Chronic Myeloproliferative Disorders

Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase

Abstract

Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03–20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in 6% of patients, except febrile neutropenia (15%). Cytopenias were noted in the majority of patients, and were manageable with dose interruptions/reductions. Dasatinib is associated with a promising rate of response in this high-risk population.

Introduction

The prognosis for patients with chronic myeloid leukemia (CML) in blast phase (BP) is poor with an overall survival after onset of BP in the range of 3–9 months.1, 2, 3, 4 Immunophenotypically, patients with BP-CML can be classified as myeloid blast phase (MBP; 50% patients), lymphoid blast phase (LBP; 25% patients), or undifferentiated (25% patients).1

Imatinib (Glivec, Gleevec; Novartis, East Hanover, NJ, USA) is currently the first-line therapy of choice for patients in all phases of CML. Although imatinib may be effective in all stages of the disease, the probability of response decreases and the duration of response is shorter as the disease progresses. In BP, sustained complete hematologic responses (CHRs) were reported in 7.9–12.5% of patients and complete cytogenetic responses (CCyRs) in 7.4–12.5%, with an estimated median duration of overall survival of approximately 7 months.5, 6 Imatinib resistance is associated with poor prognosis7 and improved treatment options for this population are therefore needed.

Dasatinib (Sprycel; Bristol-Myers Squibb, New York, NY, USA), an oral multitargeted inhibitor of several kinases including BCR-ABL and SRC-family kinases (SFKs), was rationally designed to overcome imatinib resistance in CML.8, 9 An earlier report from this study with a minimum follow-up of 8 months presented data from 74 patients with MBP-CML (START-B) and 42 patients with LBP-CML (START-L).10 After 8 months, dasatinib had induced a major hematologic response (HR) in 34 and 31% of MBP-CML and LBP-CML patients, and a major cytogenetic response (MCyR) in 31 and 50% of patients, respectively. In addition, a CCyR was attained in 27 and 43% of patients with MBP-CML and LBP-CML, respectively. To provide a more definitive assessment of the efficacy and safety of dasatinib therapy in BP-CML, data are reported from the full cohort of 157 patients with follow-up extending to 20 months (minimum 12 months in all living patients). This additional follow-up enables a fuller assessment of dasatinib therapy in this population, including an evaluation of progression-free survival and overall survival.

Design and methods

Study methodology has been described in detail previously.10 Key points are summarized below.

Study design and treatment

The START-B and START-L trials had identical designs and were phase-II, open-label, single-arm, studies conducted in 52 centers across 19 countries. Dasatinib was administered orally to patients with imatinib-resistant or -intolerant myeloid (START-B) or lymphoid (START-L) BP-CML at a starting dose of 70 mg twice daily (b.i.d.). Patients with undifferentiated BP-CML were not included in these studies. Four weeks after commencing therapy, dose escalation to 100 mg b.i.d. was permitted for patients with loss of, or an inadequate, response. The dose could be reduced to 50 mg b.i.d., and further to 40 mg b.i.d. if required, in response to cytopenias or non-hematologic toxicities. For more severe toxicities, dose interruption was permitted until recovery occurred, and dosing recommenced at the full or a reduced level depending on predefined criteria. Patients received dasatinib until disease progression, intolerable toxicity, or withdrawal from the study.

Definitions for BP-CML, imatinib resistance or intolerance, and for disease progression were as previously reported.10

Patient evaluations

The definitions of response were as previously reported.10 HR was monitored with once-weekly complete blood counts. A major HR was defined as CHR or no evidence of leukemia. Cytogenetic responses were evaluated by once-monthly bone marrow aspirates/biopsies for the first 3 months and every 3 months thereafter. A MCyR was defined as CCyR or PCyR. A pre-dose baseline blood sample was collected for BCR-ABL mutation analysis.

Study drug toxicities were assessed continuously. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Chest X-rays, with or without computed tomography scan of the chest, were performed in all patients within 4 weeks of initiation of study therapy and also in any patient who developed respiratory symptoms.

Statistical analysis

Efficacy analyses were performed for all patients who received at least one dose of dasatinib. Two-sided 95% exact confidence intervals (CIs) were calculated for responses using the Clopper–Pearson method.11 Duration of response was measured from the first day that relevant criteria were met (providing these were confirmed later) until either progression or death; response duration was censored for patients who discontinued for reasons other than progression or death at the time of their last assessment. Progression-free survival and overall survival were estimated by Kaplan–Meier methodology.

Patients undergoing subsequent SCT

Patients who withdrew from the study to receive stem-cell transplantation (SCT) were censored for both progression-free survival and overall survival at the time of their withdrawal for SCT. These included 19 patients: 12 (11%) from the MBP-CML cohort and seven (15%) from the LBP-CML cohort.

Results

Patient demographics and disease characteristics

Baseline demographics and disease characteristics were representative of patients with CML in BP (Table 1). A total of 157 patients (109 with MBP-CML; 48 with LBP-CML) were treated. The majority of patients (90%) were resistant to imatinib, with over half having received a maximum dose of imatinib of >600 mg per day. Because of the small numbers of imatinib-intolerant patients (MBP-CML, n=10; LBP-CML, n=6), combined data are reported for imatinib-resistant and imatinib-intolerant subgroups.

Table 1 Patient demographics and baseline characteristics

Efficacy

Hematologic and cytogenetic response

Fifty percent of patients with MBP-CML and 40% of patients with LBP-CML achieved an HR for at least 4 weeks with dasatinib (Table 2). A major HR was attained in 31 and 35% of evaluable patients with MBP-CML and LBP-CML, respectively, including CHR in 25 and 29% of patients, respectively. Median duration of major HR to dasatinib was not reached for patients with MBP-CML (Figure 1a). In patients with LBP-CML, major HRs had a median duration of 4.9 months (range: 1.4+ to 14.2+ months). The median time to major HR was 64 days (range: 1–12 months) for patients with MBP-CML and 36 days (range: 1–10 months) for patients with LBP-CML.

Table 2 Best confirmed hematologic and cytogenetic responses to dasatinib
Figure 1
figure1

Duration of major hematologic response (a) and duration of major cytogenetic response (b), associated with dasatinib treatment, in patients with chronic myeloid leukemia in myeloid blast phase or in lymphoid blast phase.

Thirty-three percent of patients with MBP-CML and 52% with LBP-CML achieved a cytogenetic response with dasatinib therapy (Table 2). In the MBP-CML and LBP-CML cohorts a MCyR was attained by 33 and 52% of patients, respectively. For patients with LBP-CML, MCyRs to dasatinib had a median duration of 5.6 months (95% CI, 3.1–7.9). Median duration of response had not been reached for patients with MBP-CML (Figure 1b). Median time to MCyR was 56.5 and 30 days for patients with MBP-CML and LBP-CML, respectively. A CCyR was achieved in 26% of the MBP-CML group and 46% in the LBP-CML group.

Major HR rates according to prior highest imatinib dose in patients with MBP-CML were 33% (18/54; CHR 30%, 16/54) following prior imatinib 400–600 mg, and 35% (19/54; CHR 24%, 13/54) following imatinib >600 mg. Corresponding MCyR rates were 31% (17/54; CCyR 26%, 14/54) following prior imatinib 400–600 mg per day, and 35% (19/54; CCyR 26%, 14/54) following prior imatinib >600 mg. In patients with LBP-CML, major HR rates according to prior imatinib were 36% (8/22; CHR 32%, 7/22) for those who had received imatinib 400–600 mg, and 36% (9/25; CHR 28%, 7/25) following imatinib >600 mg. MCyR rates in patients with LBP-CML were 50% (11/22; CCyR 45%, 10/22) following imatinib 400–600 mg, and 56% (14/25; CCyR 48%, 12/25) following prior imatinib >600 mg.

Among the 32 patients with MBP-CML who had any extramedullary involvement at baseline, dasatinib treatment resulted in a major HR in 31%, a CHR in 25%, a MCyR in 31%, and a CCyR in 19%. Among the 14 patients with LBP-CML who had extramedullary involvement, response rates were major HR 36%, CHR 29%, MCyR 36% and CCyR 36%.

Analysis of efficacy by stem-cell transplantation status

Rates of major HR were similar for both cohorts of patients irrespective of prior SCT status, with response rates for patients who had previously undergone SCT and for those with no prior SCT reaching 33 and 34% (MBP-CML) and 33 and 36% (LBP-CML), respectively. Rates of MCyR for patients with prior SCT and with no prior SCT were 27 and 34% (MBP-CML), and 60 and 48% (LBP-CML), respectively.

Analysis of efficacy by baseline BCR-ABL mutational status

Baseline BCR-ABL kinase domain mutation data were available for 98 of 109 patients with MBP-CML and 46 of 48 patients with LBP-CML (Table 3). Mutations were present in 42 and 65% of patients in the MBP-CML and LBP-CML cohorts, respectively.

Table 3 Response by preexisting BCR-ABL mutations

For patients with MBP-CML, response rates to dasatinib were similar irrespective of baseline BCR-ABL mutation status. In patients with no mutation or any mutation, major HRs were induced in 33 and 32%, and CCyRs were attained in 25 and 22%, respectively. In the LBP-CML cohort, major HRs were induced in 44 and 30% in patients with no mutation or any mutation, respectively; corresponding values for CCyR were 50 and 27%.

Two patients with MBP-CML had a BCR-ABL mutation in amino acid F317 and best responses attained were a minor HR with no cytogenetic response in one patient, and a minor HR with CCyR in the other patient (duration of MCyR in this patient was 54 days). In the LBP-CML cohort, one patient had a mutation in amino acid F317; best responses achieved were no HR with CCyR (duration of MCyR was 151+ days (censored)).

Progression-free survival

Median progression-free survival was 6.7 (95% CI, 3.5–10.2) months, and 3.0 (95% CI, 2.3–5.0) months in patients with MBP-CML vs LBP-CML, respectively (Figure 2a). In the MBP-CML cohort, median progression-free survival was 6.7 vs 3.6 months in patients with no prior SCT vs prior SCT, respectively. Progression-free survival was similar for patients in the LBP-CML cohort with no prior SCT vs prior SCT (median 2.8 vs 3.1 months, respectively).

Figure 2
figure2

(a) Progression-free survival in patients with chronic myeloid leukemia in myeloid blast phase (MBP) or lymphoid blast phase (LBP). (b) Overall survival in patients with chronic myeloid leukemia in MBP or LBP.

Overall survival

The median overall survival of patients with MBP-CML was 11.8 months (95% CI, 7.1–no upper bound) compared with 5.3 months (95% CI, 4.0–11.4) for those with LBP-CML (Figure 2b). For patients with MBP-CML, median overall survival was 14.6 months in patients with no prior SCT vs 4.0 months in patients who had received prior SCT. In the LBP-CML cohort, median overall survival was 5.0 months in those without prior SCT and 12.8 months for those who had received prior SCT.

Of the 49 (11%) patients in the MBP-CML cohort and 37 (17%) patients in the LBP-CML cohort who died, 28 (26%) and 13 (27%) died of CML, respectively. Other reasons for death were: cardiovascular disease, one (1%) and zero; bleeding, four (4%) and four (8%); infection, nine (8%) and five (10%); study drug toxicity, two (2%) and zero; and other, five (5%) and five (10%); for patients with MBP-CML and LBP-CML, respectively.

Safety and tolerability

Overall, dasatinib had acceptable tolerability. Adverse events were controlled in most instances with either transient treatment interruptions and/or dose reductions. Pleural effusion (all grades) occurred in 36% of patients with MBP-CML and 13% of patients with LBP-CML (Table 4). Asymptomatic pleural effusions (grade 1) were detected by chest X-rays in 4 and 2% of patients with MBP-CML and LBP-CML, respectively. Symptomatic pleural effusions (grades 2–4) occurred in 32 and 10% of patients with MBP-CML and LBP-CML, respectively. Grade 3/4 pleural effusions were uncommon (MBP-CML, 15%; LBP-CML, 6%). Most instances of pleural effusion were uncomplicated and resolved with temporary dose interruption, diuretics, and/or in some patients, with steroids. The median time to appearance of grade 2–4 pleural effusions was 3.0 months (range: 0.2–18.1 months) and 2.4 months (range: 0.2–8.0 months) for patients with MBP-CML and LBP-CML, respectively. The most common other non-hematologic adverse events were diarrhea, nausea, vomiting and fatigue. Non-hematologic events were generally mild-to-moderate in intensity (grade 1 or 2), with few grade 3 or 4 events; all grade 3/4 events were recorded in 6% of patients except for febrile neutropenia (15%).

Table 4 Treatment-related adverse events

Cytopenias were noted in the majority of patients in both cohorts (Table 4). These were usually reversible and were effectively managed with transient treatment interruptions and/or reductions. As expected in this population of patients with BP-CML, a proportion of patients had severe cytopenias before initiation of dasatinib therapy (MBP-CML, all grades: 15–93%, grades 3/4: 5–43%; LBP-CML, all grades: 38–98%, grades 3/4: 4–67%). The median duration of first dasatinib dose interruption resulting from hematologic toxicity was 16.5 days for patients with MBP-CML (range 1.0–88.0) and 17 days for patients with LBP-CML (range 4.0–42.0).

Similar tolerability was reported for both imatinib-resistant and -intolerant subgroups (data not shown).

Dasatinib treatment

Dose modifications

Dose modifications occurred in the majority of patients in both cohorts. In patients with MBP-CML, 41% required dose reductions, 52% had dose escalations, and 67% required dose interruptions (23% for cytopenias, 39% for non-hematologic toxicity, 1% for a loss of response and 4% for other reasons). In the LBP-CML cohort, 13% of patients had dose reductions, 25% had dose escalations and 40% of patients required dose interruptions (21% for cytopenias, 15% for non-hematologic toxicity and 4% for other reasons).

Duration of therapy

Analysis was performed 12 months after the entry of the last patient, ensuring that all patients were followed for a minimum of 12 months. Median duration of follow-up to most recent assessment or censorship was 3.4 months (range 0.03–20.7 months), reflecting the high number of patients who discontinued or who were censored following progression/relapse, adverse events, or death. The median duration of therapy was 3.5 (<0.1–20.2) months for the total MBP-CML cohort, and 16.0 (12.2–20.2) months for patients still in the trial. The median duration of therapy for the LBP-CML cohort was 2.9 (0.10–15.6) months for the total population, and 14.7 (13.6–15.6) months for patients still in the trial. Median average daily doses of dasatinib were 135 mg for the MBP-CML cohort (range: 48–188) and 140 mg for the LBP-CML cohort (range: 32–188).

Patient withdrawals

At the time of the present analysis, 24 (22%) of MBP-CML patients and three (6%) of LBP-CML patients were still in the study. A total of 10% of MBP-CML and 4% of LBP-CML patients had discontinued therapy because of study drug toxicity. Other reasons for discontinuation included: (MBP-CML vs LBP-CML patients) disease progression (39 vs 52%), patient request (2 vs 0%), adverse events not related to dasatinib (3 vs 2%), deterioration without progression (3 vs 6%), death (11 vs 17%), non-compliance (2 vs 0%), and other reasons including allograft, SCT, increase of white blood cells and blasts in peripheral blood, and withdrawal of consent (9 vs 13%), respectively.

Discussion

Dasatinib has been shown to induce hematologic and cytogenetic responses in imatinib-resistant or -intolerant patients with CML in chronic phase, accelerated phase and BP.10, 12, 13 The results from this extended follow-up of patients with BP-CML enrolled in the START-B/-L trials,10 which includes the full cohort of 157 patients, confirms that dasatinib induces hematologic and cytogenetic responses in a significant proportion of patients with either MBP-CML or LBP-CML.

HR rates were higher in the MBP-CML cohort, whereas CyR rates were higher in the LBP-CML cohort. The MCyR rate actually exceeded the major HR in LBP-CML patients. This finding resulted from instances in which a cytogenetic response was achieved but residual cytopenias present precluded these patients being classified as having achieved a major HR. Under these circumstances, cytogenetic response might be a more valuable end point for assessing benefit to the patient. Responses usually occurred rapidly, and 81 and 47% of those patients who achieved a major HR, and 77 and 40% of those who achieved a MCyR remained progression free at the time of evaluation, for the MBP-CML and LBP-CML cohorts, respectively.

Responses occurred among patients with a broad range of different BCR-ABL mutants, supporting previous in vitro studies.14, 15 The one exception is T315I against which dasatinib has no meaningful activity. One patient with the T315I mutation had a transient MCyR to dasatinib (54 days), but this may have been because of the copresence of transcripts with a different BCR-ABL mutation (F317L), as T315I is known to be insensitive to dasatinib inhibition.14

BP CML is frequently associated with the development of additional chromosomal abnormalities besides the Philadelphia chromosome (Ph) as well as activation of other pathways. Thus, various mechanisms of BCR-ABL-independent resistance may contribute to imatinib insensitivity.16 In addition to its potent inhibition of BCR-ABL, dasatinib inhibits various members of the SFKs in vitro,8 which may contribute to its efficacy in patients with BP-CML. Various in vitro and in vivo evidence suggests that SFKs are involved in BCR-ABL oncogenic activities, particularly in Ph-positive ALL,17, 18, 19, 20, 21 and that aberrant SFK signaling may mediate a BCR-ABL-independent mechanism of imatinib resistance.22, 23, 24, 25 However, the extent to which SFK inhibition contributes to the clinical efficacy of dasatinib in CML in blast (or any) phase is currently not known.

In this study, dasatinib was generally well tolerated. As in previous trials, fluid retention was recorded in this longer term follow-up. In MBP-CML patients the incidence of all grades of pleural effusion at a minimum follow-up of 12 months was 36% (30% at 8 months)10 with grades 3/4 pleural effusion rates similar at 8 and 12 months minimum follow-up (13 vs 14%, respectively). For LBP-CML patients, the incidence of grade 3/4 pleural effusion at a minimum of 12 months follow-up was 6 vs 4% at 8 months follow-up. In most instances, pleural effusion can be managed with diuretic and/or steroid administration.26 Currently, the mechanism by which dasatinib induces pleural effusions is not clear. One hypothesis is that it might be related to inhibition of platelet-derived growth factor receptor (PDGFR)-β, which regulates interstitial fluid homeostasis by the PI3K pathway.27 However, imatinib and nilotinib also inhibit PDGFR-β, albeit less potently, but pleural effusions occur infrequently in patients treated with these agents. Alternatively, an immune-mediated mechanism has recently been suggested.28

Although the majority of patients experienced cytopenias, rates were similar to those reported at 8 months’ follow-up, suggesting that most of the myelosuppression occurs early during the course of therapy.10 This is consistently what occurs with other tyrosine kinase inhibitors, where most cytopenias are observed during the first few months of therapy.29, 30 The high incidence of cytopenias during dasatinib treatment has been interpreted as representing the rapid elimination of the predominant malignant clone, with the remaining few normal hematopoietic progenitors unable to sustain hematopoiesis. According to this hypothesis, cytopenias may reflect the antileukemic effect of dasatinib against BCR-ABL and the very high proportion of Ph-positive hematopoietic cells present in patients with BP-CML. Baseline cytopenias in these heavily treated patients may have also contributed to the high incidence rates. Regardless of the mechanism, cytopenias could be managed effectively in most instances by transient dose interruption and/or reduction. In some instances, growth factors may assist in managing persistent cytopenias, although further investigation regarding the safety of this approach is required (Quintas-Cardama et al., Blood 2006: 108; 613a (abstract 2163)). Careful monitoring of blood counts in patients with BP-CML receiving dasatinib after failure of imatinib is warranted.

Other dasatinib-induced toxicities observed in these patient populations were generally manageable and there was a low rate of discontinuation of therapy because of toxicity. The adverse event profile of dasatinib in this setting compares favorably with that of alternative therapeutic choices for this disease state, such as cytotoxic chemotherapy.

In summary, the results reported here demonstrate that dasatinib induces hematologic and cytogenetic responses in a significant proportion of patients with either MBP-CML or LBP-CML who had failed imatinib therapy. Despite the high response rate, relapses eventually occur in most patients. Dasatinib may create the opportunity for some of these patients to undergo allogeneic SCT. For those patients not eligible for transplant, it would be important to explore options such as dasatinib-based combinations to try to improve long-term outcome.

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Acknowledgements

We acknowledge the key contributions made by the remaining primary investigators of this trial: JJ Garcia (Argentina); T Hughes, B Van Leeuwen (Australia); P Valent (Austria); G Verhoef (Belgium); CA De Souza, PE Dorlhiac-Llacer (Brazil); P Laneuville (Canada); K Porkka (Finland); G Marit, J Reiffers, F Maloisel, J-L Harrousseau (France); MC Müller (molecular analyses), T Fischer (Germany); A Nagler (Israel); F Ferrara (Italy); J-H Lee (South Korea); W Schroyens (The Netherlands); P Caguioa (Philippines); B Simonsson, M Ekblom (Sweden); A Gratwohl (Switzerland); P-M Chen (Taiwan); S Jootar (Thailand); T Holyoake (UK); A Rapoport, R Larson, C Schiffer, R Stone, A Greco, S Goldberg, K Bhalla, S Petersdorf, P Emanuel (USA). This study was supported by research funding from Bristol-Myers Squibb. Professional writing and editorial assistance, funded by Bristol-Myers Squibb, was provided by Gardiner-Caldwell US.

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Correspondence to J Cortes.

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Data contained within this article were presented at the American Society of Hematology Annual Meeting in Orlando, FL, 9–12 December 2006.

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Cortes, J., Kim, DW., Raffoux, E. et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 22, 2176–2183 (2008). https://doi.org/10.1038/leu.2008.221

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Keywords

  • dasatinib
  • chronic myeloid leukemia
  • blast phase
  • BCR-ABL
  • SRC
  • imatinib resistance

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