Hematologic toxicities of small molecule tyrosine kinase inhibitors

Barber, Nicholas A.; Afzal, Wais; Akhtari, Mojtaba

doi:10.1007/s11523-011-0202-9

Cited by 19 publications

(16 citation statements)

References 73 publications

(81 reference statements)

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“…Bone marrow analysis, the most invasive test, may be necessary in megaloblastosis, in order to rule out myelodysplastic syndrome. Treatments relying on tyrosine kinase inhibitors (TKIs), such as imatinib, sunitinib, and sorafenib, can now be counted among the possible causes of macrocytosis with previously unexplained pathomechanisms [11, 15]. …”

Section: Discussionmentioning

confidence: 99%

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

et al. 2016

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Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in ‘low’ and ‘intermediate’ Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib’s inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential.

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Section: Discussionmentioning

confidence: 99%

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

et al. 2016

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“…Therefore, despite the increased number of mature megakaryocytes in the bone marrow, inhibition of SFKs results in thrombocytopenia by compromising migration and proplatelet formation. 53,55,62 Our results show that bosutinib and dasatinib were associated more with thrombocytopenia, which is probably due to their mechanism of action against SFKs. Moreover, dasatinib may also affect PDGFRs and their downstream signalling molecules, which contribute to the compromise of platelet activation.…”

Section: Discussionmentioning

confidence: 64%

“…1,54,56,57 In addition to the c-Abl pathway, other avenues that play a key role in normal haematopoiesis are inhibited by TKIs, such as Src, KIT, and platelet-derived growth factor receptor (PDGFR) pathways, which further contributes to myelosuppression. 53,55,58,59 Our analysis shows that cytopenias were typically more frequent with the use of dasatinib in both doses (100 and 140 mg), despite 140 mg not being a usual dose in clinical practice. This drug has a broad spectrum of inhibition of tyrosine kinases (low specificity), including…”

Section: Discussionmentioning

confidence: 83%

Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta‐analysis

Fachi

Tonin

Leonart

et al. 2019

Brit J Clinical Pharma

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Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia. Methods: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA). Results: Seventeen studies were included in the network meta-analysis. Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leucopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively. Conclusion: Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity. KEYWORDS chronic myeloid leukaemia, drug-related side effects and adverse reactions, network meta-analysis, tyrosine kinase inhibitors 1 | INTRODUCTION Tyrosine kinase inhibitors (TKIs) represent a milestone in chronic myeloid leukaemia (CML) treatment. Although these drugs are effective and have an overall favourable safety profile with mild to moderate adverse events (AEs), they can also cause severe events including haematological AEs, such as anaemia, leucopenia, neutropenia and thrombocytopenia, which occur due to myelosuppression. Moreover, The authors confirm that the PI for this paper is Roberto Pontarolo and that he had responsibility for this review.

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“…Myelosuppression may develop at any time during treatment of CML but is common in the initial 2-4 weeks of therapy, especially for advanced disease [21]. Other studies have reported onset of cytopenia between 3 and 5 weeks of imatinib therapy [22]. e development of severe cytopenia rapidly in patients with a myeloid bulge shortly after TKI initiation is a phenomenon that is still under study.…”

Section: Discussionmentioning

confidence: 99%

Cytopenia among CML Patients on Imatinib in Kenya: Types, Grades, and Time Course

McLigeyo

Rajab

Ezzi

et al. 2020

Advances in Hematology

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Background. Imatinib mesylate is the gold standard for the treatment of all phases of Philadelphia-positive chronic myeloid leukemia. Patients on imatinib treatment may develop cytopenia due to drug toxicity. This study aimed to determine the types, grades, and time course of cytopenia in CML patients on imatinib at a Nairobi hospital. Methods. This was a cross-sectional descriptive study of adult patients aged ≥18 years followed up at the Glivec International Patient Access Program (GIPAP) clinic from 2007 to 2015. Patients who developed cytopenia within 12 months of initiating imatinib were eligible. Clinical and hematologic data were retrieved from the patients’ charts and entered into a study proforma. Measures of central tendency such as mean, median, mode, standard deviation, and variance were used for analysis. Results. Sixty three percent (63.6%) of the 94 patients developed a monocytopenia, with anemia seen in 34%, neutropenia in 27.6%, and thrombocytopenia in 8% of the 94 patients. Anemia plus neutropenia was the most common bicytopenia at 12.7%. Pancytopenia was seen in only 5 of the 94 patients. Most of the cytopenia was grades 2 and 3. Anemia was present at baseline while neutropenia and thrombocytopenia developed within 12 months of imatinib initiation. Anemia resolved during the first 12 months of therapy while neutropenia and thrombocytopenia resolved within 24–36 months of treatment. Conclusion. Monocytopenia, especially anemia, was the most common type of cytopenia. The cytopenia was predominantly grade 2, developed in majority of the patients within 6 months after imatinib initiation, and had resolved by 24–36 months after imatinib initiation.

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Hematologic toxicities of small molecule tyrosine kinase inhibitors

Cited by 19 publications

References 73 publications

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta‐analysis

Cytopenia among CML Patients on Imatinib in Kenya: Types, Grades, and Time Course

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