thiotepa

Carmustine in the Therapy of B-Cell Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA , , ,

DA Koroleva, EE Zvonkov

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Daria Aleksandrovna Koroleva, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-44-72; e-mail: koroleva_12-12@mail.ru

For citation: Koroleva DA, Zvonkov EE. Carmustine in the Therapy of B-Cell Lymphomas. 2021;14(4):496–502. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-496-502

ABSTRACT

Aim. To analyze the efficacy and toxicity of different high-dose chemotherapy protocols for the purpose of determining the optimal conditioning regimen with autologous hematopoietic stem cell transplantation (auto-HSCT).

Materials & Methods. The present review provides the analysis of some comparative retrospective studies. The evidence-based analysis proceeded in two stages consisting of a search and then primary processing of available literature. The PubMed database was searched for publications for the period 2004–2020.

Results. In relapsed and refractory non-Hodgkin’s lymphomas as well as in Hodgkin’s lymphoma, the literature analysis demonstrated satisfactory efficacy of carmustine as part of BEAM conditioning. With the use of the BEAM conditioning regimen with subsequent auto-HSCT, up to 50 % of complete remissions were achieved in patients with non-Hodgkin’s lymphomas and up to 70 % in patients with Hodgkin’s lymphoma. Comparative studies show that despite concerns about severe toxicity, the use of carmustine was not associated with an increase in the incidence of adverse events. Lung and liver toxicity proved to be comparable with that of being observed while using alternative programs of high-dose chemotherapy and corresponded to 9 % and 6 % on LEAM and BEAM regimens, respectively. Besides, carmustine feasibility in primary diffuse large B-cell CNS lymphoma was considered and analyzed in the context of the lack of thiotepa.

Conclusion. High efficacy of carmustine as part of BEAM conditioning with subsequent auto-HSCT was proved in extremely unfavorable patients with relapsed and refractory non-Hodgkin’s lymphomas and Hodgkin’s lymphoma with an acceptable toxicity profile. The study of carmustine in the therapy of primary CNS lymphoma seems to be аn important area of clinical studies aimed at developing rational treatment options.

Keywords: carmustine, non-Hodgkin’s lymphomas, Hodgkin’s lymphoma, auto-HSCT, lomustine, thiotepa, primary diffuse large B-cell CNS lymphoma.

Received: July 15, 2021

Accepted: September 10, 2021

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Fleming AB, Saltzman WM. Pharmacokinetics of the carmustine implant. Clin Pharmacokinet. 2002;41(6):403–19. doi: 10.2165/00003088-200241060-00002.
  2. Damaj G, Cornillon J, Bouabdallah K, et al. Carmustine replacement in intensive chemotherapy preceding reinjection of autologous HSCs in Hodgkin and non-Hodgkin lymphoma: A review. Bone Marrow Transplant. 2017;52(7):941–9. doi: 10.1038/bmt.2016.340.
  3. Fenske TS, Zhang MJ, Carreras J, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: Analysis of transplantation timing and modality. J Clin Oncol. 2014;32(4):273–81. doi: 10.1200/jco.2013.49.2454.
  4. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105(7):2677–84. doi: 10.1182/blood-2004-10-3883.
  5. Wang TF, Fiala MA, Cashen AF, et al. A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma. Bone Marrow Transplant. 2014;49(11):1366–70. doi: 10.1038/bmt.2014.163.
  6. Bachanova V, Burns LJ. Hematopoietic cell transplantation for Waldenstrom macroglobulinemia. Bone Marrow Transplant. 2012;47(3):330–6. doi: 10.1038/bmt.2011.105.
  7. Sharma A, Kayal S, Iqbal S, et al. Comparison of BEAM vs. LEAM regimen in autologous transplant for lymphoma at AIIMS. Springerplus. 2013;2(1):1–6. doi: 10.1186/2193-1801-2-489.
  8. Colita A, Colita A, Bumbea H, et al. LEAM vs. BEAM vs. CLV Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphomas. Retrospective Comparison of Toxicity and Efficacy on 222 Patients in the First 100 Days After Transplant, On Behalf of the Romanian Society for Bon. Front Oncol. 2019;9:892. doi: 10.3389/fonc.2019.00892.
  9. Kothari J, Foley M, Peggs KS, et al. A retrospective comparison of toxicity and initial efficacy of two autologous stem cell transplant conditioning regimens for relapsed lymphoma: LEAM and BEAM. Bone Marrow Transplant. 2016;51(10):1397–9. doi: 10.1038/bmt.2016.134.
  10. Tsang ES, Villa D, Loscocco F, et al. High-dose Benda-EAM versus BEAM in patients with relapsed/refractory classical Hodgkin lymphoma undergoing autologous stem cell transplantation. Bone Marrow Transplant. 2019;54(3):481–4. doi: 10.1038/s41409-018-0328-9.
  11. Joffe E, Rosenberg D, Rozovski U, et al. Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin’s and non-Hodgkin’s B-cell lymphoma. Bone Marrow Transplant. 2018;53(1):29–33. doi: 10.1038/bmt.2017.205.
  12. Duque-Afonso J, Ihorst G, Waterhouse M, et al. Comparison of reduced-toxicity conditioning protocols using fludarabine, melphalan combined with thiotepa or carmustine in allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2021;56(1):110–20. doi: 10.1038/s41409-020-0986-2.
  13. Puig N, De La Rubia J, Remigia MJ, et al. Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma. 2006;47(8):1488–94. doi: 10.1080/10428190500527769.
  14. Caimi PF, William BM, Rondon CH S, et al. Comparison of 2 Carmustine-Containing Regimens in the Rituximab Era: Excellent Outcomes Even in Poor-Risk Patients. Biol Blood Marrow Transplant. 2015;21(11):1926–31. doi: 10.1016/j.bbmt.2015.06.007.
  15. Kirschey S, Flohr T, Wolf HH, et al. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: Mature results of a phase II multicentre study. Br J Haematol. 2015;168(6):824–34. doi: 10.1111/bjh.13234.
  16. Brandes AA, Tosoni A, Amista P, et al. How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology. 2004;63(7):1281–4. doi: 10.1212/01.wnl.0000140495.33615.ca.
  17. Alnahhas I, Jawish M, Alsawas M, et al. Autologous Stem-Cell Transplantation for Primary Central Nervous System Lymphoma: Systematic Review and Meta-analysis. Clin Lymphoma Myel Leuk. 2019;19(3):е129–е141. doi: 10.1016/j.clml.2018.11.018.
  18. Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. 2015;125(9):1403–10. doi: 10.1182/blood-2014-10-604561.

Experience with the Use of Thio/Mel Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

LYMPHOID TUMORS , , , ,

SV Gritsaev1, II Kostroma1, AA Zhernyakova1, IM Zapreeva1, EV Karyagina2, ZhV Chubukina1, SA Tiranova1, IS Martynkevich1, SS Bessmeltsev1, AV Chechetkin1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

For correspondence: Ivan Ivanovich Kostroma, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(921)784-82-82; e-mail: obex@rambler.ru

For citation: Gritsaev SV, Kostroma II, Zhernyakova AA, et al. Experience with the Use of Thio/Mel Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma. Clinical oncohematology. 2019;12(3):282–8 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-282-288

ABSTRACT

Background. In multiple myeloma (MM) treatment a single autologous hematopoietic stem cell transplantation (auto-HSCT) is preceded by conditioning regimens aimed at intensifying cytoreductive effect. In the course of ongoing search for combined conditioning regimens an attractive option proved to be thiotepa/melphalan combination.

Aim. Data analysis of a pilot study of the efficacy of conditioning regimens including administration of two alkylating agents (thiotepa and melphalan) with subsequent auto-HSCT.

Materials & Methods. 9 patients received 10 auto-HSCTs with conditioning regimen including administration of 250 mg/m2 of thiotepa on Day –5 and 140 mg/m2 of melphalan on Day –2. After auto-HSCT pegylated filgrastim was administered in 8 patients. Engraftment period was calculated on the basis of absolute neutrophil count ≥ 0,5 × 109/L and thrombocyte level ≥ 20 × 109/L. Regimen toxicity was assessed according to CTCAE v5.0. Survival rates were estimated by Kaplan-Meier curves.

Results. The use of thiotepa did not require administration of any additional drugs. The incidence of mucositis and enteropathy of grade 1–2 was 100 % and 70 %, respectively. Pyrexia was reported in 7 auto-HSCTs. Pneumonia occurred in 1 patient. The infusion of 1–3 doses of platelet concentrate (median of 2 doses) was required in all patients except for one. Donor erythrocytes were transfused to 3 patients. Engraftment was reported in all patients within the period of 10–14 days. Median hospitalization duration from Day 0 to hospital discharge was 16 patient-days. After auto-HSCT the quality of response improved in 6 out of 9 patients. MM progression was reported in one patient with complex karyotype. Further follow-up showed progression in 2 patients. By December 2018 median follow-up of 9 patients from the date of auto-HSCT was 9 months (range 3–20 months), median progression-free survival was 17 months, median overall survival was not reached.

Conclusion. Acceptable toxicity, improvement of response quality, and maintenance of it for up to 20 months allow to consider combined conditioning regimen Thio/Mel to be a possible alternative to the standard Mel200 regimen.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, conditioning regimen, thiotepa, melphalan.

Received: December 26, 2018

Accepted: May 25, 2019

Read in PDF 

REFERENCES

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома: руководство для врачей. М.: СИМК, 2016. 512 с.

    [Bessmeltsev SS, Abdulkadyrov KM. Mnozhestvennaya mieloma: rukovodstvo dlya vrachei. (Multiple myeloma: manual for physicians.) Moscow: SIMK Publ.; 2016. 512 p. (In Russ)]

  2. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1-S2-1-24.

    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl 2):1–24. doi: 10.18821/0234-5730-2016-61-1-S2-1-24. (In Russ)]

  3. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046–60. doi: 10.1056/NEJMra1011442.

  4. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. 2011;117(23):6063–73. doi: 10.1182/blood-2011-02-297325.

  5. Engelhardt M, Terpos E, Kleber M, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica. 2014;99(2):232–42. doi: 10.3324/haematol.2013.099358.

  6. Sidiqi MH, Aljama MA, Bin Riaz I, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) followed by autologous stem cell transplant for multiple myeloma. Blood Cancer J. 2018;8(8):106. doi: 10.1038/s41408-018-0147-7.

  7. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–20. doi: 10.1056/NEJMoa1611750.

  8. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91–7.

  9. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. doi: 10.1056/NEJMoa1402888.

  10. Thoennissen GB, Gorlich D, Bacher U, et al. Autologous stem cell transplantation in multiple myeloma in the era of novel drug induction: a retrospective single-center analysis. Acta Haematol. 2017;137(3):163–72. doi: 10.1159/000463534.

  11. Ozaki S, Harada T, Saitoh T, et al. Survival of multiple myeloma patients aged 65–70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network. Acta Haematol. 2014;132(2):211–9. doi: 10.1159/000357394.

  12. Cavo M, Salwender H, Rosinol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase III European studies. Blood. 2013;122(21):767.

  13. Cavo M, Beksac M, Dimopoulos M, et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM trial). 2016;128(22):673.

  14. Sonneveld P, Beksac M, van der Holt B, et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM Trial). 2016;128(22):242.

  15. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 – StaMINA Trial). 2016;128(22):LBA-1.

  16. Yhim HY, Kim K, Kim JS, et al. Matched-pair analysis to compare the outcomes of a second salvage auto-SCT to systemic chemotherapy alone in patients with multiple myeloma who relapsed after front-line auto-SCT. Bone Marrow Transplant. 2013;48(3):425–32. doi: 10.1038/bmt.2012.164.

  17. Olin RL, Vogl DT, Porter DL, et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant. 2009;43(5): 417–22. doi: 10.1038/bmt.2008.334.

  18. Abbi KKS, Zheng J, Devlin SM, et al. Second autologous stem cell transplant: an effective therapy for relapsed multiple myeloma. Biol Blood Marrow Transplant. 2015;21(3):468–72. doi: 10.1016/j.bbmt.2014.11.677.

  19. Cook G, Williams C, Brown JM, et al. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(8):874–85. doi: 10.1016/S1470-2045(14)70245-1.

  20. Benson DM, Panzner K, Hamadani M, et al. Effects of induction with novel agents versus conventional chemotherapy on mobilization and autologous stem cell transplant outcomes in multiple myeloma. Leuk Lymphoma. 2010;51(2):243–51. doi: 10.3109/10428190903480728.

  21. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation following IMiD-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118(6):1585–92. doi: 10.1002/cncr.26422.

  22. Ashcroft J, Judge D, Dhanasiri S, et al. Chart review across EU5 in MM post-ASCT patients. Int J Hematol Oncol. 2018;7(1):IJH05. doi: 10.2217/ijh-2018-0004.

  23. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35(29):3279–89. doi: 10.1200/JCO.2017.72.6679.

  24. Kumar S, Lacy MQ, Dispenzieri A, et al. High-dose therapy and autologous stem cell transplantation for multiple myeloma poorly responsive to initial therapy. Bone Marrow Transplant. 2004;34(2):161–7. doi: 10.1038/sj.bmt.1704545.

  25. Kim JS, Kim K, Cheong JW, et al. Complete remission status before autologous stem cell transplantation is an important prognostic factor in patients with multiple myeloma undergoing upfront single autologous transplantation. Biol Blood Marrow Transplant. 2009;15(4):463–70. doi: 10.1016/j.bbmt.2008.12.512.

  26. Gertz MA, Kumar S, Lacy MQ, et al. Stem cell transplantation in multiple myeloma: impact of response failure with thalidomide or lenalidomide induction. Blood. 2010;115(12):2348–53. doi: 10.1182/blood-2009-07-235531.

  27. Грицаев С.В., Кузяева А.А., Бессмельцев С.С. Отдельные аспекты аутологичной трансплантации гемопоэтических стволовых клеток при множественной миеломе. Клиническая онкогематология. 2017;10(1):7–12. doi: 21320/2500-2139-2017-10-1-7-12.

    [Gritsaev SV, Kuzyaeva AA, Bessmeltsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12. doi: 10.21320/2500-2139-2017-10-1-7-12. (In Russ)]

  28. Musso M, Messina G, Marcacci G, et al. High-dose melphalan plus thiotepa as conditioning regimen before second autologous stem cell transplantation for “de novo” multiple myeloma patients: a phase II study. Biol Blood Marrow Transplant. 2015;21(11):1932–8. doi: 10.1016/j.bbmt.2015.06.011.

  29. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–46. doi: 10.1016/S1470-2045(16)30206-6.

  30. Schiffman KS, Bensinger WI, Appelbaum FR, et al. Phase II study of high-dose busulfan, melphalan and thiotepa with autologous peripheral blood stem cell support in patients with malignant disease. Bone Marrow Transplant. 1996;17(6):943–50.

  31. Zaid AB, Abdul-Hai A, Grotto I, et al. Autologous transplant in multiple myeloma with an augmented conditioning protocol. Leuk Lymphoma. 2013;54(11):2480–4. doi: 10.3109/10428194.2013.782608.

  32. Anagnostopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer. 2004;100(12):2607–12. doi: 10.1002/cncr.20294.

  33. Hari P, Reece DE, Randhawa J, et al. Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival. Bone Marrow Transplant. 2019;54(2):293–9. doi: 10.1038/s41409-018-0261-y.

  34. Auner HW, Iacobelli S, Sbianchi G, et al. Melphalan 140 mg/m2 or 200 mg/m2 for autologous transplantation in myeloma: results from the collaboration to collect autologous transplant outcomes in lymphoma and myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party. Haematologica. 2018;103(3):514–21. doi: 10.3324/haematol.2017.181339.

  35. Dimopoulos M, Wang M, Maisnar V, et al. Response and progression-free survival according to planned treatment duration in patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in the phase III ASPIRE study. J Hematol Oncol. 2018;11(1):49. doi: 10.1186/s13045-018-0583-7.

  36. Costa LJ, Landau HJ, Chhabra S, et al. Phase 1/2 trial of carfilzomib plus high-dose melphalan preparative regimen for salvage autologous hematopoietic cell transplantation followed by maintenance carfilzomib in patients with relapsed/refractory multiple myeloma. Biol Blood Marrow Transplant. 2018;24(7):1379–85. doi: 10.1016/j.bbmt.2018.01.036.