Subcutaneous immunoglobulin replacement for treatment of humoral immune dysfunction in patients with chronic lymphocytic leukemia

S Shahzad Mustafa, Saad Jamshed, Karthik Vadamalai, Allison Ramsey, S Shahzad Mustafa, Saad Jamshed, Karthik Vadamalai, Allison Ramsey

Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) experience hypogammaglobinemia and non-neutropenic infections. In this exploratory proof of concept study, our objective was to determine the prevalence of humoral immunodeficiency in patients with CLL and serum IgG ≥ 400 mg/dL, and to evaluate the efficacy of subcutaneous immunoglobulin (SCIG) in this population.

Patients and methods: Patients with CLL with serum IgG ≥ 400 mg/dL were evaluated for serum IgG, IgM, IgA, along with pre/post vaccine IgG titers to diphtheria, tetanus, and Streptococcus pneumoniae. Patients with evidence of humoral dysfunction were treated with SCIG with Hizentra every 7±2 days for 24 weeks.

Results: Fifteen patients enrolled with median IgG = 782 mg/dL [IQR: 570 to 827], and 6/15 (40%) responded to vaccination with Td, while 5/15 (33%) responded to vaccination with PPV23. 14/15 (93.3%) demonstrated humoral immunodeficiency as evidenced by suboptimal vaccine responses, and were treated with SCIG. In patients treated with SCIG, serum IgG increased from 670 mg/dL [IQR: 565 to 819] to 1054 mg/dL [IQR: 1040 to 1166] after 24 weeks (95% CI: 271-540). For streptococcus pneumoniae, the median protective serotypes at baseline was 8 [IQR: 4 to 9] and increased to 17 [IQR: 17 to 19] after 24 weeks (95% CI: 6.93-13.72). Non-neutropenic infections (NNI) decreased from 14 to 5 during treatment with SCIG.

Conclusions: Patients with CLL demonstrate humoral immunodeficiency despite IgG > 400 mg/dL. For these patients, SCIG is well tolerated and efficacious in improving serum IgG, specific IgG to streptococcus pneumoniae, and may decrease reliance on antibiotics for the treatment of NNIs.

Clinical trials registration: NCT03730129.

Conflict of interest statement

The authors have read the journal’s policy and have the following competing interests: CSL Behring provided support for this study in the form of an investigator-initiated grant awarded to SSM. SSM is on the speaker’s bureau for CSL Behring, Genentech, Regeneron, and AstraZeneca. AR is on the speaker’s bureau for Regeneron. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Figures

Fig 1. Study schematic.
Fig 1. Study schematic.
Fig 2. Serum IgG levels.
Fig 2. Serum IgG levels.
Fig 3. Number of protective serotypes for…
Fig 3. Number of protective serotypes for streptococcus pneumonia.
Fig 4. NNI prior to, during subq…
Fig 4. NNI prior to, during subq IgR, and after subq IgR.
NNI: non-neutropenic infection, subq: subcutaneous, IgR: immunoglobulin replacement.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer Statistics 2019. Cancer Journal for Clinicians 2019; 69(1): 7–34.
    1. Twomey JJ, Houston MB. Infections complicating multiple myeloma and chronic lymphocytic leukemia. Arch Int Med 1973; 132: 562–565.
    1. Morra E, Nosari A, Montillo M. Infectious complications in chronic lymphocytic leukemia. Hematological Cell Therapies 1999; 41: 145–151.
    1. Dhalla F, Lucas M, Schuh A, Bhole M, Jain R, Patel SY, et al.. Antibody deficiency secondary to chronic lymphocytic leukemia: Should patients be treated with prophylactic replacement immunoglobulin? Journal of Clinical Immunology 2014; 34(3): 277–282. doi: 10.1007/s10875-014-9995-5
    1. Sampalo A, Navas G, Medina F, Segundo C, Cámara C, Brieva JA. Chronic lymphocytic leukemia B cells inhibit spontaneous Ig production by autologous bone marrow cells: role of CD95-CD95L interaction. Blood 2000; 96(9): 3168–3174.
    1. Oscier D, Dearden C, Eren E, Fegan C, Follows G, Hillmen P, et al.. Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia. British Journal of Haematology 2012; 159(5): 541–564. doi: 10.1111/bjh.12067
    1. Gale RP, Chapel HM, Bunch C, Rai KR, Foon K, Courter SG, et al.. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia, Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. New England Journal of Medicine 1988; 319: 902–907.
    1. Jurlander J, Geisler CH, Hansen MM. Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low dose intravenous gammaglobulin. European Journal of Haematology 1994; 53: 114–118. doi: 10.1111/j.1600-0609.1994.tb01874.x
    1. Chapel H, Dicato M, Gamm H, Brennan V, Ries F, Bunch C, et al.. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. British Journal of Haematology 1994; 88: 209–212. doi: 10.1111/j.1365-2141.1994.tb05002.x
    1. Sklenar I, Schiffman G, Jonsson V, Verhoef G, Birgens H, Boogaerts M, et al.. Effect of various doses of intravenous polyclonal IgG on in vivo levels of 12 pneumococcal antibodies in patients with chronic lymphocytic leukaemia and multiple myeloma. Oncology 1993; 50: 466–477. doi: 10.1159/000227231
    1. Griffiths H, Brennan V, Lea J, Bunch C, Lee M, Chapel H. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood 1989; 73: 366–368.
    1. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinemia. Clinical Laboratory Haematology 1995; 17: 75–80. doi: 10.1111/j.1365-2257.1995.tb00322.x
    1. Molica S, Musto P, Chiurazzi F, Specchia G, Brugiatelli M, Cicoira L, et al.. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 1996; 81: 121–126.
    1. Na I, Buckland M, Agostini C, Edgar JD, Friman V, Michallet M, et al.. Current clinical practice and challenges in the management of secondary immunodeficiency in hematologic malignancies. European Journal of Hematology 2019; 102: 447–456.
    1. Patel SY, Carbone J, Jolles S. The expanding field of secondary antibody deficiency: causes, diagnosis, and management. Frontiers in Immunology 2019; 10(33): 1–22.
    1. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpiberg O. Immunoglobulin prophylaxis in hematologic malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2008. Oct 8(4): CD006501.
    1. Lachance S, Christofides AL, Lee JK, Sehn LH, Ritchie BC, Shustik C, et al.. A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia. Cur Onc 2016; 23(1): 42–51. doi: 10.3747/co.23.2810
    1. Ueda M, Berger M, Gale RP, Lazarus HM. Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation. Blood Reviews 2018; 32(2): 106–115. doi: 10.1016/j.blre.2017.09.003
    1. Sanchez-Ramon S, Dhalla F, Chapel H. Challenges in the role of gammaglobulin replacement therapy and vaccination strategies for hematological malignancy. Frontiers in Immunology 2016; (7)317: 1–11. doi: 10.3389/fimmu.2016.00317
    1. Friman V, Winqvist O, Blimark C, Langerbeins P, Chapel H, Dhalla F. Secondary immunodeficiency in lymphoproliferative malignancies. Hematol Onocol 2016; 34(3): 121–132. doi: 10.1002/hon.2323
    1. Gale RP, Chapel H, Bunch C, Rai KR, Foon K, Courter SG, et al.. Intravenous immunoglobulin for prevention of infection in chronic lymphocytic leukemia. NEJM 1998; 319(14): 902–907.
    1. Looney RJ, Huggins J. Use of immunoglobulin G (IVIG). Best Prac and Res Clin Haematol 2006; 19(1): 3–25.
    1. Berger M. Adverse effects of IgG therapy. J Allergy Clin Imunol Pract 2013; 1(6): 558–566. doi: 10.1016/j.jaip.2013.09.012
    1. Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. Biodrugs 2007; 21(2): 105–116. doi: 10.2165/00063030-200721020-00005
    1. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs 2013; 73(12): 1307–1319. doi: 10.1007/s40265-013-0094-3
    1. Compagno N, Cinetto F, Semenzato G, Agostini C. Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single center experience in 61 patients. Haematologica 2014; 99(6): 1101–1106. doi: 10.3324/haematol.2013.101261
    1. Orange JS, Ballow M, Stiehm ER, Ballas ZK, Chinen J, La Morena MD, et al.. Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the basic and clinical immunology interest section of the american academy of allergy, asthma & immunology. J Allergy Clin Immunol. 2012;130(3 Suppl):1–24.
    1. Visentin A, Compagno N, Cinetto F, Imbergamo S, Zambello R, Piazza F, et al.. Clinical profile associated with infections in patients with chronic lymphocytic leukemia. Protective role of immunoglobulin replacement therapy. Haematologica 2015; 100: e515–518. doi: 10.3324/haematol.2015.126763
    1. Griffiths H. Lea J. Bunch C, Lee M, Chapel H. Predictors of infection in chronic lymphocytic leukemia (CLL). Clinical Experimental Immunology 1992; 89: 374–377. doi: 10.1111/j.1365-2249.1992.tb06965.x
    1. Martin W, Abraham R, Shanafelt T, Clark RJ, Bone N, Geyer SM, et al.. Serum-free light chain—a new biomarker for patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Translational Research 2007; 149: 231–235. doi: 10.1016/j.trsl.2006.11.001
    1. Bernstein ZP, Fitzpatrick JE, O’Donnell A, Han T, Foon KA, Bhargava A. Clinical significance of monoclonal proteins in chronic lymphocytic leukemia. Leukemia 1992; 6(12): 1243–1245.
    1. Deegan MJ, Abraham JP, Sawdyk M, Van Slyck EJ. High incidence of monoclonal proteins in the serum and urine of chronic lymphocytic leukemia patients. Blood 1984; 64(6): 1207–1211.
    1. Svensson T, Kättström M, Hammarlund Y, Roth D, Andersson PO, Svensson M, et al.. Pneumococcal conjugate vaccine triggers a better immune response than pneumococcal polysaccharide vaccine in patients with chronic lymphocytic leukemia A randomized study by the Swedish CLL group. Vaccine 2018; 36(25): 3701–3707. doi: 10.1016/j.vaccine.2018.05.012
    1. Sinisalo M, Aittoniemi J, Oivanen P, Käyhty H, Olander RM, Vilpo J. Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia. British Journal of Haematology 2001; 114(1): 107–110. doi: 10.1046/j.1365-2141.2001.02882.x
    1. Hartkamp A, Mulder AH, Rijkers GT, van Velzen-Blad H, Biesma DH. Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia. Vaccine 2001; 19(13–14): 1671–1677. doi: 10.1016/s0264-410x(00)00409-6
    1. Mustafa SS, Jamshed S, Ramsey A. Humoral immunodeficiency in patients with chronic lymphocytic leukemia. Abstract. ACAAI Annual Meeting 2019.
    1. Wadhwa PD, Morrison VA. Infectious complication of chronic lymphocytic leukemia. Seminars in Oncology 2006; 33(2): 240–249. doi: 10.1053/j.seminoncol.2005.12.013

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