First-Line Treatment of Mantle-Cell Lymphoma: Analysis of Effectiveness and Cost-Effectiveness

LYMPHOID TUMORS , , , ,

KD Kaplanov1, NP Volkov1, TYu Klitochenko1, AL Shipaeva1, IV Matveeva1, MN Shirokova1, AC Proskurina1, NA Red’kina1, EG Gemdzhyan2

1 Volgograd Regional Clinical Oncologic Centre, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

2 National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Kamil’ Daniyalovich Kaplanov, MD, PhD, 78 Zemlyachki str., Volgograd, Russian Federation, 400138; e-mail: kamilos@mail.ru

For citation: Kaplanov KD, Volkov NP, Klitochenko TYu, et al. First-Line Treatment of Mantle-Cell Lymphoma: Analysis of Effectiveness and Cost-Effectiveness. Clinical oncohematology. 2018;11(2):150–9.

DOI: 10.21320/2500-2139-2018-11-2-150-159

ABSTRACT

Aim. To study the correlation between efficacy of mantle-cell lymphoma treatment in clinical practice and failure of first-line therapy and direct expenses depending on the first-line therapy selection.

Methods. During the period from 2008 to 2016 a comparative single-center controlled trial was performed to evaluate the effectiveness and toxicity of R-hyper-CVAD-R-HD-AraC (n = 16) regimen. The control group included patients treated with 6–8 cycles of R-CHOP (n = 39). Cytarabine dose was lower than the original regimen and contained not more than 1 g/m2 twice a day for 2 days. R-hyper-CVAD regimen included the standard drug doses. R-HD-AraC treatment started on day 28 from the beginning of the R-hyper-CVAD therapy. The R-hyper-CVAD-R-HD-AraC group consisted of patients with the following characteristics: the median age was 56 years (range 40–66), older than 60 — 6 (38 %), male patients — 12 (75 %), stage IV — 12 (75 %), bulky — 7 (44 %), with bone marrow involved — 11 (69 %), MIPIb high-risk — 8 (50 %), blastoid variant — 7 (44 %). Only 2 patients of the R-hyper-CVAD-R-HD-AraC group received high-dose consolidation treatment with autologous HSC transplantation. HSCT was not performed in the control group. The results of comparative analysis were adjusted to age. In terms of the other significant factors the groups under comparison were similar.

Results. All the patients of the study group were treated with 3 R-hyper-CVAD and 3 R-HD-AraC regimens. The rate of complete remission was significantly higher than in the control group —12 (75 %) vs. 14 (36 %). No differences were observed in the 5-year overall survival: 55 % in the R-hyper-CVAD-R-HD-AraC group and 58 % in the R-CHOP group (p = 0.75). Second-line therapy was received by 8 out of 15 (47 %) patients treated with R-hyper-CVAD-R-HD-AraC, and by 18 out of 23 (78 %) patients treated with R-CHOP. Median time before second-line therapy was significantly higher in the R-hyper-CVAD-R-HD-AraC group — 26 vs. 6 months (p = 0.018). The costs of the first and subsequent therapy lines were analysed using a Markov model. Cost analysis of first-line therapy variants to be compared was based on cost-effectiveness ratio (CER) and incremental cost-effectiveness ratio (ICER). The analysis proved the cost-effectiveness of R-hyper-CVAD-R-HD-AraC program.

Conclusion. R-hyper-CVAD-R-HD-AraC program meets eligibility criteria for effectiveness, toxicity and cost-effectiveness and can, therefore, be recommended as first-line therapy of mantle-cell lymphoma and be used for the further comparative clinical trials.

Keywords: mantle-cell lymphoma, immunochemotherapy, pharmacoeconomics, Markov model, cost-effectiveness analysis.

Received: January 7, 2018

Accepted: March 3, 2018

Read in PDF 

REFERENCES

  1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89(11):3909–18.
  2. Zelenetz AD, Gordon LI, Wierda WG, et al. Non-Hodgkin’s lymphomas, version 4.2014. J Natl Compr Canc Netw. 2014;12(9):1282–303.
  3. Aschebrook-Kilfoy B, Caces DB, Ollberding NJ, et al. An upward trend in the age-specific incidence patterns for mantle cell lymphoma in the USA. Leuk Lymphoma. 2013;54(8):1677–83. doi: 10.3109/10428194.2012.760041.
  4. Zhou Y, Wang H, Fang W, et al. Incidence Trends of Mantle Cell Lymphoma in the United States Between 1992 and 2004. Cancer. 2008;113(4):791–8. doi: 10.1002/cncr.23608.
  5. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90. doi: 10.1182/blood-2016-01-643569.
  6. Swerdlow SH, Campo E, Harris NL, et al. (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  7. Kelemen K, Peterson LC, Helenowski I, et al. CD23+ Mantle Cell Lymphoma. Am J Clin Pathol. 2008;130(2):166–77. doi: 10.1309/R94MAFJY5EA4A8C3.
  8. Vose JM. Mantle cell lymphoma: 2015 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2015;90(8):739–45. doi: 10.1002/ajh.24094.
  9. Liu Z, Dong HY, Gorczyca W, et al. CD5– mantle cell lymphoma. Am J Clin Pathol. 2002;118(2):216–24. doi: 10.1309/TE56-A43X-29TT-5H8G.
  10. Zanetto U, Dong H, Huang Y, et al. Mantle cell lymphoma with aberrant expression of CD10. Histopathology. 2008;53(1):20–9. doi: 10.1111/j.1365-2559.2008.03060.x.
  11. Torlakovic E, Nielsen S, Vyberg M, et al. Antibody selection in immunohistochemical detection of cyclin D1 in mantle cell lymphoma. Am J Clin Pathol. 2005;124(5):782–9. doi: 10.1309/TYE7-K2CQ-MQ70-7FRT.
  12. Belaud-Rotureau MA, Parrens M, Dubus P, et al. A comparative analysis of FISH, RT-PCR, PCR, and immunohistochemistry for the diagnosis of mantle cell lymphomas. Mod Pathol. 2002;15(5):517–25. doi: 10.1038/modpathol.3880556.
  13. Vegliante MC, Palomero J, Perez-Galan P, et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood. 2013;121(12):2175–85. doi: 10.1182/blood-2012-06-438937.
  14. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3(2):185–97. doi: 10.1016/S1535-6108(03)00028-X.
  15. Chandran R, Gardiner SK, Simon M, Spurgeon SE. Survival trends in mantle cell lymphoma in the United States over 16 years 1992–2007. Leuk Lymphoma. 2012;53(8):1488–93. doi: 10.3109/10428194.2012.656628.
  16. Spurgeon SE, Till BG, Martin P, et al. Recommendations for clinical trial development in mantle cell lymphoma. J Natl Cancer Inst. 2017;109(1):1–10. doi: 10.1093/jnci/djw263.
  17. Sandoval-Sus JD, Sotomayor EM, Shah BD. Mantle cell lymphoma: Contemporary diagnostic and treatment perspectives in the age of personalized medicine. Hematol Oncol Stem Cell Ther. 2017;10(3):99–115. doi: 10.1016/j.hemonc.2017.02.003.
  18. LaCasce AS, Vandergrift JL, Rodriguez MA, et al. Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. Blood. 2013;119(9):2093–9. doi: 10.1182/blood-2011-07-369629.
  19. Chen R, Li H, Bernstein SH, et al. Pre-Transplant R-Bendamustine Induces High Rates of Minimal Residual Disease in MCL Patients: Updated Results of S1106: US Intergroup Study of a Randomized Phase II Trial of R-HCVAD Vs. R-Bendamustine Followed By Autologous Stem Cell Transplants for Patients. Blood. 2015;126: Abstract 518.
  20. Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: An active regimen for aggressive mantle-cell lymphoma. J Clin Oncol. 1998;16(12):3803–9. doi: 10.1200/JCO.1998.16.12.3803.
  21. Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23(28):7013–23. doi: 10.1200/JCO.2005.01.1825.
  22. Damon LE, Johnson JL, Niedzwiecki D. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27(36):6101–8. doi: 10.1200/JCO.2009.22.2554.
  23. 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.
  24. Hermine O, Hoster E, Walewski J, et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565–75. doi: 10.1016/S0140-6736(16)00739-X.
  25. Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012;156(3):346–53. doi: 10.1111/j.1365-2141.2011.08958.x.
  26. Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: Six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: Still very long survival but late relapses do occur. Br J Haematol. 2012;158(3):355–62. doi: 10.1111/j.1365-2141.2012.09174.x.
  27. Delarue R, Haioun C, Ribrag V, et al. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood. 2012;121(1):48–53. doi: 10.1182/blood-2011-09-370320.
  28. Sachs JD. Macroeconomics and health: Investing in health for economic development. Revista Panamericana de Salud Publica. 2002;12(2):143–4. doi: 10.1590/s1020-49892002000800017.
  29. Laurell A, Kolstad A, Jerkeman M, et al. High dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial. Leuk Lymphoma. 2014;55(5):1206–8. doi: 10.3109/10428194.2013.825906.
  30. Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab maintenance after autologous stem-cell transplantation in patients with mantle cell lymphoma, final result of the LyMA trial conducted on behalf the LYSA group. Hematol Oncol. 2017;35:209. doi: 10.1002/hon.2438_74.
  31. Klener P, Fronkova E, Belada D, et al. Alternating R-CHOP and R-cytarabine is a safe and effective regimen for transplant-ineligible patients with a newly diagnosed mantle cell lymphoma. Hematol Oncol. 2017;1–6. doi: 10.1002/hon.2483
  32. Chen R, Li H, Bernstein SH, et al. Results of a randomized phase II trial of R-Hyper-CVAD versus bendamustine and rituximab followed by consolidation with ASCT in previously untreated patients with MCL. ICML 2015:062.
  33. van Keep M, Gairy K, Seshagiri D, et al. Cost-effectiveness analysis of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma. BMC Cancer. 2016;16(1):598. doi: 10.1186/s12885-016-2633-2.
  34. Widmer F, Balabanov S, Soldini D, et al. R-hyper-CVAD versus R-CHOP/cytarabine with high-dose therapy and autologous haematopoietic stem cell support in fit patients with mantle cell lymphoma: 20 years of single-center experience. Ann Hematol. 2017;97(2):277–87. doi: 10.1007/s00277-017-3180-x.
  35. Hoster E, Rosenwald A, Berger F, et al. Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: Results from randomized trials of the European mantle cell lymphoma network. J Clin Oncol. 2016;34(12):1386–94. doi: 10.1200/JCO.2015.63.8387.