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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-05-1451.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Leukemia and Bioimmunotherapy,
University of Texas M. D. Anderson Cancer Center, Houston, TX.
We investigated whether increasing the dose of imatinib mesylate
might overcome drug resistance in patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous
leukemia (CML) whose disease manifests relapse or refractoriness to
therapy. Fifty-four patients with Ph+ CML in chronic phase
and with hematologic or cytogenetic resistance or relapse on imatinib
mesylate therapy at 400 mg orally daily were treated with a
higher dose of 400 mg orally twice daily (800 mg daily, 47 patients; or
600 mg daily increased from 300 mg daily, 7 patients). Among 20 patients treated for hematologic resistance or relapse, 13 (65%)
achieved a complete (n = 9) or partial (n = 4) hematologic
response, but only 1 had a cytogenetic partial response (Ph
reduction from 100% to 10%) and 1 had a minor response (Ph reduction
from 100% to 50%). Among 34 patients treated for cytogenetic
resistance or relapse, 19 (56%) achieved a complete (n = 6) or
partial (n = 7) cytogenetic response. We conclude that higher doses
of imatinib mesylate may overcome disease-poor response to
conventional doses and that this approach deserves further evaluation as frontline therapy for newly diagnosed CML.
(Blood. 2003;101:473-475) 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- 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 Table
1. 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 Table
2.
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 Table
3.
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.
Submitted July 30, 2002; accepted August 19, 2002.
Prepublished online as Blood First Edition Paper, September 12, 2002; DOI 10.1182/blood-2002-05-1451.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jorge Cortes, Department of Leukemia, Box 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org.
1. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566[Medline] [Order article via Infotrieve]. 2. Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res. 1998;4:1661-1672[Abstract].
3.
Druker BJ, Talpaz M, Resta DJ, et al.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med.
2001;344:1031-1037
4.
Druker BJ, Sawyers CL, Kantarjian H, et al.
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med.
2001;344:1038-1042
5.
Kantarjian H, Sawyers C, Hochhaus A, et al.
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.
N Engl J Med.
2002;346:645-652
6.
Talpaz M, Silver R, Druker B, et al.
Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study.
Blood.
2002;99:1928-1937
7.
Kantarjian H, Cortes J, O'Brien S, et al.
Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase.
Blood.
2002;99:3547-3553 8. Sawyers C, Hochhaus A, Feldman E, et al. A phase II study to determine the safety and anti-leukemic effects of STI571 in patients with Philadelphia chromosome positive chronic myeloid leukemia in myeloid blast crisis [abstract]. Blood. 2000;96:503a.
9.
Kantarjian H, Talpaz M, O'Brien S, et al.
Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results.
Clin Cancer Res.
2002;8:2177-2187
10.
Weisberg E, Griffin JD.
Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines.
Blood.
2000;95:3498-3505
11.
Mahon FX, Deininger MWN, Schultheis B, et al.
Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanism of resistance.
Blood.
2000;96:1070-1079
12.
Gorre ME, Mohammed M, Ellwood K, et al.
Clinical resistance to STI571 cancer therapy caused by BCR-ABL gene mutation or amplification.
Science.
2001;293:876-880 13. Hochhaus A, Kreil S, Corbin A, et al. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001;293:2163[CrossRef][Medline] [Order article via Infotrieve].
14.
Tipping A, Manhon FX, Lagarde V, Goldman JM, Melo JV.
Restoration of sensitivity to STI571 in STI571-resistant chronic myeloid leukemia cells.
Blood.
2001;98:3864-3867 15. Vigneri P, Wang JYJ. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001;7:228-234[CrossRef][Medline] [Order article via Infotrieve]. 16. von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2001;359:487-491[CrossRef]. 17. Gambacorti-Passerini C, Barni R, Le Coutre P. Role of alpha 1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemia cells to the Abl inhibitor STI571. J Natl Cancer Inst. 2000;18;92:1641-1650[CrossRef].
18.
Le Coutre P, Tassi E, Varella-Garcia M, et al.
Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification.
Blood.
2000;95:1758-1766
19.
Branford S, Rudzki Z, Walsh S, et al.
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance.
Blood.
2002;99:3472-3475
20.
Kantarjian HM, Talpaz M, Smith TL, et al.
Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia.
J Clin Oncol.
2000;18:3513-3521 21. Kantarjian HM, O'Brien SM, Keating M, et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia. 1997;11:1617-1620[CrossRef][Medline] [Order article via Infotrieve].
22.
Peters D, Hoover R, Gerlach M, et al.
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.
Blood.
2001;97:1404-1412 23. Cortes J, Talpaz M, Giles F, et al. High-dose imatinib mesylate (STI571, gleevec) in patients with chronic myeloid leukemia (CML) resistant or intolerant to interferon-alpha (IFN) [abstract]. Proc ASCO. 2002;21:262a. 24. Kantarjian H, Cortes J, O'Brien S, et al. High rates of early major and complete cytogenetic responses with imatinib mesylate therapy given at 400 mg or 800 mg orally daily in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph + CML-CP) [abstract]. Proc ASCO. 2002;21:261a.
© 2003 by The American Society of Hematology.
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  M. Baccarani, G. Rosti, F. Castagnetti, I. Haznedaroglu, K. Porkka, E. Abruzzese, G. Alimena, H. Ehrencrona, H. Hjorth-Hansen, V. Kairisto, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study Blood, May 7, 2009; 113(19): 4497 - 4504. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tyler Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia Ann. Pharmacother., May 1, 2009; 43(5): 920 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Castagnetti, F. Palandri, M. Amabile, N. Testoni, S. Luatti, S. Soverini, I. Iacobucci, M. Breccia, G. Rege Cambrin, F. Stagno, et al. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party Blood, April 9, 2009; 113(15): 3428 - 3434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Jabbour, H. M. Kantarjian, D. Jones, J. Shan, S. O'Brien, N. Reddy, W. G. Wierda, S. Faderl, G. Garcia-Manero, S. Verstovsek, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy Blood, March 5, 2009; 113(10): 2154 - 2160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Jabbour, J. E. Cortes, and H. M. Kantarjian Suboptimal Response to or Failure of Imatinib Treatment for Chronic Myeloid Leukemia: What Is the Optimal Strategy? Mayo Clin. Proc., February 1, 2009; 84(2): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ramirez and J. F. DiPersio Therapy Options in Imatinib Failures Oncologist, April 1, 2008; 13(4): 424 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. Cho and J. H. Kim In Reply J. Clin. Oncol., March 1, 2008; 26(7): 1184 - 1186. [Full Text] [PDF]
|
|
|
|
|
|
H. M Marshall and J. M Hammond Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia Ann. Pharmacother., February 1, 2008; 42(2): 259 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Brave, V. Goodman, E. Kaminskas, A. Farrell, W. Timmer, S. Pope, R. Harapanhalli, H. Saber, D. Morse, J. Bullock, et al. Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate Clin. Cancer Res., January 15, 2008; 14(2): 352 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Cortes Imatinib and Beyond--Therapy of CML in 2008 ASCO Educational Book, January 1, 2008; 2008(1): 307 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Frame New strategies in controlling drug resistance in chronic myeloid leukemia Am. J. Health Syst. Pharm., December 15, 2007; 64(24_Supplement_15): S16 - S21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. White, V. A. Saunders, P. Dang, J. Engler, A. Venables, S. Zrim, A. Zannettino, K. Lynch, P. W. Manley, and T. Hughes Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity Blood, December 1, 2007; 110(12): 4064 - 4072. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Goldman How I treat chronic myeloid leukemia in the imatinib era Blood, October 15, 2007; 110(8): 2828 - 2837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kantarjian, R. Pasquini, N. Hamerschlak, P. Rousselot, J. Holowiecki, S. Jootar, T. Robak, N. Khoroshko, T. Masszi, A. Skotnicki, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial Blood, June 15, 2007; 109(12): 5143 - 5150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Guilhot, J. Apperley, D.-W. Kim, E. O. Bullorsky, M. Baccarani, G. J. Roboz, S. Amadori, C. A. de Souza, J. H. Lipton, A. Hochhaus, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase Blood, May 15, 2007; 109(10): 4143 - 4150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Chabner Phase II Cancer Trials: Out of Control? Clin. Cancer Res., April 15, 2007; 13(8): 2307 - 2308. [Full Text] [PDF]
|
|
|
|
|
|
S. Picard, K. Titier, G. Etienne, E. Teilhet, D. Ducint, M.-A. Bernard, R. Lassalle, G. Marit, J. Reiffers, B. Begaud, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia Blood, April 15, 2007; 109(8): 3496 - 3499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P. Shah Medical Management of CML Hematology, January 1, 2007; 2007(1): 371 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hughes ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring Hematology, January 1, 2006; 2006(1): 211 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Golemovic, S. Verstovsek, F. Giles, J. Cortes, T. Manshouri, P. W. Manley, J. Mestan, M. Dugan, L. Alland, J. D. Griffin, et al. AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, Has In vitro Activity against Imatinib-Resistant Chronic Myeloid Leukemia Clin. Cancer Res., July 1, 2005; 11(13): 4941 - 4947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W.N. Deininger Management of Early Stage Disease Hematology, January 1, 2005; 2005(1): 174 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P. Shah Loss of Response to Imatinib: Mechanisms and Management Hematology, January 1, 2005; 2005(1): 183 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Kantarjian, J. E. Cortes, S. O'Brien, R. Luthra, F. Giles, S. Verstovsek, S. Faderl, D. Thomas, G. Garcia-Manero, M. B. Rios, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-{alpha} Blood, October 1, 2004; 104(7): 1979 - 1988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Radich Targeting ALL leukemia Blood, September 1, 2004; 104(5): 1235 - 1236. [Full Text] [PDF]
|
|
|
|
|
|
M. Harata, Y. Soda, K. Tani, J. Ooi, T. Takizawa, M. Chen, Y. Bai, K. Izawa, S. Kobayashi, A. Tomonari, et al. CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells Blood, September 1, 2004; 104(5): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Stone Optimizing Treatment of Chronic Myeloid Leukemia: A Rational Approach Oncologist, June 1, 2004; 9(3): 259 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Guilhot Indications for Imatinib Mesylate Therapy and Clinical Management Oncologist, June 1, 2004; 9(3): 271 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kantarjian, M. Talpaz, S. O'Brien, G. Garcia-Manero, S. Verstovsek, F. Giles, M. B. Rios, J. Shan, L. Letvak, D. Thomas, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia Blood, April 15, 2004; 103(8): 2873 - 2878. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
M. E. O'Dwyer, M. J. Mauro, C. Blasdel, M. Farnsworth, G. Kurilik, Y.-C. Hsieh, M. Mori, and B. J. Druker Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate Blood, January 15, 2004; 103(2): 451 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O'Brien, A. Tefferi, and P. Valent Chronic Myelogenous Leukemia and Myeloproliferative Disease Hematology, January 1, 2004; 2004(1): 146 - 162. [Abstract] [Full Text] [PDF]
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|
|
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D. Marin, J. M. Goldman, E. Olavarria, J. F. Apperley, J. Cortes, and H. Kantarjian Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses Blood, October 1, 2003; 102(7): 2702 - 2703. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Zonder, P. Pemberton, H. Brandt, A. N. Mohamed, and C. A. Schiffer The Effect of Dose Increase of Imatinib Mesylate in Patients with Chronic or Accelerated Phase Chronic Myelogenous Leukemia with Inadequate Hematologic or Cytogenetic Response to Initial Treatment Clin. Cancer Res., June 1, 2003; 9(6): 2092 - 2097. [Abstract] [Full Text] [PDF]
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G. Marcucci, D. Perrotti, and M. A. Caligiuri Understanding the Molecular Basis of Imatinib Mesylate Therapy in Chronic Myelogenous Leukemia and the Related Mechanisms of Resistance: Commentary re: A. N. Mohamed et al., The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations. Clin. Cancer Res., 9: 1333-1337, 2003. Clin. Cancer Res., April 1, 2003; 9(4): 1248 - 1252. [Full Text] [PDF]
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|
|
|
|
|
J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
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