Imatinib Therapy In Chronic Myeloid Leukemia Research Articles

Imatinib-Induced Cardiotoxicity

INTRODUCTION: The success of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia (CML) has increased the focus on survivorship and late toxicity in oncological care. Cardiovascular (CV) health has emerged as an important consideration in patients of CML. Some studies have shown an increased incidence of CHF with Imatinib therapy. This study was conducted to assess the cardiac functions in patients of CML on Imatinib therapy. METHODS: Seventy newly diagnosed CML patients started on Imatinib therapy having normal baseline cardiac functions as assessed by two-dimensional echocardiography and multigated acquisition (MUGA) scan were included in the study. Further assessment of cardiac functions at 3, 6, and 12 months was done by MUGA scan. RESULTS: At 3, 6, and 12 months of follow-up, 7.14%, 10%, and 11.43% of patients, respectively, showed evidence of cardiotoxicity in the form of reduced ejection fraction and wall abnormalities on MUGA scan (P = 0.58, 0.013, and 0.006, respectively). CONCLUSION: Cardiac dysfunction was seen in 11.43% of patients on Imatinib therapy for CML, though none of them were symptomatic. CML patients on Imatinib therapy must be monitored for cardiac functions, especially if they have other CV risk factors.

Long Term Response Evaluation of Newly Diagnosed Chronic Myeloid Leukemia Patients on Imatinib Mesylate in Indian Population over 12 Years

INTRODUCTION There has been a quantum leap in the research of inhibitor drugs following the discovery of tyrosine kinase inhibitor (TKIs), Imatinib in the early 1990s. The development of Imatinib, the first BCR-ABL tyrosine kinase inhibitor revolutionized the long term outcome of Chronic Myeloid Leukemia (CML) patients. CML is one of the most common hematological malignancies diagnosed in India. The breathtaking success due to effectiveness and financial viability of Imatinib among Indian population even led to its sale in its generic formulations by pharmaceutical companies in India around early 2000s. METHODS This is a single-center retrospective observational study conducted among 232 CML patients diagnosed and followed up over 12 years from 2003 until 2015 at Kasturba Medical College and Hospital, Mangalore, Manipal University, Karnataka, India. We closely analyzed the handwritten files and the electronic medical records of each of 232 CML patients for their demographic details, symptoms, date of diagnosis, blood counts, bone marrow reports, spleen size at diagnosis, cytogenetic and molecular reports, date - dosage - change in dose - resistance - side-effects of Imatinib and outcome. Patients were followed up closely. Results Median age was 44 years (range, 10 -78 years). In the year of 2008-2012, 46.1% of patients diagnosed with CML. 66.4% were male and 33.6% were female. During the first evaluation of patients at the time of diagnosis, 90.9% of patients were in the chronic phase, 4.7% in accelerated phase and 4.3% in blast phase. 97.8% were started on Imatinib orally as first line. 176 (75.9) patients received 400 mg orally. Five patients chose not to be treated. The most common side effect of Imatinib among patients were as follows: abdominal pain (13.3%), fever (10.8%), general weakness (4.7%), blurred vision (4.7%), abdominal distention (3.4%) and joint pain (2.2%). Response to treatment with Imatinib was evaluated in terms of molecular response as measured by real-time RT Q-PCR. The 3.4% who failed to respond to Imatinib, 3.4% patients were started with second-generation TKI's (dasatinib, nilotinib, hyper CVAD cyclophosphamide, vincristine, Adriamycin and dexamethasone). The first choice for switching TKI therapy in 4 (1.7%) patients were dasatinib, in (3.1%) was nilotinib and only one patient had to use Hyper CVAD chemotherapy. Table has summarized the use of second-generation TKI's. One patient expired and 4 has progression. 181(78.0%) patients came throughout the year of 2015. Among all patients 200 (86.2%) are still alive with disease, 18 (7.8%) are alive without disease and 14 (6.0%) were expired. Overall survival (OAS) is 218 (96%) Progression free survival (86.78%). The median BCR ABL/ABL value at the end of the six months was 11% and at the end of the one year was 3.38%. Conclusion The introduction of Imatinib mesylate had phenomenal changes in the management of CML. Molecular response evaluation after six months can predict the subsequent molecular response and can also be used as a surrogate monitor of the marrow cytogenetic response to imatinib therapy in CML. We report a high overall (OAS) and progress free survival (PFR) rates with very less side effects. Table Disclosures No relevant conflicts of interest to declare.

Effect of Imatinib on Bone Marrow Morphology and Angiogenesis in Chronic Myeloid Leukemia.

Background and Objectives Chronic myeloid leukemia (CML) is characterized by hyperproliferation of myeloid precursors, increased fibrosis, and neoangiogenesis in the bone marrow. Imatinib inhibits BCR-ABL tyrosine kinase produced due to reciprocal translocation t(9;22) in neoplastic CML cells. It reduces hyperproliferation of myeloid precursors and has been found to affect bone marrow fibrosis and angiogenesis. This study was done to assess the effect of imatinib on bone marrow morphology and angiogenesis in CML. Methods 31 newly diagnosed CML patients were evaluated before and after 3 months of imatinib therapy. A marrow morphological response (MMR) score was used to assess marrow cytological and histological features including grade of fibrosis. Mean microvessel density (MVD) was also assessed. Hematological parameters and BCR-ABL transcript levels were assessed in the peripheral blood. Results 86.21% of patients showed decrease in marrow cellularity with normalization of M:E ratio. 72.42% of patients had decrease in grade of fibrosis and 17.24% showed no change while 10.34% of patients showed progression of fibrosis grade. Patients with MMR score ≥ 2 (n=4) and those with progression of fibrosis grade (n=3) showed suboptimal molecular response (BCR-ABL transcripts > 10%). Pretherapy mean MVD of patients (14.69 ± 5.28) was higher than that of controls (6.32 ± 1.64). A significant reduction of 66.51% was observed in posttherapy mean MVD (4.98 ± 2.77) of CML patients (p<0.001). Conclusion Imatinib therapy in CML not only decreases marrow cellularity, but also helps towards normalization of bone marrow microenvironment by reducing fibrosis and angiogenesis.

Influence of CYP3A5 and SLCO1 on Imatinib Response Among Egyptian Patients with Chronic Myeloid Leukemia in Chronic Phase

BackgroundImatinib (IM) was approved as a molecular target tyrosine kinase inhibitor (TKI) drug that selectively inhibits BCR/ABL1 tyrosine kinase which causes Philadelphia-positive chronic myeloid leukemia (CML) and so far has been one of the first-choice treatment option in CML with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. Although IM pharmacokinetics is influenced by several enzymes and transporters, little is known about the role of pharmacogenetic variation in IM metabolism. This study aimed to investigate the frequencies of mutational status of CYP3A5 and SLCO1 in CML patients undergoing imatinib treatment and to determine whether these two genes could predict the response to imatinib therapy in CML patients.Subjects and methodsWe investigated the mutational status of SLCO1 and CYP3A5 by Polymerase Chain Reaction followed by restricted fragment length polymorphism in 62 Philadelphia positive newly diagnosed Egyptian CML patients in chronic phase; 39 males (62.9%) and 23 females (37.1%). All patients received imatinib therapy and were followed up for at least one and half year. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response at 3rd then 6th month and molecular response at 12th month according to the European Leukemia Net criteria. ResultsTwenty-eight patients (45.2%) were CYP3A5 wild versus 34 patients (54.8%) mutant while 26 patients (41.9%) were SLCO1 wild versus 36 patients (58.1%) mutant. 85.7% of patients with wild CYP3A5 had low & intermediate Sokal score versus 76.5% of mutant CYP3A5 patients had low & intermediate Sokal score with non-significant relation (p = 0.3). There was a significant relation between mutation in CYP3A5 and poor performance state (PS) of the patients at presentation; 89.3% of patients with wild CYP3A5 had good PS versus 61.8% in the mutant group with (p = 0.01). After 3 month of imatinib therapy there was no significant relation between CYP3A5 mutational state and response to therapy however, 85.7% of patients with wild CYP3A5 reached optimal & suboptimal response versus 79.4% in the mutant group with non-significant difference (p = 0.5). We had 51 patients that continued on imatinib till 6th month of therapy whereas 11 patients shifted to 2nd line TKI after imatinib failure. 87.5% of patients with wild CYP3A5 reached optimal & suboptimal response versus 66.7% in the mutant group with difference reaching significance (p = 0.07). We have 39 patients continued imatinib therapy till 12 month whereas 12 patients shifted to 2nd line TKI after imatinib failure. 71.4% of patients with wild CYP3A5 reached MMR at 12th month of treatment however only 22.2% of mutant CYP3A5 patients reached major molecular response (MMR) with significant difference (p = 0.002). Patients with wild SLCO1 were significantly had low & intermediate Sokal score (p = 0.04). However there was no significant correlation between SLCO1 mutational state and performance state or response to imatinib therapy.ConclusionCYP3A5 mutant gene was associated with poor imatinib efficacy while the SLCO1 gene was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. DisclosuresNo relevant conflicts of interest to declare.

BCR/ABL level at 6 months identifies good risk CML subgroup after failing early molecular response at 3 months following imatinib therapy for CML in chronic phase

It is unclear if patients with CML treated with imatinib who fail to achieve BCR/ABL transcript levels <10%(IS) at 3 months i.e. an early molecular response (EMR) have a better prognosis if they achieve a response by 6 months. We reviewed 320 patients with chronic myeloid leukemia (CML) in chronic phase receiving Imatinib therapy with 3 and 6 month BCR/ABL transcript levels available, and divided them into four groups. Group I (achieved an EMR at 3 months), Group II (did not achieve an EMR at 3 months, but achieved a transcript level of <1% at 6 months), Group III (did not achieve an EMR at 3 months, then at 6 months achieved a level between 1% and 10%) and Group IV (failed to achieve a response at 3 and 6 months). Compared to Group I, Group IV showed significantly worse freedom from treatment failure (FTF; 93.1% vs 69.0%, P < 0.001), progression free survival (97.7% vs 77.3%, P < 0.001) and overall survival (98.3% vs 78.9%, P < 0.001). While, group III showed inferior PFS (98.3% vs 90.4%, P = 0.013) and OS (97.7% vs 90.4%, P = 0.037), but no difference in FTF (93.1% vs 92.0%, P = 0.520). There were no significant differences between Groups I and II. A BCR/ABL transcript level at 6 months can identify a "good-risk" subgroup among patients who fail to achieve an EMR on Imatinib therapy for CML.

Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy?

BackgroundImatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients.Subjects and methodsWe investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria.ResultsThis study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group.ConclusionCYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study.

Bilateral Visual Loss in a Patient with Chronic Myelogenous Leukemia after Initiation of Imatinib Therapy

Objective and importance: Imatinib–the principle treatment currently available for chronic myeloid leukemia (CML)–may be implicated in neovascular glaucoma (NVG) pathogenesis. Clinical presentation: A 64 year old diabetic female develops CML and receives imatinib treatment develops aggressive bilateral neovascular glaucoma within 1 month of initiation of treatment. The left eye is lost and the right eye was hardly salvaged through panretinal photocoagulation and substitution of imatinib therapy to desatinib therapy. Intervention: Systemic imatinib therapy for CML. Conclusion: Imatinib may be implicated in the causation of NVG in CML patients, who should thus receive regular thorough ophthalmic evaluation as long as imatinib therapy continues.

Normal pregnancy outcome in a woman with chronic myeloid leukemia and epilepsy: a case report and review of the literature

AbstractThe management of chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. Imatinib therapy for CML might be associated with fetal anomalies and discontinuation of the drug with disease progression. We present the achievement and management of a pregnancy in a woman with both CML and epilepsy. We describe the first uneventful pregnancy and successful delivery of a healthy, normal baby in a patient with CML and epilepsy.A 25-year-old woman with both CML and epilepsy presented with infertility to ourThe management of CML during pregnancy might be individualized on the basis of clinical manifestations, and close observation without any intervention may be an option after proper counseling of the patient. A healthy birth is possible in a well-controlled pregnancy in a woman with both CML and epilepsy.

Clinical relevance of vascular endothelial growth factor (VEGFA) and VEGF receptor (VEGFR2) gene polymorphism on the treatment outcome following imatinib therapy

BackgroundImatinib could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients. Methods, materials and patientsThe current study investigated the impact of four vascular endothelial growth factor type A (VEGFA) and three vascular endothelial growth factor receptor type 2 (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following imatinib therapy. VEGFA genotypes such as -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) loci and VEGFR2 genotypes (rs1531289, rs1870377 and rs2305948) were analyzed using matrix-assisted laser desorption/ionization time-of-flight-based method. ResultsIn single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289/rs1870377), between treatment failure and VEGFR2 genotype (rs1870377) and between progression to advanced disease and VEGFA genotypes (rs699947/rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR and treatment failure to imatinib. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure and of VEGFA genotype (rs699947) with progression to advanced disease. ConclusionThe VEGFR2 gene polymorphism correlates with cytogenetic response, treatment failure following imatinib therapy for CML, while VEGFA genotype correlates with progression to advanced disease.

IFN-γ (interferon-gamma) Genotype Predict Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia.

Abstract 2178Poster Board II-155 Purpose:Interferon therapy had served as a standard therapy before introduction of imatinib into the treatment of chronic myeloid leukemia (CML) although its action mechanism is yet fully elucidated. After introduction of imatinib therapy, it provides significant therapeutic benefit to CML patients, however its response varies person-by-person. Some patient responds quickly and maintain long-term response without development of resistance, while others do not respond well or lose their response quickly thus developing resistance to imatinib.One of interesting observation is that the patients previously treated with interferon could maintain long-term complete molecular response (CMR) even after withdrawal of imatinib therapy, suggesting interferon signaling pathway seemed to be associated with favorable response to imatinib therapy. Variable response to imatinib therapy in CML can be explained by inter-individual variation of candidate genes involved in the biologic activity of CML cells such as apoptosis or angiogenesis as well as drug transport/metabolism of imatinib in addition to Interferon gamma signaling pathway. Methods:In the current study, we investigated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n=31; BCL2, BAX, BCL2L2, BCL6, BCL2L11, BIRC5, CASP1, CASP3, CASP7,CASP8, CASP9, CASP10, FAS, FASL, APAF1, TNFR2, PDCD1, GZMB), angiogenesis (n=7; VEGFA, VEGFR2), myeloid cell growth (n=13; FLT2, CSF3, CSF2, JAK3, IL1A, IL1B, IL1R), xenobiotic metabolism (n=13; ABCB1, ABCG2, CYP3A5, HOCT1), WT1 signaling (n=7), interferon signaling (n=4; IFNG, IFNGR1, IFNGR2) and others (n=5; GNB3, ULK3, ORM, PTK2). Discovery cohort includes 244 patients treated at the Princess Margaret Hospital, Toronto, ON, Canada. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). The results were validated internally using a Bootstrap procedure, and externally in an independent validation cohort of 187 Korean CML patients treated at the Samsung Medical Center, Seoul, Korea or Chonnam National University Hwasun Hospital, Hwasun, Korea. Results:In a single marker analysis, several genotypes were found to be correlated with complete cytogenetic response (CCR; IFNG “p-value, 0.01”, FAS “0.03”, FASL “0.006”, CASP8 “0.04”, CASP10 “0.04”), major molecular response (MMR; IFNG “0.04”, FAS “0.05”, JAK3 “0.03”), loss of response (IFNG “0.02”, BIRC5 “0.02”), treatment failure (IFNG “0.07”), or dose escalation of imatinib (IFNG “0.03”, ABCG2 “0.02”, APAF1 “0.04”, CASP2, “0.03”). Bootstrap methods showed a good correlation of each genotype with clinical outcomes. External validation was performed in an independent cohort with 187 Korean CML patients, the IFNG genotype (rs2069705) was validated that is able to predict CCR (HR, 0.46; p=3×10-5) or MMR (HR, 0.51; p=7×10-5) in CML patients. Conclusions:The current study suggested that the interferon gamma genotype seemed to predict the response to imatinib therapy, proposing potential involvement of interferon-gamma signaling pathway in the action mechanism of imatinib therapy in CML. Further detailed study on IFNG genotype and functional study of interferon gamma phenotype will help us to reach a clear conclusion on the role of IFNG gene in the action mechanism of imatinib therapy in CML. Disclosures:No relevant conflicts of interest to declare.

Candidate Pathway Approach of Single Nucleotide Polymorphism On Imatinib Transport/Metabolism Pathway and DNA Repair Enzyme Pathway Associated with Response and Resistance to Imatinib Therapy in Chronic Myeloid Leukemia.

Abstract 3284Poster Board III-1 Purpose:Imatinib resistance is a major cause of imatinib treatment failure in chronic myeloid leukemia (CML) patients. In our previous study (Clin Cancer Res, 2009, 15(14):4750–8), SNP markers in the pathways of imatinib metabolism / transport could predict the response and resistance of imatinib therapy in CML. It has been known that organic cationic transporter-1 gene (OCT1, SLC22A1) is regulated by HNF4A (hepatocyte nuclear factor 4-alpha) or by PPARA (peroxisomal proliferators-activated receptor alpha) or PPARD (PPAR-delta).In addition, DNA repair machinery such as NER (nucleotide excision repair) or DSB (double strand break) repair pathway, plays an important role in the action mechanism of imatinib, in which ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5), or XRCC4 (X-ray repair complementing defective repair in Chinese hamster cells 4), were involved.The response to imatinib therapy in chronic myeloid leukemia (CML) is various according to inter-individual variation of drug delivery or metabolism. Thus, the current study investigated SNPs in the candidate genes involved in the imatinib transport/metabolism pathway and DNA repair enzyme pathway, and its association with clinical outcomes following imatinib therapy in CML patients. Methods:In the current study, we investigated 81 SNPs markers involved in the pathways of imatinib transport/metabolism pathway (n=62; ABCB1, ABCG2, CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP3A4, CYP3A5, AGP, OCT1, PPARA, PPARD, HNF4A) and DNA repair enzyme pathway (n=19; ERCC1/2/4/5, XRCC1/2/4/5). Total of 187 CML patients treated at the Samsung Medical Center, Chonnam National University Hwasun Hospital, or Kyungpook National University Hospital, Korea, were enrolled into the study. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). Results:Among the SNP markers involved in imatinib transport/ metabolism pathway, HNF4A (rs3212172) was significantly associated with high risk of loss of response (LOR; p<0.001) or treatment failure (p=0.013). CYP1A2 (rs762551) was significantly associated with high risk of LOR (p<0.001) or treatment failure (p=0.035). In addition, ERCC5 (rs17655) showed significant association with response (p=0.036 for complete cytogenetic response [CCR], 0.024 for major molecular response [MMR]) or with resistance (p=0.05 for LOR, 0.025 for treatment failure), while XRCC4 (rs963248) showed significantly consistent association with response to imatinib (p=0.025 for major cytogenetic response [MCR], 0.032 for CCR, 0.008 for MMR, and 0.06 for complete molecular response [CMR]). External validation is now ongoing and the result will be presented in the meeting. Conclusions:The current study suggested that SNP marker on HNF4A gene, regulator of OCT1 gene expression, could predict the risk of resistance to imatinib therapy, and that SNP markers on ERCC5 or XRCC4, involved in the NER and DSB repair pathway, also could predict the response to imatinib therapy, suggesting a potential involvement of DNA repair machinery in the action mechanism of imatinib in CML. Disclosures:No relevant conflicts of interest to declare.