Magnetic resonance imaging in diagnosis of non-Hodgkin’s lymphomas of the spine with spinal cord compression

A.S. Nered, N.V. Kochergina, A.B. Bludov, Ya.A. Zamogilnaya, A.K. Valiyev, K.A. Borzov, and E.R. Musayev

N.N. Blokhin Russian Cancer Research Center, RAMS, Moscow, Russian Federation


ABSTRACT

MRI features of 5 patients with non-Hodgkin’s lymphomas (NHLs) of the spine with spinal cord compression were studied. It was revealed that NHLs of the spine were characterized by the predominantly homogeneous extraosseous component of soft-tissue density tending to spread to the adjacent vertebrae through the ligaments of the spinal column, lytic cortical layer destruction with the «wrap-around» sign, and the geographic pattern within the affected vertebrae. Compression myelopathy was observed in the spinal stenosis greater than 40 % of its anatomic width.


Keywords: non-Hodgkin’s lymphoma, magnetic resonance imaging, spinal cord compression.

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Refernces

  1. Beal K., Allen L., Yahalom J. Primary bone lymphoma: treatment results and prognostic factors with long-term follow-up of 82 patients. Cancer 2006; 106: 2652–6.
  2. Ramadan K.M., Shenkier T., Sehn L.H. et al. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann. Oncol. 2007; 18: 129–35.
  3. Barbieri E., Cammelli S., Mauro F. et al. Primary NHL of the bone: treatment and analysis of prognostic factors for Stage I and Stage II. Int. J. Radiat. Oncol. Biol. Phys. 2004; 59: 760–4.
  4. Adams H., Tzankov A., d’Hondt S. et al. Primary diffuse large B-cell lymphomas of the bone: prognostic relevance of protein expression and clinical factors. Hum. Pathol. 2008; 39: 1323–30.
  5. Yuste A.L., Segura A., Lopez-Tendero P. et al. Primary lymphoma of bone: a clinico-pathological review and analysis of prognostic factors. Leuk. Lymphoma 2004; 45: 853–5.
  6. Zinzani P.L., Carrillo G., Ascani S. et al. Primary bone lymphoma: experience with 52 patients. Haematologica 2003; 88: 280–5.
  7. Salvati M., Cervoni L., Artico M. et al. Primary spinal epidural non-Hodgkin’s lymphomas: a clinical study. Surg. Neurol. 1996; 46: 339–44.
  8. Lim C.C., Chong B.K. Spinal epidural non-Hodgkin’s lymphoma: case reports of three patients presenting with spinal cord compression. Singapore Med. J. 1996; 37: 497–500. 9. Vanneuville B., Janssens A., Lemmerling M. et al. Non-Hodgkin’s lymphoma presenting with spinal involvement. Ann. Rheum. Dis. 2000; 59: 12–4.
  9. Oviatt D.L., Kirshner H.S., Stein R.S. Successful chemotherapeutic treatment of epidural compression in non-Hodgkin’s lymphoma. Cancer 1982; 49: 2446–8.
  10. Monnard V., Sun A., Epelbaum R. et al. Primary spinal epidural lymphoma: patients’ profile, outcome, and prognostic factors: a multicenter Rare Cancer Network study. Int. J. Radiat. Oncol. Biol. Phys. 2006; 65: 817–23.
  11. Genant H.K., Wu C.Y., van Kuijk C., Nevitt M.C. Vertebral fracture assessment using a semiquantitative technique. J. Bone Miner. Res. 1993; 8: 1137–48.
  12. Weissman D.E., Negendank W.G., Al-Katibb A.M., Smith M.R. Bone marrow necrosis in lymphoma studied by MRI. Am. J. Hematol. 1992; 40: 42–6.
  13. Moulopoulos L.A., Dimopoulos M.A., Vourtsi A. et al. Bone lesions with soft-tissue mass: magnetic resonance imaging diagnosis of lymphomatous involvement of the bone marrow versus multiple myeloma and bone metastases. Leuk. Lymphoma 1999; 34: 179–84.
  14. Tahiri L., Benbouazza K., Amine B. et al. Primary non-Hodgkin’s lymphoma presenting as radicular syndrome: report of two cases. Rheumatol. Int. 2009; 30: 113–7.
  15. Xinsheng Peng, Yong Wan, Yingming Chen et al. Primary non-Hodgkin’s lymphoma of the spine with neurologic compression treated by radiotherapy and chemotherapy alone or combined with surgical decompression. Oncol. Rep. 2009; 21: 1269–75.
  16. Naohisa Miyakoshi, Yoichi Shimada, Tetsuya Suzuki et al. Magnetic resonance imaging of spinal involvement by hematopoietic malignancies requiring surgical decompression. J. Orthop. Sci. 2003; 8: 207–12.

Radiotherapy in combined treatment of patients with diffuse large B-cell lymphoma

Yu.N. Vinogradova, N.V. Ilin, D.V. Larionov, M.M. Khodzhibekova, N.A. Kostenikov, and L.I. Korytova

Russian Research Centre for Radiology and Surgical Technologies, RF Ministry of Health, Saint Petersburg, Russian Federation


ABSTRACT

The study included 86 primary patients (age: 18–83) with diffuse large B-cell lymphoma, I to IV stages, who received (R)-CHOP regimen and radiotherapy at the CRIRR (at present RRCRST) over the period 2000–2012. The follow-up period median was 42 months (5–120 months). Positron emission tomography (PET) with 18F-FDG was performed in 45 patients at the various follow-up time-points. In all patients, the changes of hematologic indices were observed using baseline, pre-, and postradiation measurements. After combined treatment completed, remission was achieved in 80 out of 86 (93.0 %) patients, including complete or uncertain complete remission and partial remission in 86.0 % and 7.0 %, respectively. During the initial therapy, disease progression occurred in 6 (7.0 %) patients. After the chemotherapy stage, complete remission was noted in 56 (65.1 %) patients only. Additional radiotherapy promoted the increase in the rate of complete and uncertain complete response by 21.9 %. Disseminated disease relapses developed in 2 out of 80 (2.5 %) patients. The complete response rate in the patients who received radiotherapy using the various fractionation regimens was similar. 5-year overall, relapse-free, and progressionfree survival were 89.7 ± 3.9 %, 96.6 ± 2.4 %, and 85.4 ± 4.8 %, respectively. In 20.6 % of the patients examined after chemotherapy, PET gave positive results, while after the radiotherapy stage, all the patients examined at this time-point were PET-negative. Radiotherapy was accompanied by mainly I–II grade hematologic toxicity, and in 16–58 % of patients, no interruption of treatment were required. Neutropenia and thrombocytopenia occurred more frequently at the twice-a-day irradiation.


Keywords: diffuse large B-cell lymphoma, radiotherapy, positron emission tomography, hematologic toxicity.

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References

  1. Friedberg J.W. Pros — R-CHOP is the current standard therapy for patients with advanced stage DLBCL. Hematol. Oncol. Special Issue: 12th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, June 19–22, 2013; 31: Abstract 004.
  2. Miller T.P., Dahlberg S., Cassady J.R. et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate and high grade non Hodgkin’s lymphoma. N. Engl. J. Med. 1998; 339: 21–6.
  3. Ng A.K., Mauch P.M. Role of radiation therapy in localized aggressive lymphoma. J. Clin. Oncol. 2007; 25: 757–9. 4. Gospodarowicz M.K. Radiotherapy in non-Hodgkin lymphomas. Ann. Oncol. 2008; 19(4): 47–50.
  4. Illidge T.X. When should radiotherapy be used in lymphoma? Ann. Oncol. 2011; 22(4): 57–60.
  5. Tilly H., Vitolo U., Walewski J. et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2012; 23(7): 78–82.
  6. Асланиди И.П., Мухортова О.В., Шурупова И.В. и др. Позитронно- эмиссионная томография: уточнение стадии болезни при злокачественных лимфомах. Клин. онкогематол. 2010; 3(2): 119–29.[Aslanidi I.P., Mukhortova O.V., Shurupova I.V. i dr. Pozitronnoemissionnaya tomografiya: utochneniye stadii bolezni pri zlokachestvennykh limfomakh (Positron emission tomography: ascertaining disease stage in malignant lymphomas. In: Clin. oncohematol.). Klin. onkogematol. 2010; 3(2): 119–29.]
  7. Yahalom J., Mauch P. The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Ann. Oncol. 2002; 13(1): 79–83.
  8. Cheson B., Horning S., Coiffer B. et al. Report of an International Workshop to standardize Response Criteria for Non-Hodgkin’s Lymphomas. J. Clin. Oncol. 1999; 17(4): 1244–53.
  9. Cheson B., Pfistner B., Juweid M. et al. Revised response criteria for malignant lymphoma. J. Clin. Oncol. 2007; 25: 579–86.
  10. Cox J., Stetz J., Pajak T. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC). Intern. J. Radiat. Oncol. Biol. Phys. 1995; 31: 1341–6.
  11. Morschhauser F. R-CHOP is not the standard for high-risk DLBCL. Hematological Oncology. Special Issue: 12th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, June 19–22, 2013; 31: Abstrфсе 005.
  12. Zelenetz А.О., Abramson J.S., Advani R.H. et al. NCCN Clinical Practice Guidelines in Oncology non Hodgkin’s lymphomas. J. Natl. Compr. Canc. Netw. 2010; 8: 288–334.
  13. Phan J., Mazloom A., Jeffrey Medeiros L. et al. Benefit of consolidative radiation therapy in patients with diffuse large В cell lymphoma treated with RCHOP chemotherapy. J. Clin. Oncol. 2010; 28: 4170–6.
  14. Bonnet С., Fillet G., Mournier N. et al. CHOP alone compared with CHOP plus radiotherapy for localised aggressive lymphoma in elderly patients a study by the Groupe d Etude des Lymphomes de l’ Adulte. J. Clin. Oncol. 2007; 25: 787–92.
  15. Dabaja B., Vanderplas A., Abel G. et al. Pole of radiation in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era: a comprehensive analysis from the National Comprehensive Cancer Network (NCCN) lymphoma outcomes project. Hematol. Oncol. 2013; 31(1): 136.
  16. Zwick C., Held G., Ziepert M. et al. The role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. Results from two prospective trials of the DSHNHL. Hematol. Oncol. 2013; 31(1): 137.
  17. Sehn L.H., Klasa R., Shenkier T. et al. Long-term experience with PETguided consolidative radiation therapy (XRT) in patients with advanced stage diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP. Hematol. Oncol. 2013; 31(1): 137.
  18. Gang A. O., Strom C., Pedersen M. et al. R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group. Ann. Oncol. 2012; 23(1): 147–53.
  19. Bosly A., Bron D., Van Hoof A. et al. Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann. Hematol. 2008; 87: 277–83.
  20. Pfreundschuh M., Schubert J., Ziepert M. et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomized controlled trial (RICOVER-60). Lancet Oncol. 2008; 9(2): 105–16.
  21. Persky D.O., Unger J.M., Speir C.M. et al. Phase II study of rituximab plus 3 cycles of CHOP and involved field radiotherapy for patients with limited stage aggressive B cell lymphoma: Southwest Oncology Group Study 0014. J. Clin. Oncol. 2008; 26: 2258–63.
  22. Linch D. Today’s treatment of diffuse large B-cell lymphomas in adults. Hematol. Educ. (The education program for the annual congress of the EHA) 2011; 5: 210–6. 24. Jaeger U., TrnenyM., Melzer H. et al. Rituximab maintenance treatment versus observation in patients with aggressive B-cell lymphoma: results of the AGMT NHL13 trial. Hematol. Oncol. 2013; 31(1): 136.
  23. Swinnen L.J., Li H., Quon A. et al. Response-adapted therapy and predictive value of mid-treatment PET scanning for diffuse large B-cell lymphoma. ECOG study E3404. Hematol. Oncol. 2013; 31(1): 101.
  24. Mamot C., Klingbiel D., Renner C. Final results of a prospective evaluation of the predictive value of interim PET in patients with DLBCL under R-CHOP-14 (SAKK 38/07). Hematol. Oncol. 2013; 31(1): 100.
  25. Moskowitz C.H., Schoder H., Hamlin P.A. et al. Evaluation of dual tracer (FLT and FDG) PET imaging as part of risk-adapted therapy for patients (PTS) with advanced stage diffuse large B-cell lymphoma (DLBCL). Hematol. Oncol. 2013; 31(1): 101.

Multiple myeloma (management of newly diagnosed patients): literature review and our on data. Part II

S.S. Bessmeltsev

Russian Research Institute of Hematology and Transfusiology, FMBA, Saint Petersburg, Russian Federation


ABSTRACT

Over the last decades, survival rates for young patients with multiple myeloma markedly increased mainly due to the use of autologous stem cell transplantation (ASCT) and new highly efficacious rescue therapies. In patients with multiple myeloma over 65 years of age, a combination of melphalan and prednisone (MP) is traditionally used. Introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors substantially changed the therapeutic approach to the disease. Many double-, triple-, and quadruple-agent combinations were studied in the patients with newly diagnosed multiple myeloma. It was established that the achievement of complete response (CR) is an independent predictor of prolonged progression-free survival (PFS) and overall survival (OS). The data from prospective trials completed suggest that the best available strategy to achieve high CR rates and prolong its duration includes an induction therapy with a triple-agent bortezomib- or IMiDs-based regimen followed by ASCT and consolidation/maintenance with IMiDs or proteasome inhibitors. The vast majority of elderly patients with MM are ineligible for ASCT. Introduction of novel agents such as thalidomide, bortezomib, or lenalidomide considerably improved the treatment outcomes. MPT (MP + thalidomide), VMP (MP + bortezomib), and MPR-R (MP + lenalidomide) regimens are currently regarded as the new standards of care for elderly patients with multiple myeloma. The prognosis for multiple myeloma is determined by numerous factors, all of which should be considered when choosing the initial therapy. This review covers the new strategies based on the current studies being conducted that are aimed at optimizing treatment outcomes in the patients with newly diagnosed multiple myeloma.


Keywords: multiple myeloma, bortezomib, thalidomide, lenalidomide, treatment, complete remission, overall survival, neuropathy, autologous stem cell transplantation

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Refernces

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома. Со- временный взгляд на проблему. Алматы: Коста, 2007. [Bessmeltsev S.S., Abdulkadyrov K.M. Mnozhestvennaya miyeloma. Sovremennyy vzglyad na problemu (Multiple myeloma. Current view of the problem). Almaty: Kosta, 2007.]
  2. Kumar S.K., Rajkumar S.V., Dispenzieri A. et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111(5): 2516–20.
  3. San-Miguel J.F., Mateos M.-V. How to treat a newly diagnosed young patient with multiple myeloma. Hematology (American Society of Hematology Education Program Book, New Orleans, Louisiana, December 508, 2009) 2009: 555–65.
  4. Rajkumar S. V., Harousseau J.-L., Durie B. et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International myeloma workshop consensus panel 1. Blood, prepublished online Feb 3, 2011; doi:10.1182/blood-2010-10-299487.
  5. Dimopoulos M., Kyle R., Fermand J.-P. et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117(18): 4701–5.
  6. Landgren O., Katzmann J.A., Hsing A.W. et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin. Proc. 2007; 82(12): 1468–73.
  7. Iwanaga M., Tagawa M., Tsukasaki K. et al. Prevalence of monoclonal gammopathy of undetermined significance: study of 52,802 persons in Nagasaki City, Japan. Mayo Clin. Proc. 2007; 82(12): 1474–9.
  8. Kyle R.A., Remstein E.D., Therneau T.M. et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. New Engl. J. Med. 2007; 356(25): 2582–90.
  9. Kumar S. K., Mikhael J.R., Buadi F.K. et al. Management of Newly Diagnosed Symptomatic Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines. Mayo Clin. Proc. 2009; 84(12): 1095–110.
  10. Euler H.H., Schmitz N., Loffler H. Plasmapheresis in Paraproteinemia. Blut 1985; 50(6): 321–30.
  11. Attal M., Huguet F., Schlaifer D. et al. Intensive combined therapy for previously untreated aggressive myeloma. Blood 1992; 79: 1130–6.
  12. Alexanian R., Dimopoulos M.A., Hester I. et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84(12): 4278–82.
  13. Abdulkadyrov K.M., Bessmeltsev S.S. Use of VCAP, ARA-COP and VAD schedules in treatment of patients with multiple myeloma. Abstracts of the XVI International Cancer Congress. New Delhi (India), 1995. Abstract NA-02807.
  14. Bergsagel D.E., Pruzanski P.W. Some unusual manifestations of plasma cell neoplasma. In: Neoplastic disease of the Blood. Ed. by P.H. Wiernik. New York, 1985: 553–73.
  15. Абдулкадыров К.М., Бессмельцев С.С. Сравнительная оценка эффективности программ моно- и полихимиотерапии больных множественной миеломой. Клин. мед. 1992; 9(10): 57–60. [Abdulkadyrov K.M., Bessmeltsev S.S. Sravnitelnaya otsenka effektivnosti programm mono- i polikhimioterapii bolnykh mnozhestvennoy miyelomoy (Comparative evaluation of efficacy of mono- and polychemotherapy programs in patients with multiple myeloma. In: Clin. med.). Klin. med. 1992; 9(10): 57–60.]
  16. Birgens H.S., Hansen O.P., Clausen N.T. et al. A methodological evaluation of 14 controlled clinical trials in myelomatosis. Scand. J. Haematol. 1985; 35: 26–34.
  17. Merlini G., Riccardi A., Riccardi R.G. et al. Peptichemio, vincristine, prednisone induction treatment in multiple myeloma. Tumors 1985; 71: 581–8.
  18. Бессмельцев С.С., Стельмашенко Л.В. Сравнительная оценка различных методов лечения больных с множественной миеломой. Эфферентная тер. 2000; 2: 54–63. [Bessmeltsev S.S., Stelmashenko L.V. Sravnitelnaya otsenka razlichnykh metodov lecheniya bolnykh s mnozhestvennoy miyelomoy (Comparative evaluation of various therapeutic methods in patients with multiple myeloma. In: Efferent ther.). Efferentnaya ter. 2000; 2: 54–63.]
  19. Palva I.P., Ahrenberg P., Ala-Harja K. et al. Treatment of multiple myeloma in old patients. Eur. J. Haematol. 1989; 43: 328–31.
  20. Hernandez J.M., Garcia-Sanz R., Golvano E. et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br. J. Haematol. 2004; 127(2): 159–64.
  21. Facon T., Mary J.Y., Pegourie B. et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006; 107: 1292–8.
  22. Riccardi A., Ucci G., Luoni R. et al. Treatment of multiple myeloma according to the extension of the disease: a prospective, randomized study comparing a less with a more aggressive cytostatic policy. Cooperative Group of Study and Treatment of Multiple myeloma. Br. J. Cancer 1994; 70: 1203–10.
  23. Бессмельцев С.С. Современные подходы к химиотерапии множе- ственной миеломы. Медико-фармацевтический форум (29 октября — 2 но- ября): Тезисы докладов. М., 2002: 36–7. [Bessmeltsev S.S. Sovremennyye podkhody k khimioterapii mnozhestvennoy miyelomy. Mediko-farmatsevticheskiy forum (29 oktyabrya — 2 noyabrya): Tezisy dokladov (Current approaches to chemotherapy for multiple myeloma. Medico-pharmaceutical forum (October 29–November 2): talking points in presentations). M., 2002: 36–7.]
  24. Oken M.M., Kyle R.A., Greipp P.R. et al. Complete remission induction with combined VBMCP chemotherapy and interferon in patients with multiple myeloma. Leuk. Lymphoma 1996; 20: 447–52.
  25. Oken M.M., Harrington D.P., Abramson N. et al. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 1997; 79: 1561–7.
  26. Finnish Leukemia Group. Treatment of multiple myeloma in old patients. Eur. J Haematol. 1989; 43: 328–31.
  27. Kumar S., Lacy M.Q., Dispenzieri A. et al. Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004, advance online publication 2 August 2004; doi:10.1038/ sj.bmt. 1704633.
  28. Cook G., Clark R.E., Morris T.C. A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma. Br. J. Haematol. 2004; 126: 792–8.
  29. Munshi N.C., Anderson K.C., Bergsagel P.L. et al. Guidelines for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood, Prepublished online Feb 3, 2011; doi:10.1182/ blood-2010-10-300970.
  30. Kyle R.A., Rajkumar S.V. Multiple myeloma. N. Engl. J. Med. 2004; 351: 1060–77.
  31. Barlogie B., Shaughnessy J., Tricot G. et al. Treatment of multiple myeloma. Blood 2004; 103: 20–32.
  32. Palumbo A., Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology 2009 (American Society of Hematology Eduction Program Book, New Orleans, Louisiana, December 508, 2009): 566–77.
  33. Blade J., Samson D., Reece D. et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br. J. Haematol. 1998; 102(5): 1115–23.
  34. Durie B.G.M., Harousseau J.-L., San-Miguel J. et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467–73.
  35. Paiva B., Vidriales M.B., Cervero J. et al. Multiparameter flow cytometry remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008; 112: 4017–23.
  36. Corradini P., Cavo M., Lokhorst H. et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102: 1927–9.
  37. Brenner H., Gondos A., Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008; 111(5): 2521–6.
  38. D’Amato R.J., Loughnan M.S., Flynn E. et al. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. U S A 1994; 91: 4082–5.
  39. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99(12): 4525–30.
  40. Kyle R.A., Rajkumar S.V. Therapeutic application of thalidomide in multiple myeloma. Semin. Oncol. 2001; 28: 583–7.
  41. Rajkumar S.V., Blood E., Vesole D. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J. Clin. Oncol. 2006; 24: 431–6.
  42. Rajkumar S.V., Rosinol L., Hussein M. et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J. Clin. Oncol. 2008; 26: 2171–7.
  43. Cavo M., Zamagni E., Tosi P. et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 35–9.
  44. Lokhorst H.M., Schmidt-Wolf I., Sonneveld P. et al. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 2008; 93: 124–7.
  45. Zervas K., Mihou D., Katodritou E. et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek myeloma study group. Ann. Oncol. 2007; 18: 1369–75.
  46. Marco M., Divine M., Uzunhan Y. et al. Dexamethasone+thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma: a randomized trial. Blood 2006; 108: 57a (abstr.).
  47. Morgan G.J., Faith D., Roger O. et al. Thalidomide combinations improve response rates; results from the MRC IX study. Blood 2007; 110: 3593 (abstr.).
  48. Schafer P.H., Gandhi A.K., Loveland M.A. et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J. Pharmacol. Exp. Ther. 2003; 305(3): 1222–32.
  49. Breitkreutz I., Raab M.S., Vallet S. et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008; 22(10): 1925–32.
  50. Rajkumar S.V., Hayman S.R., Lacy M.Q. et al. Combination therapy with lenalidomide plus dexamethasone for newly diagnosed myeloma. Blood 2005; 106: 4050–3.
  51. Lacy M.Q., Gertz M.A., Dispenzieri A. et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin. Proc. 2007; 82(10): 1179–84.
  52. Kumar S., Dispenzieri A., Lacy M.Q. et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment postperipheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007; 21: 2035–42.
  53. Kumar S., Giralt S., Stadtmauer E.A. et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 2009; 114: 1724–35.
  54. Zonder J.A., Crowley J., Hussein M.A. et al. Lenalidomide and highdose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Published online before print September 27, 2010, doi:10.1182/blood-2010- 08-303487.
  55. Rajkumar S.V., Jacobus S., Callander N.S. et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma, a trial coordinated by the Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J. Clin. Oncol. 2008; 26: 8504 (abstr.).
  56. Rajkumar S.V., Jacobus S., Callander N.S. et al. Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma. An open-label randomised controlled trial. Lancet Oncol. 2010; 11: 29–37. 57. Kumar S.K., Lacy M.Q., Hayman S.R. et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: Results from a phase 2 trial. Am. J. Hematol. 2011; 86(8): 640–5.
  57. Niesvizky R., Jayabalan D.S., Christos P.J. et al. ViRD (Biaxian [clarithromycyn]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in highe complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood 2008; 111: 1101–9.
  58. Ohara T., Morishita T., Suzuki H. et al. Antibiotics directly induce apoptosis in B cell lymphoma cells derived from BALB/c mice. Anticancer Res. 2004; 24(6): 3723–30.
  59. Karin M., Cao Y., Greten F.R., Li Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2002; 2: 301–10.
  60. Mitsiades N., Mitsiades C.S., Richardson P.G. et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101: 2377–80.
  61. Bessmeltsev S., Rugal V. Stromal microenvironment and stem cells niches in multiple myeloma. Hematologica (15th Congress of the European Hematology Association, Spain, Barcelona, June 10–13, 2010, Abstract Book): 569–70 (abstr. 1422).
  62. Hideshima T., Mitsiades C., Akiyama M. et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101: 1530–4.
  63. Terpos E., Heath D.J., Rahemtulla A. et al. Bortezomib reduced serum dick-kopf-1 and receptor activator of nuclear factor-kappaB ligand concentration and normalizes indices of bone remodelling in patients with relapsed multiple myeloma. Br. J. Haematol. 2006; 135: 688–92.
  64. Von Metzler H., Krebbel M., Hecht R.A. et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 2007; 21(9): 2025–34.
  65. Zangari M., Terpos E., Zhan F., Tricot G. Impact of bortezomib on bone health in myeloma: A review of current evidence. Cancer Treatment Rev. 2012; 38: 968–80.
  66. Jagannath S., Brian D., Wolf J.L. et al. A Phase 2 Study of Bortezomib as First-Line Therapy in Patients with Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2004; 104: Abstract 333.
  67. Harrousseau J., Mathiot C., Attal M. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation in previously untreated multiple myeloma: Updated date from IFM 2005/01 trial (Abstract). J. Clin. Oncol. 2008; 26: 8505.
  68. Harrousseau J., Avet-Loiseau H., Attal M. et al. High complete and very good partial response rates with bortezomib-dexamethasone as induction prior to ASCT in newly diagnosed patients with high-risk myeloma: results of the IFM2005-01 phase 3 trial. ASH Annual Meeting Abstracts 2009; 114: 353.
  69. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Новые подходы к лечению множественной миеломы. Вестн. Рос. воен.-мед. акад. 2010; 3: 149–54. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Novyye podkhody k lecheniyu mnozhestvennoy miyelomy (Novel approaches to treatment of multiple myeloma. In: Bull. of Rus. Mil. Med. Acad.). Vestn. Ros. voyen.-med. akad. 2010; 3: 149–54.]
  70. Jagannath S., Durie B., Wolf J. et al. First-line therapy with bortezomib (formerly PS-341) in patients with multiple myeloma. Proc. Am. Soc. Clin. Oncol. 2004; 23: 568 (abstr. 6551).
  71. Oakervee H.E., Popat R., Curry N. et al. PAD combination therapy (PS- 341/bortezomib, doxorubicib and dexamethasone) for previously untreated patients with multiple myeloma. Br. J. Haematol. 2005; 129: 755–62.
  72. Sonneveld P., van der Holt B., Schmidt-Wolf I.G.H. First analysis of HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, adriamycine, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma. Blood 2008; 112: 653 (abstr.)
  73. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Борте- зомиб в терапии 1-й линии при лечении множественной миеломы. Рос. мед. вести 2009; XIV(4): 29–37. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Bortezomib v terapii 1-y linii pri lechenii mnozhestvennoy miyelomy (Bortezomib in first-line therapy for multiple myeloma. In: Rus. med. news). Ros. med. vesti 2009; XIV(4): 29–37.]
  74. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Лечение молодых пациентов с впервые выявленной множественной миеломой. Украiн. журн. гематол. и трансфузiол. 2010; 5: 5–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Lecheniye molodykh patsiyentov s vpervyye vyyavlennoy mnozhestvennoy miyelomoy (Management of young patients with newly diagnosed multiple myeloma. In: Ukraine journ. of hematol. & transfusiol.) Ukrain. zhurn. gematol. i transfuziol. 2010; 5: 5–14.]
  75. Jakubowiak A.J., Friedman J., Kendall T. et al. A phase II study of combination of bortezomib, liposomal doxorubicin and dexamethasone (VDD) as first line therapy for multiple myeloma. J. Clin. Oncol. (ASCO Meeting Abstracts) 2006; 24: 18S (abstr. 17504).
  76. Moreau P., Pylypenko H., Grosicki S. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet 2011; 12(5): 431–40.
  77. Alexanian R., Wang L.M., Weber D.M., Delasalle K.B. VTD (Velcade, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed Multiple Myeloma. Blood 2004; 104: Abstract 210.
  78. Cavo M., Patriarca F., Tacchetti P. Superior complete response rate and progression-free survival after autologous transplantation with up-front velcadethalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood 2008; 112: 158 (abstr.).
  79. Cavo M., Pantani L., Petrucci M.T. et al. Bortezomib-thalidomidedexamethasone is superior to thalidomide-dexamethasone as consolidation therapy following autologous hematopoietic stem-cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012; 120(1): 9–18.
  80. Rosinol L., Cibera M.T., Martinez J. Thalidomide/dexamethasone (TD) vs. bortesomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Velcade regimens prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma: first results of a prospective phase III PETHEMA/Gem Trial. Blood 2008; 112: 654 (abstr.).
  81. Richardson P.G., Weller E., Lonial S. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116(5): 679–86.
  82. Reeder C.B., Reece D.E., Kukreti V. et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009; 23(7): 1337–41.
  83. Kumar S., Flinn I.W., Noga S.J. et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the phase I/II multi-center EVOLUTION Study. Blood 2008; 112: 93 (abstr.).
  84. Kumar S., Flinn I.W., Paul G. et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012; 119(19): 4375–82.
  85. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Эффек- тивность леналидомида при рефрактерных/рецидивирующих формах множественной миеломы. Онкогематология 2012; 1: 6–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Effektivnost lenalidomida pri refrakternykh/retsidiviruyushchikh formakh mnozhestvennoy miyelomy (Lenalidomide efficacy in refractory/relapsing forms of multiple myeloma. In: Oncohematology). Onkogematologiya 2012; 1: 6–14.]
  86. Siegel D.S., Martin T., Wang M. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120(14): 2817–25.
  87. Demo S.D., Kirk C.J., Aujay M.A. et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007; 67(13): 6383–91.
  88. Kuhn D.J., Chen Q., Voorhees P.M. et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007; 110(9): 3281–90.
  89. Arastu-Kapur S., Anderl J.L., Kraus M. et al. Non-proteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin. Cancer Res. 2011; 17(9): 2734–43.
  90. Bruna J., Udina E., Ale A. et al. Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice. Exp. Neurol. 2010; 223(2): 599–608.
  91. Korde N., Zingone A., Kwok M. et al. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients. Blood (ASH Annual Meeting Abstracts) 2012; 120: Abstract 732.
  92. Barlogie B., Alexanian R., Docke K.A. High-dose chemoradiotherapy with autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987; 70: 869–72.
  93. Attal M., Harousseau J.L., Stoppa A.M. et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myeloma. N. Engl. J. Med. 1996; 335: 91–7.
  94. Child J.A., Morgan G.J., Davies F.E. et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N. Engl. J. Med. 2003; 348: 1875–83.
  95. Gale K. Intensive Therapy Improves Survival in Patients With Multiple Myeloma. N. Engl. J. Med. 2003; 348: 1875–83.
  96. Barlogie B., Kyle R.A., Anderson K.S. et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J. Clin. Oncol. 2006; 24: 929–36.
  97. Fermand J.P., Katsahian S., Divine M. et al. High-dose therapy and autologous blood stem-cell transplantation high-dose therapy conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J. Clin. Oncol. 2005; 23: 9227–33.
  98. Blade J., Rosinol L., Sureda A. et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106: 3755–9.
  99. Levy V., Katsahian S., Fermand J.P. et al. A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 2005; 84(4): 250–60.
  100. Sirohi B., Powles R., Mehta J. et al. Single-center results of 200 mg/ m2 melphalan and autograft in 451 myeloma patients: identifying patients with prolonged survival based upon albumin and B2-microglobulin at transplant. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting. 2002, Orlando, Florida. Abstract 1072.
  101. Tribalto M., Amadori S., Cudillo L. Autologous peripheral blood stem cell transplantation as first line treatment of multiple myeloma: an Italian Multicenter Study. Haematologica 2000; 85: 52–8.
  102. Roussel M., Huynh A., Moreau P. Bortezomib and high dose melphalan as conditioning regimen before autologous stem cell transplantation for de novo multiple myeloma: final results of the IFM Phase II Study VEL/MEL. Blood 2008; 112: 160 (abstr.)
  103. Van de Velde H.J., Liu X., Chen G. et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92(10): 1399–406.
  104. Gay F., Larocca A., Wijermans P. et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood 2011; 117(11): 3025–31.
  105. Martinez-Lopez J., Blade J., Mateos M.V. et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 2011; 118(3): 529–34.
  106. Dispenzieri A., Rajkumar S.V., Gertz M.A. et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin. Proc. 2007; 82(3): 323–41.
  107. Kumar S.K., Lacy M.Q., Dispenzieri A. et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer 2012; 118(6): 1585–92.
  108. Marjanovic S., Stamatovic D., Elez M. et al. Autologous stem cell transplantation in the treatment of patients with multiple myeloma: our experience. Bone Marrow Transplant. 2013; 48(Suppl. 2): S212 (abstr. P730).
  109. Barlogie B., Attal M., Crowley J. et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J. Clin. Oncol. 2010; 28(7): 1209–14.
  110. Barlogie B., Jagannath S., Vesole D.H. et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: 789–93.
  111. Barlogie B., Jagannath S., Desikan K.R. et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93: 55–65.
  112. Cavo M., Tosi P., Zamagni E. et al. A multicentric randomized clinical trial comparing single vs double autologous peripheral blood stem cell transplantation for patients with newly diagnosed multiple myeloma: results of an interim analysis. Bone Marrow Transplant. 2000; 25(Suppl. 1): S54.
  113. Lahuerta J.J., Grande C., Martinez-Lopez J. et al. Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Espanol de Sindromes Linfoproliferativos/Trasplante Autologo de Medula Osea phase II trial. Br. J. Haematol. 2003; 120: 296–303.
  114. Barlogie B., Tricot G., Anaissie E. et al. Thalidomide and hematopoieticcell transplantation for multiple myeloma. N. Engl. J. Med. 2006; 354: 1021–30.
  115. Barlogie B., Anaissie E.J., Schaughnessy J.D. et al. Ninety percent sustained complete response (CR) projected 4 years after onset of CR in gene expression profiling (GEP)-defined low-risk multiple myeloma treated with Total Therapy 3 (TT3): basis for GEP-risk-adapted TT4 and TT5. Blood 2008; 12: 162 (abstr).
  116. Sonneveld P., Schmidt-Wolf I.G.H., van der Holt B. et al. HOVON-65/ GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 2010; 116(21): Abstract 40.
  117. Attal M., Harousseau J.L., Facon T. et al. InterGroupe Francophone du myeloma. Single versus double autologous stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2003; 249(26): 2495–502.
  118. Gerull S., Stem M., Ben Aissa A. et al. Allogeneic haematopoietic stem cell transplantation for multiple myeloma — the Swiss experience. Bone Marrow Transplant. 2012; 47(Suppl. 1): S326 (abstr. P899).
  119. Benakil M., Ahmed Nacer R., Talbi A. et al. Allogeneic stem cell transplantation in patients with multiple myeloma: long term follow-up in a single centre. Bone Marrow Transplant. 2012; 47(Suppl. 1): S327 (abstr. P901).
  120. Garban F., Attal M., Michallet M. et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in highrisk de novo multiple myeloma. Blood 2006; 107: 3477–80.
  121. Bruno B., Rotta M., Patriarca F. et al. A comparison of allografting with autografting for newly diagnosed myeloma. N. Engl. J. Med. 2007; 356: 1110–20.
  122. Rosinol L., Perez-Simin J.A., Sureda A. et al. A prospective PETEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: 3591–3.
  123. Lokhorst H., Sonneveld P., van der Holt B. et al. Donor versus no donor analysis of newly diagnosed myeloma patients included in the HOVON 50/50 Study. Blood 2008; 112: 461 (abstr.).
  124. Bjorkstrand B., Lacobelli S., Hegenbart A. Autologous stem cell transplantation (ASCT) versus ASCT followed by reduced-intensity conditioning (RIC) allogeneic SCT with identical sibling donor in previously untreated multiple myeloma: a prospective controlled trial by the EBMT. Bone Marrow Transplant. 2009; 43: 223 (abstr.).
  125. Kroger N., Zabelina T., Ayuk F. et al. Molecular remission after autologous-allogeneic tandem transplantation in patients with multiple myeloma. Bone Marrow Transplant. 2012; 47(Suppl. 1): S45 (abstr. O256).
  126. Kharfan-Dabaja M., Hamadani M., Reljic T. Comparative efficacy of tandem autologous-autologous versus tandem autologous-reduced intensity allogeneic haematopoietic cell transplantation in multiple myeloma: results of a systematic review and meta-analysis. Bone Marrow Transplant. 2012; 47(Suppl. 1): S44 (abstr. O254).
  127. Ludwig H., Hajek R., Tothova E. et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009; 113: 3435–42.
  128. Zonder J.A., Crowley J.J., Bolejack V. et al. A randomized Southwest Oncology Group study comparing dexamethasone (D) to lenalidomide+dexamethasone (LD) as treatment of newly diagnosed multiple myeloma: impact of cytogenetic abnormalities on efficacy of LD, and updated overall study results. J. Clin. Oncol. 2008; 26: 8521 (abstr.)
  129. Rajkumar S.V., Jacobus S., Callander N. et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide+low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J. Clin. Oncol. 2008; 26: 8504 (abstr.).
  130. Gulbrandsen N., Waage A., Gimsing P. et al. A randomized placebo controlled study with melphalan/prednisone vs melphalan/prednisone/thalidomide: quality of life and toxicity. Haematologica 2008; 93: 93 (abstr. 0209).
  131. Palumbo A., Bringhen S., Caravita T. et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial. Lancet 2006; 367: 825–31.
  132. Palumbo A., Bringhen S., Liberaty A.M. et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008; 112: 3107–14.
  133. Facon T., Mary J.Y., Hulin C. et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet 2007; 370: 1209–18.
  134. Hulin C., Facon T., Rodon P. et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. Blood 2007; 110: 75 (abstr.).
  135. Wijermans P., Schaafsma M., van Norden Y. et al. Melphalan+prednisone vs melphalan+prednisone+thalidomide in induction therapy for multiple myeloma in elderly patients: final analysis of the Dutch cooperative group HOVON 49 study. Blood 2008; 112: 649 (abstr.).
  136. San Miguel J.F., Schlag R., Khuageva N.K. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 2008; 359: 906–17.
  137. Mateos M.V., Hernandez J.M., Hernandez M.T. et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica 2008; 93(4): 560–5.
  138. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Бор- тезомиб (Велкейд) в индукционной терапии множественной миеломы. Клиническая Онкогематология 2008; 1(4): 315–22.  [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Bortezomib (Velkeyd) v induktsionnoy terapii mnozhestvennoy miyelomy (Bortezomib (Velcade) in induction therapy for multiple myeloma. In: Clinical Oncohematology). Klinicheskaya Onkogematologiya 2008; 1(4): 315–22.]
  139. Бессмельцев С.С., Стельмашено Л.В., Степанова Н.В. и др. Борте- зомиб (велкейд) и мелфалан с преднизолоном в лечении множественной миеломы у пожилых больных. Онкогематология 2010; 2: 40–5.
  140. [Bessmeltsev S.S., Stelmashenko L.V., Stepanova N.V. i dr. Bortezomib (velkeyd) i melfalan s prednizolonom v lechenii mnozhestvennoy miyelomy u pozhilykh bolnykh (Bortezomib (Velcade) and melphalan with prednisolone in therapy for multiple myeloma in elderly patients. In: Oncohematology). Onkogematologiya 2010; 2: 40–5.]
  141. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Лечение пожилых пациентов с множественной миеломой на современном этапе. Онкогематология 2010; 4: 6–13. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Lecheniye pozhilykh patsiyentov s mnozhestvennoy miyelomoy na sovremennom etape (Current management of elderly patients with multiple myeloma. In: Oncohematology). Onkogematologiya 2010; 4: 6–13.]
  142. Palumbo A., Bringhen S., Rossi D. et al. A prospective, randomized, phase III study of bortezomib, melphalan, prednisone, and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma patients. Blood 2008; 112: 652 (abstr.)
  143. Morgan G.J., Davies F.E., Owen R.G. et al. Thalidomide combinations improve response rates: results from the MRC IX Study. Blood 2007; 110: 3593 (abstr.).
  144. Palumbo A., Falco P., Corradini P. et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA-Italian Multiple Myeloma Network. J. Clin. Oncol. 2007; 25: 4459–65.
  145. Gay F., Bringhen S., Offidani M. et al. Efficacy and safety of 3 lenalidomidebased combinations in elderly newly diagnosed multiple myeloma patients: results from the phase 3 community based emn01 trial. 18th Congress of the European Hematology Association, June 13–16, 2013, Stockholm. Abstract B 221.
  146. Paiva B., Martinez-Lopez J. Vidriales M.B. et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J. Clin. Oncol. 2011; 29(12): 1627–33.
  147. Ladetto M., Pagliano G., Ferrero S. et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J. Clin. Oncol. 2010; 28(12): 2077–84.
  148. Hoering A., Crowley J., Shaughnessy J.D. Jr. et al. Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in total therapy protocols. Blood 2009; 114(7): 1299–305.
  149. Myeloma Trialists’ Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br. J. Haematol. 2001; 113(4): 1020–34.
  150. Attal M., Harousseau J.L., Leyvraz S. et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006; 108: 3289–94.
  151. Hahn-Ast C., von Lilienfeld-Toal M., van Heteren P. et al. Improved progression-free survival and overall survival with thalidomide maintenance therapy in multiple myeloma: a meta-analyis of randomized trials in 2274 patients. Haematologica 2010; 95(2): Abstract 0942.
  152. Morgan G.J., Gregory W.M., Davies F.E. et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and metaanalysis. Blood 2012; 119(1): 7–15.
  153. Barlogie B., Pineds-Roman M., van Rhee F. et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008; 112: 3115–21.
  154. Sonneveld P., Schmidt-Wolf I., 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.
  155. Mellqvist U.-H., 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.
  156. 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.
  157. McCarthy P.L., Owzar K., Hofmeister C.C. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2012; 366(19): 1770–81.
  158. Palumbo A., Gay F., Caravita di Toritto T. et al. Melphalan/prednisone/ lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (mel200) in newly diagnosed multiple myeloma patients. 18th Congress of the European Hematology Association, June 13–16, 2013, Stockholm. Abstract B 222.
  159. Cavo M., Pantani L., Petrucci M.T. et al. GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) Italian Myeloma Network. Bortezomibthalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012; 120(1): 9–19.
  160. Palumbo A., Hajek R., Delforge M. et al. Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma. N. Engl. J. Med. 2012; 366: 1759–69.
  161. Mateos M.-V., Oriol A., Martinez-Lopez J. et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012; 120(13): 2581–8.
  162. Bergsagel P.L., Mateos M.V., Gutierrez N.C. et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 2013; 121: 884–92.
  163. Rajkumar S.V. Treatment of multiple myeloma. Nat. Rev. Clin. Oncol. 2011; 8(8): 479–91.
  164. Nair B., van Rhee F., Shaughnessy J.D. et al. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 2010; 115(21): 4168–73.
  165. Goldschmidt H., Neben K., Bertsch U. et al. Bortezomib-based induction therapy followed by autologous stem cell transplantation and maintenance therapy with bortezomib improves outcome in myeloma patients with gain 1q21 and t(4;14): a subgroup analysis of the HOVON-65/GMMG-HD4 trial. Blood (ASH Annual Meeting Abstracts) 2010; 116(21): 305.
  166. Kapoor P., Kumar S., Fonseca R. et al. Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood 2009; 114(3): 518–21.
  167. Jagannath S., Richardson P. G., Sonneveld P. et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21(1): 151–7.
  168. San-Miguel J., Harousseau J.L., Joshua D., Anderson K.C. Individualizing treatment of patients with myeloma in the era of novel agents. J. Clin. Oncol. 2008; 26(16): 2761–6.
  169. Barlogie B., Anaissie E., van Rhee F. et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br. J. Haematol. 2007; 138(2): 176–85.
  170. Kaufman J.L., Nooka A.K., Muppidi S. et al. Survival outcomes of early autologous stem cell transplantation followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance and patients with high-risk multiple myeloma. J. Clin. Oncol. 2012; 30: Abstract 8100.
  171. Rajkumar S.V. Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma?. Hematology doi: 10.1182/asheducation-2012.1.354 ASH Education Book 2012; 1: 354–61.
  172. Palumbo A., Cavallo F. Have drug combinations supplanted stem cell transplantation in myeloma?. Hematology doi: 10.1182/asheducation-2012.1.354 ASH Education Book 2012; 1: 335–41.
  173. Стельмашенко Л.В., Абдулкадыров К.М., Бессмельцев С.С. и др. Роль поддерживающей терапии в посттрансплантационном периоде больных множественной миеломой. Вестн. гематол. 2012; 4: 36–7.
  174. Siegel D.S., Desikan K.R., Mehta J. et al. Age is not a prognostic variable with autotransplantants for multiple myeloma. Blood 1999; 93: 51–4.
  175. Sirohi B., Powles R., Treleaven J. et al. The role of autologous transplantation in patients with multiple myeloma aged 65 years and over. Bone Marrow Transplant. 2000; 25: 533–9.
  176. Reece D.E., Bredeson C., Perez W.S. et al. Autologous stem cell transplantation in multiple myeloma patients < 60 vs >/= 60 years of age. Bone Marrow Transplant. 2003; 32: 1135–43.
  177. Palumbo A., Bringhen S., Petrucci M.T. et al. Intermediate-dose melphalan improves survival of myeloma patients ages 50 to 70: results of randomized controlled trial. Blood 2004; 104: 3052–3057.
  178. Rajkumar S.V. Thalidomide in the treatment of multiple myeloma. Expert. Rev. Anticancer Ther. 2001; 1(1): 20–8.
  179. Weber D., Rankin K., Gavino M. et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J. Clin. Oncol. 2003; 21: 16–9.
  180. Dimopoulos M.A., Eleutherakis V. Adverse effects of thalidomide administration in patients with neoplastic disease. Am. J. Med. 2004; 117: 508–15.
  181. Hall V.C., El-Azhary R.A., Bouwhuis S. et al. Dermatologic side effects of thalidomide in patients with multiple myeloma. J. Am. Acad. Dermatol. 2003; 48: 548–52.
  182. Palumbo A., Facon T., Sonneveld P. et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008; 111: 3968–77.
  183. Gunzler V. Thalidomide in human immunodeficiency virus (HIV) patients: a review of safety considerations. Drug Safety 1992; 7: 116–34.
  184. Teo S., Morgan M., Stirling D. et al. Assessment of the in vitro and in vivo genotoxicity of thalomid (thalidomide). Terat. Carcin. Mutagen. 2000; 20: 301–11.
  185. Sonneveld P., Dimopoulos M., San Miguel J. et al. Recommended management of cytopenia for len/dex in MM. Haematologica 2007; 92: 217 (abstr. PO-1122).
  186. Palumbo A., Rajkumar S.V., Dimopoulos M.A. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma . Leukemia 2008; 22(2): 414–23.
  187. Musallam K.M., Dahdaleh F.S., Shamseddine A.I., Taher A.T. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb. Res. 2009; 123(5): 679–86.
  188. Cavo M., Palumbo A., Brighen S. et al. A phase III study of enoxaparin versus low-dose warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens. Blood 2008; 112: 3017 (abstr.)
  189. Larocca A., Cavallo F., Bringhen S. et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119(4): 933–9.
  190. Faiman B.M., Spong J., Tariman J.D. Renal Complications in Multiple Myeloma and Related Disorders: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board. Clin. J. Oncol. Nurs. 2011; 15(4): 66–76.
  191. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Частота, характеристика и методы лечения периферической нейропатии у больных множественной миеломой, получающих бортезомиб (велкейд). Онкогема- тология 2008; 3: 52–62. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Chastota, kharakteristika i metody lecheniya perifericheskoy neyropatii u bolnykh mnozhestvennoy miyelomoy, poluchayushchikh bortezomib (velkeyd) (Incidence, characteristics, and therapeutic methods for management of peripheral neuropathy in patients with multiple myeloma treated with bortezomib (Velcade). In: Oncohematology). Onkogematologiya 2008; 3: 52–62.]
  192. Barohn R. Approach to peripheral neuropathy and neuronopathy. Semin. Neurol. 1998; 18: 7–18.
  193. Lopate G., Parks B., Goldstein J. et al. Polyneuropathies associated with high titre antisulphatide antibodies: characteristics of patients with and without serum monoclonal proteins. J. Neurol. Neurosurg. Psychiat. 1997; 62: 581–5.
  194. Ropper A.H., Gorson K.C. Neuropathies associated with paraproteinemia. N. Engl. J. Med. 1998; 338: 1601–7.
  195. Rajkumar S.V. MGUS and Smoldering Multiple Myeloma: Update on Pathogenesis, Natural History, and Management. Hematology (The American Society of Hematology) 2005; 1: 340.
  196. Richardson P.G., Delforge M., Beksac M. et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia 2012; 26: 595–8.
  197. Dispenzieri A., Jacobus S., Vesole D.H. et al. Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial. Leukemia 2010; 24: 1406–11.
  198. Palumbo A., Anderson K. Multiple myeloma. Engl. J. Med. 2011; 364(11): 1046–60.

Apoptotic markers in CD34-positive cells in acute leukemias

Ye.N. Parovichnikova1, Ye.Ye. Khodunova1, I.V. Galtseva1, S.М. Kulikov1, V.V. Troitskaya1, L.А. Kuzmina1, D.V. Shcheblyakov2, and V.G. Savchenko1

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

2 N.F. Gamaleya Research Institution of Epidemiology and Microbiology, RF Ministry of Health, Moscow, Russian Federation


ABSTRACT

Objective. To evaluate expression of Bcl-2, Bax, p53, CD95, and ACE on CD34+ cells of peripheral blood and bone marrow during induction chemotherapy in the patients with newly diagnosed acute leukemia.

Materials and methods. Expression of Bcl-2, Bax, p53, CD95, and ACE on CD34+ cells of the peripheral blood and bone marrow in 23 patients with AL (14 AML and 9 ALL) was measured using flow cytometry analysis. Peripheral blood and bone marrow samples were analyzed before chemotherapy and during the induction course: on Days +8, +21 (blood only), and +36–38. The control group consisted of 8 healthy donors.

Results. Bcl-2 expression on CD34+ sells in BM was 34.8 ± 6 % and significantly higher compared to the donors (11.5 ± 1.8 %) at the time of diagnosis. On Days +36–38 after the onset of chemotherapy, no significant difference between the patients and control groups were found. CD34/Bax coexpression in BM cells of ALL patients was significantly higher than in AML patients and donors. ACE and p53 expression on CD34+ cells in AL patients before and during chemotherapy was significantly lower than in the donors. CD34/ACE coexpression in PB and BM cells of AL patients and donors showed no significant differences at any time-points of evaluation.

Conclusion. The above changes suggest the imbalance between the pro- and anti-apoptotic proteins in AL patients. After chemotherapy, the expression profile of these proteins considerably changed, but did not reach the healthy donor values.


Keywords: acute leukemias, apoptosis, expression of Bcl-2, Bax, р53, CD95, and ACE.

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Refernces

  1. Hengartner M.O. The biochemistry of apoptosis. Nature 2000; 407(6805): 770–6.
  2. Lodish H., Berk A., Matsudaira P. et al. Molecular cell biology, 5th edn. New York: W.H. Freeman and Company, 2003: 961.
  3. Salminen A., Ojala J., Kaarniranta K. Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cell. Mol. Life Sci. 2011; 68(6): 1021–31.
  4. Spencer S.L., Sorger P.K. Measuring and modeling apoptosis in single cells. Cell 2011; 144(6): 926–39.
  5. Herr I., Debatin K.-M. Cellular stress response and apoptosis in cancer therapy. Blood 2001; 98(9): 2603–14.
  6. Chao D.T., Korsmeyer S. J. BCL-2 family: regulators of cell death. Ann. Rev. Immunol. 1998; 16: 395–419.
  7. Green D.R. Apoptotic pathways: The roads to ruin. Cell 1998; 94: 695–8.
  8. Chauncey T.R. Drug resistance mechanisms in acute leukemia. Curr. Opin. Oncol. 2001; 13(1): 21–6.
  9. Del Poeta G., Bruno A., Del M.I. Principe et al. Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. Curr. Cancer Drug Targets 2008; 8(3): 202–7.
  10. Testa U., Riccioni R. Deregulation of apoptosis in acute myeloid leukemia. Haematologica 2007; 92(1): 81–94.
  11. Banker D.E., Groudine M., Norwood T., Appelbaum F.R. Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood 1997; 89(1): 243–55.
  12. Stijn A., Pol M.A., Kok A. et al. Differences between the CD34+ and CD34– blast compartments in apoptosis resistance in acute myeloid leukemia. Haematologica 2003; 88(5): 497–508.
  13. Fulda S., Los M., Friesen C., Debatin K.M. Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. Int. J. Cancer 1998; 76(1): 105–14.
  14. Fulda S., Sieverts H., Friesen C. et al. The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res. 1997; 57(17): 3823–9.
  15. Барышников А.Ю., Полосухина Е.Р., Шишкин Ю.В. и др. Новый прогностический маркер острого лимфобластного лейкоза — антиген CD95 (FAS/APO-1). Гематол. и трансфузиол. 1998; 2: 8–11. [Baryshnikov A.Yu., Polosukhina Ye.R., Shishkin Yu.V. i dr. Novyy prognosticheskiy marker ostrogo limfoblastnogo leykoza — antigen CD95 (FAS/APO-1) (New prognostic marker of acute lymphoblastic leukemia — CD95 antigen (FAS/ APO-1). In: Hematol. & transfusiol.) Gematol. i transfuziol. 1998; 2: 8–11.]
  16. Molica S., Mannella A., Dattilo A. et al. Differential expression of BCL-2 oncoprotein and Fas antigen on normal peripheral blood and leukemic bone marrow cells. A flow cytometric analysis. Haematologica 1996; 81(4): 302–9.
  17. Greenblatt M.S., Bennett W.P., Hollstein M., Harris C.C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54(18): 4855–78.
  18. Ko L.J., Prives C. p53: puzzle and paradigm. Genes & Dev. 1996; 10(9): 1054–72.
  19. Levine A.J. p53, the cellular gatekeeper for growth and division. Cell 1997; 88(3): 323–31.
  20. Resnick M.A., Tomso D., Inga A. et al. Functional diversity in the gene network controlled by the master regulator p53 in humans. Cell. Cycle 2005; 4(8): 1026–9.
  21. Prokocimer M., Rotter V. Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages. Blood 1994; 84(8): 2391–411.
  22. Wada M., Bartram C.R., Nakamura H. et al. Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood. Blood 1993; 82(10): 3163–9.
  23. Cavalcanti G.B., Scheiner M.A., Simoes Magluta E.P. et al. p53 flow cytometry evaluation in leukemias: correlation to factors affecting clinical outcome. Cytometry B. Clin. Cytom. 2010; 78(4): 253–9.
  24. Beyazit Y., Aksu S., Haznedaroglu I.C. et al. Overexpression of the local bone marrow renin-angiotensin system in acute myeloid leukemia. J. Natl. Med. Assoc. 2007; 99: 57–63.
  25. Goker H., Haznedaroglu I.C., Beyazit Y. et al. Local umbilical cord blood renin-angiotensin system. Ann. Hematol. 2005; 84: 277–81.
  26. Jokubaitis V.J., Sinka L., Driessen R. et al. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues. Blood 2008; 111: 4055–63.
  27. Li J., Volkov L., Comte L. et al. Production and consumption of the tetrapeptide AcSDKP, a negative regulator of hematopoietic stem cells, by hematopoietic microenvironmental cells. Exp. Hematol. 1997; 25: 140–6.
  28. Гальцева И.В., Пашин Л.Е., Савченко В.Г. Лейкемические дендритные клетки. Тер. арх. 2008; 80(7): 84–8. [Galtseva I.V., Pashin L.Ye., Savchenko V.G. Leykemicheskiye dendritnyye kletki (Leukemic dendritic cells. In: Ther. archive). Ter. arkh. 2008; 80(7): 84–8.]
  29. Danilov S.M., Sadovnikova E., Scharenborg N. et al. Angiotensinconverting enzyme (CD 143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp. Hematol. 2003; 31(12): 1301–9.
  30. Del Poeta G., Venditti A., Del Principe M.I. et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Blood 2003; 101(6): 2125–31.
  31. El-Manallawy H.A., El-Shkankiry N.H., El-Guindy S. et al. The Expression of Bcl-2 and Bax Proteins and Their Clinical Relevance in ALL and CLL Patients. J. Egypt. Nat. Cancer Inst. 2001; 13(1): 35–42.
  32. Hogarth L.A., Hall A.G. Increased BAX expression is associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood 1999; 93(8): 2671–8.
  33. Aksu S., Beyazit Y., Haznedaroglu I.C. et al. Enhanced expression of the local haematopoietic bone marrow renin-angiotensin system in polycythemia rubra vera. J. Int. Med. Res. 2005; 33(6): 661–7.
  34. Aksu S., Beyazit Y., Haznedaroqlu I.C. et al. Over-expression of angiotensin-converting enzyme (CD 143) on leukemic blasts as a clue for the activated local bone marrow RAS in AML. Leuk. Lymphoma 2006; 47(5): 891–6.
  35. Барышников А.Ю., Шишкин Ю.В. Иммунологические проблемы апоптоза. М., 2002.  [Baryshnikov A.Yu., Shishkin Yu.V. Immunologicheskiye problemy apoptoza (Immunological problems of apoptosis). , 2002.]
  36. Miyawaki T., Uehara T., Nibu R. et al. Differential expression of apoptosisrelated Fas antigen on lymphocyte subpopulations in human peripheral blood. J. Immunol. 1992; 149(11): 3753–8.
  37. Lechner H., Amort M., Steger M.M. et al. Regulation of CD95 (APO-1) expression and the induction of apoptosis in human T cells: changes in old age. Int. Arch. Allergy Immunol. 1996; 110(3): 238–43.
  38. Kotani T., Aratake Y., Kondo S. et al. Expression of functional Fas antigen on adult T-cell leukemia. Leuk. Res. 1994; 18(4): 305–10.