Mantle cell lymphoma: program therapy for untreated patients under 65 years

LYMPHOID TUMORS , , ,

V.I. Vorobyev1, S.K. Kravchenko1, E.G. Gemdjian1, Yu. Yu. Lorie 2, A.U. Magomedova1, A.L. Melikyan1, J.K. Mangasarova1, D.S. Mar’yin1, E.I. Dubrovin1, T.N. Obukhova1, S.A. Makhinya, V.A. Zherebtsova3, M.A. Vernyuk4, N.G. Tyurina4, and V.G. Savchenko1

1 Hematology Research Center, RF Ministry of Health, Moscow, Russian Federation

2 Moscow Oncology Clinic #3, Russian Federation

3 Central Clinical Hospital with Polyclinic, RF Presidential Executive Office, Moscow, Russian Federation

4 P.A. Hertzen Moscow Oncology Research Institute, Moscow, Russian Federation

ABSTRACT

Background: Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm which is diagnosed predominantly among older men. The use of high-dose Ara-C (12 g/m2 per course), autoSCT, and rituximab at all stages of therapy is the most effective approach but it is feasible only in patients under 60–65 years. High efficacy of gemcitabine and oxaliplatin-based regimens and irinotecan in relapsed or refractory MCL justifies their use in first-line therapy.

Objective: Assessment of toxicity and efficacy of R-DA-EPOCH/R-GIDIOX- and R-DA-EPOCH/R-HD-Met-Ara-C-regimens in primary MCL patients selected for autoSCT.

Patients and Methods: Since May 2008, 41 untreated MCL pts (median age: 54 years [29–64], M/F: 73%/27%, MIPIb: 29.3% low, 36.6% intermediate, 34.1% high risk) have been enrolled. After first R-EPOCH course (W. Wilson, 2003) completed, the patients were stratified according to toxicity emerged into 2 therapeutic groups: R-DA-EPOCH/R-HD-Met-AraC or R-DA-EPOCH/R-GIDIOX. In absence of grade 4 hematological toxicity for more than 3 days, serious infectious complications, or signs of renal failure, the pts received the R-HD-Met-Ara-C (R, 375 mg/m2 on Day 0; methotrexate, 1000 mg/m2 for 24 hours, Day 1; cytarabine, 3000 mg/m2 q 12 hrs on Days 2–3) regimen. When any of the above complications was present, the pts received the R-GIDIOX (R, 375 mg/m2 on Day 0; gemcitabine, 800 mg/m2 on Days 1 and 4; oxaliplatin, 120 mg/m2 on Day 2; irinotecan, 100 mg/m2 on Day 3; dexamethasone, 10 mg/m2 IV on Days 1–5; ifosfamide, 1000 mg/m2 on Days 1–5) regimen. Then, these regimens were reversed into either R-DA-EPOCH/R-HD-Met-Ara-C or R-DA-EPOCH/R-GIDIOX. Depending on the time until the complete response was achieved, pts received 6 to 8 therapeutic courses and autoSCT (BEAM-R) with in vivo purging using rituximab. Pts with residual tumor after autoSCT underwent local irradiation. R-maintenance was performed every 3 months for 3 years. Since Nov. 2011, all pts had received intrathecal CNS prophylaxis (including the patients who had undergone autoSCT during the year preceding Nov. 2011). The protocol was approved by the local ethics committee. Pts were analyzed using the intention-to-treat model. Toxicity assessment was performed for 124 R-DA-EPOCH, 87 R-HD-Met-Ara-C, and 51 R-GIDIOX courses.

Results: The median follow-up was 22 months (range 4–60). By April 2013, 35 patients had undergone autoSCT: 21 and 14 from R-HD-Met-Ara-C- and R-GIDIOX arm, respectively. One patient died from acute renal failure and septic shock at the induction stage after first HD-Met-AraC course. R-maintenance therapy was completed in 5 patients. In all patients who had received R-HD-Met-Ara-C, CR was achieved. In the R-GIDIOX arm, OR rate was 93%: 12 CR, 2 PR, and 1 case of disease progression after 5 courses. The most common non-hematological R-GIDIOX toxicity was related to the liver with elevated aminotransferases up to Grades 1–2 and 3–4 in 64.7% and 7.8% of cases, respectively, with no clinical manifestations. The sources of stem cells was PB in 27 out of 31 patients, and in 4 cases of harvest failure after 3 R-GIDIOX and 1 HD-Met-AraC BM was used. Hematological toxicity of R-GIDIOX course included grade 4 leukopenia in 74.5% (medium duration: 5 days, range: 1–13) and grade 4 thrombocytopenia in 39.2%. The estimated 5-years OS for the R-GIDIOX and R-HD-Met-AraC groups was 93 ± 7% and 79 ± 12%, respectively. The estimated 5-years EFS for the R-GIDIOX and R-HD-Met-AraC groups was 59 ± 19% and 74 ± 12%, respectively.

Conclusions: The HD-Met-Ara-C regimen is highly toxic, and it can be used only in 2/3 of patients under 65 years. The R-GIDIOX regimen is less toxic than HD-Met-Ara-C and equally effective with regard to the response induction and mobilizing necessary amount of autologous stem cells, so it can be recommended for the patients in whom Ara-C and methotrexate in high doses carry the high risk of life-threatening consequences.

Keywords: Mantle cell lymphoma, treatment, autoSCT, maintenance therapy.

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REFERNCES

  1. Лорие Ю.Ю. Лимфома из клеток мантийной зоны: клинические формы, морфологические варианты, диагностика и лечение: Автореф. дис. … канд. мед. наук. М., 2005. [Loriye Yu.Yu. Limfoma iz kletok mantiynoy zony: klinicheskiye formy,  kand. med.¼morfologicheskiye varianty, diagnostika i lecheniye: Avtoref. dis.  nauk (Mantle cell lymphoma: clinical forms, morphological variants, diagnosis, and management. Author’s summary of dissertation for the degree of PHD). M., 2005.]
  2. Argatoff L.H., Connors J.M., Klasa R.J. et al. Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 1997; 89: 2067–78.
  3. Yatabe Y., Suzuki R., Tobinai K. et al. Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma. Blood 2000; 95: 2253–61.
  4. Wlodarska I., Meeus P., Stul M. et al. Variant t(2;11)(p11;q13) associated with the IgK-CCND1 rearrangement is a recurrent translocation in leukemic small-cell B-non-Hodgkin lymphoma. Leukemia 2004; 18: 1705–10.
  5. Komatsu H., Iida S., Yamamoto K. et al. A variant chromosome translocation at 11q13 identifying PRAD1/Cyclin Dl as the BCL-1 Gene. Blood 1994; 84: 1226–31.
  6. Vose J.M. Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management. J. Hematol. 2012; 87(6): 604–9.
  7. Vegliante M.C., Palomero J., Perez-Galen P. et al. SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma. Blood 2013; 121(12): 2175–85.
  8. Mozos A., Royo A., Hartmann E. et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 2009; 94(11): 1555–62.
  9. Fernandez V., Salamero O., Espinet B. et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res. 2010; 70(4): 1408–18.
  10. 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: 791–8.
  11. Howard O.M., Gribben J.G., Neuberg D.S. et al. Rituximab and CHOP induction therapy for newly diagnosed mantle cell lymphoma: molecular complete responses are not predictive of progression-free survival. Clin. Oncol. 2002; 20: 1288–94.
  12. Lenz G., Dreyling M., Hoster E. et al. Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle Cell Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG). Clin. Oncol. 2005; 23: 1984–92.
  13. Romaguera J., Fayad L., Feng L. et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximabhigh dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. J. Haematol. 2010; 150(2): 200–8.
  14. Geisler C.H., Kolstad A., Laurell A. et al. Nordic MCL2 trial update: sixyear follow-up after intensive immunochemotherapy for untreated mantle celllymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. J. Haematol. 2012; 158(3): 355–62.
  15. Hermine O., Hoster E., Walewski J. et al. Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net). Blood 2010; 116: Abstract 110.
  16. Pott C., Hoster E., Beldjord K. et al. R-CHOP/R-DHAP Compared to RCHOP Induction Followed by High Dose Therapy with Autologous Stem Cell Transplantation Induces Higher Rates of Molecular Remission In MCL: Results of the MCL Younger Intergroup Trial of the European MCL Network. Blood 2010; 116: Abstract 965.
  17. Tam C., Bassett R., Ledesma C. et al. Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell Lymphoma. Blood 2009; 113(1): 8.
  18. Bernstein S.H., Epner E., Unger J.M. et al. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Oncol. 2013 Mar 15.
  19. 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 2013; 121(1): 48–53.
  20. Hoster E., Dreyling M., Klapper W. et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 2008; 111: 558–65.
  21. Tiemann M., Schrader C., Klapper W. et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. J. Haematol. 2005; 131: 29–38.
  22. Geisler C., Kolstad A., Laurell A. et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood 2010; 115: 1530–3.
  23. Geisler C. Front-line therapy of MCL. Hematologica 2010; 95: 1241–3.
  24. Damon L.E., Johnson J.L., Niedzwiecki D. et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. Clin. Oncol. 2009; 27(36): 6101–8.
  25. Fayad L., Thomas D., Romaguera J. Update of the M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas. Lymph. Myeloma 2007; 8(Suppl. 2): S57–62.
  26. Vigouroux S., Gaillard F., Moreau P. et al. High-dose therapy with autologous stem cell transplantation in first response in mantle cell lymphoma. Haematologica 2005; 90(11): 1580–2.
  27. Rodriguez J., Gutierrez A., Palacios A. et al. Rituximab, gemcitabine and oxaliplatin: An effective regimen in patients with refractory and relapsing mantle cell lymphoma. Lymphoma 2007; 48: 2172–8.
  28. Corazzelli G., Capobianco G., Arcamone M. et al. Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother. Pharmacol. 2009; 64: 907–16.
  29. Corazzelli G., Russo F., Capobianco G. et al. Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing salvage regimen for relapsed and refractory aggressive non-Hodgkin’s lymphoma: results of a pilot study. Oncol. 2006; 17(Suppl. 4): iv18–24.
  30. Park B.B., Kim W.S., Eom H.S. et al. Salvage therapy with gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for B-cell non-Hodgkin’s lymphoma: a consortium for improving survival of lymphoma (CISL) trial. New Drugs 2011; 29: 154–60.
  31. Suzumiya J., Suzushima H., Maeda K. et al. Phase I study of the combination of irinotecan hydrochloride, carboplatin, and dexamethasone for the treatment of relapsed or refractory malignant lymphoma. J. Hematol. 2004; 79(3): 266–70.
  32. Hara S., Yokote T., Akioka T. et al. Successful treatment of refractory mantle cell lymphoma with irinotecan. Rinsho Ketsueki. 2005; 46(5): 358–62.
  33. Wilson W., Dunleavy K., Pittaluga S. et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. Clin. Oncol. 2008; 26: 2717–24.
  34. Cheson B., Pfistner B., Juweid M. et al. Revised response criteria for malignant lymphoma. Clin. Oncol. 2007; 25: 579–86.