With Longer Follow-Up, Imatinib Continues to Improve Response Rates in CML

ORLANDO, Florida—Updated data from two phase II trials show that imatinib mesylate (Gleevec, STI571) continues to improve response rates for patients with chronic myelogenous leukemia (CML) who did not respond to interferon therapy or are in blast crisis. With follow-up of 12 months or more, overall and complete response rates are proving to be durable and toxicities tolerable.

Imatinib inhibits the Philadelphia chromosome, a translocation between chromosomes 9 and 22 that is detected in 95% of CML patients. The Philadelphia chromosome produces Bcr-Abl, a tyrosine kinase that jams the signal to halt production of white blood cells, thus allowing the massive increase in the number of white blood cells that characterizes CML.

Imatinib is generally well tolerated. Although the majority of patients treated with imatinib experience adverse events at some time, most events are mild to moderate, as were those reported in the phase II studies. The most common side effects included nausea, fluid retention, vomiting, diarrhea, hemorrhage, muscle cramps, skin rash, fatigue, headaches, dyspepsia, and dyspnea. Serious side effects include hepatotoxicity, fluid retention syndrome, neutropenia, and thrombocytopenia.

In most countries where imatinib is approved, it is indicated for the treatment of patients in chronic phase after failure with interferon, accelerated phase CML, or blast crisis.

Failed Interferon Therapy

Updated follow-up on 532 patients who have late CML and failed interferon therapy confirmed and expanded response and survival rates. The reasons for interferon failure were hematologic resistance or refractory to interferon (152), cytogenetic failure (188), and intolerance to interferon (192).

Treatment was imatinib at a dose of 400 mg/d. The median age was 57, "similar to the age of an unselected CML population," noted Hagop P. Kantarjian, MD, of The University of Texas M. D. Anderson Cancer Center in Houston. "Currently, the median duration of treatment is 18 months, and most of the patients (90%) have been treated for longer than 1 year," Dr. Kantarjian said.

"The incidence of complete hematologic response among 454 patients who had confirmed diagnosis of Philadelphia chromosome-positive chronic-phase CML at the time they were initiated on therapy was 95%," Dr. Kantarjian said. At 18 months follow-up, the major cytogenetic response rate (complete plus partial) rose to 60% and the complete response rate to 41%.

Unlike hematologic responses, cytogenetic responses differed according to reason for interferon failure. "For example, patients who are intolerant to interferon have a significantly higher rate of both complete and major cytogenetic response, compared to those who failed due to hematologic resistance," Dr. Kantarjian said. Cytogenetic response tends to occur early, but continues to improve before reaching a plateau at about 12 months, he noted.

"Several of the known prognostic factors have been associated with a difference in major cytogenetic responses," he said. "For example, splenomegaly and anemia were associated with worse cytogenetic response rates. Age was not a prognostic factor," Dr. Kantarjian said, "and older patients respond equally well to imatinib compared to younger patients."

Patients who are treated within 1 year of diagnosis have major cytogenetic responses of 80%, and those with suppression of the Philadelphia-positive cells have major cytogenetic responses of 90%, Dr. Kantarjian reported. "This suggests that early therapy with imatinib in early-phase CML, and the use of imatinib in combination, such as with cytarabine, may improve results further," he said. Also identified as factors associated with a better rate of cytogenetic response are platelets below 450 × 10⁹/L, hemoglobin of 12 g/dL or higher, and bone marrow blasts below 5%.

At the time of the presentation, 71 patients (13%) had stopped therapy, 32 (9%) of them because of disease progression. "At a median follow-up time of 18 months, the estimated disease-free progression rate was 89%, which is very encouraging," reported Dr. Kantarjian. "Survival was also very encouraging. The estimated 18-month survival is 95% in a population where the yearly mortality usually ranges from 15% to 25%. This is relatively convincing evidence that imatinib therapy is changing the natural history of patients in late chronic phase CML following interferon failure."

Side Effects Frequent, but Mild

"Mild to moderate side effects were common," Dr. Kantarjian said. These included nausea, vomiting, diarrhea, skin rashes, muscle cramps, and fluid retention. "However, severe side effects requiring interruption of therapy occurred in less than 5% of patients." These included severe skin rashes, major fluid retention, and occasional hepatotoxicity. "Severe anemia has been observed in 8% of patients, but usually responds to erythropoietin. Severe neutropenia is seen in about 35% of patients, and there are some studies what show it responds safely to granulocyte colony-stimulating factor (G-CSF [Neupogen]). Significant thrombocytopenia is seen in about 20% of patients and requires dose reduction," he added.

Future Directions

"The longer follow-up of this study continues to demonstrate very positive results," Dr. Kantarjian concluded. "The major cytogenetic response has now increased to 60% and the complete cytogenetic response to 41%. The estimated 18-month progression-free survival was 89%, and overall survival 95%. And very importantly, there are no new worrisome side effects that have been observed and the incidence of resistance remains low in this setting of chronic-phase CML following interferon failure. Several studies are now investigating imatinib in newly diagnosed CML as well as in combinations. There is also a randomized study of interferon plus cytarabine in newly diagnosed CML. It will be important to have an early update on this study so we can direct community oncologists as to which direction they need to go in terms of advising their patients."

Patients in Blast Crisis

Most patients in the phase II study of CML in myeloid blast crisis received imatinib at the 600-mg/d dose. "We started with the dose of 400 mg with the first 37 patients, and the remaining patients we treated with 600 mg as safety information became available," reported Charles Sawyers, MD, Medicine/Hematology-Oncology, UCLA.

The study was conducted in 27 centers in France, Germany, Italy, Switzerland, the United Kingdom, and the United States. Blast crisis was confirmed in 229 patients, 148 (65%) with newly diagnosed blast crisis and 81 (35%) who had received prior therapy for CML. The median duration of treatment was 4 months.

Imatinib induced overall hematologic response in 119 patients (52%), Dr. Sawyers said. To more accurately assess response, it was separated into three categories: (1) complete hematologic response, reduction in percentage of blasts to below 5% with recovery of peripheral blood counts; (2) bone marrow response, reduction in percentage of blasts to below 5% but without recovery of peripheral blood counts; and (3) return to chronic phase.

Response Data

Of the 52% achieving hematologic response, 15% had complete response, 9% marrow response, and 28% return to chronic phase. Sustained hematologic response (lasting 4 or more weeks) occurred in 30% of patients—complete response in 8%, marrow response in 4%, and return to chronic phase in 18%. Sustained response was more likely among those receiving the 600-mg dose (24%) than those receiving the 400-mg dose (9%). Sustained response dropped quickly. "I think this reflects the fact that resistance can develop in a short period of time," Dr. Sawyers said.

Cytogenetic response was 16% overall—7% complete and 9% partial. Overall median survival is 6.9 months. Estimated survival rates are 32% at 12 months and 20% at 18 months, according to Dr. Sawyers.

In addition to receiving the higher dose, favorable prognostic factors were hemoglobin above 10 g/dL, platelets above 100 × 10⁹/L, and peripheral blood blasts below 50%.

Nonhematologic side effects, including nausea, superficial edema, and vomiting, were frequent but these were usually mild or moderate. In contrast, hematologic toxicities were usually grade 3 or 4. For example, grade 4 neutropenia occurred in 48% of patients.