Potential Breakthrough Treatment for CML Patients Who Harbor Imatinib-Resistant T315I Mutation

NEW ORLEANS, LA — Omacetaxine (Omapro) achieved durable hematologic and cytogenetic responses in patients with chronic myeloid leukemia (CML) who failed treatment with imatinib (Gleevec). All patients in this phase II/III study had developed the T3151 mutation, which confers resistance to imatinib and to the second-generation tyrosine kinase inhibitors (TKIs) nilotinib (Tasigna) and dasatinib (Sprycel).

Omacetaxine is the first drug shown to overcome this resistant mutation and has a novel mechanism of action that is different from that of a TKI, explained Jorge Cortes, MD, professor of Medicine and deputy chair in the Department of Leukemia at University of Texas MD Anderson Cancer Center in Houston, Texas, who presented these results. “Omacetaxine represents a new potential therapy for CML patients who develop the T315I mutation,” he said.

BCR-ABL mutations occur in about 50% of patients resistant to imatinib, the drug of choice for CML. Up to 20% of the resistant population harbor T315I mutations, and available TKIs are not effective in this group. Further, patients who develop T315I mutations have a poor prognosis. “Right now, development of this mutation is a relatively small problem, but it may become a growing problem through the selection process, similar to the development of antibiotic resistance,” Dr Cortes explained.

The multicenter study is still ongoing. At the 2009 Annual Meeting of the American Society of Hematology, Dr Cortes presented data on 81 patients with CML: 49 in chronic phase (CP), 17 in accelerated phase (AP), and 15 in blast phase (BP). Median age was 58 years, and median duration of CML was 54 months. All patients failed prior imatinib therapy and had the T315I mutation at baseline. Induction therapy with subcutaneous omacetaxine was administered at a dose of 1.25 mg/m² twice daily for 14 days of every 28-day cycle until evidence of hematologic response. For maintenance therapy, the same dose was given for 7 days of every 28-day cycle. Patients self-administered the drug in their homes.

At an official press conference, Dr Cortes focused his remarks on the CP patients, as these are the ones with the best chance of improved outcomes (Table 1). Complete hematologic response was obtained in 42 of 49 patients (86%); cytogenetic response was achieved in 20 patients (41%), with 13 (27%) having a major cytogenetic response and 9 (18%) having a complete cytogenetic response. In CP patients, median duration of hematologic response was 9.1 months and median duration of major cytogenetic response was 4.7 months. Median survival has not yet been reached for CP patients.

Table 1. Outcomes with Omacetaxine for CML Patients in Chronic Phase

Outcome

No. (%) of Patients

(n = 49)

Median Duration, mo

Complete hematologic response, No. (%)

49 (86)

9.1

Cytogenetic response, No. (%)

20 (41)

4.7

Major

13 (27)

Complete

9 (18)

Overall hematologic responses were seen in 35% of the AP patients, with a median duration of 7 months. Overall hematologic responses were seen in 47% of BP patients, with a median duration of 2 months. Median survival in the AP was 18.8 months, and in the BP, 2.4 months.

Grade 3-4 non-hematologic adverse events were uncommon (Table 2). The most frequent adverse events (>10%) in CP patients were diarrhea, fever, fatigue, nausea, injection erythema, asthenia, cough, arthralgia, constipation, and peripheral edema. The most common grade 3-4 hematologic adverse events in the CP patients were thrombocytopenia, anemia, neutropenia, and febrile neutropenia. Treatment is ongoing in 19 of the CP patients (39%). The complete oral presentation for this study will take place on Monday, December 7. ASH Abstract 644.

Table 2. Adverse Effects with Omacetaxine

for CML Patients in Chronic Phase

Adverse Effect

% of Patients

(n = 49)

Overall (>10%)

Diarrhea

43

Fever

33

Fatigue

29

Nausea

29

Injection erythema

18

Asthenia

25

Cough

18

Arthralgia

18

Constipation

14

Peripheral Edema

12

Grade 3-4 (most common)

Thrombocytopenia

71

Anemia

49

Neutropenia

45

Febrile neutropenia

12

In November, the FDA granted priority to a New Drug Application from ChemGenex for Omapro in patients with CML who have failed treatment with imatinib and have developed the BCR-ABL T315I mutation. Priority review shortens the review period to 6 months. Omapro currently has orphan drug designation in the United States.

Authors received research funding from ChemGenex.

Disclosures: