Imatinib resistance: diagnostic and therapeutic choices

We report a case of a 42-year-old woman with t(9;22) positive chronic myeloid leukemia (CML) who developed a sub-optimal response to therapy with imatinib mesylate due to M351T mutation and low plasma level of imatinib. Dose increase of imatinib resulted in toxicity. She obtained a complete molecular response to therapy with nilotinib, without adverse events.

Download Full-text

Tyrosine kinase inhibitor resistance in pediatric chronic myeloid leukemia: a case report

Medical Journal of Indonesia ◽

10.13181/mji.cr.203765 ◽

2020 ◽

Vol 29 (4) ◽

pp. 427-30

Author(s):

Mururul Aisyi ◽

Ayu Hutami Syarif ◽

Nur Asih ◽

Agus Kosasih

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Molecular Response ◽

Imatinib Treatment ◽

Imatinib Resistance ◽

Hematopoietic Malignancy ◽

Optimal Response

Pediatric chronic myeloid leukemia (CML) is a hematopoietic malignancy, treated by tyrosine kinase inhibitor (TKI). Previously, imatinib resistance in CML was treated with nilotinib as a second line. However, in Indonesia, where the options of TKIs are limited, no case has been reported. We describe TKI-resistance of a pediatric CML case in Dharmais Cancer Hospital, Jakarta. A 17-year-old boy presented with loss of complete hematologic response after 4 years of imatinib treatment. Diagnosis of relapsed CML with blast crisis was confirmed, and nilotinib was given accordingly. He achieved hematological and optimal response after 2 weeks and 3 months of treatment, respectively. However, in the 12-month evaluation, he failed to achieve major molecular response and acquired the second resistance to TKI. Since imatinib resistance marks the poor prognosis, initial optimal response of nilotinib treatment remains inconclusive to predict the final outcome.

Download Full-text

Safety and efficacy of nilotinib after 10 years of interferon

Clinical Management Issues ◽

10.7175/cmi.v6i2s.1140 ◽

2015 ◽

Vol 6 (2S) ◽

pp. 19-22

Author(s):

Filippo Russo

Keyword(s):

High Risk ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Standard Dose ◽

Interferon Alfa ◽

Molecular Response ◽

Major Molecular Response ◽

Safety And Efficacy ◽

Optimal Response ◽

Complete Molecular Response

Here we describe a case of a woman with chronic myeloid leukemia at high risk, according to the Sokal Index. The patient started interferon alfa-2b (IFN) at standard dose obtaining a major molecular response after about four years of treatment. After about 10 years the patient presented a toxicity from IFN and different comorbidities, so she was switched to nilotinib and achieved a complete molecular response (MR4). This case shows how nilotinib is effective and tolerable also in patients with multiple comorbidities. Keywords: Chronic myeloid leukemia; Optimal response; Nilotinib; Interferon alfa-2b

Download Full-text

Management of Adverse Events Associated With Tyrosine Kinase Inhibitor Use in Adult Patients With Chronic Myeloid Leukemia in Chronic Phase: An Advanced Practice Perspective

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.5.7 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Stephanie Bauer, RN, MSN, BC-FNP ◽

Holly Comer, MSN, APRN ◽

Brooke Ramsey, RN, MSN, ANP-BC ◽

Katy Thomas, RN, MSN, ANP-C

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Response To Therapy ◽

Molecular Response ◽

Life Management

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, nilotinib, bosutinib, and ponatinib have drastically improved the life expectancies of patients with chronic myeloid leukemia in chronic phase (CML-CP). While survival outcomes are comparable across first-line TKIs, each TKI has a unique toxicity profile that should be considered before starting or managing any treatment. Furthermore, the safety and tolerability of TKIs are particularly important in CML-CP, as the majority of patients remain on treatment for several years or for life. Management of adverse events (AEs) is critical to ensure adherence to treatment and to maintain efficacy and quality of life; management should also be considered in the context of the patient’s molecular response to therapy to avoid switching TKIs unnecessarily. We present case studies examining pleural effusion occurring with bosutinib and dasatinib, cardiovascular events associated with nilotinib and ponatinib, and myelosuppression, which is common across all TKIs. We discuss the management of these AEs based on international guidelines and present our collective experience for advanced practitioners to consider.

Download Full-text

Differential gene expression analysis of dasatinib-induced colitis in a patient with chronic myeloid leukemia followed for 3 years: a case report

BMC Gastroenterology ◽

10.1186/s12876-020-01584-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Naoki Oshima ◽

Yoshiyuki Mishima ◽

Kotaro Shibagaki ◽

Kousaku Kawashima ◽

Norihisa Ishimura ◽

...

Keyword(s):

Gene Expression ◽

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Differential Gene Expression ◽

Myeloid Leukemia ◽

Colonic Mucosa ◽

Kinase Inhibitor ◽

Molecular Response ◽

Multikinase Inhibitor ◽

Differential Gene

Abstract Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. Case presentation We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. Conclusion Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

Download Full-text

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

Cancers ◽

10.3390/cancers13071643 ◽

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.

Download Full-text

Chronic myeloid leukemia: successful therapy with nilotinib in a young patient with high Sokal risk and in sub-optimal response with imatinib

Clinical Management Issues ◽

10.7175/cmi.v4i6s.1098 ◽

2015 ◽

Vol 4 (6S) ◽

pp. 13-16

Author(s):

Fausto Palmieri

Keyword(s):

Chronic Myeloid Leukemia ◽

Young Patient ◽

Myeloid Leukemia ◽

Second Generation ◽

Kinase Inhibitor ◽

Standard Dose ◽

Chronic Phase ◽

Molecular Response ◽

Optimal Response ◽

Increased Risk

Here we describe a case of a young patient with chronic myeloid leukemia, at high-risk according to the Sokal index, who started imatinib at standard dose and obtained a sub-optimal response at 12 months. This condition was not automatically an indication to change therapy, but considering the patient as suboptimal, we decided to switch to a second-generation tyrosine kinase inhibitor (TKI), nilotinib 800 mg/die, obtaining soon a complete cytogenetic response (CCYR), thereafter a major molecular response (MMolR). Delayed achievement of cytogenetic and molecular is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving imatinib therapy. Therefore we can hypothesise that this kind of patient could be elegible for an early switch to second-generation TKI.

Download Full-text

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692117666190925115852 ◽

2020 ◽

Vol 17 (1) ◽

pp. 48-54

Author(s):

Reni Widyastuti ◽

Melva Louisa ◽

Ikhwan Rinaldi ◽

Riki Nova ◽

Instiaty Instiaty ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Kinase Domain ◽

Molecular Response ◽

Major Molecular Response ◽

Cross Sectional ◽

Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Download Full-text

Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results

Blood ◽

10.1182/blood-2010-03-277152 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1141-1145 ◽

Cited By ~ 234

Author(s):

Hagop M. Kantarjian ◽

Francis J. Giles ◽

Kapil N. Bhalla ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Study Endpoint ◽

Primary Study ◽

Molecular Response ◽

Open Label ◽

Imatinib Resistance ◽

Abl Tyrosine Kinase

Abstract Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ≥ 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure. This trial was registered at www.clinicaltrials.gov as #NCT00109707.

Download Full-text

Imatinib Mesylate Therapy in Late Ph+ Chronic Myeloid Leukemia Patients in Stable Complete Cytogenetic Response after Interferon-Alpha Results in a Very High Complete Molecular Response Rate.

Blood ◽

10.1182/blood.v108.11.2158.2158 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2158-2158

Author(s):

Giuliana Alimena ◽

Massimo Breccia ◽

Luigia Luciano ◽

Fabrizio Quarantelli ◽

Daniela Diverio ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Copy Number ◽

Myeloid Leukemia ◽

Residual Disease ◽

Cytogenetic Response ◽

Molecular Response ◽

Complete Cytogenetic Response ◽

Complete Molecular Response

Abstract Imatinib mesylate was given to 26 Philadelphia positive (Ph+) chronic myeloid leukemia (CML) patients who were in late chronic phase (CP) and in stable complete cytogenetic response (CCR) after interferon-alfa (IFN-α), but showed persistent positive residual disease at PCR analysis under this treatment. At diagnosis median age was 40 years (range 21–64) and according to Sokal’s score, 18 patients were low risk and 8 were intermediate risk. Median IFN treatment was 88 mo.s (range 15–202) and median CCR duration was 73 mo.s (range 10–148). Imatinib was administered at the standard dose of 400 mg/die, after stopping IFN for 1 week. Residual disease was measured on bone marrow (BM) cells at baseline, before starting Imatinib, at 3, 6, 12, 18 mo.s and at the last follow-up (median 32 mo.s, range 21–49), by assaying BCR-ABL transcripts using quantitative PCR (RQ-PCR). The copy number (CN) of BCR/ABL and ABL transcript were derived by the interpolation of CT values to the appropriate standard curve, and the result, for each sample, was expressed as ratio of BCR/ABL mRNA copies to ABL mRNA x 100 (normalized copy number - NCN). Imatinib treatment resulted in a progressive and consistent decline of residual disease in all but one patient, from a median of 0.89 at baseline to 0.01 at the end of follow-up. Major molecular response (BCR/ABL levels <0.1) was reached in 20 patients (77%) and BCR/ABL transcripts were undetectable in 13 (50%). Achievement of molecular response was significantly correlated with post-IFN baseline transcript level (mean 1.194 for patients achieving complete molecular response vs 18,97 for those who did not; p<0.001), but not with other clinical/biological patient characteristics. In all patients, imatinib was well tolerated with no side effects requiring drug dose reduction or dose discontinuation. Albeit obtained from an unusual subset of selected patients with favourable prognosis, and likely particularly sensitive to imatinib, present results confirm the efficacy of combining Imatinib and IFN-α and further support investigating treatment approaches employing these two drugs.

Download Full-text

Study of different mutations in chronic myeloid leukemia in India and their co-relation with drug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7083 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7083-7083

Author(s):

Priti Mitra ◽

Swati Dasgupta ◽

Chinmay Kumar Basu ◽

Firoj Hossain Gharami ◽

Subrata Mandal ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chromosomal Abnormalities ◽

Mutation Screening ◽

Resistance Mutation ◽

Tyrosine Kinase Domain ◽

Molecular Response ◽

Imatinib Resistance ◽

Imatinib Resistant ◽

Resistant Mutation

7083 Background: Emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML. Aim of our study is to investigate two potential resistance mechanisms i.e.,mutations of BCR-ABL tyrosine kinase domain (TKD) and Additional Chromosomal Abnormalities during TKI treatment in CML. Methods: Karyotyping and BCR-ABL TKD mutation screening are performed in 100 imatinib resistant CML patients who were on imatinib at the time of loss of hematologic response, cytogenetic or molecular response. Imatinib–Resistance Mutation Analysis (Qualitative) were detected by Nested RTPCR and Sanger’s Sequencing. In 100 cases, 34 received escalated imatinib, 34 nilotinib and another 32 dasatinib. Results: In 100 BCR-ABL positive imatinib, nilotinib and dasatinib resistant cases, 11 different BCR-ABL TKD mutations were detected. Analysis revealed no mutations-43 cases, M351T-12 cases, G250E-10 cases, F317L-8 cases, M244V-5 cases, E255K-4 cases, V379I-4 cases, F359V-3 cases, H396R-3 cases, Y253F-3 cases, E355G-3 cases, T315I-2 cases. 11 novel mutations (F317L, G250E, M244V, Y253F, E255K, M351T, F359V, H396R, V379I, E355G, T315I) conferring imatinib resistance, 10 nilotinib–resistant mutations (M244V, F359V, T315I, E355G, G250E) and 8 dasatinib-resistant mutations (H396R, F317L, H396R, T315I, M351T) were seen in our patient population. T315I was found more frequently in cases on dasatinib than on imatinib therapy. Conclusions: T315I which confers resistance to all TKIs was detected only in 2/100 patients who demonstrated loss of response in our population. As compared with other western studies, incidence of T315I mutation was very low in our study. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. For cases with TKI resistance, mutation and ACA screening may play role in identifying patients with poorer prognosis. In our practice if nilotinib–resistant mutation was detected, dasatinib was preferred and for dasatinib-resistant mutation, nilotinib was preferred. We are planning for using bosutinib, panotinib and omacetaxine (SC route) in third line therapy in imatinib resistant different mutation positive chronic myeloid leukemia.

Download Full-text