Infectious Complications Associated With Immunomodulating Monoclonal Antibodies Used in the Treatment of Hematologic Malignancy

Authors:
Sophia Koo From Brigham & Women's Hospital and Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts.

Search for other papers by Sophia Koo in
Current site
Google Scholar
PubMed
Close
 MD
and
Lindsey R. Baden From Brigham & Women's Hospital and Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts.
From Brigham & Women's Hospital and Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts.

Search for other papers by Lindsey R. Baden in
Current site
Google Scholar
PubMed
Close
 MD
Full access

Immunomodulating monoclonal antibodies are a relatively new addition to the armamentarium of cancer therapeutics and have been shown to improve clinical outcomes in patients with various hematologic malignancies. Because of their targeted nature, these agents are often believed to be less immunosuppressive than standard cytotoxic chemotherapeutic agents. A clear causal association between an immunomodulating therapy and its infectious sequelae is often difficult to discern because of the burden of comorbid illness, intrinsic immunosuppression from the underlying malignancy, use in the salvage setting, and prior and concomitant use of immunosuppressive agents in this patient population. This article evaluates better-established and anecdotal infectious complications associated with major immunomodulating therapies used in hematologic malignancy and hematopoietic stem cell transplantation, including rituximab, alemtuzumab, gemtuzumab ozogamicin, infliximab, dacluzimab, and basiliximab.

Correspondence: Sophia Koo, MD, Division of Infectious Diseases, Brigham & Women's Hospital, 15 Francis Street, PBB-A4, Boston, MA 02115. E-mail: skoo@partners.org

EDITORS

Brahm Segal, MD, Chief of the Infectious Disease Department, Roswell Park Cancer Institute, Buffalo, New York; Co-Chair, NCCN Prevention and Treatment of Cancer-Related Infections Panel

Disclosure: Brahm Segal, MD, has disclosed that he has served on the speaker's bureau for Merck and Pfizer and has served on the advisory board for Pfizer.

Alison G. Freifeld, MD, Director, Immunocompromised Host Infectious Diseases Program, Professor of Medicine, UNMC Eppley Cancer Center, The Nebraska Medical Center, Omaha, Nebraska

Disclosure: Alison G. Freifeld, MD, has disclosed that she has accepted financial support in the form of research support, advisory committee membership, or speaker's bureau participation from Genzyme Pharmaceuticals, Schering-Plough Corporation, Enzon Pharmaceuticals, and Astellas Pharma, Inc.

CME AUTHOR

Désirée Lie, MD, MSEd, Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California

Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.

  • Collapse
  • Expand
  • 1.

    van der Kolk LE, Baars JW, Prins MH et al.. Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 2002;100:22572259.

  • 2.

    Rafailidis PI, Kakisi OK, Vardakas K et al.. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials. Cancer 2007;109:21822189.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Spina M, Jaeger U, Sparano JA et al.. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood 2005;105:18911897.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Kaplan LD, Lee JY, Ambinder RF et al.. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 2005;106:15381543.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Boue F, Gabarre J, Gisselbrecht C et al.. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol 2006;24:41234128.

  • 6.

    Miles SA, McGratten M. Persistent panhypogammaglobulinemia after CHOP-rituximab for HIV-related lymphoma. J Clin Oncol 2005;23:247248.

  • 7.

    Byrd JC, Rai K, Peterson BL et al.. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005;105:4953.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Niscola P, Del Principe MI, Maurillo L et al.. Fulminant B hepatitis in a surface antigen-negative patient with B-cell chronic lymphocytic leukaemia after rituximab therapy. Leukemia 2005;19:18401841.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Perceau G, Diris N, Estines O et al.. Late lethal hepatitis B virus reactivation after rituximab treatment of low-grade cutaneous B-cell lymphoma. Br J Dermatol 2006;155:10531056.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Engl J Med 2001;344:6869.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Tsutsumi Y, Tanaka J, Kawamura T et al.. Possible efficacy of lamivudine treatment to prevent hepatitis B virus reactivation due to rituximab therapy in a patient with non-Hodgkin's lymphoma. Ann Hematol 2004;83:5860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Hamaki T, Kami M, Kusumi E et al.. Prophylaxis of hepatitis B reactivation using lamivudine in a patient receiving rituximab. Am J Hematol 2001;68:292294.

  • 13.

    Westhoff TH, Jochimsen F, Schmittel A et al.. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003;102:1930.

  • 14.

    Law JK, Ali JA, Harrigan PR et al.. Fatal postlymphoma chemotherapy hepatitis B reactivation secondary to the emergence of a YMDD mutant strain with lamivudine resistance in a noncirrhotic patient. Am J Hematol 2006;81:969972.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Padate BP, Keidan J. Enteroviral meningoencephalitis in a patient with non-Hodgkin's lymphoma treated previously with rituximab. Clin Lab Haematol 2006;28:6971.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Quartier P, Tournilhac O, Archimbaud C et al.. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003;36:e4749.

  • 17.

    Archimbaud C, Bailly JL, Chambon M et al.. Molecular evidence of persistent echovirus 13 meningoencephalitis in a patient with relapsed lymphoma after an outbreak of meningitis in 2000. J Clin Microbiol 2003;41:46054610.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Goldberg SL, Pecora AL, Alter RS et al.. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab. Blood 2002;99:14861488.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Matteucci P, Magni M, Di Nicola M et al.. Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody. Blood 2002;100:11041105.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Aksoy S, Harputluoglu H, Kilickap S et al.. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma 2007;48:13071312.

  • 21.

    Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001;345:1000.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Vallet S, Tempescul A, Tran A et al.. Cytomegalovirus-associated meningoradiculoneuritis after treatment of mantle cell lymphoma with a combination of chemotherapy and rituximab. Ann Hematol 2005;84:545547.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Krause PJ, Gewurz BE, Hill D et al.. Persistent and relapsing babesiosis in immunocompromised patients. Clin Infect Dis 2008;46:370376.

  • 24.

    Sharma VR, Fleming DR, Slone SP. Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab. Blood 2000;96:11841186.

  • 25.

    Song KW, Mollee P, Patterson B et al.. Pure red cell aplasia due to parvovirus following treatment with CHOP and rituximab for B-cell lymphoma. Br J Haematol 2002;119:125127.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Isobe Y, Sugimoto K, Shiraki Y et al.. Successful high-titer immunoglobulin therapy for persistent parvovirus B19 infection in a lymphoma patient treated with rituximab-combined chemotherapy. Am J Hematol 2004;77:370373.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Huang C, Slater B, Rudd R et al.. First isolation of West Nile virus from a patient with encephalitis in the United States. Emerg Infect Dis 2002;8:13671371.

  • 28.

    Mawhorter SD, Sierk A, Staugaitis SM et al.. Fatal West Nile Virus infection after rituximab/fludarabine–induced remission for non-Hodgkin's lymphoma. Clin Lymphoma Myeloma 2005;6:248250.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Morris EC, Rebello P, Thomson KJ et al.. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood 2003;102:404406.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Rai KR, Freter CE, Mercier RJ et al.. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 2002;20:38913897.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Osterborg A, Dyer MJ, Bunjes D et al.. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 1997;15:15671574.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Keating MJ, Flinn I, Jain V et al.. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:35543561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Ferrajoli A, O'Brien SM, Cortes JE et al.. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 2003;98:773778.

  • 34.

    O'Brien SM, Kantarjian HM, Thomas DA et al.. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 2003;98:26572663.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Martin SI, Marty FM, Fiumara K et al.. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 2006;43:1624.

  • 36.

    Nguyen DD, Cao TM, Dugan K et al.. Cytomegalovirus viremia during Campath-1H therapy for relapsed and refractory chronic lymphocytic leukemia and prolymphocytic leukemia. Clin Lymphoma 2002;3:105110.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Laurenti L, Piccioni P, Cattani P et al.. Cytomegalovirus reactivation during alemtuzumab therapy for chronic lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 2004;89:12481252.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Wendtner CM, Ritgen M, Schweighofer CD et al.. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission–experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia 2004;18:10931101.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Faderl S, Thomas DA, O'Brien S et al.. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood 2003;101:34133415.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Kennedy B, Rawstron A, Carter C et al.. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood 2002;99:22452247.

  • 41.

    Osterborg A, Fassas AS, Anagnostopoulos A et al.. Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukaemia. Br J Haematol 1996;93:151153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Lundin J, Kimby E, Bjorkholm M et al.. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002;100:768773.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Dearden CE, Matutes E, Cazin B et al.. High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood 2001;98:17211726.

  • 44.

    Keating MJ, Cazin B, Coutre S et al.. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol 2002;20:205213.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Uppenkamp M, Engert A, Diehl V et al.. Monoclonal antibody therapy with CAMPATH-1H in patients with relapsed high- and low-grade non-Hodgkin's lymphomas: a multicenter phase I/II study. Ann Hematol 2002;81:2632.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Lundin J, Osterborg A, Brittinger G et al.. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin's Lymphoma. J Clin Oncol 1998;16:32573263.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Enblad G, Hagberg H, Erlanson M et al.. A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood 2004;103:29202924.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Lundin J, Hagberg H, Repp R et al.. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101:42674272.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Gallamini A, Zaja F, Patti C et al.. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007;110:23162323.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Perez-Simon JA, Kottaridis PD, Martino R et al.. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002;100:31213127.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Ho AY, Pagliuca A, Kenyon M et al.. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 2004;104:16161623.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    van Besien K, Artz A, Smith S et al.. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005;23:57285738.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Chakrabarti S, Mackinnon S, Chopra R et al.. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood 2002;99:43574363.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Lamba R, Carrum G, Myers GD et al.. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant 2005;36:797802.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Chakrabarti S, Mautner V, Osman H et al.. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 2002;100:16191627.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Avivi I, Chakrabarti S, Milligan DW et al.. Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab. Biol Blood Marrow Transplant 2004;10:186194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Chakrabarti S, Avivi I, Mackinnon S et al.. Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality. Br J Haematol 2002;119:11251132.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Vu T, Carrum G, Hutton G et al.. Human herpesvirus-6 encephalitis following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2007;39:705709.

  • 59.

    Chakrabarti S, Osman H, Collingham K et al.. Polyoma viruria following T-cell-depleted allogeneic transplants using Campath-1H: incidence and outcome in relation to graft manipulation, donor type and conditioning. Bone Marrow Transplant 2003;31:379386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Heider U, Fleissner C, Zavrski I et al.. Treatment of refractory chronic lymphocytic leukemia with Campath-1H in combination with lamivudine in chronic hepatitis B infection. Eur J Haematol 2004;72:6466.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Herbert KE, Prince HM, Westerman DA. Pure red-cell aplasia due to parvovirus B19 infection in a patient treated with alemtuzumab. Blood 2003;101:1654.

  • 62.

    Crowley B, Woodcock B. Red cell aplasia due to parvovirus b19 in a patient treated with alemtuzumab. Br J Haematol 2002;119:279280.

  • 63.

    Sievers EL, Larson RA, Stadtmauer EA et al.. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001;19:32443254.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Larson RA, Sievers EL, Stadtmauer EA et al.. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005;104:14421452.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355:704712.

  • 66.

    Bongartz T, Sutton AJ, Sweeting MJ et al.. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:22752285.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Wallis RS, Broder M, Wong J et al.. Reactivation of latent granulomatous infections by infliximab. Clin Infect Dis 2005;41(Suppl 3):S194198.

  • 68.

    Jacobsohn DA, Hallick J, Anders V et al.. Infliximab for steroid-refractory acute GVHD: a case series. Am J Hematol 2003;74:119124.

  • 69.

    Marty FM, Lee SJ, Fahey MM et al.. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood 2003;102:27682776.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Couriel D, Saliba R, Hicks K et al.. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004;104:649654.

  • 71.

    Busca A, Locatelli F, Marmont F et al.. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007;82:4552.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Wolff D, Roessler V, Steiner B et al.. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant 2005;35:10031010.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73.

    Przepiorka D, Kernan NA, Ippoliti C et al.. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 2000;95:8389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74.

    Willenbacher W, Basara N, Blau IW et al.. Treatment of steroid refractory acute and chronic graft-versus-host disease with daclizumab. Br J Haematol 2001;112:820823.

  • 75.

    Srinivasan R, Chakrabarti S, Walsh T et al.. Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis. Br J Haematol 2004;124:777786.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Perales MA, Ishill N, Lomazow WA et al.. Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease. Bone Marrow Transplant 2007;40:481486.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Funke VA, de Medeiros CR, Setubal DC et al.. Therapy for severe refractory acute graft-versus-host disease with basiliximab, a selective interleukin-2 receptor antagonist. Bone Marrow Transplant 2006;37:961965.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78.

    Schmidt-Hieber M, Fietz T, Knauf W et al.. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005;130:568574.

    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 712 436 21
PDF Downloads 253 63 9
EPUB Downloads 0 0 0