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Updates found with 'parp inhibitors'

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Updates found with 'parp inhibitors'

Maintenance with PARP inhibitor is the way forward in ovarian cancer:Median PFS in platinum sensitive relapse carcinoma ovary is approximately 10 months.20% of high grade serous carcinoma ovary have somatic or germline mutation in BRCA gene.Single stranded DNA breaks are repaired Base excision repair pathways of which PARP ( poly ADP ribose polymerase) enzymes are one of the key members.In presence of PARP inhibitors these single stranded breaks are converted into double stranded breaks and the repair of these double stranded breaks require intact Homologous recombination repair pathway. BRCA proteins are integral part of these Homologous recombination pathway.In presence of BRCA gene muatation the double stranded breaks produced in presence of PARP inhibitor bring about lethal damage to the cancer cells.Olaparib is the most extensively studied PARP inhibitor and it is approved in BRCA mutation positive relapse high grade carcinoma ovary as single agent after 3 or more lines of chemotherapy. Also Olaparib has been approved as maintenance in both BRCA mutated and wild type patients in relapse platinum sensitive high grade carcinoma ovary who attain CR or PR to last line platinum doublet.The reported PFS in this setting is around 18 months in BRCA mutated (SOLO-2 trial-using tablet olaparib 300mg twice daily) v/s 9 months in BRCA wild type based on STUDY- 19 Trial (Capsule Olaparib 400mg twice daily).It is important to note that about 15% patients remain progression free at 5 years in study-19 trial on Olaparib ( these long term progression free survival benefited both BRCA wild type and BRCA mutated subgroup) .Niraparib based on the result of NOVA trial (300 mg once daily) got approval in maintenance for both BRCA mutated and wild type patients in relapse platinum sensitive high grade carcinoma ovary who attain CR or PR to last line platinum doublet. Rucaparib at a dose of 600mg twice daily awaits its approval in similar setting with the promising results of the ARIEL3 presented in ESMO 2017.Main toxicity of Olaparib is anemia, nausea and fatigue. (Discontinuation rate 6%)Main toxicity of Niraparib is nausea and haematological (Thrombocytopenia> Anemia>Neutropenia) (Discontinuation rate 15%)Main toxicity of Rucaparib is anemia and elevation of liver enzyme (Discontinuation rate 13%)
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Question- Is it possible to cure CML (CHRONIC MYELOID LEUKEMIA) one of the types of blood cancer with tablets (bcr-abl kinase inhibitor) eg imatinib, nilotinib or dasatinib?Answer- We don’t know the answer yet, but studies are now looking for stopping these tablets in patients who achieve desired response with them. This concept is called TFR (Treatment Free Remission)Question- What is TFR?Answer- TFR is defined as maintenance of less than minimal residual or undetectable BCR-ABL transcript level even after stopping BCR-ABL kinase inhibitors.Question – Which patients are ideal candidates for TFR?Answer- Ideal candidates are CML-Chronic phase patients who maintain stable and continuous DMR (deep molecular response) for more than 2 years, without any history of failure of response to any of the available TKIs (Tyrosine kinase inhibitor).Question – What percentage of these carefully selected patients maintain their TFR?Answer- Close to 50% patients maintain TFR for more than 1 year.Question- Important checklist before offering TFR?Answer- Patient compliance is of paramount importance, because regular BCR-ABL monitoring is required to detect reappearance of BCR-ABL levels and prevent transformation into accelerated or blastic phase of CML.Question- What is imatinib withdrawal syndrome?Answer- An imatinib withdrawal syndrome consist of diffuse myalgia/ arthralgia encountered after stopping TKI. Question – Is maintenance of TFR equivalent to cure?Answer- We do not know yet and longer follow up is required to answer this question.
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