scholarly journals Impact of the major BCR-ABL1 transcript type on clinical and biological parameters and molecular response in patients with chronic myeloid leukemia

2020 ◽  
Author(s):  
Mourad Nachi ◽  
Ibtissem Kihel ◽  
Badra Entasoltane ◽  
Mohamed Brahimi ◽  
Nabil Yafour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Biological Parameters ◽  
Transcript Type

scholarly journals Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

2021 ◽  
Vol 10 (14) ◽  
pp. 3146
Author(s):  
Sílvia Marcé ◽  
Blanca Xicoy ◽  
Olga García ◽  
Marta Cabezón ◽  
Natalia Estrada ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Positive Impact ◽  
Remission Rate ◽  
Progression Rate ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
Transcript Type

The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate.

Response to Imatinib in e13a2 Versus e14a2 BCR-ABL Fusion Transcripts in Chronic Myeloid Leukemia Saudi Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5453-5453
Author(s):  
Wafa M. Elbjeirami ◽  
Amal S. Alabdulwahab ◽  
Hussein G. ELSayed ◽  
Nermeen Adel Abdelghaffer ◽  
Noha Elnagdi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Laboratory Data ◽  
Molecular Response ◽  
Fusion Transcripts ◽  
Log Reduction ◽  
Transcript Type

Abstract Background: Chronic myeloid leukemia (CML) is one of the predominant hematological malignancies in Saudi Arabia (SA). Different BCR-ABL fusion mRNAs occur immediately downstream of exon 2 or 3 of the M-bcr region and result in e13a2 or e14a2 fusion transcripts and the P210 BCR-ABL1 protein. To our knowledge, there is no published data addressing the frequency of BCR-ABL1 fusion transcripts among Saudi CML patients, and whether clinical outcome and gender have any correlation with BCR-ABL transcript type. Aims: First, to determine whether BCR-ABL transcript type, gender, and response to therapy have any correlation in Saudi CML patients presented at King Abdullah Medical City (KAMC) in Makkah, western region of SA. Second, to determine the frequency of BCR-ABL transcript variants, and compare it with the occurrence reported in other neighboring populations. Methods: Peripheral blood and bone marrow samples were analyzed by nested and multiplex RT-PCR to detect and quantify BCR-ABL transcripts from 72 evaluable Saudi CML patients seen at KAMC from January 2011 to present. Clinical and laboratory data were obtained from the medical charts of the patients. Results: From January 2011 to July 2016, 179 patients with newly or previously diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. However, results discussed herein were obtained from 72 evaluable patients for whom complete clinical charts and laboratory data were available. At diagnosis, the median age was 45 years (range 16-76), and there was nearly an equal number of males (N=35; 49%) versus females (N=37; 51%). These patients had high white blood cells (87.5%), high platelet counts (86%), and splenomegaly (61%). The follow up period ranged from 2 months to 66 months with a mean/median follow up of 1.83/1.7 year, respectively. At three months, 31 evaluable patients (54.4%) achieved early molecular response (EMR; 1 log reduction) of which 51.6% (N=16) were male, and 48.4% (N=15) were female. A major molecular response (MMR; 3-4 log reduction) in one year of treatment was obtained by 26 evaluable patients (36.1%) of which 53.8% (N=14) were male, and 46.2% (N=12) were female. Ten patients (18%) discontinued treatment with imatinib in the first year and were put on second line tyrosine kinase therapy (four for resistance and six for adverse events). Notably, six patients experienced disease progression and had tyrosine kinase domain mutation. We observed two deaths (2.8%), of which one involved E255K mutation. Out of 72 patients in the study, 48.6% (N=35) patients showed e13a2 fusion transcript, while 51.4% (N=37) patients showed e14a2 transcript. There was no significant differential transcript expression associated with gender as e13a2 expression was found in 42.9% (N=15) of females and 57.1% males (N=20). Similarly, expression of e14a2 was found in 59.5% females (N=22) and 40.5% males (N=15). Of the patients who achieved MMR in e13a2 expressing group, 33.3% (N=4) were female and 66.7% (N=8) were male. In e14a2 expressing patient group who achieved MMR, 57.1% (N=8) were female and 42.9% (N=6) were male. Conclusions: Our results compare favorably with those reported from the West and some Asian countries. There was no significant correlation between sex, type of BCR-ABL transcript and clinical outcome although we acknowledge that more data is needed in the future. These results further confirm lack of any predominance of the BCR-ABL isoforms e13a2 or e14a2 in Saudi CML patients under investigation, which is discordant with similar studies conducted in other groups of neighboring countries such as Sudan, Pakistan, and Iran. Disclosures No relevant conflicts of interest to declare.

The BCR-ABL1 Transcript Type Does Not Influence the Response and the Outcome of Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1680-1680 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Massimo Breccia ◽  
Fabio Stagno ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Free Survival ◽  
Transcript Type

Abstract Abstract 1680 Background. Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 hybrid gene. Different types of BCR-ABL1 fusion transcripts can be found, but the most frequent are the e13a2 (b2a2) and the e14a2 (b3a2). In the tyrosine kinase inhibitors (TKIs) era, few data about the prognostic significance of the transcript type in early chronic phase (ECP) CML are available. Three larger studies suggested that the e13a2 transcript may have an adverse prognostic impact in ECP CML patients treated with imatinib (IM): Vega-Ruiz et al. (251 patients, ASH 2007) reported inferior molecular responses; Lucas et al. (71 patients, Haematologica 2009) reported lower cytogenetic response rates and lower event-free survival (EFS); the GIMEMA CML WP (493 patients, EHA 2011) reported a slower time to major molecular response (MMR) with inferior EFS and progression-free survival (PFS). To our knowledge this is the first evaluation of the prognostic influence of the BCR-ABL1 transcript type on the responses and the outcome of ECP CML treated frontline with nilotinib (NIL). Methods. The CML Italian Registry of Nilotinib includes 215 patients treated with NIL-based regimens. The patients were enrolled within 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the “S. Orsola-Malpighi” University Hospital (Bologna, Italy), with NIL 300 mg BID or 400 mg BID as initial treatment. All the registered patients were analyzed. Patients expressing rare transcripts and patients with both b2a2 and b3a2 transcripts were excluded: 201 out of 215 patients were evaluable, 81 (40%) with e13a2 transcript and 120 (60%) with e14a2 transcript. Differences between groups were tested using χ2 test, Fisher exact test or t-test, as appropriate. Response monitoring: conventional cytogenetic examination (bone marrow) and QPCR (peripheral blood). Definitions: MMR: BCR-ABLIS ratio <0.1% (International Scale); failures: according to 2009 ELN recommendations; events: failure or treatment discontinuation for any reason. The time-to-response and the outcome were estimated using the Kaplan-Meier method, and compared by log-rank test. Results. The baseline characteristics of the 2 groups were comparable (no significant differences in age, Sokal/Hasford/EUTOS score distribution, clonal chromosomal abnormalities in Ph+ cells, NIL dose), except for the percentage of basophils in the peripheral blood, higher in patients with e14a2 transcript (3.4% vs 2.3%, p=0.01). The median observation was 29 months (range 18–47); 92% of the patients had at least 2 year observation. The CCgR and MMR rates at 12 months were comparable in the 2 groups. The time to MMR was longer for patients with e13a2 transcript (6 months vs 3 months, p=0.04), but the overall CCgR rates (93.8 vs 91.7, p=0.79) and the overall MMR rates (85.1 vs 90.0, p=0.38) were not significantly different in patients with e13a2 or e14a2 transcript, respectively. The probability of Overall Survival (OS), Progression-Free Survival (PFS) and Failure-Free Survival (FFS) were comparable: 91.4% vs 95.8% (p=0.61), 90.7% vs 95.0% (p=0.51), and 90.7% vs 88.7% (p=0.40) in patients with e13a2 and e14a2 transcript, respectively. Conclusions. In our experience, based on 201 early CP CML patients treated frontline with NIL with a minimum follow-up of 18 months, the BCR-ABL transcript type did not show any relevant prognostic impact. The time to MMR was longer in patients with e13a2 transcript, but no response and outcome differences have been observed so far. The number of observed events was low and a longer observation is required. Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures: Castagnetti: Novartis Pharma: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Cavazzini:Novartis Pharma: Honoraria; Bristol Myers Squibb: Honoraria. Turri:Novartis: Consultancy, Novartis Other; Bristol Myers Squibb: Bristol Myers Squibb, Bristol Myers Squibb Other, Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Martinelli:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Speakers Bureau. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau.

scholarly journals Prognostic Value of BCR-ABL1 Transcript Type in Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3070-3070 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Fabio Stagno ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Response Rates ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Free Survival ◽  
Transcript Type

Abstract Background. The fusion protein encoded by the BCR-ABL1 fusion gene may differ in size, but the great majority of chronic myeloid leukemia (CML) patients have a e13a2 (b2a2) or a e14a2 (b3a2) junction. In CML patients treated frontline with imatinib, the e14a2 transcript has been recently associated to faster and deeper molecular responses; in some studies a better outcome has been also reported. Very limited information on the prognostic impact of the BCR-ABL1 transcript type in CML patients treated frontline with second generation tyrosine kinase inhibitors (TKIs) is still available: a study from MDACC reported lower molecular response rates and a trend for inferior event-free survival in e13a2 patients. Aim. To evaluate if the BCR-ABL1 transcript type (e14a2 vs e13a2) affect the response and the clinical outcome in newly diagnosed adult CML patients treated frontline with nilotinib (NIL). Methods. An analysis of 345 CML patients in early chronic phase (ECP) enrolled within 3 multicentric prospective studies of the GIMEMA CML Working Party (ClinicalTrials.gov NCT00481052, NCT00769327, NCT01535391) was performed. The initial treatment was NIL 300 mg BID or NIL 400 mg BID. Definitions: major molecular response (MMR), BCR-ABL1IS ratio < 0.1%; deep molecular response (MR4.0), BCR-ABL1IS ratio < 0.01% with > 10,000 ABL1 copies; progression, transformation to advanced phases; death, at any time and for any reason. Cumulative incidences of response were estimated under consideration of competing risks (progression, death) and compared by Gray test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank test. Results. Seven patients expressing rare transcripts (e1a2 or e19a2) and 10 patients with unknown transcript type were excluded: 328 out of 345 patients were evaluable, 124 (38%) with e13a2 transcript, 174 (53%) with e14a2 transcript and 30 (9%) expressing both transcripts. The baseline characteristics of patients with e13a2 or e14a2 transcripts were comparable: no significant differences in age, gender, Sokal or EUTOS long-term survival score distribution, presence of clonal chromosomal abnormalities in Ph+ cells, NIL dose were observed; the only difference was a higher platelet count in patients with e14a2 transcript (median 374 vs 313 x 103/µl, p=0.006). The median follow-up was 60 months in both groups (range 24-82 months). The response rates and the survival probabilities were uniformly lower in patients with e13a2 transcript (N=124) compared to patients with e14a2 transcript (N=174), but the differences were not significant: MMR by 12 months, 66% vs 72%, p=0.244; MR4.0 by 36 months, 56% vs 66%, p=0.067; estimated cumulative incidence of MMR, 82% vs 88%, p=0.135; estimated cumulative incidence of MR4.0, 60% vs 69%, p=0.101; estimated PFS, 88% vs 93%, p=0.547; estimated OS, 89% vs 94%, p=0.436 (Figure 1). The responses and the survival probabilities of patients co-expressing the e13a2 and the e14a2 transcripts (N=30) were similar to or even better than the ones of e14a2 patients. Grouping together the patients with e14a2 transcript alone and the patients with co-expression of both transcripts (N=174+30=204), and comparing them to patients with e13a2 transcript alone (N=124), the response differences became significant (cumulative incidence of MMR and MR4.0, p=0.050 and p=0.036, respectively), but no outcome differences emerged (PFS and OS, p=0.340 and p=0.276, respectively). Conclusions. Despite a trend for lower response rates and inferior outcome in patients with e13a2 transcript, the observed differences were small and mostly not significant. Further studies in larger patient cohorts are required to clarify whether nilotinib and other second generation TKIs are able to overcome the adverse prognostic impact of transcript type, potentially affecting the speed and the depth of molecular response, the probability of achieving a treatment-free remission and the patient outcome. Figure 1 Figure 1. Disclosures Castagnetti: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Bocchia:Janssen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martinelli:ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Speakers Bureau; Genentech: Consultancy; Amgen: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

2021 ◽  
Vol 22 (15) ◽  
pp. 7806
Author(s):  
Maria Moschovi ◽  
Charikleia Kelaidi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematopoietic Cell Transplantation ◽  
Adult Life ◽  
Normal Growth ◽  
Molecular Response ◽  
Treatment Paradigm ◽  
Treatment Free Remission

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment-free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and adolescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long-term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation.

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