A Pathologic Abdominal Ultrasonography At Diagnosis Of CLL Significantly Reduces The Time To Progression In Patients With Rai 0 Or Rai 1 Disease
Authors: Rossini Fausto , Cecchetti Caterina , Farina Francesca , Sassone Marianna , Scollo Chiara , Pezzatti Sara , Bolis Silvia , Belotti Angelo , Bozzani Sofia , Perego Alessandra , Pogliani Enrico Maria 
Published: October 2019

Abstract
The most common staging systems for CLL were developed many years ago and are based on blood cell count and the presence of enlarged lymph nodes by physical exam. Many studies have tried to identify prognostic factors in early stage patients. A recent paper (Muntanola et al: Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 CLL. J Clin Oncol. 25:1576-1580) showed that patients with Rai 0 disease and a pathologic abdominal CT scan had a reduced time to progression (TTP), more similar to Rai stage I disease; however CT cannot be used routinely, especially in patients with early stage CLL, whose life expectancy may be very long. When compared to CT, ultrasonography (US) can be used at diagnosis and in follow-up, when it can show progression of abdominal lymph nodes.

Patients and Methods
The aims of the study were to investigate: 1) if a pathologic ultrasonography (PU) showing the presence of abdominal lymphadenopathy at diagnosis could allow identifying patients with different risk of evolution. 2) if there is a correlation between PU and different prognostic factors, such as mutational state, absolute lymphocyte count, CD38 positivity, age 3) if patients with Rai 0 disease and with PU are prognostically similar to Rai 1.
Between 1999 and 2011, 189 patients with Rai 0 or Rai 1 CLL had a ultrasonography (US) performed at diagnosis. Lymph nodes more than 10 mm in diameter were considered abnormal. In 137 of them mutational status had been determined. Fluorescence in situ hybridization (FISH) analysis for 11,12, 13 17 was not generally performed at diagnosis but only before the beginning of treatment. The Fisher’s exact or t tests were used to analyze the association between the presence of an abnormal US and the clinical characteristics. Survival time and time to progression (TTP) were analyzed using the Kaplan-Meier method and curves were compared by means of the log-rank test.

Results
Mean age was 63.2 years (range 41-85). Patients had Rai stage 0 (n=130) disease or Rai stage 1 (n=59). Median absolute lymphocyte count was 12.2 x 10^9/L. Overall, PU were present in 40/189 (21.2%) patients, with dimensions of lymph nodes up to 120 mm. PU were significantly more frequent in patients with Rai 1 disease (23/59 – 39%) than in Rai 0 (17/130 – 13.1%) disease (p<0.01), in patients with unmutated disease (19/50 – 38%) than in patients with mutated disease (13/87 - 14.9%) (p=0.002) and in patients with absolute lymphocyte count at diagnosis > 20 x 10^9/L (15/47 – 31.9%) than in patients with absolute lymphocyte count at diagnosis < 20 x 10^9/L (25/142 – 17.6%) (p=0.03). No significant differences were present in age, hemoglobin concentration, absolute neutrophil count, platelet count or CD38 positivity. When all patients are considered, patients with PU had a shorter time to progression when compared to patients without PU (median 56 months vs not reached - p<0.02). The whole population was divided in three groups: patients with Rai 0 disease and no PU (group A), with Rai 0 disease and the presence of PU (group B), with Rai 1 (group C). The TTP is significantly different in the three groups, with median TTP not reached for gr A, 73 months for gr B and 37 months for gr C; (p <0.001 ). Among patients with Rai 1 disease, median TTP was 60 months in patients with PU and 21 in patients without PU (p=0.077).
The presence of PU has a significant prognostic significance for TTP in patients with unmutated disease with median TTP of 68 vs. 25 months (p=0.007). Among patients with mutated disease, median TTP were 112 for patients with PU and not reached for patients without PU (p=n.s.).
No differences in overall survival could be shown.

Conclusions
The presence of PU at diagnosis can identify a subgroup of Rai 0 CLL with shorter TTP; this confirms results reported with computed tomography. Patients with Rai 0 disease and PU had an intermediate but significantly different TTP between Rai 0 without PU and Rai 1. PU retains its importance also when only unmutated patients are considered; among mutated patients, a statistically significant difference could not be shown , also due to the low number of events in these patients. An ultrasonography performed at diagnosis appears to be useful in low-risk CLL patients: it is a non-toxic imaging technique that can identify subgroups of low-risk patients; in patients with PU at diagnosis, it can be repeated in follow-up to evidence progressive abdominal disease.

Disclosures:
No relevant conflicts of interest to declare.