Protective Role Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukemia: FOCUS on Subcutaneous Immunoglobulin Formulations
Authors: Visentin Andrea , Mauro Francesca Romana , Rosati Serena , Imbergamo Silvia , Scomazzon Edoardo , Pravato Stefano , Frezzato Federica , Martini Veronica , Severin Filippo , Raggi Flavia , Foà Robin , Semenzato Gianpietro , Trentin Livio 
Published: October 2019

Abstract
INTRODUCTION. Secondary antibody deficiency is a common complication in chronic lymphocytic leukemia (CLL) that could be present at diagnosis or can be acquired during the follow-up due to CLL progression, perturbation of non-neoplastic immune system and chemoimmunotherapy. Despite new and active target therapies a significant amount of CLL patients still develops severe and life-threatening infections. Intravenous immunoglobulin (IG) (IVIG) replacement therapy (IGRT) has been proven to be an effective supportive treatment in patients with primary and secondary antibody deficiency such as CLL. Subcutaneous immunoglobulin (SCIG) is a new valid treatment option that allows patients self-administration without access to the clinic which proved to be as effective as IVIG in primary immunodeficiencies. However, the activity SCIG is CLL patients with IG defect has been little investigated.
The aim of this study was to retrospectively evaluate IG levels, infection rate and safety of patients treated with SCIG as compared to those managed with IVIG.
METHODS. Inclusion criteria were: diagnosis of CLL according to iwCLL guideline, age >18 years, received at least 1 IVIG or SCIG infusion. IGRT was started according to hospital policies in patient with severe symptomatic hypogammaglobulinemia. The physician was responsible for the choice between IGRT formulations (the first patient received SCIG since Nov 2008). IG levels (IgG, IgA and IgM) were recorded within 3 months before starting IGRT (baseline), after 6 months and within three months from the last available follow-up. Continuous variables were compared with Wilcoxon's tests while categorical variables with Fisher's exact or Chi-square tests when appropriate. Time to IGRT discontinuation was calculated from the beginning IGRT to death or discontinuation (event) or last available follow-up /(censored).
RESULTS. We gathered data from 116 CLL patients followed in 2 hematology centers who received IGRT: 63% were male, the median age at diagnosis was 58 years, 77 were at Binet A stage, 48% and 16% were unmutated IGHV and harbor TP53 abnormalities, respectively. 91% received at least one therapies, the median numbers of treatments were 3 (range 0-9) and 36% died during the follow-up due to infections in 22 cases, CLL progression in 5, Richter transformation in 6 patients and 9 other causes such as second cancers or major bleedings. Forty-nine patients received IVIG and 88 SCIG (41 the 20% formulation and 47 the 16% drugs).
Despite similar basal and +6 months IgG levels, patients treated with SCIG achieved significant higher serum IgG at last available follow-up (3.99, 5.67 and 5.4 g/L vs 3.89, 6.07 and 6.22 g/L for IVIG and SCIG, p=0.0009). Both IgA and IgM levels remained stable during replacement therapy.
While the number of grade 3-4 infections remain stable during IVIG (both 80% before and after IVIG), they decrease with SCIG (88% vs 64%, p<0.0019). Furthermore, the incidence of all and grade 3-4 infections decreased to 0.59 and 0.17, and 0.30 and 0.13 events/people/year with IVIG and SCIG, respectively. Incidences of infections was not higher in patients receiving oral inhibitors (i.e. ibrutinib, idelalisib and venetoclax).
Adverse events during SCIG infusions occurred in 11% of subjects, most commonly skin reaction and pruritus. They were mild, limited to the site of infusion and easily to manage. Bruising did not increase during concomitant treatment of SCIG and ibrutinib.
After a median duration of IGRT of 3.7 years (4.7 for IVIG and 3.1 for SCIG) 71% of subjects managed with IGEV discontinued therapy as compared to 36% of SC formulation (p<0.0001), 16% due to death in the former group as opposite to 9% of the latter. The estimated 3-year time to IGRT discontinuation were 44% vs 29% for IVIG and SCIG, respectively (p=0.2089). 29 patients shit from IVIG to SCIG, while none to opposite. We also observed that patients who shift from IVIG to SCIG were able to achieved higher IgG levels at last follow-up (median IgG 4.76 vs 6.62g/L, p<0.0001).
CONCLUSIONS. In this study we described the clinical and biological characteristics of the bigger population with CLL and secondary hypogammaglobulinemia receiving IGRT. We demonstrated that SCIG are well tolerated, non-inferior to IVIG, they also allow to reach higher IgG through levels and to decrease the incidence of severe infections even during continuous CLL therapies.

Disclosures
Visentin: janssen: Consultancy, Honoraria. Mauro:abbvie: Other: board member; janssen: Other: board member. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau. Trentin:Gilead: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Janssen: Research Funding.