Original study
Should a Positive Direct Antiglobulin Test Be Considered a Prognostic Predictor in Chronic Lymphocytic Leukemia?

https://doi.org/10.1016/j.clml.2013.02.024Get rights and content

Abstract

Background

The clinical course of patients with B-cell CLL is often complicated by autoimmune phenomena. The DAT might be positive at some time during the course of the disease in up to 35% of cases. The aim of this retrospective study was to investigate the relationship between the occurrence of a positive DAT and biological features of CLL patients.

Patients and Methods

In our institution, 146 untreated patients with CLL were studied using the DAT.

Results

According to the statistical analysis, a high level of β2-microglobulin and unmutated IgHV emerged as factors significantly related to the presence of DAT positivity. Time to first TFS was significantly shorter in DAT-positive patients. The adverse effect of a DAT positive result was maintained in terms of TFS when patients with mutated IgHV status were excluded from statistical analysis.

Conclusion

These results suggest that the DAT might provide additional prognostic information regarding patients with IgHV unmutated status.

Introduction

Immune dysregulation and autoimmune-associated phenomena are frequently observed in lymphoproliferative disorders, and in particular, are a hallmark of chronic lymphocytic leukemia (CLL).

The autotoxic manifestations are mainly directed against hematopoietic cells and the 3 autoimmune hematologic phenomena frequently reported are autoimmune hemolytic anemia (AHA), immune thrombocytopenia (ITP), or pure red blood cell aplasia. In recent studies, the proportion of patients presenting with autoimmune cytopenia at some point during the course of their disease ranges from 4.3% to 9.7%.

Among these, AHA is the most frequent autoimmune disorder described in CLL and, conversely, CLL is the most common known cause of AHA.1, 2, 3, 4, 5 It has been estimated that AHA occurs in approximately 7% of CLL patients.3 AHA is usually caused by polyclonal T–cell-dependent mechanisms that result from the loss of self-tolerance. The pathogenic antibodies responsible for approximately 90% of cases of AHA are produced by nonmalignant B cells and polyclonal high-affinity immunoglobulin (Ig)G directed against red blood cells. Although CLL cells can produce monoclonal autoantibodies that are detectable in the serum, these are rare and responsible for < 10% of cases of autoimmune cytopenia.

The occurrence of AHA is related to stage and progression and it appears to be twice as common in patients with unmutated vs. mutated IgHV genes.5, 6, 7 The prevalence and the prognostic significance of the direct antiglobulin test (DAT) has been less investigated. Duek et al8 found a positive DAT in 5.7% of CLL patients at diagnosis, and among patients with progressive disease, requiring first-line treatment, a frequency of 14% was reported in the chronic lymphocytic leukemia trial 4.5

Even if it is well known that only a minority of patients with a positive DAT will develop AHA there are no methods to predict which patients with CLL will become DAT-positive and which DAT-positive patients will develop AHA.

To better define the effect of DAT positivity in natural CLL history, we retrospectively investigated the results of this test in a cohort of untreated CLL patients followed in our institution.

Section snippets

Patients and Methods

We retrospectively analyzed DAT results in 146 untreated CLL patients. The test was performed in 38 cases in patients with progressive disease requiring treatment and in the remaining 108 cases in patients during follow-up while their disease was stable. Criteria for diagnosis and for initiating therapy in CLL patients are defined by the National Cancer Institute-Sponsored Working Group guidelines for CLL.9

The DAT was performed using the anti-IgG, -C3d; polyspecific Ortho BioVue System (Ortho

Results

The clinical and disease characteristics of the 146 patients considered in our study are reported in Table 1. Median age of the whole population at diagnosis was 65 years (range, 37-89 years); 79 (54%) were male. A positive result on DAT was found in 20 patients (14%); among them, 2 patients presented active hemolysis and 1 patient AHA preceding the CLL diagnosis. During follow-up another 5 patients developed AHA. Clinical characteristics including age, sex, and Binet stage were similar when

Discussion

CLL is frequently associated with immune disturbances. The relationship between CLL and autoimmune cytopenias, particularly AHA is well established. However, the prognostic relevance of autoimmune cytopenia occurrence in CLL patients is controversial.1, 3, 4, 5, 11

Several clinical and biological features of CLL have been associated with an increased risk of developing autoimmune cytopenia. In most studies, a correlation between advanced stage and biological prognostic factors and the risk of

Conclusion

Although the results of this study warrant further confirmation from larger series, our data suggest that DAT status might be considered a useful parameter in CLL risk assessment, providing additional prognostic information also in the group of patients showing unmutated status.

Acknowledgments

F. Ricci and M. Montillo designed the study; F. Ricci, M. Montillo, C. Colombo, E. Vismara, S. Veronese, R. Cairoli, M. Nichelatti performed the analysis and the interpretation of the data; F. Ricci and A. Tedeschi draft the article; M. Montillo and E. Morra revised the manuscript.

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