Thursday, May 08, 2008

The immunodeficiency of CLL


Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnormality is hypogammaglobulinaemia which is present in up to 85% of patients [1]. Serum immunoglobulin levels are suppressed in other lymphoid malignancies but in CLL the suppression is to a far greater degree. Profound defects of cell mediated immunity also occur though these are most obvious in patients who have been treated with purine analogues. However, even untreated patients have defects of T cell numbers and function. This review will seek to explore the extent of the immune defect in CLL, its causes, clinical significance and possible remedies.

The extent of the immune defect

Infections are the major cause of death in between a quarter and a half of patients with CLL [1]. Bacterial infection of the respiratory tract, skin or urinary tract is the commonest problem and before the use of purine analogues for treatment, the usual organisms were Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. Protection against these organisms is provided principally by antibody, but only 15% of patients with CLL have completely normal serum immunoglobulins [1]. It is likely that the only patients with CLL who do not have hypogammaglobulinaemia are those in whom it will occur in the future.

The extent of hypogammaglobulinaemia depends on the stage and duration of the disease. Older papers described serum IgA as the first immunoglobulin to be reduced followed by IgM and IgG [2], but this is by no means invariable and most patients have depression of all classes of immunoglobulin. It should be stressed that the hypogammaglobulinaemia is not confined to patients who have been treated. In one study of an untreated patient with stage B disease without a detectable paraprotein, the hypogammaglobulinaemia was so profound that over 90% of the detectable immunoglobulin in the serum was idiotypic, and thus derived from the tumour [3].

Despite the low levels of serum immunoglobulins, most patients suffer no clinical consequences from this, and in one study 65% of bacterial infections occurred with serum IgG levels below 300 mg/dL [4]. It is recommended that patients with primary immunodeficiency begin immunoglobulin replacement therapy when the serum IgG falls below this level.

The non-malignant B-cell population in CLL is not well characterized [5]. The proportion and overall number of non-malignant B cells is often significantly reduced, and clearly their function is impaired since the normal immunoglobulins are suppressed. What is not clear is whether they are directly suppressed by the tumour or indirectly as a consequence of inhibitory effects elsewhere in the immune response.

Apart from bacterial infections, patients with CLL also suffer from the reactivation of herpes viruses. Most commonly this involves herpes zoster. In one series from before the era of treatment with purine analogue, the incidence of herpes zoster was given as 28.6%, with 3.5% having recurrent attacks [1]. Particularly important is the observation that attacks of shingles frequently precede the clinical diagnosis of CLL [1], suggesting that the underlying immune defect does not depend on either hypogammaglobulinaemia or the physical overwhelming of immune organs by infiltrating tumour cells.

Recurrent attacks of herpes simplex also occur in some untreated patients. Both HSV1 and HSV2 may be involved. The recent recognition that herpes simplex is implicated in many cases of Bell’s palsy [6] may explain the association of Bell’s palsy, including recurrent attacks, in patients with CLL [1].

Treatment greatly increases the risk of the reactivation of herpes viruses. Reactivation of cytomegalovirus (CMV) is of course particularly associated with treatment with alemtuzumab, symptomatic infections occurring in 15% of patients treated in one clinical trial and asymptomatic reactivation in more than half (7], but symptomatic reactivation may occur after treatment with fludarabine (D Oscier, personal communication) and asymptomatic reactivation even after treatment with chlorambucil [7].

The Epstein-Bar virus (EBV) has recently been associated with the increase in the incidence of Richter’s syndrome in patients who have been treated with fludarabine [8]

Human herpes virus 8 (HHV8) is the cause of Kaposi’s sarcoma in immunodeficient individuals. The first reported case in CLL occurred in an untreated patient [9] and the second in a patient treated with fludarabine [10]. An American SEER report noted 9 cases between 1973 and 1996 among 16,367 patients observed, a statistically significant hazard ration of 5.09 [11].

Human herpes virus 6 causes the childhood exanthem, roseola, but in adults has it has been suggested as an initiating agent in chronic fatigue syndrome and multiple sclerosis [12, 13]. Fatigue is a common symptom in CLL often dismissed by physicians yet much discussed on patient websites. Multiple sclerosis has been reported as occasionally coexisting with CLL [1]. HHV6 has also been associated with giant cell hepatitis in adults [14] and I have recently been consulted by a patient with CLL and obscure giant cell hepatitis.

A systematic study of herpes viral copy number in haematological diseases has been carried out using real-time quantitative polymerase chain reaction (RQ-PCR). Occasional patients with CLL had high copy numbers of EBV, CMV and HHV6A, but not HHV6b, HHV7 and HHV8 [15]. Although interesting, the use of leukaemic B cells as a source of DNA means that T-cell lymphotropic viruses would be missed, and no indication was given as to the stage of the patients or the degree of immunosuppression.

1. Hamblin TJ. Chronic lymphocytic leukaemia. Balliere's Clinical Haematology 1987; 1: 449 491.
2. Foa R, Catovsky D, Brozovic M, Ooyirilangkumaran T, Cherchi M, Galton DAG. Clinical staging and immunological findings in chronic lymphocytic leukaemia. Cancer 1979; 44:483-487.
3. Stevenson FK, Hamblin TJ, Stevenson GT, Tutt Al. Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med 1980; 152:1484-1496.
4. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol 1995; 17:75-80.
5. Johnston PB, Kay NE. Pathogenesis of impaired cellular immune function in CLL. In Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis and Management. Ed GB Faguet. Humana Press: Totowa, New Jersey. 2004. p 109-121.
6. Steiner I, Mattan Y, Bell's palsy and herpes viruses: to (acyclo)vir or not to (acyclo)vir? J Neurol Sci. 1999;170:19-23.
7. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23
8. Thornton PD, bellas C, Santon A. Shah G, Pocock C, Wotherspoon AC, matutes E, Catovsky D. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and Epstein-Barr virus in its pathogenesis. Leuk Res 2005; 29:389-95.
9. Contu L, Carcassi C, La Nasa G, Zurrida SM, Sirigu F, Del Giacco S, Cerimele D, Longinotti M, Pitzus F. A case of classical Kaposi's sarcoma in B-cell chronic lymphocytic leukemia (B-CLL). Tumori. 1986;72:365-74.
10. Wijermans PW, van Groningen K, van Royen EA, Bruijn JA.Kaposi's sarcoma in an HIV-negative CLL patient as the cause of thrombocytopenia. Ann Hematol. 1994;68:307-10.
11. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979-81.
12. Vojdani A, Lapp CW.Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol. 1999;21:175-202.
13. Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR.Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis. 2000;31:894-903.
14. Kuntzen T, Friedrichs N, Fischer HP, Eis-Hübinger AM, Sauerbruch T, Spengler U.Postinfantile giant cell hepatitis with autoimmune features following a human herpesvirus 6-induced adverse drug reaction. Eur J Gastroenterol Hepatol. 2005;17:1131-4.


Anonymous said...

I'd like to know your opinion of how IVIG (which is principally IgG) should be used in patients with CLL.

I have low levels of all 3 immunoglobulin types (all 3 less than 33% of lower limits of normal) and have had, perhaps, a bit more difficulty with episodes of bronchitis following URIs as well as 2 episodes of mild sinusitis during the last several years (including the 3 years prior to the diagnosis having been established), but otherwise feel fine without fatigue, etc.

I have also had an episode of Zoster about 10 years prior to diagnosis and a recurrence in the same dermatome after diagnosis, but prior to any therapy.

Shortly after completing my one recent course of therapy for CLL I developed an outbreak consistent with a herpetic skin infection which was limited to my hands and which looked most like multiple herpetic whitlows, though prompt increase in valacylovir to larger doses controlled this quite reasonably.

Thank you in advance for sharing your thoughts

Terry Hamblin said...

Be patient I'm coming to that.

Anonymous said...

IvIG has also been recommended to me. I've been lucky with this terrible disease until now; I've not had frequent infections. However, I have had two upper respiratory infections in the past five months, one pretty easy to get rid of, the latest is lingering.

I'll be interested in reading what you have to say.

Also, would the use of IvIG be helpful in the several vaccine trials that have been tried? They are often tried in late-stage patients, where the immune system is kind of shot up already.


Anonymous said...

I was just diagnosed with CMV and was diagnosed with CLL in May 2008. I am in watch and wait and with a WBC of 14K+ and steady since May. I have been plagued with fatigue and joint pain which led to the diagnosis of CMV. I am Zap 70 neg and CD38 neg. I am 13q14p deleted. What does the diagnosis of CMV mean to someone like me?

Terry Hamblin said...

Check that this is diagnosed on antigen not antibody. 80% of people have antibody to CMV, but this just means that they had an infection in the past, which was probably asymptomatic. High levels of antigen in the blood are unlikely to occur in CLL unless teh patient has had either Campath or fludarabine. Real infections need treating with gancyclovir.

Anonymous said...

I was placed on Valcyte and will check to see if it was based on Antigen as you suggested. I was told it was CMV mononucleosis if that makes a difference.

Terry Hamblin said...

Highly dubious diagnosis, but just possible. Check the antigen.

Anonymous said...

I will not see my Doctor until Wedensday to ask about antigen vs. antibody but I did get a copy of his report. It says CMV tite 269, negative 18 or less and Herpes virus 6 Titer 1:640. My Dx are fatigue secondary to CMV question herpes virus 6, supraventricular tachycardia associated with CMV infection, hpetensive vascular disease and CLL. In addition, a cold 1cm nodue in my right thyroid needs to be biopsed.

Terry Hamblin said...

Again, it is important to know whether tis is antibody, which would not be significant or antigen which might.