PRESIDENT'S CORNER: Opinions & Reports from Dr. Michael Keating
Highlights from iwCLL (October 2009)
The 13th international workshop on chronic lymphocytic leukemia (iwCLL) was
held in Barcelona, Spain from Oct 16-18, 2009. Professor Emili Montserrat commented
that 60 individuals attended the iwCLL meeting held in Barcelona 12 years ago.
This year, 1,200 doctors and researchers attended this conference. This quite
clearly demonstrates the tremendous increase in energy which has occurred in the
CLL research arena.
The topics for the sessions were divided into epidemiology (including familial
CLL), diagnosis, molecular biology, cellular biology, prognostic factors, phase
III treatments, stem cell transplantation, immune therapy and novel treatment
The group from the United Kingdom, headed by Richard Houlston, has identified
a number of areas of interest for identifying genes that are involved with familial
CLL. This research suggests susceptibility to CLL through genetic association.
On the other hand, research from Brazilian investigators suggested that the familial
linkage might not be as relevant in predicting the occurrence of CLL. Monocloncal
B-cell lymphocytosis (MBL), a potential precursor to CLL, was found to be similarly
prevalent in first degree relatives of patients with sporadic CLL as well as familial
CLL. So, the question arises as to whether there are specific familial CLL genes
or just susceptibly genes which are present not only in familial cases but also
in non-familial or sporadic cases of CLL.
The diagnosis section was dominated by discussions relating to MBL. In this
situation, a very small population of CLL cells can be identified by sophisticated
flow cytometry. This occurs in up to 10% of males over the age of 60 and approximately
5% in women of the same age group. It is now clear that these patients have a
very low risk of progressing to CLL requiring treatment even though the family
of cells is present. It can be considered a benign or pre-malignant situation,
much the same as polyps in the colon are related to colorectal cancer.
The molecular biology section was probably the most novel area. It is clear
that we are honing in on genes which regulate the progression of CLL. The C MYC
gene, identified by Dr. Carlo Croce many years ago, was found to be regulated
by B-cell stimulating molecules (B-cell activating factor or BAFF). It is now
becoming clear that the genes in CLL are fine-tuned by a process called methylation
(methyl groups added to DNA to inactivate the genes). There are emerging drugs
in CLL that change the methylation pattern which will affect the activity of the
genetic material. We can demonstrate that the chromosome changes which have been
detected by conventional cytogenetics or fluorescence in situ hybridization (FISH)
technology are accompanied by many other genetic changes detected by single nucleotide
polymorphism (SNP) studies.
The cellular biology session was also rich in new information. Evidence was
presented indicating that strangely named molecules such as HS1, PHLPP1, Interleukin
17, and CCL3 chemokine are all involved in the regulation of CLL. As we enhance
our understanding of molecular and cellular biology, we will identify key pathways
which are associated with activity of the CLL and the likelihood of progression.
The study and identification of prognostic factors is exploding. More and more
characteristics are being found which predict those patients who are likely to
progress. We are almost to the point where there is a "prognostic factor
of the month." One of the key prognostic factors is p53 which is an important
protein that allows cells to die once they are attacked by treatments which affect
DNA. The loss of the p53 gene, as detected by FISH, is important in the survival
of CLL cells. Mutations in the gene are key to predicting whether the disease
will behave in an aggressive fashion and in predicting a patient's response to
Immune Therapy and Immune Disturbance
The immune disturbance section focused largely on the abnormal regulation of
the immune T-lymphocytes in CLL. This has been very well defined in mouse models
of CLL that mimic the human experience. It is almost certain that these T-cell
abnormalities also have a major impact on whether the patients develop "rogue"
antibodies which attack normal blood cells.
During the Immunotherapy section, a variety of strategies were presented. The
Northwestern Group (Chicago) looked at a combination of antibodies to affect an
immune response. This follows upon an earlier study conducted at UT MD Anderson
Cancer Center. Dr. Tadeusz Robak presented on the recently FDA-approved antibody
ofatumumab (Arzerra). It is clear that this is a major new drug giving reason
for optimism for improved response to antibody therapy. A new concept, chimeric
antigen receptors, was also presented. Antibody-like molecules are identified
which attach specifically to proteins on the surface of CLL cells and also to
the immune cells. Essentially, this allows the immune cells to selectively kill
any identified CLL cells.
Phase III Treatment
During the treatment session (for later stage protocols), the FCR regimen was
highlighted for its demonstrated efficacy. In a separate study, increased toxicity
was observed when rituximab was replaced with alemtuzumab. The CLL physician community
has discussed at length whether CT scans are needed in the decision making process.
The German CLL Study Group showed that CT scans were influential in the treatment
decisions in less than 5% of the patients, specifically whether to treat, not
treat or change treatment.
Stem Cell Transplant
Stem cell transplant is emerging as a major potential for the cure of CLL.
It is clear that doing transplants with a patients own blood stem cell (autologous)
does not result in a cure for CLL patients. On the other hand, stem cell transplants
from relatives, unrelated donors, or cord blood can be associated with long-term
Novel Treatment Approaches
A number of new agents were presented including DMAG which attacks ZAP-70,
an important enzyme associated with proliferation or growth in CLL. A new molecule,
CAL101 is a potent inhibitor of the phosphatidylinositol-3 kinase (PI-3 kinase).
This oral medication has shown a clinical response in approximately half of the
patients. While it is unlikely that CAL101 will be a major drug by itself, it
has the potential of being combined with other established regimens.
A PARP inhibitor was shown to play an important role in controlling cell death
of CLL cells. PARPs have a major role in DNA repair mechanisms, including the
repair pathway for the tumor-suppressor proteins. Mutations in the proteins disrupt
normal repair processes and allow emergence of a tumor. PARP inhibitors, such
as the drug AZD2881, have been shown in animals to suppress the growth of CLL
cells. This agent has already shown activity in breast cancer patients and will
shortly be applied in the clinic in CLL.
There was tremendous energy at the iwCLL meeting. The quality of the abstracts
was highly significant. Abstracts that were presented during the poster sessions
generated vibrant interaction between the presenters and attendees. We are now
focusing our attention to the 14th iwCLL workshop which will be held in Houston
in 2011. At the 2011 meeting, I predict that we will hear even more about the
use of immunotherapy to kill off leukemic cells. Our challenge is to go from having
effective treatments, giving high complete remission rates, very long remission
durations and survival advantage to the next level where we can effectively cure
the disease. This is likely to occur from immunology with education of the immune
system to kill off the leukemic cells. This is a fertile area of research and
I am sure it will be very prominent at the next iwCLL meeting in 2011.