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Third-Generation Tyrosine Kinase Inhibitors Show Clinical Activity in Imatinib-Resistant CML Patients Who Harbor Resistance Mutation

Fuerst, Mark L.

doi: 10.1097/01.COT.0000368425.65797.51
Crystal structure of the bcr-abl kinase domain (green) in complex with imatinib (red)

Crystal structure of the bcr-abl kinase domain (green) in complex with imatinib (red)

NEW ORLEANS—Several third-generation tyrosine kinase inhibitors (TKIs) have shown clinical activity in patients with chronic myeloid leukemia (CML) who harbor the BCR-ABL T315I mutation and are resistant to first-line therapy with imatinib and second-line therapy with second-generation TKIs, according to data reported here at the ASH Annual Meeting.

Over the past several years, TKIs that target BCR-ABL, the abnormal protein that drives production of white blood cells characteristic of leukemia, have become the standard therapy for CML, led by imatinib. In the United States, the number of people living with CML has doubled since 2001, and this trend is expected to continue.

However, there remains a small subset of patients who do not respond to TKIs because they harbor the BCR-ABL T315I mutation. “Currently available TKIs have not demonstrated activity against this mutation,” explained Jorge Cortes, MD, Professor and Deputy Chair of the Leukemia Department at the University of Texas M. D. Anderson Cancer Center. “Despite the excellent results achieved with imatinib in CML patients, 25 to 30 percent of patients need alternative therapy because they either fail to achieve the minimum acceptable optimal response or are intolerant to imatinib. Imatinib dose escalation is effective in improving the response, particularly for patients who did achieve, but eventually lost, a cytogenetic response.”

The introduction of second-generation TKIs, such as dasatinib and nilotinib, changed the role of dose escalation with imatinib, and now this is the option most frequently considered by clinicians for patients with suboptimal response to standard-dose imatinib, he continued.

Still, nearly half of all CML patients do not achieve a complete cytogenetic response with a second-generation TKI, and others have only transient responses. “Patients who do not achieve a major cytogenetic response by 12 months from the start of therapy have the highest probability of eventually progressing,” Dr. Cortes said in an interview.

Although responses can be achieved in some patients using a second-generation TKI after the failure of one or two other TKIs, the responses tend to be short-lived, with a median failure-free survival of only 20 months for patients in chronic-phase CML and two to four months for those with more advanced disease. “New treatment options are needed for this patient population,” he said.

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At the meeting, he presented the results from clinical studies of three promising TKIs currently under development. A new subcutaneously administered drug, oma-cetaxine, appears to be safe and effective in CML patients who have the T315I mutation. Omacetaxine is a first-in-class cetaxine with clinical activity against Philadelphia-positive (Ph+) CML. The drug—previously called homoharringtonine—appears to have potential as a treatment for CML with its unique mechanism of action that is independent of tyrosine kinase inhibition, he said.

“Omacetaxine may provide a treatment option for this patient population, who currently have no available approved drug therapies.”

He reported data on 81 CML patients (49 in chronic phase, 17 in accelerated phase, and 15 in blast crisis), who had a median age of 58 years and a median disease duration of 54 months; 80% of patients had failed to respond to therapy with two or more prior TKIs.

Among chronic-phase patients, 86% achieved a complete hematologic response, 41% a cytogenetic response, and 18% a complete cytogenetic response. The median time to major cytogenetic response was four months, and the median duration of hematologic response was nine months.

In accelerated-phase CML patients, 35% had a hematologic response for a median duration of 6.6 months; and for blast-phase patients, 47% had a hematologic response for a median duration of 2 months.

The median overall survival for chronic-phase CML patients has not been reached, and 80% of patients remain alive. The median overall survival was 18.8 months for accelerated-phase patients and 2.4 months for those in blast crisis.

“With drug therapy, about 50% of all patients have reductions of the T315I clone from baseline,” Dr. Cortes said.

Grade 3/4 hematologic adverse events were frequent at the beginning of treatment. The most commonly reported events were thrombocytopenia (71%), anemia (49%), and neutropenia (45%). “With dose adjustments, myelosuppression has been reduced,” he said.

TIMOTHY HUGHES, MD: “About 15% of patients who become resistant to imatinib have a T315I mutation

TIMOTHY HUGHES, MD: “About 15% of patients who become resistant to imatinib have a T315I mutation

Nonhematologic toxicities were primarily Grade 1/2, with the most frequent diarrhea, fatigue, fever, and nausea. Grade 3/4 nonhematologic toxicities were uncommon.

Treatment is ongoing for 19 patients in chronic phase, two in accelerated, and one in blast crisis, Dr. Cortes said. The rates for those discontinuing therapy—due primarily to disease progression or lack of response— were 61%, 88%, and 93%, respectively.

“Omacetaxine given by self-administered subcutaneous injection is well tolerated and produces durable hematologic and cytogenetic responses,” Dr. Cortes said. “Myelosuppression is the most common toxicity and can be managed by dose adjustments. Omacetaxine represents a new potential therapy for patients with T315I-positive CML.”

Asked for his opinion about the study, Timothy Hughes, MD, Associate Professor of Hematology at the University of Adelaide in Australia, said, “We still have a question mark about the best management of T315I patients. I have a personal enthusiasm for targeted therapies. This is an area where we need effective drugs. About 15% of patients who become resistant to imatinib have a T315I mutation. For those resistant to dasatinib or nilotinib, 30% or more develop a T315I mutation. Several promising drugs are on the horizon, including omacetaxine.

“If a patient develops a T315I mutation, carefully consider an allograft. If that is not an option, then get the patient on a trial with one of the third-generation agents.”

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Drugs Under Development

Dr. Cortes also presented the results of safety and clinical activity against T315I and resistant mutations from a Phase I trial of the drug AP24534 in patients with refractory CML and other hematologic malignancies.

AP24534, he explained, is an orally available multiple TKI with in vitro activity against BCR-ABL, both unmutated and mutated, including T315I. It also has activity against Flt3 and c-kit.

He reported preliminary results from an ongoing Phase I, open-label, dose-escalation clinical trial to assess the safety of AP24534, establish a maximum tolerated dose and schedule for further investigation, and provide preliminary assessments of clinical activity.

Forty-four patients have been enrolled so far in six dosing cohorts from 2 to 60 mg administered orally once daily. Forty of the patients have resistant and refractory CML or Ph+ acute lymphoblastic leukemia (ALL). All 40 of these patients were resistant to first- and second-line treatments for CML; 81% of CML and Ph+ ALL patients were resistant to at least three TKIs, including imatinib, dasatinib, and nilotinib.

Of the 44 patients, 28 patients have chronic-phase CML, five have accelerated-phase CML, and five have blast-phase CML, two have Ph+ ALL, and four have non-CML hematologic malignancies. A total of 28 patients are still on study.

Of the 20 chronic-phase CML patients evaluable for cytogenetic response, five (25%) demonstrated a complete cytogenetic response, nine (45%) achieved a major cytogenetic response, and 12 (60%) experienced any type of cytogenetic response. One of the four evaluable accelerated-phase patients achieved a complete cytogenetic response. There were no responses in the seven blast-phase CML or the Ph+ ALL patients.

JORGE CORTES, MD: “Omacetaxine may provide a treatment option for this patient population, who currently have no available approved drug therapies

JORGE CORTES, MD: “Omacetaxine may provide a treatment option for this patient population, who currently have no available approved drug therapies

A complete hematologic response was achieved in 10 of 12 (83%) chronic-phase CML patients evaluable for hematologic response. A major hematologic response occurred in three of the four accelerated-phase CML patients, none of the five blast-phase CML patients, and one of the two Ph+ ALL patients.

Among patients with BCR-ABL mutations, hematologic, cytogenetic, and molecular responses were observed, Dr. Cortes reported. Of the 18 CML patients with the T315I mutation, 10 of 18 patients (55%) are currently in chronic phase, nine of whom remain on study. All of the seven chronic-phase patients evaluable for response have had a complete hematologic response, and three (43%) have had a major cytogenetic response.

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Safety data show that the drug was well tolerated, Dr. Cortes reported. There were no dose-limiting toxicities at dose levels lower than 60 mg. There were four patients with dose-limiting toxicities (chemical and clinical pancreatitis) out of 12 patients evaluable at the 60 mg dose level.

The most common drug-related adverse events were nausea, fatigue, dry eye, anorexia, arthralgia, dizziness, dry mouth, headache, hot flush, myalgia, vomiting, and QTc prolongation. Grade 3/4 thrombocytopenia occurred in about one-third of patients and Grade 3/4 neutropenia in about 40% of patients. Both types of hematologic toxicity were more frequent in patients with advanced stages of CML and Ph+ ALL.

“The drug is safe and well tolerated,” Dr. Cortes said. “Blood levels at 15 mg and above sustained target inhibition at clinical doses. The early results are encouraging, with a rate of major cytogenetic response in chronic-phase CML of 45% and 43% in T315I chronic-phase CML. Phase II studies with the drug are planned in all stages.”

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In addition, the multi-kinase aurora inhibitor danusertib (PHA-739358) also elicits clinical benefit in advanced CML and Ph+ ALL, he said, explaining that the drug shows activity against aurora kinase and BCR-ABL, even in the presence of mutations, including T315I and has anti-proliferative activity against CD34+ CML cells.

He reported on an international, multicenter, open-label, single agent, non-comparative, phase I study being conducted in patients with advanced CML and Ph+ ALL who are resistant or intolerant to imatinib and/or second-generation TKI therapy.

So far, 23 patients with CML (4 in advanced phase, 8 in blast crisis) and Ph+ ALL (11 patients) have been treated. Five dose levels have been tested, ranging from 90 mg/m2 to 200 mg/m2. Only one dose-limiting toxicity occurred, at 90 mg/m2. For now the maximum tolerated dose has not been defined, he said.

Responses were seen in six of 14 patients, including three cytogenetic responses (one complete). One severely pretreated patient with T315I mutated Ph+ ALL reached a major molecular response after nine cycles of treatment; two additional patients (one with advanced-phase CML and one with Ph+ ALL) achieved cytogenetic responses.

Significant reduction in the white blood cell count was seen in eight of 13 patients, but these were transient, he said. Peripheral blood blast counts were obtained in three of the patients.

The tolerability and safety profile of the drug was acceptable, with the most frequent adverse events were diarrhea, pyrexia, headache, dyspnea, and nausea.

“The preliminary results show that [danusertib] can elicit significant response with clinical benefit in severely pretreated populations of patients affected with advanced leukemias that are resistant or intolerant to imatinib and other second-generation TKIs,” Dr. Cortes concluded.

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‘Terrible Disease’

Asked for his opinion, Francis Giles, MB, MD, Chief of the Division of Hematology and Medical Oncology at the University of Texas Health Science Center at San Antonio, called T315I CML a terrible disease and said that drugs for the mutation are urgently needed.

“If a patient develops a T315I mutation, clinicians should provide a T315I inhibitor to try to get the disease under control as best you can, and then get the patient to transplant,” he said.

“Initially, the fear was that if we gave a potent TKI upfront, there would be selection pressure, and the patient would be predisposed to develop a T315I mutation. That has not been found to be the case. Now the goal is to reduce the tumor load as quickly as possible and hit no other targets, unless you need to.”

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Other Third-Generation TKIs Under Development

Other third-generation TKIs are also under development, said Dr. Cortes. These include XL-228, a multi-kinase inhibitor with activity against BCR-ABL, among others. “This drug inhibits several mutants of BCR-ABL, including T315I,” he said.

An ongoing Phase I study showed that the drug has induced hematologic and cytogenetic responses in about 20% of patients who had not responded to multiple prior therapies, including complete cytogenetic and major cytogenetic responses in a few patients with T315I mutations.

DCC-2036 is another multi-kinase inhibitor that impairs proliferation and induces apoptosis of cells transfected with unmutated or mutated BCR-ABL, including T315I. Phase I studies with this drug are just starting.

“There are many options in clinical trials for patients after failure to respond to several TKIs. These studies will lead us to the best long-term outcome for all CML patients,” said Dr. Cortes.

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Hear More!

Hear Jorge Cortes talk more about his studies in a “Live from ASH” OT Broadcast News podcast (Program #1) available at and on iTunes.

© 2010 Lippincott Williams & Wilkins, Inc.
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