Resistant mutations in CML and Ph+ALL – role of ponatinib

Abstract

In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013, ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of ponatinib in CML and Ph+ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of ponatinib will be highlighted, including summaries of the important clinical trials involving ponatinib as well as its current place in therapy.

Drug Therapy in the Progressed CML Patient With Multi-Tki Failure

“…The response rate and safety profile of T315I patients were comparable to those observed in the overall population of refractory CML and Ph+, ALL patients in ponatinib clinical trials 8. No mutation conferring resistance to Ponatinib, so far, has been identified 2,9,10. With longer follow-up and the availability of second and third generation TKIs, most clinically relevant ABL kinase mutations respond to change in TKI therapy following imatinib failure, with the majority of patients achieving durable cytogenetic and molecular responses.…”

Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome‐positive leukemias with the T315I mutation

“…A threonine‐to‐isoleucine substitution at position 315 (T315I mutation), the gatekeeper residue of the Abelson murine leukemia viral oncogene homolog (ABL) kinase domain, is identified in approximately 20% of patients with resistant or relapsed CML3, 4 and confers resistance to most TKIs indicated for CML treatment, such as imatinib, dasatinib, bosutinib, and nilotinib 5. Ponatinib is approved in the United States and the European Union for adult patients with refractory CML or Ph+ ALL and those with the BCR‐ABL T315I mutation, and is now the only effective TKI for treating CML or Ph+ ALL in T315I‐positive patients 3, 4, 6. Recently, it was demonstrated that omacetaxine mepesuccinate, a first‐in‐class cephalotaxine, also has inhibitory activity in TKI‐resistant CML stem cells and provides a benefit to patients who have T315I‐positive chronic phase (CP)‐CML as a single agent or in combination with a TKI 7.…”

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression

“…3 Therefore, finding bio markers of CML progression can help in timely therapeutic interventions to minimize drug resistance, treatment failures and relapses, subsequently reducing morbidities and mortalities associated with CML, significantly. 4 Mutations in BCR-ABL1 gene have been found to be a major cause of disease progression and resistance to tyrosine kinase inhibitors in CML patients. [5][6][7] Therefore BCR-ABL mutation detection using capillary sequencing remains to be a gold standard for CML patients exhibiting disease progression and/or drug resistance in European and North American guidelines.…”