Treatment of Myelodysplastic Syndromes
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《新英格兰医药杂志》
To the Editor: List et al. (Feb. 10 issue)1 report encouraging results with regard to the efficacy of lenalidomide, a thalidomide analogue, in the treatment of patients with myelodysplastic syndromes and symptomatic anemia whose condition failed to respond to erythropoietin. List et al. tested three dosing regimens, but little is said about their advantages or disadvantages. It appears that the lowest dosing regimen (10 mg per day for 21 days in a 28-day cycle) produced the best response with the least toxicity, but it is unclear what the median duration of response and the number of cytogenetic responses were with this regimen, because no comparison with the more dose-intense regimens is reported. A related question is whether patients with the highest rate of response (those with deletions on chromosome 5q) were evenly distributed among the different treatment groups.
Wee J. Chng, M.D.
National University Hospital
Singapore 119074, Singapore
chngwj@nuh.com.sg
References
List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352:549-557.
To the Editor: In their Perspective article (Feb. 10 issue),1 Drs. Cazzola and Malcovati state that treatment of myelodysplastic syndromes with antithymocyte globulin or cyclosporine is "effective in small subgroups of patients who do not require transfusions and who have low marrow cellularity." However, three studies of the use of antithymocyte globulin in the treatment of myelodysplastic syndromes2,3,4 have been performed in transfusion-dependent patients. About one third of these patients had hematologic improvement and became transfusion-independent; marrow hypocellularity was not predictive of a response. We believe that until larger studies delineate the place of lenalidomide in the treatment of myelodysplastic syndromes (especially given the drug's hematologic toxicity), a trial of immune-modulating therapy is warranted in patients with low-risk myelodysplastic syndromes.
Michael Stadler, M.D., Ph.D.
Arnold Ganser, M.D., Ph.D.
Hannover Medical School
30625 Hannover, Germany
stadler.michael@mh-hannover.de
References
Cazzola M, Malcovati L. Myelodysplastic syndromes -- coping with ineffective hematopoiesis. N Engl J Med 2005;352:536-538.
Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002;137:156-163.
Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with low-risk myelodysplasia. Br J Haematol 2003;120:679-684.
Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004;18:460-465.
Dr. List replies: Dr. Chng asks about the optimal dose and schedule of lenalidomide. Three dosing schedules were evaluated in the study, but patients were enrolled sequentially and without stratification according to disease type or karyotype. As shown in our article, there was no significant difference in the response rate among the cohorts; however, the time to a response was longer with the 21-day schedule. Among 12 subjects with a 5q31.1 deletion, 4 received 25 mg per day, 3 received 10 mg per day, and 5 received 10 mg per day for 21 days. Erythroid response was achieved in four patients, three patients, and three patients receiving the respective regimens. Although differences in the adverse-event profiles were noted, the number of patients in each cohort was insufficient to permit us to identify an optimal dose and schedule with statistical confidence. Two multicenter phase 2 trials recently completed enrollment of more than 360 transfusion-dependent participants. These trials are evaluating treatment with either 10 mg per day or the schedule of 10 mg per day for 21 of every 28 days and therefore should provide important insight with regard to tolerance, response rate, and durability with the use of these two schedules of lenalidomide therapy.
Alan F. List, M.D.
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL 33612-9497
listAF@moffitt.usf.edu
Drs. Cazzola and Malcovati reply: The use of antithymocyte globulin, for myelodysplastic syndromes is supported only by uncontrolled observations. Saunthararajah and colleagues1 identified three pretreatment variables associated with a response to antithymocyte globulin: younger age, shorter duration of the need for transfusions, and positivity for HLA-DR15. In a study conducted by the National Institutes of Health,2 it was concluded that "hypocellularity was an almost independent factor predicting response." Our summarizing statement was based on these observations.
Antithymocyte globulin is toxic. In the study by Stadler et al.,3 23 of 35 patients had adverse effects; 4 had serious toxic effects, and 1 of these patients died of cerebral mucormycosis. Thus, we cannot agree with Drs. Stadler and Ganser that "a trial of immune-modulating therapy is warranted in patients with low-risk myelodysplastic syndromes." What is warranted is controlled clinical trials that compare the quality of life and survival among patients given immunosuppressive therapy or lenalidomide and those treated exclusively with supportive care.
Mario Cazzola, M.D.
Luca Malcovati, M.D.
University of Pavia Medical School
I-27100 Pavia, Italy
mario.cazzola@unipv.it
References
Saunthararajah Y, Nakamura R, Man JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 2002;100:1570-1574.
Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002;137:156-163.
Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004;18:460-465.
Wee J. Chng, M.D.
National University Hospital
Singapore 119074, Singapore
chngwj@nuh.com.sg
References
List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352:549-557.
To the Editor: In their Perspective article (Feb. 10 issue),1 Drs. Cazzola and Malcovati state that treatment of myelodysplastic syndromes with antithymocyte globulin or cyclosporine is "effective in small subgroups of patients who do not require transfusions and who have low marrow cellularity." However, three studies of the use of antithymocyte globulin in the treatment of myelodysplastic syndromes2,3,4 have been performed in transfusion-dependent patients. About one third of these patients had hematologic improvement and became transfusion-independent; marrow hypocellularity was not predictive of a response. We believe that until larger studies delineate the place of lenalidomide in the treatment of myelodysplastic syndromes (especially given the drug's hematologic toxicity), a trial of immune-modulating therapy is warranted in patients with low-risk myelodysplastic syndromes.
Michael Stadler, M.D., Ph.D.
Arnold Ganser, M.D., Ph.D.
Hannover Medical School
30625 Hannover, Germany
stadler.michael@mh-hannover.de
References
Cazzola M, Malcovati L. Myelodysplastic syndromes -- coping with ineffective hematopoiesis. N Engl J Med 2005;352:536-538.
Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002;137:156-163.
Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with low-risk myelodysplasia. Br J Haematol 2003;120:679-684.
Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004;18:460-465.
Dr. List replies: Dr. Chng asks about the optimal dose and schedule of lenalidomide. Three dosing schedules were evaluated in the study, but patients were enrolled sequentially and without stratification according to disease type or karyotype. As shown in our article, there was no significant difference in the response rate among the cohorts; however, the time to a response was longer with the 21-day schedule. Among 12 subjects with a 5q31.1 deletion, 4 received 25 mg per day, 3 received 10 mg per day, and 5 received 10 mg per day for 21 days. Erythroid response was achieved in four patients, three patients, and three patients receiving the respective regimens. Although differences in the adverse-event profiles were noted, the number of patients in each cohort was insufficient to permit us to identify an optimal dose and schedule with statistical confidence. Two multicenter phase 2 trials recently completed enrollment of more than 360 transfusion-dependent participants. These trials are evaluating treatment with either 10 mg per day or the schedule of 10 mg per day for 21 of every 28 days and therefore should provide important insight with regard to tolerance, response rate, and durability with the use of these two schedules of lenalidomide therapy.
Alan F. List, M.D.
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL 33612-9497
listAF@moffitt.usf.edu
Drs. Cazzola and Malcovati reply: The use of antithymocyte globulin, for myelodysplastic syndromes is supported only by uncontrolled observations. Saunthararajah and colleagues1 identified three pretreatment variables associated with a response to antithymocyte globulin: younger age, shorter duration of the need for transfusions, and positivity for HLA-DR15. In a study conducted by the National Institutes of Health,2 it was concluded that "hypocellularity was an almost independent factor predicting response." Our summarizing statement was based on these observations.
Antithymocyte globulin is toxic. In the study by Stadler et al.,3 23 of 35 patients had adverse effects; 4 had serious toxic effects, and 1 of these patients died of cerebral mucormycosis. Thus, we cannot agree with Drs. Stadler and Ganser that "a trial of immune-modulating therapy is warranted in patients with low-risk myelodysplastic syndromes." What is warranted is controlled clinical trials that compare the quality of life and survival among patients given immunosuppressive therapy or lenalidomide and those treated exclusively with supportive care.
Mario Cazzola, M.D.
Luca Malcovati, M.D.
University of Pavia Medical School
I-27100 Pavia, Italy
mario.cazzola@unipv.it
References
Saunthararajah Y, Nakamura R, Man JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 2002;100:1570-1574.
Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002;137:156-163.
Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004;18:460-465.