CLL with t(11;14)(q13;q32) or t(14:18)(q32:q21) –­­ is this CLL or lymphoma? Free

Background:

The IGH rearrangements resulting from t(11;14)(q13;q32) and t(14;18)(q32;q21) typically characterize mantle cell lymphoma (MCL) or follicular lymphoma (FL), respectively. However, these rearrangements are also rarely found in chronic lymphocytic leukemia (CLL), where their impact on prognosis is controversial. As the differential diagnosis of CLL versus lymphoma is not always unequivocal and treatments may differ, it is important to determine how – by diagnostic gold standards - CLL cases showing these translocations should be further evaluated and treated.

Aims:

To characterize cases diagnosed as CLL with t(11;14)(q13;q32) or t(14;18)(q32;q21) and compare them to classical CLL, MCL and FL cases.

Methods:

5,993 CLL patients were diagnosed by immunophenotyping from 2005 and 2024 (median age: 68 y [23-96]; 36% female, 1,256 with follow-up data) and analyzed for cytogenetic aberrations by chromosome banding analysis and FISH. IGHV mutation status was determined according to ERIC recommendationsand TP53 mutation status by targeted NGS or Sanger sequencing. 94 MCL and 68 FL cases (diagnosed 2005-2022) and with whole transcriptome sequencing (WTS) data available were used as comparison. WTS and UMAP-based visualization of gene expression (GE) profiles were used to characterize a subset of 338 CLL cases (including 16 t(11;14) and 12 t(14;18)) and all MCL/FL cases. Immunophenotypes of randomly chosen CLL cases (127, including 27 t(11;14) and 13 t(14;18)), MCL (30) and FL (29) cases were analyzed by converting markers (CD103/SSC/CD11c/CD25/kappa/lambda/CD5/CD20/CD79b/CD23/FMC7/CD22/CD38/CD45/CD10) to discrete numerical values and using them for k-means clustering. Kaplan-Meier analysis was used to analyze overall survival (OS).

Results:

Out of 5,993 diagnosed CLL cases, 30 (0.5%) had a t(11;14)(q13;q32) translocation and 83 (1.3%) showed t(14;18)(q32;q21), all confirmed by FISH. k-means clustering of immunophenotype markers and GE profiling revealed that 12/12 CLL_t(14;18) cases clustered both by immunophenotype and GE profiling with all CLLs and none with FL. Immunophenotypes of 18/27 CLL_t(11;14) cases clustered with the remaining CLL cases, however 9/27 cases clustered with MCL cases. In GE profiling, 11/11 of CLL_t(11;14) cases with CLL-like immunophenotype and 3/4 MCL-like cases grouped with the remaining CLL cases and only one MCL-like case with MCL. 64% of CLL_t(11;14) cases had a mutated IGHV-status (IGHV-M) – comparable to the remaining CLL cases (57%) and significantly more than MCL (30%, p=0.003). CLL_t(14;18) and FL cases were almost exclusively IGHV-M (91% and 94%). CLL_t(14;18) cases had a median OS of 15.9 y, which was comparable to the remaining CLL cases (median not reached, p=0.38) and FL cases (12.8y, p=0.29). CLL_t(11;14) cases had reduced OS compared to remaining CLL cases (median OS=6.9 y vs not reached, p=0.002) and were comparable to MCL (9.2 y, p=0.94). Interestingly, IGHV-status did not affect OS in CLL_t(11;14) (median OS IGHV-U vs IGHV-M: 8.7 y vs 14.9 y, p=0.41) nor in MCL (7.2 y vs 11.2 y, p=0.96) but in CLL (12.1 y vs not reached, p<0.001). In line with their poor prognosis, CLL_t(11;14) cases showed an enrichment of negative prognostic markers (del(17p): 17%, TP53 mutation: 20%, complex karyotype: 47%) relative to remaining CLL cases (5%, 11%, 17%) and comparable to MCL (20%, 15%, 58%). MCL-like CLL_t(11;14) cases had particularly high proportions of these markers (22%, 33%, 56%), whereas CLL-like cases had lower values (11%, 11%, 39%). In multivariate analysis of all CLL cases, the presence of a t(11;14)(q13;q32) translocation had an independent negative prognostic impact on OS (HR=2.2, p=0.01), as had high-complex karyotype (5+ aberrations), IGHV-U status and TP53 aberrations.

Conclusion:

We have characterized 113 CLL cases with t(11;14) or t(14:18) translocations. CLL_t(14;18) cases phenotypically and by GE resemble classic CLL cases and have a comparable prognosis. However, CLL_t(11;14) cases mostly resemble CLL by GE but phenotypically segregate into MCL-like and CLL-like cases, suggesting that there may be a continuum between MCL and CLL. Also, CLL_t(11;14) cases show several similarities with MCL, such as enrichment of negative prognostic markers, no impact of IGHV-status on prognosis and a poor prognosis. Our data indicates that cases with t(11;14)(q13;q32) should be considered high-risk, regardless whether they were diagnosed as MCL or CLL.