Impact of Molecular Markers on Response and Resistance in Midostaurin-Treated Patients with Advanced Systemic Mastocytosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 945-945 ◽  
Author(s):  
Mohamad Jawhar ◽  
Juliana Schwaab ◽  
Nicole Naumann ◽  
Sebastian Kluger ◽  
Hans-Peter Horny ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Median Time ◽  
Research Funding ◽  
Sequential Analysis ◽  
Target Genes ◽  
Systemic Mastocytosis ◽  
Molecular Response ◽  
Secondary Resistance ◽  
The Impact ◽  
Kit D816v

Abstract Systemic mastocytosis (SM) arises as a consequence of aberrant activation of KIT signaling, most commonly by acquisition of the KIT D816V mutation (>80-90% of patients). A recently reported phase-II-study exploring the efficacy and safety of midostaurin, a multi-targeted KIT inhibitor, in patients with advanced SM (advSM) has demonstrated major and partial responses in 60% of patients (Gotlib et al., NEJM 374, 2016). However, recent data have highlighted that the molecular pathogenesis of SM is complex. In particular, additional mutations in SRSF2, ASXL1 and/or RUNX1 (S/A/Rpos), seen in 60-70% of patients with advSM, have a significant adverse impact on disease phenotype and prognosis (Jawhar et al., Leukemia 30, 2016). In the current study, we evaluated the impact of molecular markers on response, resistance, progression and overall survival (OS) in midostaurin-treated advSM patients: 1) the S/A/R mutation profile at diagnosis, 2) the reduction of the KIT D816V allele burden (EAB) and 3) the dynamics of the clonal architecture. Between 2009 and 2015, 38 patients (68% male; median age 67 years; range, 48-76) with advSM [SM with an associated hematological neoplasm (SM-AHN), n=22; aggressive SM (ASM), n=3; mast cell leukemia (MCL), n=4; MCL-AHN, n=9] received midostaurin at our institution and were monitored for the KIT D816V EAB by quantitative RT-PCR (RT-qPCR). In addition, serial Next Generation Sequencing (NGS) analyses were performed in 16/25 multi-mutated patients. Median time from diagnosis of advSM to start of midostaurin was 12 months (range, 1-60). Twenty-one of 38 (55%) patients died; median OS was 29 months (range, 0-88) from start of midostaurin and 40 months (range, 5-115) from diagnosis. Three patients (8%) stopped midostaurin early (median 2 months; range, 1-4) because of intolerance. In the remaining 35 (92%) patients, median treatment duration was 13 months (range, 1-88). Progression/death occurred in 6/35 (17%) patients within the first 6 months and 5 (83%) patients were S/A/Rpos. Overall response rate (ORR) according to IWG-MRI-ECNM consensus criteria and OS were significantly different between S/A/Rpos (n=23) vs. S/A/Rneg (n=12) patients [ORR: 35% vs. 75%, P=0.01; OS: P=0.01, HR 4.5 (1.3-16.2), Figure 1A]. The maximal median reduction of KIT D816V EAB in 28 patients treated for >6 months was -29% (range, -100 to 71). Depending on the KIT D816V EAB at month 6, patients were classified as responders (≥25%, n=17) or non-responders (<25%, n=11). Responders were significantly associated with a longer median time on midostaurin (25 vs. 9 months, P=0.01) and achievement of any clinical response according to IWG-MRI-ECNM criteria (13/17 vs. 2/11 patients, P=0.006). All 4 patients who lost their KIT D816V EAB response were S/A/Rpos. In univariate analyses of multiple clinical and molecular response parameters at month 6, three parameters were significantly associated with inferior OS: reduction of KIT D816V EAB <25% (P=0.0004), serum tryptase <50% (P=0.03) and alkaline phosphatase <50% (P=0.04). In multivariate analysis, only KIT D816V EAB reduction <25% remained an independent poor prognostic marker for reduced OS (P=0.004, HR 6.8 [1.8-25.3]) and was superior to the IWG-MRI-ECNM consensus criteria (P=0.005, HR 4.7 [1.5-15.5]) (Figure 1B). Serial NGS analysis of 7 deceased patients revealed acquisition of additional mutations in RUNX1 (n=2), K/NRAS (n=3), IDH2 (n=1) or NPM1 (n=1) and/or increasing mutation allele burdens while KIT D816V EAB was either low (n=2), stable (n=1) or increasing (n=4). In contrast, two patients acquired a JAK2 V617F mutation but remained in remission on midostaurin. In summary, we have found that S/A/Rneg at diagnosis and reduction of the KIT D816V EAB ≥25% at month 6 were the most favorable predictors for survival in midostaurin-treated advSM patients. S/A/Rpos at diagnosis was associated with a more aggressive phenotype, (early) resistance/progression and poor survival. Serial sequencing during treatment also revealed that secondary resistance/transformation may be caused by expansion of sub-clones exhibiting new mutations in critical target genes independent of KIT D816V. In addition to established response parameters, sequential analysis of KIT D816V EAB and other molecular aberrations add relevant information for optimal management and response assessment in midostaurin-treated patients with advSM. Disclosures Valent: Celegene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Meggendorfer:MLL Munich Leukemia Laboratory: Employment.

Impact of Variant t(9;22) and Additional Cytogenetic Aberrations at Diagnosis on Prognosis of CML

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 355-355
Author(s):  
Armin Leitner ◽  
Susanne Saussele ◽  
Claudia Haferlach ◽  
Brigitte Schlegelberger ◽  
Gudrun Göhring ◽  
...  
Keyword(s):  
Overall Survival ◽  
Y Chromosome ◽  
Median Time ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Major Molecular Response ◽  
Cytogenetic Aberrations ◽  
The Impact

Abstract Abstract 355 Introduction: The prognostic relevance of variant t(9;22) and additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukemia (CML) is conflicting. Patients and Method: We used baseline and outcome data of 1028 patients (607 male, 421 female, median age 53, range 16–88) with chronic phase CML randomized to the German CML-Study IV (imatinib [IM] 800 mg [n=264] vs IM 400 mg [n=253] vs IM 400 mg + IFN [n=281] vs IM 400 mg after IFN failure [n=108] vs IM 400 mg + AraC [n=122]) to investigate the impact of variant t(9;22) and of clonal ACA at diagnosis on time to complete cytogenetic remission (CCyR) and major molecular response (MMR), accepted markers of prognosis. Cytogenetic analysis was performed after 24- and/or 48 h culture on G-banded metaphases. If appropriate, fluorescent-in-situ-hybridization on metaphases was used in addition. Since lack of the Y chromosome is regarded as a negligible age-related, not leukemia-associated event, those patients were excluded from evaluation. Result: In total, 123/1028 patients (12%) showed additional cytogenetic findings at diagnosis: 52/1028 patients (5.1%) had variants of the t(9;22), 33/1028 patients (3.2%) lacked the Y chromosome, 38/1028 patients (3.7%) had other additional numerical or structural aberrations. 105/1028 patients (10.2%) had only one type of additional cytogenetic finding, while 18/1028 patients (1.8%) showed ≥ 2 types of additional cytogenetic findings. 905/1028 patients (88%) had no variant t(9;22) or ACA. Median age, sex and treatment were similarly distributed (Table 1). In 45/52 patients (86.5%) with variant t(9;22), one further chromosome was involved (three way translocation), whereas in 7/52 patients (13.5%) ≥ 2 chromosomes were involved (complex variant). No involvement of the chromosomes 10, 18, 20, 21, X, or Y has been found. For patients without variant t(9;22) and ACA, with variant t(9;22), with variant t(9;22) and ACA other than –Y, and with ACA other than -Y and variant t(9;22), median time (years) to CCyR was 0.98, 0.84, 1.08 and 1.34, median time (years) to MMR was 1.4, 1.55, 1.8 and 2.17, and probability (%, confidence interval) for 2 years overall survival was 0.97 (0.96-0.98), 0.96 (0.89-0.99), 0.95 (0.90-0.99) and 0.94 (0.85-0.99), respectively. There was no difference regarding time to CCyR, time to major molecular response (MMR) and 2 years overall survival between patients with variant t(9;22) or ACA compared to those without variant t(9;22) or ACA. Conclusion: We conclude that additional chromosomal abnormalities at diagnosis have no negative prognostic impact. This finding is hypothesis generating. For confirmation of this hypothesis longer observation of the course of patients with variant t(9;22) and ACA is needed. Disclosure: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

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.

Eculizumab (ECU) Significantly Improves Health-Related Quality of Life (HRQoL) in Patients with Atypical Hemolytic Uremic Syndrome (aHUS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4772-4772 ◽  
Author(s):  
Petra Muus ◽  
Christoph Licht ◽  
Tim H. J. Goodship ◽  
Larry Greenbaum ◽  
Camille L Bedrosian ◽  
...  
Keyword(s):  
Median Time ◽  
Complement Activation ◽  
Research Funding ◽  
Extension Study ◽  
Meaningful Change ◽  
Phase Ii Trials ◽  
Long Term Treatment ◽  
Self Reporting Questionnaire ◽  
The Impact

Abstract Abstract 4772 Background aHUS is a rare, genetic, life-threatening, disease caused by chronic uncontrolled complement activation, which leads to systemic thrombotic microangiopathy (TMA). Despite plasma exchange/infusion (PE/PI), >50% of patients (pts) will either die, require kidney dialysis or have permanent renal damage within the first year of diagnosis. In addition to causing progressive organ damage, the uncontrolled complement activation and subsequent TMA might be expected to impact HRQoL. In 2 prospective, controlled, single-arm phase II trials of aHUS pts receiving ECU, a terminal complement inhibitor, TMA was stopped, there was no longer a need for PE/PI or new dialysis. In one of the trials (C08-002), dramatically, 4/5 pts on dialysis permanently discontinued dialysis as of most recent follow-up. The current analysis evaluates the impact of ECU on HRQoL in aHUS pts. Methods In trial C08-002, 17 pts with aHUS resistant to PE/PI (persistent TMA despite ≥4 PE/PI sessions 1 wk before screening) received ECU. In trial C08-003, 20 pts previously received chronic PE/PI (≥1 every 2 wks and <3 per wk for ≥8 wks prior to ECU). Clinical data, including pt-reported outcomes, were collected at baseline and through the 26-wk treatment and ongoing extension studies up to data cut-off (mean [SD] duration of ECU treatment: C08-002=58 [29] wks and C08-003=60 [12] wks). HRQoL was measured with the EQ-5D self-reporting questionnaire and a 20-cm visual analogue scale (VAS) validated for a number of disease populations. EQ-5D has 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and 3 levels (no problem, some problems and extreme problems). Change in HRQoL was calculated using the US time trade-off (TTO) index and VAS valuation techniques, and ANOVA analysis. A change of >0.06 is considered a clinically meaningful change Results C08-002: 15/17 pts received ECU until Wk 26 (2 discontinued at Wks 1 and 6; protocol violation and an adverse event unrelated to ECU, respectively) and 13 continued into the extension study. Median age=28 yrs and 29% were on dialysis immediately prior to ECU. Median time from diagnosis to screening =10 mo. All patients had eGFR ≤60 mL/min/1.73m2. C08-003: 20 pts received ECU for 26 wks and 19 continued into the extension study. Median age=28 yrs. Median time from diagnosis to screening=48 mo. Median duration of eGFR ≤60 mL/min/1.73m2=180 days at baseline. HRQoL: In both cohorts of distinct trial pts, ECU substantially improved HRQoL through Wk 26, and sustained this thereafter during long-term ECU therapy (table). In trial C08-002, improvements were seen as early as Day 7 (0.12, p=0.0346). Point estimate improvement (95%CI) in HRQoL from baseline to1 yr was 0.32 (0.27-0.36) for C08-002 and 0.09 (0.05-0.14) for C08-003. On an individual pt basis, 87% and 73% of C08-002 and C08-003 pts, respectively, achieved a clinically meaningful change that represented a clinically important large or moderate improvement in HRQoL measures, respectively. Conclusions aHUS pts have an impaired HRQoL both from a direct impact of aHUS morbidity and management requirements (such as PE/PI), but also from the systemic nature of the disease. In patients with aHUS, significant improvements in HRQoL were achieved rapidly with ECU (as early as Day 7). Sustained long-term treatment with ECU maintained the improvements in HRQoL. Disclosures: Muus: Alexion: Honoraria, Research Funding. Off Label Use: The research described is a clinical trial of eculizumab in patients with aHUS, an indication in which its use is not approved. Licht:Alexion: Honoraria, Research Funding. Goodship:Alexion: Honoraria, Research Funding. Greenbaum:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding. Legendre:Alexion: Honoraria, Research Funding.

Distinct Characteristics of e13a2 versus e14a2 BCR-ABL Chronic Myeloid Leukemia under Upfront Treatment with Imatinib – an Analysis of the German CML Study IV,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3773-3773
Author(s):  
Benjamin Hanfstein ◽  
Philipp Erben ◽  
Susanne Saussele ◽  
Michael Lauseker ◽  
Ulrike Proetel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Fusion Gene ◽  
Standard Dose ◽  
White Blood Cells ◽  
Molecular Response ◽  
Significant Difference ◽  
Equity Ownership

Abstract Abstract 3773 Introduction: The vast majority of chronic myeloid leukemia (CML) patients express a BCR-ABL fusion gene mRNA encoding a 210 kDa tyrosine kinase which is constitutively activated and hence the mainspring of leukemic transformation. Two typical mRNA variants exist that differ in the presence or absence of the 75 basepair BCR exon 14: the e13a2 (lacking exon 14, also known as “b2a2”) and the e14a2 BCR-ABL transcript (“b3a2”). The significance of the additional 25 amino acid residues of the e14a2 BCR-ABL oncoprotein was extensively studied in the pre-imatinib era. However, the influence of the BCR-ABL transcript variant on the individual disease phenotype and outcome remained controversial and is still undefined in the imatinib era. Patients and methods: A total of 1,104 patients (median age 52 years, range 16–85, 40% female) expressing typical BCR-ABL transcript types (e13a2, n=447; e14a2, n=491; e13a2 and e14a2, n=166) were included in the randomized German CML study IV and treated with an imatinib based therapy consisting of imatinib 400 mg, imatinib 800 mg and combinations of standard dose imatinib with interferon alpha and low-dose cytarabine. The type of BCR-ABL transcript was defined by multiplex PCR. BCR-ABL expression was determined by quantitative RT-PCR and standardized according to the international scale (IS). Cytogenetic response was determined by conventional metaphase analyses. Response landmarks were defined according to European LeukemiaNet criteria, MR4 was defined as BCR-ABL IS ≤ 0.01% Results: No differences regarding age, sex and Euro risk were observed. A significant difference was observed comparing white blood cells (90,400/μl vs. 69,100/μl, p<0.001) and platelets (293,000/μl vs. 424,000/μl, p<0.001) at diagnosis (median, e13a2 vs. e14a2, respectively) indicating a distinct phenotype. No significant difference was observed regarding spleen size, basophils, eosinophils, blasts or adverse events under imatinib. Molecular response as determined by a transcript independent quantitative PCR assay was superior in e14a2 patients as compared to e13a2 patients (median time to major molecular response, MMR 1.5 years vs. 1.2 years, p<0.001; median time to MR4 4.2 years vs. 2.5 years, p<0.001). No difference was observed with regard to the achievement of a complete cytogenetic remission (CCyR). The superior molecular response rate of e14a2 patients did not translate into differences in progression free survival (PFS) or overall survival (OS). Conclusion: Distinct initial blood counts suggest a different phenotype of e13a2 and e14a2 driven CML. MMR and MR4 are achieved earlier by e14a2 patients whereas no difference was observed with regard to PFS and OS. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. Haferlach:Münchner Leukämie Labor: Equity Ownership. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 92-92 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Timothy P. Hughes ◽  
Richard E. Clark ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Eligibility Criterion ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Vascular Events ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

Final Results From SENSOR: Switch to Nilotinib After Molecular Suboptimal Response (SoR) to Frontline Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1815-1815 ◽  
Author(s):  
Mitsune Tanimoto ◽  
Koichi Miyamura ◽  
Toshihiro Miyamoto ◽  
Kazuhito Yamamoto ◽  
Masafumi Taniwaki ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Direct Sequencing ◽  
Assay Method ◽  
Manuscript Preparation ◽  
Molecular Response ◽  
Molecular Responses ◽  
Mutation Status ◽  
The Impact ◽  
Over Time

Abstract Background: Nilotinib elicits faster, deeper molecular responses than imatinib as frontline treatment for CML-CP and is also approved as second-line treatment for patients (pts) intolerant of or resistant to imatinib.However, the optimal management of pts with SoR to frontline imatinib treatment has not been determined. Here, we present final data from the Study to Evaluate Nilotinib in CML pts with SubOptimal Response (SENSOR, NCT0104387), in which adult pts with molecular SoR to frontline imatinib switched to nilotinib. Methods: In this multicenter, open-label study, 45 pts received nilotinib 400 mg twice daily with 24 mo of follow-up. All pts had SoR per 2009 European LeukemiaNet criteria—complete cytogenetic response (CCyR) but no major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [IS]) after ≥ 18 mo of frontline imatinib. The primary endpoint was rate of MMR at 12 mo after switch to nilotinib. BCR-ABL1IS transcript levels using ABL1as a control gene were centrally evaluated monthly (mo 1-3), then every 3 mo. Durable MMR at 24 mo was defined as MMR at both 12 and 24 mo with no intermediate loss of MMR. MR4 and MR4.5 were defined as BCR-ABL1IS ≤ 0.01% and ≤ 0.0032%, respectively. Mutation analyses by direct sequencing were performed at baseline (BL) and at end of study for all pts. Retrospective mutational analyses were performed even in pts who did not have any mutations identified at BL or at the end of study visit. Results: Pts were enrolled from Dec 2009 to Feb 2012; 39 pts completed the study and 6 discontinued. Reasons for discontinuation were adverse events (AEs; n = 3), disease progression (n = 1), and withdrawn consent (n = 2). Median dose intensity of nilotinib was 748.9 mg /day (range, 183-799 mg) for a median duration of exposure of 22.1 mo (range, 0.1-22.7 mo). The primary endpoint was met; the rate of MMR at 12 mo was 51.1% (the expected value was 40%). Median time to first MMR among pts who achieved MMR (N = 23) was 2.28 mo, and 51.1% of pts had durable MMR. The proportion of pts achieving MMR as well as deeper molecular responses (MR4, MR4.5) increased over time (Figure). Rates of MMR, MR4, and MR4.5 were 66.7%, 11.1%, and 6.7%, respectively, at 24 mo. By 24 mo, the cumulative rates of MMR, MR4, and MR4.5 were 75.6%, 13.3%, and 6.7%, respectively. Overall, BCR-ABL1 levels decreased during treatment. The median BCR-ABL1IS ratio was 0.24% (range, 0.1%-3.5%) at BL (n = 45) and 0.06% (range, ≤ 0.0032%-2.3%) at 24 mo (n = 40). The slope of BCR-ABL decline was steepest in the first 3 mo after switch to nilotinib. Univariate and multivariate analyses of factors associated with molecular responses at 24 mo will also be presented. Among 30 pts with MMR at 24 mo, 4 pts (13.3%) had BCR-ABL1 mutations at BL, and 17 pts (56.7%) had newly detected (post-BL) mutations (Table). One pt with a newly detected T315I mutation never achieved MMR, progressed to blast crisis after 5.4 mo, and died at 9.4 mo. No other pt progressed or died. The most common any-grade AEs were hyperbilirubinemia (53.3%), nasopharyngitis (46.7%), and headache (37.8%). Elevated lipase level (20.0%) and hypophosphatemia (15.6%) were the most common grade 3/4 AEs. Conclusions: Switching from imatinib to nilotinib resulted in 66.7% of pts achieving MMR at 24 mo and a cumulative incidence of MMR of 75.6% by 24 mo. Some pts achieved even deeper molecular responses. These responses were achieved regardless of BL mutation status and new mutations/splicing abnormalities detected on treatment, except for T315I. Further study is required to determine the impact of the mutations on the efficacy of nilotinib. The safety profile of nilotinib was consistent with prior studies. Figure. Molecular Responses Over Time Figure. Molecular Responses Over Time Table. MMR at 24 mo by BCR-ABL1 Mutation Status (Assay Method: Direct Sequencing) With MMRn = 30 Without MMRn = 15 BLn (%) Post-BLn (%) BLn (%) Post-BLn (%) No mutation 26 (86.7) 13 (43.3) 15 (100) 6 (40.0) Any mutation 4 (13.3) 17 (56.7) 0 9 (60.0) Insensitive T315I 0 0 0 1 E255K 1 0 0 0 Others (occurring in > 2 pts) Exon 8/9 35 base pair insertion 1 9 0 9 Exon 7 deletion 1 4 0 3 Disclosures Yamamoto: Novartis Pharma K.K.: Honoraria, Research Funding; Pfizer Inc.: Research Funding, Speakers Bureau, support with manuscript preparation, support with manuscript preparation Other; ARIAD Pharmaceuticals, Inc: Research Funding. Taniwaki:Novartis: Honoraria, Research Funding. Kimura:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Ohyashiki:Novartis Pharma K.K.: Honoraria, Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma: Honoraria. Matsumura:Novartis Pharma KK: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria. Hino:Novartis Pharma: Research Funding. Kondo:Novartis Pharma K.K.: Employment. Aoki:Novartis Pharma K.K.: Employment. Okada:Novartis: Employment. Yanada:Novartis: Consultancy.

CCL-2 Is a KIT D816V-Dependent Modulator of Bone Marrow Remodeling and Microenvironmental Alterations in Systemic Mastocytosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1635-1635
Author(s):  
Georg Greiner ◽  
Nadine Witzeneder ◽  
Klaus Schmetterer ◽  
Theresia Popow-Kraupp ◽  
Wolfgang R Sperr ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conditioned Medium ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Tissue Remodeling ◽  
Neutralizing Antibody ◽  
Boyden Chamber ◽  
Boyden Chamber Assay ◽  
Baseline Levels ◽  
Kit D816v

Abstract Systemic mastocytosis (SM) is a myeloproliferative neoplasm (MPN) characterized by mast cell (MC) infiltration in the bone marrow (BM) and/or other organs. Most patients present with the activating KIT mutation D816V. Increased production of cytokines is typically found in patients with classical MPN and has been linked to alterations of the BM microenvironment (e.g. enhanced angiogenesis and fibrosis) that are also commonly found in SM. However, little is known about mechanisms contributing to microenvironment alterations in the BM in SM and the role of MC-derived cytokines. The aim of our study was to identify cytokines that are produced in neoplastic MC in a KIT-dependent manner and contribute to increased BM angiogenesis and fibrosis in SM. In a first step, we screened for KIT D816V-dependent production of cytokines relevant to inflammation and microenvironment alterations using growth factor-dependent human cell lines (TF-1 and Mo7e). In these experiments, expression of CCL-2, IL-8, OSM, and VEGF mRNA was induced by KIT D816V but not by wild type KIT. Based on its pleiotropic effects, we focused on CCL-2, also referred to as monocyte chemotactic protein 1 (MCP-1), a CC chemokine that recruits inflammatory cells to sites of inflammation and enhances angiogenesis. KIT D816V+ HMC-1.2 cell were found to express and secrete substantial amounts of CCL-2. Midostaurin, a multikinase inhibitor suppressing the kinase activity of KIT D816V, was found to reduce expression of CCL-2 similar to RNAi-mediated knockdown of KIT. Furthermore, knockdown of STAT5, a key transcription factor downstream of KIT D816V, reduced expression of CCL-2 in HMC-1.2 cells. These results confirmed that CCL-2 expression in neoplastic MC is dependent on KIT D816V. Since CCL-2 has been reported to promote angiogenesis, we analyzed effects of conditioned medium obtained from HMC-1.2 cells on human umbilical vein endothelial cells (HUVEC) known to express the CCL-2 receptor CCR-2. Indeed, MC-derived conditioned medium induced migration of HUVEC in a wound healing assay (214% ± 38% of control, mean ± SD, p<0.01) as well as in a boyden chamber assay (126% ± 8% of control, p<0.05). Moreover, pre-incubation with a neutralizing antibody against CCL-2 significantly reduced migratory responses (p<0.01), and RNAi-mediated knockdown of CCL-2 in neoplastic MC reduced the effect of conditioned medium to baseline levels (p<0.01). These results confirmed that the migration was CCL-2 dependent. Furthermore, patients with advanced SM often present with marked eosinophilia; and eosinophils are often located in the vicinity of, or even within, BM MC infiltrates. Therefore, we also studied the effect of CCL-2 on eosinophils. Normal human eosinophils as well as the eosinophilic cell line EOL-1 were found to express CCR-2, and to migrate against recombinant CCL-2 in a modified boyden chamber assay. Conditioned medium from KIT D816V+ MC also induced a migratory response in eosinophils (200% ± 30% of control, p<0.05), and a neutralizing antibody against CCL-2 reduced this effect to baseline levels (p<0.05). Finally, SM-patients were found to have significantly elevated serum CCL-2 levels (n=35, p=0.0048, 407.4 ± 42.3 pg/ml, mean ± SEM) compared to controls (274.3 ± 15.9 pg/ml). The highest serum levels of CCL-2 were detected in patients with advanced SM where tissue remodeling in the BM is often a prominent feature. Moreover, CCL-2 levels were found to correlate with the grade of MC infiltration in the BM (r=0.656, p=0.0002). In summary, KIT D816V induces the expression of various cytokines potentially involved in tissue remodeling and microenvironment alterations in SM. Moreover, we have identified CCL-2 as a critical, KIT D816V-dependent, cytokine-mediator that interacts with structural BM cells and thereby may be involved in disease evolution and progression in SM. Whether CCL-2 may also serve as a therapeutic target in SM is currently being examined. This study was supported by Austrian Science Fund (FWF) grant P26079-B13. Disclosures Sperr: Novartis: Honoraria. Valent:Pfizer: Honoraria; Celgene: Honoraria; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

The impact of sensitive KIT D816V detection on recognition of Indolent Systemic Mastocytosis

2015 ◽  
Vol 39 (3) ◽  
pp. 273-278 ◽  
Author(s):  
Giovanna De Matteis ◽  
Roberta Zanotti ◽  
Sabrina Colarossi ◽  
Caterina De Benedittis ◽  
Andrès Garcia-Montero ◽  
...  
Keyword(s):  
Systemic Mastocytosis ◽  
The Impact ◽  
Indolent Systemic Mastocytosis ◽  
Kit D816v

scholarly journals Haplo-Cord UCB SCT with Low Cell Dose, Well Matched UCB Units. a Prospective Multicenter Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1093-1093 ◽  
Author(s):  
Koen van Besien ◽  
Hongtao Liu ◽  
Usama Gergis ◽  
Melissa M. Cushing ◽  
Stephanie Tsai ◽  
...  
Keyword(s):  
Cord Blood ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Fixed Dose ◽  
Selection Algorithm ◽  
Advisory Committees ◽  
Cell Dose ◽  
The Impact ◽  
Group 1

Abstract The outcome of umbilical cord blood transplantation is governed by UCB cell dose and matching. But stringent cell dose requirements limit access to well matched units. In haplo –cord transplant, early engraftment is determined by the adult graft. Elsewhere we have shown that excessive doses of haplo-identical cells resulted in failure of the UCB graft. Here we investigated the effect of a lower UCB cell dose threshold on ability to identify well matching units. We also prospectively evaluated the effects of UCB cell dose and matching (combined with a fixed dose haplo-graft ) on cord engraftment, platelet recovery, neutrophil recovery and acute GVHD, PFS and OS. We enrolled three consecutive cohorts with increasingly lower UCB cell dose thresholds (1) UCB cell dose >2x 10^ NC/kg (2)≥1x 10^ NC/kg and (3)≥.5x 10^ NC/kg. Additional selection criteria included (1) best HLA match (initially based on 6 HLA, as of mid 2013 based on 8 HR antigens (2)UCB viability, (3) avoidance of DSA antibodies and (4) NIMA compatibility. We continued enrollment on each cohort until at least 10 patients were evaluable for day 100 chimerism. If more than 7 of ten evaluable patients in a cohort achieved >40% UCB chimerism by d 100, the next cohort was started. This rate of success was achieved in all three cohorts, so we have continued accrual in the lowest cell dose. Sixty patients have been accrued at two institutions over 19 months. 43/60 pts had AML or MDS. The majority had ASBMT advanced and intermediate disease. Nearly half of the pts were of minority descent. Conditioning in all pts consisted of fludarabine-melphalan (three pts also received TBI 400) and GVHD prophylaxis of tacrolimus and mycophenolate. Haplo identical CD34 selected cells were co-administered at a dose of 3-5 x10^6 CD34 cells/kg. Pt characteristics and preliminary outcomes are summarized in the table below. Table Cohort 1 2 3 Minimum TNC x10^5/kg 2 1 0.5 n 15 20 25 Age 48 62 64 ASBMT Low/Int/Adv 4/5/6 7/5/7 8/6/11 Weight (kg) 73 (56-96) 72 (50-136) 85(46-122) Caucasian/Other 7/8 13/7 12/13 Median UCB TNC collected (x10^7/kg) and range 2.7 (2.1-8.3) 2.1 (1.4-2.9) 1.7 (0.9-2.7) UCB TNC/kg >3x10^7/kg 7 (46%) (0 UCB failure) 1 (5%) (0 UCB failure) 2 (8%) (0 UCB failure) 2-3 x10^7/kg 8 (54%) (0 UCB failure) 9 (45%) (2 UCB failure) (32%) (0 UCB failure) 1.5-2 x10^7/kg 0 5 (25%) (0 UCB failure) 8 4 (16%) (0 UCB failure) 1-1.5 x10^7/kg 0 5 (25%) (0 UCB failure) 10 (40%) (4 UCB failure) <1 x10^7/kg 0 0 1 (4%) (1 UCB failure) High Resolution HLA match 8/8 0 1 (5%) 4 (16%) 7/8 2 (6%) 7 (35%) 7 (28%) 6/8 0 3 (15%) 8 (32%) 5/8 6 (40%) 9 (45%) 5 (20%) <5/8 8 (54%) 0 1 (4%) Median Time to ANC>500 (range) 14 (10-60) 12 (9-18) 12 (9-51) Median Time to Plt >20 (range) 35 (15-88) 20 (13-NR) 21 (10-NR) % with >40% UCB chimerism @d100 100 83 76 * Analysis of UCB graft characteristics includes all patients. Engraftment and GVHD analysis excludes 10 patients with early fatal complications or relapse. Chimerism analysis excludes two additional patients with missing information. NR= not reached The average HLA matching was significantly better (P<.001) in groups 2 and 3 (66% with >6/8 match), than in group 1 (6% with >6/8 match). UCB cell doses were significantly lower in groups 2 and 3 (55% with UCB cell dose <2x10^7/kg vs none in group 1). There were no significant difference between the groups in hematologic recovery, OS, PFS or UCB engraftment. Seven of 50 evaluable pts had failure of the UCB graft (<40% UCB chimerism on d 100). 4 of them had 100% haplo chimerism, 2 had autologous recovery and 1 had partial <40% UCB chimerism. The incidence of UCB failure increased with decreasing UCB cell dose (P<0.001 U test), with five of seven graft failures occurring in patients receiving UCB doses <1.2 x10^7/kg. This novel cord blood selection algorithm allows identification of well-matched UCB cells (at least 6/8 HR) in two thirds of patients. In approximately one third of cases the best matching UCB unit has a cell dose <1.5 x10^7/kg. Very low UCB cell doses appear to be associated with somewhat increased risk of UCB graft failure-delay. Long-term follow up will establish the impact of this selection algorithm on OS, PFS, chronic GVHD. Disclosures van Besien: Miltenyi Biotec: Research Funding. Stock:Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mark:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau.

scholarly journals Safety and Efficacy of Dasatinib Treatment Change for Patients Previosly Treated with Imatinib with Late Warning Response. Results from the Phase II, Open, Multicenter Dasapost Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5450-5450 ◽  
Author(s):  
Valentín García-Gutierrez ◽  
Felipe Casado ◽  
Fermín Sánchez-Guijo ◽  
Rosa M. Ayala ◽  
Concepcion Boque ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Median Time ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Treatment Change ◽  
Molecular Responses ◽  
Warning Response

Abstract Background: Current European LeukemiaNet (ELN) recommendations (ELN 2013) endorse closely monitoring, due to risk of failure, for patients with so called late warning response (patients with complete cytogenetic response without major molecular response after 12 months of treatment). In this situation, for patients initially treated with imatinib, previous studies have shown a benefit of treatment change to nilotinib in terms of the achievement of deeper molecular responses. However, the role of treatment change to dasatinib in this group of patients have not been evaluated. DASAPOST is the first clinical trial evaluating efficacy and safety of dasatinib in patients with late warning responses. Methods: We are presenting results of the 18 patients enrolled in the phase II, open, multicenter DASAPOST study (NCT01802450). Main inclusion criteria were patients previously treated with imatinib with late suboptimal response by ELN2009 (CCyR without MMR after 18 months of treatment). The primary end point was rate of MMR by 6 moths after treatment change to dasatinib. Secondary end points were rate of MMR by 12 months, rate of deep molecular responses, progression free survival and safety of treatment change. Results were expressed as the proportion of patients who achieved molecular responses in the intention-to-treat (ITT) population, considering as failure if the evaluation was not performed in a specific time point. All BCR-ABL/ABL (IS) measurements were centralized in an EUTOS laboratory. Results: From April 2013 to May 2015, 18 patients were enrolled in 12 Spanish centers. Median age was 59 years (39-77). The ratio of men to women was 13/5, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median time from diagnosis to treatment change to dasatinib was 2.6 years (1.6-23) and median time while on imatinib to achieve CCyR 1.4 years (0.2-12). Median exposure to imatinib was 2.4 years (1.6-14). Seventy-two percent of the patients achieved MMR by 6 months (primary endpoint). Rates of MMR and deeper molecular responses at different time points are shown in table 1. Of interest 9/18 patients (50%) achieved MR4 by 12 months. Treatment change to dasatinib was safe, with only 3 study discontinuations (16%), due to adverse events (AE) and 4 serious AE (congestive heart failure, acute gastroenteritis, pyelonephritis and pancreatitis (only congestive heart failure was related to dasatinib). Most commonly reported (>5%) drug-related AEs are shown in table 1. Conclusions: Our study shows, for the first time, that in patients treated with imatinib and with late warning responses, switching to Dasatinib induced MMR in 2 out every 3 patients, and MR4 in half of the patients by 6 months, with a good safety profile. Table 1 Most commonly reported (>5%) drug-related AEs Table 1. Most commonly reported (>5%) drug-related AEs Table Table. Disclosures García-Gutierrez: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Casado:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Sánchez-Guijo:Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers-Squib: Consultancy, Honoraria. Martinez-Lopez:BMS: Research Funding. Steegmann:Ariad: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; BMS: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group.

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