In mid-year 2014, Teresa Altemeyer and Paul Zamecnik didn’t know each other, but were independently evaluating whether or not to begin treatment for their CLL in a clinical trial at Ohio State University under Dr. John Byrd.
The molecule being investigated was named ACP-196 (renamed Acalabrutinib in late 2015). In this article we share the paths and decisions that took each of us to this particularly remarkable trial that is considered a potentially ground breaking therapy for CLL. We have now both been on Acalabrutinib for 18 months. We were willing to take the risk of participating in a clinical trial and are both reaping the benefits. We both live today with virtually no side effects of consequence and blood counts and nodes within normal or near normal ranges. The relapsed and refractory populations who are participating in this trial have unprecedented 95% response rates.
(We refer you to Brian Koffman’s interview with Dr. Byrd regarding Acalabrutinib in the Volume 1, Issue 2 CLL Tribune. The interview was conducted after Dr. Byrd’s presentation of the amazing trial results of Acalabrutinib to the American Society of Hematologists (ASH) on December 7, 2015.)
Teresa shares, “In my search for information to help make my clinical trial decision, I emailed Brian Koffman and Wayne Wells (a frequent contributor to ACOR as well as the CLL Tribune) asking their thoughts regarding this trial and general aspects of clinical trials. Among the excellent advice I received was a comment from Wayne. He encouraged me to “seek out other CLLers, be they in a waiting room, in a support group or through any other means, as their thoughts and perspectives will prove valuable in a CLL journey”. So shortly thereafter, when I saw a query on ACOR from Paul Zamecnik of Richmond, Virginia asking if anyone knew anything about the ACP-196 trial in which he was planning to participate, I sent him an introductory email. Thus began an eighteen month long friendship as two “co-adventurers” in a clinical trial. What we want to share in this article is: How do two people with two different perspectives from two different parts of the United States make potentially life-changing decisions to be part of a clinical trial?”
The two of us have many similarities in our medical diagnosis and genetics. We have CLL disease profiles of being unmutated, 11q deletion, 13q deletion, ZAP 70 positive and some other deletions whose clinical significance is currently unknown. Unfortunately, we are both complex karyotype. All of the above serves as bad news and contributes to a poor prognosis for us. This knowledge led both of us to be as diligent as possible in keeping ourselves aware of what was going on in the CLL world, especially in the areas of research and clinical trials. Knowledge is power. We both knew we would not be the 25-year CLL patients who would die in their old age never having had treatment.
There is also a major difference between us. Although we were both wait and watch for 5 years, Paul was diagnosed in 2004 and his disease would become aggressive in 2009. I was diagnosed in 2009 and my CLL would become aggressive in 2014. Because of this five year timing difference, Paul had been treated with several harsh chemotherapies before going into this trial and Teresa was able to enter the trial never having been exposed to chemotherapy. This is because the CLL treatment world, thanks to an abundance of highly successful research clinical trials between 2009–2014, had radically changed the CLL treatment options.
Paul tells his story:
While I had a good doctor locally, I thought that it never hurts to find a specialist for a 2nd opinion. I was a regular reader of the ACOR news group where Dr. Hamblin was a routine contributor. It was easy to identify the top CLL doctors based on reading research papers, but hard to pick one out of the top 10 or so. So I sent Dr. Hamblin an email and asked for his opinion, given he was in the UK and I wasn’t going to travel there to see him. He offered his perspective on each of them, and I decided to see Dr. John Byrd at Ohio State. He was clearly one of the leaders in CLL research, and he seemed young enough that he’d be around for the many years that I also planned to be fighting the disease. So I scheduled an appointment and went up to Ohio State for a visit. Dr. Byrd confirmed that “watch and wait” was the best approach. While he didn’t think I should be treated at that time, I was glad I found him as I knew that somewhere down the road my situation would change.
I was “watch and wait” for about 5 years, as my white counts gradually rose to around 25,000. Then, in 2010 over the course of about 6 months, they shot up to 70,000. I also experienced CLL infiltration in my lower bowel. It was pretty clearly time for treatment. FCR was just becoming the standard of care at the time, so that seemed like the obvious path to take. I looked for clinical trials and saw that Dr. Byrd was the Principal Investigator (PI) for a multi-center trial that included the normal 6 courses of FCR, followed by 6 months off and then 6 months with Revlimid (Lenalidomide). The best part was that one of the institutions was here in Richmond so I didn’t need to travel to get on the study. That seemed like a perfect fit to me, as it included the best current treatment that was available, followed by treatment with an additional drug which had the potential to lengthen the remission. I wasn’t sold on doing a trial just to do a trial, but this one seemed like a particularly good fit given my situation.
The FCR went fine. I had a bit of nausea, but nothing that drugs couldn’t handle. The Revlimid was also going fine, but I had some vision issues. One eye seemed like it was higher than the other, and my contact lenses were bothering me. My ophthalmologist scheduled a CT scan which showed I had a tumor behind my left orbit that was pushing my eyeball out of place. A subsequent biopsy confirmed that the tumor was CLL. This is apparently pretty uncommon (though not unheard of), and it was enough to get me bounced off the clinical trial. I had a bunch of rounds of radiation therapy which dissolved the tumor, and from there I settled into a good remission.
I had read that the first remission is usually the best, and that transplants require a good remission. Given I was only 51 at that time, I thought I’d consider a stem cell transplant. I decided to go to MD Anderson for my potential transplant. I went through the full work up for this, and the doctor at MD Anderson recommended that I start Ofatumumab to ensure that my disease didn’t progress while I was waiting. The process began to search for a MUD (matched unrelated donor.) The good news was that they found one. The bad news was that he chose not to show up for his confirmatory typing. I posted something on Facebook trying to get to him and suggest that he perhaps reconsider. My post went viral and got coverage on our local news and was one of Yahoo’s top stories, but alas he never decided to be a donor. Eventually I decided that a transplant wasn’t the best course of action for me at this stage. I stopped the Ofatumumab, and settled into a good remission for a few years.
In 2014 it was obvious that my disease was progressing again. My nodes got really large. I felt like I had a 2nd head growing out of my neck and worse than that were the nodes inside of my body. I visited Dr. Byrd and discussed possible options with him. The obvious off-trial option was Ibrutinib, given it had been recently approved by FDA and had good results. Additionally, however, Dr. Byrd offered a couple of alternatives. ACP-196 sounded like the best of them. While it was only a phase 1 trial, he told me that it was being developed by the same researchers who developed Ibrutinib. Thus far, his experience was “efficacy that was as good as or better than Ibrutinib, with fewer side effects.” There were some other potential trials such as ABT-199, but ACP seemed like the right one for me. So in September 2014, I became patient #39 on this trial. The reduction in my nodes was nothing short of phenomenal! I dropped 10 pounds in the first week, all from nodes inside of my body, which were evaporating. After 18 months, my counts have finally worked their way down to the normal range.
Teresa tells her story:
In mid-year 2009, I had been having some problems with my right shoulder. I visited an orthopedic surgeon for an assessment and they performed an MRI. This doctor would return to the exam room with tears in his eyes and would tell me I needed to find a hematologist immediately as he was 100% certain that I had lymphoma. As this was not his field of expertise, he was deeply shaken by the experience. There were bulky nodes all throughout my underarm area. A subsequent lymph node biopsy and a short search would lead me to Dr. Jose Azar in Indianapolis, the only CLL specialist in the State of Indiana at the time. I sensed then and have continued to have the greatest confidence in Dr. Azar, but I am by nature an individual who seeks second opinions. Dr. Azar would refer me to Dr. John Byrd at Ohio State University for that opinion. In my assessment, Dr. Byrd projected that my disease would most likely become aggressive in 1-3 years. Fortunately, my disease would hold off for 5 years. During that time, I would see my CLL specialist in Indiana quarterly and Dr. Byrd annually at OSU. This is the strategy often promoted by Brian Koffman – build your team!
By July of 2014, I was still trying to deny the night sweats I was experiencing, I had mysteriously lost 10 pounds, lymph nodes formed a visible collar around my neck, I had slightly elevated white blood counts for the first time and a general sense of feeling unwell. I had required a surgery to remove CLL growing inside my throat. In my visit to Dr. Byrd, I shared my symptoms and additional blood work was done. My disease had progressed with the addition of the 11q deletion and had evolved to be complex karyotype. The overall poor prognosis and these new genetic changes and symptoms would lead Dr. Byrd to encourage me to begin treatment and he strongly recommended the ACP-196 trial. He would clearly advocate why he felt this was the best choice for me – just as he did for Paul.
This would now become the time in which my local doctor provided sort of a “reverse second opinion”. Dr. Azar would help me to meticulously review the pros and cons of what was being offered. For, if I entered the trial, I would be entering the trial as one of the small handful of individuals who would be previously untreated – this is termed “chemo-naive”. We were to conclude that this was an acceptable trial for me.
Like Paul, I had been following the host of therapies being introduced for CLL for years, as well as following the clinical trial offerings. I am a resounding believer that “chance comes to the prepared mind”. I was determined to avoid chemotherapy at all costs if possible. It was already being documented that the chemo-naive population that were participating in ongoing Ibrutinib clinical trials were experiencing superior durable outcomes than the chemotherapy pretreated, relapsed and refractory Ibrutinib population. Following the introduction and subsequent results of the newer blocking therapies like Idelalisib, Ibrutinib and ABT-199 (Venetoclax) and their success, several leading CLL experts had started asking questions about whether the patient with the more unfavorable prognosis, like myself, should perhaps be treated earlier using the blocking therapies first, instead of chemotherapy first.
Since Ibrutinib was a second-line therapy, it was not available to me. That made this trial seemed particularly desirable with its billing as a “second-generation Ibrutinib”. There was a solid base of pre-existing data on the characteristics, parameters and success of Ibrutinib that implied to me that the safety factors with this second generation offering were most likely good. Drawing these comparative evaluations was an important part of how my decision is made. A non-chemotherapy BTK blocker option, like ACP-196, clearly seemed like the only way to go.
I became patient #30 in the trial. And I have come to feel that my choice has made me one of the luckiest CLLers on earth. Each day I take 2 pills and feel as if CLL has a very remote place in my life. The promise of “greater efficacy and fewer side effects” appears true. At this point, my side effects are virtually non-existent and my world has not been invaded with toxic chemotherapies and the future problems they can introduce. I feel that, for now, I have protected my immune system in the best manner possible.
This drug has also been easy for me to tolerate. BTK blockers inhibit more than just the Bruton Tyrosine Kinase enzyme. They also block other enzymes, resulting in the often discussed undesirable side effects. In the case of Acalabrutinib, only 3 enzymes are blocked – very few in comparison. This is significant, because the result is a big diminishment in the side effect profile.
Paul and Teresa’s Recommendations
Throughout the months we have been on the ACP-196 trial, the two of us have remained in touch, periodically bouncing thoughts and questions off of each other. It is always easier to go down an unknown path with company. We came from different treatment backgrounds, but we agree on several important factors in making a clinical trial choice:
Choosing a remote location like the James Cancer Center at OSU for getting treatments is a tough decision with a lot of factors involved, but both of us wanted to make sure we had the best treatment we could find. To do this, we realized we would have to travel. In both cases, work and financial situations allowed us to travel without undue hardship. The geography from Richmond, Virginia to Columbus, Ohio was manageable via air. Teresa could make an easy three hour drive to Ohio from her home in Indianapolis. Paul says that, had he lived further South, he probably would have gone to one of the CLL leaders at MD Anderson, and had he lived on the West coast then he would have gone to UCSD. All of these centers are performing cutting edge research studies.
In essence, these studies can give a patient the opportunity to receive a treatment 3-5 years in advance of its availability on the market. Given the rapid rate of change we are seeing in leukemia drugs recently, this feels like a big advantage. Unless you are lucky enough to live near a major center, these options simply aren’t available to most people unless they are willing to travel. The ACP-196 trial was economically pretty easy to take because, in addition to the drug being free, the study reimburses participants for travel and lodging.
Clinical trials are obviously not without risks. You’ve probably read about the 2 patients who died on the initial ABT-199 trial very early on when dosage was still being determined. Deciding to do a clinical trial is not an easy decision, as there are inherently both upsides and downsides. In our cases, we both felt that the ACP trial was the perfect balance of a good upside potential, with reasonable downside risk.
Based on our experiences, we have several recommendations for anyone who is considering a clinical trial:
First, make sure you really trust your doctor as being someone who knows the treatment landscape and can match a treatment to your needs. Dr. Byrd knows of all of the ongoing research, and he was always willing to make the time to discuss options and give the personalized pros and cons. You should never feel like you are being steered in any one direction without careful justification being provided. Nor should you feel like the doctor’s goal is solely to actively recruit patients for his study. Dr. Byrd’s goal was to find the best match for us to lengthen our lives. Ultimately, it’s up to the patient to decide on the option that is right for him or her, but it helps to have an advocate that you feel is open and honest.
Second, make sure that you feel the risk is right for you. Paul says, “I’m all for helping researchers develop new treatments that might benefit others, but I wouldn’t have started on this trial unless I thought it was the best option for me. Some options are riskier than others, and some have more potential side effects. I feel there is a lot of value in learning as much about the drugs as possible and in making a decision with as much information as you can get. Frankly, there are some trials that I probably wouldn’t do — like trials involving Bendamustine. I’m sure it is a wonderful drug, but the future seems to be moving away from chemo drugs with their potential damage to your immune system.” While we’re sure that our doctors would share those perspectives with us, there is no substitute for developing as much knowledge as you can and helping chart your own course.
You can tell from Paul’s history that he is generally a fan of clinical trials. So is Teresa. Simply put, they offer the best chance for getting the latest treatment that modern science has to offer. If you are willing to take some added risk, you have the potential to get the best treatment.
We are certain that one day there will be a cure for CLL. The first people who experience this will undoubtedly be those who are willing to participate in clinical trials. There are so many new options cropping up as researchers move toward combinations of therapies. It is a tremendously exciting time for all of us. Clinical trials are a wonderful way to help yourself, while also helping others. It doesn’t get any better than that!
So we hope you will consider one of these new offerings if you need treatment, and we sincerely hope this article helps others as they navigate the same waters we have sailed over the past few years.
Paul Zamecnik was diagnosed with CLL on Valentine’s Day 2005. He has been treated with FCR, Revlimid, Ofatumumab, and radiation for a related tumor and has most recently been part of the ACP-196 trial since the fall of 2014. Paul is a member of the Leukemia and Lymphoma Society Board in Richmond Virginia, and is an active Team in Training participant. He plans to ride in his 15th 100-mile bike ride with LLS’s Team-in-Training fundraising program this summer, having raised over $100,000 in the past 10 years. Paul enjoys spending time with his wife of 29 years, and his 3 children.
Teresa Altemeyer was diagnosed with CLL in 2009. She began treatment in an ACP-196 phase 1 trial as a chemo-naive patient in 2014. Shortly after her diagnosis in 2009 she was asked by her CLL specialist to facilitate a support group in Indianapolis, Indiana. As a result of this involvement, she came to embrace the role of patient advocate. She continues in her volunteer role with the support group and she serves on the board of the Indiana Leukemia and Lymphoma Society. To support our cause she has traveled to Washington, DC several times to meet with legislators and regularly attends national conferences to keep current with the latest CLL happenings. She just became a grandmother and looks forward to years of joy in this new role.
Originally published in The CLL Tribune Q1 2016