Chronic Lymphocytic Leukemia (CLL):Management Strategies Beyond Rai Staging System
演題番号 : KL-12
1:CLL Research and Treatment Program North Shore-LIJ Health System, Long Island Jewish Medcl Ctr, USA
Although the incidence of CLL in Japan and other Asian countries is not as high as in the West, the difficulties that physicians encounter in decision-making about therapeutic management of patients with this disease are the same all over the world.
When methods of clinical staging of CLL were developed in 1975 and 1980 by Rai, etal and Binet, etal respectively, oncologists and hematologists were pleased because these systems enabled them to classify all patients into three broad categories: (i) Low-risk, (ii) Intermediate-risk and (iii) High-risk. Patients with significant degrees of anemia and/or thrombocytopenia at the time of diagnosis, had high-risk disease, shortest median life-expectancy and were recommended for prompt initiation of therapeutic intervention. Patients with only blood and bone marrow lymphocytosis without significant lymphadenopathy and without anemia or thrombocytopenia, were considered to be in low-risk category. Low-risk category patients had a long median survival time and they were recommended to be kept under observation without any anti-leukemia therapy. All other patients without anemia or thrombocytopenia, but with clinically enlarged lymph nodes or spleen, were considered in the intermediate-risk category. Their survival times was somewhere between the two extremes.
It, however, became apparent that clinical staging systems were only useful in broadly dividing all CLL patients in these three risk categories, but in individual cases, they were not adequate. Examples: some low-risk category patients started rapid progression within a year or two after diagnosis, while on the other end of the spectrum, there were patients in the high-risk category who remained stable for several years without requiring any therapy. Thus, staging systems by themselves were not helpful to clinicians in satisfactory management of all patients. Other or additional criteria were needed which could improve upon clinical staging.
Advances in understanding of molecular biology and cytogenetics in CLL between 1999 and 2004 led to four major discoveries which resulted in significant improvement in our ability to assign more accurate prognosis for virtually every patient with CLL. These are:
1. Degree of somatic hyper-mutation in the variable region of immunoglobulin heavy chain (IGHV) gene in CLL patients.
2. Expression of ZAP70 on leukemic cells in CLL
3. Expression of CD38 on leukemic cells in CLL
4. Detection of cytogenetic abnormalities, e.g., deletions in chromosomes 17p, 13q and 11q or trisomy 12.
More specifically, CLL patients with evidence of mutation in IGHV gene had significantly better prognosis (M-CLL) vs. those without mutation or unmutated IGHV.
Patients with ZAP70 negativity or CD38 negativity had significantly better prognosis than their respective counterparts with ZAP70 positive or CD38 positive CLL cells.
Patients with 13q deletions as the sole chromosomal abnormality had significantly better prognosis than those with 11q deletions or 17p deletions or trisomy 12.
Incorporating these “newer” findings in prognosis criteria of clinical staging systems has markedly improved the clinician's ability to predict a patient's overall outlook over a long period.
For example, a patient in low-risk category with mutated IGHV gene can be given an assurance with high level of reliability of excellent long-term prognosis, while another patient in low-risk category, who has unmutated IGHV, can be forewarned that the disease is likely to become active and might require therapy in the foreseeable future. Similar modifications of prognostic outlook are possible in the intermediate-risk as well as in high-risk categories.
More recent advances in molecular biology techniques using massively parallel sequencing of whole exomes and whole genomes, with sequencing of matched germline DNA, have helped identify several genes with mutations with important prognostic consequences in CLL. More prominent among these new findings are SF3B1, NOTCH-1, TP53 and ATM. Newer data suggests, for example, that NOTCH-1 mutations are associated with unmutated 1GHV and trisomy 12, and mutations in SF3B1 were associated with deletions 11q or mutations in ATM. Investigations are currently in progress to determine if any of these will have an independent prognostic role or whether any of these could, in the future, be incorporated in a yet-to-be developed, more accurate prognostic algorithm than the present methods.