Unfolding a CLL mystery

In this issue, Del Giudice and colleagues report on 9 patients with CLL who had a spontaneous regression of their tumors, providing new insights into this intriguing phenomenon.¹ 

It has been known since the 1990s, mainly through anecdotal cases, that cancer can spontaneously regress (ie, complete or partial regression, usually transient, of the disease with no therapeutic intervention).²  However, this is a rare event with an estimated incidence of 1% in chronic lymphocytic leukemia (CLL). Although described in virtually all types of cancer, this phenomenon is most frequently seen in tumors considered to be especially sensitive to immunoregulation.

The mechanisms involved in spontaneous regression of CLL are poorly characterized. Understanding the mechanisms leading to spontaneous regression would provide important biologic clues, and identify potential new treatment strategies. Which patients are most likely to undergo spontaneous tumor regression? What are the mechanisms inducing regression? What triggers it? Why is this usually a transient phenomenon?

Although spontaneous regressions of CLL have been observed in patients with both high- and low-tumor burdens, it is most frequently seen in subjects with low tumor mass. This group of patients is more commonly left untreated. In fact, all 9 patients reported by Del Giudice et al had low-risk disease and an extremely indolent course. No correlation was found with other parameters such as age, gender, or the duration of the disease and the possibility of spontaneous regression.^3-5 

In keeping with the low-tumor burden and indolent behavior, all 9 cases reported by Del Giudice et al were negative for CD38 and ZAP-70. In 7 evaluable cases, IGVH genes were mutated, meaning that these patients had a low-risk disease both clinically and biologically. The finding of a particular usage of the VH3-30 and Vk4-1 genes leads the authors to speculate that these genes could be markers of an extremely indolent disease. Unfortunately, no information on cytogenetics is given. It would be important to know whether spontaneous regressions can be observed in patients with poor risk genetic aberrations such as 17p- or 11q- or whether they mainly occur in patients with no cytogenetic abnormalities or low-risk genetic alterations. Importantly, the authors also performed microarray analysis, which revealed a distinctive genomic profile with an overrepresentation of BCR-related genes, pointing to the importance of BCR signaling in spontaneous CLL regression.

In many instances, as in the cases presented here, no events preceding spontaneous regression were identified. These cases can therefore be considered as truly spontaneous (ie, occurring without apparent external influence) tumor regressions. In other instances, infections (either viral or bacterial), small pox vaccination, or the appearance of a solid tumor precede the remission. It is often claimed that tumor regression occurs via immune-mediated mechanisms, cytokines liberation, or T-cell activation, which is appealing, but the evidence for this is weak.

Interestingly, for the cases presented, the leukemia burden of all but one patient remained low, with a median follow-up of 11 years at the time of publication. Unfortunately, in most instances, tumor regression is not complete (as in the cases reported here) and is transient. Again, understanding why tumors “escape from control” will be important from a clinical standpoint.

Although spontaneous regression in CLL is rare, clinicians should be aware of this phenomenon. As no single center will have many cases of this infrequent event, pooling of clinical data and biological samples of patients experiencing spontaneous regression and making them accessible to a wide range of researchers would certainly make sense. In this way, future broader studies including immunological, cytogenetic, and molecular analyses would continue to unfold the intriguing phenomenon of spontaneous regressions in CLL.