Magnetic Resonance Imaging of Bone Marrow and its Results as a Criterion for Administration of Maintenance Therapy After Auto-HSCT in Multiple Myeloma Patients

MV Solov’ev, LP Mendeleeva, GA Yatsyk, NS Lutsik, MV Firsova, EG Gemdzhian, VG Savchenko

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

For correspondence: Maksim Valer’evich Solov’ev, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-31-92; е-mail:

For citation: Solov’ev MV, Mendeleeva LP, Yatsyk GA, et al. Magnetic Resonance Imaging of Bone Marrow and its Results as a Criterion for Administration of Maintenance Therapy After Auto-HSCT in Multiple Myeloma Patients. Clinical oncohematology. 2018;11(4):360–7.

DOI: 10.21320/2500-2139-2018-11-4-360-367


Aim. To evaluate the efficacy of maintenance therapy in multiple myeloma (MM) patients after autologous hematopoietic stem cell transplantation (auto-HSCT) based on the results of MRI of bone marrow.

Materials & Methods. The study included 32 MM patients aged 36 to 66 years (median 57 years) with complete remission after a single auto-HSCT. MRI of spine and pelvic bones was performed to identify the nature of bone marrow lesions and to determine the volume of tumor tissue on the day 100 after auto-HSCT. As maintenance therapy after auto-HSCT 14 patients received daily 15 mg lenalidomide in the period from day 1 to day 21 of the 28-day treatment course within 1 year. Monitoring of 18 patients was conducted without maintenance therapy. Statistical analysis included the assessment of progression-free survival (PFS) and relapse risk relationship to clinical and laboratory parameters.

Results. Twenty patients had a positive MRI (tumor volume > 1 cm3). Zero variation of MR signal in bone marrow and detection of a < 1 cm3 tumor were regarded as a negative MRI, which was the case in 12 patients. After reaching the negative MRI the best rates of 2-year PFS were registered: 100 % with maintenance therapy and 84 % without maintenance therapy. In patients with tumor load on MR scans the 2-year PFS significantly (= 0.03) varied and accounted for 80 % in patients who received maintenance therapy vs. 33 % in patients without maintenance therapy. Administration of maintenance therapy after detecting residual tumor on MR scans on day 100 after auto-HSCT has a positive effect on PFS rates. Multivariate analysis confirmed the residual tumor on MR scans of bone marrow to be the most important parameter PFS depends on.

Conclusion. A negative MRI after auto-HSCT is a favourable prognostic factor determining a long-lasting (> 2 years) MM free period, despite the lack of maintenance therapy.

Keywords: multiple myeloma, magnetic resonance imaging (MRI), autologous hematopoietic stem cell transplantation (auto-HSCT), maintenance therapy, minimal residual disease.

Received: May 11, 2018

Accepted: August 29, 2018

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  1. 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(Прил.2). [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(Прил.2). (In Russ)]

  2. Kumar SK, Rajkumar SV, Dispenzieri A, et Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.

  3. Mendeleeva LP, Solovev MV, Alexeeva A, at al. Multiple Myeloma in Russia (First Results of the Registration Trial). Blood. 2017;130(Suppl 1):5408.

  4. Passweg JR, Baldomero H, Bader Р, et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018. doi: 10.1038/s41409-018-0153-1. [Epub ahead of print]

  5. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016;51(6):786–92. doi: 10.1038/bmt.2016.20.

  6. Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. Leukemia. 2017;31(8):1727–34. doi: 10.1038/leu.2016.381.

  7. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myelome. J Clin Oncol. 2014;32(25):2712–7. doi: 10.1200/JCO.2013.54.8164.

  8. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(Suppl 4):iv52–61. doi: 10.1093/annonc/mdx096.

  9. Syed YY. Lenalidomide: A Review in Newly Diagnosed Multiple Myeloma as Maintenance Therapy After ASCT. Drugs. 2017;77(13):1473–80. doi: 10.1007/s40265-017-0795-0.

  10. Goldschmidt H, Lokhorst HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018;32(2):383–90. doi: 10.1038/leu.2017.211.

  11. Rosinol L, Oriol A, Teruel AI, et al. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017;31(9):1922–7. doi: 10.1038/leu.2017.35.

  12. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013;121(23):4647–54. doi: 10.1182/blood-2012-11-464503.

  13. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55. doi: 10.1200/JCO.2011.39.6820.

  14. McCarthy PL, Owzar K, Hofmeister C, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770–81. doi: 10.1056/NEJMoa1114083.

  15. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma. N Engl J Med. 2012;366(19):1782–91. doi: 10.1056/NEJMoa1114138.

  16. 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.

  17. Solovev MV, Mendeleeva LP, Pokrovskaya OS, et al. Maintenance Therapy after Autologous Haematopoietic Stem Cell Transplantation (auto-HSCT) in Multiple Myeloma Patients with and without Minimal Residual Disease (MRD). Blood. 2016;128(22):2260.

  18. Solovev MV, Mendeleeva LP, Pokrovskaya OS, et al. The Duration of MRD-Negative Status in Multiple Myeloma (MM) Patients after Auto-HSCT Is a Criterion for Prolonged Remission without Maintenance Therapy. Blood. 2017;130(Suppl 1):3294.

  19. Dutoit JC, Verstraete KL. Whole-body MRI, dynamic contrast-enhanced MRI, and diffusion-weighted imaging for the staging of multiple myeloma. Skelet Radiol. 2017;46(6):733–50. doi: 10.1007/s00256-017-2609-6.

  20. Latifoltojar A, Hall‐Craggs M, Rabin N, et al. Whole body magnetic resonance imaging in newly diagnosed multiple myeloma: early changes in lesional signal fat fraction predict disease response. Br J Haematol. 2017;176(2):222–33. doi: 10.1111/bjh.14401.

  21. Lasocki A, Gaillard F, Harrison SJ. Multiple myeloma of the spine. Neuroradiol J. 2017;30(3):259–68. doi: 10.1177/1971400917699426.

  22. Bray TJ, Singh S, Latifoltojar A, et al. Diagnostic utility of whole body Dixon MRI in multiple myeloma: A multi-reader study. PLoS One. 2017;12(7):e0180562. doi: 10.1371/journal.pone.0180562.

  23. Sabour S. Whole-body ultra-low dose computed tomography in comparison with spinal magnetic resonance imaging in the assessment of disease in multiple myeloma; Methodological issues on Diagnostic value. Br J Haematol. 2017. doi: 10.1111/bjh.14849. [Epub ahead of print]

  24. Chantry A, Kazmi M, Barrington S, et al. Guidelines for the use of imaging in the management of patients with myeloma. Br J Haematol. 2017;178(3):380–93. doi: 10.1111/bjh.14827.

  25. Moulopoulos LA, Gika D, Anagnostopoulos A, et al. Prognostic significance of magnetic resonance imaging of bone marrow in previously untreated patients with multiple myeloma. Ann Oncol. 2005;16(11):1824–8. doi: 10.1093/annonc/mdi362.

  26. Mai EK, Hielscher T, Kloth JK, et al. Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology. Eur Radiol. 2016;26(11):3939–48. doi: 10.1007/s00330-015-4195-0.

  27. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25(9):1121–8. doi: 10.1200/JCO.2006.08.5803.

  28. Richardson PG, Holstein SA, Schlossman RL, et al. Lenalidomide in combination or alone as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma: a review of options for and against. Expert Opin Pharmacother. 2017;18(18):1975–85. doi: 10.1080/14656566.2017.1409207.

  29. Pulte ED, Dmytrijuk A, Nie L, et al. FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma. Oncologist. 2018;23(6):734–9. doi: 10.1634/theoncologist.2017-0440.

  30. Sengsayadeth S, Malard F, Savani BN, et al. Posttransplant maintenance therapy in multiple myeloma: the changing landscape. Blood Cancer J. 2017;7(3):e545. doi: 10.1038/bcj.2017.23.

  31. 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.

  32. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. doi: 10.1182/blood-2016-01-631200.

  33. Sivaraj D, Green MM, Li Z, et al. Outcomes of Maintenance Therapy with Bortezomib after Autologous Stem Cell Transplantation for Patients with Multiple Myeloma. Biol Blood Marrow Transplant. 2017;23(2):262–8. doi: 10.1016/j.bbmt.2016.11.010.

  34. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study. Blood. 2016;128(22):1143.

  35. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119(4):940–8. doi: 10.1182/blood-2011-09-379164.

  36. Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial. Blood. 2017;130(Suppl 1):436.

  37. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013;121(23):4647–54. doi: 10.1182/blood-2012-11-464503.

  38. Phase III Studies Present Additional Evidence for REVLIMID® (lenalidomide) as Maintenance Therapy in Multiple Myeloma. Available from: (accessed 2.05.2018).

  39. Соловьев М.В., Менделеева Л.П., Покровская О.С. и др. Множественная миелома: поддерживающая терапия после трансплантации аутологичных гемопоэтических стволовых клеток в зависимости от минимальной остаточной болезни. Терапевтический архив. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31.

    [Solovyev MV, Mendeleeva LP, Pokrovskaya OS, et al. Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease. Terapevticheskii arkhiv. 2017;89(7):25–31. doi: 10.17116/terarkh201789725-31. (In Russ)]


Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of New Drugs

OV Pirogova, EI Darskaya, VV Porunova, OV Kudyasheva, AG Smirnova, IS Moiseev, EV Babenko, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Ol’ga Vladislavovna Pirogova, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail:

For citation: Pirogova OV, Darskaya EI, Porunova VV, et al. Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of New Drugs. Clinical oncohematology. 2018;11(2):187–91.

DOI: 10.21320/2500-2139-2018-11-2-187-191


Background & Aims. The present retrospective single-center study analysed the impact of high-dose chemotherapy with melphalan with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) on survival in multiple myeloma (MM) in the era of new induction regimens.

Materials & Methods. The clinical trial included 133 MM patients aged from 31.2 to 78.2 years (the median age was 55.3 years). There were 66 female and 67 male patients. Bortezomib-based regimens as first-line treatment were administered in 133 MM patients, 74 of them received high-dose chemotherapy with melphalan and either single (n = 25), or double (n = 49) auto-HSCT as consolidation therapy in the period from 2006 to 2016.

Results. The overall 5-year survival (OS) rates were 86.5 % for the auto-HSCT treated group vs. 72.9 % for the non-auto-HSCT treated group (= 0.03); 5-year progression-free survival (PFS) rates were 64.9 vs. 39 % for the auto-HSCT and non-auto-HSCT treated groups, respectively (= 0.0016). MM relapse/progression occurred more frequently in the non-auto-HSCT treated patients (52.5 vs. 28.4 %; = 0.0016). In multivariate analysis the age above 60 was determined as prognostic factor of lower PFS and increase in relapse/progression rate (= 0.004 and = 0.04, respectively). The variant of monoclonal protein (Bence-Jones myeloma) was determined as prognostic factor of higher OS and decrease in relapse/progression rate (= 0.02 and = 0.04, respectively). Complete nonresponsiveness to induction therapy has proved to be an independent predictor of both poor OS and PFS (= 0.04 and = 0.041, respectively). 2-year bortezomib-based maintenance therapy following the auto-HSCT treatment resulted in a statistically significant improvement in 5-year PFS (67.4 vs. 60.7 %; = 0.03) and a decrease in relapse/progression frequency (26.1 vs. 32.1 %; = 0.05).

Conclusion. High-dose chemotherapy with melphalan with subsequent auto-HSCT is an effective MM treatment strategy, and a subsequent long-term maintenance therapy results in a PFS improvement and a decrease in relapse/progression frequency.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, maintenance therapy.

Received: November 20, 2017

Accepted: February 9, 2018

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  1. Дарская Е.И., Марами-Зонузи Н.Э., Осипов Ю.С. и др. Эффективность терапии пациентов с множественной миеломой, получавших в качестве первой линии трансплантацию аутологичных гемопоэтических стволовых клеток.Онкогематология. 2014;9(1):6–10.[Darskaya EI, Marami-Zonuzi NE, Osipov YuS, et al. Therapy efficacy in multiple myeloma patients received autologous stem cells transplantation as first line therapy. Onkogematologiya. 2014;9(1):6–10. (In Russ)]
  2. Barlogie B, Gahrton G. Bone marrow transplantation in multiple myeloma. Bone Marrow Transplant. 1991;7(2):71–9.
  3. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875–83. doi: 10.1056/nejmoa022340.
  4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335(2):91–7. doi: 1056/nejm199607113350204.
  5. Lenhoff S, Hjorth M, Holmberg E, et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Blood. 2000;95(1):7–11.
  6. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349(26):2495–502. doi: 10.1056/nejmoa032290.
  7. Singhal S, Mekta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71. doi: 10.1056/nejm199911183412102.
  8. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348(26):2609–17. doi: 10.1056/nejmoa030288.
  9. Kropff MH, Bisping G, Wenning D, et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk Res. 2005;29(5):587–90. doi: 10.1016/j.leukres.2004.11.004.
  10. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–64. doi: 10.1182/blood-2006-04-015909.
  11. Brenner H, Gondos A, Pulte D. Recent major improvements in long-term survival of younger patients with multiple myeloma. Blood. 2008;111(5):2521–6. doi: 10.1182/blood-2007-08-104984.
  12. Schaapveld M, Visser O, Siesling S, et al. Improved survival among younger but not among older patients with multiple myeloma in the Netherlands, a population- based study since 1989. Eur J Cancer. 2010;46(1):160–9. doi: 10.1016/j.ejca.2009.07.006.
  13. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.
  14. Moreau P, Avet-Loiseau H, Harrousseau JL, Attal M. Current trends in autologous stem cell transplantation for myeloma in the era of novel therapies. J Clin Oncol. 2011;29(14):1898–906. doi: 10.1200/jco.2010.32.5878.
  15. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9):1467–73. doi: 10.1038/sj.leu.2404284.
  16. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075–85. doi: 10.1016/s0140-6736(10)61424-9.
  17. Koreth J, Cutler CS, Djulbegovic B, et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007;13(2):183–96. doi: 10.1016/j.bbmt.2006.09.010.
  18. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946–55. doi: 10.1200/jco.2011.39.6820.
  19. Rosinnol L, Oriol A, Teruel AI, et al. Maintenance Therapy After Stem-Cell Transplantation for Multiple Myeloma with Bortezomib/Thalidomide Vs. Thalidomide Vs. alfa2b-Interferon: Final Results of a Phase III Pethema/GEM Randomized Trial. ASH Annual Meeting Abstracts. 2012;120(21):334.

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

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


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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  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.