Imatinib at the standard dose of 400 mg daily induces complete cytogenetic remissions (CCyRs) in 40% of patients with chronic myeloid leukemia (CML) in chronic phase who had previously failed interferon-α (IFN-α),1 and in 75% of newly diagnosed patients.2 However, the optimal treatment for patients who do not achieve or who lose a CCyR is uncertain. It is theoretically possible that such patients could benefit from higher doses of imatinib. Kantarjian et al3 recently reported that 19 (56%) of 34 patients classified as cytogenetically resistant on imatinib at 400 mg daily subsequently improved cytogenetically when the imatinib was increased to 600 or 800 mg daily; they therefore advocated this strategy for patients with primary or acquired resistance to imatinib. We report here results of increasing imatinib dosage in patients who failed to obtain CCyR on 400 mg/d.
We studied 36 consecutive patients with CML in chronic phase in complete hematologic response whose imatinib dosage was increased when they failed to achieve a CCyR on an initial dose of 400 mg daily; 9 (25%) were newly diagnosed and 27 (75%) were IFN-α failures. The median time from starting imatinib to dose increase was 383 days (range, 366-1083 days) and the median time on the increased dose (to latest follow-up) was 416 days (range, 212-790 days). At the time of dose increase, 18 patients were 100% Philadelphia positive and the 18 had varying degrees of Philadelphia negativity. Of the 36 patients, 23 (64%) were then treated with imatinib at 600 mg/d, 12 (33%) received 800 mg/d, and 1 (3%) received 1000 mg/d.
We judged the increased dose to have been effective if there was a change from partial cytogenetic response (PCyR) to CCyR, or from minor cytogenetic response (MiCyR) to PCyR or CCyR, or from no cytogenetic response to MiCyR, PCyR, or CCyR. Fourteen patients (39%) improved their cytogenetic responses and 7 (19%) achieved CCyR. Unfortunately, many of these responses were short lasting, and at latest follow-up 6 (43%) had lost their best response. At latest follow-up only 9 (25%) still had sustained improvement including 5 (14%) patients who remained in CCyR.
In multivariate analysis the only factor that predicted improved cytogenetics was the level of Philadelphia positivity when the higher dose was started. Of 18 patients who were 100% Philadelphia positive at that time only 1 (6%) had a sustained cytogenetic improvement and none achieved CCyR; conversely, of the 18 patients who had some degree of Philadelphia negativity, 8 (44%) had a sustained response and 5 (28%) achieved CCyR (P = .018 and P = .045, respectively).
We do not believe that our data support the notion that increasing the dose of imatinib can durably overcome primary or acquired resistance, particularly in patients who fail to obtain any degree of Philadelphia negativity on 400 mg daily. Our experience and that of Zonder et al4 contrast with that of Kantarjian et al.3 We conclude that there is little to be gained by increasing the imatinib dose for such patients; rather, one should consider adding other agents to the imatinib or possibly allogeneic stem cell transplantation.5
Dose escalation of imatinib may improve responses in patients with CML who fail standard-dose imatinib
We are gratified to note that Marin et al have confirmed our study regarding the clinical benefit of increasing the dose of imatinib in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) not in complete cytogenetic remission (CCyR).1 In our report, 13 (38%) of 34 patients treated achieved a major cytogenetic response (MCR). Zonder et al2 reported an MCR in 6 (38%) of 16 patients (2 additional patients with clonal evolution lost the additional clone, remaining 100% Ph-positive). These results are similar to those of Marin et al: 14 (39%) of 36 patients improved their cytogenetic response upon increasing the dose. The issue at question is the durability of these responses. Marin et al report that 43% of patients have lost their response, while 9 (25%) had sustained improvement (5 [14%] with CCyR). Zonder et al2 reported 3 of 6 responding patients maintaining their response for 18+ months. We reviewed the status of the patients that had responded in our study. With a median follow-up of 18 months, 8 (62%) of 13 patients who achieved an MCR still have an MCR (3 have a CCyR).Among 6 patients that had achieved a CCyR, 2 have now a partial response, and 1 who had a partial response has now achieved a CCyR. The median duration of the improved response is 11 months (range, 1 to 24+ months). In addition, 4 nonresponding patients in our initial report have now achieved a cytogenetic response (3 partial, 1 minor).
Thus, the 3 series support our conclusion that “higher dose imatinib mesylate may overcome disease-poor response to conventional doses.”1 The 35% to 40% response rate, with 25% to 50% durable responses speak to that. Zonder et al reached a similar conclusion: “consideration of increasing the dose to 800 mg/d for inadequate cytogenetic response after this amount of time (6 months) seems reasonable.”2 The notion of adding other agents to imatinib is interesting. We and other investigators are pursuing this approach for imatinib-resistant CML. Patients would benefit from clinical trials investigating these combinations, but to date, there is no data to suggest that any combination is superior to what is obtained with increasing the dose of imatinib. In addition, most of these options are investigational, and many patients are unfortunately not offered participation in clinical trials. The possibility of stem cell transplantation is obviously attractive, but a majority of patients are not candidates for, or refuse, transplantation. That was the case for patients in our series. Therefore, we believe the 3 series support our conclusion that these data “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.”1 Zonder et al reached a similar conclusion: “These results also suggest that future trials explore the role of initial treatment with higher doses of imatinib mesylate to determine whether the cytogenetic CR rate can be improved.”2 Our early observations3,4 with high-dose imatinib suggest this approach may be valuable.
Correspondence: Jorge Cortes, Leukemia Departmetnt, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030; e-mail: jcortes@mdanderson.org
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