|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Blood, 1 October 2003, Vol. 102, No. 7, pp. 2702-2703 Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional dosesCorrespondence: John M. Goldman, Department of Haematology, Imperial College School of Medicine at Hammersmith Hospital, Ducane Road, W12 ONN London, United Kingdom; e-mail: j.goldman{at}ic.ac.uk
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-
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- 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 References
Response:Dose escalation of imatinib may improve responses in patients with CML who fail standard-dose imatinibWe 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{at}mdanderson.org
References
  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
(IFN-
