Chronic myelogenous leukaemia: a remarkable success story
Chronic myelogenous leukaemia: a remarkable success story
Chronic myelogenous leukaemia (CML), or chronic granulocytic leukaemia, is a disease in which the body produces cancerous white blood cells. Worldwide, it accounts for approximately 10% to 15% of all adult cases of leukaemia, with an incidence of one to two cases per 100,000 people per year. It is more common in males than females and appears to be more common in the elderly. Treatment options mainly depend on the stage of the disease, defined as chronic, accelerated or blast phase. In addition to chemotherapy, during the 1980s allogenic haematopoietic stem cell transplantation (HSCT) or bone marrow transplantation proved capable of eradicating the malignant stem cell population – given suitable donors. Indeed, for several decades allogeneic HSCT remained the gold standard therapy for younger patients. Interferon also proved effective for CML: Roche’s drug Roferon A (interferon alfa 2a recombinant) reached the market in the 1990s, and Intron A (interferon alfa-2b), from Merck Inc was approved in the EU in 2000. However, interferon is dogged by serious side-effects.
A major breakthrough occurred when researchers identified cellular pathways involving tyrosine kinase as playing a role in CML and a new form of therapy was developed – the Bcr-Abl tyrosine kinase inhibitors (TKIs). This brought dramatic progress, with TKIs replacing HSCT as the first-line treatment of chronic phase CML. At the same time, the ultimate goal of cure with HSCT was superseded by the aim of deep molecular remission and long-term disease control. The first TKI was Glivec/Gleevec (imatinib), from Novartis, which was initially approved in 2001. Most patients with chronic phase CML show an excellent response to the drug: prior to imatinib, the 5-year survival rate for CML patients was 30%. With imatinib, however, almost 90% of patients hit that target. At its peak, imatinib reached annual sales of over $4 billion, and it is now available from multiple sources as a generic medicine. Resistance to imatinib led to a second generation of TKIs such as Sprycel (dasatinib), from BMS/Otsuka which was approved 2006. In trials, dasatinib induced higher rates of molecular response than imatinib, and though generally well tolerated, pleural effusions were the main complication of dasatinib therapy, and pulmonary hypertension has also been reported. Dasatinib was closely followed by Tasigna (nilotinib), from Novartis, approved in 2007. Nilotinib is a more potent and selective BCR-ABL1 inhibitor than imatinib. One of its main drawbacks is the fact that patients have to fast before and after taking it. Side-effects include skin toxicity, hyperglycaemia and progressive peripheral arterial occlusive disease. Two large clinical trials comparing these agents with imatinib demonstrated prolonged durable remissions, with nilotinib achieving major molecular response (MMR) at 3 years in 70–73% of patients compared with 53% with imatinib, and dasatinib achieving MMR in 69% compared with 55% with imatinib.
Between them, these three therapies have become the standard treatment for chronic phase CML. Sales are robust: dasatinib earns about $1.4 billion annually, a little more than nilotinib. Dasatinib and imatinib are now generic in most markets, and Novartis hopes nilotinib can step in to fill the sales gap. More importantly, up to 30% of patients become resistant to first-line TKI therapy through various mechanisms, and genetic profiling is shedding light on how resistance arises. For example, some 95% of CML patients show an abnormality in a specific chromosome – described as ‘Philadelphia positive’. Imatinib, dasatinib and nilotinib are approved for this mutation, along with a fourth drug Bosulif (bosutinib), from Pfizer. This means where secondary resistance occurs, patients can be switched to an alternative TKI. Dual kinase inhibitor bosutinib, FDA approved in 2012 and EMA approved in 2013, showed similar superiority over imatinib, with MMR rates of 41% at 12 months compared with 27% for imatinib.
For patients whose cancer cells have developed the BCR-ABL (T315I) mutation, a third generation TKI can be called upon: Iclusig (ponatinib), from Ariad Pharma, which was approved in the US in 2012 and in the EU in 2013. It is highly active in patients with resistance to multiple TKIs, against a range of resistant mutations. Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. For US patients who are no longer responding to (or could not tolerate) two or more TKIs, there is also Synribo (omacetaxine mepesuccinate), from Teva/Cephalon. This uses a different mechanism of action and is also effective against the T3151 mutation. The application for marketing authorisation in the EU was withdrawn in 2012, whereas it was approved for accelerated and chronic phase CML in the US in 2014, where it can be administered at home.
The cost of success
TKIs have proved to be the most successful class of targeted cancer therapies, exceeding almost all expectations. With TKI therapy, the annual all-cause mortality in CML declined to 2%, compared to a historical rate of 10–20%, and estimated 10-year survival has risen from below 20% to beyond 80%. Patients with CML now live near normal lifespans. However, all this comes at a cost. The price of the latest CML drugs are astronomical: ponatinib at almost $140,000 per year, omacetaxine at $28,000 for induction and $14,000 per maintenance course, and bosutinib at $118,000 per year. And though the cost of generic imatinib should fall, healthcare systems face a serious challenge in optimising the use of more expensive therapies in those patients at higher risk of progression.
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