Allogeneic and autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide conditioning therapy for relapsed/refractory non-Hodgkin lymphoma

Abstract

The optimal stem cell transplantation (SCT) conditioning therapy for relapsed/refractory non-Hodgkin lymphoma (NHL) is not clearly defined. In a retrospective analysis, we examined 25 patients with “high risk” relapsed/refractory NHL who received busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP16) conditioning with autologous or allogeneic SCT. The majority of patients had aggressive histology and 52% had primary refractory NHL. Furthermore, 48% of patients had chemotherapy-resistant disease at the time of SCT. Fifty-six percent of patients underwent allogeneic SCT, while 44% had autologous SCT. The median engraftment time for neutrophils and platelets was 13.5 and 14 days, respectively. The 100-day treatment-related mortality (TRM) was 16%, while the 2-year non-relapse mortality (NRM) rate was also 16%. At a median follow-up of 15 months, the estimated 2-year disease-free survival (DFS) rate was 64% (95% confidence interval (CI): 36%-82%) and the estimated 2-year overall survival (OS) was 69% (95% CI: 40%-86%). Furthermore, the 2-year disease-specific survival (DSS) rate was 73% (95% CI: 40%-90%). Using Cox proportional hazard modeling, the International Prognostic Index at time of relapse predicted DFS and OS. Altogether, Bu/Cy/VP16 was associated with early TRM; however, late toxicities (including NRM) were uncommon resulting in relatively good survival rates in a high-risk relapsed/refractory NHL population.

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Vidula, N. , Evens, A. , Helenowski, I. , Jovanovic, B. , Winter, J. , Mehta, J. , Singhal, S. , Williams, S. , Frankfurt, O. , Altman, J. , Monreal, J. and Gordon, L. (2013) Allogeneic and autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide conditioning therapy for relapsed/refractory non-Hodgkin lymphoma. Modern Chemotherapy, 2, 57-65. doi: 10.4236/mc.2013.24007.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Haioun, C., Lepage, E., Gisselbrecht, C., Salles, G., Coiffier, B., Brice, P., et al. (2000) Survival benefit of highdose therapy in poor-risk aggressive non-Hodgkin’s lymphoma: Final analysis of the prospective LNH87-2 protocol—a groupe d’Etude des lymphomes de l’Adulte study. Journal of Clinical Oncology, 18, 3025-3030. PMid:10944137.
[2] Milpied, N., Deconinck, E., Gaillard, F., Delwail, V., Foussard, C., Berthou, C., et al. (2004) Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. New England Journal of Medicine, 350, 1287-1295.
http://dx.doi.org/10.1056/NEJMoa031770
[3] Pettengell, R., Radford, J.A., Morgenstern, G.R., Scarffe, J.H., Harris, M., Woll, P.J., et al. (1996) Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 14, 586-592. PMid:8636775.
[4] Philip, T., Guglielmi, C., Hagenbeek, A., Somers, R., Van der Lelie, H., Bron, D., et al. (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. New England Journal of Medicine, 333, 1540-1545.
http://dx.doi.org/10.1056/NEJM199512073332305
[5] Vose, J.M., Armitage, J.O., Bierman, P.J., Weisenburger, D.D., Hutchins, M., Dowling, M.D., et al. (1989) Salvage therapy for relapsed or refractory non-Hodgkin’s lymphoma utilizing autologous bone marrow transplantation. The American Journal of Medicine, 87, 285-288.
http://dx.doi.org/10.1016/S0002-9343(89)80152-4
[6] Aggarwal, C., Gupta, S., Vaughan, W.P., Saylors, G.B., Salzman, D.E., Katz, R.O., et al. (2006) Improved outcomes in intermediate-and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen. Biology of Blood and Marrow Transplantation, 12, 770-777.
http://dx.doi.org/10.1016/j.bbmt.2006.03.016
[7] Copelan, E.A., Penza, S.L., Pohlman, B., Avalos, B.R., Goormastic, M., Andresen, S.W., et al. (2000) Autotransplantation following busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant, 25, 1243-1248.
http://dx.doi.org/10.1038/sj.bmt.1702433
[8] Escalón, M.P., Stefanovic, A., Venkatraman, A., Pereira, D., Santos, E.S., Goodman, M., et al. (2009) Autologous transplantation for relapsed non-Hodgkin’s lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: A single center experience. Bone Marrow Transplant, 44, 89-96.
http://dx.doi.org/10.1038/bmt.2008.429
[9] Hanel, M., Kroger, N., Sonnenberg, S., Bornhauser, M., Krüger, W., Kroschinsky, F., et al. (2002) Busulfan, cyclophosphamide, and etoposide as high dose conditioning regimen in patients with malignant lymphoma. Annals of Hematology, 81, 96-102.
http://dx.doi.org/10.1007/s00277-001-0413-8
[10] Kim, J.G., Sohn, S.K., Chae, Y.S., Yang, D.H., Lee, J.J., Kim, H.J., et al. (2007) Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (i.v. Bu/Cy/E) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant, 40, 919-924.
http://dx.doi.org/10.1038/sj.bmt.1705841
[11] Kim, J.E., Lee, D.H., Yoo, C., Kim, S., Kim, S.W., Lee, J.S., et al. (2011) BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: A single center comparative analysis of efficacy and toxicity. Leukemia Research, 35, 183-187.
http://dx.doi.org/10.1016/j.leukres.2010.07.016
[12] Kroger, N., Hoffknecht, M., Dreger, P., Krüger, W., Zeller, W., Krüll, A., et al. (1998) Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy. Bone Marrow Transplant, 21, 55-57. http://dx.doi.org/10.1038/sj.bmt.1701033
[13] Vaughan, W.P., Dennisone, J.D., Reed, E.C., Klassen, L., McGuire, T.R., Sanger, W.G., et al. (1991) Improved results of allogeneic bone marrow transplantation for advanced hematologic malignancy using busulfan, cyclophosphamide and etoposide as cytoreductive and immunosuppressive therapy. Bone Marrow Transplant, 8, 489-495. PMid:1790429.
[14] Bolwell, B., Kalaycio, M., Andresen, S., Goormastic, M., McBee, M., Kuczkowski, E., et al. (2000) Autologous peripheral blood progenitor cell transplantation for transformed diffuse large-cell lymphoma. Clinical Lymphoma, 1, 226-233. http://dx.doi.org/10.3816/CLM.2000.n.019
[15] Kroger, N, Hoffknecht, M., Dreger, P., Krüger, W., Zeller, W., Krüll, A., et al. (1998) Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy. Bone Marrow Transplant, 21, 55-57.
http://dx.doi.org/10.1038/sj.bmt.1701033
[16] Philip, T., Armitage, J.O., Spitzer, G., Chauvin, F., Jagannath, S., Cahn, J., et al. (1987) High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediategrade or high-grade non-Hodgkin’s lymphoma. New England Journal of Medicine, 316, 1493-1498.
http://dx.doi.org/10.1056/NEJM198706113162401
[17] Schouten, H.C., Colombat, P., Verdonck, L.F., Gorin, N.C., Bjorkstrand, B., Taghipour, G., et al. (1994) Autologous bone marrow transplantation for low-grade non-Hodgkin’s lymphoma: The European Bone Marrow Transplant Group experience. EBMT Working Party for Lymphoma. Annals of Oncology, 5, 147-149.
http://dx.doi.org/10.1093/annonc/5.suppl_2.S147
[18] Sweetenham, J.W., Proctor, S.J., Blaise, D., De Laurenzi, A., Pearce, R., Taghipour, G., et al. (1994) High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with highgrade non-Hodgkin’s lymphoma: The EBMT experience. Lymphoma Working Party of the European Group for Bone Marrow Transplantation. Annals of Oncology, 5, 155-159.
http://dx.doi.org/10.1093/annonc/5.suppl_2.S155
[19] Takvorian, T., Canellos, G.P., Ritz, J., Freedman, A.S., Anderson, K.C., Mauch, P., et al. (1987) Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin’s lymphoma with a poor prognosis. New England Journal of Medicine, 316, 1499-1505.
http://dx.doi.org/10.1056/NEJM198706113162402
[20] Weaver, C.H., Petersen, F.B., Appelbaum, F.R., Bensinger, W.I., Press, O., Martin, P., et al. (1994) High-dose fractionated total body irradiation, etoposide, and cyclophosphamide followed by autologous stem cell support in patients with malignant lymphoma. Journal of Clinical Oncology, 12, 2559-2566. PMid:7989929.
[21] Gulati, S., Yahalom, J., Acaba, L., Reich, L., Motzer, R., Crown, J., et al. (1992) Treatment of patients with relapsed and resistant non-Hodgkin’s lymphoma using total body irradiation, etoposide, and cyclophosphamide and autologous bone marrow transplantation. Journal of Clinical Oncology, 10, 936-941.
[22] Stiff, P.J., Dahlberg, S., Forman, S.J., McCall, A.R., Horning, S.J., Nademanee, A.P., et al. (1998) Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin’s lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. Journal of Clinical Oncology, 16, 48-55.
[23] Santos, E.C., Sessions, J., Hutcherson, D., Flowers, C., Langston, A. and Waller EK. (2007) Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation—A similar experience. Biology of Blood and Marrow Transplantation, 13, 746-747.
http://dx.doi.org/10.1016/j.bbmt.2007.02.006
[24] Zhang, H., Graiser, M., Hutcherson, D.A., Olufemi Dada, M., McMillan, S., Zahir, A., et al. (2012) Pharmacokinetic-directed high dose busulfan combined with cyclophosphamide and etoposide results in predictable drug levels and durable long term survival in lymphoma patients undergoing autologous stem cell transplantation. Biology of Blood and Marrow Transplant, 18, 1287-1294.
http://dx.doi.org/10.1016/j.bbmt.2012.02.006
[25] Ritchie, D.S., Szer, J., Roberts, A.W., Shuttleworth, P. and Grigg, A.P. (2002) A phase I dose-escalation study of etoposide continuous infusion added to busulphan/cyclophosphamide as conditioning prior to autologous or allogeneic stem cell transplantation. Bone Marrow Transplantation, 30, 645-650.
http://dx.doi.org/10.1038/sj.bmt.1703698
[26] Kashyap, A., Wingard, J., Cagnoni, P., Roy, J., Tarantolo, S., Hu, W., et al. (2002) Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biology of Blood and Marrow Transplantation, 8, 493-500.
http://dx.doi.org/10.1053/bbmt.2002.v8.pm12374454
[27] Wadehra, N., Farag, S., Bolwell, B., Elder, P., Penza, S., Kalaycio, M., et al. (2006) Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation. Biology of Blood and Marrow Transplantation, 12, 1343-1349.
http://dx.doi.org/10.1016/j.bbmt.2006.08.039
[28] Crilley, P., Topolsky, D., Styler, M.J., Bernstein, E., Resnick K, Mullaney, R., et al. (1995) Extramedullary toxicity of a conditioning regimen containing busulphan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogenic bone marrow transplantation. Bone Marrow Transplantation, 15. 361-365.
PMid:7599559
[29] Spitzer, T.R., Cottler-Fox, M., Torrisi, J., Cahill, R., Greenspan, A., Lynch, M., et al. (1989) Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Bone Marrow Transplantation, 4, 559-565. PMid:2676044.
[30] Kalaycio, M., Pohlman, B., Kuczkowski, E., Rybicki, L., Andresen, S., Sobecks, R., et al. (2006) High-dose busulfan and the risk of pulmonary mortality after autologous stem cell transplant. Clinical Transplantation, 20, 783-787. http://dx.doi.org/10.1111/j.1399-0012.2006.00581.x

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