МОЙ ВЫБОР

Т-клеточные лимфомы: возможности терапии при ограниченном выборе

МОЙ ВЫБОР , , , ,

В.А. Доронин

ФГБУ «РОНЦ им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

РЕФЕРАТ

Периферические и кожные Т-клеточные лимфомы (ПТКЛ и КТКЛ) представляют собой особую группу неходжкинских лимфом (НХЛ) с широким спектром молекулярных и генетических особенностей, а также разнообразными симптомами и клиническими проявлениями. Разнородность и редкость этих заболеваний создают трудности при проведении клинических исследований, а прогресс в лечении идет гораздо медленнее, чем при более распространенных В-клеточных НХЛ. Вследствие этого для Т-клеточных лимфом до настоящего времени не существует стандартов терапии. Лечение часто проводится в рамках клинических исследований. В статье рассматриваются оптимальные возможности терапии ПТКЛ и КТКЛ, обсуждаются также новые варианты лечения.

Ключевые слова: Т-клеточные лимфомы, периферическая Т-клеточная лимфома неуточненная, ангиоиммунобластная Т-клеточная лимфома, анапластическая крупноклеточная лимфома, кожные Т-клеточные лимфомы.

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ЛИТЕРАТУРА

  1. World Health Organization. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC Press, 2008.
  2. Vose J., Armitage J., Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J. Clin. Oncol. 2008; 26(25): 4124–30.
  3. Petrich A.M., Helenowski I., Galamaga R.W., Nabhan C. Blood (ASH Annual Meeting Abstracts) 2012; 120: Abstract 4264.
  4. Savage K.J., Chhanabhai M., Gascoyne R.D. et al. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann. Oncol. 2004; 15: 1467–75.
  5. Schmitz N., Trumper L., Ziepert M. et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418–25.
  6. Gallamini A., Zaja F., Patti C. et al. Alemtuzumab (Campath-1H) and CHOP сhemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007; 110: 2316–23.
  7. Mahadevan D., Unger J.M., Persky D.O. et al. Phase II trial of cisplatin plus etoposide plus gemcitagine plus solumedrol (PEGS) in peripheral T-cell non-Hodgkin lymphoma (SWOG S0350). Ann. Oncol. 2011; 22.
  8. Rodriguez J., Conde E., Gutierrez A. et al. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group. Eur. J. Haematol. 2007; 79: 32–8.
  9. Mercadal S. Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma. Ann. Oncol. 2008; 19: 958–63.
  10. Reimer P., Rudiger T., Geissinger E. et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J. Clin. Oncol. 2009; 27: 106–13.
  11. d’Amore F., Relander T., Lauritzsen G.F. et al. High-dose chemotherapy and autologuos stem cell transplantation in previously untreated peripheral T-cell lymphoma — final analysis of a large prospective multicenter study (NLGT-01). J. Clin. Oncol. 2012; 30(25): 3093–9.
  12. Farcet J.P., Gaulard P., Marolleau J.P. et al. Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta. Blood 1990; 75(11): 2213–9.
  13. Schmidt L.A., Lim M.S. T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary. J. Hematop. 2009; 2(2): 121–6.
  14. Kotlyar D.S., Osterman M.T., Diamond R.H. et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2011; 9(1): 36–41.
  15. Miyazaki K., Yamaguchi M., Imai H. et al. Gene expression profiling of peripheral T-cell lymphoma including gamma/delta T-cell lymphoma. Blood 2009; 113(5): 1071–4.
  16. Falchook G.S., Vega F., Dang N.H. et al. Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment. Ann. Oncol. 2009; 20(6): 1080–5.
  17. Willemze R., Jansen P.M., Cerroni L. et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood 2008; 111(2): 838–45.
  18. Go R.S., Wester S.M. Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer 2004; 101(6): 1404–13.
  19. Salhany K.E., Macon W.R., Choi J.K. et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am. J. Surg. Pathol. 1998; 22(7): 881–93.
  20. Jantunen E., Boumendil A., Finel H. et al. Autologous Stem Cell Transplantation (ASCT) for Enteropathy-Associated T-Cell Lymphoma (EATL): Final Analysis of a Retrospective Study On the Behalf of Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT). Blood (ASH Annual Meeting Abstracts) 2012; 120: Abstract 3105.
  21. Kim G.E., Cho J.H., Yang W.I. et al. Angiocentric lymphoma of the head and neck: patterns of systemic failure after radiation treatment. J. Clin. Oncol. 2000; 18(1): 54–63.
  22. Li Y.X., Yao B., Jin J. et al. Radiotherapy as primary treatment for stage IE and IIE nasal natural killer/T-cell lymphoma. J. Clin. Oncol. 2006; 24(1): 181–9.
  23. Kim W.S., Song S.Y., Ahn Y.C. et al. CHOP followed by involved field radiation: is it optimal for localized nasal natural killer/T-cell lymphoma? Ann. Oncol. 2001; 12(3): 349–52.
  24. Yamaguchi M., Kwong Y.L., Kim W.S. et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J. Clin. Oncol. 2011; 29(33): 4410–6.
  25. Willemze R., Kerl H., Sterry W. et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood 1997; 90: 354–71.
  26. Willemze R., Jaffe E.S., Burg G. et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–85.
  27. Macaulay W.L. Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign–histologically malignant. Arch. Dermatol. 1968; 97(1): 23–30.
  28. Bekkenk M.W., Geelen F.A., van Voorst Vader P.C. et al. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 2000; 95: 3653–61.
  29. Liu H.L., Hoppe R.T., S. Kohler et al. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J. Am. Acad. Dermatol. 2003; 49(6): 1049–58.
  30. Bijl J.J., Rieger E., van Oostveen J.W. et al. HOXC4, HOXC5, and HOXC6 expression in primary cutaneous lymphoid lesions. High expression of HOXC5 in anaplastic large-cell lymphomas. Am. J. Pathol. 1997; 151: 1067–74.
  31. Vonderheid E.C., Sajjadian A., Kadin M.E. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J. Am. Acad. Dermatol. 1996; 34(3): 470–81.
  32. Willemze R., Beljaards R.C. Spectrum of primary cutaneous CD30 (Ki-1)- positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J. Am. Acad. Dermatol. 1993; 28(6): 973–80.
  33. Paulli M., Berti E., Rosso R. et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin—clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J. Clin. Oncol. 1995; 13(6): 1343–54.
  34. Rijlaarsdam J.U., Huijgens P.C., Beljaards R.C. et al. Oral etoposide in the treatment of cutaneous large-cell lymphomas. A preliminary report of four cases. Br. J. Dermatol. 1992; 127(5): 524–8.
  35. Kim Y.H., Liu H.L., Mraz-Gernhard S. et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch. Dermatol. 2003; 139(7): 857–66.
  36. Ralfkiaer E. Controversies and discussion on early diagnosis of cutaneous T-cell lymphoma. Phenotyping. Dermatol. Clin. 1994; 12: 329–34.
  37. Vonderheid E.C., Bernengo M.G., Burg G. et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J. Am. Acad. Dermatol. 2002; 46: 95–106.
  38. Agar N.S., Wedgeworth E., Crichton S. et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J. Clin. Oncol. 2010; 28(31): 4730–9.
  39. Olsen E.A., Rook A.H., Zic J. et al. Sezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC). J. Am. Acad. Dermatol. 2011; 64(2): 352–404.
  40. Kelly W.K., O’Connor O.A., Krug L.M. et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 2005; 23(17): 3923–31.
  41. Kelly W.K., Richon V.M., O’Connor O. et al. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 2003; 9(10 Pt. 1): 3578–88.
  42. O’Connor O.A., Heaney M.L., Schwartz L. et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 2006; 24(1): 166–73.
  43. Mann B.S., Johnson J.R., Cohen M.H. et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12(10): 1247–52.
  44. Duvic M., Talpur R., Ni X. et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109(1): 31–9.
  45. Olsen E.A., Kim Y.H., Kuzel T.M. et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 2007; 25(21): 3109–15.
  46. O’Connor O.A., Pro B., Pinter-Brown L. et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J. Clin. Oncol. 2011; 29(9): 1182–9.
  47. Marchi E., Paoluzzi L., Scotto L. et al. Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin. Cancer Res. 2010; 16(14): 3648–58.
  48. Horwitz S.M., Vose J.M., Advani R. et al. Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results. ASH Annual Meeting Abstracts 2009; 114: 1674.
  49. Coiffier B., Pro B., Prince H.M. et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J. Clin. Oncol. 2012; 30(6): 631–6.
  50. Pro B., Advani R., Brice P. et al. Durable remissions with brentuximab vedotin (SGN-35): updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL). J. Clin. Oncol. 2011; 29: Abstract 8032

Фолликулярная лимфома: современные тенденции и мой выбор

МОЙ ВЫБОР ,

Г.С. Тумян

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва, Российская Федерация

РЕФЕРАТ

В этой первой публикации из серии «Мой выбор» обобщены современные данные по диагностике и лечению фолликулярной лимфомы и предложен алгоритм диагностических и лечебных мероприятий. Это позволит гематологу индивидуализировать лечение больных как при первичном обращении, так и рецидивах заболевания. Рассмотрены вопросы определения опухолевой нагрузки, трансформации болезни, кратко представлены различные варианты фолликулярной лимфомы.

Ключевые слова: фолликулярная лимфома, лечение

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ЛИТЕРАТУРА

  1. Swerdlow S.H., Campo E., Harris N.L. et al. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2008.
  2. Solal-Celigny P., Roy P., Colombat P. et al. Follicular Lymphoma International Prognostic Index. Blood 2004; 104: 1258–65.
  3. Federico M., Bellei M., Marcheselli L. et al. Follicular Lymphoma International Prognostic Index 2; A new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project. J. Clin. Oncol. 2009; 27: 4555–62.
  4. Brice P., Bastion Y., Lepage E. et al. Сomparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferonalfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J. Clin. Oncol. 1997; 15(3): 1110–7.
  5. Ardeshna K.M., Smith P., Norton A. et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advancedstage non-Hodgkin lymphoma: a randomized controlled trial. Lancet 2003; 362: 516–22.
  6. Salles G., Ghesquieres H. Current and future management of follicular lymphoma. Int. J. Hematol. 2012; 96:544–51.
  7. Young R.C., Longo D.L., Glatstein E. et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Sem. Haematol. 1988; 25: 11–6.
  8. Pugh T.J., Ballonoff A., Newman F. et al. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation. A Surveillance, Epidemiology, and End Results database analysis. Cancer 2010; 116(16): 3843–51.
  9. Seymour J.F., Pro B., Fuller L.M. et al. Long-Term Follow-Up of a Рrospective Study of Combined Modality Therapy for Stage I-II Indolent NonHodgkin’s Lymphoma. J. Clin. Oncol. 2003; 21: 2115–22.
  10. Soubeyran P., Eghbali H., Trojani M. et al. Is there any place for a waitand-see policy in stage I0 follicular lymphoma? A study of 43 consecutive patients in a single center. Ann. Oncol. 1996; 7: 713–8.
  11. Ruella M., Fillip A., Russo A.D. Addition of rituximab to involved-field radiotherapy prolongs progression free survival in stage I-II follicular Lymphomas: a multicentric, retrospective survey. Haematologica 2012; 97(s1): 0796.
  12. Ardeshna K.M., Smith P., Qian W. et al. An Intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2 and 3a). A Preliminary analysis. Blood 2010; 116: abstract 6.
  13. Martinelli G., Schmitz S.F., Utiger U. et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J. Clin. Oncol. 2010; 28(29): 4480–4.
  14. Kahl B.S., Hong F., Williams M.E. et al. Results of Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. Blood 2011, 118: abstract 6.
  15. Friedberg J., Taylor M., Cerhan J. et al. Follicular Lymphoma in the United States: First Report of the National LymphoCare Study. J. Clin. Oncol. 2009; 27(8): 1202–8.
  16. Hiddemann W., Kneba M., Dreyling M. et al. Front-line therapy with Rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone — results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2005; 106: 3725–32.
  17. Herold M., Haas A., Srock S. et al. Rituximab Added to First-Line Mitoxantrone, Chlorambucil, and Prednisolone Chemotherapy Followed by Interferon Maintenance Prolongs Survival in Patients With Advanced Follicular Lymphoma: An East German Study Group Hematology and Oncology Study. J. Clin. Oncol. 2007; 25:1986–92.
  18. Marcus R., Imrie K., Solal-Celigny P. et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma. J. Clin. Oncol. 2008; 28: 4579–86.
  19. Salles G., Mounier N., de Guibert S. et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008; 112: 4824–31.
  20. Federico M., Luminari S., Dondi A. et al. R-CVP vs R-CHOP vs R-FM for the initial treatment of patients with advanced stage Follicular Lymphoma. Preliminary results of FOLL05 IIL trial. IX ICML Lugano, Switzerland, 15–18 June 2011. Ann. Oncol. 2011; 22(Suppl. 4): 128.
  21. Nastoupil N., Sinha R., Byrtek M. et al. Effectiveness of first-line chemoimmunotherapy regimens for patients diagnosed with follicular lymphoma (FL) in the US: Data from National Lymphocare Study (NLCS). Haematologica 2012; 97 (s1): abstract 0800.
  22. Rummel M.J., Niederle N., Maschmeyer G. et al. Bendamustin plus Rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus Rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: Final results of a randomized phase III study of the STIL. Blood 2009; 110(11).
  23. Hochster H., Weller E., Gascoyne R.D. et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J. Clin. Oncol. 2009; 27(10): 1607–14.
  24. Salles G., Seymour J.-F., Offner F. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42–51.
  25. Lenz G., Dreyling M., Schiegnitz E. et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104: 2667–74.
  26. Sebban C., Mounier N., Brousse N. et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood 2006; 108: 2540–4.
  27. Gayan E., Foussard C., Bertrand P. et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113: 995–1001.
  28. Ladetto M., De Marco F., Benedetti F. et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111(8): 4004–13.
  29. Cheson B.D., Friedberg J.W., Kahl B.S. et al. Bendamustine produces durable responses with an acceptable safety profile in patients with rituximabrefractory indolent non-Hodgkin lymphoma. Clin. Lymph. Myeloma Leuk. 2010; 10(6): 452–7.
  30. Fowler N., Kahl B.S., Lee P. et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. JCO 2011; 29(25): 3389–95.
  31. Al Khabori M., Almeida J., Guyatt G., Kuruvilla J., Crump M. Autologous Stem Cell Transplantation in Follicular Lymphoma: a Systematic Review and Meta-analysis. J. Natl. Cancer. Inst. 2012; 104(1): 18–28.
  32. Bernstein S., Burack R. The incidence, natural history, biology, and treatment of transformed lymphomas. Hematology 2009; 1: 532–41.
  33. Oschlies I., Salaverria I., Mahn F. et al. Pediatric follicular lymphoma–a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin’s Lymphoma—Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials. Hematology 2010; 95(2): 253–9.
  34. Schmatz A.I., Streubel B., Kretschmer-Chott E. et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. J. Clin. Oncol. 2011; 29(11): 1445–51.
  35. Jegalian A.G., Eberle F.C., Pack S.D. et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118(11): 2976–84.
  36. Willemze R., Jaffe E.S., Burg G. et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105(10): 3768–85.
  37. Kenkre V., Kahl B. What Is the Best Initial Therapy for a Patient With Symptomatic Low-Grade Follicular Lymphoma? Cancer 2012; 18: 83Y389. 38. Salles G., Ghesquieres H. Current and future management of follicular lymphoma. Int. J. Hematol. 2012; 96: 544–51.