The patient's BCR-ABL1 Kinase Domain Mutation History Is Important for Decisions Regarding Tyrosine Kinase Inhibitor Therapy

Abstract Abstract 1692 Introduction. BCR-ABL1 kinase domain mutations are the most common known cause of resistance to tyrosine kinase inhibitors (TKIs) in CML. Some imatinib resistant mutations also confer resistance to second generation TKIs nilotinib and/or dasatinib. Therefore, it is recommended that mutation analysis be performed before changing therapy. However, BCR-ABL1 mutant clones are often de-selected upon TKI cessation or change of therapy, and may become undetectable (Hanfstein et al, Haematologica 2011). It is not known whether treatment discontinuation or long term alternative TKI therapy leads to eradication of these mutant clones. If mutant clones persist at sub-clonal levels they have the potential to be re-selected and expand clonally given favorable conditions, such as change to a TKI for which they confer resistance. We examined longitudinal data of patients with imatinib resistant mutations that became undetectable by direct sequencing to determine whether these “long dormant” mutations could reappear, and the circumstances related to reappearance. Method. All chronic phase patients who had been monitored at our institution since starting imatinib, and had mutations detectable by sequencing during imatinib therapy were analyzed; 49 patients, median follow up since starting imatinib was 4.3 years (range 0.6–11.6 years). Sensitive mutation analysis using mass spectrometry (detection limit 0.2% mutant) was performed at selected times when the mutations became undetectable by direct sequencing (detection limit 10–20%). Results. Of the 49 patients with mutations detected by sequencing during imatinib therapy, mutations became undetectable by sequencing in 21 patients (29 mutations), at a median of 2 months after changing therapy (range 1–20 months). This was associated with increased imatinib dose (3 mutations), stopping imatinib (2), hematopoietic cell transplant (6), chemotherapy (1), switching to nilotinib (3), or switching to dasatinib (14). All mutations that became undetectable by sequencing when the patient switched to nilotinib or dasatinib were those known to be sensitive to the inhibitor received (e.g. F359V in a patient treated with dasatinib). In 16 of the 21 patients whose mutations became undetectable by direct sequencing, the mutations have not been detected again with 0.1 to 6.9 years of follow up since the mutations were last detected (median 1.1 years). Of these 16 patients, 15 maintained a stable complete cytogenetic response and 1 lost a major cytogenetic response. In the other 5 patients, the same mutations as those originally detected (identical nucleotide exchange) became detectable by sequencing between 1.7 and 5.4 years after last detection (median 4.4 years), Figure. The original mutations in 4 of these patients confer resistance to nilotinib as well as imatinib (Y253H and F359V), and their reappearance was associated with initiation of nilotinib therapy, Figure. Three of these 4 patients died of their disease, and 1 lost a major cytogenetic response. Sensitive mutation analysis could detect the mutation in 1 of these patients during the time of “dormancy” and before nilotinib therapy. The 5th patient received an autologous hematopoietic cell transplant upon detection of F359V, and the mutation became undetectable by sequencing. The patient subsequently received dasatinib for 3 years and the mutation remained undetectable. Dasatinib therapy was stopped due to intolerance and F359V rapidly reappeared while the patient was off TKI therapy, having been undetectable for 4.8 years. Using sensitive mutation analysis, F359V could be detected at low levels after the transplant, suggesting that the mutant clone had not been eradicated. Conclusion. The data suggest that some BCR-ABL1 mutations may persist at sub-clonal levels for many years after changing therapy. This could lead to clonal expansion under the selective pressure of a TKI for which the mutation confers insensitivity. Alternatively, the reappearance of the mutation could be a new occurrence of the same mutation. The study highlights the importance of knowing the mutation history of individual patients to enable informed therapy choices. Disclosures: Yeung: Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cepheid: Consultancy.

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Detection of Low Level Nilotinib or Dasatinib Resistant BCR-ABL Mutations by Mass Spectrometry In CML Patients Who Fail Imatinib Is Highly Predictive of Their Subsequent Clonal Expansion When Treated with the Drug for Which Their Mutation Confers Resistance

Blood ◽

10.1182/blood.v116.21.891.891 ◽

2010 ◽

Vol 116 (21) ◽

pp. 891-891

Author(s):

Wendy T Parker ◽

Musei Ho ◽

Rebecca M Lawrence ◽

Darryl L Irwin ◽

Hamish S Scott ◽

...

Keyword(s):

Mass Spectrometry ◽

Research Funding ◽

Direct Sequencing ◽

Clonal Expansion ◽

Cytogenetic Response ◽

Kinase Domain ◽

Sensitive Detection ◽

Clinical Resistance ◽

Appropriate Therapy

Abstract Abstract 891 Imatinib (IM) resistance is commonly associated with the acquisition of BCR-ABL kinase domain (KD) mutations. Nilotinib (NIL) and dasatinib (DAS) are active against the majority of IM resistant mutations, however a small number confer clinical resistance to NIL (Y253H, E255K/V and F359V/C) or DAS (V299L, T315A and F317L/I), or both (T315I). These mutations are associated with low response rates and their detection after IM failure aids selection of the most appropriate therapy; however, mutations may be present below the detection limit of conventional direct sequencing (dir-seq, sensitivity 10–20%). We aimed to determine whether more sensitive detection of NIL/DAS resistant mutations prior to commencing NIL or DAS therapy in patients (pts) who failed IM could predict their subsequent clonal expansion in the presence of the inhibitor for which they confer resistance, and whether this affects response. These mutations will be referred to as ‘inhibitor resistant’ when detected in a patient subsequently treated with the inhibitor for which the mutation confers resistance, and conversely, ‘inhibitor sensitive’ when detected in a pt treated with the inhibitor which retains activity against the mutation. We developed 4 multiplexed genotyping assays using high throughput chip-based mass spectrometry (Sequenom MassARRAY; M-A) to detect 27 mutations that account for approx. 88% of all mutations, including all of the NIL/DAS resistant mutations (sensitivity 0.05–0.5%). Samples of 210 CML pts treated with NIL (n=85) or DAS (n=125) after IM failure (CP n=102, AP n=64, BC n=44) were retrospectively analyzed by M-A at baseline (before commencing NIL or DAS), and by dir-seq at baseline and during follow up (FU) (median FU 12 mo, r 1–36). When a mutation was detected by dir-seq, the concordance of detection by M-A was 99.4%. Dir-seq detected 26 inhibitor resistant mutations at baseline in 24 pts. However, M-A detected 22 additional inhibitor resistant mutations in 19 pts (CP 7/102 7%, AP 8/64 13%, MBC 4/44 9%). Twelve of the 22 mutations were T315I and 11 (92%) subsequently became a dominant clone detectable by dir-seq (median 3 mo, r 1–12). Of the remaining 10 inhibitor resistant mutations, 7 (70%) became dominant (median 7.5 mo, r 1–24). The exceptions were F317L in 2 pts and E255K in 1. In these 3 pts, T315I was also present at baseline (1) or became dominant at 3 or 9 mo (2), suggesting a hierarchy of emergent resistant mutations according to mutant drug sensitivity. A complete cytogenetic response (CCyR, or its BCR-ABL equivalent of <1% IS) was achieved by 0/25 pts with inhibitor resistant mutations detectable at baseline by dir-seq, and by 2/19 (10%; CP n=1, AP n=1) pts with inhibitor resistant mutations detected only by M-A (3 pts overlapped both groups). In contrast, 170 pts had no inhibitor resistant mutations detected at baseline by dir-seq or M-A and 64 (38%) achieved CCyR (P<.001; 87/170 pts were CP and 44% achieved CCyR). In addition to the mutations already discussed, 22 NIL/DAS resistant mutations were detected only by M-A in 17/210 pts at baseline who were not subsequently treated with the inhibitor for which the mutation confers resistance (inhibitor sensitive mutations), e.g. F317L in a pt subsequently treated with NIL. During FU, 3/22 inhibitor sensitive mutations subsequently emerged in 2 pts, but 19 never emerged (86%; median FU 9 mo, r 1–30). Importantly, none of the 27 mutations in the M-A assay were detected in the ABL KD of 30 normal donors or 20 replicates of a BCR-ABL-negative cell line. In conclusion, our multiplex M-A assay, with sensitivity to 0.05%, could simultaneously detect the bulk of IM resistant mutations and predict the subsequent clonal expansion of resistant mutations during NIL/DAS therapy with high confidence. Overall, 82% of the inhibitor resistant mutations detected only by M-A at baseline became a dominant mutation. In contrast, only 14% of the inhibitor sensitive mutations detected only by M-A at baseline became detectable by dir-seq, P<.0001 (table). Sensitive detection of NIL/DAS resistant mutations after IM failure offers vital information when considering therapeutic options. Table. NIL/DAS resistant mutations detectable only by M-A at baseline and their subsequent detection by dir-seq during NIL or DAS therapy T315I (12) NIL Resistant (23)* DAS Resistant (9)* Mutation Emerged on NIL 3/3 (100%) 6/7 (85%) 1/6 (17%) Mutation Emerged on DAS 8/9 (89%) 2/16 (13%) 1/3 (33%) * not T315I Disclosures: Irwin: Sequenom, Inc.: Employment. Hughes:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding.

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Multiple Low Level Mutations Identifies Imatinib Resistant CML Patients At Risk of Poor Response to Second-Line Inhibitor Therapy, Irrespective of the Resistance Profile of the Mutations

Blood ◽

10.1182/blood.v118.21.111.111 ◽

2011 ◽

Vol 118 (21) ◽

pp. 111-111

Author(s):

Wendy T Parker ◽

Musei Ho ◽

Hamish S Scott ◽

Timothy P. Hughes ◽

Susan Branford

Keyword(s):

At Risk ◽

Board Of Directors ◽

Mutation Analysis ◽

Research Funding ◽

Poor Response ◽

Advisory Committees ◽

Low Level ◽

Mass Spec ◽

Imatinib Resistant

Abstract Abstract 111 Specific imatinib resistant BCR-ABL1 mutations confer clinical resistance to nilotinib (NIL; Y253H, E255K/V, T315I, F359V/C) and/or dasatinib (DAS; V299L, T315I/A, F317L/I/V/C). Therefore, mutation analysis is recommended for CML patients (pts) after imatinib failure to facilitate selection of appropriate therapy. However, around 40% of chronic phase (CP) pts without these NIL/DAS resistant mutations also fail second line inhibitor therapy. For imatinib resistant pts without these mutations at the time of commencing NIL/DAS therapy (switchover) we investigated whether sensitive mutation analysis could identity pts at risk of poor response to subsequent therapy. Switchover samples of 220 imatinib resistant pts (DAS n=131, NIL n=89) were analysed by direct sequencing (detection limit 10–20%) and sensitive, high throughput mass spectrometry (mass spec; Sequenom MassARRAY, detection limit 0.05–0.5%), which detects 31 common BCR-ABL1 mutations (approximately 89% of mutations detected in pts receiving imatinib). We previously demonstrated that mass spec could detect NIL/DAS resistant mutations at switchover in an extra 9% of pts compared to sequencing and that these low level resistant mutations were associated with subsequent failure of these inhibitors (Parker et al, JCO. 2011 In Press). Therefore, for the current analysis, pts with NIL/DAS resistant mutations detected by either method (n=45) were excluded since response is already known to be poor in these cases. In the switchover samples of the remaining 175 pts, 159 mutations were detected in 86 pts by mass spec, but just 108 mutations were detected in 89 pts by sequencing. Thirteen rare mutations detected by sequencing were not included in the mass spec assay design. Mass spec detected all other mutations detected by sequencing, plus an additional 64 low level mutations. Multiple NIL/DAS sensitive mutations (≥2 mutations) were detected at switchover in more of the 175 pts by mass spec (34/175, 19%; 2–9 mutations per pt) than sequencing (16/175, 9%; 2–3 mutations per pt), P=.009. We divided pts into 2 groups; those with multiple mutations detected by mass spec at switchover (n=34) and those with 0/1 mutation (n=141), and investigated the impact of multiple mutations on response to subsequent NIL/DAS therapy. Pts with 0 or 1 mutation, and similarly pts with 2 or >2 mutations, were grouped together, as no difference in response was observed. The median follow up for CP, accelerated phase and blast crisis pts was 17 (2–33), 18 (1–33) and 3 (1–27) mo, and the frequency of multiple mutations was 18%, 24% and 18%, respectively. During follow up, multiple mutations at switchover was associated with lower rates of complete cytogenetic response (CCyR; 21% vs 50%, P=.003, Fig 1A) and major molecular response (MMR; 6% vs 31%, P=.005, Fig 1B), and a higher incidence of acquiring new NIL/DAS resistant mutations detectable by sequencing (56% vs 25%, P=.0009, Fig 1C). At 18 mo, the failure-free survival rate (European LeukemiaNet recommendations) for CP pts with multiple mutations at switchover was 33% compared to 51% for CP pts with 0 or 1 mutation (P=.26, Fig 1D). The number of mutations detected per pt by mass spec at switchover (max of 9, 8 of 86 pts with mutations had ≥4, 9%) far exceeded the number concurrently detected by sequencing (max of 3). This suggests that mass spec detected a pool of subclonal mutants, each with a small survival advantage after imatinib therapy that was insufficient for their clonal predominance. Multiple low level mutations may be a marker of an increased propensity for subsequent selection of resistant mutations, possibly driven by genetic instability, demonstrating the advantage of a sensitive multiplex mutation assay. In conclusion, sensitive mutation analysis identified a poor-risk subgroup with multiple mutations that were not identified by sequencing. This subgroup represented 15.5% of the total cohort (34/220), who would not otherwise be classified as being at risk of poor response on the basis of their mutation status. These pts did not have NIL/DAS resistant mutations at switchover; however, they had a lower incidence of CCyR and MMR, and higher incidence of acquiring new NIL/DAS resistant mutations during NIL/DAS therapy compared to pts with 0 or 1 mutation. This poor-risk subgroup may warrant closer monitoring or experimental approaches to reduce the high risk of kinase inhibitor failure after imatinib resistance. Disclosures: Hughes: 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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding.

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Update On Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) On Nilotinib Therapy at 24 Months: Clinical Response, Safety, and Long-Term Outcomes.

Blood ◽

10.1182/blood.v114.22.1129.1129 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1129-1129 ◽

Cited By ~ 15

Author(s):

Hagop M. Kantarjian ◽

Francis J. Giles ◽

Kapil N. Bhalla ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cytogenetic Response ◽

Study Entry ◽

Advisory Committees ◽

Transcript Levels ◽

Imatinib Resistant ◽

Efficacy Parameters

Abstract Abstract 1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months (< 1.0–36.5), with 62% of patients on therapy for at least 12 months and 42% on therapy for ≥ 24 months. Median dose intensity of nilotinib was 788.5 mg/day, very close to planned dosing. Overall, 58% of patients required dose interruption (defined conservatively ≥ 1 day of interruption regardless of reason) with a median cumulative duration of interruption of 20 days (4% of days of exposure). Importantly, 73% of patients that required treatment interruptions resumed treatment after interruption at the planned dose. The achievement of MMR in imatinib-resistant and -intolerant CML-CP patients who had BCR-ABL transcript levels available post-baseline (n=294) were included in this efficacy analysis (Table). Of these patients, 105/294 (36%) entered the study with a CHR and 189/294 (64%) did not have a CHR at study entry. The overall MMR rate was 28%; MMR was higher in patients with CHR at study entry (38% vs. 22%). Overall, CCyR was achieved in 46% of patients, among whom 56% achieved MMR. Median time to MMR was 5.6 months. Overall, 77% and 84% of responding patients maintained MCyR and CCyR at 24 months, respectively. Overall (n=321), the estimated rate of progression-free survival (PFS), defined as progression to AP/BC or discontinuation due to progression or death, at 24 months was 64%, however, only 9 patients (3%) progressed to AP/BC based on actual laboratory values. PFS rate at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). OS at 24 months is 87% for the entire patient population. The safety profile of nilotinib remains unchanged at 24 months of follow-up. The majority of first episodes of grade 3/4 bilirubin and lipase elevations occurred within the first month of therapy and were brief in duration (median duration 15 days). The incidences of hepatic and pancreatic disorders on nilotinib were 1.3 and 1.7 per 100-patient years of therapy and no cumulative risk of hepatic and pancreatic events was observed in this population with longer follow-up. Importantly, discontinuations due to hepatobiliary adverse events were uncommon (n=2; < 1.0%). Conclusions Nilotinib therapy led to the achievement of MMR in a majority of patients with CCyR, and in 38% of patients with CHR at study entry. Furthermore, the response and outcomes of patients treated with nilotinib was higher in patients with CHR at baseline suggesting that patients with imatinib resistance and intolerance who lost cytogenetic response but not hematologic response have a more favorable response compared to those patients who have lost hematologic response when switched to nilotinib. Overall, the safety profile of nilotinib remains well-tolerated with long-term follow-up. At 24 months, nilotinib therapy remains an effective and tolerable therapy for patients with imatinib-resistant or -intolerant CML. Disclosures Kantarjian: Novartis: Research Funding. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Martinelli:Novartis: 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. Shou:Novartis: Employment. Gallagher:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria.

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5-Day Decitabine with Mini Fludarabine and Busulfan Yields Comparable Outcomes to Mini Flu/Bu but with Increased Incidence of Severe Acute GvHD

Blood ◽

10.1182/blood.v128.22.3422.3422 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3422-3422

Author(s):

Melissa Baker ◽

Tracy Andrews ◽

Scott D. Rowley ◽

Andrew L. Pecora ◽

Alan P Skarbnik ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Control Group ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Advisory Committees ◽

Disease Response

Abstract Background: Studies have shown that hypomethylating agents (HMAs), including 5-AZA and decitabine (Dac) are well-tolerated antileukemic agents (Kantarjian et al, JCO, 2012). Despite its myelosuppressive effect, Dac has low extramedullary toxicities, making it an attractive drug for allogeneic hematopoietic cell transplant (HCT). Reports suggest that HMAs selectively upregulate tumor associated antigens (TAAs) on malignant cells without expression in healthy tissue (Cruijsen, 2016). We previously reported on a series of 20 patients (pts) in a phase I study of 5-day Dac plus mini fludarabine and busulfan (DacMiniFluBu) in elderly or medically infirm pts (Baker et al, Blood, 2012). In the current analysis, we compared updated results from our DacFluBu study with a historical MiniFluBu control group in pts with MDS or AML. Methods: Pts were evaluated to assess engraftment, toxicity, disease response, PFS and OS. Pts received Dac 20 mg/m2/day on days (d) -15 to -11, Flu 30 mg/m2/day, on d -7 to -3 and Bu 130 mg/m2 on d -4 and -3. The control group received Flu 30 mg/m2 on d -6 to -2 and Bu 130 mg/m2 on d -3 and -2. Both groups received thymoglobulin 2 mg/kg IV on d -3, -2 and -1, followed by infusion of donor stem cells on d 0. Immunosuppression consisted of tacrolimus starting on d -2 and MTX 5 mg/m2 IV on d +1, 3, 6, and 11. Results: 107 pts were analyzed between 5/2009 and 8/2015; 36 pts received DacMiniFluBu; 17 with MDS, and 19 with AML. 23 (64%) had unrelated donors (URD); 13 (36%) had sibling donors. 71 pts were included in the MiniFluBu control group for comparison; 33 with MDS, and 38 with AML. 53 (75%) had URD; 18 (25%) had sibling donors. Median age was 68.5 yrs compared to 66 yrs, respectively. Cohorts were comparable for gender, disease and graft source. The incidence of severe (gr III/IV) acute GVHD (aGvHD) was 22% compared to the control group of 6% (p=0.0195). Moderate or severe cGVHD was seen in 7 pts vs 22 in the control group (p=0.2535). The median follow-up in the DacMiniFluBu group was 262 d, OS was 35%, relapse incidence was 28%, and NRM at 6 mos was 22%. In the control group, the median follow-up was 424 d (p=0.2213), OS was 34%, relapse was 41%, and NRM was 15%. Median time to relapse in the study vs control group was 142 and 149 d (p=0.8722). There were 22 deaths after DacMiniFluBu and 43 after MiniFluBu (p=0.7382). 6 pts in the study group received DLI at a median of 170 d post HCT for either relapse (n=3) or falling chimerism (n=3) compared to 16 pts in the control group at a median of 183 d. Multivariate analysis was performed to estimate the cumulative incidence of severe aGvHD by regimen. Results showed that conditioning regimen (HR=3.98, 95% CI, p=0.0197), degree of match (HR=1.365, p=0.039) and non-hematologic (heme) gr IV events (HR= 4.266, p=0.029) were all significant independent factors predicting a higher incidence of severe aGvHD. Conclusions: There were no significant differences in the cumulative incidences of relapse or survival between pts receiving DacMiniFluBu and MiniFluBu. However, the risk of severe aGvHD was 4 times greater in DacMiniFluBu recipients when controlling for infections, degree of match, and non-heme gr IV events. Findings were confirmed in univariate and multivariate analyses. This may be explained by the increased expression of TAAs in healthy tissues in response to Dac, which evoke T cell responses. This is the first report showing that adding Dac to the MiniFluBu regimen was an independent risk factor for severe aGvHD. Other findings in our analysis linking age, risk stratification, and degree of match to GvHD are consistent with prior reports. The differences between our results and those of other studies warrant larger validation analyses. Dac as part of a conditioning regimen should only be used in context of a clinical trial. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Skarbnik: Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau.

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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 ◽

10.1182/blood.v114.22.1130.1130 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1130-1130 ◽

Cited By ~ 1

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.

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Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽

10.1182/blood.v114.22.3286.3286 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3286-3286 ◽

Cited By ~ 5

Author(s):

Philipp D. le Coutre ◽

Anna Turkina ◽

Dong-Wook Kim ◽

Bernadeta Ceglarek ◽

Giuliana Alimena ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Study Drug ◽

Cytogenetic Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Imatinib Resistant ◽

Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

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Outcome After Failure to Second Generation Thyrosine Kinase Inhibitors(TKI) Treatment as Frontline Therapy for Patients with Chronic Myeloid Leukemia (CML) In Chronic Phase(CP).

Blood ◽

10.1182/blood.v116.21.3442.3442 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3442-3442

Author(s):

Alireza Eghtedar ◽

Hagop Kantarjian ◽

Elias Jabbour ◽

Susan O'Brien ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Cytogenetic Response ◽

Initial Therapy ◽

Subsequent Treatment ◽

Cell Transplant ◽

2Nd Generation ◽

Frontline Therapy

Abstract Abstract 3442 Background: Imatinib has been the standard frontline therapy for patients with CML in early CP. 2nd generation TKIs (nilotinib, dasatinib) have been reported to be more effective than imatinib as frontline therapy in rates of response and transformation. Nilotinib has received regulatory approval for this indication and others (dasatinib, bosutinib) may come soon. Although fewer patients are expected to experience failure to therapy with the use of these agents, these patients will represent a management challenge. The characteristics, management and outcome of patients who fail therapy with 2nd generation TKI used as initial therapy has not been reported. Aim: To analyze the characteristics of patients who fail therapy with 2nd generation TKI used as initial therapy, their management, and outcome after failure to initial therapy. Methods: Two parallel studies of 2nd generation TKI as initial therapy for CML early CP are being conducted at MDACC, one with nilotinib and one with dasatinib. The study with nilotinib includes also patients in accelerated phase (AP) that have received no other prior therapy. The records of all patients who were taken off therapy from these trials were reviewed to investigate the reasons for failure, subsequent management and outcome. Results: A total of 172 pts have been treated with dasatinib (n=82) or nilotinib (n=90; 9 in AP) since 2005. After a median follow-up of 18.9 months, 23 pts (14%) have discontinued therapy: 13 (16%) pts in the nilotinib study (2 of them treated in AP), and 10 (12%) in the dasatinib study. Their median age 48 years (range:19–73) and they had received therapy with nilotinib or dasatinib for a median of 5.2 (0.03-48) months. Reasons for nilotinib treatment discontinuation include: toxicity 4 pts (elevated lipase, acute pancreatitis + atrial fibrillation, pericardial effusion and acute renal failure, one each), transformation to blast phase (BP) 3 pts (2 of them treated in AP), and other reasons 6 pts (2 each for insurance issues, patient request and non-compliance). Reasons for discontinuation of dasatinib include: toxicity 5 pts (2 pleural effusion, 1 prolonged thrombocytopenia, 1 bone pain, 1 congestive heart failure), 2 pts for loss of response, and 3 pts for pts' choice. Best response to frontline treatment with nilotinib or dasatinib was 6 (26%) pts major molecular response, 6 (26%) pts complete cytogenetic response, 1 (4%) pt partial cytogenetic response, 3 (13%) pts minor cytogenetic response, 1 (4%) pt with no response and 6 (26%) pts nonevaluable. At the time of failure 18 pts were in CP, 4 pts in BP (one pt transformed shortly after discontinuation) and 1 AP. At the time of treatment interruption, 14 pts had BCR-ABL sequencing and 2 were found to have mutations (F359C, Y253H); 3 pts had new additional chromosomal abnormalities (ie, clonal evolution). Subsequent treatment after failure to initial therapy include: imatinib in 8 pts, nilotinib in 2 pts, dasatinib 1 pt, Hyper CVAD with dasatinib 1 pt, Hyper CVAD with imatinib 1 pt, stem cell transplant 2 pts, bafetinib 1 pt, and unknown 4 pts (lost to follow-up). One pt died shortly after failure without further therapy. Best response to subsequent therapies were 1 pt with CMR (after stem cell transplant), 7 pts with MMR (3 pts after imatinib, 1 pt after dasatinib, 1 pt after nilotinib, 1 pt after Hyper CVAD with imatinib and 1 pt after stem cell transplant), 1 pt CHR, 1 pt minor CyR, 3 pts without response, and 8 pts were not evaluable. Of the 5 pts that achieved MMR with subsequent TKI, all were in CP and had discontinued initial therapy because of toxicity (4 pts) or personal reasons (1pt). Median duration of ongoing subsequent treatment is 8 months (range 1.7–25). The survival rate after a median follow-up of 3.9 months since failure to frontline therapy is 87%. Conclusion: Failure after frontline therapy with second generation TKI is an uncommon event, most frequently associated with toxicity or patient preference. Most of these patients respond well to alternative TKI. This adequate response should alleviate the fear of not having available effective therapy if patients fail to respond to 2nd generation TKI when used as frontline therapy. Disclosures: Kantarjian: BMS: Research Funding; NOVARTIS: Research Funding. Cortes:BMS: Research Funding; NOVARTIS: Research Funding; Pfizer: Consultancy, Research Funding.

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Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽

10.1182/blood.v118.21.1518.1518 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1518-1518

Author(s):

Hun Ju Lee ◽

Susan O'Brien ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Stefan Faderl ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cytogenetic Response ◽

Molecular Response ◽

Major Molecular Response ◽

Advisory Committees ◽

Cns Relapse ◽

Complete Hematologic Response

Abstract Abstract 1518 Background: Treatment with TKIs has greatly improved the outcome of patients with Ph+ ALL. However, many patients treated with TKI-based therapy eventually have a relapse. The response to salvage therapy and long-term outcomes of these patients are unknown. Aims: Describe the outcomes of patients with Ph+ ALL with resistance to or relapse after frontline TKI-based chemotherapy. Methods: We analyzed the outcome of patients who were treated in clinical trials at our institution between February 2001 and July 2008 with TKI-based chemotherapy for newly diagnosed Ph+ ALL who had refractory or relapsed disease. Results: One hundred thirteen patients were treated with frontline hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (HCVAD) plus imatinib (HCVAD+I; n=54) or HCVAD plus dasatinib (HCVAD+D; n=59). Of these, 35 (31%) experienced primary resistance (n=1) or relapse (n=34). The median age was 51 years [range (r): 20–85]; 12 patients (34%) were older than 60 years. Median follow-up was 21.1 mo (r: 4.2–56.7). Median white blood cell and platelet counts at diagnosis were 14.4 × 109/L (r: 1.2–292.9) and 48 × 109/L (r: 4–425), respectively. White blood cell count was >30 × 109/L in 13 patients (37%). Median peripheral and bone marrow blast percentages were 53% (r: 0–97%) and 80% (r: 1–98%), respectively. Twenty-two patients (63%) had received HCVAD+I and 13 (37%) HCVAD+D. Twenty-three patients (66%) had experienced first complete remission (CR1) with 1 cycle of induction. Median CR1 duration was 12 mo (r: 1.9–42). Four patients underwent allogeneic stem cell transplantation (ASCT) in CR1. ABL kinase domain mutations were investigated in 28 patients (80%) at relapse; 16 (57%) had mutations, including 5 (14%) with T315I (all had received HCVAD+D). Upon relapse, 31 patients received first salvage therapy (S1), 24 with chemotherapy [HCVAD+D, n=8; HCVAD+I, n=3; HCVAD+nilotinib (N), n=1; HCVAD+asparaginase (Asp), n=1; methotrexate, vincristine, Asp, and dexamethasone (MOAD), n=2; others, n=9]; 6 with a TKI only (I, n=2; D, n=1; N, n=1; others, n=2); and 1 with ASCT. Three patients were unfit for treatment. Median cycles of S1 were 2 (r: 1–8). Thirteen patients (42%) had second complete remission (CR2) (HCVAD+D, n=6; HCVAD+I, n=2; HCVAD+N, n=1; HCVAD+Asp, n=1; others, n=3). Median time to CR2 was 1.5 mo (r: 0.7–8.8). Five patients underwent ASCT in CR2. Median CR2 duration was 7.3 mo (r: 1.4–36.2). Complete cytogenetic response was seen in 11 patients (35%); major molecular response (BCR-ABL/ABL ratio <0.05%) in 9 (29%); and complete molecular response in 7 (22%); and complete hematologic response in 15 (48%). Times to complete cytogenetic response and complete molecular response were 1.3 mo (r: 0.7–10.6) and 3 mo (r: 1.5–8.7), respectively. Seven patients had second relapse. Fifteen patients (7 relapse, 8 refractory) received second salvage therapy (S2) with systemic chemotherapy (MOAD, n=2; phase I/single-agent TKI, n=8; others, n=5); 1 patient had solitary central nervous system (CNS) relapse treated with intrathecal cytarabine and methotrexate. CR3 was obtained in 1 patient, the patient with sole CNS relapse. Median disease-free survival (DFS) and overall survival (OS) after S1 were 6.5 mo (r: 0.5–45) and 7.3 mo (r: 1.4–36.2), respectively. At last follow-up, 2 patients (6%) were alive and 33 had died, 11 (33%) of infectious complications, 5 (15%) of organ failure, 3 (9%) of bleeding complications, 2 (6%) of graft-versus-host disease complications, 2 (6%) of CNS relapse, and 10 (30%) of other or unknown causes. Median OS after S2 was 2.1 mo (r: 1.4–2.6). In univariate analysis, age >60 years was associated with worse OS after S1 [4.2 vs. 12.7 mo; 95% confidence interval (CI) 1.8 to 6.7 vs. 7.5 to 17.9 (P=0.006)]. Complete hematologic response was associated with improved OS after S1 [15.4 vs. 4.3 mo; 95% CI 9.1 to 21.8 vs. 2.5 to 6.0 (P<0.001)]. Major molecular response was associated with improved OS after S1 [18.1 vs. 5.7 mo; 95% CI 9.3 to 26.8 vs. 3.6 to 7.8 (P=0.003)]. Choice of prior TKI (HCVAD+I vs. HCVAD+D) did not significantly influence CR and OS after relapse. Conclusion: Patients with refractory or relapsed Ph+ ALL after TKI-based therapy have poor outcome, particularly those who are older or have persistent BCR/ABL transcripts. New agents are needed to improve the outcome in this population. Disclosures: Kantarjian: BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Nilotinib in Imatinib-Resistant or -Intolerant Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): 48-Month Follow-up Results of a Phase 2 Study,

Blood ◽

10.1182/blood.v118.21.3770.3770 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3770-3770 ◽

Cited By ~ 3

Author(s):

Philipp D. le Coutre ◽

Francis J. Giles ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

Norbert Gattermann ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lung Neoplasm ◽

Chronic Phase ◽

Dose Intensity ◽

Advisory Committees ◽

Imatinib Resistance ◽

Imatinib Resistant ◽

Significant Difference

Abstract Abstract 3770 Background: Nilotinib is a selective and potent BCR-ABL TKI approved for the treatment of pts with newly diagnosed Ph+ CML-CP, and for pts with CML-CP or CML-AP resistant to or intolerant of imatinib. Here, we present the 48-mo follow-up data from the 2101 trial for pts with imatinib resistance or intolerance. Methods: Pts were treated with nilotinib 400 mg twice daily (BID). Key endpoints included PFS (defined as progression to AP/BC or discontinuation due to disease progression as assessed by investigator or death from any cause) and OS (includes deaths during treatment or follow-up after discontinuation). Results: 321 pts were enrolled (70% imatinib resistant; 30% imatinib intolerant with resistance). At baseline (BL), 36% of pts were in CHR. At the time of data cutoff, 224/321 pts (70%) discontinued nilotinib therapy (Table), and 31% of all pts had at least 48 mo of treatment. The median nilotinib dose intensity was 789 mg/day (range, 151–1110) and 62% of pts received ≥ 400 mg BID nilotinib as their last dose available. Pts with BL CHR had a significantly higher PFS rate at 48 mo vs pts without BL CHR (71% vs 49%, respectively; P =.001). Only 11 (3%) pts progressed to advanced disease (AP/BC) during study. Estimated 48-mo OS rate was 78% (95% CI 74%-83%). Among resistant pts, those without BL mutations (n = 92) had a significantly higher OS rate at 48 mo vs pts with sensitive mutations at BL (n = 78) (84% vs 74%, respectively, P =.029); however, there was no significant difference in OS among pts with sensitive and insensitive mutations (Y253H, E255K/V or F359C/V, n = 27) at BL (74% vs 71%, respectively, P =.804). No new safety signals were observed, and few additional AEs were reported since 24 mo follow-up (Table). Biochemical lab abnormalities were generally mild, transient, and easily managed; grade 3/4 lipase elevation (19%), hypophosphatemia (18%), and hyperglycemia (13%) were most common. Reports of any-grade pleural effusions remained low (1%), and no new cases were reported with longer follow-up. No new cases of QTcF >500 ms and 3 new cases of QTcF increases > 60 ms from BL were reported. Nine pts died during treatment or within 28 days of discontinuation: 8 deaths were previously reported and occurred in the first 24 mo of follow-up; 1 additional death due to lung neoplasm occurred between 24 and 48 mo (35 mo). Conclusions: With longer follow up, nilotinib continues to be effective and well tolerated in pts with Ph+ CML-CP resistant to or intolerant of imatinib therapy. Nilotinib prevented progression to AP/BC in the majority of pts on treatment and was associated with high OS rates. No cumulative toxicity was observed. Data demonstrating the higher rate of PFS in pts who entered the study with a BL CHR suggest that switching pts to nilotinib prior to hematologic failure on imatinib, and according to current treatment guidelines, may maximize the efficacy of nilotinib therapy. Disclosures: le Coutre: Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Giles:Novartis: Consultancy, Honoraria, Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Ottmann:Novartis: Consultancy; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Radich:BMS: Consultancy; Novartis: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hughes: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; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Müller:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shou:Novartis: Employment. Novick:Novartis: Employment, Equity Ownership. Fan:Novartis: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

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Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽

10.1182/blood.v120.21.3150.3150 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3150-3150 ◽

Cited By ~ 4

Author(s):

Raymond L. Comenzo ◽

Daniel E Fein ◽

Hani Hassoun ◽

Christina Bello ◽

Joanne F Chou ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Cumulative Incidence ◽

Research Funding ◽

Initial Therapy ◽

Novel Agents ◽

Cell Transplant ◽

Advisory Committees ◽

Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

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