scholarly journals Real-World Experience of Treating Pediatric Chronic Myeloid Leukemia: Retrospective Study from a Cancer Center in Southern India

2021 ◽  
Vol 42 (06) ◽  
pp. 561-568
Author(s):  
Sivasree Kesana ◽  
Venkatraman Radhakrishnan ◽  
Jayachandran Perumal Kalaiyarasi ◽  
Nikita Mehra ◽  
Gangothri Selvarajan ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Pediatric Population ◽  
Blast Crisis ◽  
Survival Rates ◽  
Chronic Phase ◽  
Rank Test ◽  
Cancer Center ◽  
Molecular Response

Abstract Introduction Chronic myeloid leukemia (CML) is rare in children and constitutes 2% of all leukemia. We present our institute experience in treating pediatric CML for 20 years. Objectives There is a paucity of data on pediatric CML from India, hence we would like to present treatment responses and survival rates in our pediatric population treated with tyrosine kinase inhibitors at our center. Materials and Methods Patients aged less than 18 years, diagnosed with CML from 2000 to 2019, and treated with imatinib were analyzed retrospectively considering demographic features, treatment characteristics, and survival outcomes. Descriptive analysis was done for the baseline characteristics. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method and the factors were compared using the log-rank test. Results During the study period, 95 patients were diagnosed with CML of which 54 (56.8%) were males. The most common stage at presentation was the chronic phase (CP) with 84 (88.4%) patients followed by accelerated phase (AP) and blast crisis (BC) with 6 (6.3%) and 5 (5.3%) patients respectively. The median duration of follow-up for all patients was 98 months. EFS and OS at 8 years for patients with CML-CP were 43.1% and 80.4% respectively. Complete hematological response, complete cytogenetic response, and major molecular response was documented in 91 (95.7%), 73 (76.8%), and 63 (66.3%) patients respectively. Conclusion Outcomes in pediatric CML are comparable to that of adults. Imatinib is well tolerated in children.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

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 The Role of Monitoring the Bcr-Abl Transcript Levels in the Management of Patients with Chronic Myeloid Leukemia

2013 ◽  
Vol 59 (2) ◽  
pp. 71-74
Author(s):  
Aliz-Beáta Tunyogi ◽  
I Benedek ◽  
Judit Beáta Köpeczi ◽  
Erzsébet Benedek ◽  
Enikő Kakucs ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Gvhd ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Transcript Levels

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

scholarly journals An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia

Blood ◽  
2020 ◽  
Vol 135 (26) ◽  
pp. 2337-2353 ◽  
Author(s):  
Tun Kiat Ko ◽  
Asif Javed ◽  
Kian Leong Lee ◽  
Thushangi N. Pathiraja ◽  
Xingliang Liu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
High Throughput Sequencing ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Integrative Model ◽  
Dna Hypermethylation ◽  
Molecular Alterations

Abstract Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

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.

scholarly journals Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

2020 ◽  
Vol 4 (3) ◽  
pp. 530-538 ◽  
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Leidy Isenalumhe ◽  
Samantha Shams ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Inverse Correlation ◽  
Cancer Center ◽  
Molecular Response ◽  
Starting Dose ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

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.

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.

scholarly journals Efficacy and safety of Bosutinib in Patient with Chronic myeloid leukemia who was intolerant to DASTANIB,NILOTUNIB -Case report

2021 ◽  
pp. 225
Author(s):  
Keyword(s):  
Case Report ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Symptomatic Treatment ◽  
Molecular Response ◽  
Toxicity Profile ◽  
Efficacy And Safety ◽  
Major Molecular Response

Treatment for Chronic myeloid leukemia has been revolutionized because of availability of different tyrosine kinase inhibitors. Each TKI come with its on toxicity profile as this needs to be taken in account before starting therapy with particular agent in a patient. Most of the adverse effects related to TKI are mild and can be managed by either symptomatic treatment or either by dose reduction. But some patients can become intolerant and to switch to other TKI remains the only option. Bosutinib is currently approved for treatment of chronic phase CML in patients who are either resistant or intolerant to previous TKI. We present a case of 59 year old male patient with CML who was intolerant to Dastanib and Nilotinib but showed excellent hematological and major molecular response to bosutinib

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