Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study

Key Points Imatinib-resistant/-intolerant patients with chronic myeloid leukemia in chronic phase can experience long-term benefit with dasatinib. Early (3- and 6-month) molecular and cytogenetic responses were associated with improved progression-free survival and overall survival.

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Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

Journal of Clinical Oncology ◽

10.1200/jco.2009.21.8230 ◽

2009 ◽

Vol 27 (25) ◽

pp. 4204-4210 ◽

Cited By ~ 197

Author(s):

Timothy Hughes ◽

Giuseppe Saglio ◽

Susan Branford ◽

Simona Soverini ◽

Dong-Wook Kim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Resistance ◽

Mutational Status ◽

Imatinib Resistant

Purpose Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.

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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 ◽

10.1182/blood.v110.11.736.736 ◽

2007 ◽

Vol 110 (11) ◽

pp. 736-736 ◽

Cited By ~ 6

Author(s):

Hagop M. Kantarjian ◽

Philippe Rousselot ◽

Ricardo Pasquini ◽

Nelson Hamerschlak ◽

Jerzy Holowiecki ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Reduction ◽

Myeloid Leukemia ◽

Chronic Phase ◽

High Dose ◽

Hematologic Toxicity ◽

Inadequate Response ◽

Imatinib Resistant ◽

Grade 3

Abstract Resistance to imatinib is a well-recognized problem in chronic-phase chronic myeloid leukemia (CP-CML). Increased potency of BCR-ABL inhibition by escalating imatinib doses to 800 mg/d (‘high-dose imatinib’) can be effective in some cases that are resistant to lower doses, but tolerability and durability of response limit the utility of this approach. Dasatinib (SPRYCEL®) has been shown to be effective in imatinib-resistant CML and its potency against BCR-ABL relative to imatinib (325-fold more potent against BCR-ABL in vitro) as well as its activity against nearly all imatinib-resistant BCR-ABL kinase domain mutations auger its potential in this setting. In this international phase-II study, 150 patients with CP-CML resistant to imatinib 400–600 mg/d were randomized on a 2:1 basis to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). Crossover was permitted for confirmed progression, lack of major cytogenetic response (MCyR) at 12 weeks, or intolerance despite dose reduction (grade 3–4 non-hematologic toxicity). Dasatinib dose could be escalated to 90 mg BID for inadequate response at 12 weeks, or reduced to 50 or 40 mg BID for toxicity. Dose reduction of imatinib to 600 mg/d was allowed for patients who had not previously received that dose. Median treatment duration with dasatinib was 13.7 mo and 3.1 mo with imatinib. With a median follow-up of 15 mo, complete hematologic response (CHR) rates were 93% and 82% for patients receiving dasatinib and high-dose imatinib, respectively (p=0.034). Dasatinib was also associated with higher MCyR rates (52% vs 33%, p=0.023); the difference being attributable to complete cytogenetic responses (40% vs 16%, p=0.004). For patients with no prior CyR to imatinib, 49% achieved a MCyR with dasatinib vs 7% with high-dose imatinib. Major molecular responses were also more frequent with dasatinib (16% vs 4%, p=0.038). Responses achieved with dasatinib were highly durable, and superior to historic experience with imatinib. Analyses of progression-free survival (PFS) favored dasatinib (hazard ratio [HR] 0.14, p<0.0001). Results were consistently in favor of dasatinib for PFS irrespective of the prior imatinib dose received (400 mg/d - HR 0.10, p=0.0177; 600 mg/d - HR 0.15, p=0.0005). Grade 3–4 non-hematologic toxicity was minimal for both treatment groups. All-grade superficial edema (15% vs 43%) and fluid retention (30% vs 45%) were less common with dasatinib than imatinib, whereas pleural effusion (17% vs 0%; grade 3–4, 4% vs 0%) was more common. Cytopenia was more frequent and severe with dasatinib. Treatment discontinuation attributable to toxicity occurred in 7% of patients receiving dasatinib and 18% treated with imatinib. The overall benefit-risk assessment favors dasatinib relative to high-dose imatinib in CP-CML patients with resistance to 400–600 mg imatinib. Updated results reflecting a minimum follow-up of 2 years will be presented.

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