This year's "CML Education Session" at the American Society of Hematology (ASH) Annual Meeting was entitled "Refining/Redefining the State of the Art in treating Chronic Myeloid Leukemia". ASH education sessions usually give a broad overview on recent advances in understanding of a disease, how this translates into clinical efforts to prevent disease progression and drug resistance, as well as research strategies towards long-term disease control and cure. While earlier years focused on therapies that increased survival, this education session demonstrated that the focus in CML is slowly shifting to an era where survival is close to that of the general population. Today's efforts focus on treatment-free remission and quality of life. Cure for all would of course be the next big thing, but even though much is being tested in that space, cure is still far away on the horizon for most patients.
Which TKI? An Embarrassment of Riches (Dr Tim Hughes)
- Having a normal life span (by avoiding progression of CML and therapy-induced organ damage),
- Allowing normal quality of life (by minimizing toxicity of drugs)
- Achieving treatment-free remission (through sustained deep molecular response and immune-mediated disease suppression).
On the first goal, Dr. Hughes was addressing the efficacy and safety of the multiple frontline therapy options available to patients in many countries today. In comparison to Imatinib, all three approved second-generation drugs Nilotinib, Dasatinib and Bosutinib had demonstrated faster responses, deeper responses and a significantly lower risk of disease progression. At the same time, Imatinib had demonstrated the safest toxicity profile. 30% of Nilotinib patients had experienced vascular events, even though most patients affected had prior risk factors. On Dasatinib, an increasing number of patients had experienced pleural effusion, with occurrence increasing over time (7% of patients in year 1, and an additional 5% in each of the following years 2-4) and being clearly associated with age. On Imatinib, about 40% of patients achieve deep molecular response, while these rates were estimated at 60-80% for Nilotinib and Dasatinib. Deep molecular response is the prerequisite for stopping therapies safely, which was successful in about 40% of patients.
As a recommendation for newly diagnosed patients, Dr. Hughes outlined a customized approach: at time of diagnosis, patients should be assessed according to the presence of one or more additional diseases, the individual CML risk profile (low, medium and high), and their individual priority of achieving treatment-free remission (low, medium and high). While patients either with a high biology risk or a high priority to stop treatment in deep remission should start with second generation TKI, while all others might consider to start with Imatinib and potentially following second generation drug in case of suboptimal response. The choice of medication and monitoring should also take other diseases e.g. like vascular or pleural into account.
In terms of best TKI choice after failure of other 2nd generation TKI, mutation screening was seen as critical. Some patients would still respond to another 2nd generation drug. Ponatinib was also seen as highly efficacious but connected to high risk of vascular events for high-risk patients where aggressive management of hypertension of lipid elevation, and the use of the lowest possible dose, was advised.
Update on Current Monitoring Recommendations: Practical Points for Clinical Practice (Dr. Vivian Oehler)
Dr. Vivian Oehler from the Fred Hutchinson Cancer Research Center in Seattle, USA, reviewed appropriate cytogenetic and molecular monitoring procedures that are indicated during the first few years of therapy, when the main focus is prevention of disease progression and drug resistance. According to the current recommendations by the European Leukemia Net and the NCCN, treatment milestones are no different between 1st and 2nd generation TKIs, but early molecular response below 10% BCR-ABL would provide an advantage of 10-15% better rates of progression-free survival, while a worse early response might be a sign of a more difficult underlying nature of the individual disease - or a lack of adherence to therapy. Once MMR is achieved by 12 or 18 months, the likelihood of losing response thereafter is very low. Achieving deep molecular response only provides substantial added value if the goal of treatment was to stop treatment later. However stopping the drug should be done on trials only.
Considering when to check for mutations, Dr Oehler advised to do so if BCR-ABL was still above 10% at 3 months, if no complete cytogenetic response or MMR would be achieved at 12/18 months, if a loss of a MMR or a one-log increase in BCR-ABL levels was observed, in case hematologic or cytogenetic response was lost, or before TKIs were switched.
When the next line therapy would have to be chosen, mutation tests might help identify the recommended treatment, as some mutations are resistant only against one of Nilotinib, Dasatinib or Bosutinib, while in case of T315I Ponatinib would be the only TKI option. However, Dr. Oehler again outlined that early performance stem cell transplant should be regarded as a viable option before moving to third line TKI treatment: According to the Fred Hutchison Cancer Center's data from more than 800 transplants from 1995 to present, the 13-year survival rate of patients transplanted in chronic phase was around 70%, of those transplanted while in TKI-induced remission after blast crisis about 35%, and those transplanted in blast crisis about 20%.
Dr. Oehler also explained the rationale for long-term molecular monitoring, driven by the need to detect poor drug adherence as well as to confirm the achievement of a deep molecular response. (Of note, the CML Advocates Network's adherence study was quoted in her presentation when adherence was discussed!).
Alternative Approaches to Eradicating the Malignant Clone: Tyrosine-Kinase Inhibitor Combinations and Beyond (Dr. Richard Van Etten)
In his presentation, he outlined that according to the current stop studies, TKI monotherapy is not curative for the majority of CML patients. Therefore the main questions towards a cure in this area are still whether CML stem cells are the cause of relapse, and if so, how they could be targeted, and such a biological finding could be translated into clinical practice in patients.
Dr. Van Etten then explained the critical pathways driving leukemic stem cell survival in CML and discuss the most promising approaches to leukemia eradication. More specifically, he outlined the nine different biological mechanism that are currently under investigation in 26 clinical trials (on clinicaltrials.gov) to eliminate CML stem cells: JAK2 inhibitors (like Ruxolitinib), mTOR inhibitors, COX inhibitors, GSK-3beta inhibitors, MNK inhibitors, Hedgehog pathway / SMO antagonists, 5-LO inhibitors, HSP90 inhibitors, Arsenic targets / PML degradation, Authophagy inhibitors (Chloriquine), Pan-HDAC inhibitors (like LBH589), SIRT1 inhibitors, Pan-BCL2 inhibitors and protein synthesis inhibitors. A number of those are currently in early Phase I/II studies. Furthermore, Interferon alpha (e.g. German TIGER study), four different vaccines (e.g. CML0206), one monoclonal antibody and other cell surface antigens are being investigated. Waking up sleeping stem cells with Imatinib plus G-CSF has also been tested for more than 5 years.
In summary, Dr. Van Etten said that while there are plenty of candidate drugs in hand, it would not be easy to prove the difference - also because large numbers of different cohorts of patients on similar TKIs would be required for quite a long observation time. Recruiting patients into these clinical trials might prove to be difficult, given also the high effectiveness and tolerability of current TKI treatment, so any intervention or combination needed to be safe and equally well tolerated in order to be acceptable by patients.
Giora Sharf & Jan Geissler, 17.12.2013
More reports from ASH will follow