"Smouldering" Chronic Lymphocytic Leukemia

Although clinical staging systems are useful to assess the prognosis of chronic lymphocyctic leukemia (CLL), for the large majority (up to 60%) of patients in early clinical stage no system is able to predict those who will progress ("active" disease) and those who will remain at the same stage ("smouldering" disease). To identify the latter subset of patients is important since in these patients treatment should be withhold until progression occurs. In the past few years, there have been several attempts to define "smouldering" CLL. Basically, patients in early stage (Binet's A) with: (a) moderate bone marrow infiltration (non-diffuse pattern in the biopsy or less than 80% lymphocytes in bone marrow aspirate), (b) low blood lymphocyte count (<30 × 10(9)/L), (c) Hb level in a non-anemic range (> 12 or 13 g/dL), and d) prolonged lymphocyte doubling time (> 12 months) are not likely to progress and have a life-expectancy not different from matched controls. In three different series analyzed so far, disease-progression rate is approximately 15% to 5 yrs, and survival is not different from that of controls. Approximately, 20 to 30% of all CLL patients with CLL fulfill "smouldering" criteria. Besides the above criteria, there are others that merit consideration. Thus, Rai's substages (AO vs AI + II) have been found to predict different outcomes within Binet's stage A. On the other hand, chromosome abnormalities may be useful to further assess the prognosis. Finally, the contribution of phenotypic studies to the definition of "smouldering" CLL remains uncertain, and a female sex has been associated with a better outcome. Whether or not patients with "active" stage A (e.g., those not fulfilling "smouldering" CLL criteria) should be treated is unknown. The morbidity associated to treatment (e.g. increase number of second neoplasms) and the lack of survival advantage found in recent randomized trials cast doubts on the real benefit of treating patients in early stage (Binet's A; Rai's 0). To answer this question, the separate analysis of patients with "smouldering" stage A and patients with "active" stage A included in recent trials could be of help. Moreover, prospective studies of patients in early stage followed-up with no treatment could be useful to refine the definition of "smouldering" CLL.