Overcoming resistance to tyrosine kinase inhibitors
This content has been sponsored by Incyte Biosciences UK Ltd.
Striking the right balance in CML
Chronic myeloid leukemia (CML) remains a challenging disease to manage and treat. The introduction of tyrosine kinase inhibitors (TKIs) has had a tremendous impact on patient outcomes, with a selection of 1st, 2nd and 3rd generation TKIs available for use as 1st, 2nd and 3rd line treatments. The success of TKIs has reduced the need for hematopoietic stem cell transplant (HSCT), now commonly regarded as a salvage therapy for poor responders. However, for some patients, HSCT remains the best option, due to a number of factors that result in patients being less responsive to TKIs. This article aims to provide an understanding of CML disease progression and the current treatment pathway, as well as some of the challenges of sequencing the available agents and HSCT.
Content in this article has been adapted from Innes AJ et al. Nature Reviews Clinical Oncology 2015;13(2):79-91. Prescribing information is available at the end of the article
CML progression and treatment challenges
CML is characterised by the presence of a translocation of chromosomes 9 and 22, resulting in the Philadelphia chromosome and the production of the BCR-ABL1 oncogenic protein. The disease progression of CML is characterised by 3 phases: chronic, accelerated and blast crisis phases. Patients in the blast crisis phase have the poorest outcomes and pose the greatest treatment challenge. TKIs are effective in targeting the BCR-ABL1 protein, and are a successful treatment strategy in most patients with CML. However, there is a significant subgroup of patients who do not respond to TKIs. They remain a large unmet need in the management and treatment of CML.
Overcoming TKI resistance: the recommended treatment pathway
Patients with CML typically commence their treatment with 1st generation TKI, imatinib, before continuing to 2nd generation TKIs as sequential treatments. It is not uncommon for patients to cycle through multiple 2nd generation TKIs before attempting 3rd generation TKI, ponatinib. However, literature suggests that cycling through 2nd generation TKIs may not be the best solution for all patients. Furthermore, identifying poor responders early in the treatment pathway and beginning the process of donor selection could be a more effective approach.
In the era of TKIs, where does hematopoietic stem cell transplant fit in the treatment of CML? Innes AJ et al. review the CML treatment pathway, suggesting an alternative approach for patients who may not benefit from standard TKI treatment pathways.
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See below for how to report adverse reactions.
Legal Category: POM See Summary of Product Characteristics (SmPC) before prescribing.
Adult patients with:
– Chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukaemia (CML) who are resistant/intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.
– Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant/intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.
Dosage and administration: Recommended starting dose 45 mg once daily; swallow tablets whole.
Assess and actively manage cardiovascular risk factors before starting treatment and continue throughout treatment; consider other treatment options in patients with prior myocardial infarction (MI), revascularisation or stroke (CVA).
The risk of Arterial Occlusive Events is likely to be dose‑related. Consider dose reduction to 15 mg for CP-CML patients who achieve a Major Cytogenetic Response; consult the SmPC for full details of risk:benefit and recommended monitoring of response.
Discontinue in case of disease progression or severe adverse reactions (ADRs); also, if Complete Haematological Response does not occur by 3 months.
Dose modifications, or interruptions, should be considered for haematological and non‑haematological toxicities; consult the SmPC for full details of all recommended dose modifications.
Contraindications: Hypersensitivity to ponatinib or excipients.
Warnings and precautions: Important ADRs: refer to SmPC for full details of recommended monitoring and management.
Myelosuppression: Perform Full Blood Count every 2 weeks for the first 3 months and then monthly as clinically indicated. Most severe events occurred in first 3 months; overall, events occurred more frequently in AP‑CML, BP-CML or Ph+ ALL than CP‑CML.
Arterial Occlusion: Interrupt treatment immediately. Serious reactions including MI, CVA and retinal artery occlusion have occurred in 19% of patients in the Phase 2 PACE trial of Iclusig (see SmPC for full details); events occurred more frequently in elderly patients and those with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
Venous thromboembolism: Interrupt treatment immediately. Serious reactions including retinal vein occlusion have occurred in 5% of patients.
Hypertension: monitor and manage throughout treatment; may increase risk of arterial thrombotic events including renal artery stenosis. Treatment-emergent events have occurred, including hypertensive crisis.
Congestive Heart Failure: Consider discontinuing treatment if severe. Fatal events have occurred, some related to prior vascular occlusive events.
Pancreatitis and serum lipase: check serum lipase fortnightly for 2 months and then periodically. Frequency of events is greater in the first 2 months. Caution in patients with history of pancreatitis or alcohol abuse.
Hepatotoxicity: perform LFTs before and during treatment. Hepatic failure (including fatal outcome) has been observed, mostly in first year of treatment.
Haemorrhage: Interrupt treatment if serious or severe. Most severe events, including gastrointestinal haemorrhage and subdural haematoma, occurred more frequently in AP‑CML, BP‑CML or Ph+ ALL. Caution with use of anti‑clotting agents.
Risk ofHepatitis B reactivation: test for HBV before treatment Reactivation has occurred following Iclusig treatment. Consult with hepatologist if serology is positive.
Effects on ability to drive and use machines Lethargy, dizziness and blurred vision have occurred.
QT prolongation A clinically significant effect on QT cannot be excluded.
Drug Interactions: see SmPC for details of all interactions. Avoid treatment with Iclusig and strong CYP3A4 inducers if possible. Caution when treating with strong CYP3A inhibitors; consider 30 mg starting dose of Iclusig.
Pregnancy and breastfeeding: Advise patients not to become pregnant or father a child during treatment; use effective contraception . Studies in animals have shown reproductive toxicity. Breastfeeding should be discontinued.
Undesirable effects: Reporting suspected ADRs is important to continue monitoring the benefit:risk of Iclusig. Healthcare professionals are asked to report suspected ADRs via www.yellowcard.mhra.gov.uk.
Mostcommon serious ADRs (see SmPC for details of all ADRs) Pneumonia, CVA, coronary artery disease, peripheral arterial occlusive disease, pancreatitis, pyrexia, abdominal pain, anaemia, angina, decreased platelet count, febrile neutropaenia, hypertension, MI, atrial fibrillation, CCF, sepsis, increased lipase.
Quantities and Marketing Authorisation numbers: 45 mg dose 30 tablets EU/1/13/839/004 30 mg dose: 30 tablets EU/1/13/839/006 15 mg dose:
30 tablets EU/1/13/839/005 Cost: Marketing Authorisation Holder: Incyte Biosciences UK Ltd., Riverbridge House, Guildford Road, Leatherhead, KT22 9AD. For further information phone 00-800-0002-7423 Date of preparation: October 2017; UK/ICLG/P/17/0099
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard Adverse events should also be reported to Incyte immediately by phoning the EU universal free phone number 00-800-0002-7423.
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