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In: The Lancet Haematology, Elsevier BV, Vol. 4, No. 3 ( 2017-03), p. e127-e136

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(17)30012-1

Language: English

Publisher: Elsevier BV

Publication Date: 2017

In: Leukemia and Lymphoma, Informa UK Limited, Vol. 17, No. 5 ( 1995-5-1), p. 449-453

Type of Medium: Online Resource

ISSN: 1042-8194

URL: Article

DOI: 10.3109/10428199509056856

Language: English

Publisher: Informa UK Limited

Publication Date: 1995

detail.hit.zdb_id: 2030637-4

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3603-3603

Abstract: Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adults with resistant or intolerant chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those carrying the T315I mutation. Ponatinib has been commercially available since January 2015, yet there is a paucity of data on its use in the real-world setting. The goal of the Observational study of Iclusig ® (ponatinib) Treatment in patients with CML in Italy (OITI) was to evaluate treatment patterns and outcomes, including safety and efficacy, in patients with CML treated in Italy since the approval of ponatinib. Methods. This noninterventional study included patients aged ≥18 years with CP, AP, or BP CML who initiated ponatinib treatment in routine clinical practice across 26 Italian centers (academic and hospital settings). The study population comprised a prospective cohort, including patients who started treatment with ponatinib after site activation during the 12-month enrollment period; a retrospective cohort, including patients who started treatment with ponatinib but died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and were still on treatment or in follow-up at the end of the study. Demographic, efficacy, and safety data were collected from patient medical charts at study entry and routine visits. The primary endpoint was the complete cytogenetic response (CCyR) rate in CP CML patients 6 months after starting ponatinib. In the absence of cytogenetic evaluation, molecular assessment was used, considering patients in MR2 or better to be in CCyR. Here, the primary analysis of all evaluable patients for the primary endpoint (median follow-up, 23.7 months [range, 1.3-70.8]) is presented. Results. A total of 119 patients (110 CP, 6 AP, and 3 BP CML) were analyzed. Fifty-nine (49.6%) received ponatinib in second-line (2L), 41 (34.4%) in 3L, and 19 (16.0%) in ≥4L. Prior cardiovascular disease/hypertension was recorded in 56 (47.1%) patients. Median age at ponatinib start was 60 years (range, 19-93). Of 68 evaluated patients, 24 (35.3%) had a confirmed ABL1 mutation, including 7 (10.3%) with the T315I mutation. Starting doses of ponatinib were 45 mg (37.0%), 30 mg (41.2%), or 15 mg (21.8%). Median treatment duration was 22.8 months (range, 1.4-73.6). At baseline, 56 patients with CP CML had less than CCyR and 53 were in CCyR. For 1 patient, assessment was not available. At 6 months, 80/107 evaluable patients with CP CML were in CCyR; 29/56 (51.8%) achieved and 50/50 (100%) maintained CCyR compared to baseline, respectively. For 1 patient, baseline data were unavailable. Additionally, 37 (34.6%) and 19 (17.8%) patients with CP CML achieved a major molecular response (MMR; MR3) and a deep molecular response (MR4-MR5), respectively (Table 1). Progression-free survival rates estimated for patients with CP CML at 12 and 24 months were 92.6% (95% CI, 87.8-97.7%) and 84.6% (95% CI, 77.2-92.6%), respectively. Corresponding overall survival rates were 95.4% (95% CI, 91.6-99.4%), and 88.4% (95% CI, 81.7-95.7%). Seventy-one (59.7%) patients had treatment-related adverse events (AEs), most commonly rash, hypertension (Grade 1-2), and thrombocytopenia (Grade 3). Treatment-related arterial occlusive events occurred in 2 (1.7%) patients. Dose modifications occurred in 77 patients: 37.1% were due to AEs, 13.5% were reductions after at least major cytogenetic response, 10.6% were increases due to lack of efficacy, 1.7% were medical decisions, and 37.1% were for other reasons. Thirty-three patients discontinued ponatinib due to AEs (33.3%), medical decisions (24.2%), and other reasons (42.4%), such as death, progression, and hematopoietic stem cell transplantation. Conclusions. This observational study demonstrates that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice. By 6 months, 74.8% of evaluable patients were in CCyR and 52.3% achieved at least MMR. Further, the probability of survival at 2 years was & gt;88%. No new safety signals emerged with ponatinib treatment compared to prior studies. The early use of ponatinib and careful dose selection appear key to the safety and efficacy outcomes observed in this real-world study. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Bonifacio: Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Inctye Bioscience Italy Srl: Current Employment. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146139

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4049-4049

Abstract: Background The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated a need for early molecular parameters associated with inadequate responses to Imatinib Mesylate (IM). Objective We correlated quantitative determination of BCR-ABL transcripts at diagnosis with the outcome (defined according to the 2013 European Leukemia Net recommendations) of 272 newly diagnosed CML patients receiving IM 400 mg/die. Methods BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis before patients received any pharmacological treatment using Real-Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. BCR-ABL values were then reported on the international scale (IS). Results With a median follow-up of 60 months, 65.4% of patients achieved an optimal response, 5.6% presented a response currently defined as "warning", 22.4% failed IM treatment and 6.6% switched to a different tyrosine kinase inhibitor because of intolerance to the drug. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We applied Receiver Operating Characteristic (ROC) curves to define BCR-ABL/GUSIS expression levels that would separate patients likely (i.e. below the threshold) or unlikely (i.e. above the threshold) to achieve multiple endpoints, namely: optimal response (OR), failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS). Employing the specific threshold calculated for each endpoint we found that high BCR-ABL/GUSIS levels at diagnosis were associated with inferior probabilities of OR (p 〈 0.001), FFS (p 〈 0.001) and EFS (p 〈 0.001). Elevated BCR-ABL/GUSIS levels were also associated with higher rates of disease transformation to the accelerated phase or blast crisis (p=0.029) but not with OS (p=0.132). Conclusions High BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from standard dose IM that should be considered for alternative forms of treatment. Disclosures Hochhaus: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4049.4049

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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. 4179-4179

Abstract: Background: Non-adherence to medications is recognized as one of the most important and costly worldwide healthcare problems in the 21st century; according to an EU report, non-adherence to therapies is responsible for 194,500 deaths and costs €125 billion annually. Taking into account those data, the use of adherence measurements in clinical trials could be extremely useful, in order to better understand patients (pts) behaviours and outcomes. The 8-item Morisky Medication Adherence Scale (MMAS-8, Morisky DE et al, J Clin Hypertens,2008 - Krousel-Wood MA et al, Am J Manag Care 2009- Morisky DE et al, J Clin Epidemiol. 2011) is a widely used questionnaire to asses indirectly pts adherence to medications. The first seven items are yes/no questions, and the last item is a five point Likert-scale. Ruxolitinib (RUX) is an oral JAK1/2 inhibitor approved for the treatment of symptoms and/or splenomegaly in myelofibrosis (MF) pts. ROMEI (CINC424AIT04-Ruxolitinib Observational study in Myelofibrosis treated patients in Italy) is a prospective observational study focused on real life management of MF pts with RUX; the trial enrolled 215 pts and included a prospective evaluation of MMAS-8 as a secondary endpoint. To date, no data regarding MMAS-8 and RUX are available and here we show a descriptive analysis of MMAS-8 after 24 weeks (wks) of RUX treatment. Methods: After informed consent signature, pts started RUX according to Summary of Product Characteristics; MMAS-8 questionnaire was administered at wks 4, 8, 12 and 24 after RUX initiation. MMAS-8 were analysed only if pts provided all responses to the questionnaire; a score ˂ 6 indicates low adherence, a score between 6 and 8 indicates medium adherence, and a score = 8 suggests high adherence. As per protocol, only adherence classes (low-medium-high) assessment was scheduled and in case of low or medium adherence (ie suboptimal adherence), no action in term of target education or psychological interventions was planned. Results: Out of 215 enrolled pts, 188 were evaluable for MMAS-8. The MMAS-8 was completed by 163 pts (87%) at week (wk) 4, 156 pts (83%) at wk 8, 146 pts (78%) at wk 12 and 134 pts (71%) at wk 24. A total of 101 out of 188 eligible pts (54%) completed all 4 scheduled questionnaires. MMAS-8 total score seems to remain stable over the time. Mean MMAS-8 total score was 7.54±0.77 (min; max: 4.75; 8.00) at wk 4 and 7.67±0.70 (min; max: 4.25; 8.00) at wk 24, resulting in a mean change from wk 4 of 0.14±0.79 (min; max: -2.25; 2.25). Regarding adherence classes, the distribution between low, medium and high adherence over time is shown in table 1. Likewise, if we consider pts who completed all scheduled questionnaires, MMSA-8 total score remains stable over the wks, with total score of 7.53±0.79 (min; max: 4.75; 8.00) at wk 4, 7.60±0.71 (min; max: 4.75; 8.00) at wk 8, 7.69±0.69 (min; max 4.50; 8.00) at wk 12 and 7.67±0.73 (min; max: 4.25; 8.00) at wk 24, as well as adherence classes distribution (Fig 1). Regarding adherence classes in this subgroup of pts, seems that pts with high adherence at wk 4 are more prone to maintain the same class during time. Finally, we tried to perform an exploratory analysis relating spleen response according to IWG-MRT criteria with adherence classes at each time points: considering the small number of evaluable pts with complete information regarding both available parameters, no correlation between spleen responses and adherence classes was demonstrated (data available at the meeting). Conclusion: This is the first time of MMAS-8 applied in MF pts as well as those treated with RUX. Our analysis showed a not irrelevant percentage of pts (ranging from 25% to 40%) belonging to a low-intermediate adherence classes during treatment. Surprisingly overall approximately one third of patients could be exposed to a suboptimal treatment over time and probably clinicians underestimate the number of those pts in clinical practice. Although we did not find in our cohort a correlation between adherence classes and spleen responses, probably due to low number of evaluable pts for both variables, the knowledge regarding pts attitude to therapy, especially for long-term and chronic treatments, remains crucial from clinical and pharmacoeconomic perspectives. Standardized methods to assess pts adherence such as MMAS-8 should be implemented in prospective well-designed clinical trials and could be a precious tool guiding clinicians in the everyday practice. Disclosures Palandri: Novartis: Consultancy, Honoraria. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morelli:Novartis: Employment. Passamonti:Celgene Corporation: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Breccia:Bristol-Myers Squibb, Celgene, Incyte, Novartis, Pfizer: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124730

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Frontiers in Oncology, Frontiers Media SA, Vol. 9 ( 2019-8-13)

Type of Medium: Online Resource

ISSN: 2234-943X

URL: Article

URL: Article

URL: Article

DOI: 10.3389/fonc.2019.00764

DOI: 10.3389/fonc.2019.00764.s001

DOI: 10.3389/fonc.2019.00764.s002

Language: Unknown

Publisher: Frontiers Media SA

Publication Date: 2019

detail.hit.zdb_id: 2649216-7

In: American Journal of Hematology, Wiley, Vol. 92, No. 1 ( 2017-01), p. 82-87

Abstract: Chronic myeloid leukemia (CML) treatment is based on company‐sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first‐line therapy. These studies included patients selected according to many inclusion–exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real‐life), inclusion–exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first‐line TKI but also on second‐ and third‐line TKIs. To investigate in a real‐life setting the response and the outcome on first‐line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients ( N  = 236), living in two Italian regions, registered in a prospective study according to population‐based criteria and treated front‐line with imatinib. A switch from imatinib to second‐generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5‐year overall survival (OS) and leukemia‐related survival (LRS) were 85% and 93%, respectively; the 4‐year rates of MR 3.0 and MR 4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second‐line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real‐life, according to ELN recommendations, using imatinib as first‐line treatment and second‐generation TKIs as second‐line therapy. Am. J. Hematol. 92:82–87, 2017. © 2016 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v92.1

DOI: 10.1002/ajh.24591

Language: English

Publisher: Wiley

Publication Date: 2017

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3076-3076

Abstract: Background. Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapies. However these clinical trials included patients selected according to different inclusion and exclusion criteria, particularly age and comorbidities, and with specific treatment obligations. In daily clinical practice (real life), no inclusion and exclusion criteria do exist, and treatment outcomes depend not only on choice of the first-line TKI, but also on doctor- and patient-choice of second- and third-line TKIs. Aims. To investigate the response and the outcome on first-line imatinib, with switch to 2nd generation TKIs in case of failure or toxicity, in BCR-ABL1+ CML patients enrolled in a population-based registry (real-life setting). Methods. We report here the results from a prospective study, enrolling all newly diagnosed patients (N = 236, median age 60 years) living in two Italian regions, that were registered according to population-based criteria and treated front-line with imatinib. The decision to switch to second-line treatment was up to the Local Investigator (no predefined criteria) Definitions: major molecular response (MMR or MR3.0): BCR-ABL1IS ratio 〈 0.1%; deep molecular response (MR4.0): BCR-ABL1IS ratio 〈 0.01% with 〉 10,000 ABL1 copies; failure and suboptimal response: according to 2009 European LeukemiaNet (ELN) criteria; progression: transformation to advanced phases according to ELN criteria; leukemia-related death (LRD): death after progression. Results. Median age was 60 years at diagnosis and 64 years at last contact, with a median follow up of 48 months (range 2-86 months). High risk patients according to Sokal score and new EUTOS long-term survival (ELTS) score were 23% and 18%, respectively. A switch from imatinib to a second generation TKI was reported in 14% of patients for side-effects, and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The median time to switch was 8 months for toxicity and 20 months for failure. At 12 months, 55% of all evaluable patients were in MR3.0 or better. At last contact, 75% of all evaluable patients were in MR3.0 or better and 48% were in MR4.0 or better. The molecular response of patients switching for failure or suboptimal response was evaluable in 61/63 patients: improved in 57%, not modified in 38%, worsened by at least 1 log in 5% of patients. Overall, the treatment switch was associated with a remarkable increase of MR3.0 rate: from 10% at the time of switching to 52% at last qPCR. Overall, 33% achieved a stable MR4.0, of whom 22% with imatinib alone, and 11% after switching to a second generation TKI (Table 1). The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively. Twenty-seven patients (11%) died, of whom 13 (6%) of leukemia, after disease progression and 14 (6%) of "other" causes, without any evidence of progression. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients who received nilotinib in second-line. OS was not affected by age in the interval between 18 and 69 years (5-year OS 92%, ranging from 89% to 95 % in the different decades), but 5-year OS probabilities of elderly (70-79 years) and very elderly patients (≥ 80 years) were significantly lower (78%, P = 0.003, and 34%, P 〈 0.0001, respectively). The probability of LRS was not affected by age. The Sokal score predicted OS, but not LRS. The ELTS score clearly separated low, intermediate, and high risk patients for OS and also for LRS. Conclusions. The results of this prospective population-based study emphasize the importance of second-line treatment in the clinical practice: the CML management with the 3 available TKIs in the period 2008-2012, according to current treatment recommendations for switching and without any predefined obligation, resulted in response rates and outcomes, that are in the high range of prospective interventional studies investigating the efficacy and the safety of a single TKI in selected patients. This study provides a robust dataset on the results of CML treatment with TKI in clinical practice, that will be important for interpreting and evaluating the results of the next prospective studies, arguably limited to selected patients. Disclosures Castagnetti: Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marasca:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy. Martinelli:Genentech: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Ariad: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3076.3076

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1495-1495

Abstract: The approval of three tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated an urgent need for molecular parameters predictive of unfavorable therapeutic outcomes. Recent evidence suggests that failure to achieve early molecular responses (i.e. BCR-ABL/ABLIS levels 〈 10% after 3 months or 〈 1% after 6 months of TKI treatment) results in inferior rates of both overall and progression-free survival. With the current study, we wanted to establish if high BCR-ABL transcripts at diagnosis would be associated with unfavorable responses to Imatinib Mesylate (IM). Thus, we correlated quantitative determinations of BCR-ABL levels at diagnosis with the outcome of 230 newly diagnosed CML patients that were assigned to receive IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn before exposure to any form of treatment. Real-Time Quantitative PCR (RQ-PCR) determinations were subsequently performed in triplicates using glucuronidase-beta (GUS) as the reference gene, since previous evidence has demonstrated that ABL is not a reliable control gene in samples collected at diagnosis. Values were then reported on the International Scale employing a conversion factor obtained from the laboratory of the University of Heidelberg in Mannheim, Germany. Median follow-up of the study population was 50 months. Estimated 5-year cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 97.9%, 89.5% and 64.7%. Five-year probabilities of overall survival (OS), transformation-free survival (TFS: survival without disease transformation to the accelerated phase or blast crisis) and failure-free survival (FFS: survival without IM failure as defined by the 2009 European Leukemia Net recommendations) were 93.8%, 97.8% and 76%. Elevated BCR-ABL/GUSIS correlated with inferior probabilities of optimal response (p 〈 0.001), and lower rates of CCyR after 12 months of IM (p 〈 0.001). Moreover, high BCR-ABL/GUSIS transcripts were associated with lower probabilities of FFS (p 〈 0.001) and TFS (p=0.01). When we employed the 2009 European Leukemia Net criteria to subdivide our patient cohort in optimal responders, suboptimal responders and individuals failing IM, we found that increasingly elevated BCR-ABL/GUSIS transcripts accurately distinguished the three patient groups (optimal vs suboptimal p 〈 0.001; optimal vs resistant p 〈 0.001; suboptimal vs resistant p 〈 0.001). Furthermore, using receiver operating characteristic curves we found that progressively higher BCR-ABL/GUSIS levels at diagnosis defined quantitative transcript thresholds (15.96% for Optimal Response, 16.01% for EFS, 16.09% for FFS, 20.36% for TFS and 22.04% for OS) that separated low risk from high risk patients. Finally, we wanted to determine the concordance rates between BCR-ABL/GUSIS levels at diagnosis and early molecular responses (eMRs) at 3 and 6 months. We therefore employed the 15.96% BCR-ABL/GUSIS threshold to identify subjects with high ( 〈 15.96%) or low ( 〉 15.96%) probabilities of obtaining an Optimal Response and found that 69% of patients displaying 〈 15.96% BCR-ABL/GUSIS achieved 〈 10% BCR-ABL/ABLIS levels after 3 months of IM (p 〈 0.001). Likewise, 78% of subjects presenting 〈 15.96% BCR-ABL/GUSIS at diagnosis attained 〈 1% BCR-ABL/ABLIS after 6 months of therapy (p 〈 0.001). We conclude that high BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment. Disclosures: Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1495.1495

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 9 ( 2019-05-06), p. 2226-

Abstract: A reduction in BCR-ABL1/ABL1IS transcript levels to 〈 10% after 3 months or 〈 1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values 〉 10% at 3 months but 〈 1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS 〈 10% at 3 months but 〉 1% at 6 months (event-free survival 68.2% vs. 32.7%; p 〈 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months 〉 10% but 〈 1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS 〈 10% at 3 months but 〉 1% at 6 months (75% vs. 18.2%; p 〈 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values 〈 1% at 6 months (p 〈 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms20092226

Language: English

Publisher: MDPI AG

Publication Date: 2019

detail.hit.zdb_id: 2019364-6

SSG: 12