Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3428-3428
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Yin Cameron ◽  
Elizabeth Burton ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

Clinical Characteristics and Outcome of Patients (pts) with V299L BCRABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1105-1105
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Elizabeth Burton ◽  
Jorge Cortes
Keyword(s):  
Kinase Inhibitors ◽  
Mutation Detection ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance

Abstract Background. Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. Aims. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML and Ph+ ALL at our institution, and the response following change of therapy. Results. V299L mutation was detected in 14 pts (12 CML, 2 Ph+ ALL): 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 47 pts (19%) who developed mutations on dasatinib therapy, and 4 among 18 pts (22%) who developed mutations on bosutinib therapy (p&lt;0.001); none of the 49 pts who developed mutations on nilotinib therapy acquired V299L. Median age was 55 years (range, 26–82 years). Seven pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). Nine pts developed V299L after being on dasatinib for a median of 14 mos (range, 1–30 mos); 7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib. In 4 pts V299L appeared after receiving bosutinib as 3rd TKI after imatinib and dasatinib failure, for a median of 5 mos (range, 2–8 mos). None of the 11 evaluable pts treated with 2nd generation TKIs had V299L at start of therapy. The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 4 bosutinib) was complete hematologic response only in 5 (36%, 4 dasatinib, 1 bosutinib), minor cytogenetic response in 2 (14%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (29%; 3 dasatinib, 1 bosutinib); no response in 3 pts (1 dasatinib, 2 bosutinib). The median duration of response was 14 mos. V299L was associated with primary resistance in 3 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 4 pts were in chronic (CP), 7 in accelerated (AP), 1 in blast phase (BP), and 2 with Ph+ ALL. 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 responded (major molecular response sustained for 16+ mos). One pt received INNO406 and did not respond. One pt with Ph+ ALL was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 8 mos (range, 3–29 mos), from the time V299L was detected, 4 died (1 CP, 1 BP, 2 ALL). The estimated 2-year survival from mutation detection was 74%. Conclusion. V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation.

For CML Patients in Chronic Phase Who Achieve a Cytogenetic Response to Imatinib the Finding of a BCR-ABL Mutation Predicts for Progression to Advanced Phase but It Has No Such Significance in Primary Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 323-323
Author(s):  
Hugues de Lavallade ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Simon Wagner ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Genomic Instability ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Advanced Phase

Abstract We analysed outcome for 211 CML patients treated with imatinib in chronic phase (CP) (99 newly diagnosed and 112 late chronic phase) who were screened for BCR-ABL kinase domain (KD) mutations using direct sequencing regardless of the response status. When a mutation was found all available previous cDNA samples were analysed by pyrosequencing to establish the date of its first occurrence and subsequent kinetics. The median age of patients was 47.4 years. The Sokal risk score was ‘low’ in 57 patients, ‘intermediate’ in 82 and ‘high’ in 72. The median follow up from starting imatinib was 45 months (rage 6 to 89 months). A mutation was detected in 34 of the 211 patients (16%) at a median time of 27 months from starting imatinib. Twenty-two different mutations were identified, the most frequent being M244V (n=6) and F359V (n=3). When studied serially by pyrosequencing the size of the mutant subclone never exceeded 50% of total BCR-ABL transcripts in 8 patients, while in 17 patients it exceeded 90% on at least one occasion. 48 patients discontinued imatinib while still in CP and received either dasatinib, nilotinib or an allograft. The overall progression-free survival (absence of advanced phase) at 5 years was 73%. Major (MCyR) and complete (CCyR) cytogenetic responses were achieved by 153 and 123 patients respectively; 56 patients achieved major molecular response. 24% of the patient with up front cytogenetic resistance had a mutation while 40% of the patients with acquired cytogenetic resistance develop a mutation. In an-intention-to-treat analysis, patients harboring a mutant clone had a poorer PFS at 4 years (78% versus 57%, p=0.0014). The various mutations had no differential effects based on their known imatinib IC50. By multivariate analysis, factors associated with worse PFS were the presence of a KD mutation and failure to achieve CCyR (relative risks for PFS 2.6 and 8.7 respectively, p=0.002). Interestingly, the adverse effect of the presence of a KD mutation was restricted to the patients who achieved a MCyR (PFS 91% versus 62% at 5 years, p = 0.0006); it had no adverse impact on patients who failed to achieve a MCyR (PFS 42% and 49%, p=0.73). Similar results were found when the analysis was repeated according to the achievement of CCyR (data not shown). Surprisingly patients with a continuously low percentage (≤50%) of mutated vs wild type (>50%) clones fared worse than patients in whom the mutated clone became the predominant population (PFS 14% vs 69% respectively, p=0.0005). Comparable results were obtained when the patients were censored at the point of discontinuing imatinib, correcting for the effects of subsequent treatment, ie allografting (data not shown). The fact that the adverse effect of a mutation seems to be restricted to patients who had achieved cytogenetic response, the fact that mutations present at low level seemed to have a remarkable adverse effect and the fact that the in-vitro level of resistance to imatinib of the specific mutation did not affect the PFS could all be explained if the development of a mutation is only a reflection of the genomic instability of the disease that leads to secondary resistance to imatinib and eventually to transformation. Thus genomic instability may be less important in explaining primary resistance to imatinib and eventual transformation in patients with up-front resistance.

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Nilotinib Efficacy According to Baseline BCR-ABL Mutations in Patients with Imatinib-Resistant Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3216-3216 ◽  
Author(s):  
Andreas Hochhaus ◽  
Dong-Wook Kim ◽  
Giovanni Martinelli ◽  
Timothy P. Hughes ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Clonal Selection ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Abl Kinase ◽  
Imatinib Resistant

Abstract Resistance or intolerance to imatinib in CML-CP occurs in ~20–30% of cases. The most frequent cause of resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I) indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy. The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50 ≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to nilotinib in vitro (IC50 &gt;150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, 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 28% of pts. In pts with detectable mutations, 51% achieved MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib (MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations: 34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11). Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29% vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline mutations.

Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1943-1943
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

scholarly journals Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5442-5442
Author(s):  
Eran Tallis ◽  
Hagop M. Kantarjian ◽  
Catherine Kendall Major ◽  
Maria Vazquez ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Equal Distribution ◽  
Genetics Research

Abstract Background: The introduction of tyrosine kinase inhibitors (TKIs) as the first line of treatment for CP-CML changed the natural history of the disease. The life expectancy of CML pts is now approaching that of the general population, with more pts having the option to discontinue treatments after achieving deep molecular response (DMR). In this study we sought to explore long-term outcomes of CML survivors including late relapses, durability of response, comorbidities, and feasibility of treatment discontinuation. Methods: We performed a chart review of pts with CP CML treated at our institution with frontline TKIs who have survived at least 5 yrs from initiation of their treatment. Results: We analyzed 388 pts treated with frontline TKIs between the years 2000-2011: 57% started treatment with imatinib, 22% with nilotinib and 21% with dasatinib. We grouped pts into two cohorts: those who received only one TKI throughout the entire follow up period (n= 299; 77%) and those who changed TKIs due to relapse or toxicity (n=89; 23%). The median follow up duration was 12 yrs [5-19] for both groups. Median overall Survival (OS) for pts surviving at least 5 yrs was not reached for those remaining on one TKI whereas OS for those who changed TKIs was 151 mo (p=0.27). For those who changed therapy, there was an equal distribution of initial TKI (p=0.67). Seventy patients (18%) required a change in TKI more than 5 years after starting treatment. After 5 years of treatment best response was MR4.5 in 66%, major molecular response (MMR) in 20%, complete cytogenetic response (CCyR) in 8%, partial cytogenetic response (PCyR) in 1%, and complete hematologic response (CHR) in 3%. Nine patients had lost CHR (2%) and 4 had progressed to blast phase before the 5 yr mark. At last follow up, 77% of patients had achieved MR4.5, 12% MMR, 3% CCyR, 1% PCyR, and 4% CHR. Eleven patients lost CHR (3%) with 6 patients progressing into blastic phase. Ninety two percent of patients with MR4.5 at 5 years of treatment maintained their response, and 8% lost MR4.5: 6% to MMR, 1% to CCyR, and 1% to CHR. Sixty six percent of patients with MMR at 5 years of treatment improved their response to MR4.5, 21% maintained MMR and 13% lost response - 5% to CCyR, 5% to CHR, and 3% lost CHR. Fifty five percent of patients in CCyR at 5 years improved their response to MMR (35%) or MR4.5 (19%) while 26% of patients lost cytogenetic response. Out of the patients who improved their response, 29% did so after starting a new TKI. More patients who never changed TKI achieved MR4.5 compared to those who who changed TKIs at some point (70%) (p=0.0021). Treatment discontinuation was considered for pts who sustained MR4.5. Forty nine pts (13%) discontinued TKIs after a median time of 9 yrs [5-17]. Withdrawal symptoms were observed in 24% of pts and primarily included joint or muscle pain. After a median follow up of 2 yrs [0-7] after discontinuation, 90% of pts remained in MR4.5. Five pts (10%) lost MR4.5 after discontinuation: 4 (8%) remained in MMR and 1 (2%) lost MMR to CHR. All these patients resumed therapy except for one who has sustained MMR still with no treatment. Patient's comorbidities were evaluated at initiation of treatment, at 5 yrs of follow up and at last follow up. An increase in patients' comorbidities was more pronounced for HTN and cardiovascular disease reaching up to 47% and 37% of patients at last follow up vs 26% and 13% at baseline respectively. Depression and/or anxiety were seen in 7% of patients at baseline and increased to 20% of patients at last F/U. Secondary malignancies developed in 48 pts (12%), mainly prostate cancer in 11 pts, non-melanoma skin cancer in 10 pts and melanoma in 5 pts. GU and colon cancers were seen in 1% of pts. Conclusion: Survivors of CML have a generally favorable outcome. However late relapses may occur (14% in our series) often requiring a change in treatment. This underscores the need to continued monitoring beyond 5 years. Co-morbidities and second malignancies may also occur in many patients, underscoring the need for a holistic follow-up of these patients. Disclosures Bose: Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding. Ravandi:Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Jazz: Honoraria. Kadia:BMS: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Pemmaraju:Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; samus: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; daiichi sankyo: Research Funding; plexxikon: Research Funding; novartis: Research Funding; SagerStrong Foundation: Research Funding. Daver:Kiromic: Research Funding; Novartis: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy; ImmunoGen: Consultancy; Karyopharm: Research Funding; Otsuka: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Agios: Consultancy. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; cellectis: Research Funding; abbvie: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.

Stem Cell Transplant (SCT) for Patients (pts) with Chronic Myeloid Leukemia (CML) Resistant to Tyrosine Kinase Inhibitors (TKI) with BCR-ABL Kinase Domain (KD) Mutation T315I.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2120-2120
Author(s):  
Nikolai Velev ◽  
Jorge Cortes ◽  
Richard Champlin ◽  
Hagop M. Kantarjian ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Cancer Center ◽  
Molecular Response ◽  
Cell Transplant ◽  
Best Response

Abstract Background: Resistance to TKI therapy is associated with development of KD mutations in approximately 50–60% of pts. Although many imatinib-resistant mutations respond well to second generation TKI, T315I is insensitive to all currently available TKI (imatinib, dasatinib, nilotinib) in vitro and in the clinic. SCT is frequently recommended for these pts but there is no available data about the efficacy of SCT in such pts. Aims: To investigate the efficacy and safety of SCT for patients with TKI-resistant CML with a T315I mutation. Methods: We reviewed the outcome of all pts with T315I that have received a SCT at MD Anderson Cancer Center. Results: Seven pts received 8 transplants. Their median age was 44 years (yrs) (range, 26 to 64 yrs). The median time from diagnosis to SCT was 42 months (mo) (range, 9–160 mo). All pts had become resistant to with imatinib; 5 received dasatinib and 1 nilotinib after imatinib failure, and 6 pts received other additional therapy prior to SCT. At the time of SCT 2 pts were in chronic phase (CP), both in partial cytogenetic response; 2 in accelerated (AP) with active disease; and 3 in second or greater CP from lymphoid blast phase (BP) (1 in minor cytogenetic response, 2 major molecular response, 1 complete molecular response –CMR-). Six transplants were from matched unrelated donors and 2 from cord blood. Best response after SCT was CCyR in 3 (2 AP, 1 BP), CMR in 4 (2 CP, 2 BP), and 1 unknown (died early). After a median follow-up of 11 months from SCT, 4 pts are alive; the 2 transplanted in CP are alive after 11 and 42 months after SCT and in CMR; 1 pt transplanted in AP has a sustained CCyR 20 mo after SCT with persistent T315I representing 94% of transcripts by pyrosequencing; and 1 in BP has a CMR sustained 6 mo after a second SCT (relapsed 5 months after first SCT) 3 pts have died: 1 AP and 2 BP, all with relapse. Conclusion: SCT appears to be an effective strategy for pts with CML with T315I, although longer follow up is needed. Results are significantly better when pts are transplanted in CP. Thus, SCT should be considered in pts with resistance to TKI once T315I is identified, ideally in CP.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2520-2526 ◽  
Author(s):  
Deborah White ◽  
Verity Saunders ◽  
A. Bruce Lyons ◽  
Susan Branford ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Chronic Phase ◽  
Adaptor Protein ◽  
Prognostic Indicator ◽  
Molecular Response ◽  
Log Reduction ◽  
Abl Kinase ◽  
Marked Variability

AbstractMost patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 μM (median, 0.6 μM). Patients with low IC50imatinib (IC50 ≤ 0.6 μM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the low IC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib. (Blood. 2005; 106:2520-2526)

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document