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In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 337-337

Abstract: Abstract 337 Background: 12-month results from TOPS showed an advantage for the high dose (800mg/day, HD-IM) arm for: (1) time to achievement of major molecular response (MMR); MMR rates at 3 and 6 months (mos); and (2) complete cytogenetic response (CCyR) at 6 mos (Guilhot et al. [TOPS] ASH 2008). There was no significant difference in the MMR rates at 12 mos, the primary endpoint, and results support 400 mg/day as the standard initial dose for imatinib (SD-IM) in CML-CP pts. The purpose of this update is to assess the outcome of the two arms at 24 mos, as well as the impact of dose intensity (DI) and dose interruption on pts outcome. Methods: 476 pts with newly diagnosed CML-CP were randomized 2:1 to receive HD-IM (n = 319) or SD-IM (n = 157) at 103 sites in 19 countries. The endpoints assessed at 24 mos were: rates of CCyR and MMR, event-free (EFS), progression-free (PFS), and overall survival (OS). CCyR and MMR rates were calculated based on pts with available assessments at specified timepoints. Adverse events (AE) and laboratory results were also monitored. Additional analyses were performed using DI ( 〈 600 mg/d and ≥ 600 mg/d) and number of dose interruptions (periods of zero dose of 〉 5 days) as variables. In the trial dose interruptions were specified as an AE management strategy prior to dose reduction. Results: At 24 mos, 129/157 (82%) of SD-IM and 247/319 (77%) of HD-IM pts remained on study treatment. There was no significant difference in rates of MMR at 12 mos (SD-IM: 40% vs. HD-IM: 46%), 18 mos (52% vs 47%) or 24 mos (54% vs 51%) (intention to treat analysis). There was no significant difference in the cumulative rates of CCyR at 24 mos (76% in each arm). Overall, 9 (6%) pts on SD-IM and 15 (5%) pts on HD-IM had experienced an event (loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated phase and blast crisis, or death due to any cause). There were no significant differences in estimated EFS (SD-IM: 95% vs. HD-IM: 95%), PFS (97% vs. 98%), or OS (97% vs. 98%) at 24 mos. The most common grade 3/4 hematologic AEs were neutropenia (17.8% vs. 28.2%) and thrombocytopenia (8.9% vs. 19.9%), and for the most part occurred during the first 12 mos. The most common grade 3/4 nonhematologic toxicities for SD-IM and HD-IM were rash (2.5% vs 5.7%), diarrhea (1.3% vs 6.0%) and myalgia (0.6% vs 3.5%), respectively. The most common reasons for discontinuation in both arms were AEs (4.5% vs. 10.7%) and unsatisfactory therapeutic effect (7.0% vs 7.2%). Median DI was 400 mg/d in the SD-IM arm and 728 mg/d in the HD-IM arm. Dose interruptions for 〉 5 days occurred more frequently in the HD-IM arm (71% vs. 44%). Pts in both arms combined who had ≤ 1 dose interruption during the first 12 mos achieved higher MMR rates at 12 (57.1% vs 33.3% for ≤ 1 vs 〉 1 interruption; P 〈 0.0001) and 18 mos (72.6 vs. 46.8; P 〈 0.0001), faster time to MMR (P = 0.0002), and higher CCyR rates at 12 mos (88.8 vs 63.8; P 〈 0.0001), compared with pts who had 〉 1 dose interruption during the same period. On the SD-IM arm pts with ≤ 1 (vs 〉 1) dose interruption also had higher MMR rates at 12 and 18 mos (12 mos: 49.6% vs 22.2%, P = 0.04; 18 mos: 70.9% vs 50%, P = NS). Comparing pts in the HD-IM arm with DI ≥ 600mg/d for the first 12 mos vs DI 〈 600 mg/d, the MMR rates at 12 mos (62.4% vs 34.1%, P 〈 0.0001) and 18 mos (75.2% vs 40.3%, P 〈 0.0001) were higher, the time to MMR was faster (P 〈 0.0001), duration of MMR was longer (P = 0.0141) and CCyR rates at 12 mos (89.6% vs 70.3%, P 〈 0.0001) were higher for pts with DI ≥ 600mg/d. Conclusions: TOPS continues to confirm the safety and efficacy of 400 mg/day IM for newly diagnosed pts with CML-CP, with very similar results to IRIS. HD-IM was also safe and generally well tolerated, but overall did not result in better outcomes at milestones up to 24 months. Frequent or prolonged dosage interruptions on IM adversely affect patient outcomes and should be avoided. These data emphasize the importance of maintaining dose intensity in CML-CP pts treated with imatinib. The TOPS study will continue to assess the impact of dose intensity on long-term outcomes. Disclosures: Baccarani: Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. 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; Wyeth: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: 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. Jin:Novartis: Employment. Krahnke:Novartis: Employment, Equity Ownership. Rudoltz:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.337.337

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 665-665

Abstract: Background: Achieving sustained DMR (variably described as ≥ MR4 or ≥ MR4.5) is an emerging treatment goal for patients with CML. DMR is associated with excellent long-term clinical outcomes and a higher likelihood of successful treatment-free remission (TFR) upon discontinuation of tyrosine kinase inhibitor (TKI) therapy. Biological predictors of patients likely to achieve DMR are unknown. Here, we present an exploratory analysis of gene expression signatures in order to predict DMR to TKI therapy, as well as understand the biological underpinnings that allow a DMR, based on patients treated with imatinib or nilotinib in the ENESTnd study (NCT00471497). Methods: ENESTnd is a phase 3, randomized, open-label study comparing nilotinib 300 mg twice daily (BID), nilotinib 400 mg BID and imatinib 400 mg once daily (QD) in patients with newly-diagnosed CML. To maximize the likelihood of defining predictive and biologically relevant gene signatures, samples from a group of poor responders (BCR-ABL1IS & gt; 10% by 3 months of therapy) and good responders (BCR-ABL1IS & lt; 0.01% by 12 months of therapy) were selected across all treatment arms. Whole blood samples collected prior to study treatment initiation were available from 112 such patients from the total 846 patients enrolled in ENESTnd, and were subjected to RNA sequencing. DMR was assessed using quantitative polymerase chain reaction transcript ratios standardized to the international scale (IS) and was defined as BCR-ABLIS ≤ 0.01% (MR4) or ≤ 0.0032% (MR4.5). For statistical analysis, responders were defined as patients having achieved DMR by 5 years, whereas non-responders were in the trial for ≥ 5 years without achieving DMR. Five years was selected to ensure that patients on both imatinib and nilotinib arms had adequate time to reach MR4.5. The association of clinical variables with responder status (good or poor) was assessed via a multivariate logistic regression model. Results: We correlated clinical variables (eg, Sokal risk score, TKI, age, sex) with responder status for 112 ENESTnd study patients who received 400 mg imatinib QD (n = 47), 300 mg nilotinib BID (n = 33), or 400 mg nilotinib BID (n = 32). Of the 112 patient samples, 70 were included in the analysis using MR4.5 as an endpoint, with 47 patients characterized as responders (imatinib: 16; nilotinib: 31), and 23 as non-responders (imatinib: 13; nilotinib: 10). Of the 112 samples, 42 were excluded from analysis because the patients discontinued the trial before 5 years and did not achieve MR4.5 (imatinib: 18; nilotinib: 24). Younger age ( & lt; 35 years) was associated with good response (p & lt; 0.02) in a multivariate analysis. We developed a predictive model of responder status by applying penalized regression to clinical variables and gene expression (13569 genes) in independent (clinical or gene expression) and combined gene and clinical models. The best performing model used patients with MR4.5 vs poor responders, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.87 (Figure; Table). Including clinical variables did not result in markedly different performance (AUC = 0.85). Significantly, both models outperformed a model that included clinical variables only (AUC = 0.65). Relaxing the definition of good responders to include patients with MR4 yielded similar results (Table). Detailed biomarker/pathway analysis to explore the biological pathways that separate good and poor response are underway. Conclusions: We present a gene expression model that distinguishes patients who achieved a DMR from those with a poor response to treatment at 5 years. The approach for sample selection optimized the chances of finding a biological and clinical signal and may be applicable to all CML patients initiating TKI therapy. This work could yield new therapeutic targets that could potentially turn a patient biologically determined to be a poor responder into a good responder who might even achieve a TFR. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy; Agios: Consultancy. Kantarjian:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. DeAngelo:Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Blueprint: Consultancy, Research Funding; Shire: Consultancy. Branford:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Sadek:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Sondhi:Novartis: Employment, Other: Stock; Sanofi: Other: Stock. Mishra:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals: Employment. Shrestha:Novartis: Employment. Obourn:Novartis: Employment. Druker:Cepheid: Consultancy, Honoraria; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; CureOne: Membership on an entity's Board of Directors or advisory committees; Beat AML LLC: Other: Service on joint steering committee; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Celgene: Consultancy; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124716

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1018-1018

Abstract: In Ph+ leukemia, the breakpoints within BCR cluster in 3 distinct breakpoint cluster regions (bcr). Rearrangements in the minor (m−), major (M−) and micro (m−) breakpoint cluster region (bcr) give rise to e1a2, e13/14a2 and e19a2 BCR-ABL fusion proteins that are associated with Ph+ ALL, CML and chronic neutrophilic leukemia, respectively. Atypical BCR-ABL fusions have also been reported, mostly in isolated cases. Here, we describe eight patients with an unusual e8a2 BCR-ABL transcript and provide an overview of their common characteristics. The index case (#1) was a 56 year old man diagnosed with CML in 1993. Therapy with busulfan and hydrea induced a complete hematologic remission (CHR) that was maintained until March 2001, when accelerated disease developed. Treatment with imatinib and subsequently AML-type chemotherapy were only transiently effective and the patient died from myeloid blast crisis in March 2003. Cytogenetics demonstrated a standard t(9;22)(q34;q11). Unexpectedly, FISH was consistent with an m-bcr rearrangement and multiplex PCR showed an unusually large band. Sequencing identified a fusion between BCR exon e8 and ABL exon a2, with a 55 bp insert corresponding to an inverted segment of ABL intron Ib (corresponding to nt 29861–29915, Genbank U07561). Immunoblotting of bone marrow mononuclear cells with anti-ABL antibody identified a 200 kDa protein (p200BCR-ABL). Seven additional patients with an e8a2 BCR-ABL fusion have been identified (table 1). These patients tend to have relatively high platelet counts (median 569 x 109/L, range 216 – 1123) and relatively low white counts (median 42 x 109/L, range 4.7 – 146) but no other distinguishing characteristics at diagnosis. With a median follow-up of 36 months (range, 4 –97), two patients had progressed to blast crisis and died, one died from an unrelated cause, and five were alive, one after allogeneic BMT. Remarkably, none of the patients treated with interferon-a achieved even a minor cytogenetic remission, similar to patients with p190-positive CML. Two patients besides case #1 have received imatinib, one has achieved a CHR at four months, and information on the other is not available. Compared to P190 and P210, p200 lacks the pleckstrin homology (PH) domain but retains the Dbl-like and CDC24 homology domains of BCR. Deletion of the PH domain may disrupt the function of the Dbl-like domain to serve as a GTP exchange factor for Rac, Cdc42 and Rho. This may lead to disruption of the actin cytoskeleton and would be expected to cause a disease that is biologically closer to p190 than to p210.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.1018.1018

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 376, No. 10 ( 2017-03-09), p. 917-927

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1609324

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2017

detail.hit.zdb_id: 1468837-2

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 3 ( 2010-01-20), p. 424-430

Abstract: To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and Methods A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. Results At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. Conclusion MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2009.25.3724

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2010

detail.hit.zdb_id: 2005181-5

In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 108, No. 6 ( 2023-02-02), p. 1567-1578

Abstract: Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.1% by 12 months) and poor responders (failure to meet these criteria). Predictive models based on gene expression demonstrated the best performance (area under the curve =0.76, standard deviation =0.07). All of the top 20 pathways overexpressed in good responders involved immune regulation, a finding validated in an independent data set. This study emphasizes the importance of pretreatment adaptive immune response in treatment efficacy and suggests biological pathways that can be targeted to improve response.

Type of Medium: Online Resource

ISSN: 1592-8721 , 0390-6078

URL: Article

DOI: 10.3324/haematol.2022.281878

Language: Unknown

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2023

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Leukemia, Springer Science and Business Media LLC, Vol. 33, No. 8 ( 2019-8), p. 1835-1850

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-019-0512-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 114, No. 24 ( 2009-12-03), p. 4944-4953

Abstract: Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM; among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2009-04-214221

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 335-335

Abstract: Background: IM 400 mg/d is the standard of care for pts with newly diagnosed CML-CP. Previous reports suggest the rate of major molecular response (MMR), defined as BCR-ABL/control gene (BAC) ratio of ≤ 0.1% on the International Scale, predicts for a benefit in long-term outcomes. Phase 2 trials demonstrated that IM 800 mg/d as initial treatment of CML-CP decreases the time to MMR and increases the depth of molecular response (MR), and may therefore improve long-term outcomes. Methods: TOPS is a prospective, open-label, randomized (2:1) Phase 3 trial that compared IM 800 mg/d to 400 mg/d in CML-CP. Pts were stratified by Sokal risk score. The primary endpoint is MMR rate at 12 months (mo) and secondary endpoints include: rates of complete hematological response, complete cytogenetic response (CCyR), time to CCyR and MMR, progression to accelerated phase (AP) or blast crisis (BC), eventfree survival (EFS), overall survival (OS), IM dose-intensity, pharmacokinetics, and safety. Rates were compared by Fisher’s exact test and time to event outcomes by logrank test. Results: 476 pts were enrolled (800 mg/d, n=319; 400 mg/d, n=157) at 103 sites in 19 countries between 6/05 and 12/06. Median age at diagnosis was 47 yrs, and 24% of pts had high Sokal risk score. Significantly more pts receiving IM 800 mg/d achieved MMR at 3 mo and 6 mo, but not at 12 mo when compared with 400 mg/d (Table 1). Time to MMR was faster in the 800 mg/d arm compared to 400 mg/d; P = .0038. Table 1: MMR rate (%) over time according to randomized dose of IM MMR rate (%) Intent-to-treat (ITT) population Evaluable pts (with polymerase chain reaction assessment) 400 mg (N = 157) 800 mg (N = 319) P-value 400 mg %, (n) 800 mg %, (n) P-value Month 3 3 12 .0011 4 (137) 14 (283) .0011 Month 6 17 34 .0002 20 (135) 39 (276) .0001 Month 9 36 45 .0604 41 (136) 54 (267) .0203 Month 12 40 46 .2035 46 (133) 54 (269) .1386 Achievement of MMR according to average dose over the first 12 mo of treatment was greatest when the intended dose intensity (DI) was achieved (Table 2). Table 2. MMR at 12 mo according to DI (evaluable patients) Randomized Dose MMR DI (first 12 mo) (n) MMR rate, % [95% CI] 400 mg (n =133) 46% ≥ 400 mg (74) 50 [38−62] & lt; 400 mg (59) 41 [28−54] 800 mg (n =269) 54% 800 mg (52) 63 [49−76] 600 – 799 mg (134) 62 [53−70] 400 – 599 mg (69) 38 [26−50] & lt; 400 mg (14) 21 [5−51] CCyR occurred faster in the 800 mg/d arm, indicated by a higher response rate at 6 mo (57% vs. 45%, P = .0146). At 12 mo rates of MMR and CCyR (ITT population) were higher for the 800 mg/d arm but were no longer significantly different (MMR 46% vs. 40%, P= .2035; CCyR 70% vs. 66%, P= .3470). In pts with high Sokal risk scores, rates of MMR at 12 mo were 41% and 26% (P = .1565) for the 800 mg/d and 400 mg/d arms, respectively. Exploratory analysis of MR at 3 mo and its correlation with achievement of MMR at 12 mo follow. Of the pts in the 400 mg arm with BAC ratios & gt;0.1–≤ 1%, & gt;1–≤ 10% or & gt; 10% at 3 mo, 83%, 46%, and 11% later achieved an MMR at 12 mo. In the 800 mg arm 73%, 45% and 21% of the pts with respective BAC ratios achieved an MMR at 12 mo. Based on the BAC ratio at 6 mo, the observed MMR rate at 12 months was 52%, 11%, and 0% in the 400 mg/d arm compared to 46%, 14%, and 18% in the 800 mg/d arm. In the first year of follow-up, 6 pts had documented progression to AP/BC during treatment: 3 (1.9%) in the 400 mg/d arm and 3 (0.9%) in the 800 mg/d arm. At 12 mo, 85% of pts in the 400 mg/d arm were receiving the randomized dose compared to 62% of pts in the 800 mg/d arm. Median DI was 400 mg/d in the 400 mg arm and 750 mg/d in the 800 mg arm. Dose interruptions & gt; 5 days occurred more frequently in the 800 mg/d arm (67% vs 38%). Earlier achievement of MMR correlated with IM plasma trough level at 1 mo for the overall TOPS cohort; pts with IM concentrations & lt; 1165 ng/mL (lowest quartile of the aggregate group) achieved MMR slower than those with concentrations ≥ 1165 ng/mL (p=.0149). The most common grade 3/4 nonhematologic toxicities were rash, diarrhea and myalgia occurring slightly more frequently in the 800 mg/d arm. Grade 3/4 hematologic toxicity occurred more frequently in pts receiving 800 mg/d. Conclusions: TOPS confirms the efficacy and safety of IM in newly-diagnosed CML-CP. MMR occurred earlier in pts treated with 800 mg/d and in patients with plasma IM level above the lowest quartile, reinforcing the utility of IM blood level testing to optimize treatment. DI of IM 800 mg/d was maintained and tolerability was good. Additional follow-up is required to evaluate the effect of dose and MR on long-term clinical outcomes.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.335.335

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: International Journal of Hematology, Springer Science and Business Media LLC, Vol. 99, No. 5 ( 2014-5), p. 616-624

Type of Medium: Online Resource

ISSN: 0925-5710 , 1865-3774

URL: Article

DOI: 10.1007/s12185-014-1566-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2014

detail.hit.zdb_id: 2028991-1