Yttrium-90 ibritumomab tiuxetan (Zevalin) followed by BEAM (Z-BEAM) conditioning regimen and autologous stem cell transplantation (ASCT) in relapsed or refractory high-risk B-cell non-Hodgkin lymphoma (NHL): a single institution Italian experience

  • Chiara Ciochetto
  • Barbara Botto
  • Roberto Passera
  • Marilena Bellò
  • Giulia Benevolo
  • Carola Boccomini
  • Alessia Castellino
  • Annalisa Chiappella
  • Roberto Freilone
  • Maura Nicolosi
  • Lorella Orsucci
  • Clara Pecoraro
  • Patrizia Pregno
  • Gianni Bisi
  • Umberto Vitolo
Original Article
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Abstract

Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease.

Keywords

Autologous stem cell transplantation Aggressive refractory NHL Zevalin 

Notes

Author’s contributions

Chiara Ciochetto, Barbara Botto, and Umberto Vitolo designed the study; Chiara Ciochetto, Barbara Botto, and Umberto Vitolo supervised the study, analyzed the data, and wrote the manuscript. Roberto Passera analyzed and interpreted the data, and all authors enrolled patients and reviewed and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

Umberto Vitolo was on the advisory committee of Roche, Janssen and received a lecture fee from Roche, Celgene, Janssen, Takeda, and Gilead.

The remaining authors declare no competing financial interests.

References

  1. 1.
    Coiffier B, Thieblemont C, Van Den Neste E et al (2010) Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’ Etudes des Lymphomes de l’Adulte. Blood 23(116):2040–2045CrossRefGoogle Scholar
  2. 2.
    Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D (2013) Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381(9880):1817–1826CrossRefPubMedGoogle Scholar
  3. 3.
    Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B, German High-Grade Lymphoma Study Group (DSHNHL) (2012) Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13(12):1250–1911CrossRefPubMedGoogle Scholar
  4. 4.
    Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N (2010) Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28(27):4184–4190CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mounier N, Canals C, Gisselbrecth C (2012) High dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the rituximab era: ana analysis base on data from the European Bloos and marrow transplantation registry. Biol Blood Marrow Transaplant 18:788–793CrossRefGoogle Scholar
  6. 6.
    Vose JM, Zhang MJ, Rowlings PA, Lazarus HM, Bolwell BJ, Freytes CO, Pavlovsky S, Keating A, Yanes B, van Besien K, Armitage JO, Horowitz MM, Others of the Autologous Blood and Marrow Transplant Registry Lymphoma Working Committee (2001) 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 19(2):406–413CrossRefPubMedGoogle Scholar
  7. 7.
    Caballero MD, Pérez-Simón JA, Iriondo A, Lahuerta JJ, Sierra J, Marín J, Gandarillas M, Arranz R, Zuazu J, Rubio V, Fernández de Sevilla A, Carreras E, García-Conde J, García-Laraña J, Grande C, Sureda A, Vidal MJ, Rifón J, Pérez-Equiza C, Varela R, Moraleda JM, García Ruíz JC, Albó C, Cabrera R, San Miguel JF, Conde E (2003) High dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish cooperative group. Ann Oncol 14(1):140–151CrossRefPubMedGoogle Scholar
  8. 8.
    Shimoni A, Nagler A (2007) Radioimmunotherapy and stem-cell transplantation in the treatment of aggressive B-cell lymphoma. Leuk Lymphoma 48(11):2110–2120CrossRefPubMedGoogle Scholar
  9. 9.
    Witzig TE, White CA, Gordon LI, Wiseman GA, Emmanouilides C, Murray JL, Lister J, Multani PS (2003) Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin’s lymphoma. J Clin Oncol 21(7):1263–1270CrossRefPubMedGoogle Scholar
  10. 10.
    Krishnan A, Nademanee A, Fung HC, Raubitschek AA, Molina A, Yamauchi D, Rodriguez R, Spielberger RT, Falk P, Palmer JM, Forman SJ (2008) Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and highdose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 26(1):90–95CrossRefPubMedGoogle Scholar
  11. 11.
    Nademanee A, Forman S, Molina A et al (2005) A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 106(8):2896–2902CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A (2012) A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer 118(19):4706–4714CrossRefPubMedGoogle Scholar
  13. 13.
    Musso M, Messina G, Di Renzo N et al (2016) Improved outcome of patients with relapsed/refractory Hodgkin lymphoma with a new fotemustine-based high-dose chempotherapy regimen. Br J Heamatol 172:111–121CrossRefGoogle Scholar
  14. 14.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on Lymphoma (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25(5):579–586CrossRefPubMedGoogle Scholar
  15. 15.
    Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A (2007) Yttrium 90 Ibritumomab Tiuxetan (Zevalin) combined with high dose BEAM chemotherapy and autologous stem cell transplantation for chemorefractory aggressive non-Hodgkin’s lymphoma. Exp Hematol 35(4):534–540CrossRefPubMedGoogle Scholar
  16. 16.
    Briones J, Novelli S, Garcia-Marco JA, Tomas JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernandez M, Gonzalez-Barca E, Lopez D, Caballero D, on behalf of GELTAMO (2014) Autologous stem cell transplantation after conditioning with yttrium 90 Ibritumomab Tiuxetan plus BEAM in refractory non-Hodgkin’s diffuse large B cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica 99(3):505–510CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M (2013) Phase III randomized study of rituximab carmustine, etoposide cytarabine and melfalan (BEAM) compared with iodine-131 Tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol 31:1662–1668CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Krishnan AY, Palmer J, Nademanee AP, Chen R, Popplewell LL, Tsai NC, Sanchez JF, Simpson J, Spielberger R, Yamauchi D, Forman SJ (2017) Phase II study of yttrium-90 ibritumomab tiuxetan plus high dose BCNU, etoposide, cytarabine and melphalan for non-Hodgkin lymphoma: the role of hystology. Biol Bone Marrow Transplant 23:922–929CrossRefGoogle Scholar
  19. 19.
    Kewalramani T, Zelenetz AD, Hedrick EE, Donnelly GB, Hunte S, Priovolos AC, Qin J, Lyons NC, Yahalom J, Nimer SD, Moskowitz CH (2000) High-dose chemoradiotherapy and autologous stem cell transplantation for patients with primary refractory aggressive non-Hodgkin lymphoma: an intention-to-treat analysis. Blood 96(7):2399–2404PubMedGoogle Scholar
  20. 20.
    Czuczman MS, Emmanouilides C, Darif M, Witzig TE, Gordon LI, Revell S, Vo K, Molina A (2007) Treatment-related myelodysplastic syndrome and acute myelogenous leukemia in patients treated with ibritumomab tiuxetan radioimmunotherapy. J Clin Oncol 25(27):4285–4292CrossRefPubMedGoogle Scholar
  21. 21.
    Winter JN, Inwards DJ, Spies S, Wiseman G, Patton D, Erwin W, Rademaker AW, Weitner BB, Williams SF, Tallman MS, Micallef I, Mehta J, Singhal S, Evens AM, Zimmer M, Molina A, White CA, Gordon LI (2009) Yttrium-90 ibritumomab tiuxetan doses calculated to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous transplantation in relapsed or refractory B-cell non- Hodgkin’s lymphoma. J Clin Oncol 27(10):1653–1659CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Philip T, Guglielmi C, Hagenbeek A, Somers R, van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F, Chauvin F (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–1545CrossRefPubMedGoogle Scholar
  23. 23.
    Derenzini E, Musuraca G, Fanti S, Stefoni V, Tani M, Alinari L, Venturini F, Gandolfi L, Baccarani M, Zinzani PL (2008) Pretransplantation positron emission tomography scan is the main predictor of autologous stem cell transplantation out-come in aggressive B-cell non-Hodgkin lymphoma. Cancer 113(9):2496–2503CrossRefPubMedGoogle Scholar
  24. 24.
    Poulou LS, Thanos L, Ziakas PD (2010) Unifying the predictive value of pretransplant FDG PET in patients with lymphoma: a review and meta-analysis of published trials. Eur J Nucl Med Mol Imaging 37:156–162CrossRefPubMedGoogle Scholar
  25. 25.
    Schot BW, Zijlstra JM, Sluiter WJ, van Imhoff GW, Pruim J, Vaalburg W, Vellenga E (2007) Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma. Blood 109:486–491CrossRefPubMedGoogle Scholar
  26. 26.
    Crump M, Neelapu SS, Farooq U, van den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L, Boussetta S, Feng L, Maurer MJ, Navale L, Wiezorek J, Go WY, Gisselbrecht C (2017) Outcome in refractory diffuse large B-cell lymphoma: results from the international Scholar-1 study. Blood 130:1800–1808CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Chiara Ciochetto
    • 1
  • Barbara Botto
    • 1
  • Roberto Passera
    • 1
  • Marilena Bellò
    • 1
  • Giulia Benevolo
    • 1
  • Carola Boccomini
    • 1
  • Alessia Castellino
    • 1
  • Annalisa Chiappella
    • 1
  • Roberto Freilone
    • 1
  • Maura Nicolosi
    • 1
  • Lorella Orsucci
    • 1
  • Clara Pecoraro
    • 1
  • Patrizia Pregno
    • 1
  • Gianni Bisi
    • 1
  • Umberto Vitolo
    • 1
  1. 1.Hematology DepartmentCittà della Salute e della ScienzaTurinItaly

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