Infectious Complications of Monoclonal Antibodies Used to Treat Acute Leukemia and Multiple Myeloma

Gemtuzumab ozogamicin

Gemtuzumab ozogamicin is approved for the treatment of acute myelocytic leukemia (AML). Gemtuzumab is conjugated to the toxin calicheamicin; upon internalization of the antibody-toxin conjugate in the target cell, calicheamicin binds to cell DNA and causes breaks in the DNA.45 Gemtuzumab targets CD33, an antigen found on myeloid precursor cells and AML blasts, and therefore prolonged, profound neutropenia is a major adverse event of therapy and occurs in essentially all patients.46,47 Neutropenic fever and sepsis are important potential sequelae.

Inotuzumab ozogamicin

Inotuzumab ozogamicin is approved for the treatment of acute B-cell lymphocytic leukemia (B-ALL). Inotuzumab targets CD22, a glycoprotein present on the blasts of most patients with B-ALL.48 Like gemtuzumab, it is conjugated to calicheamicin. Although CD22 expression is restricted to B cells, about half the patients in the pivotal phase 3 trial of inotuzumab ozogamicin developed neutropenia and were at risk for neutropenic fever and associated infection.49

Blinatumomab

Blinatumomab is the first approved bispecific T cell engager, indicated for the treatment of relapsed refractory B-ALL, comprised of monoclonal antibodies targeting CD19 on B cells and CD3 on cytotoxic T cells.50 Upon binding the targeted surface antigens, the CD3-positive T cells are activated and lyse the engaged B cells.50 An effect of T cell activation is cytokine release, which can result in fever and chills mimicking infection. In a phase 2 study of blinatumomab, 60% of patients developed fever.51 Cytokine release syndrome (CRS) is an important potential complication of BITE therapy, which in its most serious form is characterized by fever and hypotension; it is easily mistaken for serious infection. It is prudent to treat fever in neutropenic patients (ie, most of the refractory ALL patients treated with blinatumomab) with empiric antimicrobial therapy even if cytokine release is the suspected cause, since infections in neutropenic patients are so common. Neutropenia has not clearly been associated with blinatumomab, especially since its use is limited to patients likely to have started therapy neutropenic. Blinatumomab, by virtue of targeting CD19 on precursor and mature B cells as well as plasma cells, has been demonstrated to cause prolonged lymphopenia and hypogammaglobulinemia.50 Of note, opportunistic infections such as have been reported with rituximab anti-CD20 therapy have not been reported thus far with blinatumomab therapy. However, most patients receiving blinatumomab receive PCP prophylaxis because of recent steroid exposure with other chemotherapy regimens or for prevention of CRS. In the case of PML, the use of blinatumomab may not yet be great enough to know if there is an associated predisposition.

Daratumumab

Daratumumab, approved in the treatment of refractory multiple myeloma, is a monoclonal antibody that targets CD38 on the surface of myeloma cells.52 The expression of CD38 is not limited to plasma cells; it is also found in low levels on lymphoid and myeloid cells.53,54 Opportunistic infections have not been reported in association with daratumumab therapy. In a phase 3 trial of lenalidomide and dexamethasone with or without daratumumab, neutropenia, fever, and upper respiratory infections were more frequent in the group that received daratumumab.55 In a phase 3 trial of bortezomib and dexamethasone with or without daratumumab, neutropenia, lymphopenia, fever, and upper respiratory infections were more frequent in the group receiving daratumumab.56 Another phase 3 trial studying bortezomib, melphalan, and prednisone with or without daratumumab reported increased frequency of upper respiratory infections and pneumonia in the daratumumab group but not neutropenia or fever.57

Infectious Complications of Monoclonal Antibodies Used to Treat Solid Tumors

Bevacizumab and Ramucirumab

Vascular endothelial growth factor (VEGF) is an important promotor of angiogenesis in tumor growth.58 Bevacizumab binds to VEGF-A, which is considered the most active of the VEGF family molecules.58 It is approved for the treatment of metastatic colorectal cancer, renal cell carcinoma, and non-small cell carcinoma of the lung, as well as glioblastoma multiforme.59 Ramucirumab binds to VEGF receptor-2 to block binding of VEGF-A to the receptor used for the treatment of advanced gastric carcinoma and metastatic colorectal carcinoma.58 A meta-analysis of randomized controlled trials of bevacizumab in a variety of malignancies demonstrated a statistically significant higher rate of any grade and high-grade infections in the bevacizumab group compared with controls.59 Another meta-analysis showed that bevacizumab is associated with an increased risk for neutropenia and febrile neutropenia compared with controls.60 An increased incidence of neutropenia has also been reported in several of the phase 3 trials of ramucirumab.58

Related Articles

Cetuximab and Panitumumab

Cetuximab and panitumumab target the epidermal growth factor receptor (EGFR) and are approved for the treatment of metastatic colorectal cancer, with cetuximab also approved for the treatment of head and neck squamous cell carcinoma.61 A meta-analysis of randomized controlled trials of these monoclonal antibodies showed that both cetuximab and panitumumab are associated with an increased risk for high-grade infection, and cetuximab is associated with an increased risk for febrile neutropenia.61 A separate meta-analysis that examined the risk for neutropenia in patients treated with cetuximab in randomized controlled trials showed that cetuximab was associated with an increased incidence of neutropenia compared with controls.62

References

  1. Maino E, Bonifacio M, Scattolin AM, Bassan R. Immunotherapy approaches to treat adult lymphoblastic leukemia. Expert Rev Hematol. 2016;9:563-577.
  2. Kelesidis T, Daikos G, Boumpas D, Tsiodras S. Does rituximab increase the incidence of infectious complications? A narrative review. Int J Infect Dis. 2011;15(1):e2-e16.
  3. Gea-Banacloche J. Rituximab-associated infections. Semin Hematol. 2010;47(2):187-198.
  4. Uettwiller F, Rigel E, Hoarau C. Infections associated with monoclonal antibody and fusion protein therapy in humans. MAbs. 2011;3(5):461-466.
  5. Chang CS, Tsai CY, Yan SL. Hepatitis B reactivation min patients receiving targeted therapies. Hematology. 2017;22(10):592-598.
  6. Phipps C, Chen Y, Tan D. Lymphoproliferative disease and hepatitis B reactivation: challenges in the era of rapidly evolving targeted therapy. Clin Lymphoma Myeloma Leuk. 2016;16(1):5-11.
  7. Mozessohn L, Chan KK, Feld JJ, Hicks LK. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis. J Viral Hepatitis. 2015;22(10):842-849.
  8. Yeo W, Chan TC, Leung NWY, et al. Hepatitis B reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27(4):605-611.
  9. Yeo W, Chan PKS, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: A prospective study of 626 patients with identifiaction of risk factors. J Med Virol. 2000;62(3):299-307.
  10. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004;90(7):1306-1311.
  11. Lok ASF, Liang RHS, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study. Gastroenterology. 1991;100(1):182-188.
  12. Law MF, Ho R, Cheung CK, et al. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy. World J Gastroenterol. 2016;22(28):6484-6500.
  13. Hui CK, Cheung WW, Zhang HY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131(1):59-68.
  14. Hsu C, Tsou HH, Lin SJ, et al; Taiwan Cooperative Oncology Group. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology. 2014;59(6):2092-2100.
  15. Kim SJ, Hsu C, Song YQ, et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia lymphoma study group. Eur J Cancer. 2013;49(16):3486-3496.
  16. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22(5):1170-1180.
  17. Dong HJ, Ni LN, Sheng GF, Song HL, Xu JZ, Ling Y. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin’s lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol. 2013;57(3):209-214.
  18. Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):221-244.e3.
  19. Yeo W, Chan PK, Ho WM, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis Bs-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol. 2004;22(5):927-934.
  20. Loomba R, Rowley A, Wesley R, et al. Systematic review: The effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148(7):519-528.
  21. Ziakas PD, Karsaliakos P, Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica. 2009;94(7):998-1005.
  22. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017;152(6):1297-1309.
  23. Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312(23):2521-2530.
  24. Huang YH, Hsaio LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31(22):2765-2772.
  25. Reddy KR, L, Hammond SP, et al. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):215-219.
  26. Zaky AH, Bakry R, El-sayed MI, Elwanis MA, Nabih O. Impact of treatment-related toxicity on outcome of HCV-positive diffuse large B-cell lymphoma in rituximab era. Hematology. 2014;19(7):412-416.
  27. Martin-Garrido I, Carmona EM, Specks U, Limper AH. Pneumocystis pneumonia in patients treated with rituximab. Chest. 2013;144(1):258-265.
  28. Aksoy S, Harputluoglu H, Kilickap S, et al. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma. 2007;48(7):1307-1312.
  29. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113(20):4834-4840.
  30. Bohra C, Sokol L, Dalia S. Progressive multifocal leukoencephalopathy and monoclonal antibodies: a review. Cancer Control. 2017;24(4). doi:1073274817729901.
  31. Kim SJ, Moon JH, Kim H, et al. Non-bacterial infections in Asian patients treated with alemtuzumab: a retrospective study of the Asian lymphoma study group. Leuk Lymphoma. 2012;53(8):1515-1524.
  32. Helfrich M, Ison MG. Opportunistic infections complicating solid organ transplantation with alemtuzumab induction. Transpl Infec Dis. 2015;17(5):627-636.
  33. Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infec Dis. 2006;43(1):16-24.
  34. O’Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin Lymph Myeloma. 2006;7(2):125-130.
  35. Raisch DW, Rafi JA, Chen C, Bennett CL. Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse event reporting system. Expert Opin Drug Saf. 2016;15(8):1003-1011.
  36. Peleg AY, Hussin S, Kwak EJ, et al. Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody. Clin Infec Dis. 2007;44(2):204-212.
  37. Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk, and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. B J Haematol. 2005;132(1):3-12.
  38. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. New Engl J Med. 2018;378(4):331-344.
  39. Teo EC, Chew Y, Phipps C. A review of monoclonal antibody therapies in lymphoma. Crit Rev Oncol Hematol. 2016;97:72-84.
  40. FDA drug safety communication: new boxed warning and contraindication for adcetris (brentuximab vedotin) effects [news release]. Silver Spring, MD: U.S. Food and Drug Administration. Updated March 10, 2016. Accessed April 24, 2018.
  41. Wagner-Johnston ND, Bartlett NL, Cashen A, Berger JR. Progressive multifocal leukoencephalopathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma. 2012;53(11):2283-2286.
  42. Carson KR, Newsome SD, Kim EJ, et al. Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer. 2014;120(16):2464-2471.
  43. Gopal AK, Ramchandren R, O’Connor OA, et al. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 120(3):560-568.
  44. Tudesq J, Vincent L, Lebrun J, et al. Cytomegalovirus infection with retinitis after brentuximab vedotin treatment for CD30+ lymphoma. Open Forum Infect Dis. 2017;4(2):ofx091.
  45. Appelbaum FR, Bernstein ID. Gemtuzumab ozogamicin for acute myeloid leukemia. Blood. 2017;130(22):2373-2376.
  46. Leopold LH, Berger MS, Heingold J. Acute and long-term toxicities associated with gemtuzumab ozogamicin (Mylotarg) therapy of acute myeloid leukemia. Clin Lymphoma. 2002;2 (1):S29-S34.
  47. Larson RA, Sievers EL, Stadtmauer EA, et al. Final report on the efficacy and safety of gentuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104(7):1442-1452.
  48. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. New Engl J Med. 2016;375(8):740-753.
  49. Jabbour EJ, DeAngelo DJ, Stelljes M, et al. Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer. 2018;124(8):1722-1732.
  50. Ribera J. Efficacy and safety of bispecific T-cell engager blinatumumab and the potential to improve leukemia-free survival in B-cell acute lymphoblastic leukemia. Expert Rev Hematol. 2017;10(12):1057-1067.
  51. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57-66.
  52. Bringhen S, De Wit E, Dimopoulos M. New agents in multiple myeloma: an examination of safety profiles. Clin Lymphoma Myeloma Leuk. 2017;17(7):391-407.e5.
  53. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
  54. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New Engl J Med. 2015;373(13):1207-1219.
  55. Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. New Engl J Med. 2016;375(14):1319-1331.
  56. Palumbo A, Chanan-Khan A, Weisel K, et al; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. New Engl J Med. 2016;375(8):754-766.
  57. Mateos MV, Dimopoulos MA, Cavo M, et al; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. New Engl J Med. 2018;378(6):518-528.
  58. Aguilar-Company J, Fernandez-Ruiz M, Garcia-Campelo R, Garrido-Castro AC, Ruiz-Camps I. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies: an infectious diseases perspective- cell surface receptors and associated signaling pathways [published online February 7, 2018]. Clin Microbiol Infect. doi:10.1016/j.cmi.2017.12.027
  59. Qi W, Fu S, Zhang Q, Guo X. Bevacizumab increases the risk of infections in cancer patients: a systematic review and pooled analysis of 41 randomized controlled trials.  Crit Rev Oncol Hematol. 2015;94(3):323-336.
  60. Schutz FAB, Jardim DLF, Je Y, Choueiri TK. Haematologic toxicities associated with the addition of bevacizumab in cancer patients. Eur J Cancer. 2011;47(8):1161-1174.
  61. Funakoshi T, Suzuki M, Tamura K. Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: a systematic review and meta-analysis. Cancer Treat Rev. 2014;40(10):1221-1229.
  62. Wang L, Chen Y, Shi D, Shi XY, Zou Z, Zhao JH. Incidence and risk of severe neutropenia in advanced cancer patients treated with cetuximab: a meta-analysis. Drugs R D. 2011;11(4):317-326.