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CML Highlights: ASH 2016
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Exciting and new developments in CML are highlighted in key abstracts in major categories including treatment discontinuation, extended use of TKIs, and the treatment of young adults. These abstracts were presented at the ASH meeting in San Diego in December, 2016.

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Hello, my name is Naveen Pemmaraju.  I'm an Assistant Professor of Leukemia at the MD Anderson Cancer Center in Houston, Texas. I had the opportunity to attend and participate in the ASH meeting.  
Today, I would like to update all of you on the exciting and new developments in the world of Chronic Myeloid Leukemia, or CML. To do this, I would like to highlight several key abstracts in major categories, including treatment discontinuation, extended use of tyrosine kinase inhibitors, and the treatment of adolescents and young adults.

The first abstract by Dr. Clark and Dr. Copland and colleagues from Great Britain, dealt with CML patients with stable molecular responses who may safely decrease the dose of their tyrosine kinase inhibitor (TKI). This data was presented from what's called the British DESTINY Study, and is really based on the principle that was started by multiple European groups, but actually adds a key element, a de-escalation phase of the TKI which then led to actually stopping it.

So, in this study, patients with CML were de-escalated when they were already on a stable dose of their tyrosine kinase inhibitor after approximately one year and then went to actually stopping it. Over the period of two years, 174 patients were recruited in this multi-center study all throughout Great Britain. Most of these patients were on a imatinib, with 16 and 10 patients respectively on second generation inhibitors nilotinib and dasatinib.  
The key finding from this abstract was that in CML patients with stable molecular response, termed MR3 or better, that decreasing the TKI treatment to half of the standard dose that they started on, appeared to be safe in quite a few of the patients. This was also associated with an improvement in the TKI-related side effects, and it meant that there are a subset of patients with stable responses who may be able to benefit from treatment de-escalation and ultimately stopping treatment overall. The conclusion is that more studies such of this with de-escalation ultimately stopping are wanted to further validate these findings.

The second abstract I'd like to highlight was by Dr. François-Xavier Mahon and colleagues. This abstract was entitled "Cessation of Tyrosine Kinase Inhibitors:  Treatment in CML Patients with Deep Molecular Response: Results of the EURO-SKI Trial."  Some patients with CML who have been doing well on a stable dose of their tyrosine kinase inhibitor and have achieved what's called a DMR, a deep molecular response, some subset of these patients may be able to stop treatment after some point.  A quite large number of patients, 821 patients with chronic phase CML, were recruited to this study over just two years all throughout Europe, 11 European counties.

Notably, the key finding, is that molecular relapse re-survival at six months was 65.5% for those treated on a imatinib greater than five to six years, and 42.6% for treatment in those patients less than 5.8 years. One of the more interesting findings of the study was that the group included a pharmacoeconomic analysis. They estimated that the total savings could amount to over 27 million euro for those patients who are able to stop imatinib therapy earlier than others, meaning cost savings to the healthcare system. Finally, in this study, longer duration of imatinib therapy, in this study the statistical cutoff was greater than 5.8 years prior to the stopping of the TKI, was associated with a higher probability of this molecular recurrence free survival, or MRFS.

This takes us to the next study conducted by Dr. Andreas Hochhaus and colleagues. This abstract focused more on quality of life, that is patient reported quality of life, or QOL, after stopping treatment on a TKI and following patients with a prospective validated survey approach. This study was conducted in the ENESTfreedom study which is an ongoing Phase II trial, evaluating the potential for patients to stop therapy with their TKI, which in this case was nilotinib.

Just for background, the initial results from the ENESTfreedom according to the abstract, showed that 51.6% of patients who attempted this TFR, treatment-free remission, remained off treatment without the loss of major molecular response, or MMR, at 48 weeks. I thought there were two important points to highlight from this. First, the existence of validated tools in CML as well as other chronic diseases. For CML, the MD Anderson Symptom Inventory, or MDASI, was used along with another study called the EQ-5D-5L questionnaire. The second point is the results were quite compelling. Among 215 patients enrolled, investigators found that 190 patients remained sustained DMR, or deep molecular response, during the consolidation phase, and they entered into this treatment-free phase.

In conclusion, they stated that minimal changes in patient reported outcomes were observed after stopping treatment, and that this may be related to patients having either a relatively high quality of life before they stopped the treatment in the first place, given that they were already stable for two years or more on nilotinib.  It also suggests that there was a signal for higher frequency of musculoskeletal pain related adverse events even when patients entered in the treatment-free phase, although this did not substantially affect or impact patient’s overall quality of life. 

Now we turn our attention to another abstract that was important at this year's ASH, and this was conducted by Dr. Fiorina Giona, our colleagues from Italy. In this abstract entitled, "Management of CML in Children and Adolescents According to Local Guidelines: The Italian Experience," the investigators put forward a very thoughtful look at patients, especially focusing on outcomes in adolescents and young adults with CML. This abstract is important as it highlights that before the year 2000, allogeneic stem cell transplant was actually the only potential treatment for children and young adults with CML in the chronic phase, but since that time there's been a revolution in the treatment of CML, including the inclusion of second generation tyrosine kinase inhibitors and other treatment options.

So, in this study, 57 patients with CML with a very young age compared to most of our series , a median age of only 11.4 years were included, and they were followed between 2001 and 2015, so quite a long follow-up time. These patients were managed and treated at a number of different centers, and all but one patient, 50 out of the 51 patients, achieved a cytogenetic or molecular remission, and 7 of the 50 responders, or 14%, actually underwent a stem cell transplant from an HLA-related or matched unrelated donor. This was all before 2009. Importantly, 11 patients were rescued with second generation TKI, those are patens who were losing or had lost a response to the imatinib. Five patients restarted continuous imatinib and two patients underwent a transplant from a match unrelated donor. Of importance, all 57 patients analyzed were alive at a median follow-up of 72 months, with a range anywhere to 12 to 184 months.
Next, we turn our attention to a very compelling abstract by Dr. Rea and colleagues, which is entitled, "The ENESTPath: A Phase 3 Study to Assess the Effect of Nilotinib Treatment Duration on Treatment-Free Remission in Patients with CML." This study is one of the larger studies in the field of CML as it involved a Phase 3 randomized study, and it focuses on a second generation TKI called nilotinib and patients who are able to stop therapy. Patients with CML chronic phase who have achieved a chronic cytogenetic response but not yet achieved the fullest, deep molecular response (MR4), after two years or more on imatinib, are included in the study. Those patients are then going to two cohorts.
One is that they go into the treatment-free phase immediately, so they go off of therapy, or in a second cohort, they continue nilotinib for another year and then go into the treatment discontinuation. Importantly, these patients at that point are in a stable molecular remission. A very large number of patients have been enrolled in this study, 619 in total, of which 300 patients are now available for this first interim analysis. There are two key findings. One, in this first 300 patients after two years of nilotinib therapy, there is a cumulative incidence of MR4 or deep molecular remission, in approximately 70% of patients who were not in MR4 at baseline. The second important finding, is the majority of the adverse events were low-grade, and the most common adverse events, notwithstanding relationship of the study drug, were manageable side effects, including itching, hypercholesterolemia, rash, asthenia, and arthralgia.

Finally, we turn our attention to one last abstract presented by Dr. David Yeung and colleagues from Australia. In this abstract entitled, "Upfront Imatinib with Selective Early Switching to Nilotinib Leads to Excellent Achievement of Deep Molecular Response in CML." This five-year analysis was conducted of the TIDEL-II study. The background of this study was that patients were treated with upfront imatinib with selective early switching strategy to the second generation TKI, nilotinib. They were already known to have an excellent deep molecular response for this cohort.

There's two important and interesting key elements to this abstract. This is one of the few approaches that you will see that has a higher starting dose of imatinib than the traditional 400 mg in most studies. So, in this study, patients actually began at a dose of imatinib 600 mg. One arm was that the imatinib, if there was not an optimal response, was increased to 800 mg of imatinib, and then patients were switched to nilotinib, or in the second arm, patients were switched to nilotinib directly in the setting of sub-optimal response.

So, the study overall enrolled 210 patients and the investigators found that 181 patients achieving MMR in the study, 24% or 44 did so after switching to nilotinib. The combination of imatinib and nilotinib appeared to compare favorably with other up-front treatment strategy with MR4.5 of 59% by 60 months. 

I'd like to conclude by telling everyone out there thank you very much. These are the highlights that I saw from ASH with regards to our patients and research in the field of Chronic Myeloid Leukemia. I look forward to 2017 for more breakthroughs for our patients. Thank you very much.