I had indolent WM for twenty years, but amyloid deposits in my lung hospitalized me eighteen months ago. I discuss my experiences with Rituxan, ibrutinib, and an autologous stem cell transplant (ASCT).
I am now 68 years old. 23 years ago, during a routine physical exam, my physician noted an unexpectedly high total serum protein level. The elevated protein was composed primarily of IgM, and lead to a diagnosis of Monoclonal Gammopathy of Unknown Significance (MGUS), which can progress to Waldenstrom’s Macroglobulinemia (WM). Over the next twenty years, my lab results never became alarming, and I was otherwise symptom-free and in good health. I changed jobs, moved cross-country, and my wife and I went about our lives raising our daughters. While “watchful waiting” was the correct strategy during those two decades, I was mindful of the potential for disease progression, and kept waiting for “the other shoe to drop.”
On New Year’s Day of 2014 my wife of 28 years died of cardiac amyloidosis. She had not been “feeling right” for several years, and was eventually referred to a cardiologist. But light chain amyloidosis is sufficiently rare that the correct diagnosis was made only in November, and by that time she was referred directly for a heart transplant. She died six weeks later, while still being worked up for the transplant. The best description I read of cardiac amyloidosis was that her heart was “starched”, sufficiently inflexible to no longer pump blood effectively even when beating. Because of this intimate acquaintance with amyloidosis and its devastating effects, and knowing that a subset of WM patients develop amyloidosis, I requested that my hematologist make monitoring my serum free light chain part of my routine blood tests, in addition to serum IgM.
I am a PhD analytical biochemist whose professional career has been in the biopharmaceutical industry, the last twenty years at Genentech. I tend to obsess on data, and have found that habit both professionally satisfying, and an emotional escape as my wife’s and my own illnesses unfolded. In July of 2015, the data from my lab results became progressively more concerning. Yet when my hematologist asked how I was feeling, I responded, “Great. I just got back from a week of hiking and bicycling at Lake Tahoe (elevation 6,300ft).” “OK”, he said, “see you in January.”
Just before Christmas I was again at Lake Tahoe, vacationing with my daughters and their families. One morning I awoke at about 4 AM, unable to get comfortable in any position in bed. My heart was racing; I had mild chest pains and some difficulty breathing. My daughters were adamant that I go to a local urgent care center. Once there, I was informed I was not having a heart attack, but should proceed directly to the local hospital Emergency Room. The urgent care doctor said, quite calmly, he would forward my chest X-ray to them, and “they will be expecting you.” In lightly falling snow my younger daughter and I drove off to the hospital fifteen miles away.
In the ER I was informed I had a lung infection with bleeding, and a 10×14 cm (4 x 5.5 inch) mass in my right lung. The most immediately life threatening concerns were my infection (treated with antibiotics) and my blood loss (replaced with five units of blood). But being informed that one has a large, presumably malignant, mass in the lung was traumatic. As I had suspected, the biopsy showed the mass was mostly amyloid deposit, WM lymphocytes, and plasma cells. An abdominal fat biopsy also showed amyloid deposits, which indicated that these deposits were likely occurring throughout my body. The good news was that I showed no loss of cardiac or kidney function – so no amyloid damage to those organs, yet. My amyloidosis had been identified much earlier than my wife’s.
I was given six cycles of IV Rituxan at three-week intervals, combined with weekly Velcade, cyclophosphamide and dexamethasone. Ironically, Rituxan was the first drug I had worked on as a biochemist at Genentech. Some thoughts about getting a drug I had helped to develop are covered in a blog I wrote for the American Association of Pharmaceutical Scientists (see aapsblog.aaps.org/?s=Vanderlaan&search=Go(link is external))
All of this treatment occurred while both daughters had returned to their lives, well away from San Francisco, where I live and was being treated. Without local family to help during this five-month ordeal, I was able to marshal the assistance of friends using the website(link is external). I recommend this web tool to anyone facing a similar challenge where you would like to rely on friends to provide rides to infusions, an occasional home-cooked meal, conversation, or emotional support.
My last Rituxan infusion was in April 2016. By June my hemoglobin level and lung capacity both had returned to near normal, and gradually I built up the endurance to walk about five miles a day in my hilly neighborhood. A bone marrow biopsy showed about 10% abnormal lymphocytes and plasma cells, and my serum IgM and free light chain remained high. The decision was made to start me on oral ibrutinib, which, in the published literature, shows promise for WM patients with the common WM genetic mutation that I have.
During the oral ibrutinib treatment I suffered no side effects. I felt well enough to take a five-week vacation in Europe with my younger daughter, as a belated college graduation present to her. This trip was a treasured parent-adult child bonding for the two of us, especially since she had lived through her mother’s death and my hospitalization two years later, both related to amyloidosis. We also scheduled our trip to be in Amsterdam to coincide with the International Workshop on Waldenstrom’s Macroglobulinemia (IWWM-9), which I attended.
By January 2017, unfortunately, it became obvious that the ibrutinib had not had its desired effect of lowering my IgM and light chain. I suffered another lung infection, and a total body PET-CT scan showed that the mass in my lung was approximately the same size. In addition, a similar mass – assumed to be an amyloid deposit – was noted in the soft tissue of my lower abdomen near my pancreas and kidneys. The danger that this might progress to amyloid deposits in my organs was very concerning, and my physicians and I agreed that it was time to take the next step and prepare me for an autologous stem cell transplant (ASCT).
I will go into detail on the ASCT process for the benefit of readers who might be considering this treatment. Over three days in early March I received abdominal injections of Neupogen (also called G-CSF or filgrastim) followed by a single injection of another drug called plerixafor to cause the stem cells to proliferate to the point that they spill out into the blood stream. I shaved my beard, and had my hair cut “military short” in anticipation of my hair falling out. I mentioned to the nurse managing my case that the ASCT was now becoming very real, after all the preliminary testing. Her wise reply was that I should focus on the destination, not the journey. While the next few weeks would be rough, I would arrive at “a better place” and that should be my guiding thought in enduring the procedure.
The next step in the treatment was to harvest my stem cells from my blood stream. This began with having a tube or catheter inserted into the jugular vein in my neck, leaving a rather odd protrusion of tubes for external connections. The next day I spent about eight hours hooked up by these tubes to a device that separated stem cells out from my whole blood then returned the remaining components of my blood to my body. The total amount of blood so processed was about three times my total blood volume. At the end of the day the resulting bag of stem cells was sent off to the lab to get a stem cell count and to be frozen in liquid nitrogen.
The hospital staff informed me that the minimum number of stem cells they needed for the stem cell transplant was two million stem cells/kg body weight, but that an ideal number would be five million or more. My count for the first day of harvest was three million/kg, so another round of harvesting was planned for the next day – another eight hours on the machine. To my surprise and disappointment, that second day yielded only another 950,000 stem cells/kg. With this drop-off in collection on the second day, it was decided not to collect on additional days. In the background of my mind was the fear, “what if they don’t have enough?” After all, it was these cells that I would depend on for recovery.
I was admitted to the University of California, San Francisco’s transplant ward. My first evening there I was given melphalan by IV over about thirty minutes. This is the drug used to kill your bone marrow cells to prepare for the transplant. It also kills other fast-growing cells such as those in your intestines, skin, and hair follicles. I was advised to suck on chipped ice starting fifteen minutes before and continuing through fifteen minutes after the infusion. The cold causes the tiny blood vessels in your mouth to contract, minimizing the melphalan dose to the mouth tissues and thus reducing the risk of mouth sores developing later while you are immune-suppressed. Since the total time for the chipped ice and melphalan is about an hour, I advise patients going through this procedure to have planned something else to focus on for this period. In my case, my daughter and I pulled out our phones and reviewed pictures from our Europe trip. It was a wonderful distraction, a reminder of better times, and kept my mind off of what was dripping into my vein.
The next day was unquestionably the worst day of the entire procedure. My nausea was such that even moving from the hospital bed to an adjacent chair was an ordeal. This day allowed the melphalan to clear from my system.
A day later, it was time to infuse my stem cells. A machine with the bags of cells was brought to my bedside. Individual bags were gently thawed and then given to me by IV. As each bag was being given, the next bag was being thawed so no bag remained thawed for more than a few minutes before being dripped into my vein. Several hours were taken for this process on the first day, with the process being repeated on the next day until all of the stem cells that had been collected were returned to my body. The idea was that they would then find their way to my bone marrow and “set up shop” for healthy blood cell proliferation and immune system fortification. The day you begin re-infusing your stem cells is considered “day-zero” in the ASCT process, i.e., the “birthday” for your new immune system. This “birthday” was celebrated with a surprise birthday cupcake and candle from the nurses.
Over the next few days I responded to the anti-nausea medications and was able to eat a bit. Daily blood cell counts were posted on the whiteboard visible at the foot of my hospital bed. Gradually the remaining pre-transplant white and red blood cells, platelets, and neutrophils diminished to near zero. “Come on stem cells, start replacing these dying cells,” I thought. My hair fell out. My energy level fell. By about the fifth day post-transplant, the neutrophil count – the cells most important for my immune system to begin protecting me again – increased slightly. “OK, one day does not a trend make, but it is a basis for hope,” I thought. Over the next few days all the cell counts increased steadily, slowly, each day rising higher than the day before. “Maybe, just maybe, this whole process is working for me the way it has been described, and my stem cells are rescuing me.” This is not to say that there were not complications. As is not unusual, I needed a couple of units of blood to offset my anemia, and there were frightening episodes of fevers that luckily – and thanks to all of the hospital’s precautions – did not blossom into serious infections. And I was exhausted.
I spent 21 days in the UCSF transplant ward, and then a month at home under “house arrest”. My gradual recovery in both places was greatly facilitated by the loving care given to me by my younger daughter and my girlfriend. Both took time off from their jobs to be with me for the seven weeks. Having two caregivers allowed them to balance being with me and their own lives. Anyone planning a stem cell transplant should be sure to plan for adequate assistance.
I learned that recovery from ASCT seldom is linear, and found the backward steps to be frustrating and depressing. Each patient has unique experiences during ASCT recovery and mine might not be reflective of what others experience. In looking for the source of the possible infections during the fever spikes, total abdominal CT scans were performed. While no infection site was ever positively identified, a doubling in size of the previously noted abdominal mass was incidentally noted. This led to some frightening questions: How could something be growing when I just had high-dose melphalan? Was the hypothesis that this mass was an amyloid deposit valid? The last thing I wanted was another kind of cancer. The biopsy results came back, indicating amyloid deposit, inflammatory cells, and a few WM cells. Somehow the timing of my ASCT had coincided with a large deposition of amyloid proteins in the soft tissues of my abdomen.
Lying in bed gives one lots of time to speculate. Supposing the abdominal amyloid deposition had preceded the one in my lung eighteen months ago? My vague bloated feeling and dull pain in my back around my kidneys might well have been misdiagnosed by me as something intestinal – probably chalked up to something I ate. Or I might have thought it to be mere back-muscle strain. My odyssey of treatments might not have begun until something more serious had happened.
The three-month post-transplant period involved more extensive testing. A bone marrow biopsy showed that the abnormal cells were not at zero but were down almost 100-fold from my pre-transplant value. And the abdominal CT showed that the abdominal mass had shrunk an amazing 80%. The scientist in me is still analyzing and puzzling over the large personal data set I have collected for serum IGM, free light chain, and other test data under conditions of various therapies. Expected correlations of values are often not there, and I speculate about multiple sources of these values. I wonder whether there are separate clones producing these serum proteins, each clone with its own dynamics. Or maybe the amyloid deposits are non-cellular reservoirs that can provide a source for serum proteins. Or maybe differences in clearance rates obscures differences in production. I would be more than happy to discuss any of this in detail with those of you who share this interest and curiosity. In spite of these questions, I am relieved that the current findings are largely positive.
My overall energy level is back nearly to the level of last fall and my hair is growing back. I am walking 4 – 5 miles a day. It is time to go back to the mountains of Tahoe, and immerse myself in the forests. This winter had quite heavy snows, and the streams are flush with snow-melt. Spring has come and gone, the wildflowers are in full bloom, and all the trees show vigorous green new growth. So it is for my stem cells. They, too, are recovering from their winter of liquid nitrogen, and are showing vibrant growth, celebrating a new spring of proliferation and differentiation. Life is good.
San Francisco, California