Imatinib Plus Interferon Produces High Rate of Hematologic Response in CML

Oncology NEWS InternationalOncology NEWS International Vol 11 No 2
Volume 11
Issue 2

ORLANDO, Florida-Two phase I/II studies indicate that combination treatment with imatinib mesylate (Gleevec, also known as STI571) produces a high rate of hematologic response in patients in the chronic phase of chronic myelogenous leukemia (CML). Dose-limiting toxicities were mainly hematologic, and researchers advocate further studies were recommended to establish efficacy and recommended dosing.

ORLANDO, Florida—Two phase I/II studies indicate that combination treatment with imatinib mesylate (Gleevec, also known as STI571) produces a high rate of hematologic response in patients in the chronic phase of chronic myelogenous leukemia (CML). Dose-limiting toxicities were mainly hematologic, and researchers advocate further studies were recommended to establish efficacy and recommended dosing.

Study Rationale

Michael E. O’Dwyer, MD, of the Leukemia Center at Oregon Health and Science University in Portland, cited previous studies with imatinib that demonstrated remarkable response rates in chronic phase CML patients who have failed interferon therapy. Approximately 50% of these patients, however, do not achieve a major cytogenetic response. Even among those who achieve complete cytogenetic remissions, most have detectable Bcr-Abl. These studies, along with concern about patients developing resistance to imatinib as a single agent, plus in vitro studies showing an additive or synergistic effect when interferon (IFN)-alfa is used in combination with imatinib, led to a phase I/II trial evaluating imatinib in combination with IFN-alfa. "Clearly this does provide a strong rationale for combination therapy, which may maximize the chances of achieving molecular remission and prevent emergence of resistance," Dr. O’Dwyer said.

Maximum Tolerated Dose

"The primary objective of this study was to establish the maximum tolerated dose," Dr. O’Dwyer explained. For the purposes of the study, maximum tolerated dose was defined as the dose that produces grade 3/4 nonhematologic toxicity in less than 33% of patients. Patients were excluded if they had a history of greater than grade 3 nonhematologic toxicity due to interferon. Hematologic and cytogenetic response rates were secondary end points.

Data were reported on nine patients—four males and five females, all positive for the Philadelphia chromosome. The median age of patients was 53 years (range: 37-71), and the median duration of disease was 2.5 months (range: 1-37 months). All patients but one have had prior treatment with at least hydroxyurea, three have been treated with interferon, and one with imatinib.

For the first 2 weeks of the trial, patients were treated with imatinib at 400 or 600 mg/d. Then IFN-alfa was added at either 3 million IU per day or three times per week.

"Overall, this combination has been well tolerated to date," Dr. O’Dwyer reported. The major nonhematologic toxicities were nausea, diarrhea, muscle cramps, fluid retention, and depression. "The most common toxicity overall was hematologic toxicity," he said. "A total of three patients had at least grade 2 thrombocytopenia, one of whom had grade 3. A total of seven patients had at least grade 2 neutropenia, of whom 3 patients had grade 3. No grade 4 hematologic toxicities were seen."

One patient required a dose interruption and another required a dose reduction. Seven patients continue to receive 400 mg/d of imatinib plus 3 million IU of interferon daily or three times per week.

100% Hematologic Response

The hematologic response was 100%, with all patients having a reduction in white blood cell count. Cytogenetic follow-up in six patients found complete cytogenetic response in two.

"In conclusion," Dr. O’Dwyer said, "imatinib at 400 mg/d plus IFN-alfa at 3 million IU daily is a safe combination. It does not induce any unexpected nonhematologic toxicities. However, it does appear to be more myelosuppressive than imatinib alone," Dr. O’Dwyer stated.

"Although the sample size is really too small to establish efficacy, cytogenetic responses have been seen. This combination is safe to administer to newly diagnosed patients and may maximize the chances to achieve hematologic activity. However, before we can advocate it as up-front therapy, more data on safety and efficacy are needed."

Dr. O’Dwyer pointed out that the maximum tolerated dose has not yet been established. Enrollment was scheduled to start soon for a cohort to test the combination of 600 mg/d of imatinib plus 5 million IU of IFN-alfa daily.

Defining Tolerability

A high rate of hematologic response was also seen in a phase I/II trial to define the tolerability of interferon and imatinib in combination. The study enrolled 49 patients in 19 centers in the United Kingdom, reported Stephen O’Brien, MD, Department of Hemotology, University of Newcastle. The median age was 52 years (range: 30-74) and two-thirds of patients were newly diagnosed.

The study was designed so that there was a 2-week run-in period of imatinib monotherapy, given at 400 mg/d. Peginterferon alfa-2b (PEG-Intron) was then introduced at 0.5 µg/kg/wk and scheduled to be increased monthly. Because of grade 3/4 hematologic toxicity, however, only 19 of the 46 evaluable patients increased to the second dose level (1 µg/kg/wk), with 11 patients going on to the third dose level (2 µg/kg/wk) and 4 to the fourth level (3 µg/kg/wk). When two lower-dose levels were introduced, 27 patients (58.7%) dropped to a dose of imatinib at 200 mg/d plus peginterferon alfa-2b at 0.5 µg/kg/wk; 12 patients had to further reduce peginterferon alfa-2b to 0.25 µg/kg/wk. "It seems unlikely that high dose levels will be achieved," said Dr. O’Brien.

Adverse Events

Nonhematologic adverse events were mostly grade 1/2, occurring in 71.4% of the 49 patients. Grade 3/4 nonhematologic adverse events were encountered in 22.4%. Hematologic toxicities were primarily grade 3, with neutropenia the most common. There have been 12 incidents of serious adverse events, resulting in 5 patients withdrawing from the study. Three other patients are no longer in the study because of disease progression, including one death.

Hematologic responses have included normalization of the blood and reduction in splenomegaly. The overall hematologic response was 100%, with 73% of patients sustaining response at 6 months, including 37% in complete remission, Dr. O’Brien reported. For the newly diagnosed patients, the rates were 82.4% overall response and 41.2% complete response. "Reassuringly, we see that just over one-half of the late responses observed are at the low dose," he added. Major cytogenetic response was 82.4% at 3 months.

Dr. O’Brien said that the phase II study showed that the combination of peginterferon alfa-2b was "highly effective." Recommended dosing schedules still need to be established in a phase III trial.

Related Videos
Additional analyses of patient-reported outcomes and MRD status in the QuANTUM-First trial are also ongoing, says Harry P. Erba, MD, PhD.
Overall survival data with blinatumomab in the phase 3 E1910 study may be an “important development” in CD19-positive B-ALL.
Investigators must continue to explore the space for lisocabtagene maraleucel in mantle cell lymphoma, according to Manali Kamdar, MD.
Those with CML should discuss adverse effects such as nausea or fatigue with their providers to help optimize their quality of life during treatment.
Patients with CML can become an active part of their treatment plan by discussing any questions that come to mind with their providers.
Jorge E. Cortes, MD, emphasizes proper communication between patients with chronic myeloid leukemia and their providers during the treatment course.
Dietary interventions or other medications may help mitigate diarrhea in patients who undergo therapy for chronic myeloid leukemia.
Considering notable adverse effects associated with treatment may be critical when selecting therapy options for those with CML.
Adverse effects associated with oral azacitidine in low- or intermediate-risk MDS are typically transient, according to Mikkael A. Sekeres, MD, MS.
Ongoing genomic profiling analyses in the ASC4FIRST trial may further determine which patients with CML may benefit from treatment with asciminib.
Related Content