HCL Meeting 2010 Table I. Immune deficiencies associated with HCL prior to therapy.
Immune abnormality Monocytopenia
. Cause for the consistent monocytopenia still unclear and not well understood
. Monocytes are known to produce IFNa, and defects in IFN production have also been reported
Decreased numbers of dendritic cells (DCs)
Hyper-gammaglobulinemia T cell dysfunction
. Abnormal antigen presentation and defects in DC activity probably translate into an increased infection rate, mostly by intracellular pathogens
. Mostly polyclonal . Hairy cells secrete a factor inducing IgG synthesis
. Presence of oligo/monoclonal T cell populations . Defects of the beta variable region
. Increased numbers of activated T cells, mostly CD8þT cells, resulting in an inverted CD4þ/CD8þratio
CD200 . Overexpression of CD200, with immunosuppressive activity Natural killer (NK) function defects . Low levels of NK activity in the peripheral blood HCL, hairy cell leukemia; IFNa, interferon a; IgG, immunoglobulin G. [2,3] [3] [3,4]
Reference(s) [2,3]
39
[5] [6]
patients had nadir CD4þ counts of5200 mL. The duration of CD4þ lymphopenia lasted for more than 12 months, and was accompanied by a marked
decline in T cell function [7]. In vitro studies showed deterioration in T cell function, manifested by low proliferative responses, while in vivo studies evalu- ated their ability to display a delayed type hypersen- sitivity reaction to a panel of antigens, which again showed decreased responsivenes to most of the antigens used. Normal B lymphocyte numbers also decreased after therapy but recovered quicker than the T cells, and the monocytopenia and natural killer (NK) cell dysfunction, initially evident before treat- ment, reversed to within normal limits after success- ful therapy of the disease [7]. The Ohio State group [8] also performed a
prospective evaluation of the immune system in 13 patients before treatment with pentostatin and at varying times after completion of pentostatin therapy. The beneficial effects described for monocytes and NK cells were also evident for granulocytes, and neutropenia also reversed back to normal after therapy [8]. But at the same time there was no effect on immunoglobulin levels in these patients. Similarly to Urba et al. they reported a significant reduction in
the CD4 and CD8þ T cell compartment, but noted a much greater impact on the number of B cells [8]. When analyzing the T cell subpopulations it was evident that T-suppressor cells were more sensitive to pentostatin than T-helper lymphocytes. In con- trast to other studies, skin test reactivity was not affected by therapy, and after clinical follow-up of up
to 4 years, levels of immune effectors were seen to return to within normal limits. They also noted that the immunosuppressive effect was dose related [8]. Another important study with a longer clinical
follow-up was performed by Seymour et al. [9]. Here the follow-up period was 7 years, enabling them to estimate the duration of lymphopenia over a longer
period of time. For CD4þ lymphocytes, the median time to recovery to the normal range was 54 months,
and 36 months for CD8þ cells [9]. Splenectomized patients with HCL had a significantly faster recovery
of their CD4þ and CD8þ lymphocytes than non- splenectomized individuals with HCL. Although the
immunosuppression was durable, the CD4þ and CD8þ subsets recovered slowly without undue clinical manifestations, and there was no evidence of late opportunistic infections [9].
Immune suppression induced by cladribine Seymour et al. [10] also reported a study aimed at assessing the severity, duration, and clinical sequel of cladribine therapy, which included 40 patients who received cladribine at a dose of 4 mg/m2 by continuous infusion for 7 days. Most of the patients started with normal baseline levels of CD4 cells, and
a mild decrease in CD8þ numbers. After treatment there was profound and prolonged suppression
of CD4þ cell counts, with an average number of 139/mL (normal: 365–2400/mL) CD4 cells and a median recovery of 40 months, reaching low limits of normal. In contrast to CD4 cells, CD8þ
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