Report on ASH 2014 – Part 3
American Society of Hematology annual meeting, San Francisco, USA, December 6-9, 2014
CML is treated with a first- or second-generation TKI (tyrosine kinase inhibitor), such as Gleevec, Tasigna or Sprycel. But for those who don’t respond well enough to these medications, there are two additional TKI options: Iclusig (ponatinib), and Bosulif (bosutinib).
The most recent study of Iclusig is EPIC, a phase III trial in which people newly-diagnosed with CML took either Iclusig or Gleevec. Preliminary results of the EPIC study were presented at last year’s American Society of Clinical Oncology meeting (see CML-IQ: ASCO 2014 – Overview of recent drug studies).
The trial was stopped early because of cardiovascular problems. This was unfortunate because Iclusig was shown to be highly effective. One-third of people achieved a major molecular response within three months (Lipton and colleagues. ASH 2014; abstract 519). At six months, 62% reached MMR and one-third achieved a 4-log reduction.
Because of safety concerns, Iclusig is no longer considered to be a first-choice treatment, but is kept in reserve for people who develop a drug-resistant mutation (called T315I). The effectiveness of Iclusig in drug-resistant people was examined in the phase II PACE trial, and updated results are now available (Cortes and colleagues. ASH 2014; abstract 3135). Although most people in this study had not responded to three or more CML treatments, 70% were able to achieve a complete cytogenetic response (CCyR), and 58% reached MMR on Iclusig (Mauro and colleagues. ASH 2014; abstract 4552). A major hematologic response was also seen in 61% of people with accelerated-phase CML, and 29% with blast-crisis CML. Serious side effects included thromboembolic events (14%), pneumonia (7%), and pancreatitis (6%).
The other TKI for people who don’t respond to one of the first-choice medications is Bosulif (bosutinib). A phase I/II study looked at the effectiveness of Bosulif as a third-line agent found (Gambacorti-Passerini and colleagues. ASH 2014; abstract 4559). Many of these people had one or more mutations. One-third of this drug-resistant group of people was able to achieve a major cytogenetic response. Overall survival at two years was 84%. Severe side effects included diarrhea (9% of people), nausea or vomiting (1%), low platelet count (26%) or other blood abnormalities, and cardiac disorders (8%). Most people experienced side effects during treatment, which could be managed in some cases by lowering or delaying the dose.
Two studies at ASH looked at whether adding another medication to a TKI provided an added benefit. A study at Princess Margaret Hospital in Toronto examined its medical records to see if people taking a statin medication while on Gleevec did better than those taking Gleevec alone (Kim and colleagues. ASH 2014; abstract 1804).
Statins are commonly used to lower chlolesterol levels. This class of drugs includes Lipitor (atorvastatin), Crestor (rosuvastatin), Zocor (simvastatin), Pravachol (pravastatin) and Lescol (fluvastatin). One of the side benefits of these medications is that they’ve also been shown to induce destruction of tumour cells.
Over an average six-year period of the analysis, statins didn’t appear to improve one’s chances of achieving a cytogenetic response. However, those taking a statin were more likely to achieve a major molecular response within the first 18 months of starting a TKI than those not taking a statin (67% vs. 49%). So this provides preliminary evidence that taking a statin along with a TKI may help people achieve a deeper molecular response.
A new approach that is being researched in CML is to try to interrupt biological pathways in the body that promote leukemia (see also our three-part series, Exploring New Ideas for Treatment, starting on Nov. 6, 2014). One such pathway has the curious name of Hedgehog, and these signals control the body’s response to stress, injury and healing. One protein involved in Hedgehog has the equally curious name of Smoothened (SMO), and researchers have found that SMO is active in BCR-ABL cells and leukemic stem cells. The hope is that by blocking this protein, treatment can eradicate the leukemic stem cells hiding in the bone marrow (Cortes and colleagues. J Natl Compr Canc Netw 2012;10 Suppl 3:S1-S13). Animal studies have shown that inhibiting SMO can prolong survival, so several companies are now developing drugs that will block SMO.
One such agent is BMS-833923, and phase I results were presented at ASH (Shah and colleagues. ASH 2014; abstract 4539). A total of 22 people at different phases of CML participated in the study and were evaluable. All were taking Sprycel, and BMS-833923 was slowly added in. Unfortunately, the new drug didn’t appear to do much and was associated with a number of side effects, such as hair loss, weight loss, muscle spasms and fatigue. No added benefit was seen in people with accelerated-phase or blast-crisis CML, and there was no evidence that the new drug killed off leukemic stem cells. So these were very disappointing results.