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Lymphoma

Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy

Bone Marrow Transplantation volume 29, pages 303–312 (2002)Cite this article

Abstract

Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m2) + etoposide (2.0 g/m2) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m2) on day −5, BCNU (300 mg/m2) + gemcitabine (1.0 g/m2) on day −2, melphalan (140 mg/m2) on day −1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m2) weekly for 4 weeks + GM-CSF (250 μg thrice weekly) (weeks 4–8); post-transplant involved-field radiotherapy (HD): 30–40 Gy to pre-transplant areas of disease (weeks 4–8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m2/day)/etoposide (30 mg/m2/day)/cisplatin (15 mg/m2/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m2, day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m2)/cisplatin (75 mg/m2) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan–Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan–Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3–4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.

Bone Marrow Transplantation (2002) 29, 303–312. doi:10.1038/sj.bmt.1703363

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References

  1. Surbone A, Armitage JO, Gale RP . Autotransplantation in lymphoma: better therapy for healthier patients? Ann Intern Med 1991 114: 1059 1060

    Article  CAS  PubMed  Google Scholar 

  2. Longo DL, Duffey PL, Young RC et al. Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy. The low probability for cure J Clin Oncol 1992 10: 210 218

    Article  CAS  PubMed  Google Scholar 

  3. Wheeler C, Strawderman M, Ayash L et al. Prognostic factors for treatment outcome in autotransplantation of intermediate grade and high-grade non-Hodgkin's lymphoma with cyclophosphamide, carmustine, and etoposide J Clin Oncol 1993 11: 1085 1091

    Article  CAS  PubMed  Google Scholar 

  4. Weaver CJ, Peterson FB, Appelbaum FR et al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma J Clin Oncol 1994 12: 2559 2566

    Article  CAS  PubMed  Google Scholar 

  5. Horning SJ, Negrin RS, Chao NJ et al. Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma J Clin Oncol 1994 12: 2552 2558

    Article  CAS  PubMed  Google Scholar 

  6. Vose JM, Zhang MJ, Rowlings P et al. Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry J Clin Oncol 2001 19: 406 413

    Article  CAS  PubMed  Google Scholar 

  7. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma Bone Marrow Transplant 1999 6: 561 567

    Article  Google Scholar 

  8. Kewalramani T, Zelenetz AD, Hedrick EE et al. High-dose chemotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis Blood 2000 96: 2399 2404

    CAS  PubMed  Google Scholar 

  9. Stiff PJ, Dahlberg S, Forman SJ et al. 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 J Clin Oncol 1998 16: 48 55

    Article  CAS  PubMed  Google Scholar 

  10. Copelan EA, Penza SL, Pohlman B et al. Autotransplantation followoing busulfan, etoposide and cyclophosphamide in patients with non-Hodgkin's lymphoma Bone Marrow Transplant 2000 25: 1243 1248

    Article  CAS  PubMed  Google Scholar 

  11. Chen CI, Crump M, Tsang R et al. Autotransplants for histologically transformed follicular non-Hodgkin's lymphoma Br J Haematol 2001 113: 202 208

    Article  CAS  PubMed  Google Scholar 

  12. Rapoport AP, Lifton R, Constine LS et al. Autotransplantation for relapsed or refractory non-Hodgkin's lymphoma (NHL): long-term follow-up and analysis of prognostic factors Bone Marrow Transplant 1997 19: 883 890

    Article  CAS  PubMed  Google Scholar 

  13. Lancet JE, Rapoport AP, Brasacchio R et al. Autotransplantation for relapsed or refractory Hodgkin's disease: long-term follow-up and analysis of prognostic factors Bone Marrow Transplant 1998 22: 265 271

    Article  CAS  PubMed  Google Scholar 

  14. Sweetenham JW, Carella AM, Taghipour G et al. High-dose therapy and autologous stem-cell transplantation for adult patients with Hodgkin's disease who do not enter remission after induction chemotherapy: results in 175 patients reported to the European Group for Blood and Marrow Transplantation Lymphoma Working Party J Clin Oncol 1999 17: 3101 3109

    CAS  PubMed  Google Scholar 

  15. Fleming Dr, Wolff SN, Fay JW et al. Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group Leuk Lymphoma 1999 35: 91 98

    Article  CAS  PubMed  Google Scholar 

  16. Lazarus HM, Rowlings PA, Zhang M-J et al. Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the autologous blood and marrow transplant registry J Clin Oncol 1999 17: 534 545

    Article  CAS  PubMed  Google Scholar 

  17. Neben K, Hohaus S, Goldschmidt H et al. High-dose therapy with peripheral blood stem cell transplantation for patients with relapsed or refractory Hodgkin's disease: long-term outcome and prognostic factors Ann Hematol 2000 79: 547 555

    Article  CAS  PubMed  Google Scholar 

  18. Lazarus HM, Loberiza FR Jr, Zhang MJ et al. Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR) Bone Marrow Transplant 2001 27: 387 396

    Article  CAS  PubMed  Google Scholar 

  19. Sureda A, Arranz R, Iriondo A et al. Autologous stem-cell transplantation for Hodgkin's disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/Transplante Autologo de Medula Osea Spanish Cooperative Group J Clin Oncol 2001 19: 1395 1404

    Article  CAS  PubMed  Google Scholar 

  20. Goldstein LJ, Galski H, Fojo A et al. Expression of a multidrug resistant gene in human cancers J Natl Cancer Inst 1989 81: 116 124

    Article  CAS  PubMed  Google Scholar 

  21. Miller TP, Grogan TM, Dalton WS et al. P-glycoprotein in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil J Clin Oncol 1991 9: 17 24

    Article  CAS  PubMed  Google Scholar 

  22. Wilson WH, Teruya-Feldstein J, Fest T et al. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin's lymphomas Blood 1997 89: 601 609

    CAS  PubMed  Google Scholar 

  23. Hermine O, Haioun C, Lepage E for the Groupe d'Etude des Lymphomes de l'Adulte (GELA) et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma Blood 1996 87: 265 272

    CAS  PubMed  Google Scholar 

  24. Kramer MHH, Hermans J, Parker J et al. Clinical significance of bcl-2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study JCO 1996 14: 2131 2138

    Article  CAS  Google Scholar 

  25. Weinstein JN, Myers TG, O'Connor PM et al. An information-intensive approach to the molecular pharmacology of cancer Science 1997 275: 343 349

    Article  CAS  PubMed  Google Scholar 

  26. Heinemann V, Hertel LW, Grindey GB et al. Comparisons of the cellular pharmacokinetics and toxicity of 2’2’-difluorodeoxycytidine and 1-β-D-arabinofuranosylcytosine Cancer Res 1988 48: 4024 4031

    CAS  PubMed  Google Scholar 

  27. Hertel LW, Boder GB, Kroin S et al. Evaluation of the antitumor activity of gemcitabine (2′2′-difluoro-2′deoxycytidine) Cancer Res 1990 50: 4417 4422

    CAS  PubMed  Google Scholar 

  28. Waud WR, Gilbert KS, Grindey GB et al. Lack of in vivo crossresistance with gemcitabine against drug-resistant murine P388 leukemias Cancer Chemother Pharmacol 1996 38: 178 180

    Article  CAS  PubMed  Google Scholar 

  29. Santoro A, Devizzi L, Bonfante V et al. Phase II study with gemcitabine in pretreated patients with Hodgkin's (HD) and non-Hodgkin's lymphomas (NHL): results of a multicenter study Proc Am Soc Clin Oncol 1997 16: 21a (Abstr. 71)

    Google Scholar 

  30. Charak BS, Agah R, Mazumder A . Granulocyte–macrophage colony-stimulating factor-induced antibody-dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation Blood 1993 15: 3474 3479

    Google Scholar 

  31. Ragnhammar P, Frodin JE, Trotta PP, Mellstedt H . Cytotoxicity of white blood cells activated by granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor and macrophage-colony-stimulating factor against tumor cells in the presence of various monoclonal antibodies Cancer Immunol Immunother 1994 39: 254 262

    Article  CAS  PubMed  Google Scholar 

  32. Nagler A, Shur I, Barak V, Fabian I . Granulocyte–macrophage colony-stimulating factor dependent monocyte-mediated cytotoxicity post-autologous bone marrow transplantation Leuk Res 1996 20: 637 643

    Article  CAS  PubMed  Google Scholar 

  33. Stockmeyer B, Elsasser D, Dechant M et al. Mechanisms of G-CSF- or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies J Immunol Methods 2001 248: 103 111

    Article  CAS  PubMed  Google Scholar 

  34. Munshi NC, Desikan KR, Jagannath S et al. Dexamethasone, cyclophosphamide, etoposide and Cis-platinum (DCEP), an effective regimen for relapse after high-dose chemotherapy and autologous transplantation (AT) Blood 1996 88: (Suppl. 1) 586a (Abstr. 2331)

    Google Scholar 

  35. Santoro A, Bredenfeld H, Devizzi L et al. Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study J Clin Oncol 2000 18: 2615 2619

    Article  CAS  PubMed  Google Scholar 

  36. Haldar S, Jena N, Croce CM . Antiapoptosis potential of bcl-2 oncogene by dephosphorylation Biochem Cell Biol 1994 72: 455 462

    Article  CAS  PubMed  Google Scholar 

  37. Wilson WH, Chabner BA, Bryan TG et al. Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas J Clin Oncol 1995 13: 381 386

    Article  CAS  PubMed  Google Scholar 

  38. Younes A, Ayoub JP, Sarris A et al. Paclitaxel activity for the treatment of non-Hodgkin's lymphoma: final report of a phase II trial Br J Haematol 1997 96: 328 332

    Article  CAS  PubMed  Google Scholar 

  39. Younes A, Preti A, Romaguera J et al. Activity of taxol and high-dose cytoxan with granulocyte colony-stimulating factor (G-CSF) in 54 patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) Proc Am Soc Clin Oncol 1997 16: (Suppl. 1) 21a (Abstr. 74)

    Google Scholar 

  40. Kaplan EL, Meier P . Nonparametric estimation from incomplete observation J Am Stat Assoc 1958 53: 457 481

    Article  Google Scholar 

  41. Cox DR . Regression models and life tables J R Stat Soc B 1972 74: 187 220

    Google Scholar 

  42. Horwitz SM, Breslin S, Negrin RS et al. Adjuvant rituximab after autologous peripheral blood stem cell transplant (APBSCT) results in delayed immune reconstitution without increase in infectious complications Blood 2000 96: (Suppl. 1) 384a (Abstr. 1657)

    Google Scholar 

  43. Carella AM, Cavaliere M, Lerma E et al. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma J Clin Oncol 2000 18: 3918 3924

    Article  CAS  PubMed  Google Scholar 

  44. Laport GG, Liebowitz DN, Williams SF et al. Adoptive transfer of CD3/CD28 ex vivo costimulated T-cells in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL) following high dose chemotherapy (HDC) with CD34-selected peripheral blood stem cell (PBSC) support Blood 2000 11: (Suppl. 1) 407 (Abstr. 1751)

    Google Scholar 

  45. Titzer S, Christensen O, Manzke O et al. Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects Br J Haematol 2000 108: 805 816

    Article  CAS  PubMed  Google Scholar 

  46. Reichardt VL, Okada CY, Liso A et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma – a feasibility study Blood 1999 93: 2411 2419

    CAS  PubMed  Google Scholar 

  47. Lim SH, Bailey-Wood R . Idiotypic protein-pulsed dendritic cell vaccination in multiple myeloma Int J Cancer 1999 83: 215 222

    Article  CAS  PubMed  Google Scholar 

  48. Hsu FJ, Caspar CB, Czerwinski D et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma-long-term results of a clinical trial Blood 1997 89: 3129 3135

    CAS  PubMed  Google Scholar 

  49. Hsu FJ, Benike C, Fagnoni F et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells Nat Med 1996 2: 52 58

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Michele Mullins for expert assistance in the preparation of this manuscript and thank the BMT nurses of the Greenebaum Cancer Center for excellent and compassionate care of these study patients. APR is a Clinical Scholar of the Leukemia and Lymphoma Society. This study was supported in part by a grant from Immunex Corp.

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Authors and Affiliations

  1. Greenebaum Cancer Center and Stem Cell Transplantation Program, University of Maryland School of Medicine, Baltimore, MD, USA

    AP Rapoport, B Meisenberg, C Sarkodee-Adoo, SR Frankel, B Mookerjee, N Takebe, R Fenton, M Heyman, A Badros, A Kennedy, M Jacobs, R Hudes, K Ruehle, R Smith, L Kight, S Chambers, M MacFadden, T Chen & G Phillips

  2. University of Arkansas Myeloma Research Center, Little Rock, AR, USA

    A Fassas, M Cottler-Fox & G Tricot

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Rapoport, A., Meisenberg, B., Sarkodee-Adoo, C. et al. Autotransplantation for advanced lymphoma and Hodgkin's disease followed by post-transplant rituxan/GM-CSF or radiotherapy and consolidation chemotherapy. Bone Marrow Transplant 29, 303–312 (2002). https://doi.org/10.1038/sj.bmt.1703363

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