CML Education Session at ASH 2017: Stopping treatment, cardiovascular toxicities of CML drugs, and eradicating leukemia stem cells

ASH2017EDU mahonpanelAbout 30.000 people are meeting in Atlanta (and due to snowfall that happens usually once every five years, it currently feels more like Alaska) to discuss latest science in blood diseases. The Education Sessions are a core element of the conference programme, providing a broad overview on key topics in specific diseases. In the CML education session 2017, stopping CML treatment, cardiovascular issues of current TKI treatment, and eradicating CML stem cells were chosen as the “hot topics” this year.

Francois Mahon, the French CML expert that started the first trials investigating to stop CML treatment in deep molecular response, gave a broad summary of recent studies on stopping treatment in deep molecular response.  Key drivers to stop treatment includes family planning and pregnancy, avoiding inhibition of body growth of children on TKI treatment, patient preferences e.g. on quality of life, as well as financial reasons (= significant drug costs of a life-long therapy). Francois Mahon introduced the session by describing the results of the first stop study, STIM, which now has 8 years of follow-up data. Overall, more than 2500 CML patients have stopped treatment in clinical trials so far. He then summarized a meta-analysis of 509 patients in 15 stop studies that was published in the journal EJC recently, which revealed that the mean molecular relapse rate of CML was 51% - so about half of the patients could safely stop treatment, while the other half needed to reinitiated treatment. Four out of five patients relapsed within the first 6 months, so in most patients, recurrence of the CML happens quickly after stopping – but not in all, which underlines the need for strict monitoring. Only one patient in those 15 studies had progressed to blast crisis.

2nd generation TKI stop studies like ENESTop and ENESTfreedom (Nilotinib) and DASFREE (Dasatinib) had shown similar rates of recurrence of CML like Imatinib, even though the proportion of patients who achieved deep molecular response was higher in those taking 2nd generation drugs. The duration of deep molecular response before stopping seemed to have the most impact on success of stopping.  Interestingly, the largest stop study, EURO-SKI with about 800 patients enrolled, has shown also late relapses after 30 months, so there is no “plateau” which means – continuous PCR monitoring even years after stopping is required. A peculiar TKI withdrawal syndrome (muscoskeletal pain, joint pain and arthralgia) in patients is being observed frequently, but mostly lasts for a short period of time.

Official guidance to physicians on when to stop is yet lacking. Treatment guidelines have not yet provided recommendations regarding stopping treatment, except the US-NCCN Guideline, but standardisation of PCR monitoring is lacking in the USA. The ELN guidelines are currently being updated and will include recommendations on the institutional requirements to allow safe stopping of therapy, but they are still to be published. ASH2017EDU mahonrecommendationsDr. Mahon presented his personal guidance on stopping treatments in good responder patients outside of clinical trials.

Dr Mahon concluded that TKI discontinuation is increasingly attempted in select CML patients who are in deep molecular response. Discontinuation is already occurring outside of clinical trials. Multiple studies conducted with more than 2500 CML patients with sustained deep molecular response have shown that about half of the patients remain in remission for years upon TKI discontinuation. Patients who need retreatment seemed to regain their response promptly.

Dr. Javid Moslehi discussed the side effects of current TKI treatments, focusing on cardiovascular toxicity. He reviewed what is currently known about the impact of TKIs on the cardiovascular system and discussed potential mechanisms underlying the cardiovascular adverse events. He outlined that Nilotinib had shown better and faster molecular responses than Imatinib, but could not demonstrate an improvement of overall survival. Dasatinib, with similar efficacy, had shown increased pulmonary hypertension, while Nilotinib had shown an increase in cardiovascular events and increased glucose levels. The mechanisms why this happens are not yet fully understood. He also explained the what happened with Ponatinib in 2013 where cardiovascular toxicities of Ponatinib led the FDA to restrict the label of the drug, but its mechanisms of cardiovascular toxicity are not yet clear as well. Dr Moslehi suggested that just as precision medicine has revolutionized cancer treatment, a similar personalized approach should be incorporated in toxicity assessment.

Looking at the NCCN Guidelines, he noted that very little is being said about cardiovascular management of CML patients, and provided provisional recommendations. Dr. Moslehi underlined a stronger cooperation between hematologists and cardiologists. He mentioned the platform, which will provide a drug database on cancer drugs and their risk of cardiovascular toxicity.ASH2017EDU cardiotoxrecomm

In summary, Dr Moslehi outlined that CML as a chronic disease demonstrates all the pros and cons of long-term chronic treatment. Due to the relatively high incidence of cardiovascular events in CML TKI treatment, he recommends that cardiovascular care considerations should be incorporated into care of CML patients and in CML clinical trials.

Dr. Ravi Bhatia presented on novel approaches to CML therapy with a focus on eradicating persistent leukemic stem cells. The need for novel approaches to CML therapies arises from limitations of current TKI therapies (intolerance, resistance, relapse and progression as well as persistence of leukemia stem cells). In terms of resistance, primary resistance (at the time of diagnosis) is quite uncommon in CML, and may be connected to how the drugs are metabolized and transported in the body. Acquired resistance (developed during the course of therapy) may appear when mutations of the “binding site” of TKI (kinase domain mutations) happen, as well as when kinase-independent pathways emerge, e.g. alternative signalling pathways which may have commonalities with persistent stem cells.

The rationale to target residual leukemic stem cells with novel drugs is to enhanceASK2017EDU Resistance the future possibility of treatment discontinuation, and to avoid long-term treatment, reducing the risk of non-compliance and long-term side effects as well as teratogenicity (e.g. in case of pregnancies) as well as the financial burden to patients and their families.

Persistent leukemic stem cells usually represent a minority at diagnosis, but become a predominant population during treatment. They have a distinct biological profile which may be addressed by novel therapies which are currently investigated in lab studies and clinical trials. For example, the combination of Nilotinib and the JAK2-inhibitor Ruxolitinib is currently being tested. A phase II trial adds Ruxolitinib to TKI treatment after a failure to stop TKI treatment. Pioglitazone (known as a diabetes drug) is also tested in combination with Imatinib in patients with a response level between MMR and MR4 the ACTIM study in France as well as in the PIO2STOP study. The CHOICES study combines Imatinib with Hydroxychloroquine to eliminate step cells.

Dr Bhatia shared some “lessons learned” for future studies that may have the goal of eradicating residual CML stem cells: Recruiting patients for these studies is hard, so thinking about the reasons why patients would join the studies needs to be well considered. Study-related visits and procedures are a disincentive for patients to join these trials, given the high comfort level of CML treatment today. Additional agents must be well tolerated. It may be best to plan these studies in connection to the goal of TKI discontinuation, or in the setting when TKI discontinuation has failed, to motivate patients to go into those studies. A randomisation to a TKI-alone arm would be preferable.


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