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Vojdeman et al. J Transl Genet Genom 2021;5:182-88 https://dx.doi.org/10.20517/jtgg.2021.03 Page 184

examined by Kaplan-Meier curves, and log-rank tests as well as graphical illustrations were performed in
Graph Pad Prism 9 (GraphPad software Inc., La Jolla, CA, USA) and SAS enterprise guide 7.1 (SAS
institute, Cary, USA). A PFS event was defined as no response to treatment, progression, or death. P-values
were two-sided and considered statistically significant if P < 0.05.

RESULTS
IGHV sequences from 192 out of 272 patients were available. Of these, 178 (93% of all patients) were
technically suitable for analysis; all further analyses were restricted to this population. The original full
sequences had to be available for analysis to be technically suitable for analysis. Thirty-eight patients (21%)
could be assigned to one of the 19 major subsets: Subset #2 was the most frequent (n = 12, 6.7%), followed
by 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. Compared with
the 94 patients excluded, the 178 patients included had similar baseline characteristics such as age group
above 65 years, sex, treatment arm, Binet stage, WHO performance status, or CLL-IPI risk groups
[Table 1]. Furthermore, there were no differences in PFS or OS between the excluded and included patients
(PFS: P = 0.96; OS: P = 0.70).

Patients with unmutated immunoglobulin heavy chain variable genes (UM-IGHV) belonging to Subset #2
tended to have a longer median PFS than patients with UM-IGHV not utilizing IGHV3-21 [UM-IGHV
Subset #2 median PFS 61.3 months (n = 8) vs. non-IGHV3-21 UM IGHV patients median PFS 32.1 months
(n = 139), log rank P = 0.12, Figure 1A]. However, when PFS for patients with UM-IGHV belonging to
Subset #2 were compared with PFS for UM-IGHV 3-21-utilizing non-Subset #2 patients, they had a
significantly longer PFS [UM-IGHV 3-21 non-Subset #2 median PFS 22.3 months (n = 6), P = 0.01,
Figure 1A]. Overall, no significant differences in PFS between groups were found for patients with M-IGHV
(M-IGHV Subset #2 median PFS 49.6 months, M-IGHV non-Subset #2 median PFS 38.1 months, P = 0.6,
Figure 1A) and for all patients with regard to OS (UM-IGHV Subset #2 median OS not reached, Figure 1B
and Table 1). The survival rate of the 12 Subset #2 patients treated with either chemo- or
chemoimmunotherapy in the HOVON 68 trial was comparable to that reported in other recent chemo- or
chemoimmunotherapy trials [9-11] [Table 1]. In addition, there were no differences in PFS or OS between
treatment arms for patients belonging to Subset #2 (data not shown). Compared with patients with UM-
IGHV not utilizing IGHV3-21, Subset #2 patients did not differ significantly with regard to most of their
baseline characteristics. However, they were older, had more advanced disease, did not harbor del17p or
trisomy 12, and more often had SF3B1 mutations [Table 1].

DISCUSSION
The longer PFS after chemo- or chemoimmunotherapy for Subset #2 patients with UM-IGHV compared
with patients with UM-IGHV or non-Subset #2 IGHV3-21 utilizing patients in this high-risk CLL cohort is
somehow surprising when considering that Subset #2 patients are reported to have a median time to first
treatment of only 22-24 months [12,13] . However, a report based on a large cohort of patients with CLL showed
a median survival after first line treatment of 7.3 years (88 months) in the pre-chemoimmunotherapy era
[14]
and 10.7 years (128 months) in the chemoimmunotherapy era for patients belonging to Subset #2 . In
contrast to this, Jaramillo et al. found that advanced stage CLL patients belonging to Subset #2 with both
[1]
M-IGHV and UM-IGHV had PFS similar to patients with UM-IGHV after chemotherapy- or rituximab
chemoimmunotherapy-based regimens, but at the same time these advanced stage CLL patients belonging
to Subset #2 tended to have a longer OS. Thus, Subset #2 patients might have longstanding benefit from
first-line chemo- or chemoimmunotherapy, as administered in the HOVON 68 trial. The lack of TP53