Stopping CML therapies and eradicating CML: Patient perspective from EHA
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Recent CML therapies have turned CML into a chronic disease for most patients. However, even if most patients are responding well, some of them suffer from side effects, from being reminded day by day that they have cancer, or struggle to be fully adherent to a life-long medication. In addition, due to the excellent survival rates of CML patients on current therapies, the economical burden of CML rises. From these perspectives, being able to stop therapies at some point in time has become a desirable goal. Two potential pathways towards achieving that goal were discussed at EHA2011: "Operational cure" by stopping TKI therapy in case of stable complete molecular response, and new approaches to eradicate residual cancerous stem cells.
Update on stopping therapies: Difference for 2nd generation TKIs?
Much has been said about stopping TKI therapy since the French STIM (STop IMatinib) study was published in autumn 2010. To be able to participate in that study, patients needed to be in complete molecular remission (PCR below 0.01%) for a minimum of 2 years. The study demonstrated that about two thirds of patients relapse quickly, mostly within the first 6 months after stopping therapy - but could then safely return and respond to treatment. The other third of patients had remained in molecular remission without receiving any further treatment. However, under Imatinib, the number of "operationally cured" CML patients remains considerably small, because only about 10%-15% of patients under Imatinib ever achieve a complete molecular response, and of those, about two thirds relapse when stopping Imatinib.
Because recent Dasatinib and Nilotinib trials have shown to achieve higher rates of major and complete molecular remissions, CML experts started to consider whether the new drugs could increase the proportion of "operational cures" - of patients that achieve very low residual disease and maintain that remission when stopping therapy. To investigate that further, a French research group around Dr. Delphina Rea started a study of patients that had been under treatment of Imatinib, Dasatinib or Nilotinib for at least 36 months, and were under 2nd generation TKI treatment with undetectable BCR-ABL for at least 24 months. After joining the study, 19 patients stopped all CML treatments, and were then monitored with a monthly PCR in the first 12 months. Cytogenetics (bone marrow) and mutational analysis was conducted in case of a 10 fold increase of bcr-abl. The goal of the study was to assess the stability of at least major molecular response (PCR <0,1%) at 6, 12, 18 and 24 months after cessation of therapy.
At EHA 2011, Dr. Rea now presented the 6 months follow up data, however with a very small sample size: 14 patients were analyzed by the time of the report. 13 of these patients switched to Dasatinib or Nilotinib because of intolerance to Imatinib, and 1 because of resistance. 9 were on Dasatinib, 5 on Nilotinib. Of these 14 patients, 4 lost major molecular response after a median time of 3 months, and 5 restarted TKI therapy and regained undetectable bcr-abl. 9 remained free of treatment until today (for 6-19 months), with bcr-abl either undetectable or detectable at very low levels. In summary, Dr. Rea said that, based on what can be said in such a small sample size, 2nd generation TKI treatment after unsatisfactory Imatinib treatment may potentially be discontinued in patients with stable undetectable residual disease. At least this small group of patients did not jeopardize their outcome, as relapsed patients returned to remission after restarting therapy.
The steps to cure CML: Eradicating CML Stem Cells
Beyond addressing these "operational cures", the eradication of residual CML stem cells which are not eradicated by any of the current drugs has been widely discussed by basic researchers for many years. At EHA 2011, Dr. Holyoake presented an update on current stem cell research in CML. In 1999, her lab identified persistent CML stem cells, and since then, researchers were trying to find out why a small number of CML stem cells are able to survive despite effective inhibition of bcr-abl through TKIs. Earlier studies had shown that these CML stem cells were locked in sleeping mode (quiescence), and as the mechanisms of current TKIs rely on cell division, these cells were resistant to imatinib.
To assess this further, the team isolated persistent CML stem cells that did not carry any TKI-resistant mutation. They were cultivated for 12 days in the lab with exposition to extremely high Dasatinib doses that would not achievable in the human body. The team observed that these cells were able to survive in "growth arrest" even in such an environment. As a conclusion, survival of these stem cells seems to be independent of known CML resistance mechanisms and of bcr-abl kinase activity. There must be other survival mechanisms which are not fully understood so far.
In her presentation, Dr. Holyoake outlined the researcher's increasing understanding about the difference of normal stem cells and CML stem cells. This understanding is needed to identidy potential strategies to exploit these differences. Quite some research effort is currently being invested to identify and manipulate pathways in order to force these "sleeping" CML stem cells into cell division, so that they can then be targeted and killed by current TKIs. Dr. Holyoake highlighted e.g. the FOXO transcription factor that plays a major role in cell cycle arrest and cell death. Interferon-Alpha has shown to have anti-quiescent and apoptotic effects on CML as well. Further pathways currently being investigated are e.g. Wnt, CXCR4, JAK2, Hedgehog, Histone, PP2A, SMO or Autophagy. Some of them are already assessed in early CML trials in combination with Imatinib, and some are still in lab research. Examples of compounds under investigation are Hydroxychloroquine (CHOICES Trial), SMO inhibitor BMS-833923, Zileuton (asthma drug 5-lipoxygenase, targeting PP2A) or HDAC inhibitors (e.g. LBH589 or LA0824).
Discussion
There are a number of exciting approaches that may help us towards ultimate goal of curing CML.
"Stopping therapy" might be viable approach for those that reach a very low level of residual disease. Researchers are trying to identify factors that might tell us which patients are less likely to relapse when stopping their therapies. Given that more and more CML patients are getting Dasatinob or Nilotinib right after diagnosis, and given they induce higher rates of deep molecular responses, the group eligible for stopping all therapies might grow in the near future.
However, stopping CML therapy should not be done outside of a trial, given that relapses were seen to occur quickly and forcefully. Another publication at this year's EHA has indicated that time passed from the point of relapse to restarting effective therapy has a considerable influence on later response. Monthly PCR in a good lab as well as observation by a CML expert seems to be essential when stopping therapies. New European studies that will assess stopping therapies, e.g. the German CML-5 study and the pan-European EuroSKI study, are currently being prepared in the CML study groups.
Eradicating residual stem cells however seems to be most important in a path to cure, as it would complement TKI therapy with "laying the axe of the roots of CML". Research is actively working on turning CML from a chronic into a past disease. However, much of this is still far away from clinical application in patients today. In practice, many approaches might sound great in theory but prove dysfunctional or intolerable when tried in the human body. For today's patients, it creates strong hopes, but not yet options.
In that sense, as Dr. Rosti said at the recent "New Horizons in CML" meeting, the best way to stop CML therapies at some point in time in the future is to strictly adhere to effective CML treatments today. Current studies across therapies agree that once patients have achieved minimum residual disease, they are very unlikely to lose response when therapy is continued in a strict manner. Time is working for these patients, and probably in some years, patients will get the clinical options to finally wipe the CML from their bodies.
