Unfolding a CLL mystery

[Guest guest]

Blood, 16 July 2009, Vol. 114, No. 3, pp. 498.

Unfolding a CLL mystery

Emili Montserrat

UNIVERSITY OF BARCELONA

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.

Footnotes

Conflict-of-interest disclosure: The author declares no competing financial

interests.

REFERENCES

1.. Del Giudice I, Chiaretti S, Tavolaro S, et al. Spontaneous regression of

chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood.

2009;114:638-646.[Abstract/Free Full Text]

2.. Gaylor H, Glowes G. On the spontaneous cure of cancer. Surg Gynecol

Obstet. 1906;2:633-658.

3.. Ribera JM, Viñolas N, Urbano-Ispizua A, et al. " Spontaneous complete

remissions in chronic lymphocytic leukemia: report of three cases and review of

the literature. Blood Cells. 1987;12:471-479.[Medline] [Order article via

Infotrieve]

4.. Papac RJ. Spontaneous regression of cancer. Cancer Treat Rev.

1996;22:395-423.[CrossRef][Medline] [Order article via Infotrieve]

5.. R, Ribeiro I, Shepherd P, et al. Spontaneous clinical regression in

chronic lymphocytic leukaemia. Br J Haematol. 2002;116:341-345.[Medline] [Order

article via Infotrieve]

----------

No virus found in this outgoing message.

Checked by AVG - www.avg.com

Version: 8.5.375 / Virus Database: 270.13.18/2243 - Release Date: 07/17/09

06:08:00