Lymphocytes are a type of white blood cell that defend the body against infections and play a vital role in the body’s immune response. Lymphocyte count is a frequently used prognostic indicator in lymphoid cancers.

Previous research has shown that immune system may be linked to the development of MDS (see related Beacon article).

Currently, prognoses for MDS are determined using the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS).  Disease progression and survival is predicted in IPSS and WPSS by blood counts, transfusion-dependence, genetic structures, and percentage of blasts in the bone marrow. 

Researchers had previously shown that low lymphocyte count predicts poor prognoses in MDS patients with the chromosomal abnormality del-5q.

In this study, they investigated if lymphocyte count could also be used to predict outcome in MDS patients without the chromosomal abnormality.

The researchers evaluated records of 503 untreated MDS patient who were diagnosed between 1996 and 2007 at the Mayo Clinic.   The study analyzed the relationship between the initial lymphocyte count taken at diagnosis and overall survival time.  Patients were grouped as having lymphocyte levels greater or less than 1.2 x 10⁹/L, the group’s median count. 

At median follow-up of 15.5 months, 41 percent of the patients who had a lymphocyte count greater than 1.2 x 10⁹/L were still living, compared to 29 percent of patients with counts lower than 1.2 x 10⁹/L.  Researchers concluded that patients with the higher lymphocyte counts at diagnosis had longer overall survival. 

The researchers pointed out that this was the first time that a lymphocyte count at diagnosis had been determined as a reliable predictor for survival in patients without the del-5q mutation.  . 

The researchers suggested lymphocyte count be used as a complementary prognosis tool to IPSS and WPSS.  A complete blood count, which includes a lymphocyte count, is part of normal diagnosis and is an inexpensive and universally available test. “The absolute lymphocyte count is an easily obtained blood parameter that may offer some additional prognostic information that is independent of the IPSS”, said Dr. David Steensma, one of the study authors.

The researchers recommended further studies investigate the specific role of the immune system in MDS, as well as the effects of available treatments on patient immune systems.  “If there were a way of re-awakening the immune system to attack malignant cells it could have quite a profound effect on how we treat MDS,” said Dr. David Steensma.

Studies have yet to find the exact reason why individuals have lower levels of lymphocytes than others.  The main potential reasons include stem cell defects that disrupt normal blood cell development or other immune system abnormalities.

According to Dr. Shernan Holtan, one of the study authors, the biological importance of lymphocytes and the immune system in the development of MDS will continue to be a research topic of great interest. 

“Cancer research has, in general, predominantly focused on the tumor.  I believe that understanding the [patient] response to cancer is every bit as valuable.  Research into factors [within the patient] responsible for disease progression and survival is really an unmet need in myeloid malignancies,” said Dr. Holtan.

For more information, please see  the study in the American Journal of Hematology (abstract).

Her presentation on May 7, called “Controlling the ‘Fate’ of T-Cells in MDS,” focused on natural killer T-cells, white blood cells that are the immune system’s first non-specific defense against foreign pathogens and defective cells. Natural killer cells are normally functional in low-risk MDS patients, but they may become exhausted with time and lose their ability to suppress cancer cells. As a result, numbers of abnormal leukemic cells may increase, allowing MDS to progress to Acute Myeloid Leukemia (AML). Her talk highlighted research about why T-cells lose their ability to suppress cancer cells, and increasing evidence that receptors that activate them may play a role in their fate. The immune system seems to be linked to MDS through this research, as reduced natural killer function is associated with higher-risk MDS.

Dr. Burnette’s team is also exploring other aspects of immunology that are important in MDS, such as specific gene sequences that have been found to be linked to patient responses to treatments. Corresponding gene markers are being developed to predict responses and possible underlying autoimmune disorders. Such markers can become an important part of distinguishing MDS from other possible diseases and ensuring that patients receive the most appropriate therapy as soon as possible. Studies have shown that MDS patients with autoimmune diagnoses have better responses to immunosuppressive drugs than only MDS-specific therapies. To date, the National Heart Blood and Lung Institute (NHLBI) at the National Institutes of Health (NIH) has shown that younger patients with lower-risk MDS and the HLA-DR15 gene sequence (genotype) respond most favorably to immunosuppressive drugs.

Patients who need to address compound autoimmune-MDS disorders will benefit from establishment of gene biomarkers. Identification of genotypes, such as HLA-DR15, can increase the rate of successful MDS treatments by specifying patients who will have good responses to immunosuppressive therapy.

“If these markers are confirmed to be predictive for response to immunosuppressive therapy in an independent study, then patients with the biomarkers will be placed on immunosuppressive drugs as a first line of therapy,” says Epling-Burnette.

As research in immunopathology clarifies the relationship between autoimmune disorders and MDS, combination therapies can become more individualized.

“We are working on better predictive biomarkers to indicate which patients have autoimmunity so that immunosuppressive therapy can be given to the right patient,” says Epling-Burnette. “Since the currently available immunosuppressive therapies work non-specifically, we hope to develop novel treatment modalities based on specific immune abnormalities in MDS.”

A video of her interview following her presentation can be viewed at the MDS Foundation International Symposium Web site.