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Gleevac (Imatinib Mesylate) Appears to Provide Prolonged Efficacy with Approved 400 mg Daily Dose

EAST HANOVER, NJ -- December 6, 2004 -- New data on GleevecŪ (imatinib mesylate)* demonstrated that newly diagnosed patients with a certain form of leukemia** receiving 400 mg daily maintained their response to therapy long term. A separate study found patients receiving 800 mg daily had better outcomes compared to patients receiving 400 mg daily. Patients receiving 800 mg daily were found to be more likely to achieve a major molecular response.

An update to the landmark International Randomized Interferon versus STI571 (IRIS) study was presented on December 5 at the American Society of Hematology (ASH) annual meeting in San Diego. The study results demonstrated a link between rapid, early cytogenetic response and long-term outcome during treatment with Gleevec in newly diagnosed patients with chronic-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Patients who achieved cytogenetic responses early in the study had improved rates of progression-free survival compared to those who did not achieve early responses.

In a separate study also presented at ASH, researchers at the M.D. Anderson Cancer Center in Houston, Texas, found that patients with newly diagnosed chronic phase Ph+ CML who took an 800 mg daily dose of Gleevec were more likely to achieve a complete cytogenetic response (CCR) than patients taking the approved 400 mg daily starting dose. In addition to a higher rate of CCR, the study found 67% of patients taking 800 mg daily achieved a major molecular response (MMR) at a median follow-up of 19 months, compared to 47% of patients taking 400 mg daily at a median follow-up of 36 months. MMR is defined as the near absence of disease at a molecular level. Molecular response may prove a possible new benchmark for evaluating effectiveness of drug therapy and disease prognosis.

* Known as GlivecŪ (imatinib) outside the U.S.

** The studies were conducted in patients with newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML).

"The more data we see on Gleevec, the more it appears that patients obtain better long-term outcomes when they reduce their leukemic loads rapidly, which we know can be achieved in more patients with an optimized dose," said Jorge Cortes, MD, Department of Leukemia, M.D. Anderson Cancer Center. "These new data show that patients who have good early responses may have the greatest protection from relapse."

Study details

Abstract # 21: Guilhot F on behalf of the IRIS Study Group. Sustained durability of responses plus high rates of cytogenetic responses result in long-term benefit for newly diagnosed chronic-phase chronic myeloid leukemia treated with imatinib therapy: update from the IRIS study

The study was conducted in 1,106 patients. At the 42-month follow-up, 98% of newly diagnosed patients treated with Gleevec had achieved complete hematologic response (CHR), while 91% had achieved a major cytogenetic response (MCR) and 84% had achieved a complete cytogenetic response (CCR).

For patients who had achieved CCR and a thousand-fold (3 log) or greater reduction in Bcr/Abl transcript level -- a molecular response -- at 12 months, the probability of remaining progression-free was 98% at 42 months, compared with 90% for patients with CCR and less than a thousand-fold reduction in Bcr- Abl transcript level and 75% for patients who had not achieved CCR. Responses to Gleevec were found to be durable at the 42-month follow-up, with an estimated 91% of patients maintaining CHR, 91% of patients maintaining MCR and 87% of patients maintaining CCR.

In CML, a molecular response is the disappearance or reduction in the quantity of Bcr-Abl transcripts that produce the abnormal protein responsible for driving the proliferation of white blood cells that occurs in CML patients. CHR refers to the normalization of blood counts, lasting for at least four weeks. However, the cells containing the Philadelphia chromosome (the genetic abnormality that characterizes most cases of CML) may still be present. In MCR, less than 35% of cells containing the Philadelphia chromosome are detected.

The most common adverse events to first-line treatment with Gleevec in this study were hematologic and hepatic toxicities and included severe (NCI Grades 3/4) neutropenia (16.2%), anemia (4.0%), thrombocytopenia (9.3%) and elevated liver enzymes (5.4%). Other drug-related adverse events occurred in 15.8% of patients.

Abstract #999: Cortes J, et al. High-dose imatinib mesylate treatment in patients with previously untreated early chronic phase chronic myeloid leukemia

The second study, conducted by researchers at the M.D. Anderson Cancer Center, in Houston, Texas, consisted of three consecutive trials. In these trials, a total of 222 previously untreated early chronic phase CML patients were split into two groups. In one group, patients were treated with the 400 mg daily dose of Gleevec, while another group of patients was treated with 800 mg daily. Median follow-up of patients on 400 mg daily was 36 months and median follow-up of patients on 800 mg daily was 19 months.

Patients in the higher dose group had an estimated progression-free survival rate of 99% at 12 months compared with 92% in the standard dose group. Researchers concluded that the 800 mg daily Gleevec dose resulted in higher rates of complete cytogenetic and molecular remissions.

Extramedullary toxicity (toxicity outside the bone marrow) was similar in the two groups, but myelosuppression was more common with the high dose. Severe (NCI Grades 3/4) anemia, neutropenia and thrombocytopenia occurred in 7%, 39% and 27% of patients receiving the high dose, respectively, and 4%, 20% and 12% of patients receiving the standard dose, respectively. At 12 months, the median actual dose for the high-dose group was still 800 mg daily, with 40 of 112 (36%) evaluable patients having required dose reduction. This compares with 7 of 43 (14%) of those treated with the standard dose.

About Gleevec

Gleevec is indicated for the treatment of newly diagnosed adult patients with Ph+ CML in chronic phase. Follow-up is limited. Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

Contraindications, warnings and adverse events*

The majority of CML patients who received Gleevec in clinical studies experienced adverse events, but they were usually mild or moderate in severity. The most frequently reported adverse events (all grades) regardless of suspected relationship to treatment were superficial edema (53%-74%)**, nausea (43%-73%), muscle cramps (28%-62%), vomiting (15%-58%), diarrhea (30%- 57%), musculoskeletal pain (34%-49%), and rash (32%-47%). In most cases, these events were managed without having to reduce the dose of Gleevec or interrupt treatment. Gleevec was discontinued because of adverse events in only 4% of patients in chronic phase, 5% in accelerated phase, and 5% in blast crisis.

Severe (NCI Grades 3/4) neutropenia (2%-48%), anemia (<1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (3%-6%), severe fluid retention (e.g.; pleural effusion, pulmonary edema, and ascites) and superficial edema (<1%-11%)**, hemorrhage (<1%-19%) and musculoskeletal pain (2%-9%) were reported among Gleevec recipients. Severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600mg/day) and is more common in the elderly.

In patients taking Gleevec, bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have also been reported.*** There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure and papilledema.

Use of Gleevec is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec.

Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec.

Gleevec should be taken with food and a large glass of water to minimize GI irritation.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse events, or hematologic adverse events.

Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, phenytoin, and St. John's Wort (an herbal product). Please see full Prescribing Information for potential drug interactions.

For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Patients at a total dose of 1200 mg daily may have an increased susceptibility to excess iron. If routine blood sampling indicates sustained increases in iron levels, attempts to lower other sources of iron exposure should be undertaken.

* Numbers indicate the range in percentages in four studies among patients with CML in blast crisis, accelerated phase, and chronic phase.

** Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life threatening.

*** In some cases, the reaction recurred upon rechallenge. Several foreign postmarketing cases note a resolution or improvement of bullous reaction following dose reduction with or without supportive care.







SOURCE: Novartis

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