Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: Two-year follow-up of a randomized phase 2 study (START-R)

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230-1402, USA.
Cancer (Impact Factor: 4.89). 07/2009; 115(18):4136-47. DOI: 10.1002/cncr.24504
Source: PubMed


In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg.
A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49).
At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012).
After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.

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Available from: Nelson Hamerschlak,
    • "Results from a 15-month follow up of a phase 2 dasatinib study (START-C trial; n = 387) in imatinib-resistant/intolerant CP-CML patients showed that dasatinib-induced notable responses, with 91% and 59% patients achieving complete hematologic response (CHR) and MCyR respectively while PFS and OS were 90% and 96%, respectively.[8] In another phase 2 study where imatinib-resistant CP-CML patients were randomized to receive either dasatinib (n = 101) or high dose imatinib, (800 mg/day, n = 49) after a 2-year follow-up dasatinib demonstrated higher rates of CHR (93% vs 82%; P = 0.034), MCyR (53% vs 33%; P = 0.017), CCyR (44% vs 18%; P = 0.0025) and a better PFS (86% vs. 65%; P = 0.0012) than high dose imatinib.[9] Similarly, in a phase 2 nilotinib study in imatinib-resistant/intolerant CP-CML patients (n = 321), rates of MCyR and CCyR after a minimum follow up of 19 months were 59% and 44%, respectively, and the estimated survival at 24 months was 88%.[10] "
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    ABSTRACT: The prognosis of patients with chronic myeloid leukemia (CML) has changed radically since the advent of imatinib mesylate, a selective inhibitor of BCR-ABL tyrosine kinase. Shortly thereafter, more potent BCR-ABL inhibitors (dasatinib and nilotinib) were introduced for use in patients resistant to or intolerant of imatinib. All three drugs are now approved for initial therapy for chronic phase CML. Response to tyrosine kinase inhibitor (TKI) treatment is assessed with standardized quantitative reverse transcriptase polymerase chain reaction (Q-RTPCR) and/or cytogenetics at 3, 6 and 12 months. Clinical trials have clearly demonstrated that early and deeper cytogenetic and molecular response to TKI therapy is associated with lower rate of disease progression and improved long-term outcomes. In recent times, molecular response as determined by BCR-ABL transcript levels at defined time points is rapidly gaining popularity as a predictive marker for subsequent outcomes in CML. Optimal response is defined as BCR-ABL transcript levels of ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward while >10% at 6 months and >1% from 12 months onward define failure. Patients who do not achieve molecular milestones at 3 or 6 months with 3 months being highly predictive are less likely to achieve cytogenetic responses eventually; early identification of such patients who have a low probability of achieving an adequate response are thus candidates for alternative treatment. Review of literature by electronic search of MEDline, Google Scholar was done using keywords and data was identified and systematically evaluated.
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    • "Spostrzeżenie to ma dużą wartość praktyczną szczególnie w przypadku chorych, u których stan biologiczny nie pozwala na wykonanie alogenicznej transplantacji komórek hemopoetycznych. Podobnie jak w poprzednim, także w tym badaniu tolerancja dazatynibu była dobra, również u osób z objawami uprzedniej nietolerancji IM [41]. Analiza tolerancji dazatynibu w badaniach START wykazała , że skuteczność dazatynibu stosowanego w dawkach 100 mg 1 Â, 50 mg 2 Â, 140 mg 1 Â i 70 mg 2 Â dziennie w fazie przewlekłej jest porównywalna, a dawkowanie 1 Â 100 mg dziennie związane jest z istotnie mniejszą częstością występowania objawów toksyczności terapii, rzadszą koniecznością redukcji dawki i stosowania przerw w leczeniu [42] [43]. "
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    Acta haematologica Polonica 10/2013; 44(4). DOI:10.1016/j.achaem.2013.07.008
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    • "CCyR rates were 44 and 18 %, respectively (p = 0.0025). Although no formal statistical comparison between the study arms was planned, the data suggested relatively greater efficacy for dasatinib compared with imatinib (Kantarjian et al. 2009a). These responses were also durable, as a pooled analysis (N = 387) of the START-C and START-R studies showed that 90 % of patients achieving a CCyR maintained this level of response after 24 months (Baccarani et al. 2008). "
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