Originally posted in Volume 1: Issue 1 of the CLL Tribune.
I was trained in survey methods, statistics, and medical sociology. I’ve been a member of the American Statistical Association for over 30 years. For 20 years, I supported the Biostatistics Branch of the National Cancer Institute, managing studies of many different types of cancer. But I never studied chronic lymphocytic leukemia until my husband Larry was diagnosed with it in 2012.
This is the story of my reaction to my husband being diagnosed with chronic lymphocytic leukemia at the age of 64. And being treated at age 67. And being treated again at age 68. I will share how I reacted to his diagnosis initially, how I went about seeking information about CLL, and how we made treatment decisions.
There Must Be Some Mistake
I am a member of a cancer family. My mother died at age 64 of lung cancer. Her mother died at age 83 of gallbladder cancer. Her father died at age 91 of prostate cancer. Her maternal grandmother died in her 40’s of breast cancer. Her paternal grandfather died, at an indeterminate age, of head and neck cancer. Pretty much, I expect to die of cancer. Someday. Not soon, I hope.
But my husband was not, we thought, in a cancer family. Although his mother was treated (successfully) for colon cancer and breast cancer, she died at age 92 of heart failure. Because of his mother’s colon cancer diagnosis my husband was careful to get colonoscopies at age 50 and 55 and 60. No polyps. Not a one. He was concerned about the possibility of heart disease. He did not have high blood pressure, but his bad cholesterol tended to be high; his good cholesterol tended to be low. He ate oatmeal for breakfast, tried to be careful about the rest of his diet, and exercised when he could, although he traveled a lot and was not highly successful at these things. He tried several statins, but had side effects to all of them. So, he was worried about heart disease and had an annual physical ever since turning 50. But cancer was not on his radar screen.
On March 19, 2012, our internist called and asked to speak to my husband. “Sorry; he’s in Copenhagen. We’ll Skype later today. What do you need?” “Well, one of his blood counts is elevated. Is he feeling well? Has he had an infection of any kind?” “He’s feeling fine. What count is elevated?” “His white cell count is elevated. It could indicate a variety of things. When he comes in next week for his physical, we’ll repeat it and see what it looks like then.” “OK. I’ll tell him.”
And I did. What I said was, “Brent called. He said your white blood cell count was elevated, and he wants to get another sample when you go in next week for your physical. Who were you standing in line with at the lab?” “Well, there was a tall, skinny old lady ahead of me. I think her name was Mrs. Finkelstein. Why?” “How did she look? Did she look healthy?” “Why?” “Well, I think they might have mislabeled your samples, and so you got Mrs. Finkelstein’s results, and she got yours. Right now her doctor is telling her that her cholesterol is too high and she has to stop eating red meat. Or maybe the lab didn’t calibrate their Coulter counter that morning. Or you might have been fighting off an infection. Anyway, they’ll draw another blood sample next week and run it again.”
And they did. Unfortunately the new results replicated the earlier results. Our internist explained that Larry could have chronic lymphocytic leukemia, and he should see a hematologist and have further tests done. He could not discern any swollen lymph nodes or an enlarged spleen. So my emails informed friends and family that if Larry had CLL, it was almost certainly Rai stage 0.
I knew virtually nothing about CLL. So I visited the National Cancer Institute’s web site at cancer.gov and headed for the health professionals’ tab. I did not print what I read, but as I recall there was soothing information about etiology (basically, no one had a clue, except for Agent Orange exposure), diagnosis (a high white blood cell count was not enough), US and European staging schemes, a few prognostic markers such as FISH, IgVH mutational status, ß2M, and ZAP-70, and some information about treatment that focused on chemo-immunotherapy. Pretty much I skipped the treatment section because from what I could tell, Larry was decades away from needing treatment even if it turned out that he did have CLL, which was portrayed as a generally very indolent cancer. I informed my husband that CLL had a median survival of 12 years, meaning that half the patients lived longer than 12 years. “Yeah?” he said. “What do the other half do?”
Still laboring under the illusion that this was all going to be a big fat mistake, I turned to Google. After all, why dig into professional journals when the Internet is close at hand? Go ahead: Google CLL. Skip the ads. You’ll find sites offered by the Mayo Clinic, the American Cancer Society, the National Cancer Institute, Wikipedia, the Leukemia and Lymphoma Society, the Lymphoma Research Foundation, webmd, Cancer Treatment Centers of America, Patient Power, Memorial Sloan Kettering, CLL Forum, MD Anderson and many more. I confess that initially I stuck with Mayo and Wikipedia. Then I started calling girlfriends who were physicians.
My former college roommate, who remains a close friend, is a family physician. The wife of one of my husband’s college roommates is a physician at the Centers for Disease Control and Prevention. Some of our neighbors are physicians. Some of my former colleagues and clients are physicians. But here’s the thing: unless you happen to be related to or live next door to one of the real experts in CLL, your friends and relatives who are physicians may not know that much about CLL. They may never have seen a case of CLL. Or, if they have, they may have seen just a patient or two, a very narrow slice of CLL. My college roommate said, “Oh, don’t worry! CLL is really indolent. I’ve never had a patient die of CLL.” To which my husband responded, “I definitely want Susi to be my doctor.”
Our internist referred Larry to a local hematologist/oncologist for further testing. He ran another complete blood count. No miracles. He examined Larry and found enlarged lymph nodes and an enlarged spleen. Flow cytometry confirmed that Larry had CLL. The FISH test came back negative, so Larry did not have the favorable 13q14 deletion; he had a normal karotype. The hematologist/oncologist ordered CT scans of Larry’s chest, abdomen and pelvis. I did not protest, although I knew that the radiation burden was high, because I assumed (erroneously!) that a baseline CT must be “standard.” The CT scans showed that Larry had enlarged lymph nodes in his chest, abdomen, and pelvis, and his spleen was enlarged. He was officially promoted to Rai Stage II, which, together with some of the other results suggested an “intermediate” prognosis (i.e. 7-8 years as the median survival). I could feel myself passing through the denial stage and moving on to the thinly concealed rage stage.
The hematologist/oncologist was relentlessly cheerful about follow-up appointments at six-month intervals, probably for years, and eventually treating him with fludarabine/cyclophosphamide/rituximab (FCR). I had read about some trials comparing bendamustine/rituximab (BR) to FCR, but the hematologist/oncologist seemed unaware of them. Larry was adamantly opposed to chemotherapy anyway. It seemed like it might be time to seek a different specialist, start reading journal articles, attend some professional meetings and, well, dig in.
Larry had had a couple of successful surgeries at Johns Hopkins Hospital, so I began the search for a more specialized specialist there. When we found a likely doc who was a full professor in oncology AND the college roommate of the husband of one of my friends and colleagues, we had our guy. He was smart, well-informed, and he had a sense of humor. He ordered an IgVH mutational status test immediately. Larry was unmutated. Larry’s white cell count had continued to rise. His lymph nodes had continued to enlarge. The Hopkins specialist now proposed 3-month follow-up visits.
I began to grasp that Larry’s CLL might not be as indolent as we had hoped, and that he might need treatment sooner rather than later. This specialist clearly kept up with the literature, but Hopkins really had nothing going on with clinical trials for CLL patients.
By this time I had discovered several helpful websites and had amped up my reading to include journal articles automatically delivered to my email box through National Center for Biotechnology Information (NCBI) searches. My personal favorite websites at the time (this was pre-CLL Society) were the Leukemia and Lymphoma Society, which offered some webinars with CLL experts; Patient Power, which offered Andrew Schorr’s insightful interviews with CLL experts around the world; and CLL Topics, which offered Chaya Venkat’s clear and thoughtful interpretation of the published literature. Also, my college roommate had shown me how to tie into some continuing medical education sites for health professionals. Yes, I seemed well on the way to saving my husband’s life by studying his disease. Or maybe not.
My husband’s lab results continued to get worse. His lymph nodes and spleen continued to enlarge. In 2013 he had another CT scan (I DID try to talk him out of that one!) that, in addition to documenting the continuing ravages of CLL, revealed that he had a thoracic aortic aneurysm. What!?! Time out to read about that, talk to cardiologists at Hopkins and Cleveland Clinic, etc.
In the fall Larry’s hematologist/oncologist left Hopkins. He referred us to another Hopkins doc, but we did not hit it off. In January 2014, I was doctor shopping again. By this time Larry had also had several mysterious infections. So, I was looking for a doc who would be knowledgeable about more cutting edge treatment than the standard of care. What I was really looking for was a doc who was the principal investigator for a nice Phase II clinical trial of a BtK inhibitor for treatment-naïve patients.
I don’t remember exactly how I was introduced to Dr. Adrian Wiestner. It might have been through the Patient Power video published on January 9, 2014, in which Andrew Schorr interviewed Dr. Wiestner. The topic was Understanding Clinical Trials. Or I may have just looked at clinicaltrials.gov and noticed that in addition to a natural history study of CLL, Dr. Wiestner had been involved in a Phase II trial of ibrutinib. In any event, the day after that Patient Power recording was published, I contacted Dr. Wiestner’s study nurse and indicated that Larry would be interested in enrolling in the Natural History Study of CLL. After reviewing some of Larry’s medical records, the nurse contacted me and indicated that Dr. Wiestner would be happy to have Larry join the study. But the Natural History Study of CLL was not a treatment trial, so Larry needed another local hematologist/oncologist.
The National Cancer Institute has 69 NCI-designated cancer centers located in 35 states throughout the US. There are 17 Cancer Centers, 45 Comprehensive Cancer Centers (most affiliated with university medical centers) and 7 Basic Laboratory Cancer Centers. Now that it looked like Larry might be getting closer to needing treatment, I started looking more closely at the docs at those centers and at the clinical trials they had in play.
Ultimately we chose Dr. Bruce Cheson, a hematologist/oncologist at Georgetown’s Lombardi Cancer Center, and scheduled an appointment for February. At Larry’s February visit we learned that Georgetown expected to join a 3-arm Phase III trial comparing bendamustine/rituximab, the “standard of care” for those over 65) with ibrutinib/rituximab and with ibrutinib alone. This was a trial I had thought we might have had to move to La Jolla to join. (I had actually been looking at condos in La Jolla for months online!) What a relief to know that when Larry needed treatment, he might be able to join this local trial with pretty good odds of getting ibrutinib up front. For free. (By this time ibrutinib had been approved for CLL patients who had had at least one prior treatment, and we knew the asking price for the drug was about $100,000 per year.)
How to Decide What to Do
Still, it seemed like we had a little time, so why not consult more broadly? I made another appointment for Larry with Dr. Wiestner for late June, and an appointment for Larry with Dr. Michael Keating at MD Anderson for early July. But then the ante was raised. Following the appointment with Dr. Wiestner, Larry ended up in the hospital for three days with a sinus infection and viral and bacterial skin infections. We added an infectious disease specialist and an otolaryngologist to his list of physicians, which already included an internist, hematologist, cardiologist, dermatologist, orthopedic surgeon, and urologist. I canceled the appointment with Dr. Keating because Larry had become so neutropenic that he was advised to avoid crowds and air travel. Larry cancelled all of his summer travel and enrolled in the Phase III trial at Georgetown.
You’re wondering to which arm he was randomized, aren’t you? Bendamustine/rituximab. Standard of care. I was so upset that I was unable to sleep the night before the trial began. And, sad to say, the trial was kind of a bust for Larry. During Cycle I, he had only a mild infusion reaction to the rituximab, but he became severely neutropenic 4 weeks later. He developed a full body rash a few days after Cycle I concluded. Then he developed pneumonia. Cycle II had to be delayed 5 weeks until his absolute neutrophil count reached the level specified by the protocol. During Cycle II, despite the cautious approach of the Georgetown nursing staff, Larry had a couple of serious infusion reactions, one requiring a trip from the infusion unit to the ER. He developed purpura from his thighs to his ankles. Ultimately, per the protocol, the rituximab had to be discontinued entirely. The dose of bendamustine had to be halved. We consulted with several physicians at other institutions, and Larry decided to drop out of the trial.
Back to watch and wait. And back to trial-spotting. Larry works full time and he normally travels to Europe or Asia about once a month. Because he did not want to retire or curtail his traveling, he wanted an oral drug that did not have killer side effects. Dr. Wiestner had mentioned that he thought Larry might require treatment again in about a year, and that by then NIH might be involved in a Phase II trial of ACP-196, a kinder, gentler and perhaps more effective BtK inhibitor. Dr. Cheson mentioned that he thought Georgetown would have a trial of ACP-196 plus pembrolizumab by that time. I looked at a couple of ABT-199 trials at other centers and contacted Dr. Richard Furman’s study nurse to ask about his trial of ABT-199. But once again, we were caught by surprise. Larry began having a chronic viral infection on his nose and feeling fatigued, his blood counts began to go south, and we ran out of time for trial shopping. Because of his desire to work and travel, Larry chose the ACP-196 trial at NIH, directed by Dr. Mohammed Farooqui. Larry is now in Cycle 2. So far, so good. (Well, except for the headaches, which are the most common side effect of ACP-196, a little insomnia, and a scare about lymphoplasmacytic lymphoma a few weeks ago.)
Here is what I wrote last summer to a friend who is a doc and a cancer survivor:
Despite looking at several blogs, corresponding with one doc with CLL in Newport Beach (Brian Koffman), corresponding with the journalist who does Patient Power (who has CLL), being on a CLL listserv to which all sorts of CLL patients and caregivers contribute, attending professional meetings, participating in continuing medical education, and reading journal articles, I feel like I know NOTHING! Really: NOTHING! All the side effects, even though I have read about them, catch me totally by surprise. What? Neutropenia? NOW? 28 days after treatment when nothing was going on during the so-called nadir? And a rash? NOW? 30 days following Cycle 1? What is that about? And I imagine every side effect is going to be the worst — like, not just a rash, but toxic epidermal necrolysis or something, because they are ALL listed as potential side effects!
But I do know more now than I did when Larry was diagnosed. I know that we, as patients and caregivers, need to find at least one expert doc (preferably more), keep current with the literature, pay close attention to what goes on at ASH and ASCO and international professional meetings, and follow clinical trials and new drug approvals closely. And did I mention luck? We all need a little of that, as well.
Linda Lannom holds an M.A. in Sociology and a law degree. For 20 years she supported the Biostatistics Branch of the National Cancer Institute, managing case-control studies, cohort studies, and intervention trials in the US. and abroad. Currently she does consulting for the Elder Justice Initiative of the U.S. Department of Justice.
Originally published in The CLL Tribune Q3 2015