on behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia Abstract Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated withimatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop orT315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.Imatinib mesylate (1 -5) is a potent and selective inhibitor of the oncogenic BCR-ABL tyrosine kinase, which is deregulated in as many as 95% of chronic myeloid leukemia (CML) patients and in f20% of adult Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients. Despite its striking efficacy, however, resistance is observed in a proportion of patients, especially those with Ph+ ALL or advanced-stage CML.Through the contribution of several research groups, the past 4 years have brought us considerable knowledge on the molecular mechanisms underlying resistance to imatinib (reviewed in ref. 6). Reactivation of BCR-ABL tyrosine kinase activity within the leukemic clone is most commonly associated with the emergence of point mutations in the ABL kinase domain that impair imatinib binding without affecting ATP
The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (⌬4-7) and by removal of exons 2 through 7 (⌬2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the ⌬4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the ⌬2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronicphase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAGmediated recombination. (Blood. 2009;
T he striking efficacy of imatinib mesylate in chronic myeloid leukemia (CML) 1,2 has established this therapy as the new standard of care for the disease. However, resistance is an emerging problem which has prompted the design of several second-generation Bcr-Abl inhibitors. One of these, dasatinib , is now in advanced clinical development. 4 In vitro assays 5,6 and crystallographic studies 7 have suggested that the less stringent conformational requirements for Bcr-Abl binding are likely to render dasatinib active against many of the kinase domain mutants responsible for imatinib resistance. One remarkable exception appears to be the T315I, which has been shown to disrupt a hydrogen bond critical for dasatinib binding and to create steric hindrance which interferes with the entrance of the inhibitor into the ATP-binding site. In order to assess which pre-existent or emerging mutations are associated with decreased clinical efficacy of dasatinib, we analyzed BCR-ABL kinase domain sequences before and during treatment in Philadelphia chromosome-positive (Ph + ) leukemia patients who failed to respond to or relapsed during dasatinib therapy. Design and MethodsIn a phase II program (sponsored by Bristol-Myers Squibb) we treated with dasatinib 70 mg twice daily a total of 45 patients with either CML (n=35) or Ph + acute lymphoblastic leukemia (ALL) (n=10) who were resistant to or intolerant of imatinib. Their median age was 50 years (range, 18-74), the median duration since the diagnosis of CML was 32 months (range, 4-158); and the median duration of imatinib treatment was 17 months (2-57). At the time of writing, with a median follow-up of 12 months (range, 1-19), 21 patients have shown evidence of either primary or acquired resistance, defined as a failure to achieve a hematologic response or loss of hematologic response during treatment, respectively. All the patients provided written informed consent to their participation in this study. Hematologic response was assessed according to the criteria already described for the phase I study.4 Cytogenetic ABSTRACT Brief ReportThe emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph + ) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph + patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317. Hematology and Medical Oncology "L. e A. Seràgnoli", S. OrsolaMalpighi Hospital, Massarenti 9, 40138 Bologna, Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selec...
Dasatinib and nilotinib are tyrosine kinase inhibitors (TKIs) developed to overcome imatinib resistance in Philadelphiapositive leukemias. To assess how BcrAbl kinase domain mutation status evolves during sequential therapy with these TKIs and which mutations may further develop and impair their efficacy, we monitored the mutation status of 95 imatinib-resistant patients before and during treatment with dasatinib and/or nilotinib as second or third TKI. We found that 83% of cases of relapse after an initial response are associated with emergence of newly acquired mutations. However, the spectra of mutants conferring resistance to dasatinib or nilotinib are small and nonoverlapping, except for IntroductionResistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in chronic myeloid leukemia (CML) and Philadelphiapositive (Ph ϩ ) acute lymphoblastic leukemia (ALL) is often caused by selection of mutations in the Bcr-Abl kinase domain (KD), [1][2][3][4][5][6][7][8][9] altering residues that are directly or indirectly critical for IM binding. To overcome this problem, novel TKIs have been developed. Dasatinib and nilotinib [10][11][12][13] have been the first ones to enter clinical evaluation and to receive marketing approval in IMresistant patients. Preclinical experience with these agents showed that they are active against several IM-resistant Bcr-Abl mutants, with the exception of T315I. 10,11,14 However, both TKIs have been hypothesized to retain their own "Achilles heels." Recent studies have tried to profile mutations that will probably emerge under dasatinib and nilotinib, inducing random mutagenesis and then selecting for cell clones retaining viability when cultured in the presence of the inhibitors. [15][16][17][18] Results suggested that, besides T315I, other mutants might be critical. To assess how Bcr-Abl KD mutation status evolves under the selective pressure of sequential therapy with novel TKIs and which mutations among those predicted by in vitro studies may indeed develop in patients who relapse on dasatinib or nilotinib, we have monitored the mutation status of 95 IM-resistant patients before and during sequential treatment with one or both of these agents. Methods Patients and definitionsThis report focuses on 95 patients (Table 1) who were referred to our laboratory for mutation analysis at the time of IM failure and who received up to 2 subsequent TKIs (dasatinib and/or nilotinib). Thirty-eight patients had chronic-phase (CP) CML, 46 patients had advanced-phase CML (accelerated-phase [AP], n ϭ 11; myeloid blast crisis [BC], n ϭ 18; lymphoid BC, n ϭ 17), and 11 patients had Ph ϩ ALL. For CML patients, IM failure was defined according to European LeukemiaNet recommendations. 19 Similar criteria were applied to define IM failure in Ph ϩ ALL. All 95 patients received a second TKI (dasatinib, n ϭ 55; nilotinib, n ϭ 40). Twenty-six of 95 patients received a third TKI after relapse on second TKI (dasatinib, n ϭ 16; nilotinib, n ϭ 10). For the purpose of this analysis, response to dasat...
The online version of this article has a Supplementary Appendix. BackgroundIn patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy. Design and MethodsWe retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphiapositive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample. ResultsMutations at relatively low levels (2-4 clones out of 200) could be detected in all patients -eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib. ConclusionsOur results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors. Haematologica 2011;96(4):552-557. doi:10.3324/haematol.2010 This is an open-access paper.Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis
The association of clonal mast cell disorders with hymenoptera allergy seems to be more specific than that with food- or drug-induced systemic reactions.
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