HOX11L2 Genotyping Identifies Subset of Adult Thymic T-ALL with Inferior Outcome.

Background: Studies evaluating the prognostic impact of the expression of the oncogenes HOX11 and HOX11L2 in adult T-ALL have been controversial so far.

Methods: In the two consecutive German Multicenter ALL (GMALL) therapy trials 5/93 and 6/99, 503 T-ALL pts were recruited between 4/93 and 10/03. Of these, 286 patients with adult T-ALL have been retrospectively investigated for the expression of HOX11 and HOX11L2. This represents the largest cohort of adult T-ALL patients investigated so far. Expression was measured in pretreatment peripheral blood and bone marrow blasts by comparative real-time RT-PCR.

Results: The median age was 30 (16–65)yrs, 76% were male, 69% had a mediastinal tumor, 24% WBC > 100.000 and 7% CNS involvement. 61 patients (21%) showed a high and 57 patients (20%) a low HOX11 expression, 165 patients (59%) did not express HOX11. In comparison, 29 patients (10%) expressed HOX11L2 whereas 256 (91%) did not show a HOX11L2 expression. The prevalence of HOX11L2 expression was higher in the youngest age group (median 20 yrs vs. 31 yrs in “negative” pts, p=0,025). CNS involvement was more frequently found in the high HOX11 expression group (p=0,025). High HOX11 expression and HOX11L2 expression were both significantly associated with the thymic immunophenotype (p=0.0077 and 0,031, respectively). There were no significant differences in CR rates between the HOX11- and HOX11L2-expression subgroups. In contrast, HOX11L2 positive patients showed a higher relapse rate (52% vs. 28%; P=0.011). The overall survival (OS) was higher for pts. with high HOX11 expression (OS at 5 years: high 69% vs low 36% vs negative 41%; p=0.007), and disease free survival (DFS) was significantly longer in the high HOX11 expression group (at 5 years high 73% vs low 41% vs negative 47%; p=0.007). For HOX11L2 expression the difference in OS did not reach statistical significance regarding all T-ALL patients (at 5 yrs: positive 13% vs negative 49%; p=0.06). Controlling for the immunophenotype, a significant difference in OS became evident (at 5 yrs: positive 19% vs negative 64%; p=0.01). DFS was significantly shorter in HOX11L2 positive patients (at 5 yrs: positive 24% vs negative 56%; p=0.03). In a multivariate analysis the expression of HOX11 could not be confirmed as independent prognostic factor for OS or DFS (p≥0,05). In contrast, HOX11L2 expression was found to be the only relevant prognostic factor besides the immunophenotype: The hazard ratio of death was 1,8 for HOX11L2 positive T-ALL patients (95% CI 1.1–3,0; P=0,021), and the hazard ratio for a relapse was 2,0 (95% CI 1.1–3,7; P=0.023).

Conclusions: HOX11 expression is highly associated with the thymic immunophenoytpe and is not an independent prognostic factor. The expression of HOX11L2 is also predominantly found in thymic T-ALL. Whereas the majority of thymic T-All patients do not express HOX11L2 and have an improved outcome, HOX11L2 expression identifies a small subset of thymic T-ALL patients with a reduced OS and DFS, similarly to early and mature T-ALL. If this can be confirmed prospectively, thymic T-ALL patients need to be treated according to their HOX11L2 expression status as different entities: HOX11L2 positive thymic T-ALL patient requiring a rather aggressive therapeutical management.