Prognosis Prediction for CLL

Chronic lymphocytic leukemia (CLL) is one of the great medical mysteries of our time. While there are many incurable cancers, many patients with CLL live a long time and early treatment isn’t always best.

If chronic lymphocytic leukemia patients with a good or poor prognosis could be identified at the time of diagnosis, physicians would have better possibilities to adjust their therapeutic and follow-up strategies.

Now researchers at Uppsala University, together with international colleagues, have discovered a new correlation between specific molecular features of the disease and subgroups of patients with different prognosis.

The results have been published in the journal Lancet Haematology.

Chronic lymphocytic leukemia (CLL) is an incurable tumor disease that can progress very differently in different patients. Some patients require therapy relatively soon after diagnosis whereas others can live for a long time with their disease, even without treatment. Prognosis depends on general health, the stage of the disease, spread of the lymphocytes throughout the bone marrow, response to treatment, change (or type of change) in the DNA and the CLL’s possible progression to lymphoma or prolymphocytic leukemia.

Thus, it is important to identify features of the disease that can be associated with a better or poorer prognosis. Ideally, these features would be present at diagnosis and remain stable throughout the evolution of the disease.

In the present study, researchers from Uppsala University have collaborated with international research groups and analyzed samples from more than 8,500 CLL patients. These were classified into subsets based on the expression of very similar B-cell receptors in the white blood cells that grow uncontrolled in CLL. When they studied the disease course for patients in the different subsets they found a clear correlation.

“It was evident that patients within a specific subset followed the same clinical course and that this was different from patients in other subsets,” explained Panagiotis Baliakas, MD in the Department of Immunology, Genetics and Pathology at Uppsala University, and one of the coordinators of the study. “For instance, patients in subset #2 showed an aggressive disease course, with an average time to first treatment of only 2 years. On the other hand, subset #4 patients had an indolent disease that did not require treatment until after, on average, 11 years.”

Andre Goy, MD, chief of John Theurer Cancer Center at Hackensack University Medical Center’s division of lymphoma, is encouraged by both this particular study and the broader industry trend of molecular studies with split entities.

“This study looked at different subsets of CLL with similar markers,” he said. “It’s interesting that when you look at some less frequent subsets, they don’t share the same abnormalities. If you have subset that could respond to worse outcome, it doesn’t have the chromosome 17p deletion that’s typical of CLL. Subset trumps other abnormalities. When you look at new classification, it’s still early. If you have subsets with similarities, it makes sense. When you look deeper at B cell receptors downstream, there is data showing correspondence to same antigenic simulation among different patients. This is why similarity of surface receptors translates into similar better or worse outcomes. It reflects differences in the disease.”

Anti-Chemotherapy Movement
Integrating the classification based on similar B-cell receptors with other prognostic markers will also refine the prognostication of CLL patients and increase the possibilities to identify patients that are at high risk already at the time of diagnosis.

“But it is also important, both for medical and psychosocial reasons, to be able to identify patients with the lowest probability of requiring treatment. Especially considering that these subsets are enriched for young patients who could be reassured about the indolent nature of their disease”, says Panagiotis Baliakas.

As CLL is typically a disease of the elderly, many can’t tolerate an aggressive treatment regimen.

“You don’t always want to expose elderly patients to chemotherapy and it’s increasingly possible to predict outcomes when using a non-chemo regimen,” he shared. “Patients stand the best chance of a prolonged recovery if you can treat it the completely the first time around and knowing the prognosis is a step toward a deeper, prolonged recovery.”

Goy added that this study offers further evidence in pursuing treatment besides chemotherapy for patients with CLL. Currently, the gold standard treatment involves fludarabine(Fludara) and cyclophosphamide(Cytoxan), with the monoclonalantibody, rituximab (Rituxan). This combination, known as FCR, cause suppression of the immune system, a depression in normal blood counts and DNA damage which may contribute to the causation of second cancers.

“Sometimes, patients are reluctant to try chemotherapy and this may give them some documentation,” he said. “The field of CLL therapies is changing and more novel therapies are replacing chemotherapy.”

Robin Hocevar is on staff at ADVANCE. Contact [email protected].

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