By Darrell E. Ward
Photograph by Roman Sapecki
Fifty years ago, Bertha A. Bouroncle, MD, published a landmark paper on hairy cell leukemia. A triumph of cancer research followed, but recurrence remains a problem for some.
Eric H. Kraut, MD
Professor of Internal Medicine, hematologist-oncologist and researcher with the OSUCCC Experimental Therapeutics Program
Bertha A. Bouroncle, MD
Professor emeritus of Internal Medicine
Michael R. Grever, MD
Chair of Internal Medicine, hematologist-oncologist and co-leader of the OSUCCC Experimental Therapeutics Program
The year 2008 marked the 50th anniversary of the discovery by Ohio State hematologist Bertha A. Bouroncle, MD, of a relatively rare and formerly fatal form of leukemia.
In her landmark 1958 paper in the journal Blood, Bouroncle and coauthors Bruce K. Wiseman, MD, and Charles A. Doan, MD, two famous hematologists, called the disease leukemic reticuloendotheliosis because of the atypical cells then called reticulocytes in the blood and bone marrow.
Then, probably in the mid-1960s, the ragged edge of the malignant cells, which display fine, hair-like projections under the phase contrast microscope, earned the disease the name hairy cell leukemia (HCL).
Bouroncle’s report was a highly detailed description of 26 cases, the most in one place up to that time, that identified the condition as an independent hematologic and pathologic entity. “Dr. Bouroncle’s paper represents a substantial accomplishment in the field of clinical research,” wrote David Golden and Mark Weiss of Memorial Sloan-Kettering Cancer Center in a 2000 historical perspective on HCL.
The most common physical symptoms of the 26 adult patients, 21 of whom were male, were an enlarged spleen, followed by an enlarged liver and lymphadenopathy. Sixteen of the patients had died. After the onset of symptoms, their survival had ranged from less than one year in four patients, to nearly 16 years in one patient. Pneumonia or other infections and hemorrhage were often the cause of death.
“The paper was talked about across the country because it provided the first comprehensive description of the disease,” says Michael R. Grever, MD, chair of Internal Medicine and co-leader of the Ohio State University Comprehensive Cancer Center (OSUCCC) Experimental Therapeutics Program. “Many hematologists and oncologists had seen one or two of these cases during their career, and this report helped them understand what it was.”
Charles A. Doan, the fifth president of the American Society of Hematology, became dean of Ohio State’s College of Medicine and built it into a national medical center.
How to manage the disease and identifying the cell of origin became the subject of many meetings. Into the 1970s, the disease was linked to, or misdiagnosed as, acute leukemia and treated as such. “The standard chemotherapy of the day made patients worse,” says Grever, who worked with Bouroncle, first as a hematology fellow then as a junior faculty member in the late 1970s.
Splenectomy was the only therapy for 25 years. “About 80 percent of HCL patients have enlargement of the spleen,” Grever says. “Some became massive and involved the entire abdomen.” Removing the spleen raised blood counts and eased symptoms for a time but did nothing to eliminate the malignant hairy cells from the blood or bone marrow.
Then, in the span of several years in the 1980s, three therapies for this disease emerged and remain the primary treatments for HCL today. Grever, working with Eric H. Kraut, MD, then also a junior Ohio State faculty member, largely developed one of the most important of those, the purine analogue deoxycoformycin, or pentostatin, as therapy for HCL.
The other drugs were interferon alpha (IFN-) and a second purine analogue, 2-chlorodeoxyadenosine (2-CDA). These therapies have improved survival and have reduced splenectomy to a minor role in HCL management.
“This has been a remarkable success story,” Grever says. “We’ve gone from a disease that wasn’t treatable, other than removing the spleen, to now trying to determine how best to keep people in complete remission,” Grever says. “We changed the natural history of this disease in our lifetime.”
“Unfortunately, our success has led many to believe that HCL is no longer a problem, yet, 40 percent of patients still experience recurrence,” Grever says. “It’s like taking the ball down to the five-yard line and not trying to score the touchdown.”
Hardly ready to quit, Grever is rallying the team.
About 500 cases of HCL are diagnosed yearly in the U.S., accounting for about 2 percent of all leukemias. In 1974, evidence emerged that it was a B cell malignancy, and diagnosis improved with identification of characteristic surface markers, including CD25, the interleukin-2 receptor.
Hairy cell leukemia gets its name from the ragged edge of the malignant cells, which display fine, hair-like projections under a phase contrast microscope.
The first treatment breakthrough for the disease came with a January 1984 paper in the New England Journal of Medicine showing that IFN- improved the blood counts in about 80 percent of the patients studied. However, only about 10 percent of patients enter complete remission with interferon and, if the therapy is discontinued, patients relapse.
“Nothing had been effective until then, except removing the spleen, which helped only for a while, so this paper was of great interest and Dr. Bouroncle was very excited about it,” Grever recalls.
In the early 1970s, research showed that loss of the enzyme adenosine deaminase (ADA) caused severe combined immunodeficiency syndrome in children. Research also linked the lymphopenia associated with the condition to the intracellular accumulation of deoxyadenosine triphosphate (dATP), which caused the cells to die by apoptosis. This knowledge gave rise to the idea that a drug that inhibited ADA might kill malignant cells in patients with lymphoid malignancies, although there was a real concern that such an agent might also lead to overwhelming immune suppression.
Pentostatin was known to be a potent ADA inhibitor that was being tested in Europe in patients with acute leukemia. Clinical trials, however, raised concerns that the drug was too toxic.
Grever began studying pentostatin in 1979, and showed two years later that the dose needed for acute leukemia exceeded the maximum tolerated dose. He also showed that lower doses of the drug were well tolerated, and that they were sufficient to achieve complete remission in patients with chronic lymphocytic leukemia (CLL).
The drug proved unsuitable for acute leukemia patients because acute leukemia cells have high levels of ADA, requiring high doses of pentostatin, while chronic leukemia cells have low levels of the enzyme, permitting a safe and effective dose in CLL patients.
“When we treated patients with advanced CLL with pentostatin, we saw dramatic improvement,” says Grever, who serves as the principal investigator for the phase I clinical trials program at Ohio State.
In about 1984, Kraut was contemplating how to help a patient with progressing hairy cell leukemia who had already had a splenectomy. He wondered if pentostatin might also help his patient. “I consulted with Mike and with the patient,” he recalls. “We were concerned about the risk of immune suppression and infection, but we agreed that we should try it. We treated the man on a phase I study after securing approval from the National Cancer Institute, and he significantly improved.”
In December 1984, a paper by A.S.D. Spiers and two co-authors appeared in the Journal of Clinical Oncology reporting the treatment of three HCL patients with pentostatin, two of whom had advanced, untreated disease.
That paper reported “prompt clearance of hairy cells from the blood, regression of splenomegaly and lymphadenopathy … .” Side effects were tolerable, and both patients achieved complete remission and remained in remission at nine and six months. The third patient was undergoing treatment, with disappearance of splenomegaly and clearance of hairy cells from the blood at 10 weeks.
“Now, 25 years after we started the initial trial, most of our patients are still alive…a disease that was deadly for some within three or four years of diagnosis was now often treatable.”
“That increased our enthusiasm for our trial,” Grever says.
“Not only did my original patient have a good response, but we saw good responses, without severe problems in many other patients,” Kraut says. The success of that study led to a phase II trial of the drug in HCL, with Grever, Kraut and Bouroncle collaborating on the study.
When Kraut presented the outcomes of their first eight patients at the Central Society for Clinical Research meeting in Chicago in November 1985, a few found the results too good to believe. In particular, those who favored interferon therapy questioned whether such dramatic results were possible.
“We continued adding patients to our study, and other groups started looking at the drug, and lo and behold, we found that our early results were genuine,” he says.
The Ohio State group then reported the outcomes of 10 patients in the November 1986 issue of Blood, noting that nine had achieved complete remission. “Low-dose deoxycoformycin administered intravenously every other week represents an extremely effective therapy for hairy cell leukemia,” they concluded.
“Now, 25 years after we started the initial trial, most of our patients are still alive,” Kraut says. He still sees several of those original patients in clinic.
“This led to this amazing advance, in which a disease that was deadly for some within three or four years of diagnosis was now often treatable.”
A Third Therapy Emerges
The third therapy for HCL was described in an April 1990 issue of the New England Journal of Medicine. The paper presented a study showing lasting remissions in 12 HCL patients treated with a new drug, 2-chlorodeoxyadenosine (2-CDA).
“We came to the conclusion that both pentostatin and 2-CDA are highly effective for treating HCL, and that the long-term follow-up is almost identical,” Grever says.
In 1999, a recombinant immunotoxin was developed at the National Cancer Institute (NCI) and tested in a phase I trial in a group of patients with hematologic malignancies. Four HCL patients included in the group responded to the therapy, with one experiencing complete remission and the other three showing a 98 to 99.9 percent reduction in malignant circulating cells. The patients had lived with the disease for 12 to 17 years and were resistant to 2-CDA, IFN- and, in one case, pentostatin.
The immunotoxin targets the interleukin-2 receptor, also known as CD25, on the malignant cells. Of the patients in the trial, four had HCL. The study, published in Blood, concluded that LMB-2 “may be an effective new therapy for patients with chemotherapy resistant CD25+ HCL.”
The agent, which remains in phase II testing, was developed by Robert J. Kreitman, MD, who today is a senior NCI researcher and head of the Clinical Immunotherapy Section, and who received his medical degree at Ohio State.
The 2008 American Society of Hematology (ASH) conference recognized the 50th anniversary of Bouroncle’s original Blood paper, and Grever and a group of colleagues used the occasion to rally interest in new research on HCL.
“Too many people seem to feel that this disease is no longer a problem,” he says, noting that only three abstracts had been submitted to the 2007 ASH conference by people doing research on the disease.
“Yet, 35 to 40 percent of people still relapse,” he says. “Those who get HCL at age 70 will probably lead a relatively normal life span, but someone who is 40 may not. We can’t simply forget about those patients.”
Men are four to five times more likely to develop hairy cell leukemia than women.
Grever organized a symposium for the 2008 ASH meeting that brought together HCL experts from across the country and from Italy and Great Britain. With the backing of the Rockefeller Foundation, they organized an international consortium for HCL, with representatives from the United States, United Kingdom, Canada, Germany, Italy and Sweden (see www.hairycell.org).
An initial goal of the consortium is to identify HCL experts in the U.S., Canada and Europe for patients seeking a second opinion about, for example, when treatment should begin, Grever says.
“We are collectively working on guidelines that help us decide when therapy is indicated and about what therapy to use,” he says, “but telling patients that we can watch their disease for a while may make them want a second opinion.”
Patients with infections and who need therapy raise additional questions. “We would prefer not to treat people with an active infection, but we can,” Grever says.
Combination therapy for HCL is also being studied. “Rituximab is being used in conjunction with 2-CDA or pentostatin, and we think that might be useful,” Grever says, “but it needs careful study.” Some centers give the two drugs in series, while others use them together.
“No one knows which is more effective,” Grever notes. Several clinical trials under way at Ohio State and other centers hope to find the answer.
Other questions include the significance of residual disease. “If we look carefully at the marrow, the majority of patients show signs of residual leukemia. It just stays quiet for years and years.
“We tend to think that those patients will be in that 40 percent who relapse,” he says, “but should we wait until they relapse to resume therapy, or would it be better to treat them with rituximab, for example?”
Research on HCL at the molecular level is also needed, he notes, to learn why hairy cells are much more sensitive to these drugs than CLL cells. “This might reveal ways to make CLL more responsive to therapy,” Grever says.
Kraut’s involvement in the development of pentostatin for HCL impressed upon him the importance of drug development research and fate and timing in life. “I tell the story of HCL to patients who come to me with a disease that is not yet curable or treatable as an example of how things can change pretty quickly, and how miracles can happen,” he says.
“The development of pentostatin at Ohio State is an example of the right people being in the right place at the right time. Because Bertha was here, we had enough HCL patients for a clinical trial. Mike Grever had the expertise with pentostatin, and he championed the drug. And I was fortunate to have the patient and the thought at the time to try the drug. It was an example of a tremendous partnership.”
“The story of progress in hairy cell leukemia at Ohio State emphasizes something that the people at this university do very well,” Grever says. “We work hard to improve therapy for people.
“Ohio State is committed to high quality clinical and translational research, and it has a large patient base. This gives us opportunities to make real breakthroughs.”