Stage C or not stage C…?

In this issue of Blood, Moreno and colleagues report that autoimmune cytopenias in CLL are associated with poor prognostic markers, but not with the poor survival expected for patients with cytopenias due to bone marrow infiltration.¹ 

Since the 1970s, clinicians treating patients with chronic lymphocytic leukemia (CLL) have relied on a staging system that defines the poorest risk disease as that characterized by the presence of anemia, thrombocytopenia, or both (Rai stages III and IV; Binet stage C).^2,3  These staging systems have been endorsed in the recent guidelines for the diagnosis and treatment of CLL produced by the International Workshop on CLL,⁴  and remain standard practice worldwide. CLL patients with Binet stage C or Rai III/IV disease have shown consistently poorer response to treatment and shorter overall survival in clinical trials.⁵  In neither staging system is the origin of the cytopenia specified. In their article, Moreno et al have redefined the advanced clinical stage (Binet stage C) as “immune” or “infiltrative” based on the cause of the anemia or thrombocytopenia. In their series of 960 patients with CLL, those with advanced clinical stage due to an immune mechanism (n = 19) had significantly better survival (median 7.4 years vs 3.7 years) than those in whom the advanced stage was due to heavy bone marrow infiltration (n = 54). Patients with stage C “immune” were more likely to revert to normal counts after therapy, usually only with steroids, than those with stage C “infiltrative,” explaining in part their superior outcome. However, patients with stage C “immune” still had shorter survival compared with uncomplicated early stage A patients, suggesting that autoimmune cytopenias may be a marker of a more aggressive CLL (see figure). This is likely, given the association with other poor prognostic variables such as short lymphocyte doubling time and high B2M, ZAP70⁺, CD38⁺, and unmutated IGHV genes, as shown in this and other studies.⁶ 

Despite the relatively common occurrence of autoimmune cytopenias in patients with CLL (7% in the report by Moreno et al¹ ), the pathogenesis, treatment, and clinical outcomes of this complication are still poorly understood. Whether autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP) are associated with poorer patient outcomes remains controversial and Moreno et al discuss the conflicting reports, mostly from single institution retrospective studies. A prospective randomized controlled trial of previously untreated CLL patients showed that, in multivariate analysis, development of AIHA was associated with poorer 5-year survival.⁷  This was in a group of patients selected by their requirement for therapy; the poorer outcome may have been partly related to the fact that these patients received less CLL therapy because it was discontinued after development of AIHA. Some of the conflicting results may also be explained by the specific patient cohorts studied and the distribution between early stage A patients who have a very favorable outcome and in whom an autoimmune complication may have less impact on survival and those who develop autoimmune cytopenias in association with disease progression.

Another long-standing issue in relation to autoimmune cytopenias is whether exposure to certain treatments, notably purine analogs, poses a greater risk for development of this complication. Moreno et al found that the incidence of AIHA was slightly lower after fludarabine-based therapy (4%) than after chlorambucil treatment (5%), in agreement with other studies.⁷  There is thus no increased risk for a patient of developing hemolysis on fludarabine-combination therapy and no contraindication to its use in patients who have a history of autoimmune complications. However, not all patients presenting with autoimmune cytopenias will necessarily require treatment for the underlying CLL. After successful treatment with corticosteroids patients with stage C immune may be “down-staged” to Binet stage A and thus no longer fulfill the criteria for initiation of treatment for CLL. This makes a clear understanding of the origin of cytopenia in a patient with CLL even more important before a decision about treatment is made.

The definition of stage C immune therefore provides us with a new clinical prognostic group in CLL that needs to be distinguished from stage C infiltrative to appropriately guide treatment decisions and inform prognosis. Indeed, should we call this stage C at all? That is the question.