High-Dose Imatinib Mesylate (Gleevec®) for CML

Abstract & Commentary

Synopsis: Imatinib was administered to newly diagnosed patients with chronic-phase myelogenous leukemia at a dose (800 mg daily) double what is commonly prescribed. Cytogenetic and molecular responses were significantly better than observed in an historical cohort of similar patients treated with 400 mg daily. Furthermore, although toxicity was greater, the dose was maintained in nearly two-thirds of the patients. Additional research is needed, but higher-dose imatinib may offer a better chance for long survival and even cure for some patients with this disease.

Source: Kantarijian H, et al. Blood. 2004;103: 2873-2878.

Imatinib mesylate (st1571, gleevec®) has become the standard first-line treatment for chronic phase chronic myelogenous leukemia (CML). Typically, patients are treated with a dose of 400 mg daily; and prior experience indicates that 95% of such patients experience complete hematological responses and 60-75% are shown to have complete cytogenetic responses.1,2 However, complete molecular response (undetectable levels of BCR-ABL assessed by polymerase chain reaction) are significantly less common (5-15%). A molecular response has become the goal of therapy inasmuch as such patients have experienced 10-year survival rates of 70-85%.2-4

In the current report from M.D. Anderson Cancer Center, 114 patients with newly diagnosed CML were treated with imatinib mesylate 400 mg twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete cytogenetic response (Ph 0%). With a median follow-up of 15 months, no patient had progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) showed BCR-ABL/ABL percentage ratio decreased to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = 0.0005), major molecular response (QPCR < 0.05%; P = 0.00001), and complete molecular response (undetectable BCR-ABL; P = 0.001).

With regard to adverse effects, high-dose imatinib was associated with more frequent myelosuppression, and for many the doses had to be reduced. Dose reductions were necessitated by myelosuppression in 18 patients (15%, thrombocytopenia in 11, neutropenia in 6, both in 1), skin rash (n = 13, 11%), fatigue (n = 4, 3%), bone pain (n = 7, 6%), fluid retention (n = 5, 4%), congestive heart failure (n = 3), fever or infection (n = 3), liver dysfunction (n = 2), and gastrointestinal (n = 2). Anemia occurred in 40 patients and was treated with erythropoietin. No dose reductions resulted from the occurrence of anemia.

By 3 months of therapy, 68% were receiving the planned dose, whereas the remainder (n = 37) had doses reduced to 600 mg daily (n = 27) or 300 to 400 mg daily (n = 10). The imatinib dose was maintained at 800 mg daily at 6 months in 70 (64%) and in 52 (66%) of 79 evaluable patients at 12 months. Dose reduction to 600 mg daily resolved the toxicity in most patients.

Thus, close to two-thirds of new chronic phase CML patients were able to maintain a dose of imatinib of 800 mg daily, and for the group as a whole, response rates, including molecular responses, were significantly higher than those of a comparable group of 50 patients treated at that institution with a dose of 400 mg daily.

Comment by William B. Ershler, MD

The treatment of chronic myelogenous leukemia has evolved dramatically since the introduction of imatinib. With prior therapies, such as busulfan and hydroxyurea, the duration of chronic phase was clearly prolonged but accelerated phase and blast crisis invariably involved in a matter of two to three years. Instituting curative treatment strategies during the chronic phase often involved intensive chemotherapy with allogeneic transplantation, the aggressiveness of which often precluded the major population of those with this disease, patients over the age of 60 years. Even interferon, which clearly enhanced survival, has proven to be a difficult therapy for many patients to tolerate. Imatinib, at 400 mg daily, is clearly well tolerated, even by more frail patients, and has resulted in significantly better response rates and survival. The question raised by the current research is whether higher doses can be sufficiently well tolerated to result in a more effective response, namely a higher rate of molecular remissions. The data presented are intriguing, but must be considered preliminary. Before practicing oncologists adopt the higher dose regimen as the standard approach a larger, prospective trial must be undertaken. One such trial might include a randomization to either standard dose (400 mg daily) to high dose (800 mg daily) with a third arm receiving interferon.

References

1. Kantarjian HM, et al. Blood. 2003;101:97-100.
2. O’Brien SG, et al. N Engl J Med. 2003;348:994-1004.
3. Mahon F, et al. J Clin Oncol. 2003;20:214-220.
4. Garcia-Manero G, et al. Cancer. 2003;98:437-457.

William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.