The Role of Alpha-Interferon in Patients with Chronic Myeloid Leukemia Autografted in Chronic Phase

1994 ◽  
pp. 30-38
Author(s):  
Paolo de Fabritiis ◽  
Rita Pinto ◽  
Giovanna Meloni ◽  
Enrico Montefusco ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Alpha Interferon

scholarly journals Molecular biology of bcr-abl1–positive chronic myeloid leukemia

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1619-1630 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Jorge Cortes
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Oncogenic Signaling ◽  
Stem Cell Quiescence ◽  
Oncogenic Signaling Pathways

Abstract Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.

scholarly journals Loss of expression of both miR-15/16 loci in CML transition to blast crisis

2021 ◽  
Vol 118 (11) ◽  
pp. e2101566118
Author(s):  
Francesca Lovat ◽  
Pierluigi Gasparini ◽  
Giovanni Nigita ◽  
Karilyn Larkin ◽  
John C. Byrd ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Oncogenic Driver

Despite advances that have improved the treatment of chronic myeloid leukemia (CML) patients in chronic phase, the mechanisms of the transition from chronic phase CML to blast crisis (BC) are not fully understood. Considering the key role of miR-15/16 loci in the pathogenesis of myeloid and lymphocytic leukemia, here we aimed to correlate the expression of miR-15a/16 and miR-15b/16 to progression of CML from chronic phase to BC. We analyzed the expression of the two miR-15/16 clusters in 17 CML patients in chronic phase and 22 patients in BC and in 11 paired chronic phase and BC CML patients. BC CMLs show a significant reduction of the expression of miR-15a/-15b/16 compared to CMLs in chronic phase. Moreover, BC CMLs showed an overexpression of miR-15/16 direct targets such as Bmi-1, ROR1, and Bcl-2 compared to CMLs in chronic phase. This study highlights the loss of both miR-15/16 clusters as a potential oncogenic driver in the transition from chronic phase to BC in CML patients.

The Role of Imatinib Plasma Level in the Achievment of Complete Cytogenetic Response (CCyR) in Chronic Myeloid Leukemia (CML) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3789-3789
Author(s):  
Sergey Kutsev ◽  
Oxana Oxenjuk ◽  
Sergey Mordanov ◽  
Yuri Shatokhin ◽  
Tatiana Pospelova ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Female Ratio ◽  
Male Female Ratio

Abstract Abstract 3789 Background. The treatment of patients with chronic phase (CP) Ph-positive chronic myeloid leukemia (CML) with imatinib has resulted in high rates of cytogenetic and molecular responses. There are evidences that the achievement of CCyR and MMR to imatinib therapy is related with Imatinib plasma level (IPL) in some studies1,2 but not in others 3. This discrepancy may be possibly explained by the heterogeneity in the analysed cohort patients differing with respect to the phase of the disease and imatinib dose. The Aim of our study was to elucidate the trough role of IPL in the achievement of CCyR in homogeneous cohort of CP CML patients. Methods. IPL were detected in 321 CP CML patients with Imatinib treatment duration more than 12 months (the median – 90,3). Imatinib doses was 400 mg QD. The age of patients was 54,6 (24–76). Male/female ratio was 157/164. All patients gave informed consent before blood sampling. Blood samples were collected in 21–27h after the last Imatinib dose intake. Imatinib concentrations (C trough) were determined by validated LC/MS/MS method. Results. The patients were subdivided in 4 quartiles (Q): Q1 (n=81) with IPL 0 – 670 ng/ml, Q2 (n=80) with IPL 671 – 1042ng/ml, Q3 (n=80) with IPL 1043 – 1362ng/ml, Q4 (n=80) with IPL 1363 – 3826/ml. The results of imatinib treatment in each quartile were estimated according ELN recommendation. The obtained findings have shown that 48,1% CP CML patients in Q1 have achieved CCyR whereas 77,5%, 81,3% and 85% - in Q2,Q3 and Q4 respectively (Fig.1.). Conclusion. Our findings show that the achievement of CCyR in large cohort of CP CML patients (n=321) on imatinib with 400 mg/QD depends on IPL. The low level of IPL may indicate the nonadherence of some CML patients as well as some intrinsic mechanisms of imatinib plasma concentration decrease. Disclosures: Kutsev: Novartis: Research Funding, Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Khoroshko:Novartis: Speakers Bureau.

Differential Expression of BIRC Family Genes In The Course Of Chronic Myeloid Leukemia – BIRC3 and BIRC8 As Potential New Candidates To Identify Disease Progression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2718-2718
Author(s):  
Eliza Glodkowska-Mrowka ◽  
Iwona Solarska ◽  
Piotr Mrowka ◽  
Katarzyna Bajorek ◽  
Joanna Niesiobedzka-Krezel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Blood Donors ◽  
Chronic Phase ◽  
Blastic Phase ◽  
Significant Difference ◽  
Tki Resistance ◽  
Sequential Samples

Abstract Although majority of chronic myeloid leukemia (CML) patients benefit from targeted therapy, there is an unmet need to identify as early as possible patients who develop resistance to tyrosine kinase inhibitors (TKI) and/or patients who progress to blastic phase (CML-BP). Searching for potential candidates of disease progression we have focused on BIRC (baculoviral IAP repeat-containing) genes expression in various stages of CML. This family includes eight functionally- and structurally-related proteins, most of them are believed to serve as endogenous inhibitors of apoptosis. Overexpression of various BIRC genes has been associated with cancer progression, multidrug resistance, poor prognosis and short survival in several types of neoplasms including hematological malignancies. In CML so far expression of BIRC5 (encoding survivin) and BIRC4 (encoding XIAP) has been associated with progression of the disease. However, there is no data on the role of other BIRC members in myeloproliferative diseases. To study the expression of BIRC genes in CML we employed RT-qPCR following MIQE guidelines. We analyzed sequential samples of peripheral blood leukocytes obtained from CML patients at various stages of the disease. Initially we looked at the samples from patients in chronic phase (CML-CP): at the diagnosis and after development of TKI resistance (confirmed as a loss of cytogenetic response, n=5). Then we analyzed samples from patients who progressed either to accelerated phase (CML-AccPh) or to blastic phase (CML-BP) (n=6). Among eight BIRC genes we observed significant decrease in BIRC3 (encoding cIAP2) and BIRC8 (encoding ILP2) expression. This was associated both with TKI resistance and with progression of CML to accelerated or blastic phase. Simultaneously, we observed marked increase in BIRC5 expression in samples from CML-AccPh and BP as compared to chronic phase (as was previously shown by others) but we observed no significant difference in BIRC5 expression between CML-CP diagnostic and TKI-resistant samples. Expression of BIRC1 (NAIP), BIRC2 (cIAP1), BIRC4 (XIAP), BIRC6 (BRUCE) and BIRC7 (LIVIN) was comparable in sequential samples from CML-CP and CML-BC and was not related to TKI-resistance. We verified these results by comparing larger group of patients in either CML-CP at the diagnosis prior to any treatment (n=15) or CML-BP (n=11). To compare the expression of BIRC family in CML to normal hematopoietic cells, we included also cDNA from healthy blood donors (n=10). In accordance with paired samples analysis, we observed downregulation of BIRC3 and BIRC8 expression in CML-BP (as compared to CML-CP and healthy blood donors), while BIRC5 was upregulated in CML-BP patients (as compared to CML-CP and healthy blood donors). There was no difference in expression of other BIRC family members. In conclusion, this is the first comprehensive analysis of the expression of all eight BIRC genes in the course of CML. In addition to the previously described upregulation of BIRC5, we observed significant downregulation of BIRC3 and BIRC8 associated with TKI-resistance and also with progression to accelerated or blastic phase. Recently Rossi D. et al. (Blood 2012;119: 2854-62) described potential role of disruption of BIRC3 (through mutation or gene deletion) in resistance to fludarabine in chronic lymphocytic leukemia. Together with our results this shows that current view linking BIRC genes upregulation with tumor progression and drug resistance may not be true for all of BIRC genes. Our results suggest novel and unexpected role of BIRC3 and BIRC8 in the clonal evolution of CML and open a new area for further exploration of the role of BIRC in CML progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Alteration and Clinical Significance of Th22/Th17/Th1 Cells in Patients with Chronic Myeloid Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Ping Chen ◽  
Min Wang ◽  
Daqi Li ◽  
Yan Jia ◽  
Na He ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Tumor Development ◽  
Negative Relationship ◽  
Chronic Phase ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Th Cell

T helper- (Th-) cell immunodeficiency plays important roles in tumor development and their effects in chronic myeloid leukemia (CML) remain unclear. In the present study, we mainly investigated the role of Th22, Th17, and Th1 cell and their related cytokines (IL-22, IL-17, and IFN-r) in the pathophysiology of CML. Bone marrow (BM) and peripheral blood (PB) were extracted from newly diagnosed (ND), chronic phase- (CP-) CML patients, and controls. Th subsets were examined by flow cytometry. Plasma IL-22, IL-17, and IFN-r concentrations were measured by ELISA. AHR and RORC mRNA expressions were examined by RT-PCR. The frequencies of Th22, Th17, and Th1 cells, along with the expression of specific transcription factors RORC and AHR, were significantly decreased in ND patients compared with healthy controls, while all these abnormality recovered in CP patients. In addition, there existed a significantly positive relationship between Th22 and Th17 cells in PB or BM. A significantly negative relationship was found between Th cells (Th22, Th17, or Th1) and BCR-ABL (%) IS or the number of PB white blood cells. All these results demonstrated that Th22, Th17, and Th1 cells might be important therapeutic targets in CML and could facilitate a better outcome for tumor immunotherapy.

scholarly journals The Role of BCR-ABL Levels Fluctuations and Loss of Deep Molecular Response after Treatment Discontinuation in Patients with Chronic Myeloid Leukemia in the Prospective Trial RU-SKI

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31
Author(s):  
Anna Petrova ◽  
Ekaterina Yu. Chelysheva ◽  
Oleg A. Shukhov ◽  
Anastasiya Bykova ◽  
Irina Nemchenko ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Observational Studies ◽  
Prospective Trial ◽  
Chronic Phase ◽  
Principal Investigator ◽  
Rank Test ◽  
Molecular Response ◽  
Deep Molecular Response

Background The criteria of molecular relapse in different treatment-free remission (TFR) trials in patients (pts) with chronic myeloid leukemia (CML) varied. In the early trials molecular relapse was defined as loss of deep molecular response (DMR) including MR4 loss. In recent ELN guideline (Hochhaus et al, 2020) major molecular response (MMR) loss was a criterion of molecular relapse. We consider it reasonable to evaluate the role of MR4 loss in connection with MMR loss and time of treatment-free observation and to describe the pattern of minimal residual disease (MRD) in this context. Aim To evaluate the role of MR4 loss on further MMR loss in CML pts during early and late period after TKI cessation and to describe the pattern of MRD during TFR. Patients and methods In total 98 CML pts with chronic phase who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (at least MR4 or BCR-ABL ≤0.01% by international scale (IS)) during ≥2 yrs) were enrolled into the prospective TFR study RU-SKI. The BCR-ABL level (IS) was evaluated by RQ-PCR monthly during the first 6 months (mo) after TKI cessation, every 2 mo from 6 to 12 mo and every 3 mo thereafter. MR4 loss was considered if BCR-ABL was >0,01% and <0,1%. TKI were resumed in pts with molecular relapse which was considered as MMR loss (BCR-ABL>0,1%). Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results Меdian (Me) time after TKI discontinuation was 40 mo (range 28-57). MMR loss and MR4 loss was observed in 48(49%) and 38(39%) pts respectively. In 42(87%) pts MMR loss was observed within first 6 mo after treatment cessation. MRFS at 36 mo was 51% (95% CI 41 - 61%). No MMR loss occurred in 10(26%) pts with MR4 loss while 28(74%) pts with MR4 loss subsequently lost MMR. The MRFS after the first documented MR4 loss was 29% (95% CI 15 - 44%) and 24% (95% CI 10,5 - 38%) at 12 and 24 mo respectively. MRFS at 24 mo was significantly higher in pts with late MR4 loss (>3 mo) than in pts with early MR4 loss (<3 mo): 53% and 8% respectively. (р=0,0004, figure 1). The pattern of MRD in 50 pts who continued a treatment-free observation after TKI cessation was represented by 3 main variants: 1) stable undetected MRD in 17(34%) pts; 2) transient short-term or long-term fluctuations without MR4 loss in 23(46%) pts; 3) fluctuations with transient MR4 loss but without MMR loss in 10(20%) pts (figure 2). Interestingly, 8 of 10 pts with MR4 fluctuations subsequently achieved MRD-negative status. Conclusion We confirmed that MR4 loss after TKI cessation in most cases (74%) preceded the molecular relapse which was considered as MMR loss. However, the MRFS was significantly higher in pts with late MR4 loss than in those with early MR4 loss during the first 3 mo of TKI cessation and comparable with MRFS in the whole pts cohort. We found that only 34% pts who maintained a molecular remission had stable undetected MRD while 66% of pts had fluctuations of MRD during TFR. About a quarter of pts (26%) with MR4 loss could remain in TFR and achieve the MRD-negative status. We support the importance of regular MRD monitoring both in early and late terms during TFR observation to benefit for the safety of the pts. Disclosures Chelysheva: Novartis: Other: performed lectures; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy, Other: performed lectures; Pfizer: Consultancy, Other: performed lectures. Ionova:BMS: Other: principal investigator of the observational studies sponsored by BMS; Takeda: Other: principal investigator of the observational studies sponsored by Takeda. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria.

scholarly journals Goals for chronic myeloid leukemia TK inhibitor treatment: how little disease is too much?

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 234-239 ◽  
Author(s):  
Michael J. Mauro
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Traditional Role ◽  
Inhibitor Treatment

Abstract Tyrosine kinase inhibitors, now numbering 5 for the treatment of Philadelphia chromosome–positive leukemia, have proven ability to reduce clonal disease burden rapidly, dramatically, and durably, especially in chronic myeloid leukemia in the chronic phase. Deep molecular remissions are likely in most chronic phase patients and expectations on timing of response have been developed, validated as best as possible, and evolved over time. Increasing attention has been given to the initial decline of Bcr-Abl1 transcripts and the ultimate depth of molecular remission, overshadowing but not displacing the traditional role of cytogenetic response. This chapter reviews the evolution of response milestones for chronic phase chronic myeloid leukemia and tries to answer the question of how little disease is too much.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

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