 12 evaluable patents in the chronic phase, 11 (92%) had a hematologic complete response (53% had suppression of Ph+ and 35% had disappearance of Ph+). Of those in accelerated phase, 76% had a hematologic response, 55% had PCyR, and 14% had CCyR. In patients in the blastic phase, a hematologic response was achieved in 42%, 29% had PCyR, and 4% had CCyR. Among the 13 ALL patients, two patients responded. At six months, all patients in chronic phase were alive; three accelerated patients died, as did 13 in blastic phase. Eighty-one patients were evaluable for mutations; 42 mutations were identified in 35 patients, and one patient had the T315I mutation—the only patient with no response, Dr. Kantarjian noted. “We are excited about these results. We are reassured that side effects are dose-dependent and reversible. The drug is safe and active, and we may be able to use it in newly diagnosed patients. These studies are a paradigm for targeted therapies to overcome resistance,” Dr. Kantarjian said. T3151: Resistant Mutation Regarding the one mutation that dasatinib and AMN-107 failed to inhibit, Dr. Hochhaus said that T315I is resistant to all kinase inhibitors. “T315I appears to develop later in the course of disease, which makes it really important to reduce BCR-ABL rapidly at the start of treatment,” he commented. There are two schools of thought about how to overcome resistance to T315I, he continued. “One strategy is to develop new drugs, and another is to hit early and hit hard with treatment to avoid the T315I mutation. “In the future, we might use multiple drugs to keep the leukemia load levels lower, or we may have the technology to identify mutations and design a ‘treatment du jour’ aimed at each mutation.” Dr. Hochhaus said that both new drugs are more potent and better tolerated than imatinib. “Imatinib has six years of follow-up. We may find over time that the new drugs have significant toxicity or more likely, as the data mature, the new kinase inhibitors may be safer and more effective than imatinib.Figure: Hagop Kantarjian, MD: “We are excited about these results with AMN-107. We are reassured that side effects are dosedependent and reversible. The drug is safe and active, and we may be able to use it in newly diagnosed patients. These studies are a paradigm for targeted therapies to overcome resistance. We saw encouraging response rates across chronic, accelerated, and blastic phases of CML in patients with imatinib resistance due to BCR-ABL mutations. Phase II studies are now ongoing.”“Over the next three to five years, these two medications may replace imatinib as the standard of care, or the combination of two drugs may replace imatinib.” Combinations with Imatinib Being Studied Combinations with imatinib are already being studied. Phase I studies of AMN107 plus imatinib are being conducted at Oregon Health and Science University, and Phase I studies of dasatinib/imatinib are under way at UCLA. An ongoing study is comparing imatinib at 400 mg vs imatinib at 800 mg, and plans are under way to add AMN107 as a third arm in this trial.