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With the introduction of tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia, the course of the disease has been altered from an acute, rapidly progressive terminal disorder to a serious condition with high remission rates when patients are compliant with long-term treatment. The goal of therapy is to prevent transformation to the...
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Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in...
Key Clinical Message
Extramedullary involvement of the central nervous system (CNS) in Chronic Myeloid Leukemia (CML) is an uncommon relapse. In this case, we present a unique instance of a 43‐year‐old male diagnosed with CML experiencing a CNS blast crisis.
Nilotinib is a second-generation tyrosine kinase inhibitors that has been approved for the first-line treatment of chronic phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib vs. imatinib (ENESTnd). Apart from this registration study, very few data are currently available on nilotinib first-line. We r...
Blast crisis develops in a minority of patients with chronic myeloid leukemia even in the era of tyrosine kinase inhibitor (TKI) therapy. Reports suggest that we know little about the mechanism of BCR-ABL and AML1-ETO co-expression in blast crisis of chronic myeloid leukemia, and that other chromosomal abnormalities also coexist. Here, we document...
Citations
... 3 However, MMR is proven to be superior as outcome measurement, especially for predicting long-term relapse. 4 Failure to achieve a therapeutic response can be caused by resistance to therapy. 2 The mechanisms of resistance can be either BCR-ABL dependent, caused by genetic mutations in the BCR-ABL gene itself, or BCR-ABL independent, which can be caused by various factors, including increased production of reactive oxygen species (ROS). 5-7 ROS play a significant role in maintaining genome integrity as they can damage DNA through direct or indirect processes. ...
Introduction
Currently, Imatinib (IM) which is a Tyrosine Kinase Inhibitor (TKI), is the main treatment for patients with chronic myeloid leukemia (CML). Major molecular response (MMR) is used as therapeutic response. Resistance to IM may be caused by hypoxia which is regulated by hypoxia inducible factor (HIF) 2-α. The role of HIF2-α is currently not researched extensively. This study aimed to analyse the differences in HIF-2α expression between chronic phase CML patients that achieved MMR and those that did not achieve MMR.
Methods
This study used a cross-sectional method which analysed secondary data from whole blood samples in chronic phase CML patients aged 18–60 years that received hydroxyurea (HU) before IM, aged 18–60 years, received IM therapy for more than 12 months, and were willing to participate in the study. The exclusion criteria for this study were patients who were receiving IM at a dose of more than 400 mg/day. HIF-2α protein expression was examined using the enzyme-linked immunosorbent assay (ELISA) method. Differences between HIF-2α protein expression in groups that achieved MMR versus not achieving MMR was analysed using the Mann–Whitney test.
Results
A total of 79 subjects were obtained. The median HIF-2α was 90.56 pg/mg protein (3.01–4628.74). There was no statistically significant difference in expression of HIF-2α in the group that reached MMR and did not reach MMR, namely 123.45 pg/mg protein and 89.25 pg/mg protein respectively (p 0.718).
Conclusion
This study found no statistically significant difference between HIF-2α expression level and MMR achievement of chronic phase CML patients who received HU before IM therapy.
... A complete hematological response (CHR) is defined as a normal leukocyte count, a normal platelet level, a normal differential result, and the disappearance of CML symptoms. 97 A partial hematological response is defined as a decrease in leukocyte count of less than 50% of the leukocyte level before treatment, or normalization of the leukocyte level with persistent splenomegaly or the presence of blasts in the peripheral blood. Meanwhile, a complete cytogenetic response (CCR) is defined as the absence of metaphase Ph+ in the bone marrow cells. ...
... Meanwhile, a complete cytogenetic response (CCR) is defined as the absence of metaphase Ph+ in the bone marrow cells. 97 Currently, the major molecular response is more often used to monitor therapy, especially for TKI therapy. 97 Treatments such as chemotherapies and interferon alpha rarely achieve a major molecular response. ...
Chronic myeloid leukemia (CML) is one of the most common leukemias occurring in the adult population. The course of CML is divided into three phases: the chronic phase, the acceleration phase, and the blast phase. Pathophysiology of CML revolves around Philadelphia chromosome that constitutively activate tyrosine kinase through BCR-ABL1 oncoprotein. In the era of tyrosine kinase inhibitors (TKIs), CML patients now have a similar life expectancy to people without CML, and it is now very rare for CML patients to progress to the blast phase. Only a small proportion of CML patients have resistance to TKI, caused by BCR-ABL1 point mutations. CML patients with TKI resistance should be treated with second or third generation TKI, depending on the BCR-ABL1 mutation. Recently, many studies have shown that it is possible for CML patients who achieve a long-term deep molecular response to stop TKIs treatment and maintain remission. This review aimed to provide an overview of CML, including its pathophysiology, clinical manifestations, the role of stem cells, CML treatments, and treatment-free remission.
... The response criteria to imatinib used in our study have been previously defined (see Supporting Information Methods for further details). 22,23 Only patients with optimal hematological, molecular and cytogenetic responses with a minimal follow-up of 12 months were considered responders. Patients with a suboptimal and resistant response after 12 months of follow-up were considered nonresponders. ...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first‐line treatment for CML, though ~40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to TKI. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and an open‐chromatin epigenetic mark in CT22. Altogether our results suggest that large‐scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated into a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.
... This is indeed one of the clinical criteria followed to monitor patients and to define CML remission, but it is not the only one. As [26] and [35] describe, jointly with the hematological criterion of cell complete blood count adopted here, physicians also use cytogenetic and molecular tests. Today, the recommended criterion by the European Leukemi-aNet 2020 is based on the quantification by PCR analysis of the BCR-ABL1 fusion gene, a molecular marker of CML. ...
... However, although this molecular test is the most sensitive assay available at present and leads to very accurate measures of the response to treatment and disease remission, the unknowns regarding BCR-ABL transcription and action mechanisms (see [36]- [42]) and the lack of the necessary volume of reliable and homogeneous data as a result of the novelty of this method (see [43] and [44]), currently make the formulation of a useful mathematical model explaining BCR-ABL1 levels impossible. Accordingly, we follow the hematological criterion (see [35] and [45]) to define the total remission of CML. This hematological analysis is accomplished by obtaining a complete blood count, and defines the eradication of CML as the non-existence of cancer HSC and DC, and the recovery of the number of normal HSC and DC in the blood, called complete hematological response (CHR). ...
... For our purposes, we will consider that CHR is reached when the number of cancer HSC is lower than 1, the number of cancer DC is undetectable and then lower than e-4 of the total number of DC (see [47]- [51]), and the number of normal HSC and DC are those in a healthy individual, given by 11000 and 3.48e+15 (see [28]). For this representative patient and according to clinical evidence, this happens before the third month of treatment (see [26], [35], [52]- [55]). Finally, according to the quoted references, the standard recommended treatments consist of daily doses of imatinib ranging from 100 mg to 400 mg, and not exceeding 800 mg. ...
The advances in the mathematical explanation of the dynamics underlying treated cancer has opened the door to the mathematical design of optimal therapies. In parallel, the improvements and cost reductions in experimentation and data analysis techniques have made the formulation of personalized therapies possible. However, the design of cancer therapies making use of optimal control theory has not fully considered this possibility in detail. In this paper we contribute to the existing literature by analyzing the diverse alternatives that optimal therapy models offer to design personalized treatments. Taking as the starting point the Chronic Myeloid Leukemia (CML) optimal therapy model in [25], we design personalized optimal therapy models for patients with: CML; CML with intrinsic and/or induced resistance to the administered drug; CML and suffering high drug toxicity and/or allergy to the administered drug; and CML with presence of adverse factors. Along the paper we show that the clinical and medical applicability-the ultimate objective of this biomathematical research-of our proposed personalized models relies on the joint and proper use of the implemented calibration, simulation, and mathematical approaches and techniques. All the theoretical results generated by our personalized optimal therapy models are corroborated by clinical evidence.
... Chronic myeloid leukemia (CML) belongs to the spectrum of myeloproliferative disorders (MPD), which are myeloid lineage clonal disorders that also include essential thrombocythemia, polycythemia vera, and myelofibrosis [1]. It accounts for 15-20% of all adult leukemia cases, with an estimated incidence of fewer than 5,000 new cases in the United States per year [2,3]. CML is characterized by the excess of white blood cells (WBCs) resulting from the uncontrolled proliferation of mature granulocytes and their precursors [3]. ...
... It accounts for 15-20% of all adult leukemia cases, with an estimated incidence of fewer than 5,000 new cases in the United States per year [2,3]. CML is characterized by the excess of white blood cells (WBCs) resulting from the uncontrolled proliferation of mature granulocytes and their precursors [3]. When patients present with isolated thrombocytosis, testing for the Philadelphia chromosome or BCR-ABL is essential to identify CML cases among them [4]. ...
Chronic myeloid leukemia (CML) represents a common condition in the spectrum of myeloproliferative disorders (MPD). It classically exhibits leukocytosis, but rarely presents with isolated thrombocytosis. This paper is designed to review the clinicopathologic features, treatment, and outcomes of patients with CML who present with isolated thrombocytosis.
We searched PubMed, MEDLINE®, ScienceDirect, and Scopus for English-language articles about case series and case reports for the period 2000-2020 with the terms “chronic myeloid leukemia” and “thrombocytosis” and pooled them with a case from our institution. Cases were also incorporated from the reference list and screened for inclusion. A total of 20 cases were included in the final cohort. The male-to-female ratio was 1:1.86. The mean age of the patients at the time of initial diagnosis was 40.5 years (range: 9-77 years). Out of 17 cases with available data, seven (41%) were asymptomatic and found to have thrombocytosis incidentally upon routine blood work. Five cases (29.4%) either had a history of thrombotic events or presented with severe thrombotic complications, including ischemic cerebrovascular accidents (CVA), myocardial infarction (MI), pulmonary embolism (PE), and/or miscarriages. Four cases (23.5%) had more than one symptom at presentation, including headache, syncope, and bruising. The average platelet count was 1,923 × 109/L (range: 584-8,688 × 109/L), and one case (5%) had anemia. The bone marrow (BM) examination showed normal cellularity and normal myeloid to erythroid (M/E) ratio in seven (50%) and 11 (84.6%) out of the 14 and 13 cases with reported data, respectively. Moreover, megakaryocytes in the BM were small in 10 cases (71.4%), pleomorphic in three cases (21.4%), and dysplastic in one case (7.1%).
Accurate differentiation among MPD subtypes and the exclusion of CML is critical in reaching a proper diagnosis to decide on proper therapy and eventually modify outcomes. Prompt evaluation for the precise diagnosis of patients presenting with isolated marked thrombocytosis will help expedite their diagnosis and initiation of a specific tyrosine kinase inhibitor (TKI) therapy, thereby promptly inducing remission, preventing thrombotic complications, and avoiding adverse drug events, which would eventually improve outcomes.
... The response criteria to imatinib used in our study have been previously defined (see Supporting Information Methods for further details). 22,23 Only patients with optimal hematological, molecular and cytogenetic responses with a minimal follow-up of 12 months were considered responders. Patients with a suboptimal and resistant response after 12 months of follow-up were considered nonresponders. ...
... 22) translocation and resulting encoding of a chimeric protein with constitutive tyrosine kinase activity is a hallmark of chronic myeloid leukaemia (CML). The genesis of this rearrangement is related to the topological organization of chromatin in the nucleus. ...
During interphase, chromosomes occupy a distinct, limited space within the nucleus, referred to as chromosome territory (CT). It has been postulated that the non-random CT’s spatial organization within the cell nucleus contributes to determining the outcome of chromosomal translocations. Comparative analysis of the spatial arrangement of translocation partners and their frequency of translocation suggest that translocations occur preferentially among proximally positioned genome regions. The consistence appearance of t(9;22) in pluripotent hematopoietic stem cells, apart from being etiological factor for chronic myeloid leukemia (CML), is a clear example of what is considered a non-random chromosome aberration.
In order to highlight the importance of spatial proximity and topological features in determining the t(9;22) formation, we evaluated these elements using three-dimensional fluorescence in situ hybridization and 3D Structure Illumination Microscopy. This analysis was carried out in CD34+ cells from 5 CML patients in complete response, in Mobilized Bone Marrow (MBM) from 5 healthy donors, and also in peripheral blood mononuclear cells (PBMC). 3D reconstructions from at least 25 cells per sample were analyzed. We determined the nucleus’ and CTs’ volume, the distance between BCR and ABL (BA) genes and their CTs, and the distances between them and the nuclear center.
We found that nuclear volumes were significantly larger in CD34 + cells from MBM and CML patients compared to PBMC controls. Likewise, the absolute CTs volume analysis shows a major volume of CT9 compared to CT22. In order to avoid the bias of size differences due to nuclear volumes, we normalized the CTs’ volumes and expressed them as a percentage of the nuclear volume in each studied population, however it does not show a significant variation. After normalizing the distance between the CTs a
To determine the distance between BA genes and their CTs we calculated the nearest distance between the mass center of CT9 and CT22. Shorter distances were observed between BA from MBM and CML patients in complete response compared to PBMC samples. After normalizing the distance between the CTs and BA genes against the radius of the nucleus. We observed that the location of CT22 tended towards the center, whereas that of CT9 towards the nuclear periphery. Meanwhile BA genes were located closer to the nuclear center than the respective CTs’ geometrical center.
Given that CTs are discrete chromatin domains, histone modifications might have a significant role in dictating the topological CTs characteristics. Therefore, we have mapped some relevant histone modifications like H3K9ac and H3K27me3 across CT9 and 22 using 3D immuno-FISH. The enrichment of H3K27me3 seems to be greater in CT22 from samples of CML patients in complete response. These are preliminary results and we pretend increase the sample size to delineate conclusive results.
Note: This abstract was not presented at the meeting.
Citation Format: Eunice Fabián-Morales, Yameli Lizeth Rodríguez Torres, David G. Vallejo Escamilla, Rodrigo González-Barrios, Alfredo De La Torre Luján, Alejandro López-Saavedra, Clementina Castro-Hernández, Luis A Herrera Montalvo. Topological characterization of chromosome territories 9 and 22 and BCR-ABL1 genes in bone marrow CD34+ cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5176.
BACKGROUND
Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t (9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies.
OBJECTIVES
The aim of this study was to assess efficacy and safety of Bosutinib as a 2 nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response.
PATIENTS AND METHODS
Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment.
RESULTS
The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response ( P = 0.0001).
CONCLUSION
Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.
Objectives
Among Chronic Myeloid Leukemia (CML) patients treated with Tyrosine Kinase Inhibitor (TKI-imatinib-nilotinib), some showed a suboptimal response. Based on pharmacokinetic studies, TKI trough level ( ${C}_{min}\hat{\infty }$ ) is associated with clinical outcomes, reflected by the BCR-ABL ratio. However, the interindividual pharmacokinetic variability of imatinib and nilotinib is found to be moderate–high. This study aims to analyze the relationship between TKI ${C}_{min}\hat{\infty }$ and BCL-ABL ratio in chronic-phase CML patients.
Methods
Cross-sectional study to CML chronic-phase patients treated with imatinib 400 mg daily or nilotinib 400 or 800 mg daily for ≥12 months. The exclusion criteria were therapy discontinuation within 29 days (imatinib) or 8 days (nilotinib) before the sampling day. Blood samples were drawn 1 h before the next dose. Imatinib-nilotinib ${C}_{min}\hat{\infty }$ and BCR-ABL ratio were measured using HPLC and RT-qPCR. The relationship was analyzed using bivariate correlation Spearman’s rho test.
Results
Twenty-three imatinib and 11 nilotinib patients met the inclusion criteria. The mean imatinib and nilotinib ${C}_{min}\hat{\infty }$ were 1,065.46 ± 765.71 and 1,445 ± 1,010.35 ng/mL respectively. There were large interindividual variations in both groups (71.87% vs. 69.88%). Half of the patients in each group were found to reach ${C}_{min}\hat{\infty }$ target (≥1.000 ng/mL, imatinib; ≥800 ng/mL nilotinib), but only 12 (35,29%) of them result in BCR-ABL ratio ≤0.1%. ${C}_{min}\hat{\infty }$ imatinib was found to be significantly associated with BCR-ABL ratio. But, not with the nilotinib group.
Conclusions
There were high interindividual variations of imatinib and nilotinib correlated with BCR-ABL ratio, but no correlation in nilotinib.
