The ironies of new therapies

Late one Wednesday afternoon in the hem/onc fellows’ clinic, a telephone call came through from a referring physician. The physician had a 65-year-old male patient in his office, mildly short of breath and profoundly pancytopenic. He had performed a bone marrow biopsy a few days prior that revealed some unusual appearing cells and about 10% blasts, although he wasn’t sure about this latter number because of the quality of the specimen. Cytogenetic evaluation would turn out to be markedly abnormal, with monosomies of chromosomes 5 and 7 besides two other lines of cytogenetic changes.

The referring physician said the patient looked too well to be admitted to the hospital, but he wasn’t sure what to do. I remembered the on-call fellow taking the telephone call, and because the conversation stood out in my mind among the many conversations that day, I had a feeling that I’d be hearing more about this patient as time went on.

William Wood

This man was eventually admitted to our hospital, where he received another bone marrow biopsy, this time formally read as M6a acute myeloid leukemia with 30% blasts. Using a novel approach, the inpatient care team did not start standard induction chemotherapy but instead used a 10-day course of IV decitabine (Dacogen, Eisai) at a dose of 20 mg/m² per day. He did very well with this treatment, experienced no adverse effects or neutropenic fevers, and required only minimal transfusion support. He found that his exercise tolerance was no worse than before, and he soon began to improve.

On day 28 of therapy, the patient underwent another bone marrow biopsy, showing a substantial reduction in bone marrow blasts, now 7%, and an improvement in cytogenetic abnormalities by fluorescence in situ hybridization (FISH), now 8.5%. As an outpatient, he received decitabine at the same dose for another 5 days. One month later, he underwent a third bone marrow biopsy. This time, he had a normocellular marrow with less than 5% blasts. He had no cytogenetic abnormalities detectable by FISH or routine cytogenetics. His platelet count, 10,000 at diagnosis, was now 250,000, indicating restored normal hematopoiesis. He was in a complete remission.

Strategy after remission

I had witnessed something remarkable. This was a patient with a very high-risk presentation — older age, AML probably arising from myelodysplastic syndrome (MDS), and a highly unfavorable karyotype. He had avoided standard induction antileukemia therapy, and he had succeeded. His side effects were minimal to nonexistent; from the first day of receiving treatment and every day thereafter, he felt better than he had the day before. His quality of life was excellent.

I was prepared to seize this moment and to implement a potentially curative strategy. I considered him for the CALGB 100801 transplant trial, a reduced-intensity conditioning busulfan-fludarabine approach with post-transplantation hypomethylating therapy using 5-azacytidine. I assumed that my patient would share my enthusiasm, and I was only a little surprised when he and his wife didn’t seem to react with quite the excitement that I had expected. I reasoned that as educators and statisticians (both were teachers), they just needed a little more time to process the information and to feel comfortable with the still substantial risks of a reduced-intensity conditioning allogeneic transplant.

I was more surprised when I talked with my transplant nurse coordinator the next week and learned that the patient wished to cancel his unrelated donor search. A few days later, I met with the patient in a clinic room to discuss his thoughts and to see what he wanted to do next.

Faith in treatment

In the exam room that day, my patient and his wife appeared stoic and resolute in their body language and in their words. He noted that he hadn’t felt poorly since starting treatment. Aside from mild dyspnea and fatigue at presentation, his life hadn’t been affected much by his disease. Instead of taking this as the success that I took it to be, he interpreted it as evidence that he didn’t need more aggressive measures for disease control. I felt that my reliance on statistics and prognosis to guide my discussion was falling on unwilling ears.

He then volunteered that he was a man of faith, and that he had been praying since diagnosis for healing. He recalled experiences as a child in which he could see God at work, and he knew that he was protected then as he would be now. In fact, what he wanted at this point was not just to forgo transplantation, but to indefinitely postpone any further treatment, decitabine or otherwise, to see how long his remission would last.

I tried, to little avail, to discuss the implications of high risk MDS/AML. This man was in a privileged position that many others such as him would never achieve, having had excellent response to initial therapy, and a chance to pursue long-term consolidation of what would otherwise most likely be a temporary remission. I talked about the data regarding relapse after discontinuation of hypomethylating agents and the considerable challenges of treating relapsed disease.

I also shared personal stories of my friends and patients, many of them men and women of faith, who had succumbed to the biology of cancer despite the most fervent prayers for healing and cure. Despite this discussion, my patient wasn’t moved. He thanked me for my concern, but he was determined to proceed with no further therapy. We agreed, at least, on periodic blood count checks.

In the end, I was struck by the ironies in this patient’s case. A new treatment approach had radically changed the usual experience of having leukemia; instead of the toxicities and multi-week hospitalization of standard induction, this man hardly knew that he was ill, and thus interpreted his illness, and his future treatment options, in a way different than many others with his disease. This man of faith was relying on a divine intervention made possible (or at least facilitated) by a recently developed, man-made cancer treatment. And I found myself — a religious man on a personal level and a professional believer that less treatment is often better — questioning the limits of faith and advocating for greater treatment intensity.

Cancer care is complicated but all the more compelling because of the complexities of the patients we treat. We can do our best as providers to discuss the breadth and limitations of what we know, or think we know, but in the end, it is our patients who must make the hardest decisions for themselves.

William Wood, MD, is assistant professor of medicine, division of hematology/oncology, at the University of North Carolina, Chapel Hill. Dr. Wood may be reached at william_wood@med.unc.edu. Disclosure: Dr. Wood reports no relevant financial disclosures.

For more information:

• Blum W. Proc Natl Acad Sci U S A. 2010;107:7473-7478.

Not being much of a man of faith, I must mention that Dr. Vercellotti (a man of faith) and I have taken care of two patients with sudden complete remissions from MDS/AML that lasted several years. In one, remission rapidly followed a severe transfusion reaction suggesting immunologic destruction of the disastrous clonal hematopoiesis.

– Harry S. Jacob, MD, FRCPath (Hon)

HemOnc Today Chief Medical Editor

Disclosure: Dr. Jacob reports no relevant financial disclosures.