Advances in the Management of Chronic Myeloid Leukemia

Posted on January 21st, 2008 by

<p>Advances in the Management of Chronic Myeloid Leukemia: A Report from the 2007 American Society of Hematology (ASH) Meeting</p> <p>

Introduction
Initial Treatment of Newly Diagnosed Patients
Are Higher Doses of Imatinib More Effective?
Imatinib in Elderly Patients
Supportive Care in Patients Receiving Tyrosine Kinase Inhibitors for CML
Newer Tyrosine Kinase Inhibitors (TKI): When to Treat Imatinib Failures?
Dasatinib for Patients Failing Imatinib
Nilotinib for Patients Failing Imatinib
Nilotinib for Patients Failing Imatinib and Dasatinib
Dasatinib for Newly Diagnosed Patients
Nilotinib for Newly Diagnosed CML Patients
New Tyrosine Kinase Inhibitors
Allogeneic Stem Cell Transplants
Summary

Introduction

Imatinib mesylate is the standard initial treatment of newly diagnosed chronic myeloid leukemia (CML). Imatinib produces high rates of complete cytogenetic responses (70% to 85%) and of major molecular responses (20% to 40%) and has improved progression-free and overall survival.1 2 However, imatinib does not eradicate the BCR-ABL clones in most patients as detected by polymerase chain reaction (PCR) monitoring. Furthermore, a small but significant fraction of patients will develop imatinib-resistance or are intolerant to the drug. Patients who fail or are intolerant to imatinib now have treatment alternatives other than allogeneic stem cell transplantation.

Dasatinib and nilotinib are two new agents that have been developed for the treatment of patients with BCR-ABL-positive CML and acute lymphoblastic leukemia (ALL) that appear to have great promise for the treatment of patients who fail imatinib. Dasatinib and nilotinib are both approved by the US Food and Drug Administration for treatment of patients who fail or are intolerant to imatinib. Other tyrosine kinases are under development and being tested in the clinic.

For practicing physicians taking care of patients with CML this meeting provided some helpful answers to the following questions:

  • How durable are imatinib-maintained responses?
  • What is the appropriate dose of imatinib for initial treatment?
  • What are the current treatments for imatinib failures and how should failure be defined?
  • What are the effects of imatinib on very elderly patients with CML?
  • Are there supportive care issues in patients receiving tyrosine kinases?

Initial Treatment of Newly Diagnosed Patients

Researchers affiliated with the International Randomized Study of Interferon versus STI571 (IRIS) study have reported follow-up data on over 500 patients in the imatinib arm.3 The current analysis focused on overall survival and rates of transformation of patients with CML treated on the imatinib arm of the IRIS study with a six year follow-up. The median dose of imatinib received was 400 mg/day. The five-year survival of the 553 patients on the imatinib arm is 89%. Sixty-six percent of patients remain on treatment with imatinib at six years. Only 2.5% of patients in this study crossed over and received interferon. Thirty-two percent of patients discontinued imatinib for the following reasons: adverse events 4%; poor response 12%; non-medical reasons 11%; allogeneic stem cell transplant 3%; and death 2%.

The following results were reported: complete hematologic response 97%; major cytogenetic response 89%; complete cytogenetic response 82%; 71% of patients achieving a complete cytogenetic response have maintained this status; event-free survival 83%; progression-free survival 93%.

It was reported that the annual rate of adverse events decreased significantly in every year of follow-up as did annual relapse rates and toxicities. Sixty-six patients (12%) have died, 19 after stem cell transplantation and 27 from causes other than CML. Less than 5% of deaths were due to CML. The estimated six-year overall survival rate was 88%. No long-term molecular data were presented at this talk.

The time to achieving a complete cytogenetic response had no impact on OS, EFS or PFS.4 The following table summarizes outcomes of 447 newly diagnosed CML patients who were treated for one year with imatinib.

Percent

Time to CCyR (months)

No. Patients

OS

EFS

PFS

&lt; 6

265

94

93

97

6-12

99

95

90

97

12-18

34

91

87

97

&gt;18

49

98

89

98

No CCyR

62

63

33

63

This study shows that patients who achieve a late CCyR do not have a worse outcome than those achieving this status earlier. However, no data were presented on how often dose escalation of imatinib was required to achieve a late CCyR. This is important since one of the unresolved issues is when to intervene with second-line therapies.

Are Higher Doses of Imatinib More Effective?

In the original IRIS study, there was dose escalation to 600 or 800 mg/day of imatinib if patients were "poor responders". Criteria included lack of complete hematological response by 3 months, a minor cytogenetic response by 12 months, or loss of a major cytogenetic response or disease progression at any time. At ASH 2007, Dr. Kantarjian reported the outcomes of 106 patients (19%) in the IRIS study who had dose escalation of imatinib.5 The median time to dose escalation was 22 months, and the median dose delivered was 600 mg/day. The median time of treatment was 19 months. At last follow-up 85% of these patients were taking 600 mg/day or more of imatinib. Six of 7 patients who had not achieved a complete hematologic response at 3 months did so with dose escalation, and 2 of them had a complete cytogenetic response. Four of 8 patients who had a minor cytogenetic response at 12 months achieved a complete cytogenetic remission on dose escalation. Nine of 18 patients who lost a major cytogenetic response re-achieved a major cytogenetic response, and 3 of these were complete responses. The estimated PFS and OS at 36 months were 89% and 84%, respectively. The authors concluded that dose escalation of imatinib benefited poor and slow responders and is of benefit in patients who lose a response while receiving 400 mg/day of imatinib.

Another analysis of the IRIS data suggested that patients with suboptimal and failure of response at 6, 12 and 18 months had a worse outcome (transformation or other event) than patients with optimal response.6 This study showed that patients with suboptimal responses after 6 months had a poor outcome. Importantly, patients having a suboptimal response at 5 months had a worse outcome if they were receiving 400 mg/day of imatinib versus higher doses.

Retrospective comparisons suggest that increasing doses of imatinib lead to more rapid induction of cytogenetic remissions. Kantarjian et al have reported the results of a phase II study of 800 mg/day of imatinib in 114 newly diagnosed patients with CML.7 The complete cytogenetic response rate was 90%. They also reported that 63% of those who achieved a cytogenetic response had PCR reductions to less than 0.05%, and 28% had undetectable PCR levels. They also stated that 82% of patients continue to receive more than 600 mg of imatinib per day. They compared these results with 50 patients previously treated with 400 mg per day of imatinib and concluded that the results with higher doses were significantly greater for the fraction achieving a complete cytogenetic response, for the cumulative incidence of major molecular response and the fraction of patients achieving a complete molecular response. They also reported that no patient had transformed during the observation period in the high-dose group which was different than the historical control group. However, there were no differences in survival since only 3 of the 167 total patients died. The major side effects were an increased incidence of neutropenia and thrombocytopenia compared to the standard-dose group. At 12 months 60% of patients were receiving the 800 mg dose and 20% were receiving 600 mg per day, showing that 80% of patients tolerated a higher dose of imatinib.

Dr Jabbour presented the results of treating 102 patients with CML in chronic phase with imatinib 800 mg/day at the MD Anderson Cancer Center.8 All patients had failed standard doses of imatinib of 300 or 400 mg/day and had dose escalation to 600 or 800 mg/day. 89 of these patients had received imatinib after interferon failure. Patients were categorized as cytogenetic resistance or relapse. The response rate to increased imatinib dosing was 74% and some of the resonses were complete cytogenetic remissions and complete molecular remissions which were sustained.

French researchers also reported that imatinib dose escalation benefited poor responders with a 100% complete cyogenetic response and a 50% major molecular response.9 This study involved 24 patients who were deemed poor responders by failing to achieve a complete cytogenetic or molecular response.

Since there have been no randomized trials of 400 mg/day of imatinib vs 800 mg/day, the advantages of higher doses of imatinib remain undefined. A randomized Italian and Nordic study comparing 400 mg/day of imatinib to 800 mg/day in newly diagnosed patients with high risk features is currently being carried out and had accrued 223 patients at the time of ASH 2007.10 The premise of this study is that patients who are high risk by Sokal criteria (20% of all patients) stand the most to benefit from dose escalation of imatinib. The median Sokal risk was 1.6 for patients on this study. They reported a 17% failure rate for the entire cohort of patients. Approximately 50% of patients in this study tolerated the higher dose of imatinib. No data were available at the time of the meeting comparing the two arms of this study.

Imatinib in Elderly Patients

Although imatinib is the initial treatment of choice for newly diagnosed patients with CML, little has been reported concerning the tolerance and effectiveness of imatinib in very elderly patients. A study from MD Anderson in 2003 concluded that older age had lost its poor prognostic significance with the use of imatinib in contrast to earlier therapies.11 They compared outcomes of 138 patients less than 60 years of age with 49 who were 60 years of age or older. However, these are relatively small numbers and age 60 is probably too young a cutoff to be meaningful. An evaluation of patients over the age of 65 or 70 years would be more meaningful given the demographics of newly diagnosed patients with CML.

At ASH 2007 researchers from Germany reported that the median age of patients with CML participating in nine published clinical trials of Gleevec ranged from 45 to 56 years.12 They also reported that data from the SEER Cancer Statistics review showed a median age of 68 years for newly diagnosed CML in the US. They reported that the median age for newly diagnosed patients with CML in one area of Germany participating in clinical trials was 54 years in contrast to a median of 65 years for those not participating in a clinical trial. They estimated that 36% of patients with newly diagnosed CML were not registered in a clinical trial and most of these patients were over 65 years of age.

Researchers from France reported the outcomes of 30 patients with newly diagnosed CML who were 70 years of age or older.13 Patients in this study were enrolled between 2002 and 2004. Patients were equally distributed between low
, intermediate and high risk. The median follow-up was 45 months. The starting dose of imatinib was 400 mg/day and the median delivered dose was 392 mg/day. Grade 2-3 neutropenia was observed in 22% of patients; one patient received G-CSF. Grade 2-3 anemia occurred in 32%, and 86% of these patients received erythropoietin. Edema occurred in 71% of patients and gastrointestinal symptoms in 38%. Sixty-five percent of patients had cardiovascular abnormalities, with two patients having heart failure. Three patients discontinued imatinib, two for heart failure and one for skin toxicity. Complete cytogenetic remission occurred in 71% of patients at 12 months and in 77% at 24 months. The cumulative incidence of major molecular response was 25%, 56% and 59% at 12, 24 and 36 months. The molecular response was complete in 25% of those with a major molecular response at 36 months. The authors suggested that patients at very high risk of cardiac toxicity (category 3 CIRS-G) may not have a favorable benefit/risk ratio for treatment with imatinib based on the two cardiac deaths in high-risk individuals. However, for all other elderly patients, a high level of sustained cytogenetic and molecular responses was observed irrespective of age.

Supportive Care in Patients Receiving Tyrosine Kinase Inhibitors for CML

Researchers from the MD Anderson Cancer Center have reported that the use of erythropoiesis agents (ESA) such as epoetin alfa and darbepoetin alfa do not affect survival of patients with CML treated with imatinib.14 The use of ESAs has been associated with an increased relapse rate in some studies in patients with breast cancer, head and neck cancer and lung cancer. However, most studies have not shown an increase in relapse rates or decreased survivals in patients with cancer receiving ESAs after chemotherapy. An earlier study from MD Anderson reported that ESA administration could correct the anemia associated with treating patients with imatinib. This study also suggested that patients with anemia had a worse outcome than patients without anemia.

The current analysis included 306 previously untreated patients and 259 who were previously treated with interferon. The following table summarizes overall survival (OS) and event-free survival (EFS) outcomes of these two groups of patients treated with Gleevec.

Percent With Outcome

Interferon Failures

Frontline imatinib

ESA Use

OS

EFS

OS

EFS

No

84

75

92

84

Yes

82

68

8

8

The authors concluded that there was no evidence that the use of ESA to manage anemia associated with imatinib therapy in patients with CML in chronic phase adversely affected long-term overall survival or event-free survival.

Newer Tyrosine Kinase Inhibitors (TKI): When to Treat Imatinib Failures?

Dasatinib and nilotinib are two new drugs approved by the US FDA for the treatment of patients with CML who are refractory to or intolerant of imatinib. Researchers from the MD Anderson Cancer Center concluded that the probability of response to second generation TKIs was dependent on prior response to imatinib and disease burden at the start of therapy.15 There were 120 patients who had CML in chronic phase who were treated with nilotinib or dasatinib. They reported that patients who had achieved a cytogenetic response at any time imatinib had a better outcome than patients who had not achieved a cytogenetic response. Patients who were in complete hematologic response at the time of treatment with dasatinib or nilotinib also had a better response. Another study from this same institution suggested that early intervention, at the time of cytogenetic resistance, with dasatanib was better than waiting until hematologic resistance developed.16 These researchers suggested that close monitoring of treatment response to imatinib was necessary for a timely use of alternative therapies.

Dasatinib for Patients Failing Imatinib

An international study of 119 patients with CML in accelerated concluded that dasatinib resulted in significant responses and was well tolerated.17 All patients in this study had failed or were intolerant to imatinib. Complete hematologic remission was achieved in 21% of patients and 12% returned to chronic phase. Major cytogenetic responses occurred in 29% of patients, with 19 of these 35 patients having a complete response.

Researchers affiliated with the START-C (CA180-013) international multi-center study reported the outcome of 387 patients with chronic phase CML resistant or intolerant to imatinib who where treated with dasatinib.18 Median time from diagnosis to treatment with dasatinib for this group of patients was 61 months for this group of patients. 65% had also received interferon, 10% had received a stem cell transplant and 55% had received 600 mg/day or more of imatinib. Complete hematologic remission was achieved in 91% and major cytogenetic response in 59%. Responses were higher in patients with intolerance rather than resistance to imatinib. Responses occurred across all mutation except T3151. The major molecular response rate was 25%. Progression-free survival was 90% at 15 months with an overall survival of 96%. Dose interruptions were required for the majority of patients. These authors conclude that dasatinib responses appeared to be durable with a minimum 2 year follow-up.

Researchers affiliated with the START-R (CA180-017) international multi-center study reported that dasatinib is more effective than imatinib 800 mg/day for patients with CML in chronic phase who are resistant to imatinib 400-600 mg/day.19 150 CML patien
ts who were resistant to standard doses of imatinib but still in chronic phase were randomly allocated on a 2:1 basis to receive dasatinib or 800 mg/day of imatinib. The median treatment duration for patients receiving dasatinib was over one year compared to 3 months for patients receiving imatinib 800 mg/day.Complete hematologic remissions occurred in 92% of dasatinib treated patients and 82% of imatinib treated patients. Major cytogenetic responses occurred in 52% of dasatinib treated patients and 33% of imatinib treated patients. Complete cytogenetic response occurred in 40% of dasatinib treated patients and 16% of imatinib treated patients. Major molecular responses were observed in 16% of dasatinib treated patients and 4% of imatinib treated patients. Progression-free survival was also better in the dasatinib group. There were more cytopenias and pleural effusions in the dasatinib group but more discontinuations of therapy due to toxicity in the imatinib group. These authors concluded that dasatinib was superior to imatinib 800 mg for the treatment of imatinib resistance.

Nilotinib for Patients Failing Imatinib

Data on 320 patients with CML in chronic phase who had failed or were resistant to imatinib and were treated with nilotinib were presented.20 The complete hematological remission rate was 91% for the 206 patients not in remission at the start of therapy. A major cytogenetic response was observed in 56% and 40% had a complete cytogenetic response. These data confirm that nilotinib is an effective treatment for patients in chronic phase who are resistant to or intolerant of imatinib.

Nilotinib for Patients Failing Imatinib and Dasatinib

An international study evaluated nilotinb in 67 patients who had failed both imatinib and dasatinib.21 There were 22 patients with CML in chronic phase. 11 of 17 patients not in hematological remission achieved a complete hematological response to nilotinib. 7 of 22 patients in chronic phase had a major cytogenetic response with 3 being complete responses. Only 2 patients treated in chronic phase have progressed. All patients in accelerated phase were progression-free at 4 months. 3 of 20 patients in blast crisis had a complete hematologic response. These authors concluded that these were impressive responses for this group of patients.

Dasatinib for Newly Diagnosed Patients

Researchers from the MD Anderson Cancer Center have reported that dasatinib produced rapid and complete cytogenetic responses in a high percentage of 40 newly diagnosed patients with CML.22 Patients in this trial compared the rate of complete cytogenetic responses in patients receiving dasatinib or imatinib at a dose 400 or 800 mg/day. The following Table summarizes the main findings of this trial to date.

% CompleteCytogenetic Response

Duration of Therapy(months)

Gleevec 400 mg/D

Gleevec 800 mg/D

Dasatinib

3

37

62

79

6

54

82

94

12

65

86

100

Dasatinib was well tolerated, the main toxicity being musculo-skeletal pain. The authors suggested that dasatinib produced more rapid and possibly more complete cytogenetic responses than 400 mg/day of imatinib. Dasatinib may or may not be superior to 800 mg/ day of imatinib.

Nilotinib for Newly Diagnosed CML Patients

Researchers from the MD Anderson Cancer presented data on 32 newly diagnosed patients with CML treated with nilotinib.23 The median age of this group was 47 years and 70% were low risk by Sokal criteria. Patients in this trial compared the rate of complete cytogenetic responses in patients receiving nilotinib or imatinib at a dose 400 or 800 mg/day. The following Table summarizes the main findings of this trial to date.

% Complete Cytogenetic Response

Duration of Therapy (month)

Imatinib 400 mg/D

Imatinib 800 mg/D

Nilotinib

3

37

62

95

6

54

82

100

12

65

86

100

The authors concluded that dasatinib produced rapid and complete cytogenetic responses within 3 months in all patients treated.

New Tyrosine Kinase Inhibitors

Bosutinib (SKI-606): Bosutinib, a 7-alkoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile, is a potent inhibitor of Src kinase activity. Researchers from Europe and the US presented data on bosutinib treatment of patients with CML in accelerated (AP) and blast phase (BP).24 In patients with AP and no prior exposure to tyrosine kinase inhibitors a major cytogenetic response was achieved in 3/6 patients in AP and 2/5 in BC. 4 of 21 patients with prior exposure to tyrosine kinase inhibitors had a major cytogenetic response which was complete in 3. Responses occurred across and wide variety of mutations and the toxicity profile was favorable. Side effects included diarrhea, nausea, vomiting and abdominal pain. Grade 3 and 4 toxicities (rash, thrombocytopenia) occurred in 5% of patients.

Researchers involved in an international study reported data on 98 patients with CML in CP who were treated with bosutinib.25 All patients in this study had failed or were intolerant to imatinib and some had failed interferon, dasatinib, nilotinib or an allogeneic stem cell transplant. One third of patients who were imatinib resistant had a complete cytogenetic reponse to bosutinib; some of these patients had a complete molecular response. Complete cytogenetic responses were also observed in patients resistant to dasatinib and nilotinib. The toxicity profile was reported to be favorable.

INNO-406: INNO-406 is a dual inhibitor of Abl and Lyn kinases. A Phase I study involving 41 patients with advanced CML or ALL with imatinib intolerance or resistance was presented.26 Preclinical studies have shown that INNO-406 is a more active Bcr-Abl tyrosine kinase inhibitor than imatinib and also augments apoptosis. Hematologic and cytogenetic responses were observed in this high-risk group of patients. Complete cytogenetic responses occurred in 2/7 patients with CML in CP who had only failed imatinib. Phase II studies with this agent are planned.

Allogeneic Stem Cell Transplants

Allogeneic stem cell transplants are no longer indicated for initial treatment of patients with CML. However, stem cell transplants may be of significant utility in the small fraction of younger patients failing imatinib, dasatinib and nilotinib. In the IRIS study only 3% of patients in the imatinib arm ultimately were treated with an allogeneic stem cell transplant. One of the concerns is whether or not prior TKI treatment will compromise the success of stem cell transplantation. At ASH 2007 researchers affiliated with the Center for International Blood and Marrrow Transplantation compared outcomes of 409 patients with CML who had been treated with imatinib with 900 comparable patients not treated with imatinib. For patients in chronic phase at the time of transplant there was a better survival for patients previously treated with imatinib than in the historical controls. In patients with more advanced disease there was no effect of imatinib on outcomes. These data suggest that delaying transplantation until failure of imatinib was not a factor in outcome of transplantation.

Summary

There continues to be rapid progress in the treatment of patients with CML in chronic phase with tyrosine kinase inhibitors. Patients with CML post failure on imatinib 400 mg/day, can be treated with increasing doses of imatinib or the newer agents, dasatinib or nilotinib. Two new agents have also emerged which are effective in CML: bosutinib and INNO-406. The development of guidelines for intervention with second line therapies are important for optimizing therapy. As in other diseases, physicians are becoming more aware of the need to have meaningful data on very elderly patients with and without significant co-morbidities, as they comprise the majority of patients with CML and are usually not included in clinical trials. Supportive care issues, especially among the elderly, need to be further evaluated in patients with CML.

References:


1 Kantarjian HM, Talpaz M, O'Brien S, et al. Survival benefit with imatinib mesylate versus interferon alfa based regimens in newly diagnosed chronic phase chronic myelogenous leukemia. Blood. 2006;108:1835-1840.

2 Roy L, Guilhot J, Krahnke T, et al. 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. 2006;108:1478-1484.

3 Hochhaus A, Druker BJ, Larson RA, et al. IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML) treated with imatinib. Blood. 2007;110:15a, abstract number 25.

4 Guilhot F, Larson RA, O'Brien SG, et al. Time to complete cytogenetic response (CCyR) does not affect long-term outcomes for patients on imatinib therapy. Blood. 2007;110:16a, abstract 27.

5 Kanatarjian HM, Druker BJ, Guilhot F, et al. Imatinib dose escalation is effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2007;110:317a, abstract 1047.

6 Alvarado Y, Kantarjian H, Faderl S, et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in long-term outcome for patients (Pts) with chronic phase (CP) chronic myeloid leukemia (CML). Blood. 2007;110:573a, abstract 1932.

7 Kantarjian H, Talpaz M, O'Brien S, et al. High-Dose Imatinib Mesylate Therapy in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia. Blood. 2004;103:2873-2878.

8 Jabbour E, Kantarjian H, Atallah E, et al. Impact of imatinib mesylate dose escalation and sub-optimal responses to standard-dose therapy in patients (pts) with chronic myeloid leukemia (CML). Blood. 2007;110:313a.

9 Rea D, Etienne G, Corm S, et al. Imatinib mesylate dose escalation improves disese response in chronic-phase chronic myeloid leukaemia patients after cytogenetic or molecular responses to standard doses of imatinib. Blood. 2007;110:3118a, abstract number 1052.

10 Baccarani M, Castagnetti F, Porkka K, et al. A prospective study on imatinib 400 mg vs 800 mg frontline in high risk PH+ chronic myeloid leukemia (CML). Blood. 2007;110:16a, abstract 26.

11 Cortes J, Talpaz M, O'Brien, et al. Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia-chromosome positive chronic myelogenous leukemia. Cancer. 2003;98:1105-1113.

12 Rohrbacher M, Berger U, Hochhaus A, et al. Clinical trials underestimate age of chronic myeloid leukemia (CML): Epidemiological study in a representative area in Germany. Blood. 2007;110:868a, abstract 2955.

13 Rousselot P, Nicolini F, Mahon FX, et al. High efficiency and particular safety profile of imatinib mesylate (Glivec®) in elderly patients with CML in chronic phase: Results of the AFR04 prospective study. Blood. 2007;110:315a, abstract 1039.

14 Alvarado Y, Kantarjian H, Verma D, et al. Long-term prognostic impact of the use of erythropoiesis-stimulating agents (ESA) in patients (pts) with chronic myeloid leukemia (CML) treated with imatinib. Blood. 2007;110:869a,abstract number 2959.

15 Jabbour E, Kantarjian H, Shan J, et al. Prognostic significance of prior best response to imatinib in patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) treated with second generation tyrosine kinase inhibitors (TKI's). Blood. 2007;577, abstract number 1942.

16 Kantarjian HM, Quintas-Cardama A, O'Brien S, et al. Importance of early intervention with dasatiib at cytogenetic rather than hematologic resistance to imatinib. Blood. 2007;110:314a, abstract number 1036.

17 Le Coutre P, Giles FJ, Apperly J, et al. Nilotinib is safe and effective in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib resistance or intolerance. Blood. 2007;145a, abstract 471.

18 Stone RM, Kantarjian HM, Baccarani M, et al. Efficacy of dasatinib in patients with chronic-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-year follow-up data from START-C (CA180-013). Blood. 2007;110:225a, abstract number 734.

19 Kantarjian H, Rousselot P, Pasquini R, et al. Dasatinib or high-dose imatinib for patients with chronic phase chronic myeloid leukemia resistant to standard-dose imatinib: 2-year follow-up data from START-R (CA180-017). Blood. 2007;110:226a, abstract number 736.

20 Kantarjian HM, Hochhaus A, Cortes J, et al. Nilotinib is highly active and safe in chronic phase chronic myelogenous leukemia (CML-CP) patients with imatinib resistance or intolerance. Blood. 2007;225a, abstract 735.

21 Giles FJ, le Coutre P, Bhalla KN, et al. Nilotinib therapy after dasatinib failure in patients with imatinib-resistant or intolerant chronic myeloid leukemia in chronic phase (CP), accelerated phase (AP) or blast crisis. Blood. 2007;110:311a, abstract 1029.

22 Cortes J, O'Brien S, Jones D, et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood. 2007;110:17a, abstract 30.

23 Cortes J, O'Brien S, Jabbour E, et al. Efficacy of nilotinib (AMN107) in patients (pts) with newly diagnosed previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood. 2007;17a. abstract number 29.

24 Gambacorti-Passerini C, Kantarjian H, Bruemmendorf T, et al. Bosutinib (SKI) demonstrates clinical activity and is well tolerated among patients with AP and BP CML and Ph+ALL. Blood. 2007;110:146a, abstract number 473.

25 Cortes J, Bruemmendorf T, Kantarjian H, et al. Efficacy and safety of bosutinib (SKI-606) among patients with chronic phase PH+ chronic myelogenous leukemia. Blood. 2007;225a, abstract 733.

26 Kantarjian HM, Cortes J, le Coutre P, et al. A phase I study of INNO-406 in patients with advanced Philadelphia (PH+) chromosome-positive leukemias who are resistant or intolerant to imatinib and second generation tyrosine kinase inhibitors. Blood. 2007;110:144a, abstract 469.

Tags: Chronic Myeloid Leukemia, News

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