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Previous Volume 346:645-652 February 28, 2002 Number 9 Next

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ABSTRACT

Background Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase.

Methods A total of 532 patients with late–chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated.

Results Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred.

Conclusions Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

CML is potentially curable with allogeneic stem-cell transplantation, but fewer than 30 percent of patients have suitably matched donors.^1,3,7,13 Treatment with interferon alfa can induce a complete cytogenetic response in 5 to 20 percent of patients and result in longer survival than that achievable with chemotherapy, but it is associated with serious toxic effects.^1,3,13,14,15 Patients in whom interferon therapy fails are usually treated with hydroxyurea, busulfan, or investigational agents. The rate of hematologic response with these second-line agents is approximately 50 percent, but cytogenetic responses are uncommon. Furthermore, the rate of response decreases rapidly as the time from the initial diagnosis to the initiation of second-line therapy increases, particularly when such therapy is started in the late chronic phase, defined as more than 12 months after the initial diagnosis.

Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland), formerly called STI571, is a potent and selective competitive inhibitor of the BCR-ABL protein tyrosine kinase.^{16,17,18,19,20} In a phase 1 dose-escalation study, daily doses of 300 mg or more of imatinib induced durable hematologic responses in nearly all patients with chronic-phase CML with minimal toxic effects.²¹ Activity was also observed in patients whose CML was in the blastic phase.²² We conducted this phase 2 study to characterize the efficacy and safety profiles of imatinib in a large group of patients with chronic-phase CML in whom previous interferon therapy had failed.

Methods

Study Patients

Patients were eligible for the study if they were 18 years of age or older and had chronic-phase, Ph-chromosome–positive CML that had failed to respond to interferon therapy according to one of the criteria described below. The chronic phase was defined by the presence of less than 15 percent blasts, less than 20 percent basophils, and less than 30 percent blasts plus promyelocytes in the peripheral blood and marrow and a platelet count of at least 100,000 per cubic millimeter. Hematologic failure was defined as either hematologic resistance (failure to achieve a complete hematologic response after at least six months of interferon treatment) or relapse after a complete hematologic response had been achieved, with white-cell counts increased to at least 20,000 per cubic millimeter during interferon therapy. Whether they had hematologic or cytogenetic failure, patients were allowed to receive hydroxyurea for up to 50 percent of the duration of interferon treatment. Cytogenetic failures were defined as either cytogenetic resistance (at least 65 percent of cells in metaphase were Ph-chromosome–positive after at least one year of interferon therapy), or relapse after a major cytogenetic response had been achieved. A relapse was considered to have occurred if the proportion of Ph-chromosome–positive cells in metaphase increased by at least 30 percent or to at least 65 percent. Intolerance of interferon was defined by the presence of any nonhematologic toxic effect of grade 3 or higher (as defined by the National Cancer Institute Common Toxicity Criteria, in which a grade of 0 indicates no adverse effects and a grade of 5 life-threatening effects) that persisted for more than one month during therapy with interferon at a dose of 25 million units or more per week.

Patients were required to have levels of liver aminotransferases, serum bilirubin, and serum creatinine that were no higher than twice the upper limit of normal. Women with childbearing potential were required to have a negative pregnancy test before starting treatment, and all patients at risk were required to use barrier contraceptive measures. Patients were excluded from the study if their Eastern Cooperative Oncology Group performance score was 3 or higher (poor), or if they were in New York Heart Association functional class III or IV. Patients were excluded if they had received treatment with hydroxyurea within 7 days, interferon or cytarabine within 14 days, or any other investigational agent within 28 days before starting the study treatment.

All patients gave written informed consent according to institutional regulations. The study was performed in accordance with the Declaration of Helsinki.

Study Design and Treatment

In this single-group multicenter, phase 2 trial, patients received imatinib in a daily oral dose of 400 mg. An increase to 400 mg twice daily was permitted in patients in whom a complete hematologic response had not been achieved after 3 months of treatment, those whose disease relapsed within 3 months after the achievement of a complete hematologic response, and those in whom a major cytogenetic response had not been achieved after 12 months of therapy.

The study was designed by the investigators and representatives of the sponsor, Novartis. The data were collected with the data management and statistical support systems of Novartis and analyzed and interpreted by a statistician from Novartis in close collaboration with all the investigators. All academic investigators had access to the data. The paper was written by a committee consisting of Drs. Kantarjian, Sawyers, and Druker, along with three Novartis employees (Resta, Capdeville, and Zoellner). All academic authors received grant support from Novartis for the conduct of the study. Cytogenetic studies were performed at the cytogenetic laboratories of the individual investigators, and were centrally reviewed and audited by employees of Novartis.

Dose Modifications because of Side Effects

If grade 2 nonhematologic toxic effects occurred and did not resolve during treatment, therapy was interrupted until the effects had been ameliorated to grade 1 or better and then resumed at the original dose. If grade 2 toxic effects recurred, treatment was again interrupted until the effects had been ameliorated to grade 1 or better and then resumed at a reduced daily dose of 300 mg. If grade 3 or 4 nonhematologic toxic effects occurred, therapy was interrupted until the effects had been ameliorated to grade 1 or better and then resumed at the reduced daily dose of 300 mg. If a patient had a grade 3 or 4 hematologic toxic effect (a neutrophil count of less than 1000 per cubic millimeter, or a platelet count of less than 50,000 per cubic millimeter), therapy was interrupted until the effect was ameliorated to grade 2 or better and then resumed at the same dose if the effect had reached the grade 2 level within two weeks and at a reduced daily dose of 300 mg if it had persisted at grade 3 or 4 for more than two weeks. Patients with anemia received blood transfusions at the discretion of the investigator.

Anticancer drugs were not administered concomitantly. Treatments with anagrelide or leukapheresis were permitted during the first three weeks of the study treatment.

Evaluation of Patients

A complete blood count and a differential blood count were obtained weekly for the first 12 weeks, every other week for the next 12 weeks, and every 6 weeks thereafter. Bone marrow morphology and cytogenetics were evaluated every 12 weeks, when extramedullary involvement was also evaluated by physical examination. Adverse effects were evaluated at each visit and graded according to the National Cancer Institute Common Toxicity Criteria.

The primary efficacy end point was the rate of major cytogenetic response, which was categorized as either complete (0 percent Ph-chromosome–positive cells in metaphase in bone marrow) or partial (1 to 35 percent Ph-chromosome–positive cells in metaphase). Other categories of cytogenetic response were minor response (36 to 65 percent Ph-chromosome–positive cells in metaphase), minimal response (66 to 95 percent Ph-chromosome–positive cells in metaphase), and no response (more than 95 percent Ph-chromosome–positive cells in metaphase). Evaluation of the cytogenetic response was based on the examination of at least 20 cells in metaphase in marrow samples.

Secondary efficacy end points were the rate of complete hematologic response, the time to progression, and overall survival. Complete hematologic response was defined by a white-cell count of less than 10,000 per cubic millimeter, a platelet count of less than 450,000 per cubic millimeter, the presence of less than 5 percent myelocytes and metamyelocytes and less than 20 percent basophils in peripheral blood, the absence of blasts and promyelocytes in peripheral blood, and the absence of extramedullary involvement. Accelerated-phase CML was defined by the presence of 15 to 29 percent blasts in blood or marrow, the presence of at least 30 percent blasts plus promyelocytes in blood or marrow, or the presence of at least 20 percent basophils in blood. Blast-phase CML was defined by the presence of at least 30 percent blasts in blood or marrow or the presence of extramedullary blastic disease. Time to progression was defined as the time from the start of treatment to the onset of an accelerated or blastic phase, discontinuation of therapy because of unsatisfactory therapeutic effect, or death. Survival was calculated from the beginning of therapy until the time of death from any cause.

Statistical Analysis

We aimed to demonstrate a major cytogenetic response rate of at least 20 percent among patients with previous hematologic failure and at least 30 percent among those with previous cytogenetic failure. On the basis of a Fleming procedure for single-stage, single-group testing (one-sided alpha, 0.025; power, 90 percent), sample sizes of at least 132 patients with previous hematologic failure and 79 with previous cytogenetic failure were considered necessary. Allowing for withdrawals, the sample size was set at 150 patients with previous hematologic failure and 100 patients with previous cytogenetic failure. In addition, we anticipated enrollment of up to 100 patients with an intolerance to interferon, so that we could study the activity of imatinib in this population of patients. Patients who discontinued treatment before a response was reported were counted as not having had a response. Time to progression and survival were computed with the use of standard Kaplan–Meier methods.

Univariate and multivariate analyses were performed to test the associations between potential prognostic factors and a major cytogenetic response. The chi-square test was used to identify factors with prognostic value at a significance level of less than 0.2; these factors were then included as terms in a multivariate regression model. Factors whose association with major cytogenetic response was not significant at a level of less than 0.1 in multivariate analysis were removed; those remaining in the multivariate model were interpreted as independently predictive of major cytogenetic response.

Results

Patients and Treatment

A total of 532 patients were enrolled at 28 centers between December 1999 and May 2000; data were collected through July 31, 2001. After central review of data, the diagnosis of chronic-phase CML was confirmed in 454 patients (85 percent). Such a diagnosis could not be confirmed for 17 patients who had characteristics of the accelerated phase of CML, 12 patients who had characteristics of the blast phase (for 11 of whom this diagnosis was based on enlarged lymph nodes only), and 49 patients with missing data.

The characteristics of the patients were typical of patients with interferon-treated, late–chronic-phase CML (Table 1). The median duration of treatment with imatinib was 17.9 months (range, 0.5 to 20.3); 90 percent of the patients were treated for at least 12 months. Of the 532 patients who were enrolled, 87 percent are still receiving imatinib treatment, and 71 patients (13 percent) have discontinued therapy because of disease progression (in 42 patients), adverse events (in 12 patients), abnormal laboratory findings (in 1 patient), protocol violations (in 3 patients), withdrawal of consent (in 7 patients), administrative reasons (in 1 patient), or death (in 5 patients).

View this table: [in this window] [in a new window]   Table 1. Base-Line Characteristics of the Patients.

 
Efficacy

Of the 454 patients with a confirmed diagnosis of chronic-phase CML, 272 (60 percent) had a major cytogenetic response and 343 (76 percent) had a major, minor, or minimal cytogenetic response. Of the 272 patients with a major cytogenetic response, 188 (69 percent; 41 percent of the total) had a complete response (Table 2). Cytogenetic response rates were highest among patients who had had a cytogenetic relapse while receiving interferon and lowest among patients with hematologic resistance (P=0.001 by the chi-square test). The time to onset of a major cytogenetic response ranged from 2.4 to 19 months.

View this table: [in this window] [in a new window]   Table 2. Cytogenetic and Hematologic Responses.

 
Of the 272 patients in whom a major cytogenetic response was achieved, 228 (84 percent) continue to have such a response as of last follow-up, whereas the other 44 (16 percent) had a cytogenetic relapse (defined as at least 65 percent Ph-chromosome–positive cells in metaphase or an increase of at least 30 percent from the previous study). The median time to cytogenetic relapse was 12 months (range, 6 to 19) from the start of therapy and 6 months (range, 3 to 14) from the initial achievement of a major cytogenetic response. Of these 44 patients, 5 had progression to an accelerated or blast phase of CML and have discontinued treatment with imatinib. The remaining 39 patients are still receiving the drug. In 15 of these 39 patients, the cytogenetic relapse had reverted to a major cytogenetic response by the time of the karyotypic analysis.

Complete hematologic responses were reported for 430 of the 454 patients studied (95 percent) (Table 2). The median time to a complete hematologic response was 0.7 month; 86 percent of patients who had a response did so within 3 months.

The estimated rate of progression-free survival at 18 months was 89 percent (95 percent confidence interval, 86 to 92 percent), and was similar for the three subgroups of patients (those with hematologic failure, those with cytogenetic failure, and those with intolerance to interferon) (Figure 1). The achievement of a cytogenetic response at three months was associated with a higher rate of progression-free survival, according to a landmark analysis (Figure 2).

View larger version (5K): [in this window] [in a new window]   Figure 1. Time to Progression to Accelerated Phase or Blast Phase of CML. Of the 454 patients studied, disease had progressed to the accelerated or blast phase in 47 (10.4 percent) by the time of the analysis. However, only 35 of these 47 patients discontinued medication because of this progression. The estimated rate of progression-free survival was 91.9 percent (95 percent confidence interval, 89.4 to 94.5) at 12 months and 89.2 percent (95 percent confidence interval, 86.2 to 92.3) at 18 months. Tick marks indicate the dates on which data were censored for a given patient.

 

View larger version (6K): [in this window] [in a new window]   Figure 2. Landmark Analysis of Time to Progression According to the Cytogenetic Response at Three Months. All patients remaining in the study at three months were categorized according to the presence or absence of a major cytogenetic response, and these subgroups were analyzed for time to progression (as defined in the Methods section). The analysis included the 343 patients in whom at least 20 cells in metaphase had been cytogenetically analyzed by three months. Of these 343 patients, 152 had a major cytogenetic response (no more than 35 percent Ph-chromosome–positive cells in metaphase). Whereas CML progressed in only 5 of the patients with a major cytogenetic response (3.3 percent), disease progression has been documented in 22 of the 191 patients without such a response (11.5 percent; P=0.005 by the log-rank test). Tick marks indicate the dates on which data were censored for a given patient.

 
A total of 149 patients had their dose increased during the study. Among these patients, a hematologic response was achieved in 14 (9 percent) after the dose was increased, and a cytogenetic response was achieved in 17 (11 percent). The estimated survival rate at 18 months for the 454 patients studied was 95 percent and was similar for the three subgroups of patients (data not shown).

Prognostic Factors

Associations between base-line variables and the rates of major cytogenetic response are shown in Table 3. Data for two base-line variables (the percentage of Ph-chromosome–positive metaphases and the presence or absence of clonal evolution, defined as the presence of cytogenetic abnormalities other than a variant Ph chromosome, loss of the Y chromosome, or constitutional chromosomal aberrations) were unavailable for several patients. Therefore, we performed two separate multivariate analyses — one excluding these factors (Table 3) and one considering all factors but excluding the patients with missing data.

View this table: [in this window] [in a new window]   Table 3. Prognostic Factors Associated with a Major Cytogenetic Response According to a Multivariate Analysis.

 
According to univariate analyses, 14 base-line variables were predictive of higher rates of major cytogenetic response, including response to previous interferon therapy (the presence or absence of hematologic or cytogenetic relapse or resistance). According to the multivariate analyses, the five base-line variables that independently predicted a high rate of major cytogenetic response were the absence of blasts in peripheral blood, a hemoglobin level of more than 12 g per deciliter, the presence of less than 5 percent blasts in marrow, a time from diagnosis of CML to start of treatment of less than one year, and a history of cytogenetic relapse during interferon therapy. The inclusion of clonal evolution as a factor did not change the outcome of the multivariate model; the predictive value of the percentage of Ph-chromosome–positive cells in metaphase at the start of treatment was significant (P<0.01).

Efficacy According to the Intention-to-Treat Analysis

The results with regard to efficacy among all 532 enrolled patients were similar to those among the 454 patients with confirmed chronic-phase CML. The rate of major cytogenetic response in the larger group was 60 percent, and the rate of complete hematologic response was 95 percent. At 18 months, the estimated rate of progression-free survival was 88 percent, and estimated survival was 94 percent. The rates of cytogenetic and hematologic responses were similar among the 17 patients with features of accelerated-phase CML (59 percent and 88 percent, respectively) and the 12 with features of blastic-phase CML (75 percent and 92 percent, respectively).

Safety

Common adverse events included superficial edema, nausea, and muscle cramps (Table 4). Grade 3 or 4 events were infrequent; the most common grade 3 or 4 event was weight gain. Grade 3 or 4 neutropenia was noted during the study in 35 percent of the patients, and thrombocytopenia was found in 20 percent of the patients (Table 4). The median time to a first grade 3 or 4 episode of neutropenia was 62 days (range, 8 to 463); the median time to a first grade 3 or 4 episode of thrombocytopenia was 57 days (range, 8 to 581). The median duration of thrombocytopenia was 18 days, and the median duration of neutropenia was 21 days.

View this table: [in this window] [in a new window]   Table 4. Adverse Events Related to Treatment with Imatinib Mesylate.

 
Drug-related adverse events — including thrombocytopenia, nausea, vomiting, fever, hepatic toxic effects, arthralgia, hemorrhagic stroke, exanthem, and rash — led to the discontinuation of therapy in 11 patients (2.1 percent). Serious drug-related adverse events were reported in 29 patients (5.5 percent); these events included rash (in 4 patients), febrile neutropenia (in 4 patients), hepatic toxic effects (in 4 patients), neutropenia, thrombocytopenia, nausea, vomiting, fever, and fluid retention and diarrhea (in 2 patients each). Five patients died during therapy — one from myocardial infarction attributed to preexisting cardiovascular disease, one from a cerebrovascular accident, one from progressive CML, one from subarachnoid hemorrhage, and one from cerebral hemorrhage. Eight patients died within 28 days after the discontinuation of therapy for progressive disease — five from progressive CML, one from sepsis, one from cardiogenic shock, and one from pulmonary embolism.

Discussion

In this phase 2 study of imatinib mesylate in patients with chronic-phase CML in whom treatment with interferon had failed, the rates of major and complete cytogenetic responses were 60 percent and 41 percent, respectively. Treatment was well tolerated; serious drug-related adverse events occurred in less than 6 percent of patients, and hematologic toxic effects were manageable.

The rates of major and complete cytogenetic responses we observed were higher than those reported in patients treated with interferon (15 percent and 5 to 7 percent, respectively) or homoharringtonine, a plant alkaloid, either alone²³ or in combination with low-dose cytarabine.²⁴ The estimated 18-month progression-free survival rate of 89 percent is also higher than in trials of interferon or homoharringtonine.^23,24,25 Our results cannot be attributed to a bias in favor of patients with a favorable prognosis, since the factors associated with a poor prognosis in this trial were similar to those in other studies of patients with CML in the late chronic phase.^23,25 In these published series, the failure of interferon therapy was also predictive of a poor subsequent outcome, with an annual mortality rate of 10 to 20 percent.

In our study, factors associated with a high rate of major cytogenetic response were similar to those identified in previous studies and tend to be associated with less advanced disease or a history of hematologic or cytogenetic responsiveness to treatment with interferon. Anemia, low platelet counts, and high blast counts in peripheral blood or marrow correlated with a poor outcome in this study, as well as in other studies of imatinib in advanced phases of CML.²² Longer follow-up of the patients enrolled in this trial should allow the identification of factors associated with the progression of disease as well as those associated with longer survival.

Because imatinib is well tolerated, it may be feasible to combine it with other agents to treat interferon-resistant CML in the late chronic phase or to optimize the status of the disease before performing allogeneic stem-cell transplantation. In this study, disease progression occurred in nearly 10 percent of patients within 18 months. Regimens that combine imatinib with other agents may improve results further, and ongoing clinical trials are testing the feasibility of these approaches. The activity of imatinib is also being investigated in patients with newly diagnosed CML in a randomized phase 3 study comparing imatinib with standard interferon plus low-dose cytarabine.²⁶

Note added in proof: Updated follow-up data were available for 149 patients as of February 1, 2002 (median follow-up, 26 months). Among these patients, the overall rate of major cytogenetic response was 64 percent, and the rate of complete cytogenetic response was 49 percent. The estimated rate of progression-free survival at 24 months was 87 percent, and the estimated 24-month survival rate was 92 percent. A total of 13 of the 149 patients (9 percent) have died, 9 from progressive disease and 4 from other causes.

Supported by a grant from Novartis Pharmaceuticals, East Hanover, N.J.

Presented in part at the 42nd annual meeting of the American Society of Hematology, San Francisco, December 1–5, 2000.

We are indebted to the coinvestigators, members of the nursing and research staff, the clinical trial monitors, and the data managers and programmers at Novartis for their contributions; to Dr. David Parkinson and Dr. Greg Burke for their support; to Dr. Manuel Litchman for assistance in implementing the protocol; to Marianne Rosamilia, Elisabeth Wehrle, Dr. Sandra Silberman, and Mary Beth Rios for their collaboration; and to Dr. Thomas Brown for assistance in the preparation of the manuscript.

^* Other participating investigators are listed in the Appendix.

Source Information

From the M.D. Anderson Cancer Center, Houston (H.K., M.T.); the University of California at Los Angeles, Los Angeles (C Sawyers); Universitätsklinikum Mannheim der Universität Heidelberg, Mannheim, Germany (A.H.); Centre Hospitalier Universitaire de Poitiers, Poitiers, France (F.G.); Wayne State University, Detroit (C Schiffer); San Gerardo Hospital and National Cancer Institute, Milan, Italy (C.G.-P.); University of Leipzig, Leipzig, Germany (D.N.); Novartis Pharmaceuticals, East Hanover, N.J., and Basel, Switzerland (D.R., R.C., U.Z.); and Oregon Health Sciences University, Portland (B.D.).

Address reprint requests to Dr. Kantarjian at the Department of Leukemia, Box 428, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at hkantarj{at}mdanderson.org.

References

1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340:1330-1340. [Free Full Text]
2. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med 1999;131:207-219. [Free Full Text]
3. Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood 1993;82:691-703. [Free Full Text]
4. Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukemia seen at a referral centre over a 16-year period. Br J Haematol 1997;96:111-116. [CrossRef][Web of Science][Medline]
5. Speck B, Bortin MM, Champlin R, et al. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet 1984;1:665-668. [Medline]
6. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988;25:49-61. [Medline]
7. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-293. [CrossRef][Medline]
8. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960;132:1497-1497. 
9. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature 1990;344:251-253. [CrossRef][Medline]
10. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990;247:824-830. [Free Full Text]
11. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A 1990;87:6649-6653. [Erratum, Proc Natl Acad Sci U S A 1990;87:9072.] [Free Full Text]
12. Elefanty AG, Hariharan IK, Cory S. bcr/abl, The hallmark of chronic myeloid leukemia in man, induces multiple haematopoietic neoplasms in mice. EMBO J 1990;9:1069-1078. [Web of Science][Medline]
13. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood 1999;94:1517-1536. [Free Full Text]
14. Kantarjian HM, O'Brien S, Smith TL, et al. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon-alfa and low-dose cytarabine. J Clin Oncol 1999;17:284-292. [Free Full Text]
15. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 1997;337:223-229. [Free Full Text]
16. 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. [CrossRef][Web of Science][Medline]
17. Deininger MW, Goldman JM, Lydon N, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997;90:3691-3698. [Free Full Text]
18. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis 1997;23:380-394. [CrossRef][Web of Science][Medline]
19. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105:3-7. [Web of Science][Medline]
20. le Coutre P, Mologni L, Cleris L, et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst 1991;91:163-168. 
21. 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. [Free Full Text]
22. 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. [Erratum, N Engl J Med 2001;345:232.] [Free Full Text]
23. O'Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 1995;86:3322-3326. [Free Full Text]
24. 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. [Free Full Text]
25. Rodriguez J, Cortes J, Smith T, et al. Determinants of prognosis in late chronic-phase chronic myelogenous leukemia. J Clin Oncol 1998;16:3782-3787. [Free Full Text]
26. Goldman JM, Druker BJ. Chronic myeloid leukemia: current treatment options. Blood 2001;98:2039-2042. [Free Full Text]

In addition to the authors, the following investigators participated in the International STI571 CML Study: United Kingdom — J. Goldman (Hammersmith Hospital, Imperial College School of Medicine, London), S.G. O'Brien (Royal Victoria Infirmary, University of Newcastle upon Tyne, Newcastle upon Tyne), N. Russell (City Hospital, Nottingham); Germany — T. Fischer (Johannes Gutenberg-Universität, Mainz), O. Ottmann (Johann Wolfgang Goethe-Universität, Frankfurt); France — P. Cony-Makhoul (Laboratoire de Greffe de Moelle, Universite Victor Segalen, Bordeaux), T. Facon (Hôpital Claude Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille); United States — R. Stone (Dana Farber Cancer Institute, Boston), C. Miller (Johns Hopkins Oncology Center, Baltimore), M. Tallman (Northwestern University Medical School, Chicago), R. Brown (Washington University School of Medicine, St. Louis), M. Schuster (New York Presbyterian Hospital–Weill Medical College of Cornell University, New York), T. Loughran (University of South Florida, Tampa, Fla.); Switzerland — A. Gratwohl (Universitätsklinik, Kantonspital, Basel); Italy — F. Mandelli (Universita La Sapienza, Rome), G. Saglio (Universita di Torino, Orbassano), M. Lazzarino (Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia), D. Russo (Udine University Hospital, Udine), M. Baccarani (Universita di Bologna, Bologna), E. Morra (Azienda Ospedaliera Niguarda Ca'Granda, Milan). All statistical analyses were performed by U. Zoellner and I. Gathmann.

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• Milojkovic, D., Nicholson, E., Apperley, J. F., Holyoake, T. L., Shepherd, P., Drummond, M. W., Szydlo, R., Bua, M., Foroni, L., Reid, A., Khorashad, J. S., de Lavallade, H., Rezvani, K., Paliompeis, C., Goldman, J. M., Marin, D. (2010). Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. haematol 95: 224-231 [Abstract] [Full Text]  
• Amin, D. N., Sergina, N., Ahuja, D., McMahon, M., Blair, J. A., Wang, D., Hann, B., Koch, K. M., Shokat, K. M., Moasser, M. M. (2010). Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver. Sci Transl Med 2: 16ra7-16ra7 [Abstract] [Full Text]  
• Cortes, J. E., Jones, D., O'Brien, S., Jabbour, E., Konopleva, M., Ferrajoli, A., Kadia, T., Borthakur, G., Stigliano, D., Shan, J., Kantarjian, H. (2010). Nilotinib As Front-Line Treatment for Patients With Chronic Myeloid Leukemia in Early Chronic Phase. JCO 28: 392-397 [Abstract] [Full Text]  
• Cortes, J. E., Jones, D., O'Brien, S., Jabbour, E., Ravandi, F., Koller, C., Borthakur, G., Walker, B., Zhao, W., Shan, J., Kantarjian, H. (2010). Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia. JCO 28: 398-404 [Abstract] [Full Text]  
• McWeeney, S. K., Pemberton, L. C., Loriaux, M. M., Vartanian, K., Willis, S. G., Yochum, G., Wilmot, B., Turpaz, Y., Pillai, R., Druker, B. J., Snead, J. L., MacPartlin, M., O'Brien, S. G., Melo, J. V., Lange, T., Harrington, C. A., Deininger, M. W. N. (2010). A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood 115: 315-325 [Abstract] [Full Text]  
• Guilhot, F., Druker, B., Larson, R. A., Gathmann, I., So, C., Waltzman, R., O'Brien, S. G. (2009). High rates of durable response are achieved with imatinib after treatment with interferon {alpha} plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial. haematol 94: 1669-1675 [Abstract] [Full Text]  
• Liu, P. C.C., Caulder, E., Li, J., Waeltz, P., Margulis, A., Wynn, R., Becker-Pasha, M., Li, Y., Crowgey, E., Hollis, G., Haley, P., Sparks, R. B., Combs, A. P., Rodgers, J. D., Burn, T. C., Vaddi, K., Fridman, J. S. (2009). Combined Inhibition of Janus Kinase 1/2 for the Treatment of JAK2V617F-Driven Neoplasms: Selective Effects on Mutant Cells and Improvements in Measures of Disease Severity. Clin. Cancer Res. 15: 6891-6900 [Abstract] [Full Text]  
• Garg, R. J., Kantarjian, H., O'Brien, S., Quintas-Cardama, A., Faderl, S., Estrov, Z., Cortes, J. (2009). The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood 114: 4361-4368 [Abstract] [Full Text]  
• Sos, M. L., Fischer, S., Ullrich, R., Peifer, M., Heuckmann, J. M., Koker, M., Heynck, S., Stuckrath, I., Weiss, J., Fischer, F., Michel, K., Goel, A., Regales, L., Politi, K. A., Perera, S., Getlik, M., Heukamp, L. C., Ansen, S., Zander, T., Beroukhim, R., Kashkar, H., Shokat, K. M., Sellers, W. R., Rauh, D., Orr, C., Hoeflich, K. P., Friedman, L., Wong, K.-K., Pao, W., Thomas, R. K. (2009). Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc. Natl. Acad. Sci. USA 106: 18351-18356 [Abstract] [Full Text]  
• Jabbour, E., Jones, D., Kantarjian, H. M., O'Brien, S., Tam, C., Koller, C., Burger, J. A., Borthakur, G., Wierda, W. G., Cortes, J. (2009). Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 114: 2037-2043 [Abstract] [Full Text]  
• Maher, C. A., Palanisamy, N., Brenner, J. C., Cao, X., Kalyana-Sundaram, S., Luo, S., Khrebtukova, I., Barrette, T. R., Grasso, C., Yu, J., Lonigro, R. J., Schroth, G., Kumar-Sinha, C., Chinnaiyan, A. M. (2009). Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl. Acad. Sci. USA 106: 12353-12358 [Abstract] [Full Text]  
• Renouf, D. J., Wilson, L., Blanke, C. D. (2009). Successes and Challenges in Translational Research: The Development of Targeted Therapy for Gastrointestinal Stromal Tumours. Clin. Cancer Res. 15: 3908-3911 [Abstract] [Full Text]  
• Noens, L., van Lierde, M.-A., De Bock, R., Verhoef, G., Zachee, P., Berneman, Z., Martiat, P., Mineur, P., Van Eygen, K., MacDonald, K., De Geest, S., Albrecht, T., Abraham, I. (2009). Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 113: 5401-5411 [Abstract] [Full Text]  
• Baccarani, M., Rosti, G., Castagnetti, F., Haznedaroglu, I., Porkka, K., Abruzzese, E., Alimena, G., Ehrencrona, H., Hjorth-Hansen, H., Kairisto, V., Levato, L., Martinelli, G., Nagler, A., Lanng Nielsen, J., Ozbek, U., Palandri, F., Palmieri, F., Pane, F., Rege-Cambrin, G., Russo, D., Specchia, G., Testoni, N., Weiss-Bjerrum, O., Saglio, G., Simonsson, B. (2009). 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 113: 4497-4504 [Abstract] [Full Text]  
• Castagnetti, F., Palandri, F., Amabile, M., Testoni, N., Luatti, S., Soverini, S., Iacobucci, I., Breccia, M., Rege Cambrin, G., Stagno, F., Specchia, G., Galieni, P., Iuliano, F., Pane, F., Saglio, G., Alimena, G., Martinelli, G., Baccarani, M., Rosti, G., for the GIMEMA CML Working Party, (2009). 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 113: 3428-3434 [Abstract] [Full Text]  
• Lavallard, V. J., Pradelli, L. A., Paul, A., Beneteau, M., Jacquel, A., Auberger, P., Ricci, J.-E. (2009). Modulation of Caspase-Independent Cell Death Leads to Resensitization of Imatinib Mesylate-Resistant Cells. Cancer Res. 69: 3013-3020 [Abstract] [Full Text]  
• Jabbour, E., Kantarjian, H. M., Jones, D., Shan, J., O'Brien, S., Reddy, N., Wierda, W. G., Faderl, S., Garcia-Manero, G., Verstovsek, S., Rios, M. B., Cortes, J. (2009). Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113: 2154-2160 [Abstract] [Full Text]  
• Wong, S.-F. (2009). Dasatinib dosing strategies in Philadelphia chromosome-positive leukemia. J Oncol Pharm Pract 15: 17-27 [Abstract]  
• Redaelli, S., Piazza, R., Rostagno, R., Magistroni, V., Perini, P., Marega, M., Gambacorti-Passerini, C., Boschelli, F. (2009). Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants. JCO 27: 469-471 [Full Text]  
• Shan, Y., Seeliger, M. A., Eastwood, M. P., Frank, F., Xu, H., Jensen, M. O, Dror, R. O., Kuriyan, J., Shaw, D. E. (2009). A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc. Natl. Acad. Sci. USA 106: 139-144 [Abstract] [Full Text]  
• Fujita, A., Shishido, T., Yuan, Y., Inamoto, E., Narumiya, S., Watanabe, N. (2009). Imatinib Mesylate (STI571)-Induced Cell Edge Translocation of Kinase-Active and Kinase-Defective Abelson Kinase: Requirements of Myristoylation and src Homology 3 Domain. Mol. Pharmacol. 75: 75-84 [Abstract] [Full Text]  
• Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood 112: 4808-4817 [Abstract] [Full Text]  
• Jabbour, E., Kantarjian, H. M., Jones, D., Reddy, N., O'Brien, S., Garcia-Manero, G., Burger, J., Cortes, J. (2008). Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood 112: 4839-4842 [Abstract] [Full Text]  
• Hughes, T. P., Branford, S., White, D. L., Reynolds, J., Koelmeyer, R., Seymour, J. F., Taylor, K., Arthur, C., Schwarer, A., Morton, J., Cooney, J., Leahy, M. F., Rowlings, P., Catalano, J., Hertzberg, M., Filshie, R., Mills, A. K., Fay, K., Durrant, S., Januszewicz, H., Joske, D., Underhill, C., Dunkley, S., Lynch, K., Grigg, A., on behalf of the Australasian Leukaemia and Lympho, (2008). Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 112: 3965-3973 [Abstract] [Full Text]  
• Zhou, L. L., Zhao, Y., Ringrose, A., DeGeer, D., Kennah, E., Lin, A. E.-J., Sheng, G., Li, X.-J., Turhan, A., Jiang, X. (2008). AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. JEM 205: 2657-2671 [Abstract] [Full Text]  
• Khorashad, J. S., de Lavallade, H., Apperley, J. F., Milojkovic, D., Reid, A. G., Bua, M., Szydlo, R., Olavarria, E., Kaeda, J., Goldman, J. M., Marin, D. (2008). Finding of Kinase Domain Mutations in Patients With Chronic Phase Chronic Myeloid Leukemia Responding to Imatinib May Identify Those at High Risk of Disease Progression. JCO 26: 4806-4813 [Abstract] [Full Text]  
• Brenner, H., Gondos, A., Pulte, D. (2008). Recent trends in long-term survival of patients with chronic myelocytic leukemia: disclosing the impact of advances in therapy on the population level. haematol 93: 1544-1549 [Abstract] [Full Text]  
• Schilsky, R. L., Gordon, G., Gilmer, T. M., Courtneidge, S. A., Matrisian, L. M., Grad, O., Nelson, W. G., on behalf of the Translational Research Working Gr, (2008). The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics). Clin. Cancer Res. 14: 5685-5691 [Abstract] [Full Text]  
• Wu, J., Meng, F., Kong, L.-Y., Peng, Z., Ying, Y., Bornmann, W. G., Darnay, B. G., Lamothe, B., Sun, H., Talpaz, M., Donato, N. J. (2008). Association Between Imatinib-Resistant BCR-ABL Mutation-Negative Leukemia and Persistent Activation of LYN Kinase. JNCI J Natl Cancer Inst 100: 926-939 [Abstract] [Full Text]  
• Capdeville, R., Krahnke, T., Hatfield, A., Ford, J. M., Van Hoomissen, I., Gathmann, I. (2008). Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias. Ann Oncol 19: 1320-1326 [Abstract] [Full Text]  
• Fleming, I. N., Hogben, M., Frame, S., McClue, S. J., Green, S. R. (2008). Synergistic Inhibition of ErbB Signaling by Combined Treatment with Seliciclib and ErbB-Targeting Agents. Clin. Cancer Res. 14: 4326-4335 [Abstract] [Full Text]  
• Jabbour, E., Kantarjian, H., Jones, D., Breeden, M., Garcia-Manero, G., O'Brien, S., Ravandi, F., Borthakur, G., Cortes, J. (2008). Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 112: 53-55 [Abstract] [Full Text]  
• Hexner, E. O., Serdikoff, C., Jan, M., Swider, C. R., Robinson, C., Yang, S., Angeles, T., Emerson, S. G., Carroll, M., Ruggeri, B., Dobrzanski, P. (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 111: 5663-5671 [Abstract] [Full Text]  
• Mayerhofer, M., Gleixner, K. V., Mayerhofer, J., Hoermann, G., Jaeger, E., Aichberger, K. J., Ott, R. G., Greish, K., Nakamura, H., Derdak, S., Samorapoompichit, P., Pickl, W. F., Sexl, V., Esterbauer, H., Schwarzinger, I., Sillaber, C., Maeda, H., Valent, P. (2008). Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib. Blood 111: 2200-2210 [Abstract] [Full Text]  
• Zheng, H., Matte-Martone, C., Li, H., Anderson, B. E., Venketesan, S., Sheng Tan, H., Jain, D., McNiff, J., Shlomchik, W. D. (2008). Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 111: 2476-2484 [Abstract] [Full Text]  
• Garcia, A. A. (2008). Small Molecules: Big Changes in the Cancer Treatment Paradigm. Journal of Pharmacy Practice 21: 17-35 [Abstract]  
• Lin, W. M., Baker, A. C., Beroukhim, R., Winckler, W., Feng, W., Marmion, J. M., Laine, E., Greulich, H., Tseng, H., Gates, C., Hodi, F. S., Dranoff, G., Sellers, W. R., Thomas, R. K., Meyerson, M., Golub, T. R., Dummer, R., Herlyn, M., Getz, G., Garraway, L. A. (2008). Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma. Cancer Res. 68: 664-673 [Abstract] [Full Text]  
• Duncan, E. A., Goetz, C. A., Stein, S. J., Mayo, K. J., Skaggs, B. J., Ziegelbauer, K., Sawyers, C. L., Baldwin, A. S. (2008). I{kappa}B kinase {beta} inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells. Molecular Cancer Therapeutics 7: 391-397 [Abstract] [Full Text]  
• Hochhaus, A., Druker, B., Sawyers, C., Guilhot, F., Schiffer, C. A., Cortes, J., Niederwieser, D. W., Gambacorti-Passerini, C., Stone, R. M., Goldman, J., Fischer, T., O'Brien, S. G., Reiffers, J. J., Mone, M., Krahnke, T., Talpaz, M., Kantarjian, H. M. (2008). Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-{alpha} treatment. Blood 111: 1039-1043 [Abstract] [Full Text]  
• Brave, M., Goodman, V., Kaminskas, E., Farrell, A., Timmer, W., Pope, S., Harapanhalli, R., Saber, H., Morse, D., Bullock, J., Men, A., Noory, C., Ramchandani, R., Kenna, L., Booth, B., Gobburu, J., Jiang, X., Sridhara, R., Justice, R., Pazdur, R. (2008). Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate. Clin. Cancer Res. 14: 352-359 [Abstract] [Full Text]  
• Palandri, F., Iacobucci, I., Martinelli, G., Amabile, M., Poerio, A., Testoni, N., Soverini, S., Castagnetti, F., De Vivo, A., Breccia, M., Specchia, G., Abruzzese, E., Martino, B., Cilloni, D., Saglio, G., Pane, F., Liberati, A. M., Rosti, G., Baccarani, M. (2008). Long-Term Outcome of Complete Cytogenetic Responders After Imatinib 400 mg in Late Chronic Phase, Philadelphia-Positive Chronic Myeloid Leukemia: The GIMEMA Working Party on CML. JCO 26: 106-111 [Abstract] [Full Text]  
• Frame, D. (2007). Introduction. Am J Health Syst Pharm 64: S2-S3 [Full Text]  
• Fausel, C. (2007). Targeted chronic myeloid leukemia therapy: Seeking a cure. Am J Health Syst Pharm 64: S9-S15 [Abstract] [Full Text]  
• Branford, S., Seymour, J. F., Grigg, A., Arthur, C., Rudzki, Z., Lynch, K., Hughes, T. (2007). BCR-ABL Messenger RNA Levels Continue to Decline in Patients with Chronic Phase Chronic Myeloid Leukemia Treated with Imatinib for More Than 5 Years and Approximately Half of All First-Line Treated Patients Have Stable Undetectable BCR-ABL Using Strict Sensitivity Criteria. Clin. Cancer Res. 13: 7080-7085 [Abstract] [Full Text]  
• Cortes, J., Jabbour, E., Kantarjian, H., Yin, C. C., Shan, J., O'Brien, S., Garcia-Manero, G., Giles, F., Breeden, M., Reeves, N., Wierda, W. G., Jones, D. (2007). Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 110: 4005-4011 [Abstract] [Full Text]  
• Kantarjian, H. M., Giles, F., Gattermann, N., Bhalla, K., Alimena, G., Palandri, F., Ossenkoppele, G. J., Nicolini, F.-E., O'Brien, S. G., Litzow, M., Bhatia, R., Cervantes, F., Haque, A., Shou, Y., Resta, D. J., Weitzman, A., Hochhaus, A., le Coutre, P. (2007). Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 110: 3540-3546 [Abstract] [Full Text]  
• Zandy, N. L., Playford, M., Pendergast, A. M. (2007). Abl tyrosine kinases regulate cell cell adhesion through Rho GTPases. Proc. Natl. Acad. Sci. USA 104: 17686-17691 [Abstract] [Full Text]  
• Kebriaei, P., Detry, M. A., Giralt, S., Carrasco-Yalan, A., Anagnostopoulos, A., Couriel, D., Khouri, I. F., Anderlini, P., Hosing, C., Alousi, A., Champlin, R. E., de Lima, M. (2007). Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood 110: 3456-3462 [Abstract] [Full Text]  
• Press, R. D., Galderisi, C., Yang, R., Rempfer, C., Willis, S. G., Mauro, M. J., Druker, B. J., Deininger, M. W.N. (2007). A Half-Log Increase in BCR-ABL RNA Predicts a Higher Risk of Relapse in Patients with Chronic Myeloid Leukemia with an Imatinib-Induced Complete Cytogenetic Response. Clin. Cancer Res. 13: 6136-6143 [Abstract] [Full Text]  
• Jabbour, E., Kantarjian, H. M., Abruzzo, L. V., O'Brien, S., Garcia-Manero, G., Verstovsek, S., Shan, J., Rios, M. B., Cortes, J. (2007). Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 110: 2991-2995 [Abstract] [Full Text]  
• Gollard, R., Wierda, W., Trent, J. (2007). Chronic Myeloid Leukemia and Gastrointestinal Stromal Tumor: Simultaneous Presentation. JCO 25: 4682-4683 [Full Text]  
• Ottmann, O., Dombret, H., Martinelli, G., Simonsson, B., Guilhot, F., Larson, R. A., Rege-Cambrin, G., Radich, J., Hochhaus, A., Apanovitch, A. M., Gollerkeri, A., Coutre, S. (2007). Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 110: 2309-2315 [Abstract] [Full Text]  
• Quintas-Cardama, A., Kantarjian, H., O'Brien, S., Borthakur, G., Bruzzi, J., Munden, R., Cortes, J. (2007). Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure. JCO 25: 3908-3914 [Abstract] [Full Text]  
• Atallah, E., Durand, J.-B., Kantarjian, H., Cortes, J. (2007). Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 110: 1233-1237 [Abstract] [Full Text]  
• Dasmahapatra, G., Yerram, N., Dai, Y., Dent, P., Grant, S. (2007). Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation. Clin. Cancer Res. 13: 4280-4290 [Abstract] [Full Text]  
• Peng, C., Brain, J., Hu, Y., Goodrich, A., Kong, L., Grayzel, D., Pak, R., Read, M., Li, S. (2007). Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells. Blood 110: 678-685 [Abstract] [Full Text]  
• Kuo, Y.-Y., Chang, Z.-F. (2007). GATA-1 and Gfi-1B Interplay To Regulate Bcl-xL Transcription. Mol. Cell. Biol. 27: 4261-4272 [Abstract] [Full Text]  
• Fabarius, A., Haferlach, C., Muller, M. C., Erben, P., Lahaye, T., Giehl, M., Frank, O., Seifarth, W., Hehlmann, R., Hochhaus, A. (2007). Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure. haematol 92: 834-837 [Abstract] [Full Text]  
• Guilhot, F., Apperley, J., Kim, D.-W., Bullorsky, E. O., Baccarani, M., Roboz, G. J., Amadori, S., de Souza, C. A., Lipton, J. H., Hochhaus, A., Heim, D., Larson, R. A., Branford, S., Muller, M. C., Agarwal, P., Gollerkeri, A., Talpaz, M. (2007). Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109: 4143-4150 [Abstract] [Full Text]  
• Jiang, X., Saw, K. M., Eaves, A., Eaves, C. (2007). Instability of BCR-ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells. JNCI J Natl Cancer Inst 99: 680-693 [Abstract] [Full Text]  
• Langley, R. R., Fidler, I. J. (2007). Tumor Cell-Organ Microenvironment Interactions in the Pathogenesis of Cancer Metastasis. Endocr. Rev. 28: 297-321 [Abstract] [Full Text]  
• Yancovitz, M., Yoon, J., Mikhail, M., Gai, W., Shapiro, R. L., Berman, R. S., Pavlick, A. C., Chapman, P. B., Osman, I., Polsky, D. (2007). Detection of Mutant BRAF Alleles in the Plasma of Patients with Metastatic Melanoma. J. Mol. Diagn. 9: 178-183 [Abstract] [Full Text]  
• Braiteh, F., Kurzrock, R. (2007). Uncommon tumors and exceptional therapies: paradox or paradigm?. Molecular Cancer Therapeutics 6: 1175-1179 [Abstract] [Full Text]  
• Schellings, M. W., Lowenberg, B., Pinto, Y. M., Strebhardt, K. (2007). Another Look at Imatinib Mesylate. NEJM 356: 1183-1183 [Full Text]  
• Hochhaus, A., Kantarjian, H. M., Baccarani, M., Lipton, J. H., Apperley, J. F., Druker, B. J., Facon, T., Goldberg, S. L., Cervantes, F., Niederwieser, D., Silver, R. T., Stone, R. M., Hughes, T. P., Muller, M. C., Ezzeddine, R., Countouriotis, A. M., Shah, N. P. (2007). Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 109: 2303-2309 [Abstract] [Full Text]  
• Jimeno, A., Rubio-Viqueira, B., Amador, M. L., Grunwald, V., Maitra, A., Iacobuzio-Donahue, C., Hidalgo, M. (2007). Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Molecular Cancer Therapeutics 6: 1079-1088 [Abstract] [Full Text]  
• Kantarjian, H. M., Giles, F., Quintas-Cardama, A., Cortes, J. (2007). Important Therapeutic Targets in Chronic Myelogenous Leukemia. Clin. Cancer Res. 13: 1089-1097 [Abstract] [Full Text]  
• Holtz, M., Forman, S. J., Bhatia, R. (2007). Growth Factor Stimulation Reduces Residual Quiescent Chronic Myelogenous Leukemia Progenitors Remaining after Imatinib Treatment. Cancer Res. 67: 1113-1120 [Abstract] [Full Text]  
• Ma, W., Tseng, R., Gorre, M., Jilani, I., Keating, M., Kantarjian, H., Cortes, J., O'Brien, S., Giles, F., Albitar, M. (2007). Plasma RNA as an alternative to cells for monitoring molecular response in patients with chronic myeloid leukemia. haematol 92: 170-175 [Abstract] [Full Text]  
• Rubio-Viqueira, B., Mezzadra, H., Nielsen, M. E., Jimeno, A., Zhang, X., Iacobuzio-Donahue, C., Maitra, A., Hidalgo, M., Altiok, S. (2007). Optimizing the development of targeted agents in pancreatic cancer: tumor fine-needle aspiration biopsy as a platform for novel prospective ex vivo drug sensitivity assays. Molecular Cancer Therapeutics 6: 515-523 [Abstract] [Full Text]  
• Rosti, G., Iacobucci, I., Bassi, S., Castagnetti, F., Amabile, M., Cilloni, D., Poerio, A., Soverini, S., Palandri, F., Cambrin, G. R., Iuliano, F., Alimena, G., Latagliata, R., Testoni, N., Pane, F., Saglio, G., Baccarani, M., Martinelli, G. (2007). Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party. haematol 92: 101-105 [Abstract] [Full Text]  
• Steensma, D. P., Richard, R. E. (2007). Myeloproliferative disorders. ASH-SAP 2007: 172-227 [Full Text]  
• Kantarjian, H. M., Talpaz, M., Giles, F., O'Brien, S., Cortes, J. (2006). New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance. ANN INTERN MED 145: 913-923 [Abstract] [Full Text]  
• Soverini, S., Colarossi, S., Gnani, A., Rosti, G., Castagnetti, F., Poerio, A., Iacobucci, I., Amabile, M., Abruzzese, E., Orlandi, E., Radaelli, F., Ciccone, F., Tiribelli, M., di Lorenzo, R., Caracciolo, C., Izzo, B., Pane, F., Saglio, G., Baccarani, M., Martinelli, G., on behalf of the GIMEMA Working Party on Chronic M, (2006). Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin. Cancer Res. 12: 7374-7379 [Abstract] [Full Text]  
• Druker, B. J., Guilhot, F., O'Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., Deininger, M. W.N., Silver, R. T., Goldman, J. M., Stone, R. M., Cervantes, F., Hochhaus, A., Powell, B. L., Gabrilove, J. L., Rousselot, P., Reiffers, J., Cornelissen, J. J., Hughes, T., Agis, H., Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A., Nielsen, J. L., Radich, J. P., Simonsson, B., Taylor, K., Baccarani, M., So, C., Letvak, L., Larson, R. A., the IRIS Investigators, (2006). Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. NEJM 355: 2408-2417 [Abstract] [Full Text]  
• Luo, F. R., Yang, Z., Camuso, A., Smykla, R., McGlinchey, K., Fager, K., Flefleh, C., Castaneda, S., Inigo, I., Kan, D., Wen, M.-L., Kramer, R., Blackwood-Chirchir, A., Lee, F. Y. (2006). Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure. Clin. Cancer Res. 12: 7180-7186 [Abstract] [Full Text]  
• Puttini, M., Coluccia, A. M. L., Boschelli, F., Cleris, L., Marchesi, E., Donella-Deana, A., Ahmed, S., Redaelli, S., Piazza, R., Magistroni, V., Andreoni, F., Scapozza, L., Formelli, F., Gambacorti-Passerini, C. (2006). In vitro and In vivo Activity of SKI-606, a Novel Src-Abl Inhibitor, against Imatinib-Resistant Bcr-Abl+ Neoplastic Cells. Cancer Res. 66: 11314-11322 [Abstract] [Full Text]  
• Frame, D. (2006). Chronic myeloid leukemia: Standard treatment options.. Am J Health Syst Pharm 63: S10-S14 [Abstract] [Full Text]  
• DeAngelo, D. J., Stone, R. M., Heaney, M. L., Nimer, S. D., Paquette, R. L., Klisovic, R. B., Caligiuri, M. A., Cooper, M. R., Lecerf, J.-M., Karol, M. D., Sheng, S., Holford, N., Curtin, P. T., Druker, B. J., Heinrich, M. C. (2006). Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 108: 3674-3681 [Abstract] [Full Text]  
• Tikkanen, J. M., Hollmen, M., Nykanen, A. I., Wood, J., Koskinen, P. K., Lemstrom, K. B. (2006). Role of Platelet-derived Growth Factor and Vascular Endothelial Growth Factor in Obliterative Airway Disease. Am. J. Respir. Crit. Care Med. 174: 1145-1152 [Abstract] [Full Text]  
• Agulnik, M., Oza, A. M., Pond, G. R., Siu, L. L. (2006). Impact and Perceptions of Mandatory Tumor Biopsies for Correlative Studies in Clinical Trials of Novel Anticancer Agents. JCO 24: 4801-4807 [Abstract] [Full Text]  
• Kometani, K., Aoki, M., Kawamata, S., Shinozuka, Y., Era, T., Taniwaki, M., Hattori, M., Minato, N. (2006). Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL-Expressing Hematopoietic Progenitors in a Mouse Model.. Cancer Res. 66: 9967-9976 [Abstract] [Full Text]  
• Mologni, L., Sala, E., Cazzaniga, S., Rostagno, R., Kuoni, T., Puttini, M., Bain, J., Cleris, L., Redaelli, S., Riva, B., Formelli, F., Scapozza, L., Gambacorti-Passerini, C. (2006). Inhibition of RET tyrosine kinase by SU5416.. J Mol Endocrinol 37: 199-212 [Abstract] [Full Text]  
• Baccarani, M., Saglio, G., Goldman, J., Hochhaus, A., Simonsson, B., Appelbaum, F., Apperley, J., Cervantes, F., Cortes, J., Deininger, M., Gratwohl, A., Guilhot, F., Horowitz, M., Hughes, T., Kantarjian, H., Larson, R., Niederwieser, D., Silver, R., Hehlmann, R. (2006). Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108: 1809-1820 [Abstract] [Full Text]  
• Arana-Yi, C., Quintas-Cardama, A., Giles, F., Thomas, D., Carrasco-Yalan, A., Cortes, J., Kantarjian, H., Verstovsek, S. (2006). Advances in the Therapy of Chronic Idiopathic Myelofibrosis. The Oncologist 11: 929-943 [Abstract] [Full Text]  
• Roy, L., Guilhot, J., Krahnke, T., Guerci-Bresler, A., Druker, B. J., Larson, R. A., O'Brien, S., So, C., Massimini, G., Guilhot, F. (2006). Survival advantage from imatinib compared with the combination interferon-{alpha} plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 108: 1478-1484 [Abstract] [Full Text]  
• von Bubnoff, N., Manley, P. W., Mestan, J., Sanger, J., Peschel, C., Duyster, J. (2006). Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 108: 1328-1333 [Abstract] [Full Text]  
• Ferrari-Amorotti, G., Keeshan, K., Zattoni, M., Guerzoni, C., Iotti, G., Cattelani, S., Donato, N. J., Calabretta, B. (2006). Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha}. Blood 108: 1353-1362 [Abstract] [Full Text]  
• Quintas-Cardama, A., Cortes, J. E. (2006). Chronic Myeloid Leukemia: Diagnosis and Treatment. Mayo Clin Proc. 81: 973-988 [Abstract] [Full Text]  
• Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., Cortes, J., O'Brien, S., Nicaise, C., Bleickardt, E., Blackwood-Chirchir, M. A., Iyer, V., Chen, T.-T., Huang, F., Decillis, A. P., Sawyers, C. L. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.. NEJM 354: 2531-2541 [Abstract] [Full Text]  
• Kantarjian, H., Giles, F., Wunderle, L., Bhalla, K., O'Brien, S., Wassmann, B., Tanaka, C., Manley, P., Rae, P., Mietlowski, W., Bochinski, K., Hochhaus, A., Griffin, J. D., Hoelzer, D., Albitar, M., Dugan, M., Cortes, J., Alland, L., Ottmann, O. G. (2006). Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.. NEJM 354: 2542-2551 [Abstract] [Full Text]  
• Ye, D., Wolff, N., Li, L., Zhang, S., Ilaria, R. L. Jr (2006). STAT5 signaling is required for the efficient induction and maintenance of CML in mice. Blood 107: 4917-4925 [Abstract] [Full Text]  
• Schein, P. S., Scheffler, B. (2006). Barriers to efficient development of cancer therapeutics.. Clin. Cancer Res. 12: 3243-3248 [Full Text]  
• Press, R. D., Love, Z., Tronnes, A. A., Yang, R., Tran, T., Mongoue-Tchokote, S., Mori, M., Mauro, M. J., Deininger, M. W., Druker, B. J. (2006). BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood 107: 4250-4256 [Abstract] [Full Text]  
• Ault, P., Kantarjian, H., O'Brien, S., Faderl, S., Beran, M., Rios, M. B., Koller, C., Giles, F., Keating, M., Talpaz, M., Cortes, J. (2006). Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib. JCO 24: 1204-1208 [Abstract] [Full Text]  
• Dimopoulou, I., Bamias, A., Lyberopoulos, P., Dimopoulos, M. A. (2006). Pulmonary toxicity from novel antineoplastic agents. Ann Oncol 17: 372-379 [Abstract] [Full Text]