Adam shares the story of his fast moving CLL and his struggles to control it especially in the context of two different clinical trials.
His gritty tale of courage spares no details and is not for the faint of heart, though it does finish on an upbeat note.
As you read this, please also remember that we are all different.
Both the strong benefits and adverse events experienced by Adam during his use of the various drugs and remedies could be very different for each of us. His choices and decisions are not recommendations. His opinions are his and we ask you to check references and get medical counsel before assuming the correctness of all Adam’s assertions.
While neither Adam or the CLL Society mean to ever give medical advice, I think it is always instructive to learn what others have gone through, how they coped, how they have made decisions, how they have fought to get what they wanted, and what they found that worked for them and what they found that did not.
Here is the story of one patient’s wild and fast moving ride.
If you have a CLL story you want to share, please reach out to us at email@example.com
Brian Koffman, MD
From One Trial to Another: An Aggressive CLL Journey
“You may be relapsing.” My supportive nurse practitioner at Ohio State looked at my less than stellar blood counts in October, 2015, and I brushed it aside, but I knew he was right. I was relapsing and ibrutinib was failing me.
It was a good run. In 2011, my son was married, and I took Ofatumumab to tune me for the wedding. It seemed like a safe choice, except delayed-onset neutropenia caught me by surprise and Ofatumumab activated a Hepatitis B infection, acquired in my 20s, which had always been dormant. Naturally, I should have been on prophylaxis for hepatitis, but these were early days and Ofatumumab did not yet carry a black box warning about virus activation.
To me it seems impossible for a patient to be more actively involved in his care than I am, but I missed the risk this drug posed. By the time we figured out why I was so sick, from a raging hepatitis infection, my infection was refractory to every Hepatitis B drug on the market. But eventually a combination of anti-viral drugs gave me a negative test, thanks to one of the marvelous specialists at Weill Cornell in NY City, and I could turn my attention back to treating active CLL.
It was raging.
I should have been an attractive clinical trial subject for ibrutinib in those heady days of 2013, when ibrutinib was starting to help so many and looked like a silver bullet. I am young in CLL terms, diagnosed with CLL at age 45 in February, 2006. I’m in shape, I have no co-morbidities, and I have aggressive 17P deleted CLL, just the type of patient which ibrutinib was helping in dramatic fashion. But no one would consider me. NIH? Forget it. Ibrutinib was not yet approved by the FDA, and hepatitis was a complicating factor which the Pharmacyclics staff and the universities and agencies running studies didn’t want. Dr. Furman, who had been my CLL specialist since 2006, had an ibrutinib trial spot for me, until he didn’t. With a positive hepatitis test, his hands were tied.
But Ohio State was very active, opening new studies frequently and giving me a glimmer of hope that I could be accepted for an ibrutinib study. Brian Koffman was supportive and offered important guidance. Compassionate and knowledgeable Dr. Joe Flynn at Ohio State assumed the challenge of keeping me in the pool of study subjects, and eventually a negative hepatitis test led to my being accepted as a study subject. I’ll never forget Joe Flynn’s kindness and the kindness of others who influenced my outcome for the better. Dr. Flynn is now the Executive Director at the Norton Cancer Institute in Louisville, KY.
A long-time friend followed a different path and didn’t have as much help and support as me. He accepted an alphabet soup of chemo-immunotherapy administered at an institution that didn’t offer a less-toxic approach. He might have been helped by ibrutinib, since an idelalisib study gave him welcome relief for a year, so he and his partner sought compassionate use access to ibrutinib. These efforts were heroic, but access to the drug on a compassionate use basis never materialized and we buried my friend that fall. Perhaps those efforts influenced the expanded compassionate use program Janssen introduced soon after.
I was always suspicious of chemotherapy, and made a substantial effort to avoid it by pursuing experimental treatments in Cologne, Germany and Salzburg, Austria. My experience supports a sage comment by Dr. Terry Hamblin – evidence is not the plural of anecdote. Doctors on my team reasonably asked why these treatments didn’t work, or told me there’s no evidence they work: One said, “the studies I’ve seen are negative studies.” In other words, the treatment didn’t confer benefit.
I took FCR Lite in 2009 without regret because it saved my life. With hindsight, I think my suspicion of chemo-immunotherapy was protective. I got less F (Fludarabine), less C (cyclophosphamide) and perhaps less toxicity, with the same benefits as the full dose. My dominant 17p deleted clone would have survived the higher doses of the more commonly used FCR protocol.
My Dad had CLL in the days when there was only Chlorambucil, a notably less effective chemotherapeutic agent. Mom remembers little pills, and Dad died in 1997 from complications of CLL. Perhaps Dad developed the disease because of his work with chemical warfare agents at the MIT Chemical Warfare Laboratory during WW II. Military and civilian colleagues died of nasty lymphomas and leukemia shortly thereafter. But Dad was diagnosed at age 70 and had co-morbidities which were bound to influence his long-term survival. He did well for a number of years with fairly indolent disease, and our family was glad for it. The literature on familial CLL, which reflects my experience, says onset for subsequent generations is typically at a younger age with more aggressive disease, and the youngest male in the family is most likely to develop CLL. I’m glad I didn’t know this beforehand; I had no idea until my diagnosis in 2006 that I could be prone to developing CLL.
My hemoglobin (Hgb) was 6.0 by the time I took my first ibrutinib capsules in July, 2013. Hgb of 6.0 made me so weak that my wife Irina pushed me through the airport in a wheelchair when we traveled to Columbus to begin taking ibrutinib.
By the time I started on study, I was weak and thin. This was a great moment on July 10, 2013, which I recorded on my calendar as my re-birthday.
Ibrutinib is an “easy” drug
What a great run I had from July 2013 until January 2015. I swallowed three capsules at bedtime to minimize GI upset from ibrutinib and lived my life.
I enjoyed dedicated piano studies. I walked my dog and absorbed the pleasure of his steady companionship. I gardened.
Raffi is a certified therapy dog and a decent gardener.
I was no longer active in my business – I didn’t have the physical or psychological strength for it, and I moved to a different phase of my life without regret despite the enormous financial consequences. A senior staff member complained, “you’ve changed.” I had changed, and didn’t have the energy for other people’s problems that I once had. A serious malignancy will do that.
On January 4, 2015, severe diarrhea began. I remember the day because it was two days after my wife and I met my daughter’s future in-laws for the first time, in NYC.
The diarrhea never ended, but I learned to manage it using a tip from my local oncologist, Dr. Michael Nissenblatt, a special and compassionate physician. Mike suggested common nutmeg, ½ to 1 tsp a day in applesauce or pudding, and this muted the worst symptoms and allowed me to reclaim some normalcy. But I missed a family ski trip that February in favor of a hospital stay to treat dehydration caused by the diarrhea. Everyone said I should go off ibrutinib for a week to determine causality with my GI problems. What no one expected was a blazingly fast CLL relapse after four days off ibrutinib. The CLL cells in my body were numerous, but they were quiescent while I took ibrutinib. Later, once it was clear I relapsed and I suspended ibrutinib to begin another study in January 2016, the CLL raged immediately. My abdomen was so filled with big lymph nodes and fluid (ascites) that it was difficult to eat.
Adam’s Top 10 Unwelcome ibrutinib Side Effects
- Deeply ridged fingernails that crack and break easily
- Thick, scaly skin on my feet
- Unpredictable, angry rashes on my back, torso and legs
- Breakouts of blood-filled blisters on my legs – especially during the first 6 months on ibrutinib.
- Noticeable rosacea on my cheeks.
- More hair recession (I can’t really blame ibrutinib for this but I will anyhow)
- Manageable diarrhea
- Unmanageable, severe diarrhea leading to dehydration.
By December, 2015 it became clear that I had a lot of disease progression. Something was filling my abdomen, causing me to feel full after a few bites of food. Later, it became clear there were large lymph nodes (12 cm by scan) and ascites that didn’t clear until my tumor burden was reduced.
BCR inhibitors like ACP-196 were not available to me because I have unexplained resistance to them, placing me in the group of 20% of patients who relapse without mutations in BTK or PLCG2. Perhaps I could have tried idelalisib, but my GI tract was already a mess and idelalisib wasn’t likely to provide a lasting solution.
Dr. Furman offered me ABT-199 (Venetoclax) as his first choice, with CAR-T through a University of Pennsylvania program for CLL as the second long-term solution he could offer. I didn’t feel ready for CAR-T, which I have tracked carefully for years, so the choice was easy. I was aware that several patients died from tumor lysis syndrome in the Phase 1 trials of ABT-199, but new protocols minimized the risk. The sponsor, Abbvie, classified me as high-risk, and Dr. Furman registered me for a study for patients who relapsed on ibrutinib. Study NCT02141282 was open and available just when I needed it. This time I was lucky compared with when I was trying to get on a study for ibrutinib in 2013.
But a high-risk classification required every dose escalation of ABT-199 to be done as a hospital in-patient to protect my organs from tumor lysis syndrome. This would cause grave, unintended complications.
The scariest part of qualifying for the ABT-199 study was the PET scan. No CLL specialist wants to miss a Richter’s Transformation (RT), and developing a transformation has been my biggest fear for years. Thankfully my PET scan was clear, with low glucose uptake throughout my body.
The three-day washout period for ibrutinib seemed like a short time, but I knew it would be a problem for me after my aggressive relapse while temporarily off ibrutinib in February. Ibrutinib was still providing some disease control, and we were about to take all the brakes off. Predictably, I became much sicker very quickly.
After 10 years with progressive disease, I know all the signs and feelings intimately. By the time I took my first 20 mg dose of ABT-199/Venetoclax on January 21, 2016 my situation was becoming dire. Dr. Furman, in his usual smart and sensible style, summarized the data for me and told me I have a 50% chance of a deep response that may stave off disease progression for a long time. If I don’t achieve that response I’ll need another solution. It’s possible ABT-199/Venetoclax will kill the CLL clones which are resistant to BCR inhibitors like ibrutinib and ACP-196 reopening that door to me.
ABT-199/Venetoclax and me
To date this BCL-2 inhibiting drug is as potent for me as the data suggest. Because my disease was rapidly progressive, my first five weeks of dose escalations have been condensed to three weeks. Three weeks into the study I am at the maximum defined dose, 400 mg (the stepwise dose increases were 20 mg to 40 mg to 100 mg to 200 mg to 400 mg), my spleen has essentially returned to normal size, and my neck and abdominal nodes are no longer palpable. I feel much better and my appetite has returned. My grotesquely distended abdomen is nearly normal. My blood counts have a long way to go to recover, but after several red blood cell and platelet infusions my marrow is again functioning well and making lots of red blood cells (high reticulocyte count demonstrates this). My platelets and Hgb are stable and generally rising. ABT-199 seems to cause reductions in my neutrophil count, but those reductions are manageable.
My thanks to the excellent staff at Weill Cornell Medical Center in NYC and to Dr. Furman and his team.
This article is dedicated to the memory of family friend Gary, who lost his long struggle with CLL over two years ago, and to Brian, Gary’s honorable and loving partner.
February 22, 2016