Like every year in December, about 21.000 hematologists and health professionals (as well as a small group of patient advocates) convened at the Annual Meeting of the American Society of Hematology (ASH) to hear latest news from research in leukemias, lymphomas and other blood disorders.
We have attended the scientific CML sessions at ASH 2011 and are now summarizing the most important presentations and posters, complemented by a patients' perspective. This report covers key presentations on Nilotinib, Dasatinib, Bosutinib, Ponatinib, DCC-2036, Imatinib-Interferon combination, STOP studies, as well as some studies on CML and diabetes or fatigue.
The patients perspective on ASH 2011
“Can we aim at a cure?” This was probably the leading question lingering behind many presentations at ASH this year. The question was first expressed by Junia V Melo (Adelaide) in the Education Session on CML, but also in many other presentations and posters discussing ‘operational’ vs ‘real’ cure, therapy optimisation to increase complete molecular response rates, discontinuation studies, new mechanisms to target stem cells, and improvement of diagnostics to detect minimal residual disease on a very low molecular level.
Apart from the continuous improvement of performance over time on the approved CML therapies, exciting news were presented on Ponatinib (AP24534) and very early data on DCC-2036. Both drugs have the capabilities of targeting T315I, which may be the “last bastion” in chronic phase CML. With Imatinib, Dasatinib and Nilotinib as approved therapies, Bosutinib striving for market authorisation, Ponatinib demonstrating very convincing data even way beyond T315I, we’re moving towards a situation not dreamt of just 10 years ago: With CML patients having an equivalent risk of dying from CML than dying from any other cause and, and with a series of highly effective drugs available for battling any kind of nasty mutation - if CML is diagnosed early. Important research findings on quality of life data, data on co-morbidities like diabetes, and the special challenges of elderly patients have been presented as well - which is important for patients facing life-long treatment of a chronic disease.
Unfortunately, there is little progress on the front of advanced phase and blast phase CML. A rough estimate of 90% of all presentations addressed only chronic phase CML, while information how to treat very advanced phase CML beyond high-risk transplant is scarce. Stem cell transplant remains the only viable option then, but outlook is grim even for the strongest. Junia Melo raised the question how cured patients really are after stem cell transplant, even in the case that they survived it and achieved complete absence of CML.
With the prospect of having generic Imatinib in 2015 and 2016 in many markets, some presentations this year seemed already to take account of new market dynamics that will arise. In many talks with experts, you could feel that Imatinib might get a second rise, or might remain first line treatment in many less well-off countries for a while. Current findings on assessing early response to Imatinib and early switching to more powerful second generation drugs in case of not surpassing 10% BCR-ABL/ABL might become even more relevant.
We patient advocates were particularly pleased that Andreas Hochhaus’s presentation drew special attention to the special role of CML patient advocates. “The CML community is an outstanding example of global patient advocacy – not to be seen in many other cancers,” Hochhaus said, “Patient advocates have become an independent, strong community, credible partners, advisors of clinicians, research projects and industry, as well as a strong political voice”.
We’ll continue to support CML patients world-wide - until CML is a “ticked box” where every patient can be saved. And we’d like to reflect our gratitude to all clinicians and industry researchers on their continued efforts to strive for the final cure of CML, and to the International CML Foundation (iCMLf) for hosting an important ASH meeting for physicians from emerging countries.
In any case, here are now our detailed summaries of a selection of presentations and posters at ASH 2011 that we found most relevant:
Updates on Nilotinib
Giuseppe Saglio presented the 3 year follow-up data of the ENESTnd study that compared Nilotinib with Imatinib as a first-line treatment. 846 patients were enrolled in 217 centers and 35 countries. 95% of all trial patients are still monitored today. Compared to the 24 month data presented at ASH, there have been no surprises - which is good news for patients: no increase in liver events, no patient discontinued due to blood sugar levels, no heart issues observed. 73% of all Nilotinib 2x300mg patients, compared to only 53% of all Imatinib patients, achieved major molecular response (MMR). A difference of 24% between the two groups was also observed in terms of 4log reduction (MR4, BCR-ABL/ABL < 0,01%). Only 3.2% of Nilotinib 2x300mg patients progressed into advanced phases, compared to 6.7% on Imatinib. However, overall survival after 3 years is similar (95% vs. 94%), while for those that progressed on any therapy, median survival was only 10.5 months. In summary, the 3 years follow-up demonstrates that Nilotinib is superior to Imatinib for treating newly diagnosed CML patients, with faster and higher response rates across all risk groups, and a significantly lower risk of progression, and connected to that, lower risk of death.
To assess whether dose escalation of Nilotinib to 2x400mg, or a switch from Imatinib to Nilotinib 2x400mg, is an option for those that responded on ENESTnd suboptimally or failed therapy, Andreas Hochhaus presented the ENESTnd extension study. In that study, those patients enrolled in ENESTnd could receive 2x400mg Nilotinib while continuing to be monitored in a trial setting. Both efficacy and safety of Nilotinib 2x400mg were consistent with previous studies of Nilotinib in second line treatment, with minimal additional adverse events on the higher dose. The switch to 2x400mg was beneficial for a majority: 58% of patients received a complete cytogenetic response, 34% major molecular response. In a summary, dose optimization is safe and increases responses.
To assess whether switching to 2x400mg Nilotinib is beneficial for those achieving major molecular response but not PCR negativity on long-term Imatinib therapy, Tim Hughes presented the ENESTcmr study. In summary, those patients that switched from Imatinib to Nilotinib despite good molecular response on Imatinib still achieved faster and deeper molecular response, which might increase their eligibility for future TKI discontinuation studies.
Nilotinib and safety: Cardiac events and Diabetes
Some earlier worries about the safety profile of nilotinib did not persist. A sub study of the ENESTnd trial denied a potential cumulative effect of nilotinib exposure on cardiac safety already in 2010, being not significantly different to Imatinib.
This year, there was an additional poster investigating nilotinib in diabetic patients. The reason is that Nilotinib increases blood sugar levels in diabetic and non-diabetic patients, so there was a concern that high sugar levels may be a particular problem for diabetic patients that might compromise either CML therapy or management of diabetes. As a result of an analysis of the ENESTnd data presented by MD Anderson Cancer Center, Nilotinib continues to be a safe and active medication in CML patients with diabetes. None of the CML patients with diabetes had to reduce dosing of Nilotinib, and only one had to change from oral diabetes therapy to insuling. Close monitoring and adequate management of Diabetes allows diabetic CML patients to safely receive Nilotinib therapy (ASH-Poster 2764).
Update on Dasatinib
Unfortunately no 30 month update of the DASISION study comparing Dasatinib and Imatinib in first line was presented at ASH 2011 (while at EHA 2011, both 24 month data of Nilotinib and Dasatinib was presented, allowing a comparison of both new 2nd generation drugs).
At ASH2011, only some results of the 24 month DASISION trial was presented on a poster. According to the poster, Dasatinib continued to show faster and deeper molecular responses, with a higher proportion of patients achieving a BCR-ABL level below 10% on Dasatinib (84% vs 64%). This was associated with an increased likelihood of achieving MMR and CCyR by 12 and 24 months, lower progression rates and higher overall survival of patients receiving Dasatinib. One additional poster on the impact of dose reductions and interruptions on response rates concluded that CCyR and MMR rates with Dasatinib remained higher than with Imatinib, independent of dose reductions and interruptions, but rates remained highest when a daily dose of more than 80mg could be maintained (ASH-Poster 2768).
Update on Imatinib-Interferon combination therapy
Hyacinthe Johnson-Ansah presented on the French SPIRIT trial. In the French study, Imatinib 400mg/day, Imatinib 600mg/day, Imatinib+AraC and Imatinib+PegIFN(90µg dosis) was compared in a randomized study. After a first interim analysis after 12 months, it was demonstrated that the 90µg dosis was obviously set too high, with 54% of patients suffering from too low blood counts. In the second phase, the Peg-IFN dosis was lowered to 45µg. As an effect, the tolerability was largley improved, while duration of treatment with Interferon was increased, increasing response rates. In summary, the MMR rates at 12 months were 60% on the Imatinib-PegIFN45µg combination, and only 38% on Imatinib alone. A 4log reduction (MR4) was achieved by 28% of patients on the combination arm and only 10% on the Imatinib-only arm. The study clearly suggests that the Imatinib-PegIFN combination is clearly superior to Imatinib alone.
Update on STOP Studies
François-Xavier Mahon presented an update on the Imatinib discontinuation study “STIM”. The 100 patients enrolled in the study had to be PCR-negative for at least 24 months prior to stopping therapy. 61% of patients lost their molecular response, with 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20 and 22. 10 of the 61 patients did not return to PCR negativity, and 5 remained at a median BCR-ABL level of 0,19% because they did not resume therapy immediately after relapse. Prognostic factors to preduct recurrence were the Sokal score and the duration of therapy. Dr Mahon clearly stated that he would recommend discontinuation only within a clinical trial with close molecular monitoring. Taking into account the number of months without treatment in the study, Dr Mahon added that the savings within the STIM trial for the French healthcare system were estimated at 4 millions Euros.
Delphine Rea presented a study of discontinuation of Dasatinib or Nilotinib. The rationale of this study was to observe whether the second generation drugs, with their increased molecular response rates compared to Imatinib, would give greater chances for therapy discontinuation. As in the STIM study, patients had to be PCR-negative for at least 24 months. The endpoint of the study was however the maintenance of MMR (BCR-ABL/ABL < 0,1%), so patients could lose PCR-negativity but did not fail the goal of the study and resume with TKI therapy as long as their BCR-ABL was above 0,1% (on International Scale). Blood counts and PCR was done once each month after the stop of therapy. Of the 33 patients that took part in the study, 8 patients (27%) lost MMR within 6 months, with the relapses happening quickly (median 2 months after cessation). 25 patients (73%) are still off any therapy after a median follow-up of 11 months. No predictive factor for identifying patients with stable treatment-free MMR could be identified at this short period of time.
More STOP studies were presented on posters:
The Korean DISCONTI study replicated the French STIM study design, assessing 20 patients that had been at least at MR4.5 (BCR-ABL/ABL < 0,0032%) for 24 months before stopping Imatinib - however the median CMR duration before cessation was much longer (Korean DISCONTI: 60 months, French STIM: 35 months) and the follow-up period of this report much shorter (median 10 months). Of the 20 patients enrolled, only 3 relapsed. However it needs to be noted that the period of observations was quite short. (ASH-Abstract 3765)
A Japanese study group also replicated the STIM Study. Of 30 patients that were in complete molecular response on Imatinib for a median of 55 months, 14 relapsed within 6 months and restarted therapy. All these patients responded to therapy (Imatinib or Dasatinib) again. Median observation time by the time of the poster report was only 8 months (ASH-Abstract 3759).
Prognostic importance of early response to TKI therapy
Long-term safety of Imatinib has been observed in a whole decade, while 2nd generation drugs like Dasatinib and Nilotinib are clearly superior in terms of higher response rates and lower progression rates. The question whether the 2nd generation drugs should be applied as first line therapy, or whether early switch from Imatinib to other therapies in case of slow response remains still unanswered.
Two studies presented at ASH 2011 assessed whether the response level at 3 months after start of Imatinib/Dasatinib is a reliable predictor for the long-term survival, and whether patients should change treatment already when not meeting the 10% milestone after 3 months of therapy.
According to findings of the German CML-IV study presented by Benjamin Hanfstein, the achievement of 10% BCR-ABL/ABL after 3 months of imatinib treatment is clearly predictive for long term survival. Having a BCR-ABL level of more than 10% at 3 months is associated with a 5-year overall survival of 87%, while a BCR-ABL level below 1% shows an overall survival of 97%. No significant difference was observed between the < 1% and 1-10% BCR-ABL groups. In conclusion, missing the 10% BCR-ABL landmark at 3 months predicts inferior long-term outcome, and suggests an early change of therapies to those slow responders (ASH-Abstract 783).
Steve O’Brien (UK) presented data of the Dasatinib arm of the SPIRIT2 study. The study observed that a PCR at 3 months can identify those patients that are more likely to obtain complete cytogenetic response, major molecular response or complete molecular response. 10% BCR-ABL/ABL is seen as a useful threshold at 3 months for Dasatinib as well (ASH-Abstract 785).
Similar findings have also been demonstrated by the Australian TIDEL-II study, which investigated Imatinib first-line followed by switchover to high-dose Imatinib or Nilotinib in case treatment milestones are not met, e.g. 10% BCR-ABL at 3 months. Progression rates on this regimen were close to transformation rates of the ENESTnd and DASISION first-line studies, and molecular response in the 3rd month was also clearly prognostic for long-term outcome.
About 25% of patients treated first-line with Imatinib and 8,5% of patients on first-line Dasatinib fail the 10% BCR-ABL/ABL target at 3 months. Following the above findings, experts suggest that assessing the response level at 3 months after start of therapy, and switching therapies on failure of achieving 10% BCR-ABL/ABL may be important. It might be calmative for patients who are in the 1-10% area by 3 months that there seems to be no major prognostic survival advantage of having a faster response than being at 10% at that time.
News on Bosutinib
Jorge Cortes presented the 24 month follow-up data of the BELA trial with Bosutinib. Bosutinib is a second generation TKI that is highly selective on BCR, being active against dasatinib-resistant mutations (F317L) and nilotinib-resistant mutations (Y253H, E255K/V, F359C/V), but not against T315I and V299L. By 24 months, 63% of all Bosutinib patients are still on treatment. 37% had to discontinue therapy, with 24% due to adverse event. Main adverse events were diarrhea (70% of patients), vomiting (32%), nausea 32%, rash 24%, pyrexia 18%, abdominal pain (14%), increased ALT (23%). The gastrointestinal events and liver toxicities were manageable and disappeared soon after start of therapy. While rates of achieving complete cytogenetic responses were not different between Bosutinib and Imatinib, MMR rates were significantly superior (67% vs. 52%), less transformations into advanced phases, fewer treatment failures, fewer CML-related deaths were observed. Treatment failure was significantly lower on Bosutinib (4%, vs. 13% on Imatinib).
In summary, Bosutinib may offer a new therapeutic option for patients with newly diagnosed CML, and was submitted for marketing approval in Europe (1st line treatment) and USA (2nd line). Whether it can obtain regulatory approval remains to be seen - the opinions of the doctors we spoke to varied largely, given that the drug did not show superiority to imatinib in its primary endpoint complete cytogenetic response (CCyR) - however MMR data is convincing. From a patients’ perspective, it seems to be an option not only in case of resistance, but maybe also in terms of intolerance against the existing drugs and potential low-level toxicity in long-term TKI therapy.
Ponatinib (AP24534) is a oral pan-BCR ABL TKI with potent activity against native and mutated BCR-ABL and other kinases. Its molecule was rationally designed to get around the molecular changes made to BCR-ABL by the T315I mutation.
The PACE phase II trial (PACE = Ponatinib Ph+ ALL and CML Evaluation) aims to investigate the efficacy of ponatinib in patients with CML or Ph+ALL who are resistant or intolerant to dasatinib or nilotinib, with or without the T315I mutation. The trial is fully enrolled with 449 patients. At ASH, efficacy data was reported on 392 patients in six cohorts at 45 mg/day. Patients were assigned to a cohort based on their phase of disease (chronic-phase, accelerated-phase or blast-phase CML/Ph+ALL) and T315I mutation status (with or without the mutation). 94% of the patients in the trial had received at least two tyrosine kinase inhibitors prior to enrollment, 59% had received three or more. Across all evaluable chronic-phase patients in the trial, 39% achieved a complete cytogenetic response. Of the 57 chronic-phase CML patients with T315I, 58% achieved a CCyR and 33% a MMR. Ponatinib seems to be well tolerated. The most common adverse events considered related to ponatinib included rash (in 38% of patients), thrombocytopenia (37%), dry skin (29%), abdominal pain (22%), headache (20%), fatigue (17%), myalgia (15%), arthralgia (16%), elevated lipase (16%), constipation (15%) and nausea (10%). These effects were mostly grade 1 or 2 and were well tolerated by patients in the trial. The incidence of pancreatitis was 6%, but no patient discontinued due to that side effect. Four patients on study died, having complex medical conditions, including pneumonia, fungal pneumonia, gastric hemorrhage and cardiac arrest. There was no evidence of any ponatinib-specific findings emerging.
In summary, Ponatinib has substantial anti-leukemic activity in this heavily pretreated population, with a favourable side effect profile. Responses were observed in all cohorts and were improving over time. Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory/relapsed CML, not only patients with T315I.
Jorge Cortes presented the data of the DCC-2036 study, a novel switch-control kinase inhibitor that inhibits BCR-ABL mutants including T315I. inhibits SFK and FLT3, but spares c-KIT. The data presented is from a phase 1 (dose escalation) study in patients with T315I or failure/intolerance to at least 2 TKIs. 30 patients were enrolled in the study, 3 continue to receive DCC-2036 today. 27 of 30 discontinued due to progression (9 patients), lack of response (8), adverse events (6), death (1), lost to follow-up (1), withdrawal of consent (2). In summary, the drug is well tolerated at 2x 150mg/day. Additional 15 patents will be enrolled.
Fatigue in TKI therapy
One poster addressed the issue that many patients experience fatigue when treated with Tyrosine Kinase Inhibitors, compromising quality of life and requiring drug reductions or interruptions. A study of patients at the MD Anderson Cancer Center concluded that while Fatigue is a common symptom in TKI treatment in CML, neither disease status nor the drug correlated with the extent of fatigue. Fatigue was however closely linked with severity of other symptoms. Marital and working status were the only socio-demographic variables correlating with fatigue levels. Further investigations of potential interventions on fatigue are needed (ASH-Poster 3785).
See also other articles about ASH 2011:
- CML Advocates Network: ASH 2011: Summary of Education Session on CML
- Files: Key presentations & posters presented at ASH 2011 (for CML Advocates Network members only)
- iCMLf Forum 2011 at ASH: Physicians spotlight challenges of managing CML in emerging countries
- Biotech Strategy Blog: CML update from 2011 ASH annual meeting (by Biotech Strategy Blog),
- American Society of Hematology: ASH Abstracts 2011
Giora Sharf (photos), Jan Geissler (report)
CML Advocates Network
San Diego, 13 Dec 2011