Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas

VO Sarzhevskii, AA Samoilova, VYa Melnichenko, YuN Dubinina, NE Mochkin, DS Kolesnikova, DA Fedorenko, EG Smirnova, AE Bannikova, VS Bogatyrev

NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Anastasiya Aleksandrovna Samoilova, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-17; e-mail: samoylove03@gmail.com

For citation: Sarzhevskii VO, Samoilova AA, Melnichenko VYa, et al. Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas. Clinical oncohematology. 2020;13(2):185–92 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-185-192


ABSTRACT

Aim. To assess the safety and efficacy of BeEAC as a conditioning regimen prior to autologous hematopoietic stem cell transplantation (auto-HSCT) in relapsed and primary resistant lymphomas (ClinicalTrials.gov NCT03315520).

Materials & Methods. The trial included 113 patients with Hodgkin’s (HL) and non-Hodgkin’s lymphomas (NHL). The patients were included into the protocol during the period from February 2016 to June 2018. Median follow-up was 26 months. Among the patients there were 58 men and 55 women. Median age was 33 years (range 18–65 years). In 72 patients HL and in 41 patients NHL (in 15 diffuse large B-cell lymphoma, in 8 primary mediastinal (thymic) large B-cell lymphoma, in 10 mantle cell lymphoma, in 4 peripheral T-cell lymphoma unspecified, and in 4 patients follicular lymphoma) were diagnosed. BeEAC conditioning regimen consisted of administering 160–200 mg/m2 bendamustine in increasing doses on Day –6 and Day –5 combined with fixed doses of 200 mg/m2 cytarabine every 12 hours, 200 mg/m2 etoposide, and 140 mg/kg cyclophosphamide from Day –4 to Day –1.

Results. In phase 1, when bendamustine dose was increased from 160 mg/m2 to 200 mg/m2, no dose-limiting toxicity was observed. Afterwards patients received 200 mg/m2 of bendamustine. The assessment of tumor status in 2–3 months after auto-HSCT showed that complete remission was achieved in 62.9 % (n = 71) of patients, partial remission in 16.8 % (n = 19) of patients, stabilization in 0.9 % (n = 1) of patients and progression in 15 % (n = 17) of patients. In 5 patients the treatment effect was not assessed. Early post-transplant mortality (up to Day +30) was 3.6 % (n = 4) and overall mortality within the follow-up period (median 26 months) was 23 % (n = 26). Overall survival in the whole cohort of patients for 12, 18, 24, and 36 months was 88 %, 82 %, 78 %, and 64 %, respectively, and progression-free survival was 61 %, 57 %, 54 %, and 40 %, respectively.

Conclusion. BeEAC proved to be relatively safe when applied as a conditioning regimen prior to auto-HSCT in HL and NHL patients. Further data need to be collected to finally assess the efficacy of this regimen and to conduct a retrospective comparative analysis of it and other conditioning regimens in lymphomas.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cell transplantation, conditioning regimens, bendamustine, toxicity.

Received: September 6, 2019

Accepted: March 3, 2020

Read in PDF


REFERENCES

  1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA: A Cancer J Clin. 2019;69(1):7–34. doi: 10.3322/caac.21551.

  2. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):1540–5. doi: 10.1056/nejm199512073332305.

  3. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27(36):6101–8. doi: 10.1200/JCO.2009.22.2554.

  4. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003;21(21):3918–27. doi: 10.1200/JCO.2003.10.023.

  5. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2018. 155 с.

    [Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines on diagnosis and treatment of lymphoproliferative disorders.) Moscow: Buki Vedi Publ.; 155 p. (In Russ)]

  6. Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem cell support: still very long survival but late relapses do occur. Br J Haemotol. 2012;158(3):355–62. doi: 10.1111/j.1365-2141.2012.09174.x.

  7. Carreras E, Dufour C, Mohty M, Kroger N. (eds.) The EBMT Handbook. Hematopoietic Stem Cell Transplantation and Cellular Therapies. Springer International Publishing; 2019. 702 р. doi: 10.1007/978-3-030-02278-5.

  8. Visani G, Malerba L, Stefani PM, et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011;118(12):3419–25. doi: 10.1182/blood-2011-04-351924.

  9. Chantepie SP, Garciaz S, Tchernonog E, et al. Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers. Am J Hematol. 2018;93(6):729–35. doi: 10.1002/ajh.25077.

  10. Carella AM, Santini G, Giordano D, et al. High-Dose Chemotherapy and Non-Frozen Autologous Bone Marrow transplantation in Relapsed Advanced Lymphomas or Those Resistant to Convential Chemotherapy. Cancer. 1984;54(12):2836–9. doi: 10.1002/1097-0142(19841215)54:12<2836::aid-cncr2820541203>3.0.co;2-r.

  11. Caballero MD, Rubio V, Rifon J, et al. BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Bone Marrow Transplant. 1997;20(6):451–8. doi: 10.1038/sj.bmt.1700913.

  12. Jo JC, Kang BW, Jang G, et al. BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: comparative analysis of efficacy and toxicity. Ann Hematol. 2008;87(1):43–8. doi: 10.1007/s00277-007-0360-0.

  13. Shi Y, Liu P, Zhou S, et al. Comparison of CBV, BEAM and BEAC high‐dose chemotherapy followed by autologous hematopoietic stem cell transplantation in non‐Hodgkin lymphoma: Efficacy and toxicity. Asia-Pacific J Clin Oncol. 2017;13(5):e423–e429. doi: 10.1111/ajco.12610.

  14. Sureda A, Constans M, Iriondo A, et al. Prognostic factors affecting long- term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16(4):625–33. doi: 10.1093/annonc/mdi119.

  15. Rauf MS, Maghfoor I, Elhassan TAM, Akhtar S. High-dose chemotherapy and auto-SCT for relapsed and refractory Hodgkin’s lymphoma patients refractory to first-line salvage chemotherapy but responsive to second-line salvage chemotherapy. Med Oncol. 2015;32(1):388. doi: 10.1007/s12032-014-0388-7.

  16. Vose JM, Rizzo DJ, Tao-Wu J, et al. Autologus transplantation for diffuse aggressive non-Hodgkin lymphoma in first relapse or second remission. Biol Blood Marrow Transplant. 2004;10(2):116–27. doi: 10.1016/j.bbmt.2003.09.015.

  17. Vose JM, Zhang MJ, Rowlings PA, et al. Autologous Transplantation for Diffuse Aggressive Non-Hodgkin’s Lymphoma in Patients Never Achieving Remission: A Report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol. 2001;19(2):406–13. doi: 10.1200/jco.2001.19.2.406.

Outcome of Classical Hodgkin’s Lymphoma Treatment Based on High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation: The Experience in the NI Pirogov Russian National Medical Center of Surgery

NE Mochkin, VO Sarzhevskii, YuN Dubinina, EG Smirnova, DA Fedorenko, AE Bannikova, DS Kolesnikova, VS Bogatyrev, NM Faddeev, VYa Mel’nichenko

NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Nikita Evgen’evich Mochkin, MD, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: 8(495)603-72-17; e-mail: nickmed@yandex.ru

For citation: Mochkin NE, Sarzhevskii VO, Dubinina YuN, et. al. Outcome of Classical Hodgkin’s Lymphoma Treatment Based on High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation: The Experience in the NI Pirogov Russian National Medical Center of Surgery. Clinical oncohematology. 2018;11(3):234–40.

DOI: 10.21320/2500-2139-2018-11-3-234-240


ABSTRACT

Aim. To estimate the long-term outcome of the programmed treatment of classical Hodgkin’s lymphoma (cHL) including high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (auto-HSCT) as well as the effect of various factors on the achieved results in a single-center study.

Materials & Methods. In the A.A. Maksimov Clinical Center of Hematology and Cellular Therapy of the NI Pirogov Russian National Medical Center of Surgery 260 cHL patients received HDCT combined with auto-HSCT within the period from December 2006 to March 2017. The median age was 29 years (range 17–62). The study included 40 % men (n = 104), and 60 % women (n = 156). The median pretransplantation chemotherapy line was 3 (range 2–9). At this stage, prior to auto-HSCT, complete remission (CR) rate was 26.5 %, partial remission (PR) rate was 52.3 %, disease stabilisation rate was 13.5 %. HDCT with auto-HSCT was applied beyond progression as a salvage therapy in 7.7 % of patients. In 79.6 % of patients the standard BEAM and CBV conditioning regimens were used.

Results. After HDCT combined with auto-HSCT overall 5-year survival (OS) of 260 cHL patients was 74 %, and 5-year progression-free survival (PFS) was 48 %, which corresponds to the results of some international studies. 5-year OS rates were significantly higher after HDCT and auto-HSCT performed during the first CR or PR (85 %) vs the second and subsequent CR and PR (71 %). Neither gender (= 0.4) nor ECOG status (= 0.2) effects on OS and PFS were revealed. 5-year OS rates were significantly higher after HDCT and auto-HSCT performed during CR or PR (82 %) vs disease stabilisation and progression (54 %) as well as upon achieving CR (93 %) vs PR (77 %).

Conclusion. In cHL tumor sensitivity to chemotherapy is the essential indication for HDCT combined with auto-HSCT. The optimal time for HDCT and auto-HSCT in cHL is the first CR/PR, and the best treatment outcome is achieved in patients with complete response prior to HDCT and auto-HSCT.

Keywords: classical Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cell transplantation.

Received: February 9, 2018

Accepted: May 3, 2018

Read in PDF 

REFERENCES

  1. Российские клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Под ред. И.В. Поддубной, В.Г. Савченко. М.: Буки Веди, 2016.[Poddubnaya IV, Savchenko VG, eds. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. (Russian clinical guidelines in diagnosis and treatment of lymphoproliferative disorders). Moscow: Buki Vedi Publ.; 2016. (In Russ)]
  2. Skoetz N, Trelle S, Rancea M, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(10):943–52. doi: 10.1016/S1470-2045(13)70341-3.
  3. Kuruvilla J, Keating A, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood. 2011;117(16):4208–17. doi: 10.1182/blood-2010-09-288373.
  4. Thomas RK, Re D, Zander T, et al. Epidemiology and etiology of Hodgkin’s lymphoma. Ann Oncol. 2002;13(Suppl. 4):147–52. doi: 10.1093/annonc/mdf652.
  5. Linch D, Winfield D, Goldstone A, et al. Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin disease: results of a BNLI randomized trial. Lancet. 1993;341(8852):1051–4. doi: 10.1016/0140-6736(93)92411-L.
  6. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin disease: a randomized trial. Lancet. 2002;359(9323):2065–71. doi: 10.1016/S0140-6736(02)08938-9.
  7. Josting A, Franklin J, May M, et al. New prognostic score based on treatment outcome of patients with relapsed Hodgkin’s lymphoma registered in the database of the German Hodgkin’s lymphoma study group. J Clin Oncol. 2002;20(1):221–30. doi: 10.1200/JCO.2002.20.1.221
  8. Ljungman P, Bregni M, Brune M, et al. Allogenic and autologous transplantation for haematological disease, solid tumors and immune disorders: current practice in Europe 2009. Bone Marrow Transplant. 2010;45(2):219–34. doi: 10.1038/bmt.2009.141.
  9. Perales M-A, Ceberio I, Armand Ph, et al. Role of cytotoxic therapy with hematopoietic cell transplantation in the treatment of Hodgkin lymphoma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(6):971–983. doi: 10.1016/j.bbmt.2015.02.022.
  10. Hoppe RT, Advani RH, Ai WZ, et al. NCCN Clinical Practice Guidelines in Oncology. Hodgkin Lymphoma. Version 1.2018. Available from: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf (accessed 05.03.2018).
  11. Moscowitz CH, Kewalramani T, Nimer SD, et al. Effectiveness of high-dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin’s disease. Br J Haematol. 2004;124(5):645–52. doi: 1111/j.1365-2141.2003.04828.x.
  12. Sirohi B, Cunningham D, Powles R, et al. Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma. Ann Oncol. 2008;19(7):1312–9. doi: 10.1093/annonc/mdn052.
  13. Moskowitz CH, Nimer SD, Zelenets AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97(3):616–23. doi: 10.1182/blood.V97.3.616.
  14. Phillips JK, Spearing RL, Davies JM, et al. VIM-D salvage chemotherapy in Hodgkin’s disease. Cancer Chemother Pharmacol. 1990;27(2):161–3. doi: 10.1007/bf00689103.
  15. The International ChlVPP Treatment Group. ChlVPP therapy for Hodgkin’s disease: experience of 960 patients. Ann Oncol 1995;6(2):167–72.
  16. Colwill R, Crump M, Couture F, et al. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol. 1995;13(2):396–402. doi: 10.1200/JCO.1995.13.2.396.
  17. Rodriguez MA, Cabanillas FC, Hagemeister FB, et al. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol. 1995;6(6):609–12. doi: 10.1093/oxfordjournals.annonc.a059252.
  18. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol. 1999;10(5):593–5. doi: 10.1023/a:1026454831340.
  19. Martin A, Femandez-Jimenez MC, Caballero MD, et al. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease. Br J Haematol. 2001;113(1):161–71. doi:1046/j.1365-2141.2001.02714.x.
  20. Josting A, Rudolph C, Reiser M, et al. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13(10):1628–35. doi: 10.1093/annonc/mdf221.
  21. Abali H, Urun Y, Oksuzoglu B, et al. Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest. 2008;26(4):401–6. doi: 10.1080/07357900701788098.
  22. European Society for Blood and Marrow Transplantation Annual Report 2016. Available from: http://www.ebmt.org/sites/default/files/migration_legacy_files/document/Annual%20Report%202016_EBMT.pdf. (accessed 28.03.2018).
  23. Passweg JR, Baldomero H, Bregni M, et al. Hematopoietic SCT in Europe: data and trends in 2011. Bone Marrow Transplant. 2013;48(9):1161–7. doi: 10.1038/bmt.2013.51.
  24. Жуков Н.В., Усс А.Л., Миланович Н.Ф. и др. Оптимальные сроки проведения аутологичной трансплантации клеток предшественников гемопоэза при неблагоприятном течении лимфомы Ходжкина. Зарубежные рекомендации и отечественная практика. Онкогематология. 2014;2:37–44.[Zhukov NV, Uss AL, Milanovich NF, et al. The optimal time for autologous hematopoietic progenitor cell transplantation during treatment of Hodgkin’s lymphoma. Foreign recommendations and Russian experience. Onkogematologiya. 2014;2:37–44. (In Russ)]
  25. Мочкин Н.Е., Саржевский В.О., Дубинина Ю.Н. и др. Высокодозная химиотерапия с трансплантацией аутологичных кроветворных стволовых клеток при лимфоме Ходжкина. Десятилетний опыт ФГБУ «НМХЦ им. Н.И. Пирогова» Минздрава России. Российский журнал детской гематологии и онкологии. 2017;4(2):85–90. doi: 10.17650/2311-1267-2017-4-2-85-90.[Mochkin NE, Sarzhevskii VO, Dubinina YuN, et al. High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with Hodgkin’s lymphoma. 10-year experience of the NI Pirogov Russian National Medical Center of Surgery. Rossiiskii zhurnal detskoi gematologii i onkologii. 2017;4(2):85–90. doi: 17650/2311-1267-2017-4-2-85-90. (In Russ)]
  26. Sasse S, Alram M, Muller H, et al. Prognostic relevance of DHAP dose-density in relapsed Hodgkin lymphoma: an analysis of the German Hodgkin-Study Group.Leuk Lymphoma.2016;57(5):1067–73. doi: 10.3109/10428194.2015.1083561.
  27. Moskowitz AJ, Hamlin PA, Perales M-A, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–60. doi: 10.1200/JCO.2012.45.3308.
  28. Visani G, Malerba L, Stefani PM, et al. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011;118(12):3419–25. doi: 10.1182/blood-2011-04-351924.
  29. Caballero MD, Rubio V, Rifon J, et al. BEAM chemotherapy followed by autologous stem cell support in lymphoma patient: analysis of efficacy, toxicity and prognostic factors. Bone Marrow Transplant. 1997;20(6):451–8. doi: 10.1038/sj.bmt.1700913.
  30. Jagannath S, Armitage JO, Dicke KA, et al. Prognostic factors for response and survival after high-dose cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation for relapsed Hodgkin’s disease. J Clin Oncol. 1989;7(2):179–85. doi: 10.1200/jco.1989.7.2.179.
  31. Provencio M, Sanchez A, Sanchez-Beato M. New drugs and targeted treatments in Hodgkin’s lymphoma. Cancer Treat Rev. 2014;40(3):457–64. doi. 10.1016/j.ctrv.2013.09.005.

Diagnostic and Prognostic Value of Biochemical Markers of Infectious Complications of High-Dose Therapy with Autologous Hematopoietic Stem Cell Transplantation in Malignant Lymphoproliferative Diseases

VO Sarzhevskii, YuN Dubinina, VYa Mel’nichenko

NI Pirogov National Medical and Surgical Center under the Ministry of Health of the Russian Federation, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Dubinina YuN, Mel’nichenko VYa. Diagnostic and Prognostic Value of Biochemical Markers of Infectious Complications of High-Dose Therapy with Autologous Hematopoietic Stem Cell Transplantation in Malignant Lymphoproliferative Diseases. Clinical oncohematology. 2017;10(1):113–9 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-113-119


ABSTRACT

Aim. To evaluate diagnostic and prognostic value of C-reactive protein (CRP), procalcitonin (PCT) and presepsin (PSP) in patients with malignant lymphoproliferative disorders after a high-dose chemotherapy and auto-HSCT.

Methods. 28 patients were included in the study (20 women and 8 men; 12 of them with Hodgkin’s lymphoma, 6 with non-Hodgkin’s lymphomas, and 10 with multiple myeloma). The median age was 40 years (23–66 years). The conditioning regimens were CBV, BEAM or melphalan 200 mg/m2. PSP, PCT and CRP levels were evaluated on the day of admission (DA), D+1, D+3, D+7 and on the day of discharge (DD). Depending on the presence of infectious complications, the patients were divided into 2 groups: group 1 — patients without complications (n = 12), group 2 — patients with complications (n = 16). In group 2 there were 15 patients with febrile neutropenia (FN) and 1 with sepsis.

Results. The median (range) of FN development was 5.5 days. Median CRP level on the DA and the DD in group 1 was 2.25 mg/l (0.6–20.4) and 14.85 mg/l (3.7–50), respectively (= 0.001), while in group 2 it was 3.2 mg/l (0.2–53) and 19.7 mg/l (5.1–152.2), respectively (= 0.025). However, CRP did not significantly differ between groups 1 and 2 at any point of analysis. The study also demonstrated a significant increase in the PCT levels in both groups after allo-HSCT. Median PCT level on the DA and the DD in group 1 was 0.023 ng/ml (0.02–0.112) and 0.07 ng/mL (0.02–0.356), respectively (= 0.04), and in group 2 — 0.039 ng/ml (0.02–0.158) and 0.106 ng/mL (0.045–3.67), respectively (= 0.001). Comparison of PCT levels on study days demonstrated no significant difference between groups. On the DA the median PSP level in group 1 was 166.5 pg/ml (77.2–476), on the DD it was 199 pg/ml (90–298) (= 0.78). Median PSP levels in group 2 on the DA (129 pg/ml, range 84.2–501) and also on the DD (288.5 pg/ml, range 83.4–1345) were significantly different (= 0.03). In the comparative analysis of PSP in groups 1 and 2, there were no significant differences on the DA and on the D+1. Significant difference in PSP levels between the analyzed groups was on the D+3, D+7 and on the DA.

Conclusion. The preliminary data showed that PSP is the most sensitive marker of infectious complications in patients with lymphoproliferative diseases after auto-HSCT.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, infection, presepsin, procalcitonin, C-reactive protein.

Received: July 28, 2016

Accepted: December 10, 2016

Read in PDF (RUS)pdficon


REFERENCES

  1. Bhatt VR, Loberiza FR Jr, Jing H, et al. Mortality patterns among recipients of autologous hematopoietic stem cell transplantation for lymphoma and myeloma in the past three decades. Clin Lymph Myel Leuk. 2015;15(7):409–15.e1. doi: 10.1016/j.clml.2015.02.024.
  2. Zhang W, Zhao Q, Huang H. Febrile neutropenic infection occurred in cancer patients undergoing autologous peripheral blood stem cell transplantation. Transplant Proc. 2015;47(2):523–7. doi: 10.1016/j.transproceed.2015.01.013.
  3. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065-71. doi: 10.1016/s0140-6736(02)08938-9.
  4. Massaro K, Macedo R, de Castro B, et al. Risk factor for death in hematopoietic stem cell transplantation: are biomarkers useful to foresee the prognosis in this population of patients? Infection. 2014;42(6):1023–32. doi: 10.1007/s15010-014-0685-2.
  5. Saarinen U, Strandjord S, Warkentin P, et al. Differentiation of presumed sepsis from acute graft-versus-host disease by C-reactive protein and serum total IgE in bone marrow transplant recipients. Transplantation. 1987;44(4):540–6. doi: 10.1097/00007890-198710000-00017.
  6. Bonig H, Schneider DT, Sprock I, et al. ‘Sepsis’ and multi-organ failure: predictors of poor outcome after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2000;25(Suppl 2):S32–4. doi: 10.1038/sj.bmt.1702350.
  7. Yonemori K, Kanda Y, Yamamoto R, et al. Clinical value of serial measurement of serum C-reactive protein level in neutropenic patients. Leuk Lymphoma. 2001;41(5–6):607–14. doi: 10.3109/10428190109060351.
  8. Hamalainen S, Kuittinen T, Matinlauri I, et al. Severe sepsis in autologous stem cell transplant recipients: microbiological aetiology, risk factors and outcome. Scand J Infect Dis. 2009;41(1):14–20. doi: 10.1080/00365540802454706.
  9. Assicot M, Bohuon C, Gendrel D, et al. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341(8844):515–8. doi: 10.1016/0140-6736(93)90277-n.
  10. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004;39(2):206–17. doi: 10.1086/421997.
  11. Sbrana A, Torchio M, Comolli G, et al. Use of procalcitonin in clinical oncology: a literature review. New Microbiol. 2016;39(3):174–80.
  12. Massaro KS, Costa SF, Leone C, et al. Procalcitonin (PCT) and C-reactive protein (CRP) as severe systemic infection markers in febrile neutropenic adults. BMC Infect Dis. 2007;7(1):137. doi: 10.1186/1471-2334-7-137.
  13. Giamarellou H, Giamarellos-Bourboulis E, Repoussis P, et al. Potential use of procalcitonin as a diagnostic criterion in febrile neutropenia: experience from a multicentre study. Clin Microbiol Infect. 2004;10(7):628–33. doi: 10.1111/j.1469-0691.2004.00883.x.
  14. Koivula I, Hamalainen S, Jantunen E, et al. Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia. Scand J Infect Dis. 2011;43(6–7):471–8. doi: 10.3109/00365548.2011.554855.
  15. Camussi G, Mariano F, Biancone L, et al. Lipopolysaccharide binding protein and CD14 modulate the synthesis of platelet-activating factor by human monocytes and mesangial and endothelial cells stimulated with lipopolysaccharide. J Immunol. 1995;155:316–24.
  16. Shozushima T, Takahashi G, Matsumoto N, et al. Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome. J Infect Chemother. 2011;17(6):764–9. doi: 10.1007/s10156-011-0254-x.
  17. Olad E, Sedighi I, Mehrvar A, et al. Presepsin (scd14) as a marker of serious bacterial infections in chemotherapy induced severe neutropenia. Iran J Pediatr. 2014;24(6):715–22.
  18. Koh H, Aimoto M, Katayama T, et al. Diagnostic value of levels of presepsin (soluble CD14-subtype) in febrile neutropenia in patients with hematological disorders. J Infect Chemother. 2016;22(7):466–71. doi: 10.1016/j.jiac.2016.04.002.
  19. Urbonas V, Eidukaite A, Tamuliene I. The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy-induced febrile neutropenia. Cytokine. 2013;62(1):34–7. doi: 10.1016/j.cyto.2013.02.030.
  20. Freifeld GA, Bow JE, Sepkowitz AK, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2011;52(4): e56–93. doi: 10.1093/cid/cir073.
 

Biochemical Markers of Cardiotoxicity of High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with Malignant Lymphoproliferative Disorders

VO Sarzhevskii, DS Kolesnikova, VYa Mel’nichenko

NI Pirogov National Medical and Surgical Center, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Kolesnikova DS, Mel’nichenko VYa. Biochemical Markers of Cardiotoxicity of High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation in Patients with Malignant Lymphoproliferative Disorders. Clinical oncohematology. 2016;9(4):465–73 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-465-473


ABSTRACT

Background. High-dose chemotherapy (HDCT) with autologous hematopoietic stem cells transplantation (auto-HSCT) is an effective therapeutic option for patients with Hodgkin’s lymphoma and aggressive non-Hodgkin’s lymphomas in those cases, when the standard chemotherapy combined with the radiation therapy proves to be ineffective. The HDCT and auto-HSCT are also basic treatment options for multiple myeloma. However, toxic effects of the transplantation, including cardiotoxicity, may significantly worsen the prognosis of patients who receive this treatment.

Aim. To evaluate changes in biochemical markers of cardiotoxicity (troponin and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) in patients with malignant lymphomas (receiving HDCT and auto-HSCT).

Materials & Methods. 157 patients were enrolled in the study. The sensitivity threshold of the troponin T test was 0.1 ng/mL and troponin I 0.001 ng/mL (highly sensitive troponin). Troponin T (conventional troponin) was measured in 56 patients, troponin I was assessed in 101 patients. Serum troponin levels were evaluated before the conditioning, on D0, D+7, and D+12. The level of NT-proBNP was assessed before the conditioning, on D0 and D+12.

Results. Increased troponin T level was observed in 2 of 56 patients (3.6 %), increased troponin I level — in 27 of 101 patients (26.7 %) (< 0.01). Troponin levels were within normal limits in all patients at admission. Troponin T levels increased only on D+7. Troponin I level increased in 4 patients (4 %) on D0, in 17 patients (16.8 %) on D+7 and in 11 patients (10.9 %) on D+12. The median concentration of troponin I was 0.215 ng/mL after HDCT completion, 0.74 ng/mL on D+7 and 0.21 ng/mL on D+12. No cases of myocardial infarction were observed. NT-proBNP levels in most patients were within normal limits at admission (median level 79.2 pg/mL). The situation changed significantly after conditioning: in most patients the level was almost twice as high as the upper normal limit (medial 240.6 pg/mL). Significant differences in levels of NT-proBNP (< 0.05) were observed at comparison of data before conditioning and D0, and before conditioning and D+12.

Conclusion. The data obtained confirm a significant impact of HDCT and auto-HSCT on the cardiovascular system of patients with malignant lymphomas. Further studies and observation of the patients are needed to clarify the prognostic significance of the findings related to cardiotoxicity (in particular, congestive heart failure).


Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, cardiotoxicity, troponin, NT-proBNP.

Received: June 13, 2016

Accepted: June 14, 2016

Read in PDF (RUS)pdficon

REFERENCES

  1. Blay J, Gomez F, Sebban C, et al. The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood. 1998;92(10):3562–8.
  2. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323):2065–71. doi: 10.1016/s0140-6736(02)08938-9.
  3. NCCN Guidelines Version 3.2016, Non-Hodgkin’s lymphomas. pр. 56, 65. [Internet] Available from: https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf (accessed 14.06.2016).
  4. NCCN Guidelines Version 2.2016, Hodgkin lymphoma. pp. 20 [Internet]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf (accessed 14.06.2016).
  5. Cazin B, Gorin NC, Laporte JP, et al. Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer. 1986;57(10):2061–9. doi: 10.1002/1097-0142(19860515)57:10<2061::aid-cncr2820571031>3.0.co;2-h.
  6. Murdych T, Weisdorf DJ. Serious cardiac complications during bone marrow transplantation at the University of Minnesota, 1977–1997. Bone Marrow Transplant. 2001;28(3):283–7. doi: 10.1038/sj.bmt.1703133.
  7. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(3):337–41. doi: 10.1038/bmt.2012.5.
  8. Chi AK, Soubani AO, White AC, et al. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest. 2013;144(6):1913–22. doi: 10.1378/chest.12-1708.
  9. Chow EJ, Wong K, Lee SJ, et al. Late cardiovascular complications after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20(6):794–800. doi: 10.1016/j.bbmt.2014.02.012.
  10. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol. 2000;36(2):517–22. doi: 10.1016/S1062-1458(00)00186-0.
  11. Cardinale D, Sandri MT, Martinoni A, et al. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol. 2002;13(5):710–5. doi: 10.1093/annonc/mdf170.
  12. Sandri MT, Cardinale D, Zorzino L, et al. Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high-dose chemotherapy. Clin Chem. 2003;49(2):248–52. doi: 10.1373/49.2.248.
  13. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003;82(4):218–22.
  14. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749–54. doi: 10.1161/01.cir.0000130926.51766.cc.
  15. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351(2):145–53. doi: 10.1056/nejmoa035153.
  16. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005;16(5):798–804. doi: 10.1093/annonc/mdi152.
  17. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation. 1997;96(8):2641–8. doi: 10.1161/01.cir.96.8.2641.
  18. Suzuki T, Hayashi D, Yamazaki T, et al. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J. 1998;136(2):362–3. doi: 10.1053/hj.1998.v136.89908.
  19. Nousiainen T, Jantunen E, Vanninen E, et al. Acute neurohumoral and cardiovascular effects of idarubicin in leukemia patients. Eur J Haematol. 1998; 61(5):347–53. doi: 10.1111/j.1600-0609.1998.tb01099.x.
  20. Snowden JA, Hill GR, Hunt P, et al. Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant. 2000;26(3):309–13. doi: 10.1038/sj.bmt.1702507.
  21. Chung T, Lim W-C, Sy R, et al. Subacute cardiac toxicity following autologous haematopoietic stem cell transplantation in patients with normal cardiac function. Heart. 2008;94(7):911–8. doi: 10.1136/hrt.2007.123299.
  22. Horacek JM, Pudil R, Tichy M, et al. Biochemical markers and assessment of cardiotoxicity during preparative regimen and hematopoietic cell transplantation in acute leukemia. Exp Oncol. 2007;29(3):243–7.
  23. Masuko M, Ito M, Kurasaki T, et al. Plasma brain natriuretic peptide during myeloablative stem cell transplantation. Intern Med. 2007;46(9):551–5. doi: 10.2169/internalmedicine.46.6188.
  24. Zver S, Zadnik V, Bunc M, et al. Cardiac toxicity of high-dose cyclophosphamide in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Int J Hematol. 2007;85(5):408–14. doi: 10.1532/ijh97.e0620.
 

Role of Positron-Emission Tomography in Prognosis of Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Hodgkin’s Lymphoma

VG Potapenko1,2, NB Mikhailova1, BI Smirnov4, IA Skorokhod2, DA Chaginskaya2, VV Ryabchikova2, IA Samorodova2, EI Podol’tseva2, VV Ipatov3, IV Boikov3, VN Semelev3, DA Gornostaev3, TG Potapenko5, TG Kulibaba5, NV Medvedeva2, BV Afanas’ev1

1 Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Municipal Hematological Center, Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

3 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

4 VI Ul’yanov (Lenin) St. Petersburg State Electrotechnical University LETI, 5 Professora Popova str., Saint Petersburg, Russian Federation, 197376

5 St. Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

For correspondence: Vsevolod Gennad’evich Potapenko, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)230-19-33; е-mail: potapenko.vsevolod@mail.ru

For citation: Potapenko VG, Mikhailova NB, Smirnov BI, et al. Role of Positron-Emission Tomography in Prognosis of Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Hodgkin’s Lymphoma. Clinical oncohematology. 2016;9(4):406–12 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-406-412


ABSTRACT

Aim. To perform a comparative analysis of the prognostic significance of positron-emission tomography (PET) with other prognostic factors of the efficacy of high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with Hodgkin’s lymphoma.

Methods. Data on 84 patients with Hodgkin’s lymphoma receiving treatment over the period from October 2007 till November 2015 were analyzed. The median age was 26.6 years (range: 10–62). The median follow-up was 25 months (range: 1–81 months). The prognostic significance of sex, response to the initial chemotherapy, time to relapse, second-line chemotherapy regimen type, B-symptoms, tumor size (>5 cm in cases of relapse prior to the HDCT), serum LDH and albumin levels, CT findings, the number of chemotherapy lines, conditioning regimen before the auto-HSCT, and the metabolic activity before the HDCT (PET1, n = 82) and after auto-HSCT (PET2, n = 57) was analyzed.

Results. The two-year overall (OS) and event-free (EFS) survival rates were 70.6 % and 58.7%, respectively. Prognosis was the worst in patients with CT-confirmed lymphoma progression by the initiation of HDCT. In the presence of a CT-response, the PET status of lymphoma has a prognostic significance. The 2-year OS and EFS rates of PET1-negative and PET1-positive patients were 82 % vs. 62 % (= 0.056) and 74 % vs. 44 % (= 0.003), respectively. In PET2-negative and PET2-positive patients, the OS and EFS rates were 90 % vs. 65 % (= 0.013) and 72 % vs. 52 % (= 0.014), respectively. From the prognostic point of view, PET2 findings prevailed over PET1 findings. The multivariate analysis confirmed only PET2 significance for OS prediction.

Conclusion. The tumor sensitivity to the chemotherapy assessed by the CT is the most important prognostic factor. In case of a positive CT dynamics, the achievement of PET1 or PET2 negativity before or after HDCT/auto-HSCT is a favorable prognostic factor. The worst prognosis was observed in patients with tumor metabolic activity before or after HDCT/auto-HSCT.


Keywords: positron-emission tomography (PET), Hodgkin’s lymphoma, high-dose chemotherapy, auto-HSCT.

Received: June 23, 2016

Accepted: August 29, 2016

Read in PDF (RUS) pdficon

REFERENCES

  1. Жуков Н.В., Румянцев А.Г., Усс А.Л. и др. Эффективность и безопасность высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток у больных с неблагоприятным течением лимфомы Ходжкина. Опыт трансплантационных центров России, Украины и республики Беларусь. Вопросы гематологии, онкологии и иммунопатологии в педиатрии. 2014;13(1): 22–31. [Zhukov NV, Rumyantsev AG, Uss AL, et al. Efficacy and safety of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with unfavorable course of Hodgkin’s lymphoma. Experience of transplantation centers in Russia, Ukraine, and Belarus. Voprosy gematologii, onkologii i immunopatologii v pediatrii. 2014;13(1):22–31. (In Russ)]
  2. Федоренко Д.А., Мельниченко В.Я., Ионова Т.И. и др. Клиническая оценка эффективности аутологичной трансплантации кроветворных стволовых клеток при лимфомах. Вестник Национального медико-хирургического центра им. Н.И. Пирогова. 2013;8(4):62–5. [Fedorenko DA, Mel’nichenko VYa, Ionova TI, et al. Clinical evaluation of efficacy of autologous hematopoietic stem cell transplantation in lymphomas. Vestnik Natsional’nogo mediko-khirurgicheskogo tsentra im. N.I. Pirogova. 2013;8(4):62–5. (In Russ)]
  3. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048–58. doi: 10.1200/jco.2013.53.5229.
  4. Асланиди И.П., Мухортова О.В., Шурупова И.В. и др. Позитронно-эмиссионная томография: уточнение стадии болезни при злокачественных лимфомах. Клиническая онкогематология. 2010;3(2):119–29. [Aslanidis IP, Mukhortova OV, Shurupova IV, et al. Positron emission tomography for staging of patients with malignant lymphomas. Klinicheskaya onkogematologiya. 2010;3(2):119–29. (In Russ)]
  5. Moskowitz СH, Yahalom J, Zelenetz AD. High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol. 2010;148(6):890–7. doi: 10.1111/j.1365-2141.2009.08037.x.
  6. Nieto Y, Popat U, Anderlini P, et al. Autologous stem cell transplantation for refractory or poor-risk relapsed Hodgkin’s lymphoma: effect of the specific high-dose chemotherapy regimen on outcome. Biol Blood Marrow Transplant. 2013;19(3):410–7. doi: 10.1016/j.bbmt.2012.10.029.
  7. Schot BW, Zijlstra JM, Sluiter WJ, et al. Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma. Blood. 2007;109(2):486–91. doi: 10.1182/blood-2005-11-006957.
  8. Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high dose chemotherapy and stem cell transplantation. Blood. 2003;102(1):53–9. doi: 10.1182/blood-2002-12-3842.
  9. Svoboda J, Andreadis C, Elstrom R, et al. Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant. 2006;38(3):211–6. doi: 10.1038/sj.bmt.1705416.
  10. Becherer A, Mitterbauer M, Jaeger U, et al. Positron emission tomography with [18F]2-fluoro-D-2-deoxyglucose (FDG-PET) predicts relapse of malignant lymphoma after high-dose therapy with stem cell transplantation. Leukemia. 2002;16(2):260–7. doi: 10.1038/sj.leu.2402342.
  11. Filmont JE, Czernin J, Yap C, et al. Value of F-18 fluorodeoxyglucose positron emission tomography for predicting the clinical outcome of patients with aggressive lymphoma prior to and after autologous stem-cell transplantation. Chest. 2003;124(2):608–13. doi: 10.1378/chest.124.2.608.
  12. Devillier R, Coso D, Castagna L, et al. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy. Haematologica. 2012;97(7):1073–9. doi: 10.3324/haematol.2011.056051.
  13. Arai S, Letsinger R, Wong RM, et al. Phase I/II trial of GN-BVC, a gemcitabine and vinorelbine-containing conditioning regimen for autologous hematopoietic cell transplantation in recurrent and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2010;16(8):1145–54. doi: 10.1016/j.bbmt.2010.02.022.
  14. Castagna L, Bramanti S, Balzarotti M, et al. Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy. Br J Haematol. 2009;145(3):369–72. doi: 10.1111/j.1365-2141.2009.07645.x.
  15. Akhtar S, Al-Sugair AS, Abouzied M, et al. Pre-transplant FDG-PET-based survival model in relapsed and refractory Hodgkin’s lymphoma: outcome after high-dose chemotherapy and auto-SCT. Bone Marrow Transplant. 2013;48(12):1530–6. doi: 10.1038/bmt.2013.88.
  16. Crocchiolo R, Canevari C, Assanelli A, et al. Pre-transplant 18FDG-PET predicts outcome in lymphoma patients treated with high-dose sequential chemotherapy followed by autologous stem cell transplantation. Leuk Lymphoma. 2008;49(4):727–33. doi: 10.1080/10428190701885545.
  17. Gentzler RD, Evens AM, Rademaker AW, et al. F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Br J Haematol. 2014;165(6):793–800. doi: 10.1111/bjh.12824.
  18. Jabbour E, Hosing C, Ayers G, et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer. 2007;109(12):2481–9. doi: 10.1002/cncr.22714.
  19. Cohen JB, Hall NC, Ruppert AS, et al. Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle-cell lymphoma. Bone Marrow Transplant. 2013;48(9):1212–7. doi: 10.1038/bmt.2013.46.
  20. Dickinson M, Hoyt R, Roberts AW, et al. Improved survival for relapsed diffuse large B cell lymphoma is predicted by a negative pre-transplant FDG-PET scan following salvage chemotherapy. Br J Haematol. 2010;150(1):39–45. doi: 10.1111/j.1365-2141.2010.08162.x.
  21. Palmer J, Goggins T, Broadwater G, et al. Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma. Bone Marrow Transplant. 2011;46(6):847–51. doi: 10.1038/bmt.2010.203.
  22. Alousi AM, Saliba RM, Okoroji GJ, et al. Disease staging with positron emission tomography or gallium scanning and use of rituximab predict outcome for patients with diffuse large B-cell lymphoma treated with autologous stem cell transplantation. Br J Haematol. 2008;142(5):786–92. doi: 10.1111/j.1365-2141.2008.07277.x.
  23. Bondly C, Johnston PB, Lowe V, et al. Positive positron emission tomography (PET) pre-autologous stem cell transplant (ASCT) in non-Hodgkin lymphoma (NHL) does not preclude successful outcome. Biol Blood Marrow Transplant. 2006;12(2):18–9. doi: 10.1016/j.bbmt.2005.11.060.
  24. Qiao W, Zhao J, Xing Y. Predictive value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography for clinical outcome in patients with relapsed/refractory diffuse large B-cell lymphoma prior to and after autologous stem cell transplant. Leuk Lymphoma. 2014;55(2):276–82. doi: 10.3109/10428194.2013.797974.
  25. Sucak GT, Ozkurt ZN, Suyani E, et al. Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol. 2011;90(11):1329–36. doi: 10.1007/s00277-011-1209-0.
  26. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  27. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86. doi: 10.1200/jco.2006.09.2403.
  28. David G, Kleinbaum MK. Survival Analysis. A Self-Learning Text. 2nd edition. Springer; 2002. рр. 583. doi: 10.1111/j.1541-0420.2006.00540_18.x.
  29. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Первично-рефрактерное течение лимфомы Ходжкина и аутологичная трансплантация гемопоэтических стволовых клеток. Результаты одноцентрового проспективного исследования. Российский онкологический журнал. 2015;20(3):4–11. [Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Primary refractory Hodgkin’s lymphoma and autologous stem cell transplantation: results of the single-center prospective study. Rossiiskii onkologicheskii zhurnal. 2015;20(3):4–11. (In Russ)]
  30. Crocchiolo R, Fallanca F, Giovacchini G, et al. Role of 18FDG-PET/CT in detecting relapse during follow-up of patients with Hodgkin’s lymphoma. Ann Hematol. 2009;88(12):1229–36. doi: 10.1007/s00277-009-0752-4.
  31. Gupta D, Lis ChG. Pretreatment Serum Albumin as a Predictor of Cancer Survival: A Systematic Review of the Epidemiological Literature. Nutrition J. 2010;9(1):69–116. doi: 10.1186/1475-2891-9-69.
  32. Демина Е.А. Лимфома Ходжкина: прогностические признаки сегодня. Современная онкология. 2006;4:4–7. [Demina EA. Hodgkin’s lymphoma: prognostic factors today. Sovremennaya onkologiya. 2006;4:4–7. (In Russ)]
  33. Czyz A, Lojko-Dankowska A, Dytfeld D, et al. Prognostic factors and long-term outcome of autologous haematopoietic stem cell transplantation following a uniform-modified BEAM-conditioning regimen for patients with refractory or relapsed Hodgkin lymphoma: a single-center experience. Med Oncol. 2013;30(3):611. doi: 10.1007/s12032-013-0611-y.
  34. Villa D, Seshadri T, Puig N, et al. Second-line salvage chemotherapy for transplant-eligible patients with Hodgkin’s lymphoma resistant to platinum-containing first-line salvage chemotherapy. Haematologica. 2012;97(5):751–7. doi: 10.3324/haematol.2011.047670.
  35. Colpo A, Hochberg E, Chen YB. Current status of autologous stem cell transplantation in relapsed and refractory Hodgkin’s lymphoma. Oncologist. 2012;17(1):80–90. doi: 10.1634/theoncologist.2011-0177.

Role of Positron-Emission Tomography in Prognosis of Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Hodgkin’s Lymphoma

VG Potapenko1,2, NB Mikhailova1, BI Smirnov4, IA Skorokhod2, DA Chaginskaya2, VV Ryabchikova2, IA Samorodova2, EI Podol’tseva2, VV Ipatov3, IV Boikov3, VN Semelev3, DA Gornostaev3, TG Potapenko5, TG Kulibaba5, NV Medvedeva2, BV Afanas’ev1

1 Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 Municipal Hematological Center, Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

3 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

4 VI Ul’yanov (Lenin) St. Petersburg State Electrotechnical University LETI, 5 Professora Popova str., Saint Petersburg, Russian Federation, 197376

5 St. Petersburg State University, 7/9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

For correspondence: Vsevolod Gennad’evich Potapenko, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)230-19-33; е-mail: potapenko.vsevolod@mail.ru

For citation: Potapenko VG, Mikhailova NB, Smirnov BI, et al. Role of Positron-Emission Tomography in Prognosis of Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation in Hodgkin’s Lymphoma. Clinical oncohematology. 2016;9(4):406–12 (In Russ).

DOI: http://dx.doi.org/10.21320/2500-2139-2016-9-4-406-412


ABSTRACT

Aim. To perform a comparative analysis of the prognostic significance of positron-emission tomography (PET) with other prognostic factors of the efficacy of high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with Hodgkin’s lymphoma.

Methods. Data on 84 patients with Hodgkin’s lymphoma receiving treatment over the period from October 2007 till November 2015 were analyzed. The median age was 26.6 years (range: 10–62). The median follow-up was 25 months (range: 1–81 months). The prognostic significance of sex, response to the initial chemotherapy, time to relapse, second-line chemotherapy regimen type, B-symptoms, tumor size (>5 cm in cases of relapse prior to the HDCT), serum LDH and albumin levels, CT findings, the number of chemotherapy lines, conditioning regimen before the auto-HSCT, and the metabolic activity before the HDCT (PET1, n = 82) and after auto-HSCT (PET2, n = 57) was analyzed.

Results. The two-year overall (OS) and event-free (EFS) survival rates were 70.6 % and 58.7%, respectively. Prognosis was the worst in patients with CT-confirmed lymphoma progression by the initiation of HDCT. In the presence of a CT-response, the PET status of lymphoma has a prognostic significance. The 2-year OS and EFS rates of PET1-negative and PET1-positive patients were 82 % vs. 62 % (= 0.056) and 74 % vs. 44 % (= 0.003), respectively. In PET2-negative and PET2-positive patients, the OS and EFS rates were 90 % vs. 65 % (= 0.013) and 72 % vs. 52 % (= 0.014), respectively. From the prognostic point of view, PET2 findings prevailed over PET1 findings. The multivariate analysis confirmed only PET2 significance for OS prediction.

Conclusion. The tumor sensitivity to the chemotherapy assessed by the CT is the most important prognostic factor. In case of a positive CT dynamics, the achievement of PET1 or PET2 negativity before or after HDCT/auto-HSCT is a favorable prognostic factor. The worst prognosis was observed in patients with tumor metabolic activity before or after HDCT/auto-HSCT.

Keywords: positron-emission tomography (PET), Hodgkin’s lymphoma, high-dose chemotherapy, auto-HSCT.

Received: June 23, 2016

Accepted: August 29, 2016

Read in PDF (RUS) pdficon
 

REFERENCES

  1. Жуков Н.В., Румянцев А.Г., Усс А.Л. и др. Эффективность и безопасность высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток у больных с неблагоприятным течением лимфомы Ходжкина. Опыт трансплантационных центров России, Украины и республики Беларусь. Вопросы гематологии, онкологии и иммунопатологии в педиатрии. 2014;13(1): 22–31. [Zhukov NV, Rumyantsev AG, Uss AL, et al. Efficacy and safety of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with unfavorable course of Hodgkin’s lymphoma. Experience of transplantation centers in Russia, Ukraine, and Belarus. Voprosy gematologii, onkologii i immunopatologii v pediatrii. 2014;13(1):22–31. (In Russ)]
  2. Федоренко Д.А., Мельниченко В.Я., Ионова Т.И. и др. Клиническая оценка эффективности аутологичной трансплантации кроветворных стволовых клеток при лимфомах. Вестник Национального медико-хирургического центра им. Н.И. Пирогова. 2013;8(4):62–5. [Fedorenko DA, Mel’nichenko VYa, Ionova TI, et al. Clinical evaluation of efficacy of autologous hematopoietic stem cell transplantation in lymphomas. Vestnik Natsional’nogo mediko-khirurgicheskogo tsentra im. N.I. Pirogova. 2013;8(4):62–5. (In Russ)]
  3. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048–58. doi: 10.1200/jco.2013.53.5229.
  4. Асланиди И.П., Мухортова О.В., Шурупова И.В. и др. Позитронно-эмиссионная томография: уточнение стадии болезни при злокачественных лимфомах. Клиническая онкогематология. 2010;3(2):119–29. [Aslanidis IP, Mukhortova OV, Shurupova IV, et al. Positron emission tomography for staging of patients with malignant lymphomas. Klinicheskaya onkogematologiya. 2010;3(2):119–29. (In Russ)]
  5. Moskowitz СH, Yahalom J, Zelenetz AD. High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging. Br J Haematol. 2010;148(6):890–7. doi: 10.1111/j.1365-2141.2009.08037.x.
  6. Nieto Y, Popat U, Anderlini P, et al. Autologous stem cell transplantation for refractory or poor-risk relapsed Hodgkin’s lymphoma: effect of the specific high-dose chemotherapy regimen on outcome. Biol Blood Marrow Transplant. 2013;19(3):410–7. doi: 10.1016/j.bbmt.2012.10.029.
  7. Schot BW, Zijlstra JM, Sluiter WJ, et al. Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma. Blood. 2007;109(2):486–91. doi: 10.1182/blood-2005-11-006957.
  8. Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of pretransplantation positron emission tomography using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high dose chemotherapy and stem cell transplantation. Blood. 2003;102(1):53–9. doi: 10.1182/blood-2002-12-3842.
  9. Svoboda J, Andreadis C, Elstrom R, et al. Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant. 2006;38(3):211–6. doi: 10.1038/sj.bmt.1705416.
  10. Becherer A, Mitterbauer M, Jaeger U, et al. Positron emission tomography with [18F]2-fluoro-D-2-deoxyglucose (FDG-PET) predicts relapse of malignant lymphoma after high-dose therapy with stem cell transplantation. Leukemia. 2002;16(2):260–7. doi: 10.1038/sj.leu.2402342.
  11. Filmont JE, Czernin J, Yap C, et al. Value of F-18 fluorodeoxyglucose positron emission tomography for predicting the clinical outcome of patients with aggressive lymphoma prior to and after autologous stem-cell transplantation. Chest. 2003;124(2):608–13. doi: 10.1378/chest.124.2.608.
  12. Devillier R, Coso D, Castagna L, et al. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy. Haematologica. 2012;97(7):1073–9. doi: 10.3324/haematol.2011.056051.
  13. Arai S, Letsinger R, Wong RM, et al. Phase I/II trial of GN-BVC, a gemcitabine and vinorelbine-containing conditioning regimen for autologous hematopoietic cell transplantation in recurrent and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant. 2010;16(8):1145–54. doi: 10.1016/j.bbmt.2010.02.022.
  14. Castagna L, Bramanti S, Balzarotti M, et al. Predictive value of early 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) during salvage chemotherapy in relapsing/refractory Hodgkin lymphoma (HL) treated with high-dose chemotherapy. Br J Haematol. 2009;145(3):369–72. doi: 10.1111/j.1365-2141.2009.07645.x.
  15. Akhtar S, Al-Sugair AS, Abouzied M, et al. Pre-transplant FDG-PET-based survival model in relapsed and refractory Hodgkin’s lymphoma: outcome after high-dose chemotherapy and auto-SCT. Bone Marrow Transplant. 2013;48(12):1530–6. doi: 10.1038/bmt.2013.88.
  16. Crocchiolo R, Canevari C, Assanelli A, et al. Pre-transplant 18FDG-PET predicts outcome in lymphoma patients treated with high-dose sequential chemotherapy followed by autologous stem cell transplantation. Leuk Lymphoma. 2008;49(4):727–33. doi: 10.1080/10428190701885545.
  17. Gentzler RD, Evens AM, Rademaker AW, et al. F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Br J Haematol. 2014;165(6):793–800. doi: 10.1111/bjh.12824.
  18. Jabbour E, Hosing C, Ayers G, et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer. 2007;109(12):2481–9. doi: 10.1002/cncr.22714.
  19. Cohen JB, Hall NC, Ruppert AS, et al. Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle-cell lymphoma. Bone Marrow Transplant. 2013;48(9):1212–7. doi: 10.1038/bmt.2013.46.
  20. Dickinson M, Hoyt R, Roberts AW, et al. Improved survival for relapsed diffuse large B cell lymphoma is predicted by a negative pre-transplant FDG-PET scan following salvage chemotherapy. Br J Haematol. 2010;150(1):39–45. doi: 10.1111/j.1365-2141.2010.08162.x.
  21. Palmer J, Goggins T, Broadwater G, et al. Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma. Bone Marrow Transplant. 2011;46(6):847–51. doi: 10.1038/bmt.2010.203.
  22. Alousi AM, Saliba RM, Okoroji GJ, et al. Disease staging with positron emission tomography or gallium scanning and use of rituximab predict outcome for patients with diffuse large B-cell lymphoma treated with autologous stem cell transplantation. Br J Haematol. 2008;142(5):786–92. doi: 10.1111/j.1365-2141.2008.07277.x.
  23. Bondly C, Johnston PB, Lowe V, et al. Positive positron emission tomography (PET) pre-autologous stem cell transplant (ASCT) in non-Hodgkin lymphoma (NHL) does not preclude successful outcome. Biol Blood Marrow Transplant. 2006;12(2):18–9. doi: 10.1016/j.bbmt.2005.11.060.
  24. Qiao W, Zhao J, Xing Y. Predictive value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography for clinical outcome in patients with relapsed/refractory diffuse large B-cell lymphoma prior to and after autologous stem cell transplant. Leuk Lymphoma. 2014;55(2):276–82. doi: 10.3109/10428194.2013.797974.
  25. Sucak GT, Ozkurt ZN, Suyani E, et al. Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol. 2011;90(11):1329–36. doi: 10.1007/s00277-011-1209-0.
  26. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  27. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86. doi: 10.1200/jco.2006.09.2403.
  28. David G, Kleinbaum MK. Survival Analysis. A Self-Learning Text. 2nd edition. Springer; 2002. рр. 583. doi: 10.1111/j.1541-0420.2006.00540_18.x.
  29. Петрова Г.Д., Мелкова К.Н., Чернявская Т.З. и др. Первично-рефрактерное течение лимфомы Ходжкина и аутологичная трансплантация гемопоэтических стволовых клеток. Результаты одноцентрового проспективного исследования. Российский онкологический журнал. 2015;20(3):4–11. [Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Primary refractory Hodgkin’s lymphoma and autologous stem cell transplantation: results of the single-center prospective study. Rossiiskii onkologicheskii zhurnal. 2015;20(3):4–11. (In Russ)]
  30. Crocchiolo R, Fallanca F, Giovacchini G, et al. Role of 18FDG-PET/CT in detecting relapse during follow-up of patients with Hodgkin’s lymphoma. Ann Hematol. 2009;88(12):1229–36. doi: 10.1007/s00277-009-0752-4.
  31. Gupta D, Lis ChG. Pretreatment Serum Albumin as a Predictor of Cancer Survival: A Systematic Review of the Epidemiological Literature. Nutrition J. 2010;9(1):69–116. doi: 10.1186/1475-2891-9-69.
  32. Демина Е.А. Лимфома Ходжкина: прогностические признаки сегодня. Современная онкология. 2006;4:4–7. [Demina EA. Hodgkin’s lymphoma: prognostic factors today. Sovremennaya onkologiya. 2006;4:4–7. (In Russ)]
  33. Czyz A, Lojko-Dankowska A, Dytfeld D, et al. Prognostic factors and long-term outcome of autologous haematopoietic stem cell transplantation following a uniform-modified BEAM-conditioning regimen for patients with refractory or relapsed Hodgkin lymphoma: a single-center experience. Med Oncol. 2013;30(3):611. doi: 10.1007/s12032-013-0611-y.
  34. Villa D, Seshadri T, Puig N, et al. Second-line salvage chemotherapy for transplant-eligible patients with Hodgkin’s lymphoma resistant to platinum-containing first-line salvage chemotherapy. Haematologica. 2012;97(5):751–7. doi: 10.3324/haematol.2011.047670.
  35. Colpo A, Hochberg E, Chen YB. Current status of autologous stem cell transplantation in relapsed and refractory Hodgkin’s lymphoma. Oncologist. 2012;17(1):80–90. doi: 10.1634/theoncologist.2011-0177.

Single-Photon Emission Computed Tomography Synchronized with ECG as Method for Evaluation of Cardiotoxicity of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoproliferative Disorders

VO Sarzhevskii, DS Kolesnikova, MN Vakhromeeva, VYa Melnichenko

N.I. Pirogov National Medical and Surgical Center under the Ministry of Health of the Russian Federation, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Vladislav Olegovich Sarzhevskii, PhD, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii VO, Kolesnikova DS, Vakhromeeva MN, Mel’nichenko VYa. Single-Photon Emission Computed Tomography Synchronized with ECG as Method for Evaluation of Cardiotoxicity of High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoproliferative Disorders. Clinical oncohematology. 2015;8(1):84–90 (In Russ).


ABSTRACT

Background. High-dose chemotherapy (HDC) with autologous hematopoietic stem cells transplantation (auto-HSCT) is currently widely used for the treatment of relapsed and refractory to standard chemotherapy cases of malignant lymphoproliferative disorders. Cardiac monitoring of patients treated with HDC with subsequent auto-HSCT is performed by means of ECG and Echo-CG in most cases. The method of single-photon emission computed tomography of the left ventricle (LV) synchronized with ECG (gated-SPECT) is rarely used to assess cardiotoxic effect of HDC and auto-HSCT.

Objective. To evaluate perfusion and regional myocardial function of the left ventricle (LV) in patients with malignant lymphomas receiving HDC and auto-HSCT.

Methods. The study included 69 patients (37 with Hodgkin’s lymphoma, 19 with non-Hodgkin’s lymphoma, and 13 with multiple myeloma). The median age was 36 year (range from 19 to 66 years); 40 females, 29 males. Perfusion and regional LV function at rest before the HDC and auto-HSCT (point 1) and at discharge (point 2) were assessed. Each study was performed on a double-headed rotating gamma camera Forte (Philips, USA). 740 MBq of technetium-99m-methoxyisobutylisonitrile (99mTc-MIBI) was used as a radiopharmaceutical. Semiquantitative assessment of tomoscintigrams was performed using polar diagrams (20-segment model); they were used for complex analysis of perfusion and LF myocardium function parameters.

Results. The total area of hypoperfusion, expressed as a percentage of the area of the LV myocardium, did not change significantly during treatment (> 0.05). However, the segmental analysis demonstrated a statistically significant decrease in the median uptake level of the radiopharmaceutical in 1, 2, 4, 7, 8, 10, 13, 16, 17, and 19 segments (< 0.05). The total ejection fraction (TEF) did not change (median TEF was 59.5 % at point 1 and 58 % at point 2). But it showed a statistically significant decrease in median of local systolic thickening in 2, 3, 5, 7, 8, 9, 10, 11, 12, 15, 17, 18, 19, and 20 segments of the left ventricle (< 0.05).

Conclusions. HDC and auto-HSCT significantly change perfusion and regional LV myocardial function in patients with malignant lymphomas. The changes demonstrate diffuse myocardial damage. Gated-SPECT can be considered a promising method for assessing cardiotoxicity of HDC and auto-HSCT.


Keywords: high-dose chemotherapy, autologous hematopoietic stem cells transplantation, cardiotoxicity, gated-SPECT.

Received: July 23, 2014

Accepted: November 5, 2014

Read in PDF (RUS)pdficon


REFERENCES

  1. Passweg JR, Baldomero H, Peters C, et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant. 2014;49(6):744–50. doi: 10.1038/bmt.2014.55.
  2. Popplewell LL, Forman SJ. Is there an upper age limit for bone marrow transplantation? Bone Marrow Transplant. 2002;29(4):277–84. doi: 10.1038/sj.bmt.1703382.
  3. Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114(3):600–7. doi: 10.1046/j.1365-2141.2001.02976.x.
  4. Germano G, Kiat H, Kavanagh P, et al. Automatic quantification and review of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med. 1995;36:2138–47.
  5. Germano G, Kavanagh P, Berman D, et al. An automatic approach to the analysis quantification and review of perfusion and function from myocardial perfusion SPECT imaging. Intern J Card Im. 1997;13(4):337–46.
  6. Girinsky T, Cordova A, Rey A, et al. Thallium-201 scintigraphy is not predictive of late cardiac complications in patients with Hodgkin’s disease treated with mediastinal radiation. Int J Radiat Oncol Biol Phys. 2000;48(5):1503–6. doi: 10.1016/s0360-3016(00)00807-5.
  7. Glanzmann C, Kaufmann P, Jenni R, et al. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol. 1998;46(1):51–62. doi: 10.1016/s0167-8140(97)00125-4.
  8. Gustavsson A, Eskilsson J, Landberg T, et al. Late cardiac effects after mantle radiotherapy in patients with Hodgkin’s disease. Ann Oncol. 1990;1:355–63.
  9. Salloum E, Jillella AP, Nadkarni R, et al. Assessment of pulmonary and cardiac function after high dose chemotherapy with BEAM and peripheral blood progenitor cell transplantation. Cancer. 1998;82(8):1506–12. doi: 10.1002/(sici)1097-0142(19980415)82:8<1506::aid-cncr12>3.0.co;2-8.
  10. Hertenstein B, Stefanic M, Schmeiser T, et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol. 1994;12(5):998–1004.
  11. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749–54. doi: 10.1161/01.cir.0000130926.51766.cc.
  12. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003;82(4):218–22.
  13. Pihkala J, Saarinen UM, Lundstrоm U, et al. Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplant. 1994;13(2):149–55.
  14. Zver S, Zadnik V, Cernelc P, et al. Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Int J Hematol. 2008;88(2):227–36. doi: 10.1007/s12185-008-0112-5.

Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug?

GD Petrova1, KN Melkova1, TZ Chernyavskaya1, NV Gorbunova1, BV Afanasev2, EA Demina1, VN Kostrykina1, VA Doronin1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Galina Dmitrievna Petrova, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-13-59; e-mail: galina_petrova@bk.ru

For citation: Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug? Clinical oncohematology. 2015;8(3):321–30 (In Russ).


ABSTRACT

Background & Aims. The role of single and double autologous hematopoietic stem cell transplantations (autoSCT) in patients with primary refractory Hodgkin’s lymphoma (HL) has not been determined yet. The aim of the study is to present the results of a one-center prospective study evaluating the role of single and double autoSCT in patients with HL who have not achieved the complete remission (CR) after first line induction polychemotherapy (PCT).

Methods. 62 HL patients were enrolled in the study over the period from 2007 till 2014. High-dose chemotherapy (HDCT) with autoSCT was performed once in 53 patients, and twice in 10 patients.

Results. The study demonstrated an unfavorable prognostic impact of the large volume of previous chemotherapy on the overall survival (OS) rate after the autoSCT (= 0.03). Results of the 1st autoSCT had an independent prognostic value for the OS rate (= 0.004). The study identified the main indication for the 2nd autoSCT, namely, partial remission (PR) or stable disease (SD) achieved after the 1st autoSCT (when the 2nd HDCT with autoSCT should be preferred to the alternative treatment; = 0.004). Progressive disease (PD) after the first autoSCT is a contraindication for the second one. Due to low efficacy and high toxicity, the 2nd autoSCT does not improve outcomes when compared to alternative approaches (= 0.6). The importance of achieving CR at any stage of treatment which is associated with a long life span with no signs of disease and good quality of life has been demonstrated.

Conclusion. AutoSCT is an effective treatment option for patients without complete remission after the first line antitumor treatment. Carrying out 2nd autoSCT is advisable for patients who have reached the PR/SD after the first one. Patients with PD after the 1st autoSCT require an alternative treatment option.


Keywords: Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cell transplantation, primary resistance, double autoSCT.

Received: May 5, 2015

Accepted: June 2, 2015

Read in PDF (RUS)pdficon


REFERENCES

  1. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109(12):5143–50. doi: 10.1182/blood-2006-11-056028.
  2. Kantarjian H, Giles F, Bhalla K, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141–5. doi: 10.1182/blood-2010-03-277152.
  3. Лазорко Н.С., Ломаиа Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Нилотиниб и дазатиниб в первой линии терапии больных хроническим миелолейкозом в хронической фазе. Современная онкология. 2011;13(1):38–40. [Lazorko NS, Lomaia EG, Sbityakova EI, Zaritskii AYu. Nilotinib and dazatinib as first line therapy of patients in chronic phase of chronic myeloid leukemia. Sovremennaya onkologiya. 2011;13(1):38–40. (In Russ)]
  4. Ломаиа Е.Г., Романова Е.Г., Сбитякова Е.И., Зарицкий А.Ю. Эффективность и безопасность ингибиторов тирозинкиназ 2-го поколения (дазатиниб, нилотиниб) в терапии хронической фазы хронического миелолейкоза. Онкогематология. 2013;2:22–33. [Lomaia EG, Romanova EG, Sbityakova EI, Zaritskii AYu. Efficacy and safety of 2nd generation tyrosine kinase inhibitors (dasatinib, nilotinib) in teatment of chronic phase of chronic myeloid leukemia. Onkogematologiya. 2013;2:22–33. (In Russ)]
  5. Туркина А.Г., Хорошко Н.Д., Гусарова Г.А. и др. Российский опыт применения нилотиниба во второй линии терапии больных хроническим миелолейкозом с резистентностью или непереносимостью иматиниба: оценка безопасности и эффективности в исследовании ENACT (расширенный доступ к нилотинибу в клинических исследованиях). Вестник гематологии. 2010;1(2):92–3. [Turkina AG, Khoroshko ND, Gusarova GA, et al. Russian experience in use of nilotinib in second line therapy of patients with chronic myeloid leukemia and imatinib resistance or intolerance: evaluation of safety and efficacy in ENACT trial (Expanding Nilotinib Access in Clinical Trials). Vestnik gematologii. 2010;1(2):92–3. (In Russ)]
  6. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
  7. Kantarjian H, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540–6. doi: 10.1182/blood-2007-03-080689.
  8. Saglio G, Kim D, Issaragrisil S, et al. Nilotinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9. doi: 10.1517/14656566.2011.534780.
  9. Hochhaus A, Kantarjian H, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9. doi: 10.1182/blood-2006-09-047266.
  10. Kantarjian H, Shah N, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70. doi: 10.1056/nejmoa1002315.
  11. Shah R. Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction. Adv Drug React Toxicol Rev. 1999;18:181–233.
  12. Russmann S, Kullak-Ublick G, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem. 2009;16(23):3041–53.
  13. Teo YL, Ho HK, Chan A. Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis. Cancer Treat Rev. 2013;39(2):199–206. doi: 10.1016/j.ctrv.2012.09.004.
  14. Saglio G, Pinilla-Ibarz J, Cortes J, et al. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia. Blood. 2011;117(4):688−697. doi: 10.1002/cncr.25648.
  15. Rosti G, Castagnetti F, Gugliotta G, et al. Dasatinib and nilotinib in imatinib resistant Philadelphia-positive chronic myelogenous leukemia: a ‘head-to-head’ comparison. Leuk Lymphoma 2010;51(4):583–91. doi: 10.3109/10428191003637282.
  16. Shah R, Morganroth J, Shah D. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Saf. 2013;36(7):491–503. doi: 10.1007/s40264-013-0048-4.
  17. Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417–25. doi: 10.1177/42.11.7523489.
  18. Grichnik J, Burch J, Burchette J, Shea C. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol. 1998;111(2):233–8.
  19. Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115(18):4136–47. doi: 10.1002/cncr.24504.
  20. Irvine E, Williams C. Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Pharmacotherapy. 2013;33(8):868–81. doi: 10.1002/phar.1266.
  21. Van Etten RA. Cycling, stressed-out and nervous: cellular functions of cAbl. Trends Cell Biol. 1999;9(5):179–86. doi: 10.1016/s0962-8924(99)01549-4.
  22. Wasle B, Edwardson J. The regulation of exocytosis in the pancreatic acinar cell. Cell Signal. 2002;14(3):191–7. doi: 10.1016/s0898-6568(01)00257-1.
  23. Mooren F, Hlouschek V, Finkes T, et al. Early changes in pancreatic acinar cell calcium signalling after pancreatic duct obstruction. J Biol Chem. 2003;278(11):9361–9. doi: 10.1074/jbc.m207454200.
  24. Fitter S, Vandyke K, Gronthos S, Zannettino AC. Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogsis and adiponectin secretion. J Mol Endocrinol. 2012;48(3):229–40. doi: 10.1530/jme-12-0003.
  25. Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica. 2013;98(10):e124–6. doi: 10.3324/haematol.2013.086355.
  26. le Coutre P, Giles F, Hochhaus A, et al. Analysis of glucose profiles in imatinib resistant or intolerant chronic myelogenous leukemia (CML) patients treated with nilotinib: lack of correlation between glucose levels and nilotinib efficacy. Blood. 2007;110: Abstract 4588.
  27. Breccia M, Alimena G. Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development. Exp Opin Drug Saf. 2010;9(5):713–21. doi: 10.1517/14740331003742935.
  28. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008;141(5):745–7. doi: 10.1111/j.1365-2141.2008.07108.x.
  29. Porkka K, Khoury H, Paquette R, et al. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116(2):377–86. doi: 10.1002/cncr.24734.
  30. Shah N, Kantarjian H, Kim D, et al. Six-year (yr) follow-up of patients (pts) with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. J Clin Oncol. 2012;30:6506.
  31. Hasinoff BB. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol Appl Pharmacol. 2010;244(2):190–5. doi: 10.1016/j.taap.2009.12.032.
  32. Albini A, Pennesi G, Donatelli F, et al. Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst. 2010;102(1):14–25. doi: 10.1093/jnci/djp440.
  33. Strevel E, Ing D, Siu L. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol. 2007;25(22):3362–71. doi: 10.1200/jco.2006.09.6925.
  34. Haverkamp W, Breithardt G, Camm A, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21(15):1216–31. doi: 10.1053/euhj.2000.2249.
  35. Priori S, Schwartz P, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. doi: 10.1056/nejmoa022147.
  36. Sauer A, Moss A, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329–37. doi: 10.1016/j.jacc.2006.08.057.
  37. Center for Drug Evaluation and Research: Nilotinib Pharmacology/Toxicology Review and Evaluation; 2007.
  38. Le Coutre P, Ottmann O, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834–9. doi: 10.1182/blood-2007-04-083196.
  39. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. doi: 10.1056/nejmoa055104.
  40. Kim T, Rea D, Schwarz M, et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27(6):1316–21. doi: 10.1038/leu.2013.70.
  41. Larson R, Hochhaus A, Hughes T, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197–203. doi: 10.1038/leu.2012.134.
  42. Aichberger K, Herndlhofer S, Schernthaner G, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–9. doi: 10.1002/ajh.22037.
  43. Verma D, Verstovsek S, Kantarjian H, et al. Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood. 2011;118(16):4353–8. doi: 10.1182/blood-2011-06-362889.
  44. Hoffmann V, Baccarani M, Hasford J. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia. 2015;29(6):1336–43. doi: 10.1038/leu.2015.73 [Epub 2015 Mar 18]

Case of Pneumocystis Pneumonia after High-Dose Chemotherapy with Autologous Hematopoietic Transplantation

V.O. Sarzhevskii1, V.Ya. Melnichenk1, D.S. Kolesnikova1, O.Yu. Bronov1, V.M. Sotnikov2, N.N. Smoltsova2

1 N.I. Pirogov National Medical and Surgical Centre under the Ministry of Health of the Russian Federation, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

2 Russian Scientific Center of Roentgenoradiology under the Ministry of Health of the Russian Federation, 86 Profsoyuznaya str., Moscow, Russian Federation, 117997

For correspondence: V.O. Sarzhevskii, PhD, Associate Professor, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel: +7(495)603-72-18; e-mail: vladsar@pochta.ru

For citation: Sarzhevskii V.O., Mel’nichenko V.Ya., Kolesnikova D.S., Bronov O.Yu., Sotnikov V.M., Smol’tsova N.N. Case of Pneumocystis Pneumonia after High-Dose Chemotherapy with Autologous Hematopoietic Stem Cell Transplantation. Klin. Onkogematol. 2014; 7(4): 583–586 (In Russ.).


ABSTRACT

Pneumocystis pneumonia is a rare complication of a high-dose chemotherapy and autologous bone marrow/peripheral hematopoietic stem cells transplantation in patients with hematological malignances. The absence of typical clinical symptoms and the probability of a lethal outcome require a special approach to this problem. A brief review of literature and presented clinical case give an idea of clinical manifestations, course, diagnostic approaches, prevention, and treatment of pneumocystis pneumonia in this category of patients.


Keywords: autologous bone marrow transplantation, high-dose chemotherapy, pneumocystis pneumonia

Accepted: September 19, 2014

Read in PDF (RUS)pdficon

REFERENCES

  1. Walzer P.D., Perl D.P., Krogstad D.J. et al. Pneumocystis carinii pneumonia in the United States: epidemiologic, diagnostic, and clinical features. Natl. Cancer Inst. Monogr. 1976; 43: 55–63.
  2. Green H., Paul M., Vidal L. et al. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and metaanalysis of randomized controlled trials. Mayo Clin. Proc. 2007; 82(9): 1052–9.
  3. Colby C., McAfee S., Sackstein R. et al. A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/ sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1999; 24(8): 897–902.
  4. Sattler F.R., Cowan R., Nielsen D.M. et al. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study. Ann. Intern. Med. 1988; 109(4): 280–7.
  5. Hughes W., Leoung G., Kramer F. et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N. Engl. J. Med. 1993; 328(21): 1521–7.
  6. Metzner B., Gruneisl R., Gebauer W. et al. Late infectious complications after high-dose therapy and autologous blood stem cell transplantation. Med. Klin. (Munich) 2002; 97(11): 650–8.
  7. Decaudin D., Brousse N., Brice P. et al. Efficacy of autologous stem cell transplantation in mantle cell lymphoma: a 3-year follow-up study. Bone Marrow Transplant. 2000; 25(3): 251–6.
  8. Chen C.S., Boeckh M., Seidel K. Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 32(5): 515–22.
  9. Chuu W.M., Catlett J.P., Perry D.J. Concurrent Pneumocystis carinii and cytomegalovirus pneumonia after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1999; 23(10): 1087–9.
  10. Kato H., Yamamoto K., Taji H. et al. Interstitial pneumonia after autologous hematopoietic stem cell transplantation in B-cell non-Hodgkin lymphoma. Clin. Lymphoma Myeloma Leuk. 2011; 11(6): 483–9.
  11. Munker R., Lazarus H.M., Atkinson K. The BMT Data Book, 2nd ed. Cambridge University Press, 2009: 245.