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Sriman Swarup, Anita Sultan, Somedeb Ball, Francis Mogollon-Duffo, Nimesh Adhikari, Yin M. Myat, Myo H. Zaw, Catherine Jones and Kyaw Z. Thein

Background: Breast cancer is the most common cancer in women, and the majority of breast cancers express the estrogen receptor or progesterone receptor. Inhibition of CDK4/6 signaling pathway has shown survival benefit in advanced breast cancer by overcoming endocrine therapy resistance. Yet, there are considerable hematologic toxicities associated with CDK 4/6 inhibitors and hence, we performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018 were queried. RCTs that mention anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II studies) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: anemia, 3.494 (95% CI: 2.535–4.814; P<.0001); thrombocytopenia, 6.066 (95% CI: 3.055–12.046; P<.0001); leukopenia, 10.376(95% CI: 7.236–14.879; P<.0001); and neutropenia, 14.387 (95% CI: 10.877–19.031; P<.0001). The RR of high-grade adverse effects were as follows: anemia, 2.251 (95% CI: 1.393–3.637; P=.001); thrombocytopenia, 3.696 (95% CI: 1.417–9.642; P=.008); leukopenia, 22.083(95% CI: 12.126–40.217; P<.0001); neutropenia, 33.527(95% CI: 17.271–65.082; P<.001). Neutropenic fever was noted in 71 (3.73%) in CDK 4/6 inhibitors group vs 28 (2.18%) in control arm. The pooled RR was statistically significant at 12.056 (95% CI: 1. 352–3.127; P=.001) and RD was 0.014 (95% CI: −0.002–0.029; P=.078) Conclusion: CDK 4/6 inhibitors–based regimen significantly contributed to all hematologic toxicities as well as febrile neutropenia. The improved efficacy outcomes and manageable toxicities with CDK 4/6 inhibitors are observed with proper supportive care and close monitoring.

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Sriman Swarup, Anita Sultan, Nusrat Jahan, Upama Sharma, Nimesh Adhikari, Yin M. Myat, Ye Aung, Myo H. Zaw and Kyaw Z. Thein

Background: VEGFR, KIT, RET, and MET pathways are implicated in several solid tumors. Cabozantinib is an oral inhibitor of these kinase pathways, and hence has found its use in treatment of multiple malignancies. However, it has several side effects that can limit tolerance amongst patients. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events in patients with advanced solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 30, 2018. Phase 3 trials that mention HRQOL events like pain, arthralgia, fatigue, and reduced appetite as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: 4 phase 3 RCTs with a total of 2,703 patients with medullary thyroid cancer, prostate cancer, renal cell carcinoma, and hepatocellular carcinoma were eligible. Studies comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone were included in the analysis. The relative risks of all-grade side effects were as follows: fatigue, 1.378 (95% CI: 1.236–1.536; P<.0001); asthenia, 1.704 (95% CI: 1.190–2.441; P=.004); reduced appetite, 2.088 (95% CI: 1.471–2.964; P<.0001); back pain, 1.047 (95% CI: 0.871–1.259; P=.626); pain in limbs, 1.444 (95% CI: 1.128–1.847; P=.004); arthralgia, 0.982 (95% CI: 0.707–1.363; P=.912). The RR of high-grade side effects were as follows: fatigue, 1.937 (95% CI: 1.483–2.528; P<.0001); asthenia, 2.211 (95% CI: 1.536–3.184; P<.0001); reduced appetite, 4.329 (95% CI: 2.372–7.900; P<.0001); back pain, 1.227 (95% CI: 0.738–2.040; P=.431); pain in limbs, 2.933 (95% CI: 1.127–7.635; P=.028); arthralgia, 0.820 (95% CI: 0.394–1.709; P=.597). Conclusion: Our meta-analysis showed that cabozantinib contributed to significant toxicity of all grades of fatigue, asthenia, pain in limbs, and reduced appetite. Identifying and addressing these toxicities will be important in improving quality of life for these patients.

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Nimesh Adhikari, Myo H. Zaw, Sriman Swarup, Anita Sultan, Upama Sharma, Wai P. Thi, Nay N. Yee, Khaing K. Htwe, Tun W. Naing and Kyaw Z. Thein

Background: Bruton’s tyrosine kinase (BTK), a kinase downstream of the B-cell receptor, involves in the B cell survival and proliferation and has become an attractive therapeutic target. Ibrutinib is an oral potent, covalent inhibitor of BTK and hence employed in many hematologic malignancies. We performed a systematic review and pooled analysis of randomized controlled trials (RCTs) to determine the risk of atrial fibrillation (AF) and pulmonary toxicities among patients treated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 2018. Phase 3 RCTs that mention AF and pulmonary toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 4 phase III RCTs with a total of 1,383 patients with chronic lymphocytic leukemia or small lymphocytic lymphoma were eligible. Studies comparing Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R, and I vs R were included in the analysis. The AF incidence was 41 (5.686%) in the ibrutinib group vs 8 (1.208%) in the control arm. The relative risk (RR) for AF was statistically significant at 3.825 (95% CI: 1.848–7.917; P<.0001) and RD was 0.041 (95% CI: 0.023–0.059; P<.0001). The RR of all-grade side effects was as follows: cough, 1.133 (95% CI: 0.724–1.773; P=.584); edema, 1.375 (95% CI: 0.943–2.006; P=.098); pneumonia, 1.227 (95% CI: 0.884–1.703; P=.221); and upper respiratory infections (URI), 1.075 (95% CI: 0.809–1.429; P=.616). The RR of high-grade side effects was as follows: cough, 0.373 (95% CI: 0.063–2.209; P=.277); edema, 1.232 (95% CI: 0.199–7.649; P=.822); pneumonia, 1.277 (95% CI: 0.847–1.926; P=.243); and URI, 1.555 (95% CI: 0.239–10.127; P=.644). Conclusion: Our meta-analysis demonstrated that patients on ibrutinib noted a significant increase in the risk of atrial fibrillation with a relative risk of 3.825. However, the risk of pulmonary toxicities was not statistically increased in the ibrutinib group.