Updated first line data of Nilotinib, Dasatinib and Bosutinib presented at EHA 2011


At the European Hematology Association's Annual Congress 2011 in London, CML experts presented updates on the first line trials with Nilotinib, Dasatinib and Bosutinib. The following summarizes the findings from a patient's perspective.

Nilotinib first line / ENESTnd trial

Prof. Andreas Hochhaus presented the 24 months data from the ENESTnd study. The trial has three arms: 400mg Nilotinib twice daily, 300mg Nilotinib twice daily, and 400mg Imatinib. Earlier trial results had already shown some benefit of 2x300mg of Nilotinib over 2x400mg of Nilotinib, hence 300mg was suggested as the standard Nilotinib dose in first line treatment of CML in chronic phase. Nilotinib has been approved by authorities for first line treatment in over 40 countries, even though reimbursement remains a challenge in many countries. The ENESTnd study recruited 846 patients in 217 centers in 35 countries. Primary endpoint was major molecular response (MMR) at 12 months. At 24 months, more than 90% of all study participants are still being observed, with 67% in the Imatinib arm still being on Imatinib and 74% still on Nilotinib - this means every third (Imatinib) to fourth (Nilotinib) patient had to quit the first line therapy because of strict protocol requirements, adverse events (most frequent), progression (rarer) or death (rare). In terms of achievement of MMR by 24 months, 71% of Nilotinib 2x300mg patients and only 44% of Imatinib patients achieved an MMR, maintaining the advantage over Imatinib of around 27%. Similarly, complete molecular response (PCR <0,0032%, with 4.5log sensitivity) was achieved by 25% of patients taking Nilotinib 2x300mg and only 9% of patients on Imatinib. However, most importantly, only 0,7% of Nilotinib patients but 4,2% of Imatinib patients progressed into accelerated or blast phase. New mutations were only observed in 10 patients on the 2x300mg Nilotinib arm but in 20 patients in the Imatinib arm. Nilotinib was well tolerated - fluid retention, diarrhea, muscle cramps, nausea, vomiting and neutropenia occurred much more rarely on Nilotinib than on Imatinib, while headache, pruritus and rash were more frequent. Prof. Hochhaus concluded that longer follow-up confirmed the superiority of Nilotinib over Imatinib for the treatment of patients with newly diagnosed CML in chronic phase.

Dasatinib first-line / DASISION Trial

In another session, Prof. Hochhaus also presented the 24 months data of the DASISION study comparing Dasatinib 100mg with Imatinib 400mg in newly diagnosed CML patients. The study included 519 patients in 108 centers in 26 countries. The primary endpoint was complete cytogenetic response confirmed at two consecutive assessments. At 24 months, 77% of Dasatinib patients and 75% of Imatinib patients still being on trial - this means every fourth had left the study. Reasons for leaving were progression or treatment failure (8% on Dasatinib, 11% on Imatinib), adverse events (7% vs. 5%), and death (2% on Dasatinib and <1% on Imatinib). In terms of achievement of MMR, by 24 months, 64% of Dasatinib and 46% of Imatinib patients achieved an MMR, maintaining the advantage of around 18% for Dasatinib patients. Complete molecular response (PCR <0,0032%, with 4.5log sensitivity) was achieved by 17% of Dasatinib patients and 8% of Imatinib patients. 2.3% of Dasatinib patients and 5% of Imatinib patients progressed. No patient who had achieved MMR transformed to accelerated or blast phase later on, but 9 patients who achieved a complete cytogenetic response progressed, underlining the prognostic value of achieving MMR. 6 patients died in the Dasatinib arm (3 due to CML progression), and 5 died in the Imatinib arm (4 due to progression). Of the patients that discontinued the treatment, only about 15% of those showed detectable mutations in both study arms. However, the spectrum of mutations after Imatinib therapy was much wider than the spectrum of mutations after Dasatinib therapy. T315I mutations were observed in 7 patients after Dasatinib but in none of the imatinib treated patients.

Most frequent side effects on Dasatinib were fluid retention (25%), myalgia (22%), diarrhea (19%), pleural effusions (14%), edema (11%) - and except pleural effusions, they were all less frequent than on Imatinib. Prof. Hochhaus concluded that longer follow-up continues to support the use of Dasatinib 100mg as first-line treatment for newly diagnosed CML in chronic phase.

Bosutinib first-line / BELA Trial

Dr. Brümmendorf presented the 18 month data of the BELA trial comparing Bosutinib 500mg/day with Imatinib 400mg/day in newly diagnosed patients. 502 patients were enrolled in 139 centers in 31 countries. Primary endpoint of the study was complete cytogenetic response. Dose interruptions were required by 64% of patients on Bosutinib and 43% on Dasatinib, and 67% of Bosutinib patients and 74% of Dasatinib are still on study treatment today. Brümmendorf mentioned that major reason for treatment discontinuation was adverse events (23%) and disease progression (13%). Complete cytogenetic responses at 18months were reached by 79% on both treatment arms, which means the there was no advantage of Bosutinib over Imatinib in terms of achieving complete cytogenetic response. 2% of Bosutinib and 5% of Imatinib patients progressed to advanced disease, 2% (Bosutinib) and 5% (Imatinib) of patients died. The most frequent side effect was diarrhea (69% of patients) which usually began within 3 days after starting treatment, and resolved in 87% of patients. Of those patients that interrupted treatment because of diarrhea, 68% of patients restarted treatment successfully. Liver functions were also impacted, but 80% with elevated liver enzymes could successfully continue treatment after a restart. Dr. Brümmendorf concluded that responses were faster with Bosutinib than with Imatinib, with fewer events of progression. The drug was well tolerated as long as initial gastrointestinal and liver side effects were managed well, e.g. with dose modifications or temporary interruptions.


This year's EHA was the first time that 24 months data of both Dasatinib and Nilotinib first line were presented at once. Furthermore, the 18 months data of Bosutinib was more conclusive than what was presented at ASH.

So in summary, what do the first line presentations at EHA mean for us patients? It was a pity that the three first line presentations were not held in the same session at the EHA congress, as this might have sparked an expert discussion in the plenary when comparing the results. Of course, from a scientific standpoint, the data of these trials cannot be compared head to head, given the studies had different designs, definitions of response and endpoints. However, in reality, clinicians and patients need to take comparative decisions based on the best available knowledge today. When disregarding access issues, newly diagnosed CML patients are in the comfortable position of having the choice between three approved drugs and one investigational compound, all being very effective to treat CML. Nilotinib and Dasatinib are both significantly more potent in Imatinib, resulting in lower rates of progression and less deaths. The 2nd generation treatments and their speed of response seem to prevent progression. Higher rates of molecular response - both major and complete - might even provide hope to eventually increase the number of patients that are able to safely stop therapy altogether in the future.

Do we still need Bosutinib? Dr Kantarjian commented in his educational presentation at EHA 2011 that he hoped that Bosutinib as "one of the most targeted CML drugs" would be taken to approval, given it is the most targeted compound of the four TKIs, focusing on bcr-abl while inhibiting other kinases only on a lower level. He mentioned that the BELA trial was unfortunate: unsatisfactory clinical management of diarrhea and liver enzyme elevations at the start of therapy led to too high discontinuation rates for no good reason. This is why the primary endpoint of the trial, demonstrating a significant difference in complete cytogenetic response between Bosutinib and Dasatinib, was missed. The trial demonstrated clear advantages in other areas like progressions, deaths or side effect profiles though.

So which ones to pick when newly diagnosed with CML? It is difficult to give a general answer, given it depends on certain individual factors of each patient. For example co-morbidities: as Prof Hochhaus pointed out in the EHA education session, when a patient suffers from pancreatitis or diabetes, caution is appropriate when administering Nilotinib. When hypertension, heart or lung diseases pre-exist, Dasatinib might be of lower priority. In case of prolongation of the Qt interval (rhythm of the heart), patients need careful monitoring on both drugs. On Dasatinib, the impact of pleural effusions and the slightly higher occurrence of T315I mutations need to be observed in the studies. Bosutinib might be the most targeted inhibitor, but still it is far from being an approved treatment and made widely available. In terms of achievement of molecular response levels, frequency of mutations and low progression rates, Nilotinib seems to be most interesting.

When treated by an expert with state of the art knowledge, survival of newly diagnosed CML is just 1% less than the healthy population today - which is fantastic progress compared to the deadliness that CML had just 10 years ago. However we also need to remember that despite all these success stories, still about one fourth of patients who started on either Imatinib or any of the three second generation drugs eventually had to change therapy for numerous reasons. Even with Imatinib, Dasatinib, Nilotinib and Bosutinib, CML is far from being a "ticked box" for all patients today. More research needs to be done - and is being done - to help those patients that are diagnosed in advanced disease, do not tolerate any of the drugs, or do not respond or relapse on treatment. And eventually, patients still want a cure.

Jan Geissler, CML Advocates Network, 16 June 2011