Nilotinib in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib-resistance or -intolerance: Update of a phase II study

Coutre, Philipp le; Giles, Francis J.; Apperley, JF; Ottmann, O. G.; Larson, RA; Haque, Ariful; Gallagher, Neil J.; Rosti, G.; Cortés, Jorge E.; Kantarjian, Hagop

doi:10.1200/jco.2008.26.15_suppl.7050

Cited by 17 publications

(18 citation statements)

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“…The efficacy of another Bcr-Abl inhibitor, nilotinib (Tasigna, Novartis), has recently been evaluated in CML-AP. 29 In an open-label, phase 2 study among 136 patients (median treatment duration, 210 days), a confirmed HR was achieved in 54% (69 of 129) with 34 patients (26%) achieving a CHR. Major CyR was achieved by 40 patients (31%) with 24 patients (19%) achieving a CCyR.…”

Section: Discussionmentioning

confidence: 99%

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Kantarjian

Cortes

Kim³

et al. 2009

Blood

151

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Dasatinib is the most potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Studies have demonstrated the benefits of dasatinib 70 mg twice daily in patients with acceleratedphase chronic myeloid leukemia intolerant or resistant to imatinib. A phase 3 study compared the efficacy and safety of dasatinib 140 mg once daily with the current twice-daily regimen. Here, results from the subgroup with acceleratedphase chronic myeloid leukemia (n ‫؍‬ 317) with a median follow-up of 15 months (treatment duration, 0.03-31.15 months) are reported. Among patients randomized to once-daily (n ‫؍‬ 158) or twice-daily (n ‫؍‬ 159) treatment, rates of major hematologic and cytogenetic responses were comparable (major hematologic response, 66% vs 68%; major cytogenetic response, 39% vs 43%, respectively). Estimated progression-free survival rates at 24 months were 51% and 55%, whereas overall survival rates were 63% versus 72%. Once-daily treatment was associated with an improved safety profile. In particular, significantly fewer patients in the once-daily group experienced a pleural effusion (all grades, 20% vs 39% P < .001). These results demonstrate that dasatinib 140 mg once daily has similar efficacy to dasatinib 70 mg twice daily but with an improved safety profile. This trial is registered at www. IntroductionChronic myeloid leukemia (CML) is characterized by a triphasic natural course comprising a chronic phase (CP), typically followed by an accelerated phase (AP), and finally a blast phase (BP). 1,2 Approximately two-thirds of patients progress to BP via AP with a median survival for patients in AP of 1 to 2 years. 1,3 Although the mechanisms behind progression to advanced phase disease in CML have not been fully elucidated, several processes may play a role, including additional cytogenetic abnormalities (clonal evolution), genetic mutations and deletions, and up-regulation of specific genes. [3][4][5][6] Current first-line therapy for AP-CML is imatinib mesylate (Glivec [in the United States, Gleevec]; Novartis, Basel, Switzerland), an oral tyrosine kinase inhibitor of BCR-ABL. 7-9 Although imatinib induces notable hematologic and cytogenetic responses in patients with accelerated-phase chronic myeloid leukemia (CML-AP), these responses are frequently short-lived, with a median progression-free survival (PFS) of 8.8 months. 7 Development of resistance to imatinib represents an important clinical issue affecting approximately 50% of patients with CML-AP within 2 years of treatment. 10 Because progression on imatinib is associated with poor prognosis, 11 alternative treatment options are required.Dasatinib (SPRYCEL; Bristol-Myers Squibb, Stamford, CT) was the first agent approved to overcome the problems of imatinib therapy in patients with CML. Dasatinib is structurally unrelated to imatinib and is approximately 325-fold more potent than imatinib at inhibiting unmutated BCR-ABL in vitro. 12 Preclinical studies have also shown that dasatinib has potent activity against ot...

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Section: Discussionmentioning

confidence: 99%

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Kantarjian

Cortes

Kim³

et al. 2009

Blood

151

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“…Correlative studies in mice and cell lines revealed that imatinib-induced inhibition of ABL led to an endoplasmic reticulum stress response, collapse of the mitochondrial membrane potential, Figure 1 Structures of current and investigational tyrosine kinase inhibitors for the treatment of CML. 100 Adapted from Weisberg et al 106 …”

Section: Differential Kinase Inhibition Profiles Of Tkis In CML Treatmentioning

confidence: 99%

“…Cross-intolerance of dasatinib treatment is most typically a result of neutropenia and/or thrombocytopenia. [95][96][97][98][99][100] Patients who switched to dasatinib because of imatinib intolerance subsequently discontinued dasatinib due to intolerance at similar levels to nilotinib.…”

Section: C-kit Inhibition: Dermatologic Toxicity Myelosuppression Anmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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“…The incidences of grade 3-4 thrombocytopenia and neutropenia were similar to that observed with the dasatinib 100 mg once daily [77]. Nilotinib's specificity for the ABL kinase and comparably minimal inhibition of c-KIT and PDGFR also alters its toxicity profile.…”

Section: Nilotinibmentioning

confidence: 48%

“…After a follow-up of at least 12 months, MCyRs were achieved in 31% of patients [77]. At 12 months the percentage of patients who were progression-free was 57%, and the overall survival rate was 81%.…”

Section: Nilotinibmentioning

confidence: 79%

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

Martin

DiPersio

2009

Oncol Rev

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Tyrosine kinase inhibitors (TKIs) are the mainstay for treatment of chronic myelogenous leukemia (CML). Imatinib was the first TKI approved for use in CML, but resistance to this therapy has emerged as a significant issue, and second-line options are often necessary. Increased-dose imatinib may elicit responses in some patients, but clinical evidence suggests only a minority experience sustained benefit. The second-generation TKIs, dasatinib and nilotinib, have demonstrated efficacy in patients resistant or intolerant to imatinib. Changes in therapy, with the aim of inducing durable response, should occur promptly after imatinib failure is identified as all agents are more effective in chronic phase disease than in later stages. Selection of second-line agents should be driven by efficacy and safety: dasatinib may be more effective in patients with P-loop or F359C mutations; nilotinib may be more effective in those with F317L mutations.

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Nilotinib in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib-resistance or -intolerance: Update of a phase II study

Cited by 17 publications

References 0 publications

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

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