Prognostic factors in CLL and their relation to outcome ?
The diagnosis of CLL generally requires detection of >5,000
CLL-type cells per microliter of peripheral blood. CLL cells typically
express CD19, weak CD20, and CD23 (B-cell antigens), along with CD5 (a
T-cell antigen); these are usually assessed by flow cytometry
Cytogenetic, molecular, and flow cytometric testing play an important role in prognostication for CLL patients.
Genetics of chronic lymphocytic leukaemia progression?
The overall genomic mutation load seems to be similar in monoclonal B lymphocytosis (MBL) and early stage chronic lymphocytic leukaemia (CLL), as determined in both whole-exome sequencing and whole- genome sequencing studies. When CLL evolves from early stages to overt disease, discrete acquisition of genetic lesions occurs, suggesting that B cell receptor (BCR) signalling and/or
the microenvironment contribute to disease progression41. After the constraints exerted by treatment with chemoimmunotherapy (CIT) or the BCR signalling inhibitor ibrutinib, CLL cells with genetic lesions conferring drug resistance become clonally selected (orange cells).
Finally , CLL can transform from advanced- stage disease to an aggressive lymphoma termed Richter syndrome (RS), although the concurrent diagnosis of CLL and RS is rare In most cases, the RS cells (red cells) derive from the original CLL clone (blue cells) by developing additional genetic lesions.
NOTCH1 mutations, MYC activation and TP53, CDKN2A and CDKN2B disruptions are characteristic genetic lesions of RS65. Patients with CLL receiving ibrutinib can progress in two different ways.
First, in approximately 5% of patients, the disease can evolve in <2 years on treatment to a RS that is clonally related to the underlying CLL.
The time and clinical presentation suggest that ibrutinib selects for a pre- existing RS clone.
Second, 15% of patients, who typically show progression after >2 years of treatment, can develop mutations associated with resistance to ibrutinib (that is, BTKC481S, PLCG2 or ITPKB mutations).
These mutations can be detected using highly sensitive techniques even before the start of ibrutinib treatment (orange cells) and up to 15 months preceding clinical progression, which is characterized by an increase in the size of the lymph nodes and a rise in lymphocyte count and serum lactate dehydrogenase (LDH) levels.