Radioimmunotherapy — Hot New Treatment for Lymphoma
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《新英格兰医药杂志》
Follicular lymphoma, one of the two most common lymphoid neoplasms in North America and Europe,1 is diagnosed in approximately 15,000 adults in North America each year.2 More than 90 percent of patients with this B-cell lymphoma have disseminated disease at diagnosis, and although the disease usually evolves slowly, most patients die of the lymphoma or complications of its treatment. Current treatments are effective in controlling the disease temporarily, often for years. The median overall survival from the time of diagnosis is approximately eight years, but survival is strongly influenced by age, the extent of disease, and the biology of the tumor cell.
An intensive search for more effective treatment has yielded advances that reflect an improved understanding of the biology of the disease. Much current attention is focused on targeted agents, such as molecules that selectively interfere with the antiapoptotic BCL2 oncogene,3 which is constitutively overexpressed in most cases of follicular lymphoma, and monoclonal antibodies against CD20, a membrane-spanning protein on B cells.
The use of a radioimmunoconjugate consisting of a monoclonal antibody against CD20 linked to a radionuclide is particularly attractive for the treatment of follicular lymphoma because of its selectivity for the lymphoma, which consists of malignant B cells that are markedly radiosensitive. Two such agents, iodine-131–labeled tositumomab (131I-tositumomab) and yttrium-90–labeled ibritumomab tiuxetan, have recently been approved by the Food and Drug Administration for treating recurrent follicular lymphoma. Building on the substantial effectiveness of these radioimmunoconjugates in patients with recurrent, advanced disease who had previously received many other treatments,4,5,6 Kaminski et al., in this issue of the Journal,7 report on the use of 131I-tositumomab in previously untreated patients with a new diagnosis of follicular lymphoma. The interesting results of this study deserve scrutiny and raise questions about how best to integrate this exciting new treatment into clinical practice.
Interpretation of the importance and clinical usefulness of any new therapeutic agent requires careful attention to its effectiveness and toxicity, both of which must be assessed in comparison with those of alternative treatments. Essentially, we want to know whether the new treatment works better because it provides superior control of the disease or because it is safer.
With respect to safety, the results with 131I-tositumomab are reassuring. Short-term toxic effects are mild; they include immediate infusion reactions, moderate myelosuppression, and an influenzalike reaction, all of which can be managed on an outpatient basis. Although it was not mentioned by the authors, radiation from the conjugate may pose risks to people in physical contact with the patient during the immediate post-treatment phase. Fortunately, straightforward protocols for the safe outpatient administration of 131I-tositumomab can be followed for almost all patients, thereby avoiding costly inpatient isolation.
Long-term toxic effects also seem to be easily managed; hypothyroidism occurred in about 10 percent of patients, and no cases of myelodysplasia have yet been noted. This last observation must, however, be interpreted cautiously, given the small number of patients in this series and the possibility of the subsequent manifestation of this potentially serious complication. It is reassuring that no serious infections were seen; normal B lymphocytes were only temporarily depleted, and there was no evidence of an effect on overall antibody levels. The appeal of an effective systemic treatment for disseminated follicular lymphoma that can be completed entirely within a few weeks on a convenient outpatient basis with very modest toxicity is obvious.
How effective is 131I-tositumomab? At first glance, the results are strikingly positive: 95 percent of the 76 patients with advanced follicular lymphoma had a response, and 75 percent had a complete response. With a median follow-up of slightly more than five years, the projected five-year rate of progression-free survival for all patients was 59 percent, and the rate of overall survival was 89 percent. These patients are doing well. The question is, however, how are they doing in relation to what would have happened with a different treatment?
Lacking a randomized trial that includes a comparison group, we must examine very closely the characteristics of the patients at the start of the trial by Kaminski et al. I find that they are a very special group. The median age of 49 years at the time of enrollment was more than 15 years below the median for all patients with follicular lymphoma. Indeed, only seven patients were over 60 years of age. The median time from diagnosis to treatment with 131I-tositumomab was eight months, and the time exceeded a year for almost 40 percent of patients, indicating a slow rate of disease progression. Although 64 percent of patients had bone marrow involvement, in no patients did lymphoma involve more than 25 percent of the marrow, as required by the protocol and dictated by the increased myelosuppression of 131I-tositumomab when the marrow is more extensively involved. We are told that 43 percent of the patients had at least one tumor mass of at least 5 cm in greatest diameter, but in a preliminary description of this same patient population,8 the authors indicated that the total tumor volume was not more than an estimated 500 g in 71 percent of the patients — a tumor burden that is frequently exceeded in typical cases of this lymphoma. Thus, the report by Kaminski et al. describes the outcome for a highly select group of younger-than-average patients with a low-to-moderate tumor burden and a slowly progressive disease at the time of treatment.
With the very favorable prognostic profile of the patients in mind, let us examine the outcomes. Both the very high response rate and the fact that slightly more than 50 percent of the patients remain in a continuous complete remission with a minimum follow-up of more than four years are encouraging. Only four relapses have been observed in the approximately 25 patients followed for longer than five years. For a treatment accomplished in just a few weeks with modest toxicity, these results are especially impressive. But how impressive? Sufficient to claim that patients are being cured? No, relapses are still occurring in 4 percent to 5 percent of patients per year, even after five years. Sufficient to justify adoption of treatment with 131I-tositumomab as primary treatment for follicular lymphoma? No. Sufficient to justify additional clinical trials? Yes.
These results, as impressive as they are, are not unequivocally superior to what might have been achieved with a judicious mixture of watchful waiting; single-agent treatment with chlorambucil, fludarabine, or rituximab; mild combinations such as cyclophosphamide, vincristine, prednisone, and rituximab; radiation treatments to the involved area for isolated symptomatic sites of disease; and escalation to more intensive treatment when dictated by disease behavior. Evidence of the superiority of the new treatment can emerge only from carefully designed prospective, randomized trials. The results of the study by Kaminski et al. with 131I-tositumomab alone also justify trials of that agent alone as compared with chemotherapy or chemotherapy plus rituximab for selected patients. Such trials should also include an economic analysis to answer the important question of cost for this potentially very expensive new treatment.
It has taken more than 20 years since the original description of radioimmunoconjugates in the treatment of lymphoma for their potential to begin to be realized at the bedside. The article by Kaminski et al. on the use of 131I-tositumomab for newly diagnosed follicular lymphoma is part of the logical development of this new kind of treatment. It takes us one step further in determining the best use of targeted but systemic radiation. As clinicians, we should all support the clinical investigations still needed to define the proper role for radioimmunoconjugates in the management of follicular lymphoma, so that one day an editorial such as this can focus on not just better disease control but the best strategy for cure.
Source Information
From the British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada.
References
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Canadian Cancer Society. Non-Hodgkin's lymphoma. (Accessed January 14, 2005, at http://www.cancer.ca/ccs/internet/standard/0,3182,3172_367655_194217223_langId-en,00.html.)
Webb A, Cunningham D, Cotter F, et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997;349:1137-1141.
Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003;101:391-398.
Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002;20:2453-2463.
Davies AJ, Rohatiner AZ, Howell S, et al. Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2004;22:1469-1479.
Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352:441-449.
Kaminski MS, Tuck M, Estes J, et al. Iodine 131 tositumomab therapy for previously untreated follicular lymphoma (FL). Prog Proc Am Soc Clin Oncol 2000;19:5a. abstract.(Joseph M. Connors, M.D.)
An intensive search for more effective treatment has yielded advances that reflect an improved understanding of the biology of the disease. Much current attention is focused on targeted agents, such as molecules that selectively interfere with the antiapoptotic BCL2 oncogene,3 which is constitutively overexpressed in most cases of follicular lymphoma, and monoclonal antibodies against CD20, a membrane-spanning protein on B cells.
The use of a radioimmunoconjugate consisting of a monoclonal antibody against CD20 linked to a radionuclide is particularly attractive for the treatment of follicular lymphoma because of its selectivity for the lymphoma, which consists of malignant B cells that are markedly radiosensitive. Two such agents, iodine-131–labeled tositumomab (131I-tositumomab) and yttrium-90–labeled ibritumomab tiuxetan, have recently been approved by the Food and Drug Administration for treating recurrent follicular lymphoma. Building on the substantial effectiveness of these radioimmunoconjugates in patients with recurrent, advanced disease who had previously received many other treatments,4,5,6 Kaminski et al., in this issue of the Journal,7 report on the use of 131I-tositumomab in previously untreated patients with a new diagnosis of follicular lymphoma. The interesting results of this study deserve scrutiny and raise questions about how best to integrate this exciting new treatment into clinical practice.
Interpretation of the importance and clinical usefulness of any new therapeutic agent requires careful attention to its effectiveness and toxicity, both of which must be assessed in comparison with those of alternative treatments. Essentially, we want to know whether the new treatment works better because it provides superior control of the disease or because it is safer.
With respect to safety, the results with 131I-tositumomab are reassuring. Short-term toxic effects are mild; they include immediate infusion reactions, moderate myelosuppression, and an influenzalike reaction, all of which can be managed on an outpatient basis. Although it was not mentioned by the authors, radiation from the conjugate may pose risks to people in physical contact with the patient during the immediate post-treatment phase. Fortunately, straightforward protocols for the safe outpatient administration of 131I-tositumomab can be followed for almost all patients, thereby avoiding costly inpatient isolation.
Long-term toxic effects also seem to be easily managed; hypothyroidism occurred in about 10 percent of patients, and no cases of myelodysplasia have yet been noted. This last observation must, however, be interpreted cautiously, given the small number of patients in this series and the possibility of the subsequent manifestation of this potentially serious complication. It is reassuring that no serious infections were seen; normal B lymphocytes were only temporarily depleted, and there was no evidence of an effect on overall antibody levels. The appeal of an effective systemic treatment for disseminated follicular lymphoma that can be completed entirely within a few weeks on a convenient outpatient basis with very modest toxicity is obvious.
How effective is 131I-tositumomab? At first glance, the results are strikingly positive: 95 percent of the 76 patients with advanced follicular lymphoma had a response, and 75 percent had a complete response. With a median follow-up of slightly more than five years, the projected five-year rate of progression-free survival for all patients was 59 percent, and the rate of overall survival was 89 percent. These patients are doing well. The question is, however, how are they doing in relation to what would have happened with a different treatment?
Lacking a randomized trial that includes a comparison group, we must examine very closely the characteristics of the patients at the start of the trial by Kaminski et al. I find that they are a very special group. The median age of 49 years at the time of enrollment was more than 15 years below the median for all patients with follicular lymphoma. Indeed, only seven patients were over 60 years of age. The median time from diagnosis to treatment with 131I-tositumomab was eight months, and the time exceeded a year for almost 40 percent of patients, indicating a slow rate of disease progression. Although 64 percent of patients had bone marrow involvement, in no patients did lymphoma involve more than 25 percent of the marrow, as required by the protocol and dictated by the increased myelosuppression of 131I-tositumomab when the marrow is more extensively involved. We are told that 43 percent of the patients had at least one tumor mass of at least 5 cm in greatest diameter, but in a preliminary description of this same patient population,8 the authors indicated that the total tumor volume was not more than an estimated 500 g in 71 percent of the patients — a tumor burden that is frequently exceeded in typical cases of this lymphoma. Thus, the report by Kaminski et al. describes the outcome for a highly select group of younger-than-average patients with a low-to-moderate tumor burden and a slowly progressive disease at the time of treatment.
With the very favorable prognostic profile of the patients in mind, let us examine the outcomes. Both the very high response rate and the fact that slightly more than 50 percent of the patients remain in a continuous complete remission with a minimum follow-up of more than four years are encouraging. Only four relapses have been observed in the approximately 25 patients followed for longer than five years. For a treatment accomplished in just a few weeks with modest toxicity, these results are especially impressive. But how impressive? Sufficient to claim that patients are being cured? No, relapses are still occurring in 4 percent to 5 percent of patients per year, even after five years. Sufficient to justify adoption of treatment with 131I-tositumomab as primary treatment for follicular lymphoma? No. Sufficient to justify additional clinical trials? Yes.
These results, as impressive as they are, are not unequivocally superior to what might have been achieved with a judicious mixture of watchful waiting; single-agent treatment with chlorambucil, fludarabine, or rituximab; mild combinations such as cyclophosphamide, vincristine, prednisone, and rituximab; radiation treatments to the involved area for isolated symptomatic sites of disease; and escalation to more intensive treatment when dictated by disease behavior. Evidence of the superiority of the new treatment can emerge only from carefully designed prospective, randomized trials. The results of the study by Kaminski et al. with 131I-tositumomab alone also justify trials of that agent alone as compared with chemotherapy or chemotherapy plus rituximab for selected patients. Such trials should also include an economic analysis to answer the important question of cost for this potentially very expensive new treatment.
It has taken more than 20 years since the original description of radioimmunoconjugates in the treatment of lymphoma for their potential to begin to be realized at the bedside. The article by Kaminski et al. on the use of 131I-tositumomab for newly diagnosed follicular lymphoma is part of the logical development of this new kind of treatment. It takes us one step further in determining the best use of targeted but systemic radiation. As clinicians, we should all support the clinical investigations still needed to define the proper role for radioimmunoconjugates in the management of follicular lymphoma, so that one day an editorial such as this can focus on not just better disease control but the best strategy for cure.
Source Information
From the British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada.
References
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Vol. 3 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2001.
Canadian Cancer Society. Non-Hodgkin's lymphoma. (Accessed January 14, 2005, at http://www.cancer.ca/ccs/internet/standard/0,3182,3172_367655_194217223_langId-en,00.html.)
Webb A, Cunningham D, Cotter F, et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997;349:1137-1141.
Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003;101:391-398.
Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002;20:2453-2463.
Davies AJ, Rohatiner AZ, Howell S, et al. Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2004;22:1469-1479.
Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352:441-449.
Kaminski MS, Tuck M, Estes J, et al. Iodine 131 tositumomab therapy for previously untreated follicular lymphoma (FL). Prog Proc Am Soc Clin Oncol 2000;19:5a. abstract.(Joseph M. Connors, M.D.)