**9. Future directions**

*Advances in Hematologic Malignancies*

for suspected patients with RT.

**8.1 CLL and hypogammaglobulinemia**

**(AIHA)**

regimens as the standard therapy to treat RT. Fit patients who achieve a complete response or good partial response achieve benefit from a post induction strategy involving stem cell transplant [72]. Novel combinations, PDL-1 blockade and CAR-T or bispecific antibodies are being currently investigated as potential treatment options [72]. **Figure 3** below shows a suggested treatment approach algorithm

**8. Hypogammaglobulinemia and autoimmune hemolytic anemia** 

Hypogammaglobulinemia is the most predominant inherent immune defect in CLL patients, with subtypes IgG3 and IgG4 particularly affected.

aspect of IVIG therapy is that it replaces neither IgM nor IgA.

CLL is frequently associated with autoimmune phenomena, the most common being autoimmune hemolytic anemia (AIHA) [75]. Up to 33% of CLL cases have a positive direct antiglobulin test (DAT) during the course of disease, but overt AIHA occurs much less frequently. In a report of 1203 patients with CLL consecutive cases reported from a single institution, 52 (4.3%) cases of AIHA were observed, 19 at the time of diagnosis [76]. The prevalence of AIHA in patients with CLL have been reported in the range of 4–10%. It increases with disease stage. The autoantibodies that cause AIHA can be produced by nonmalignant B cells or, less commonly, by the malignant CLL clone itself [77, 78]. In practice, AIHA may occur in patients with no other requirement for treatment, or in patients in whom chemotherapy treatment is imminent or already started. Factors associated with an increased risk of development of AIHA at diagnosis included a high white blood count, older age, and male sex. AIHA alone was not itself associated with poor prognosis. The diagnosis of

Hypogammaglobulinemia becomes more pronounced with longer disease duration and advanced-stage disease. There is generally no reversal in this defect, even with response to therapy. However, in one report, ibrutinib therapy resulted in partial reconstitution of humoral immunity, with an increase in IgA levels [73]. The most common site of infection in CLL patients is the respiratory tract, which may be related to serum IgA and IgG4 deficiencies and possibly to mucosal immune defects. The majority of patients with CLL will develop hypogammaglobulinemia at some point in the course of their disease. The use of prophylactic intravenous immunoglobulin (IVIG) to restore IgG levels is controversial. For most patients with CLL, prophylactic IVIG is **not** recommended. For patients with CLL who have had recurrent infections requiring intravenous (IV) antibiotics or hospitalization and who also have a serum IgG <500 mg/dL, it is reasonable to administer IVIG. The usual dose is 200–400 mg/kg by IV infusion, given at three- to four-week intervals. The goal is to maintain the trough serum IgG in treated patients above 500–700 mg/dL as a general guideline. If there is a substantial decrease in the incidence of infections, treatment at gradually extended intervals may be considered. There is no good endpoint for when such therapy can be discontinued. The randomized trials of prophylactic IVIG found that patients who receive IVIG have a decreased incidence of minor and moderate, but not major, bacterial infections. However, IVIG does not appear to increase quality of life or survival [74]. Potential toxicities related to IVIG include anaphylaxis, fever, chills, "flu-like" symptoms, and headache. Another important

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**8.2 CLL and AIHA**

In summary, there has been a significant change in how we manage patients in CLL over the last 5 years. We have shifted away from chemoimmunotherapy towards novel agents such as BTK, PIK3, and BCL-2 inhibitors, which are not only more efficacious but are also safer and better tolerated. New prognostic models are being developed, and it appears that MRD directed therapy will become the norm in the future. Many clinical trials are looking at various combinations of novel therapies, with a defined period of treatment based on MRD analysis, to enable patients to have a period of treatment-free remission instead of continuous therapy.
