scholarly journals Philadelphia-negative acute myeloid leukemia with new chromosomal abnormalities developing after first-line imatinib treatment for chronic phase chronic myeloid leukemia

2008 ◽  
Vol 83 (9) ◽  
pp. 755-755 ◽  
Author(s):  
Carmen Fava ◽  
Jorge Cortes
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
First Line ◽  
Acute Myeloid

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evaluation of Peroxiredoxins (PRDX1, PRDX2 and PRDX6) Expression in Patients with Chronic Myeloid Leukemia (CML) Treated with Imatinib in First Line

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5545-5545
Author(s):  
Cintia Mascarenhas ◽  
Lara Woldmar ◽  
Maria Helena Almeida ◽  
Rosangela Vieira Andrade ◽  
Anderson Ferreira Cunha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Blood Donors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Cdna Synthesis ◽  
First Line

Abstract Introduction: Satisfactory response is present for the majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP) treated with tyrosine kinase inhibitors (ITK) . However, some pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The oxidative stress modulation is tightly related with the physiopathology of various hematologic diseases and can cause cell death, apoptosis and necrosis. Peroxiredoxins (Prdx) are a family of multifunctional antioxidant thioredoxin-dependent peroxidases that protect cells against oxidative stress and modulate signaling cell proliferation pathways and may influence the metabolism of ITKs.The aim of this study was to analyze PRDX1, PRDX2 and PRDX6 levels of CML pts and correlate with cytogenetics and molecular responses. Methods: PRDX1, PRDX2 and PRDX6 expression was evaluated in 20 blood donors, 18 newly diagnosed CML pts and 22 previously treated pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis or during treatment and RNA samples were submitted to the synthesis of complementary DNA (cDNA) using the kit RevertAid™ HMinus First Strand cDNA Synthesis Kit (Fermentas, Life Sciences). For cDNA synthesis, 3 ug of RNA was used and peroxiredoxins expression was evaluated by real-time PCR with Syber Green (Applied Biosystems) and endogenous (β-Actina and GAPDH) controls. The results were analyzed using 2-ΔΔCT. Statistical analysis were made by using Mann Withney’s T test. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RQ-PCR. Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1% (IS). Results: 40 CML pts, 55% male, median age of 53 years (23-84) were evaluated, 60% in chronic phase (CP), 30% in accelerated phase (AP) and 10% in blast crisis (BC). The mean of PRDX transcript levels in the total group was (PRDX1: 0.006 and 10.10 / PRDX2: 0.002 and 16.26 / PRDX6: 0.003 and 49.97) respectively (PRDX1: 1.2 / PRDX2: 0.9 / PRDX6: 15.36). The results showed that there are a significantly difference (p<0.05) in the PRDX gene expression between pts and blood donors. All PRDX expression was reduced in responsive patients, and increase expression in pts resistant to TKI. The median duration of imatinib treatment was 29 months (1-104) and 97% achieved complete hematological response, 75% complete cytogenetic response and 65% major or complete molecular response. The analysis showed that higher levels of PRDX were maybe correlated with a no reduction of BCR-ABL transcripts (p<0.05). As well as, there was may influence of the PRDX levels at diagnosis in the response at 24 months of treatment. Conclusion:Is known that that the increase of ROS in CML leads to an increase of DNA damage, triggering genomic instability and resulting in accumulation of mutations and chromosomal aberrations, and contribute to the mechanism of acquisition of resistance to TKI inhibitors. The decrease of Peroxiredoxins expression observed in the responsive group, could contribute to this process, since the detoxification of these species are compromising and the effects caused by oxidative stress are even more drastic, leading to mutations that could be followed by TKi resistance. The relation between Prdx and CML not yet been elucidated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myeloid Blast Crisis of Philadelphia Positive Chronic Myeloid Leukemia and Philadelphia Positive Acute Myeloid Leukemia Treated at the AP-HP in Paris: A Retrospective Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Matteo Dragani ◽  
Rathana Kim ◽  
Clémence Loiseau ◽  
Madalina Uzunov ◽  
Felipe Suarez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Advisory Committees ◽  
Lost To Follow Up ◽  
Acute Myeloid

Introduction :Since the introduction of tyrosine kinase inhibitors (TKIs) the prognosis of Philadelphia positive (Ph+) diseases like chronic myeloid leukemia (CML) dramatically improved (Sasaki K, Lancet Haematol 2015). Nonetheless, myeloid blastic crisis of CML (MBC-CML) and Ph+ acute myeloid leukemia (AML) represent a clinical challenge due to their rarity, the absence of a standard therapy and mutations. Methods :We collected clinical data of patients treated in Paris in 5 different hospitals with confirmed diagnosis in patients with CML successively transformed in MBC-CML, and in patients with MBC-CML straight away or Ph+ AML. We performed descriptive analysis as well as analysis on overall survival (OS) and event-free survival (EFS). Results :We found 64 patients (24 F/40 M) treated since 2001 to present days. 35/64 patients had an history of CML before MBC of which 30 were diagnosed in chronic phase (Sokal risk: low 3 pts, intermediate 8 pts, high 4 pts, NA 15 pts) and 5 in accelerated phase according to ELN classification. Lines of treatment before MBC for these 35 patients were principally TKIs, IFN, hydroxyurea and homoarringtonine: 11 pts experienced only 1 line of treatment, 15 pts 2 lines, 5 pts 3 lines, 1 pt 4 lines and 3 pts 5 lines. Best response before MBC was complete hematological remission (CHR) for 14 pts, complete cytogenetic remission (CCyR) for 7 pts, molecular remission for 6 pts (4 pts MR3, 1 pt MR4, 1 pt CMR TKI free), whereas 8 pts never gained any response. 21/64 pts were in MBC at diagnosis and 8/64 pts were classified as Ph+ AML. At diagnosis of MBC/AML median age was 49 years old (11-73). 12/64 pts had an extramedullary/central nervous system (CNS) involvement of which 2 pts presented a solitary CNS disease and 3 patients had lesions compatible with myeloid sarcomas without marrow blasts. 46/64 pts (72%) received a classical induction therapy (mostly cytarabine + anthracycline combination) combined in 40 pts with a TKI (15 pts Imatinib, 13 pts Dasatinib, 2 Nilotinib and 10 Ponatinib). 11/64 pts (17%) started Azacytidine (1 pt in combination with Imatinib, 2 pts with Nilotinib, 6 pts with Dasatinib, 1 pt with Ponatinib and 1 pt with Venetoclax). 2/64 pts (3%) received Dasatinib monotherapy. 1/64 pt (2%) received ATRA+ATO+Dasatinib combination. 4/64 pts (6%) received only best supportive care. At first revaluation after therapy 47 pts (78%) were in CR/CRi, 9 pts (15%) were refractory, 2 pts (3%) died during induction, 1 pt (2%) induction therapy is ongoing, in 1 pt (2%) lost to follow up. Most patients who obtained CR/CRi after induction continued with consolidations, mostly high-dose Cytarabine associated with a TKI. 41 pts (68%) were transplanted (40 alloHSCT, 1 autoHSCT), 38 pts in first CR (CR1), 1 pt in second CR (CR2) and 2 pts in progressive disease. Notably, 1 pt who had only Dasatinib monotherapy without any form of chemotherapy nor allotransplant is still alive and in second chronic phase after more than two years of follow up. Median follow up for patients who received an active treatment was 23 months. Median OS was 44 months and median EFS was 29 months (figure 1). The only factor whose impact was significant for both OS and EFS in our cohort was transplant (p&lt;0.0001, median OS not reached and median EFS was 93 months for transplanted patients). At last follow up, 30 pts (47%) are still alive (29 in CR, 1 pt with active refractory disease), 30 pts (47%) died, 4 pts (6%) are lost to follow up. Causes of death were progression of disease for 18 pts, sepsis for 7 pts, GVHD for 3 pts, ischemic stroke for 1 pt, cardiovascular complications for 1 pt. Conclusion :We showed here a multicentric experience about an unselected cohort of patients with MBC CML and Ph+ AML who received different treatments according to age, comorbidities, performance status, TKI availability. Survival of this cohort was mostly linked to the possibility to achieve CR and to perform an allotransplant. Already published experiences showed a generical dismal prognosis with median OS which doesn't exceed 1-2 years (16 months, Deau B, Leukemia Research 2011 ; 12 months, Palandri F, Haematologica 2008 ; 6.4 months, Fruehauf S, Cancer 2007) whereas in our real life cohort median OS was longer. For fit and potentially « transplantable » patients, combination with classic chemotherapy plus a TKI seems reasonable and associated with good outcomes in terms of OS and EFS. Disclosures Rousselot: Incyte:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Bristol-Myers Squibb:Consultancy;Novartis:Consultancy;Takeda:Consultancy.Itzykson:Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Honoraria;BMS (Celgene):Honoraria;Sanofi:Honoraria;Astellas:Honoraria;Oncoethix (now Merck):Research Funding;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Research Funding;Stemline:Membership on an entity's Board of Directors or advisory committees;Karyopharm:Membership on an entity's Board of Directors or advisory committees;Otsuka Pharma:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria.Cayuela:Incyte:Speakers Bureau;Novartis:Speakers Bureau.Rea:BMS:Membership on an entity's Board of Directors or advisory committees;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees;Incyte:Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Nilotinib early switch efficacy in non-optimal responder CML patient after first line imatinib treatment

2015 ◽  
Vol 5 (6S) ◽  
pp. 11-16
Author(s):  
Ferdinando Porretto
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Complete Cytogenetic Response ◽  
First Line Therapy ◽  
Line Therapy

We report a case of a patient with chronic myeloid leukemia in chronic phase who was treated with Imatinib as first line therapy. He showed a suboptimal response by 2006 ELN criteria after six months, for this reason we performed a mutational analysis that showed the mutation F486S. Due to this finding we made an early switch to Nilotinib (Nil); patients started Nil at 300 bid mg/day obtaining at six month a complete cytogenetic response (CCyR) and a MMolR (RQ-PCR ratio BCR-ABL1/ABL1%IS: 0.05). The patient is now on 24 months Nil treatment showing a RQ-PCR ratio BCR-ABL1/ABL1%IS: 0.004.

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