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Page 183 Vojdeman et al. J Transl Genet Genom 2021;5:182-88 https://dx.doi.org/10.20517/jtgg.2021.03

Methods: Based on IGHV mutational analyses from participating centers in Sweden, Norway, Finland, Denmark,
Poland, and the Netherlands, B-cell receptor stereotyped subsets were assigned using the ARResT/AssignSubsets
software. Analysis for recurrent mutations was performed by next-generation sequencing by a 454-base platform.
All other clinical data were extracted from the HOVON database by November 2016.

Results: In total, 178 out of 192 patients with sequences available were technically suitable for analysis. Thirty-eight
patients (21%) were assigned to one of the 19 major subsets: Subset #2 (n = 12, 6.7%), Subset #8 (n = 7, 3.9%),
Subset #6 (n = 6, 3.4%), and Subset #1 (n = 5, 2.8%). Other subsets found were: Subsets #3, #5, #31, and #64B.
By November 2016, a PFS event had occurred for 150 patients (84%) and 79 patients (44%) had died. The median
follow-up time for patients still alive was 78.9 months. Patients with UM-IGHV belonging to Subset #2 had
significantly longer PFS than UM-IGHV 3-21-utilizing non-Subset #2 patients [UM-IGHV Subset #2 median PFS
61.3 months (n = 8) vs. UM-IGHV 3-21 non-Subset #2 median PFS 22.3 months (n = 6), P = 0.01]. Overall, no
significant differences in PFS between groups were found for patients with M-IGHV.

Conclusion: In the HOVON 68 trial. Subset #2 patients had a good treatment outcome comparable to the outcome
for non-high-risk patients with chronic lymphocytic leukemia following fludarabine-cyclophosphamide-rituximab-
based treatment.

Keywords: Chronic lymphocytic leukemia, B-cell stereotypy subsets, treatment outcome

INTRODUCTION
The impact of B-cell receptor stereotypy on treatment outcome for patients with chronic lymphocytic
leukemia (CLL) has recently been examined across multicenter clinical trials of both early stage and patients
[1]
in need of treatment, treated with chemo-immunotherapies . The HOVON 68 trial compared
chemotherapy with fludarabine and cyclophosphamide (FC) to chemo-immunotherapy with the addition of
low-dose alemtuzumab as first-line treatment in high-risk patients with CLL .
[2]

Approximately one third of patients with CLL carry a stereotyped B-cell receptor. These receptors can be
divided into subsets based on homology of their complementarity determining region 3 (CDR3)
[3]
sequence . At present, 19 major subsets have been described accounting for approximately 13% of patients
with CLL . Subsets #1 and #2 are associated with particularly poor prognosis similar to TP53-aberrant
[4]
cases, while Subset #8 is the subset with the highest risk of Richters transformation . Subset #2 is defined by
[5]
usage of IGHV3-21/IGLV3-21 genes, a mixed somatic hypermutation status, and a particularly short
[3,6]
CDR3 . The HOVON 68 trial included high-risk patients with CLL defined as having 17p deletion
[del(17p)], 11q deletion [del(11q)], trisomy 12, unmutated IGHV, and/or IGHV3-21 (see trial registration
[2]
at www.trialregister.nl as trial No. NTR529). We here assessed the impact of B-cell receptor stereotypy on
progression-free survival (PFS) and overall survival (OS) in patients from the HOVON 68 trial. Our data
show a favorable outcome for patients with CLL belonging to the stereotyped Subset #2 in this selected
high-risk population.

METHODS
Based on IGHV mutational analyses from participating centers in Sweden, Norway, Finland, Denmark,
Poland, and the Netherlands, B-cell receptor stereotyped subsets were assigned using the
[7]
ARResT/AssignSubsets software . Analysis for recurrent mutations was performed by next-generation
sequencing by a 454-base platform (Roche Diagnostics Corporation, Indianapolis, USA) . All other clinical
[8]
data were extracted from the HOVON database at closure of the trial by November 2016. Chi square or
Fisher’s exact tests were used for contingency table analysis. OS and PFS from date of randomization were