scholarly journals Mutational Profiles during the Progression of Chronic Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3596-3596
Author(s):  
Mengxing Xue ◽  
Zhao Zeng ◽  
Qinrong Wang ◽  
Lijun Wen ◽  
Yi Xu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
The Other ◽  
Molecular Response ◽  
Dismal Prognosis

Abstract Background: Despite significant improvements in the prognosis of chronic myeloid leukemia (CML) achieved by targeted therapy with tyrosine kinase inhibitors (TKIs), a small proportion of cases may not respond to TKIs or may relapse after an initial response, and then progress from chronic phase (CP) to blastic crisis (BC), characterized by a dismal prognosis. It remained uncertain whether the genetic lesions in addition to the BCR-ABL1 fusion could predict clinical outcomes of CML in the TKI era. Aim: To study the mutational profiles at each stage of CML and the prognostic significance of somatic mutations in addition to the BCR-ABL1 fusion in the TKI era. Patients and Methods: We performed targeted sequencing in 81 CML patients chosen retrospectively. 10 patients had optimal response to TKIs by European LeukemiaNet criteria and maintained durable major molecular response more than 5 years. 71 patients had progressed to accelerated phase (AP) or BC, of whom 43 had sequencing performed at paired CP and AP/BC samples, 28 at AP or BC samples. Totally, we analyzed 53 CP, 20 AP, and 61 BC samples. The targeted resequencing gene panel, covering 386 genes which were recurrently mutated in hematologic malignancies, were performed on a HiSeq 4000 NGS platform (Illumina). Results: Among the 53 CP samples, 20 (37.7%) had mutations involving 14 genes, and the number of mutated genes in each patient was 0-3 (median 0). ASXL1 was the most commonly mutated gene, 10/53 (18.9%) patients had this mutation, followed by KMT2D (4/53, 7.5%), PC (2/53, 3.8%), ERBB4 (2/53, 3.8%). ASXL1 mutation mainly existed in 43 patients with progressed disease , while only one case carried this mutation in 10 patients responsive to TKIs (20.9% vs 10%). 17/20 (85%) AP samples (including 10 patients progressed to AP and the other 10 patients who eventually progressed to BC from AP ) carried mutations involving 18 genes, the number of mutated genes in each patient was 0-6 (median 1.5). ABL1 was the most commonly mutated gene, and 8/20 (40%) patients had this mutation. The second was the ASXL1 mutation, 7 (7/20, 35%) patients carried this mutation. The other genes mutated in more than 2 patients included BCORL1 (3/20, 15%), RUNX1 (2/20, 10%), PHF6 (2/20, 10%), KMT2D (2/20, 10%), ATM (2/20, 10%). 54/61 (88.5%) BC samples (44 with myeloid crisis, 14 with lymphoid crisis, 3 with mixed phenotypic crisis) carried mutations, involving 41 genes, and the number of mutated genes in each patient was 0-9 (median 2). Similar to the mutation status in AP, the most commonly mutated gene was also ABL1, 24/61 (39.3%) patients carried this gene mutation, followed by ASXL1 mutation (13/61, 21.3%), and the other genes were in order, RUNX1 (11/61, 18.0%), WT1 (8/61, 13.1%), GATA2 (6/61, 9.8%), MED12 (5/61, 8.2%), IDH1 (5/61, 8.2%), TP53 (4/61 , 6.6%), KMT2D (4/61, 6.6%), etc. (Figure 1A) Among all the samples, 34 nonsynonymous variants in the ASXL1 gene were identified in 31 samples of 21 patients ( 3 samples with two variants). All the variants were frameshift and nonsense mutations, localized at the last exon of the ASXL1 gene. 13/21 patients with ASXL1 mutations had multi-stage samples. The median VAF of the ASXL1 mutations in the advanced stage was 31.4% (0-47.0%), which was significantly higher than that in CP at diagnosis (7.0%, 0-27.2%, P=0.033). Most of the ASXL1 mutations detected in CP expanded at the advanced disease, and were accompanied with other additional gene abnormalities, such as ABL1, RUNX1 and WT1 mutations, with the VAF similar to or lower than that of the ASXL1 mutations. In a few cases, the ASXL1 mutant clones in the CP disappeared, suggesting that some ASXL1 mutations may be clonal hematopoiesis unrelated to disease progression.(Figure 1B) In order to evaluate the effects of ASXL1 mutations on sensitivity to TKIs in vitro. We co-expressed P210-BCR-ABL1 fusion and ASXL1 mutation (G646Wfs*12) in Ba/F3 cells. Compared to Ba/F3 cells co-expressing BCR-ABL1 fusion and ASXL1 mutation (Ba/F3-BA/As), Ba/F3-BCR-ABL1 cells without ASXL1 mutation (Ba/F3-BA/Ve) showed higher sensitivity to TKIs, including imatinib, dasatinib and nilotinib.(Figure 1C) Conclusions: These results demonstrated the genetic lesions accumulated during the progression of CML from CP to BC. ASXL1 mutations were the most common genetic lesion in CP at diagnosis and may confer a poor prognosis, as it reduced the sensitivity to TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Therapeutic Immune Monitoring of Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Focus on CD4+ CD25+ t Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4036-4036
Author(s):  
Ziyuan Lu ◽  
Na Xu ◽  
Xuan Zhou ◽  
Guanlun Gao ◽  
Lin Li ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Similar Proportion

Abstract Background and Objectives: In clinical, conventional Tyrosine Kinase Inhibitors (TKIs) including imatinib, dasatinib, and nilotinib are remarkably effective forms of therapy for certain types of solid cancers as well as Ph+ leukemias. In addition to the BCR-ABL target oncoprotein, they also inhibit certain off-target kinases (Eph, c-KIT, TEC, SRC). Some TKIs affect immune reconstitution as well as the proliferation, function, and activation of T cells. Certain TKIs have been known to have an especially strong effect on CD4+CD25+ T cells, also known as regulatory T Cells (Tregs). There is currently a gap in the clinical data available about on this area of study. Patients and methods: In this study, we collected 108 Peripheral Blood (PB) samples from patients in the Chronic Phase (CP) of Chronic Myeloid Leukemia (CML) at the time of diagnosis (n=31) and also the TKIs treatment. Groups consisted of individuals treated with TKIs like imatinib (n=12), dasatinib (n=11) and nilotinib (n=8), as well as healthy controls (n=15). We evaluated the quantity and function of Tregs from patients in the CML-CP at the time of diagnosis and during treatment with TKIs. Results: It was found that at diagnosis, patients with CML had a similar proportion and absolute number of lymphocytes compared to healthy donors. After TKIs treatment, proportions and absolute numbers of total T cellsACD4+ T cells and Tregs decreased at different degree. Moreover, thedecrease would be more and more significant as time goes on.Our results indicated that although these three TKIs show similar inhibitory effects in the proportion and number of Tregs in vivo, they have differential effects on the functions of Tregs in vitro. The proliferation, suppression, and expression of suppressive cytokines (IL-4,IL-10 and TGF-β) as well as suppression-associated molecules (FoxP3, GITR, and CTLA-4) of Tregs decreased in groups treated with imatinib and dasatinib. The decrease was not significant in the nilotinib-treated group. Conclusions: The results showed that imatinib and dasatinib have stronger inhibitory roles than nilotinib when it comes to regulating the number and functions of Tregs. These findings can be used to argue in favor of calls for personalized treatment and follow-up of CML patients during TKIs treatment, particularly for those patients who received combination therapy with allo-transplantation and post-transplant TKIs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2232-2235 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Rajyalakshmi Luthra ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Blast Phase ◽  
Complete Hematologic Response ◽  
Risk Patients

Abstract The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

scholarly journals Prognostic significance of early molecular response in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 240-243 ◽  
Author(s):  
David T. Yeung ◽  
Michael J. Mauro
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Costal Margin ◽  
International Scale ◽  
Left Costal Margin

Abstract A 55-year-old man presented with splenomegaly (10 cm below left costal margin) and leucocytosis (145 × 109/L). Differential showed neutrophilia with increased basophils (2%), eosinophils (1.5%), and left shift including myeloblasts (3%). A diagnosis of chronic myeloid leukemia in chronic phase was established after marrow cytogenetics demonstrated the Philadelphia chromosome. Molecular studies showed a BCR-ABL1 qPCR result of 65% on the International Scale. Imatinib therapy at 400 mg daily was initiated due to patient preference, with achievement of complete hematological response after 4 weeks of therapy. BCR-ABL1 at 1 and 3 months after starting therapy was 37% and 13%, respectively (all reported on International Scale). Is this considered an adequate molecular response?

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

In Vitro Sensitivity to Tyrosine Kinase Inhibitors Is One of Possible Predictive Parameters for Therapy Switch In Patients with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2747-2747
Author(s):  
Marketa Zackova ◽  
Tereza Lopotova ◽  
Zuzana Ondrackova ◽  
Hana Klamova ◽  
Jana Moravcova
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Transcript Level ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Therapy Switch

Abstract Abstract 2747 Backround: Tyrosine kinase inhibitors (TKI) are very effective in chronic myeloid leukemia (CML) suppression, however, the problem with development of resistance in some patients exists. It is necessary to find optimal methods for therapy response prediction and for detection of resistance. Many studies on the resistance to imatinib therapy were performed on cell lines or model systems. However, these systems are not fully consistent with CML situation in vivo. Sensitivity to imatinib and its predictivity to molecular response in patients with de novo CML were tested in vitro on patients′ leukocytes by White et al. [Blood 2005; 106: 2520]. They found that IC50 values could be predictive mainly in patients with low Sokal score. Aims: To optimize in vitro method for evaluation of patients′ sensitivity to various TKIs and to test its predictivity for molecular response in therapy and/or after therapy change. Methods: The sensitivity to TKIs: imatinib, nilotinib and dasatinib were studied on leukocytes isolated from CML patients at diagnosis and various responses to treatment. Cell lines were used as controls. Isolated leukocytes/cell lines were cultivated with/without TKIs. Optimization of cultivation was performed on cell lines (ML-2, K562, CML-T2, JURL-MK1) and on leukocytes from CML newly diagnosed patients (15) and healthy donors (6). Various incubation times (4, 24, 48 and 72h) were tested. Concentrations of TKI were used in values near to physiological levels: 2 –3 concentrations for each inhibitor (1uM, 10uM imatinib, 0,5uM and 2uM nilotinib and 1nM, 10nM and 100nM dasatinib). In given time-points the cells were harvested and lysed for protein and mRNA analyses. Sensitivity to TKIs was tested by BCR-ABL kinase inhibition – via Crkl phosphorylation (western blots) and also by WT1 transcript level kinetics [Cilloni et al, Cancer 2004; 101: 979]. Quality of cultivation was tested by apoptosis level (RNA degradation, Annexin staining – Agilent Bioanalyzer 2100). Results: We found 48 h to be the optimal time for in vitro cultivation. This time was long enough to see TKIs dependent changes on protein as well as mRNA level. At this time the intensity of apoptosis was relatively low and did not influence results. The predictive ability of cultivation with TKIs was tested on patients at diagnosis (15), with optimal (5) and suboptimal response (5) and patient with therapy failure (13). The disease state of all patients was further monitored in range from 6 to 21 months (median 12 months) after cultivation. Mostly all of newly diagnosed patients were in vitro sensitive to all three TKIs, 10 of them achieved MMR (median 7 months, range 5 – 16) on imatinib. In patients with resistance to imanitib therapy the good sensitivity to one of 2nd generation TKI on in vitro tests represented the good response to this inhibitor, 4 patients from 10 on dasatinib achieved MMR (within 4 months), the other responded to therapy with continual decrease of BCR-ABL transcript level. Thus, the cultivation test can help with the therapy switch. However, the prognosis of patients with additive chromosomal aberration was poor even if they were sensitive to TKIs in vitro. Only one of 3 patients with 8 trisomy sensitive to dasatinib in vitro achieved MMR at 4th month after starting of dasatinib. Two patients with T315I were not sensitive to any of TKIs in vitro and in vivo, as it was expected. We continue to follow up of all patients. In conclusion, the results from in vitro cultivations of patients′ leukocytes with TKIs can help with the choice of efficient inhibitor for individual patient′s therapy, however, it is necessary to take into consideration the results of cytogenetic analyses of patients and other factors influencing CML. Supported by MZOUHKT2005. Disclosures: No relevant conflicts of interest to declare.

Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML), the Experience At Tawam Hospital, Abudhabi, UAE

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4458-4458
Author(s):  
Arif Alam ◽  
Sabir Hussain ◽  
Amar Lal ◽  
Donna Lee ◽  
Jorgen Kristensen
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Technique ◽  
Molecular Response ◽  
Female Ratio

Abstract Abstract 4458 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Monitoring of the CML is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique. Twenty nine patients were diagnosed with CML in chronic phase between January 2009 till June 2012. The median age was 32 years (range 22–68 years). Male to female ratio was4.14:1. Three patients were lost from follow up after diagnosis and are excluded. Molecular response is available for 16 patients. Nine patients were treated with Imatinib 400 mg daily, four with Dasatinib 100 mg daily and three with Nilotinib 400 mg BID daily as upfront therapy. Twelve patients have achieved MMR/CMR (75 %) within 18months of starting therapy. Four patients have failed to achieve MMR by 24 months. All non responders were on Imatinib. Interestingly six (37.5%) patients achieved MMR/CMR within 9 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2nd generation TKIs (Nilotinib 3 and Dasatinib 2). MMR report from Enestnd trial is 67–71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with MMR/CMR of 75 %. Until today there has been no case of progressive disease. Our data is limited but shows that the median age is much lower compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. Disclosures: Alam: BMS/Novartis: Consultancy, Honoraria. Hussain:BMS: Consultancy, Honoraria.

scholarly journals The HIGH BCR-ABL1 GENE PERCENTAGE AT TIME OF PRESENTATION: A TOOL TO PREDICT FAILURE IN ACHIEVING EARLY MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA (CML): A TERTIARY CARE CENTER EXPERIENCE

2021 ◽  
Vol 71 (Suppl-1) ◽  
pp. S71-75
Author(s):  
Amjad Khan ◽  
Riaz Ahmed ◽  
Sarah Fatimah ◽  
Muhammad Nadeem ◽  
Shama Iqbal ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Military Hospital ◽  
Molecular Response ◽  
Number Of Patients

Objective: To determine the relationship of baseline quantitative BCR ABL1 gene percentage and therapeutic response i.e. Early Molecular Response (EMR) at 3 months with first generation Tyrosine kinase inhibitors (Imatinib) in patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP). Study Design: Prospective observational study. Place and Duration of Study: Combined Military Hospital, Rawalpindi, Pakistan, and Armed Forces Institute of Pathology Rawalpindi, Pakistan from Oct 2017 to Oct 2019. Methodology: One hundred and seventy patients, 18 years of age or older with newly diagnosed Chronic Myeloid Leukemia (CML) in chronic phase (CP) with quantitative baseline BCR-ABL (IS) transcript were included in the study. All enrolled patients were placed on Imatinib therapy (400 mg/day) and Reverse transcription polymerase chain reaction (RT-PCR) for BCR ABL transcript was repeated at 3 months to document EMR (BCR-ABL (IS) <10%). Patients who were in accelerated/blast phase, or already taking any Tyrosine Kinase Inhibitors (TKI) or chemotherapy were excluded from the study. Results: In our study 101 (59.4%) patients achieved early molecular response. Out of these 80 (70.8%) patients with BCR-ABL<50% at baseline value showed early molecular response. However, only 21 (36.8%) with BCRABL >50% at baseline achieved early molecular response (p-value <0.001). Conclusion: A significant number of patients achieved early molecular response with Imatinib therapy that had BCR ABL below 50%, however those with baseline BCR ABL >50%, the rate of EMR was comparatively lower.

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