Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia

Imatinib mesylate (Gleevec, STI571), a selective BCR-ABL tyrosine-kinase inhibitor, has shown significant activity against Philadelphia chromosome–positive (Ph⁺) chronic myelogenous leukemia (CML) and Ph⁺ acute lymphocytic leukemia.1-10 The estimated 2-year incidence of resistance to imatinib mesylate was 80% in blastic phase, 40% to 50% in accelerated phase, and 10% in chronic phase post–interferon-α failure. Mechanisms of resistance to imatinib mesylate include overexpression of Bcr-Abl, BCR-ABL oncogene amplification, mutations within the ABL-activation site, increased levels of plasma α1 acid glycoprotein, and cytogenetic clonal evolution.11-20 Several strategies to overcome imatinib mesylate resistance are being investigated.11-22 One approach is to increase the dose of imatinib mesylate. The rationale for this is the overexpression of Bcr-Abl and amplification of BCR-ABL as mechanisms of resistance; the preclinical studies and clinical experience showing a dose-response effect; the experience in CML accelerated phase in which a dose of 600 mg imatinib mesylate was independently associated with significantly better time to transformation and better survival compared with 400 mg; and anecdotal experience of responsiveness to higher doses of imatinib mesylate in patients whose CML had become resistant to lower doses. Here, we summarize our experience in patients with Ph⁺ CML in chronic phase post–interferon failure who received an escalated dose of 800 mg or 600 mg orally daily after demonstrating a poor response or relapse at the standard dose.

We analyzed the treatment course of 261 patients with Ph⁺ CML in chronic phase post–interferon failure treated on 2 Novartis-sponsored trials (East Hanover, NJ): the pivotal study (study 110; 149 patients treated at the M. D. Anderson Cancer Center, Houston, TX), and the expanded-access study (study 113; 112 patients). Both studies were approved by the M. D. Anderson Cancer Center institutional review board and all patients signed an informed consent according to institutional guidelines. The entry criteria, pretreatment, and follow-up studies, and dose-modification guidelines have been previously detailed.3,5 9 The protocol design allowed for dose escalation of imatinib mesylate from 400 mg daily to 400 mg twice daily, or to 600 mg daily if the dose had been reduced to 300 mg daily, under the following circumstances: (1) failure to achieve a complete hematologic response (CHR) after 3 months of therapy (hematologic resistance); (2) failure to achieve a major cytogenetic response (Ph⁺ cells, fewer than 35%) after 12 months of therapy (cytogenetic resistance); (3) hematologic relapse; or (4) cytogenetic relapse, defined as an increase of Ph⁺ cells by at least 30% documented on 2 consecutive occasions.

Response criteria were previously described.5 9 A CHR required normalization of peripheral counts and differential, and disappearance of all signs and symptoms of CML. Cytogenetic responses were defined as follows: complete, Ph 0%; partial, Ph 1% to 34%; minor, Ph 35% to 90%. A major cytogenetic response included complete and partial cytogenetic responses, that is, Ph below 35%. A partial hematologic response (PHR) was similar to CHR except for persistence of peripheral immature cells (blasts, promyelocytes, myelocytes) or persistence but more than 50% improvement in splenomegaly or in degree of thrombocytosis. Toxicities were graded according to the National Cancer Institute (NCI) Common Toxicity Criteria.

Among the 261 patients treated, 54 patients fulfilled the above resistance/relapse criteria, and agreed to be treated at the higher dose. Their characteristics are shown in Table1. Their median age was 58 years (range, 24-77 years). The median time from diagnosis to therapy was 32 months (range, 5-131 months), and the median duration of imatinib mesylate therapy was 13 months (range, 3-27 months). Forty-seven patients received 800 mg imatinib mesylate daily, and 7 received 600 mg imatinib mesylate daily. Response to standard-dose imatinib mesylate are detailed by category in Table2.

Among 9 patients who lost their complete (n = 3) or partial cytogenetic response (n = 6), 5 (56%) achieved a major cytogenetic response (complete, 3; partial, 2).

Among 4 patients who had loss of a minor cytogenetic response, 2 achieved a complete and 1 a partial cytogenetic response. The fourth patient has improved from 100% Ph to 40%.

Twenty-one patients had cytogenetic resistance. Among 14 patients without any cytogenetic response, 1 achieved a partial cytogenetic response. Three additional patients have improved from 100% Ph⁺ to 45%, 45%, and 55% Ph⁺. Among 7 patients with a minor cytogenetic response, 1 achieved a complete and 4 a partial cytogenetic response.

Fourteen patients were treated for hematologic relapse: 6 achieved CHR, and 4 PHR; 1 has achieved a minor cytogenetic response (Ph 100% to 50%). Six patients were treated for hematologic resistance: 3 achieved CHR, and 1 of them had a partial cytogenetic response.

Thus, among 20 patients treated for active CML disease not responding to standard-dose imatinib mesylate, 13 (65%) achieved a hematologic response (9 CHR, 4 PHR), but only 1 (5%) has achieved a major cytogenetic response. Among 34 patients treated for cytogenetic resistance or relapse, 13 patients (38%) have achieved a major cytogenetic response: 6 complete and 7 partial. Six patients have shown minor responses or improvements, and 4 continue on therapy. The details of cytogenetic responses are shown in Table3.

Twenty-two patients had reductions in the dose of imatinib mesylate from 800 mg to 600 or 400 mg owing to severe pancytopenia (n = 13) or other toxicities (n = 9; fatigue, gastrointestinal, skin rash, bone aches, edema, and dizziness). The median actual dose delivered at 3 (n = 47) and 6 (n = 41) months was 800 mg. After a median follow-up of longer than 8 months (range, 1-26+ months), 38 patients remained on imatinib mesylate in chronic phase while 16 patients discontinued therapy because of hematologic (n = 8) or cytogenetic (n = 2) resistance, transformation to accelerated (n = 3) or blastic phase (n = 2), or sudden unrelated death (n = 1). Eleven patients have died, 10 following discontinuation of imatinib mesylate, and 1 while on imatinib mesylate (infection, 2; cardiac failure, 2; blastic phase, 4; bleeding, 1; other, 2).

Overcoming resistance to imatinib mesylate therapy in CML can be achieved through several hypothetical approaches. These include increasing the dose of imatinib mesylate, using inhibitors of downstream pathways to Bcr-Abl (eg, farnesyl transferase inhibitors), combining imatinib mesylate with established (interferon-alpha, cytarabine), or investigational (homoharringtonine, decitabine) therapies, or circumventing specific mechanisms of resistance (eg, multidrug resistance [MDR] blocking agents). The present analysis demonstrates that higher doses of imatinib mesylate may reinduce hematologic response or improve the cytogenetic responses in some patients whose CML had shown hematologic or cytogenetic resistance to standard-dose imatinib mesylate. Although we cannot rule out the possibility that responses would occur with continuation of standard-dose imatinib mesylate, many of the responders had already lost their response. In addition, the larger experience with imatinib mesylate suggests that hematologic responses typically occur within 3 months, and major CG responses occur infrequently after 12 months of therapy.5 All patients with hematologic failure had received imatinib mesylate for at least 3 months, and those with cytogenetic failure had received imatinib mesylate for at least 12 months. Some patients in this report have achieved only a minor cytogenetic response with short follow-up, and it is possible that some of these responses may become major responses with longer therapy.

Several mechanisms of resistance have been described after imatinib mesylate therapy; these include clonal evolution, point mutations, and overexpression and amplification of Bcr/Abl. The mechanism of resistance to standard dose was not evaluated in this study. This could be an important factor in determining which patients might respond to increasing doses of imatinib mesylate, and this should be addressed in future studies.

The preclinical rationale, the positive current clinical experience, and the experience with higher doses of imatinib mesylate (600 mg) in accelerated phase, all encourage the investigation of high-dose imatinib mesylate as frontline therapy in patients with newly diagnosed CML or in late chronic-phase CML, to obtain better and more durable complete cytogenetic and, possibly, molecular remissions.23 24 

J.C. is a Clinical Research Scholar for The Leukemia and Lymphoma Society.