Specific Chromosomal IG Translocations Have Different Prognosis In Chronic Lymphocytic Leukemia

Abstract 582

Chromosomal translocations (t) are usually analyzed as one group, and are associated with poor prognosis in chronic lymphocytic leukemia (CLL). Translocations involving immunoglobulin (IG) genes are recurrent, but uncommon (< 5%) in CLL. The two most frequent IG-partners are BCL2 (18q21) and BCL3 (19q13). On the behalf of the Groupe Francophone de Cytogenetique Hematologique (GFCH), we report an extensive analysis of 75 t(14;18)-CLLs, and a comparison to our previously published series of 29 t(14;19)-CLLs (Chapiro et al, Leukemia 2008).

The 75 t(14;18)-CLLs or variant BCL2-t have been collected between 1985 and 2009. The morphological and immunological reviews were performed by KM, CS, and HM-B. All karyotypes were reviewed by the GFCH. Fluorescence in situ hybridization analyses were performed to detect IG and BCL2 rearrangements, trisomy 12, and deletions of 11q22 (ATM), 17p13 (TP53), 6q21, 13q14 (D13S319). IGHV mutation analyses were performed by referring laboratories. Statistical analyses were carried out using the Fisher's exact test, and continuous data using the Mann-Whitney test. Overall survival (OS) and treatment free survival (TFS) calculated from diagnosis were estimated using the Kaplan-Meier method, and the statistic significance was determined using log-rank test.

Among BCL2-CLL, the sex ratio was 57M/18F, the median age at diagnosis was 66 years; of 68 patients with available data, 63 (93%) presented with Binet stage A; median lymphocytosis was 14.6×10⁹/l. There were 47/75 (63%) “classical” CLL and 28/75 (37%) “atypical” CLL, with more than 10% of lymphoplasmacytoid cells and/or large cells. All tested cases (58/58) were CD10-, 69/73 (94%) were CD5+, and 44/63 (70%) were CD38-; 57/68 (84%) had a Matutes score > 4, 7/68 (10%) a score = 3, 4/68 (6%) a score < 3. We observed 62 t(14;18) and 13 variant translocations [11 t(18;22), 2 t(2;18)]. The karyotype was complex (> 3 abnormalities) in 15/74 (20%) cases, and the BCL2-t was isolated in 25/74 (34%) cases. There were 33/75 (44%) tri12, 32/68 (47%) del13q14, 1/72 (1%) delTP53, 0/72 (0%) delATM, 0/59 (0%) del6q21. Of 42 analyzed cases, 33 (78%) were mutated. Finally, the median time from diagnosis to first therapy was 24 months (m).

Comparisons with the BCL3-CLL showed no difference in sex ratio, age, and Binet stages. The lymphocytosis was lower in BCL2-CLL (14.6 vs 24.4 x10⁹/l, p<0.008), and splenomegaly was less frequent (3/61 (5%) vs 13/28 (46%), p<0.0001). There were more “classical” morphologies in BCL2-CLL group (63% vs 9/29 (31%), p<0.005), more Matutes score > 4 (84% vs 5/20 (25%), p<0.001), and more CD38- (70% vs 1/5 (20%), p<0.05). BCL2-t were more frequently single (35% vs 1/28 (3%), p<0.0008). There were less complex karyotypes (20% vs 13/28 (46%), p<0.02), more del13q14 (47% vs 4/27 (15%), p<0.005), and less tri12 (44% vs 20/29 (69%), p<0.03), del6q (0% vs 5/25 (20%), p<0.002) and delTP53 (1% vs 4/23 (17%), p<0.02) in BCL2-CLLs. The IGHV status of BCL2-CLLs was more frequently mutated (78% vs 2/20 (10%), p<0.0001). Finally, the TFS interval was longer in BCL2-CLLs (p<0.0001, median 48 vs 1.2 m,); and the median OS was longer (not reached with 75% alive at 204 m) (p<0.0001).

Comparison to common CLL showed that BCL2-CLLs had more tri12 (p<0.00001), and lacked delATM (p<0.0001) and del6q (p<0.05). The majority were CD38-, and mutated (p<0.0001). Finally, even if the median TFS was 48m, the median OS was more than 204m, which is longer than the median OS of the prognostically most favorable subgroup reported by Döhner et al (group with isolated del13q, 133m) (Döhner et al, N Eng J Med, 2000). The presence of BCL2-t remains a favorable marker even in patients who also exhibit markers of intermediate prognosis such as tri12.

Compared to BCL3-CLLs, BCL2-CLLs have a much less aggressive behavior, indicating that distinguishing the individual translocations and the cytogenetic partners would allow a better patients' stratification.