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L. Paschold et al.
19) years (cohort 1), 16 NLPHL cases (33 samples) with subsequent NLPHL relapses (cohort 2) and ten cases (20 samples) with transformation to NHL at relapse (cohort 3). The clinical characteristics of cohorts 1-3 are listed in Online Supplementary Table S1. Patients in cohort 3 were generally older at first diagnosis than cases in cohorts 1 and 2 (median age: 50.5 vs. 17 years and 25.5 years, respec- tively) (Figure 1A) suggesting that higher age may be a risk factor for transformation. Time to relapse/transformation was numerically, but not statistically different in cohorts 2 and 3 (Figure 1B). A clear male predominance was observed in all NLPHL cohorts, with relatively more females in cohort 2 (Figure 1C). There was a clear correla- tion of IgD status and transformation, in that cohort 3 cases were only rarely IgD-positive (Figure 1C). Moreover, this cohort included more cases with variant histological patterns (Figure 1C).
IGH repertoire characteristics of nodular lymphocyte-predominant Hodgkin lymphoma that did or did not subsequently transform into non-Hodgkin lymphoma
We used IGH NGS on DNA derived from paraffin- embedded lymphoma tissue to investigate whether NLPHL cases with subsequent transformation harbored characteristic B lineage patterns predictive of transforma- tion to NHL. In addition to our three cohorts, 28 control samples (DLBCL, T-cell/histiocyte-rich large B-cell lym- phoma, lymphadenitis, progressive transformation of ger- minal centers) were available for this analysis. For reper-
AB
toire metrics analyses, all IGH sequences including the malignant LP-cell rearrangement as well as those deriving from the bystander B-cell repertoire were used. We found that NLPHL cases that subsequently underwent transfor- mation (cohort 3) showed NHL-typical quantitative reper- toire metrics characterized by significantly lower B lineage diversity and richness as well as higher clonality compared to other NLPHL and non-malignant lymphoproliferations (Figure 2A, B). In addition, principal component analysis based on IGHD/J gene usage of IGH repertoires demon- strated a significant segregation of cohort 3 from NLPHL without transformation at both the NLPHL and DLBCL stages of the disease with the transformation cases cluster- ing close to NHL cases already at the pre-transformation stage (Figure 2C). These data suggest that global IGH repertoire metrics (lower diversity, higher clonality) may be predictive of later transformation of NLPHL to NHL.
Characteristics of lymphocyte-predominant-cell IGH rearrangement in nodular lymphocyte-predominant Hodgkin lymphoma cases with subsequent relapse or transformation
We set out to characterize the properties of the malig- nant clone’s LP-cell IGH rearrangement to be able to com- pare it between NLPHL cases with relapse and transfor- mation. For this analysis bulk lymphoma tissue from involved lymph nodes or other organs was used without microdissection of LP cells, so the sequenced IGH reper- toires contained the LP-cell rearrangement along with the rearrangements of all other B lineage cells present in the B-
Figure 1. Clinical and pathological characteristics of cohorts 1-3 with nodular lymphocyte-predominant Hodgkin lymphoma. (A) Age at initial diagnosis. (B) Years between initial diagnosis and relapse/transformation. (C) Sex, IgD status and histological variant pattern of patients with nodular lymphocyte-predominant Hodgkin lymphoma in cohort 1 (no relapse/transformation), cohort 2 (relapsing cases) and cohort 3 (transforming cases). Bars corre- spond to the mean + standard deviation. Statistical test: unpaired, two-tailed t-test. ID: initial diagnosis; Rel: relapse/transformation; NLPHL: nodular lymphocyte-predominant Hodgkin lymphoma; DLBCL: diffuse large B-cell lymphoma.
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haematologica | 2021; 106(10)