Annals of Hematology

, Volume 94, Issue 4, pp 593–601 | Cite as

Non-pegylated liposomal doxorubicin in lymphoma: patterns of toxicity and outcome in a large observational trial

  • Ines Wasle
  • Gabriele Gamerith
  • Florian Kocher
  • Patrizia Mondello
  • Thomas Jaeger
  • Alois Walder
  • Jutta Auberger
  • Thomas Melchardt
  • Werner Linkesch
  • Michael Fiegl
  • Michael MianEmail author
Original Article


The anthracycline doxorubicin plays a major role in the treatment of lymphoproliferative disorders. However, its use is often limited due to cardiac toxicity, which seems to be much less in the liposomal non-pegylated formulation (Myocet®). The aim of this study was the evaluation of efficacy and toxicity of Myocet®-containing treatment regimens, with a focus on cardiotoxicity during treatment in lymphoma patients. A total of 326 consecutive patients, treated between March 2008 and December 2013 in 11 Austrian and 1 Italian cancer centers, were retrospectively assessed. Patients’ baseline and treatment-related parameters were obtained by reviewing hospital records. Median age was 74 years (range 26–93). The most common histology was DLBCL (60 %), followed by FL (13 %) and MCL (8 %). At least one cardiovascular comorbidity was present in 72 % of patients. Most common grade 3/4 toxicities were hematologic, namely, leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia in 44, 40, 17, and 16 %. Overall, 43 patients suffered a cardiac event (any grade) with most patients developing congestive heart failure. Parameters significantly associated with severe cardiac events (grades 3–5) were the presence of cardiovascular comorbidities, chronic obstructive pulmonary disease, and elevated baseline NT-proBNP. Treatment response after first line Myocet®-containing therapy was ≥58 % among all entities (range 58–86 %) and therefore comparable to those of conventional therapeutic regimens. Herein, we provide a detailed toxicity profile of Myocet®-containing chemotherapy regimens. Despite the high rate of patients with preexisting comorbidities, the number of adverse events was encouraging. However, these results need to be confirmed in a prospective randomized trial.


Anthracycline Cardiac toxicity Lymphoma Myocet R-CHOP 



The authors thank Stephan Gritsch (Innsbruck), August Zabernigg (Kufstein), Reinhard Stauder (Innsbruck), Wolfgang Willenbacher (Innsbruck), Michael Steurer (Innsbruck), Günther Gastl (Innsbruck), Günther Zangerl (Zams), Michael Schnallinger (St. Johann) and Stephan Schreieck (Reutte), for providing patient data and advice.

Conflict of interest

This study was supported by the “Verein für Tumorforschung.” Ines Wasle, PhD student, received an unrestricted research grant by the Austrian Ratiopharm Arzneimittel Vertriebs-GmbH. Michael Fiegl received honoraria for lectures (Roche, TEVA). Michael Fiegl and Michael Mian are consultants of TEVA.

Supplementary material

277_2014_2250_MOESM1_ESM.docx (33 kb)
Supplementary Table 1 (DOCX 33 kb)


  1. 1.
    Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328(14):1002–1006. doi: 10.1056/NEJM199304083281404 CrossRefPubMedGoogle Scholar
  2. 2.
    Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Ferme C, Tilly H (2010) Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 116(12):2040–2045. doi: 10.1182/blood-2010-03-276246 CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Green M (1998) Anthracycline cardiotoxicity, no longer an issue? Ann Oncol Off J Eur Soc Med Oncol / ESMO 9(7):691–693CrossRefGoogle Scholar
  4. 4.
    Limat S, Demesmay K, Voillat L, Bernard Y, Deconinck E, Brion A, Sabbah A, Woronoff-Lemsi MC, Cahn JY (2003) Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma. Ann Oncol Off J Eur Soc Med Oncol / ESMO 14(2):277–281CrossRefGoogle Scholar
  5. 5.
    Dixon DO, Neilan B, Jones SE, Lipschitz DA, Miller TP, Grozea PN, Wilson HE (1986) Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol Off J Am Soc Clin Oncol 4(3):295–305Google Scholar
  6. 6.
    Allen TM, Martin FJ (2004) Advantages of liposomal delivery systems for anthracyclines. Semin Oncol 31(6 Suppl 13):5–15CrossRefPubMedGoogle Scholar
  7. 7.
    Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW (2001) Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 19(5):1444–1454Google Scholar
  8. 8.
    Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E, Group TDS (2002) Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94(1):25–36CrossRefPubMedGoogle Scholar
  9. 9.
    van Dalen EC, Michiels EM, Caron HN, Kremer LC (2010) Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev 5, CD005006. doi: 10.1002/14651858.CD005006.pub4 PubMedGoogle Scholar
  10. 10.
    Dell’Olio M, Scalzulli RP, Sanpaolo G, Nobile M, Mantuano FS, La Sala A, D’Arena G, Miraglia E, Lucania A, Mastrullo L, Nicola C (2011) Non-pegylated liposomal doxorubicin (Myocet(R)) in patients with poor-risk aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma 52(7):1222–1229. doi: 10.3109/10428194.2011.572321 CrossRefPubMedGoogle Scholar
  11. 11.
    Corazzelli G, Frigeri F, Arcamone M, Lucania A, Rosariavilla M, Morelli E, Amore A, Capobianco G, Caronna A, Becchimanzi C, Volzone F, Marcacci G, Russo F, De Filippi R, Mastrullo L, Pinto A (2011) Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high ‘life threat’ impact cardiopathy. Br J Haematol 154(5):579–589. doi: 10.1111/j.1365-2141.2011.08786.x CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Tilly H, Vitolo U, Walewski J, da Silva MG, Shpilberg O, Andre M, Pfreundschuh M, Dreyling M, Group EGW (2012) Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol / ESMO 23(Suppl 7):vii78–vii82. doi: 10.1093/annonc/mds273 Google Scholar
  13. 13.
    Heintel D, Skrabs C, Hauswirth A, Eigenberger K, Einberger C, Raderer M, Sperr WR, Knobl P, Mullauer L, Uffmann M, Dieckmann K, Gaiger A, Jager U (2010) Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age. Ann Hematol 89(2):163–169. doi: 10.1007/s00277-009-0796-5 CrossRefPubMedGoogle Scholar
  14. 14.
    Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C, European Organisation for R, Treatment of C (2011) 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 47(1):8–32. doi: 10.1016/j.ejca.2010.10.013 CrossRefPubMedGoogle Scholar
  15. 15.
    Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol Off J Am Soc Clin Oncol 17(4):1244Google Scholar
  16. 16.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ, International Workshop on Chronic Lymphocytic L (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111(12):5446–5456. doi: 10.1182/blood-2007-06-093906 CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Kyle RA, Rajkumar SV (2014) Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 28(4):980. doi: 10.1038/leu.2014.11 CrossRefGoogle Scholar
  18. 18.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on L (2007) Revised response criteria for malignant lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 25(5):579–586. doi: 10.1200/JCO.2006.09.2403 CrossRefGoogle Scholar
  19. 19.
    Mian M, Wasle I, Gamerith G, Mondello P, Melchardt T, Jager T, Linkesch W, Fiegl M (2014) R-CHOP versus R-COMP: are they really equally effective? Clin Oncol. doi: 10.1016/j.clon.2014.05.012 Google Scholar
  20. 20.
    Fridrik MA, Petzer AL, Keil F, Willenbacher W, Jaeger U, Lang A, Burgstaller S, Andel J, Krieger O, Oberaigner W, Greil R (2011) Non-pegylated liposomal encapsulated doxorubicin reduces cardiotoxicity in 1st line treatment of diffuse large B-Cell lymphoma (DLBCL). Final results of a randomized trial. ASH annual. Meet Abstr 118(21):2676Google Scholar
  21. 21.
    Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, Jones A (2010) Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 10:337. doi: 10.1186/1471-2407-10-337 CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346(4):235–242. doi: 10.1056/NEJMoa011795 CrossRefPubMedGoogle Scholar
  23. 23.
    Hershman DL, McBride RB, Eisenberger A, Tsai WY, Grann VR, Jacobson JS (2008) Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 26(19):3159–3165. doi: 10.1200/JCO.2007.14.1242 CrossRefGoogle Scholar
  24. 24.
    Bovelli D, Plataniotis G, Roila F, Group EGW (2010) Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol Off J Eur Soc Med Oncol / ESMO 21(Suppl 5):v277–v282. doi: 10.1093/annonc/mdq200 CrossRefGoogle Scholar
  25. 25.
    Jurczak W, Szmit S, Sobocinski M, Machaczka M, Drozd-Sokolowska J, Joks M, Dzietczenia J, Wrobel T, Kumiega B, Zaucha JM, Knopinska-Posluszny W, Spychalowicz W, Prochwicz A, Drohomirecka A, Skotnicki AB (2013) Premature cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen—a national multicenter study. Int J Cardiol 168(6):5212–5217. doi: 10.1016/j.ijcard.2013.08.033 CrossRefPubMedGoogle Scholar
  26. 26.
    Nousiainen T, Jantunen E, Vanninen E, Hartikainen J (2002) Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer 86(11):1697–1700. doi: 10.1038/sj.bjc.6600346 CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Luminari S, Montanini A, Caballero D, Bologna S, Notter M, Dyer MJ, Chiappella A, Briones J, Petrini M, Barbato A, Kayitalire L, Federico M (2010) Nonpegylated liposomal doxorubicin (MyocetTM) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial. Ann Oncol Off J Eur Soc Med Oncol / ESMO 21(7):1492–1499. doi: 10.1093/annonc/mdp544 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ines Wasle
    • 1
    • 3
  • Gabriele Gamerith
    • 1
  • Florian Kocher
    • 1
    • 8
  • Patrizia Mondello
    • 2
  • Thomas Jaeger
    • 3
  • Alois Walder
    • 4
  • Jutta Auberger
    • 5
  • Thomas Melchardt
    • 5
  • Werner Linkesch
    • 6
  • Michael Fiegl
    • 1
  • Michael Mian
    • 1
    • 7
    Email author
  1. 1.Department of Internal Medicine V (Haematology and Oncology)Medical University of InnsbruckInnsbruckAustria
  2. 2.Department of Medical OncologyUniversity of MessinaMessinaItaly
  3. 3.Department Internal Medicine E/OncologyLandeskrankenhaus RankweilRankweilAustria
  4. 4.Department Internal MedicineBezirkskrankenhaus LienzLienzAustria
  5. 5.3rd Medical DepartmentParacelsus Medical University SalzburgSalzburgAustria
  6. 6.Department of Internal Medicine, Division of HaematologyMedical University of GrazGrazAustria
  7. 7.Department of Hematology and CBMTHospital of BolzanoBolzanoItaly
  8. 8.Tyrolean Cancer Research InstituteInnsbruckAustria

Personalised recommendations