Blood Journal
Leading the way in experimental and clinical research in hematology

Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis

  1. Jorge Cortes1,
  2. Philippe Rousselot2,
  3. Dong-Wook Kim3,
  4. Ellen Ritchie4,
  5. Nelson Hamerschlak5,
  6. Steven Coutre6,
  7. Andreas Hochhaus7,
  8. Francois Guilhot8,
  9. Giuseppe Saglio9,
  10. Jane Apperley10,
  11. Oliver Ottmann11,
  12. Neil Shah12,
  13. Philipp Erben7,
  14. Susan Branford13,
  15. Prasheen Agarwal14,
  16. Ashwin Gollerkeri14, and
  17. Michele Baccarani15
  1. 1M. D. Anderson Cancer Center, Houston, TX;
  2. 2Hospital Saint Louis, Centre d'Investigation Clinique, Paris, France;
  3. 3Uijeongbu St Mary's Hospital, Kyunggi-Do, Republic of Korea;
  4. 4Weill Medical College–Cornell University, New York Presbyterian Hospital, New York, NY;
  5. 5Hospital Israelita Albert Einstein, Sao Paulo, Brazil;
  6. 6Stanford University School of Medicine, Stanford, CA;
  7. 7Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany;
  8. 8Hôpital Jean Bernard, Poitiers, France;
  9. 9Azienda Ospedaliera S. Luigi, Orbassano, Italy;
  10. 10Hammersmith Hospital, London, United Kingdom;
  11. 11Johann Wolfgang Goethe Universität, Frankfurt-am-Main, Germany;
  12. 12University College of Los Angeles, CA;
  13. 13Division of Hematology, Institute of Medical and Veterinary Science, Adelaide, Australia;
  14. 14Bristol-Myers Squibb, Wallingford, CT;
  15. 15Istituto di Ematologica E Oncologica Medica, Policlinico S. Orsola, Bologna, Italy

Abstract

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.

Introduction

Blast crisis is the terminal phase of chronic myeloid leukemia (CML), a hematopoietic malignancy characterized by the presence of the constitutively activated tyrosine kinase BCR-ABL.1,2 Blast crisis CML (BC-CML) is of myeloid phenotype (myeloid blast crisis [MBC]) in approximately two thirds of patients and of lymphoid phenotype (lymphoid blast crisis [LBC]) in most of the remaining patients, with occasional patients having an undifferentiated or a mixed-lineage phenotype.3 The prognosis for patients with all forms of BC-CML remains poor; overall survival from the onset of BC is approximately 3 to 6 months.4 Allogeneic stem cell transplantation (SCT) induces durable remission in less than 10% of patients with CML in BC,5 and imatinib (Gleevec; Novartis, East Hanover, NJ) yields sustained complete hematologic responses (CHRs) in less than 15%.5,6 Cytogenetic response is even rarer.5,6 Failure to respond to imatinib (primary resistance) is particularly common during BC compared with earlier stages of the disease.7

Dasatinib (Sprycel, formerly BMS-354825; Bristol-Myers Squibb, New York, NY) is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases (SFKs) that has been rationally designed to overcome mechanisms of resistance associated with imatinib therapy. In vitro studies have shown that dasatinib has 325-fold greater potency than imatinib in cells transduced with unmutated BCR-ABL8 and is active against all tested BCR-ABL mutations except one (T315I) that confer imatinib resistance.8,9 This is attributed, at least in part, to the ability of dasatinib to bind to the active and the inactive conformations of BCR-ABL.8 Dasatinib also inhibits the SFKs implicated in resistance to imatinib.8,10 In a phase 1 dasatinib dose-escalation study, hematologic and cytogenetic responses were observed in all phases of imatinib-resistant and -intolerant CML and in Philadelphia-chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), and dasatinib was very well tolerated.11

Based on these dasatinib results, the START (SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib) phase 2 program in CML by phase of disease was initiated. This report presents data from the first 74 and 42 patients from the cohorts with MBC-CML (START-B) and LBC-CML (START-L), respectively. Analyses of data representing follow-up of 6 and 8 months, respectively, show significant rates of hematologic response (the primary end point) and complete and partial cytogenetic remission.

Patients, materials, and methods

Patients

Patients 18 years of age and older were eligible for inclusion if they had CML in MBC or LBC and were resistant to or intolerant of imatinib therapy. Blast crisis CML was defined as 30% or greater blasts (myeloid or lymphoid) in peripheral blood or bone marrow or extramedullary leukemic infiltrates (other than in spleen or liver) with peripheral blood blast (myeloid or lymphoid) cell morphology.

Imatinib resistance was defined as progression from chronic phase to blast crisis while receiving 400 mg/d or more imatinib or from accelerated phase to blast crisis while receiving 600 mg/d or more imatinib (or 400 to less than 600 mg/d if the patient was intolerant of 600 mg/d or more). Patients initially diagnosed in blast crisis were classified as having imatinib-resistant CML if they met the criteria for blast crisis after 4 or more weeks (2 weeks for patients whose disease progressed rapidly) on imatinib 600 mg/d or more (or 400 to less than 600 mg/d if the patient was intolerant of 600 mg/d or more). Imatinib intolerance was defined as discontinuation of therapy because of toxicity considered at least possibly related to an imatinib dose of 400 mg/d or less or to an inability to tolerate imatinib doses higher than 400 mg/d.

For inclusion in the study, patients were required to have adequate hepatic and renal function and an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower. Exclusion criteria included previous dasatinib therapy, imatinib therapy within 7 days of initiation, uncontrolled or significant cardiovascular disease, or history of a significant bleeding disorder unrelated to CML.

Study design and treatment

START-B and START-L were phase 2, open-label, single-arm, multinational studies with identical designs. These studies were conducted in accordance with the Declaration of Helsinki and were consistent with International Conference on Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory requirements. The study protocol, amendments, and patient informed consent received appropriate approval of the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) before study initiation at each site. Written informed consent was obtained from each patient before clinical trial participation. START-L also included adults with Ph-positive ALL; results for these patients will be reported separately.

Primary objectives of both trials were to determine the rates of major hematologic response (MaHR, which includes complete hematologic response [CHR] and no evidence of leukemia [NEL]) and of overall hematologic response (OHR, which includes CHR, NEL, and minor hematologic response [MiHR]) in patients with imatinib-resistant CML in MBC or LBC after treatment with dasatinib and to assess its safety and tolerability. Secondary objectives included the evaluation of rates of cytogenetic response (CyR), duration of hematologic response, frequency and type of BCR-ABL mutation(s), and safety.

CHR was defined as white blood cell (WBC) count less than or equal to the institutional upper limit of normal (ULN); absolute neutrophil count (ANC) 1.0 × 109/L or higher; platelet count 100 × 109/L or higher; marrow blasts 5% or less with no peripheral blasts or promyelocytes; peripheral myelocytes + metamyelocytes less than 5%; basophils in peripheral blood less than 2%; and no evidence of extramedullary involvement. NEL was defined as CHR without full recovery of platelets and neutrophils (platelet count 20 × 109/L to less than 100 × 109/L and ANC 0.5 × 109/L to less than 1.0 × 109/L). Minor hematologic response was defined as (1) blasts less than 15% and blasts + promyelocytes less than 30%, (2) peripheral blood basophils less than 20%, blasts less than 15%, and blasts + promyelocytes less than 30%, and (3) no extramedullary disease other than in spleen and liver.

Cytogenetic responses were determined by the percentage of Ph-positive metaphases after analysis of at least 20 metaphases from a bone marrow aspirate sample. Complete cytogenetic response (CCyR) was defined as 0% Ph-positive cells; partial CyR (PCyR) as 1% to 35% Ph-positive cells; minor CyR (MiCyR) as 36% to 65% Ph-positive cells; minimal CyR as 66% to 95% Ph-positive cells; and no response as 96% to 100% Ph-positive cells. An overall CyR was defined as complete, partial, plus minor CyR, and a major cytogenetic response (MCyR) was defined as CCyR plus PCyR.

Dasatinib was administered orally at a starting dose of 70 mg twice daily.11 Modification of the dasatinib dose was permitted after 4 weeks of treatment. Dose escalation to 100 mg dasatinib twice daily was permitted for patients meeting any of the following criteria: (1) increasing percentage of blasts on 2 consecutive hematologic assessments at least 1 week apart; (2) no CHR within 1 month of dasatinib initiation; (3) no CCyR 3 months or more after dasatinib initiation; or (4) loss of response.

The dose could be reduced or interrupted in response to hematologic or nonhematologic toxicity, as defined by the National Cancer Institute (NCI) common toxicity criteria (CTC); the first dose reduction level was 50 mg twice daily, and the second was 40 mg twice daily. For patients with grades 2-4 nonhematologic toxicity considered to be at least possibly related to dasatinib, treatment was interrupted until recovery to grade 1 or less or to baseline levels. For a grade 2 event, treatment was reinitiated at the same dose but was reduced by one dose level if it recurred and by another dose level if recurrence continued. For a grade 3 event, treatment was reduced initially by one dose level and was reduced by an additional dose level for a recurrence. Patients experiencing grade 3 or higher organ toxicity (eg, renal, cardiac, central nervous system) judged to be related to dasatinib or QTc interval of 530 msec or longer were taken off therapy.

Dose reductions or interruptions because of hematologic toxicity were considered for patients with grade 4 neutropenia (ANC less than 0.5 × 109/L) only after 14 days of treatment. Bone marrow aspirate and biopsy were performed, and if marrow cellularity was less than 10%, treatment was interrupted until ANC was higher than 1.0 × 109/L. If grade 4 neutropenia persisted for 4 weeks, treatment was interrupted irrespective of biopsy results. Treatment was reinitiated at the same dose for the first event and at one dose level lower for recurring events. If grade 4 neutropenia occurred a fourth time, a decision on further dose reductions or discontinuation was made by the investigator in conjunction with the medical monitor from the sponsor (Bristol-Myers Squibb Pharmaceutical Research Institute). Patients whose therapy was interrupted were required to reinitiate treatment within 21 days; further delays were permitted if the investigator considered that continued dasatinib therapy was in the best interest of the patient.

Patients were treated with dasatinib until progression of disease despite dose escalation, intolerable toxicity, or withdrawal from the study. All patients were followed up for at least 30 days after the last dose of study therapy or until recovery from all adverse events (AEs), whichever was longer, and then at least every 4 weeks until all study-related toxicities resolved to baseline or grade 1, stabilized, or were deemed irreversible.

No treatment for CML other than dasatinib—except anagrelide and hydroxyurea for treatment of elevated platelet counts (higher than 700 × 109/L) and WBC counts (higher than 50 × 109/L), respectively—was permitted during the study. Use of hydroxyurea was limited to a period of 2 weeks. Administration of colony-stimulating factors and recombinant erythropoietin was permitted at the discretion of the investigator.

Patient evaluation for efficacy

Patients were monitored with once-weekly complete blood counts (CBCs). Confirmed hematologic responses were required to be maintained for a minimum of 4 weeks, and no concomitant anagrelide or hydroxyurea was to be used during this interval. The duration of a confirmed hematologic response was measured from the first day the criteria were met until progression or death. Duration of response was censored at the last hematologic assessment for patients who discontinued for reasons other than progression or death. Progression in responding patients was defined as patients who achieved MaHR or MiHR but subsequently lost this response on all assessments over a consecutive 2-week period after starting their maximum dasatinib dose. Progression was defined as no decrease from baseline levels in percentage blasts in peripheral blood or bone marrow on all assessments over a 4-week period after start of the maximum dasatinib dose.

Cytogenetic responses were evaluated by once-monthly bone marrow aspirates/biopsies for the first 3 months and every 3 months thereafter. Patients were also assessed for molecular response with real-time polymerase chain reaction (PCR) for BCR-ABL transcript levels monthly, and results were expressed as a BCR-ABL/ABL ratio. For each patient, a predose baseline blood sample was collected for BCR-ABL mutation analysis. The complete ABL kinase domain of the BCR-ABL allele was analyzed using reverse transcriptase PCR (RT-PCR), followed by direct sequencing.

Patient evaluation for safety

Study drug toxicities were assessed continuously. In particular, a targeted physical examination for assessment of AEs, including assessment of skin and mucosa, was conducted weekly for the first 2 months and every other week thereafter. AEs were evaluated according to NCI CTC version 3.0.

Statistical analysis

Efficacy analyses were performed for the treated population, which included all patients who received at least 1 dose of dasatinib. Two-sided 95% exact confidence intervals (CIs) were calculated for the primary end points, CHR and OHR, using the Clopper-Pearson method.12

Results

Patients and treatment

Patients in the MBC-CML cohort were enrolled from December 30, 2004 to May 17, 2005, whereas patients in the LBC-CML cohort were enrolled from January 5, 2005 to May 23, 2005. In total, 74 patients with MBC-CML and 42 patients with LBC-CML received at least one dose of study drug and were included in this analysis. In the MBC-CML cohort, 68 patients had imatinib-resistant disease, and 6 patients were intolerant of imatinib. Reasons for imatinib intolerance were hematologic toxicity (2 patients), hepatic toxicity (2 patients), rash (1 patient), and gastrointestinal symptoms (1 patient). In the LBC-CML cohort, 37 patients had imatinib-resistant CML, and 5 patients were intolerant of imatinib. Reasons for imatinib intolerance were hematologic toxicity (4 patients) and gastrointestinal symptoms (1 patient).

Patient demographics and baseline disease characteristics were representative of patients with CML in BC (Table 1) and were generally comparable between the imatinib-resistant and the imatinib-intolerant subgroups. Nearly half of all patients had received an imatinib dose higher than 600 mg/d, and a similar proportion of the MBC-CML cohort had received imatinib for more than 3 years. Response to previous imatinib therapy included CHR in 84% and 67% of patients in the MBC- and LBC-CML cohorts, respectively, and CCyR in 32% and 33% of patients before disease progression. In the MBC-CML cohort, 66% of patients had received chemotherapy, 55% received interferon-α (IFN-α) therapy, and 12% had undergone stem cell transplantation (SCT). In the LBC-CML cohort, 79% of patients had received chemotherapy, 48% had received IFN-α, and 33% had undergone SCT. Approximately half the patients in both cohorts had BCR-ABL kinase mutations at baseline (MBC-CML, 43%; LBC-CML, 56%).

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Table 1

Patient demographics and baseline characteristics

At the 6-month follow-up, 32 (43%) patients in the MBC-CML cohort remained on study; the median duration of therapy for the total cohort was 3.5 months (less than 0.1 to 9.2 months); by the 8-month follow-up, 23 (31%) patients remained on study, and the median duration of therapy was 3.5 months (range, 0.1-12.0 months) for the total MBC-CML cohort. In the LBC-CML cohort, 7 (17%) and 5 (12%) patients remained on study at the 6- and 8-month follow-ups, respectively. The median duration of therapy for the total LBC-CML cohort was 2.8 months (range, 0.1-6.4 months at 6-month follow-up and 0.1-9.2 months at 8-month follow-up). A summary of patient on-study disposition for both cohorts at the 8-month follow-up is provided in Table 2, outlining reasons for treatment discontinuation, median duration of study therapy, and median dasatinib dosage.

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Table 2

Treatment discontinuation and dosing information at 8-month follow-up

Efficacy

Dasatinib induced MaHR and MCyR in a significant number of patients in the MBC- and LBC-CML cohorts (Tables 3, and 4).

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Table 3

Best-confirmed hematologic response to dasatinib

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Table 4

Best cytogenetic response to dasatinib

MBC-CML cohort.

At 6 months, 32% of patients—34% in the imatinib-resistant subgroup and 17% in the imatinib-intolerant subgroup—had achieved MaHR. These response rates increased at 8 months to 34% overall—35% in the imatinib-resistant subgroup and 17% in the imatinib-intolerant subgroup. The OHR rate was 53% (53% in the imatinib-resistant subgroup and 50% in the imatinib-intolerant subgroup) at the 6- and 8-month follow-ups.

Major hematologic responses to dasatinib occurred rapidly and were durable: the median time to MaHR was 57 days (range, 27-171 days), and the median duration of MaHR had not been reached at the 8-month follow-up (Figure 1A). Major cytogenetic responses were observed in 23 (31%) patients. Of these, 20 (87% [or 27% of the total]) were complete cytogenetic responses.

Figure 1

Outcomes over time in patients with CML MBC receiving dasatinib. (A) Duration of major hematologic response. (B) Progression-free survival.

Three patients (all in the imatinib-resistant subgroup) experienced disease progression. The median duration of progression-free survival in imatinib-resistant MBC-CML patients was 5.0 months (Figure 1B).

LBC-CML cohort.

In the LBC-CML cohort, 31% of patients achieved MaHR (32% in the imatinib-resistant subgroup and 20% in the imatinib-intolerant subgroup) after 6 months of therapy; these response rates were maintained at the 8-month follow-up. The OHR rate was 36% at the 6- and 8-month follow-ups (38% in the imatinib-resistant subgroup and 20% in the imatinib-intolerant subgroup).

Responses to dasatinib treatment were rapid and durable: median time to MaHR was 34.5 days for patients with imatinib-resistant LBC-CML and 29 days for the patients with imatinib-intolerant LBC-CML. Response duration for the total LBC-CML cohort ranged from 1.6 to 8.4 months. Six of the 13 patients who achieved MaHR maintained that response at the 8-month follow-up (Figure 2A).

Figure 2

Outcomes over time in patients with CML LBC receiving dasatinib. (A) Duration of major hematologic response. (B) Progression-free survival.

MCyR was achieved in 21 (50%) patients with LBC-CML. These included 18 (43%) patients with CCyR. Median duration of progression-free survival was 2.8 months (Figure 2B); no patient with imatinib-intolerant LBC-CML had disease progression (Figure 2A-B).

Correlation of response with BCR-ABL genotype

Data from baseline mutational analyses of the ABL kinase domain were available for 70 of the 74 patients in the MBC-CML cohort and 40 of the 42 patients in the LBC-CML cohort (Tables 5, 6).

In the MBC-CML cohort (Table 5), 23 different imatinib-resistant mutations were observed in 30 patients (28 imatinib resistant, 2 imatinib intolerant); mutants G250E and Y253H (6 patients each) were the most common. Despite the poor prognosis for these patients, dasatinib elicited MaHRs and MCyRs in 33% and 27% of patients with any BCR-ABL mutation, respectively. Rates of MaHR and MCyR were 33% and 28% for patients with mutations in the P-loop region of the kinase. Eight of the observed mutations (M244V, G250E, Y253H, E255K, E255V, T315I, F359V, H396R) were associated with very high resistance to imatinib (more than a 5-fold increase in IC50 compared with unmutated BCR-ABL in vitro); among MBC-CML patients with these mutations, rates of MaHR and MCyR were 30% and 22%, respectively.

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Table 5

Response by baseline BCR-ABL mutation analysis of patients with CML in MBC

In the LBC-CML cohort (Table 6), 16 imatinib-resistant mutations were detected among 24 patients (23 with imatinib-resistant CML and 1 with imatinib-intolerant CML). Rates of MaHR and MCyR, respectively, were 25% and 42% in patients with any BCR-ABL mutation, 30% and 40% with P-loop mutations, and 13% and 25% with a high-resistance mutation.

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Table 6

Response by baseline BCR-ABL mutation analysis of patients with chronic myeloid leukemia in lymphoid blast crisis

Safety and tolerability

Dasatinib was generally well tolerated in both cohorts, with similar tolerability reported for imatinib-resistant and imatinib-intolerant subgroups. At the 8-month follow-up, only 11% of MBC-CML patients (all with imatinib-resistant CML) had discontinued therapy because of study drug toxicity. Dose interruptions were required by 64% of patients (23% for cytopenias, 38% for nonhematologic toxicity, and 3% for other reasons), and dose escalations were introduced for 54% of patients. Among LBC-CML patients, only one patient (2%; imatinib intolerant) discontinued therapy because of study drug toxicity. Dose interruptions were required for 33% of patients (19% for cytopenias, 10% for nonhematologic toxicity, and 5% for other reasons), and dose escalations were introduced for 26% of patients.

Adverse events.

Nonhematologic events were generally mild to moderate in intensity (grade 1 or 2). The most frequent AEs of any grade related to study drug are shown in Table 7. Gastrointestinal disorders (including diarrhea, nausea, vomiting) were the most frequent events of any severity in the MBC- and LBC-CML cohorts. Fluid retention events in the MBC-CML cohort included peripheral edema (19%) and pleural effusion (28%). In general, pleural effusions were reversible with temporary dose interruption, diuretics, and, in some patients, pulse steroids. Grade 3-4 abnormalities in albumin were reported for 2 (3%) patients, in alanine aminotransferase (ALT) for 6 (8%) patients, in aspartate aminotransferase (AST) for 3 (4%) patients, and in bilirubin for 6 (8%) patients.

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Table 7

Adverse events possibly related to dasatinib

Fluid retention events of any grade appeared to occur less often in the LBC-CML cohort than in the MBC-CML cohort, though rates of fatigue (29%) were higher (Table 7). Grade 3-4 abnormalities in albumin were reported for 2 (5%) patients, in ALT for 3 (7%) patients, in AST for 2 (5%) patients, and in bilirubin for 3 (7%) patients.

Cytopenias.

Cytopenias were common (Table 8) but were generally reversible in the MBC- and LBC-CML cohorts and could be managed effectively by dose interruptions or reductions. However, as might have been expected in a population of heavily pretreated patients with CML in BC, a considerable proportion of patients had severe cytopenias before the initiation of dasatinib therapy, making assessment of the relative contribution of therapy to myelosuppression difficult in many instances. In the MBC-CML cohort at baseline, 22% of patients had severe (grade 3 or 4) neutropenia, 46% had severe thrombocytopenia, and 14% had severe anemia. In the LBC-CML cohort, 46% of patients had severe neutropenia, 64% had severe thrombocytopenia, and 5% had severe anemia. Febrile neutropenia (12%) was the most commonly reported grade 3-4 AE in the LBC-CML cohort, but it did not result in any discontinuations from the study.

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Table 8

Grade 3-4 cytopenias associated with dasatinib

Discussion

CML in blast crisis remains a challenging clinical entity. The efficacy and safety results of this study can be considered of significant clinical relevance. Patients had extensive histories of CML and were heavily pretreated; 90% of patients had imatinib-resistant disease, and 10% had imatinib-intolerant disease.

Dasatinib therapy resulted in complete hematologic and partial and complete cytogenetic responses in a large proportion of patients with imatinib-resistant or -intolerant CML, irrespective of phenotype. Responses have been durable with the extent of follow-up currently available. With a minimum of 8 months' follow-up, 34% and 26% of patients with MBC-CML achieved MaHR and CHR, respectively; 31% achieved MCyR, and most (87%) of those were complete. Similarly, among patients with LBC-CML, 31% and 26% achieved MaHR and CHR, respectively, and 50% achieved MCyR, 86% of which were CCyR.

Responses usually occurred rapidly. Median time for imatinib-resistant patients to achieve MaHR was approximately 1 month for the LBC-CML cohort and approximately 2 months for the MBC-CML group. Responses were also durable; 74% of BC-CML patients who achieved MaHR remained free of disease progression at the 8-month follow-up.

The percentage of LBC-CML patients whose disease was in major cytogenetic remission exceeded the percentage of patients with MaHR because in some cases a cytogenetic response was achieved but residual cytopenia was present, thus precluding a classification of MaHR response. In these instances, cytogenetic response might be a more valuable end point.

Responses observed with dasatinib treatment may, at least in part, be attributable to the increased potency of dasatinib against unmutated BCR-ABL relative to imatinib and the ability of dasatinib to inhibit a spectrum of imatinib-resistant BCR-ABL mutants.8,9

Mechanisms of resistance, other than mutations, have also been described, many of them BCR-ABL independent. In our study population, 36 of the 64 imatinib-resistant MBC-CML patients and 12 of the 35 imatinib-resistant LBC-CML patients had no detectable BCR-ABL mutations at baseline. The ability of dasatinib to potently inhibit SFKs in addition to BCR-ABL8 might have contributed to its marked efficacy in the LBC-CML patients, particularly given the suspected involvement of SFK activity in the pathophysiology of LBC-CML.1316

Dasatinib was also effective in patients with a variety of mutations in the BCR-ABL kinase domain, including those associated with high levels of resistance to imatinib. Mutations in the BCR-ABL kinase P-loop are thought to contribute to increased oncogenicity of the kinase and can be associated with a lower life expectancy among patients treated with imatinib.17,18 However, rates of major hematologic and cytogenetic responses with dasatinib were similar irrespective of the presence of P-loop or other mutations compared with no mutation. This could reflect the less stringent requirements for dasatinib–BCR-ABL binding compared with imatinib.19 Indeed, analysis of the ABL kinase domain crystal structure in complex with dasatinib may indicate that contacts with the P-loop are not as important for dasatinib binding to BCR-ABL as they are for imatinib.20

Dasatinib was generally well tolerated in this population of patients with disease in blast crisis. Cytopenias, though frequent, could be managed through dose interruption or reduction. Cytopenia may be a reflection of the increased potency of dasatinib against BCR-ABL, the resultant antileukemic activity, and the very high proportion of Ph-positive hematopoietic cells present in patients with advanced CML. Baseline cytopenia and the limited reserve of the heavily pretreated bone marrow in these patients probably contributed to the incidence and duration of apparent myelosuppression in cohorts. Despite the occurrence of neutropenia with or without fever on study, no patients discontinued therapy because of cytopenia-related infection as a result of dasatinib therapy at the time of this analysis. Nevertheless, careful monitoring of blood counts in patients in blast crisis receiving dasatinib after failure of imatinib therapy is clearly warranted.5,21

Toxicity observed in these studies was reversible and could be considered acceptable in light of the available alternative therapeutic choices, including conventional cytotoxic chemotherapy, highlighting the potential benefit of this targeted molecular therapy. Patients with imatinib-intolerant CML were not disproportionately affected by cytopenia or nonhematologic AEs, suggesting that cross-intolerance between imatinib and dasatinib is minimal. Although the number of CML patients with imatinib intolerance was low, only one LBC-CML patient and no MBC-CML patients withdrew from the study because of drug toxicity after 8 months of follow-up.

Pleural effusions seen were reversible with dose interruption and diuretic or steroid administration. Severe congestive heart failure/cardiac dysfunction was seen in 2 patients, both with myeloid blast-phase disease; all patients receiving dasatinib had been heavily pretreated with extensive previous therapies that included imatinib.

In summary, the results observed in these studies demonstrate that potent, multitargeted kinase inhibition of BCR-ABL and SFKs with dasatinib induced hematologic and cytogenetic responses in a large proportion of patients with imatinib-resistant or -intolerant blast crisis CML. The rates of CCyR observed in this study could, in fact, be considered particularly noteworthy. In general, responses seemed to be slightly more frequent in LBC-CML but slightly more durable in MBC-CML. Given the poor overall survival of patients with CML blast crisis,4,22 the progression-free survival achieved to date with dasatinib is clinically meaningful. Responses achieved with dasatinib in blast crisis CML may open a window of opportunity for allogeneic SCT for many of these patients.

Based on the present experience, which is consistent with results observed with dasatinib in other phase 2 studies of the START program,2325 clinical trials of dasatinib in patients with earlier stages of CML, including those previously untreated, have been initiated. Our results indicated that dasatinib represents a potentially important new therapeutic option for patients with imatinib-resistant or imatinib-intolerant MBC-CML or LBC-CML and will undoubtedly affect the treatment paradigm for CML.

Authorship

Contribution: J.C. designed and performed research, analyzed the data, and wrote the paper. P.R. performed research. D.W.K. performed research. E.R. performed research. N.H. performed research. S.C. designed and performed research and analyzed the data. A.H. designed and performed research, analyzed the data, and wrote the paper. F.G. performed research. G.S. performed research. J.A. was the study investigator and performed research. O.G.O. performed research. N.S. designed and performed research, analyzed the data, and wrote the paper. P.E. designed and performed research and analyzed the data. S.B. performed research. P.A. analyzed the data. A.G. designed research and analyzed the data. M.B. performed research and analyzed the data.

Conflict-of-interest disclosure: All authors have received financial support from Bristol-Myers Squibb. J.C. has received grants from Bristol-Myers Squibb and Novartis. D.W.K. has received a clinical research fund and a central referral laboratory fund from Novartis and had a clinical research fund from Bristol-Myers Squibb. A.H. has received research support and honoraria from Bristol-Myers Squibb. N.S. has received honoraria from Bristol-Myers Squibb. P.E. has received research support from Bristol-Myers Squibb. P.A. and A.G. are employees of Bristol-Myers Squibb.

Correspondence: Jorge Cortes, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org.

Acknowledgments

This work was supported by research funding from Bristol-Myers Squibb.

The following primary investigators participated in this trial: (USA) M. Talpaz, J. H. Khoury, R. T. Silver, A. Rapoport, R. Larson, C. Schiffer, R. Stone, A. Greco, S. Goldberg, K. Bhalla, J. P. Radich (molecular analyses), S. Petersdorf, P. Emanuel, S. Cheng, V. Iyer, C. Nicaise; (Switzerland) A. Gratwohl; (Germany) C. Bokemeyer, T. Fischer, M. Mueller (molecular analyses); (Argentina) J. J. Garcia; (Australia) T. Hughes, B. Van Leeuwen; (Austria) P. Valent; (Belgium) G. Verhoef; (Israel) A. Nagler; (France) H. Dombret, G. Marit, J. Reiffers, M. Michallet, T. Facon, F. Maloisel, J.-L. Harrousseau; (Italy) F. Ferrara; (The Netherlands) W. Schroyens; (Brazil) C. A. De Souza, P. E. Dolhiac Llacer; (Canada) P. Laneuville, C. Gambacorti-Passerini; (Finland) K. Porkka; (Korea) J.-H. Lee; (Philippines) P. Caguioa; (Sweden) B. Simonsson, M. Ekblom; (Taiwan) J.-L. Tang, P.-M. Chen; (Thailand) S. Jootar; (United Kingdom) T. Holyoake.

Footnotes

  • An Inside Blood analysis of this article appears at the front of this issue.

  • The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

  • Submitted September 13, 2006.
  • Accepted December 4, 2006.

References

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