LUGANO, Switzerland—The prognosis for patients with follicular lymphoma has greatly improved over the past decade, and oncologists/hematologists should tell their patients to be optimistic. So said James O. Armitage, MD, in his John Ultmann Memorial Lecture here at the 10th International conference on Malignant Lymphoma.
Improved treatments are the main reason for increased survival, particularly immunotherapy, said Dr. Armitage, Professor of Internal Medicine in the Section of Hematology/Oncology at the University of Nebraska Medical Center. “Our treatments are getting better, and there is a subset of patients, albeit small today, who survive for a very long time free of the disease. Patients in that subset may actually be cured of follicular lymphoma, and we can hope with our patients that they might be in that group.”
Dr. Armitage's presentation took the audience through studies and analyses all pointing to the fact that the natural history of the disease is changing for the better.
He concluded that clinicians should take advantage of the new treatments: “Based on data I showed today, a new patient should always be treated with some form of passive immune therapy, if the drug is available. For most patients that would be rituximab, because there is really striking data that that improves survival.”
He added that some data show that rituximab should be included in the initial therapy for follicular lymphoma, but he said that issue is not completely resolved.
“Despite the fact that we know much more about this disease than we did in the past, there is still very much to be learned, and we should encourage our patients whenever possible to participate in clinical studies.”
Dr. Armitage said many oncologists believe follicular lymphoma to be a fairly simple disease to diagnose and treat. Survival is long, and patients respond to many different therapies and continue to respond after relapse unlike in many other malignancies.
Follicular lymphoma is apparently the most reproducibly diagnosed lymphoma, he said, and pathologists generally do not need immunophenotyping to identify it with a high degree of accuracy and reproducibility.
More Complex than Sometimes Recognized
But follicular lymphoma is a much more complex disorder than is sometimes recognized, he said. For example, it has a propensity to undergo spontaneous regression; responses have been seen secondary to the graft-versus-lymphoma effect of allogeneic hematopoietic stem cell transplantation; and follicular lymphoma probably has the highest incidence of spontaneous regression among human cancers.
“From one-sixth to one-third of patients followed without therapy regressed to a degree that might have been considered a response had they in fact been treated,” he said. And he cited data presented at the meeting earlier by Randy Gascoyne, MD, a hematopathologist at the British Columbia Cancer Agency, on the role played by the microenvironment of the tumor, suggesting that antibody treatment does not simply kill lymphoma cells, but might in some way alter the microenvironment making tumor cells less able to divide.
For many years, the survival rates for follicular lymphoma patients hardly changed. Dr. Armitage showed data from a Stanford University study in which the survival curves of patients treated there were virtually superimposable during the decades of 1987–1996, 1976–1987, and 1960–1976.
But since the late 1990s, survival has been increasing, he noted, citing a Southwest Oncology Group study that showed that overall four-year survival during the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) era was 69%, rising to 79% with ProMace (prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide) to 91% today with CHOP plus a monoclonal antibody.
Other findings from the University of Nebraska and from the University of Texas M. D. Anderson Cancer Center, and from SEER data, also show that survival is changing in a favorable way. Dr. Armitage examined possible reasons.
Lead time bias would be a consideration, but he said he did not believe there is any reason to think that systematic change in the time of diagnosis is an explanation for increasing survival.
Another possibility is the “Will Rogers phenomenon”—Dr. Armitage explained to the largely international audience how the American humorist once claimed that when Dust Bowl “Oakies” migrated from Oklahoma to California, they raised the IQ of both states.
Similarly, he said, “more accurate diagnosis of follicular lymphoma could have moved poor-risk patients from a good prognosis group to a poor prognosis group, raising survival rates in both groups because the worst of the best moved to become the best of the worst.”
This phenomenon has occurred in osteosarcoma, he noted, with the coincident application of CT scans and adjuvant chemotherapy. And it probably also occurred with the overestimation of the benefits of complex chemotherapy regimens in diffuse aggressive lymphoma in the 1980s.
But as for follicular lymphoma, Dr. Armitage said he believed that this effect would apply only in Grade 3 disease, as various studies have identified Grade 3 marker levels that are more similar to marker levels in diffuse large B-cell lymphoma and less similar to Grade 2 follicular lymphoma.
“This might suggest that Grade 3 follicular lymphoma is a curable disease,” he said, but he cited a chemotherapy study from Vancouver presented at the meeting showing that Grade 3 follicular lymphoma with no diffuse component appears incurable with anthracycline-based regimes.
“The survival plateaus were the same with or without anthracycline chemotherapy,” he said.
This is important to the question of a change in the natural history of the disease, he said, because if Grade 3 patients—whose survival has usually been shorter than Grade 1 and 2—are being taken out of clinical trials, that could artificially improve the survival rates of those left in the trial.
“My experience in talking with oncologists in the US is that more and more are treating people with follicular lymphoma Grade 3 with something like CHOP-R and not putting them in trials,” he said. Nonetheless, Dr. Armitage said, he did not see that as a major explanation for the increasing survival.
He also discounted advances in supportive care, such as hematopoietic growth factors, better antibiotics, and use of blood products. While these are a major factor in increased survival for patients with acute leukemia, he said, he does not feel they are as significant here.
“The most obvious explanation is improved treatment, and far and away, the treatment that seems to have the greatest impact is passive immunotherapy with antibodies.”
If survival is improving and treatments are improving, Dr. Armitage said, it might be time to revisit the idea of whether some patients with low-grade follicular lymphoma can be cured.
“The potential for cure is likely or possible in patients with localized disease,” he stated. While patients diagnosed with very early-stage disease are rare, he said, nine studies of such patients treated with radiotherapy reported 10-year freedom from treatment failure rates of 41% to 49%, and 10-year overall survival from 56% to 79%.
And while most physicians would think that patients with disseminated disease treated with traditional chemotherapy regimens cannot be cured, Dr. Armitage said that might not be true. He cited a British National Lymphoma Investigation study in 1996 of 398 patients in whom the freedom-from-relapse rate was predicted to be 55% for Stage I, 28% for Stage II, 18% for Stage III, and 11% for Stage IV.
His take-home message, therefore, was one of hope and optimism that clinicians can pass on to their newly diagnosed patients.
Comment from Dr. Sandra Horning
Asked for her opinion about Dr. Armitage's talk, Sandra J. Horning, MD, Professor of Medicine at Stanford University School of Medicine, who chaired several of the sessions at the meeting, said afterwards that the analysis Dr. Armitage presented clearly indicated that patients with follicular lymphoma are living longer than ever before.
Dr. Horning agreed with Dr. Armitage's hypothesis that the advent of monoclonal antibody treatment in particular has made a major impact in management of follicular lymphoma: “We are all still learning how best to use it, how long to use it, when to use it, and understanding if its benefit continues through multiple treatments.”
Dr. Horning said she agreed with Dr. Armitage as to the relevance of supportive care in longer survivals and noted that an analysis of relative survival in follicular lymphoma patients was conducted at her institution that took into account other causes of mortality.
While the analysis did not directly address the supportive care question, she said, it did address competing causes of death and suggested that it is unlikely that supportive care is playing a major role.
Dr. John Ultmann
Pioneering lymphoma expert John E. Ultmann, MD, who died in 2000, was particularly well known for his work in using staging to guide lymphoma treatment. Dr. Armitage began his presentation by saying he knew Dr. Ultmann when the latter was a visiting professor at the University of Nebraska and that he was proud to honor Dr. Ultmann “by giving a presentation John would have liked.”