Tuesday, March 17, 2015

Leukemia, and My Brother and Me

In the summer of 2005, my brother Dan noticed that the long flights of stairs he climbed each workday to exit the New York subways seemed to get more difficult to manage, until he could barely make the climb. Normally a hearty guy who tended to ignore discomfort, he at last admitted to himself that something was wrong. Within weeks he was diagnosed with acute myelogenous leukemia (AML). He was 54 years old.

AML leukemia is a bone marrow cancer that causes white blood cells to stop developing while they’re still in an immature state. In some cases it’s caused by abnormal genes being activated through genetic abnormalities. Cancerous cells proliferate rapidly and do not go through normal cell death. They accumulate in the marrow, blood, spleen, and liver. In the bone marrow they create a fibrous substance (Karen Seiter, MD, (Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College) Acute Myelogenous Leukemia, “E Medicine from Web MD” http://www.emedicine.com/med/topic34.htm , Jan. 24, 2006).

AML is more common in industrialized countries. (There were about 11,960 new cases of AML in the United States in 2005, somewhat more in men than in women.) Prognosis is not cheerful: approximately 25-30 percent of adults younger than 60 survive longer than 5 years—that’s considered a cure (Seiter, 2006).

Tests showed that Dan had a dangerously small amount of blood in his arteries and veins, and very little of it was the healthy white blood cells called leukocytes, because his body had nearly stopped producing white blood cells. Too little blood can stop the action of the heart, among other things. Too few white blood cells leaves you vulnerable to infection. He wasn’t producing enough platelets, either, which can lead to bleeding to death (Seiter, 2006).

There are several causes of AML. In patients 60 and older, other blood diseases can develop into AML. Leukemia that develops in childhood is often results from one of several congenital disorders, including Down’s syndrome. There are also other genetic disorders associated with an increased risk of AML, including mutated forms of enzymes that protect the body against cancer-causing chemicals--for example, several forms of an enzyme that metabolizes benzene derivatives. There are also some hereditary conditions that predispose people to AML (Seiter, 2006), but my family hasn’t had any recorded cases of AML in the last three generations.

My brother and I grew up in northern New Jersey. New Jersey is mostly low and flat with some areas of rolling hills and a good deal of swamp land. Northeastern New Jersey is highly industrialized, and has a history of organized crime, which involved itself in the waste disposal industry, among others. When we were very young children (until he was 9 and I was 6), we spent a lot of our time exploring the second-growth woodlands and swamplands around our home. After his diagnosis, my brother reminded me, “You know, there was significant barrel dumping in those swamps we used to run around in” --suggesting that industrial waste had been improperly disposed of in our semi-wild playground and that we might have been exposed there to substances that caused mutations in our DNA.

Some months further into his treatment, my brother told me about a job he had as a teenager. He remembered working in a dye factory, where he stirred open vats of dye, which included, he thought, benzene as a solvent. “Every day I was a different color. You should have seen me the day I came home green,” he reminisced.

For my brother, then, the origin of leukemia was most likely epigenetic, that is, something that happened after he was born that altered some critical genes. One of the common epigenetic causes of AML is chemotherapy for a previous cancer, but my brother had never had cancer before. Smoking, which he did from about age 14 until his diagnosis, increases the risk of AML slightly. The other likely agents of genetic change are radiation and benzene (Seiter, 2006).  It’s possible that Dan was exposed to radioactive substances or benzene--products of heavy industry--that might have been dumped in the New Jersey swamps we played in as children. The other possible source of early radiation exposure was the nuclear weapons testing, both above and below ground, that the United States and several other countries engaged in throughout our childhoods (Joni PradedGlowing in the Dark, Baby Teeth Studies Reveal Childhood Radiation Exposure,”  www.emagazine.com/may-june_2002/0502gl_health.html,  Jan. 14, 2003). There have been no published government studies on the effects of that testing on the U.S. population.

The treatment my brother underwent for leukemia involved doses of chemotherapy potent enough to completely kill his bone marrow, which was full of those fibrous, cancerous tumors. (It also damaged his liver, but a damaged liver can regenerate.) The combination of its extremely dense population, the excellence of its medical schools, and cancer-causing heavy industry has netted the New York-New Jersey area some very fine cancer-treatment facilities. Sloan-Kettering is the best-known. My brother had his initial treatment at NYU Medical School Hospital, and subsequent treatments at the obscure but excellent University of Hackensack Medical School Cancer Center.

He was then allowed to recover his health for a couple of months as best he could while being pumped full of other people’s donated blood, antibiotics, and steroids. While he was recovering from the trauma of chemotherapy, my sister Sara and I were tested for human leukocyte antigen (HLA) class I and II gene compatibility with my brother in order to qualify as his bone marrow stem cell donors. Leukemia is all about the immune system, and these immune system antigens, if they don't match in donor and host, will cause post-transplant complications like rejection of the transplanted cells, and the converse of rejection, known as graft versus host disease, where the donated immune system attacks the body into which it's been transplanted. Death is another side-effect. Post-transplant risks increase with the number of HLA mismatches (Effie W. Petersdorf, “HLA matching in allogeneic stem cell transplantation,” Current Opinion in Hematology, 11(6):386-391, November 2004, abstract on http://www.co-hematology.com/pt/re/cohematology/abstract.00062752-200411000-00003.htm accessed Nov. 26, 2006).

HLA testing is done in two stages. The first stage is relatively crude but inexpensive (about $100). It distinguishes HLA on a broad basis within the blood (Petersdorf, 2006).

My sister’s HLA complex flunked out at this stage, but mine passed and I went on to the second stage of HLA matching. It examines the DNA of donor and recipient. DNA typing reveals a surprising diversity of HLA genes in humans (Petersdorf, 2006). This test is roughly ten times more expensive, and of course the stakes were higher in other ways as well. Even mismatches of genes for minor histological factors can cause graft versus host disease and transplant failure (A. Perez-Garcia, et al., “Minor histocompatability antigen HA-8 mismatch and clinical outcome after HLA-identical sibling donor allogenetic stem cell transplantation,” Haematologica. 2005 Dec;90(12):1723-4. www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16330460&dopt=Citation). Luckily for all concerned, my relevant genetics matched my brother’s closely, and I was qualified to donate bone marrow stem cells to him.

We had reason to hope that Dan would have a relatively low risk of relapse, even if he was plagued by graft-versus-host (GVH) disease. A study by Sophia Randolph from the Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington and the Department of Medicine, University of Washington School of Medicine in Seattle found that “…Compared with other sex combinations, male recipients of sister transplants had the lowest risk for relapse. . . A reduction in relapse after female to male stem cell transplants [between siblings] was observed in patients with . . . acute myelogenous leukemia. . .” Unfortunately, this benefit seems to come with the substantial drawback of increased risk for GVH disease, which can itself be fatal, and even if it isn't, can make post-transplant living an exhausting balancing act between GVH symptoms and steroid side-effects (Sophia S. B. Randolph, et al., “Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants,”  Blood, 1 January 2004, Vol. 103, No. 1, pp. 347-352. http://www.bloodjournal.org/cgi/content/abstract/103/1/347,  accessed Nov. 26, 2006).

From the time I was qualified as a donor until the procedure was complete, I felt strangely fragile. If I died, my brother’s chances of living much longer became very poor. Once siblings from the same parents are eliminated as donors, doctors told me, you might as well just go to the national donor database. And there the chances of finding a good match are one in millions. This pre-transplant period is the closest I’ve ever come to the experience of being pregnant, of “living for two.” Genetic research has created the need for new metaphors. How can a woman without a uterus give birth to her older brother? Metaphorically, this is how. At the same time, I knew I was in robust good health after three years of triathlon training, and I felt confident that I’d be able to donate high-quality bone marrow.

In October 2005, I went to New Jersey to prepare for the stem cell transplant. Until recently, plugs of bone marrow itself were transplanted. But that procedure involved drilling about 20 holes in the donor’s pelvis--which was painful and, I suppose, discouraged donors somewhat. What’s more, in 2000, stem cell transplant was discovered to be more effective (Ray Powles MD, et al., “Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial,” The Lancet, Volume 355, Issue 9211 , 8 April 2000, Pages 1231-1237).

Stem cells that are designated to become bone marrow normally are present in the bloodstream in small numbers. To produce the large number needed for successful donation, production must be artificially boosted. The substance used to prompt the donor’s body to churn out bone marrow stem cells is protein called filgrastim. The biotech firm Amgen markets filgrastim under the trademark Neupogen (“Neupogen Filgrastim,” http://www.amgen.com/pdfs/misc/neupogen_pi.pdf.) Product packaging describes Neupogen as produced by Escherichia coli (E coli) bacteria into which has been inserted the gene that codes for "human granulocyte colony-stimulating factor." The protein has an amino acid sequence that is identical to the natural sequence predicted from human DNA sequence analysis‚ except it’s modified to allow E. coli to produce it (“Neupogen Filgrastim,” http://www.amgen.com/pdfs/misc/neupogen_pi.pdf).
According to the manufacturer, “colony-stimulating factors" act on the cells that can become blood cells by binding to specific receptor chemicals on the cell surface. They then stimulate the cell to reproduce‚ encourage it to develop into a bone marrow cell‚ and begin performing its appointed task.

The filgrastim must be injected subcutaneously, twice a day for four days. Diabetics inject insulin this way, but indefinitely, not just for a few days. The cancer center has nurses who are trained to teach donors to inject themselves, and self-injection got pretty routine by the end of the four days. The fact is, sticking yourself with a super-thin needle, although it goes against one’s deepest impulses, doesn’t hurt.

A couple of days into the routine, I began to feel some aching in my elbows and hips, as doctors predicted I would, caused by the unusually high level of stem cell production going on in my bone marrow.

After four days, I went to the hospital for apheresis or “harvesting” of the stem cell crop. In apheresis, my blood was extracted by one port, centrifuged, the stem cells removed, and then the remaining blood returned to my system by a second port. Both ports were in my femoral artery, because the usual blood vessels in the crook of my elbows are hard to tap. I lay on a comfortable exam table listening to a book on tape for about four hours and dozing on and off. During the process, I could see my blood cells in a clear plastic bag, spun out into four different groups: red cells at the bottom, stem cells (which look plump, and a bit like the crushed ice at the bottom of a bloody Mary), white blood cells, and plasma.

Any individual donor will produce a different number of stem cells with the filgrastim treatment. Counting is done by the lab overnight, so I was told I would have to stay in the hospital to await the results next morning, in case they needed to repeat the process to get more cells. The next morning, however, the nurse told me with a little smile that not only had they been able to harvest enough cells in one session, but that the cells were happily dividing in the bag—which, I took it, boded well for their future usefulness in my brother’s system. The stem cells were then frozen, partly to keep them fresh, and partly, I believe, as a way of killing possible bacteria and viruses.

Dan then took up residence in the hospital, and underwent a second, less traumatic round of chemotherapy. Following that, the stem cells were injected into my brother’s bloodstream. He described the feeling as “an incredible rush.” As we hoped, his body accepted the stem cells with no rejection. He experienced some graft versus host disease, and within a couple of months had a full complement of red and white blood cells and platelets.

Problems with rejection and graft-versus-host disease, as well as the way Social Security disability is administered, usually prevent people from returning to work full-time. But well within a year of the transplant, Dan was back at his demanding job as a computer network administrator for a large financial firm, working nearly full-time. He is in good health, with no signs of leukemia, but some GVH symptoms.

Here’s another of those ways that recent advances in genetics mess with our old metaphors. Before people knew anything about genetics, they believed that parents’ traits were passed down to their children in the mother’s blood--you had “blood relatives.” When scientists learned about DNA, of course, that idea was no longer taken literally, although it lingers in the language. Now, though, Dan’s blood is actually exactly like mine, because his bone marrow is from my cells. Does this make us “blood absolutes”?


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