is “very swayed by the long-term data.” These include three
studies demonstrating plateaus in PFS curves among pa-
tients with IGHV-mutated CLL treated with FCR. 2,3,4 One
of these studies, from MD Anderson Cancer Center, 5 has
the longest follow-up of patients with the IGHV mutation
treated with firstline FCR. 5
“If patients had mutated disease, that plateau at about
11 to 16 years is out at about 60%,” Dr. O’Brien said. “If
the patient experiences minimal residual disease negativ-
ity, that plateau rises to 80%. I firmly believe that there is
a cure fraction there.”
In his rebuttal, Dr. Stilgenbauer again pointed to limi-
tations in the research, noting that the MD Anderson
study was a single-arm, single-center trial done at a high-
ly specialized center. “That plateau is beyond the median
follow-up, so it is statistically invalid,” he said.
Case #2: An Older Patient With CLL
Next, Drs. O’Brien and Stilgenbauer discussed the treat-
ment of an older patient diagnosed with IGHV-mutated
CLL. The 74-year-old patient had normal FISH results and
had good performance status, renal function, and liver
function.
In this situation, Dr. O’Brien said she would opt
against chemotherapy, supported by data from two
trials. First, the iLLUMINATE trial showed that ibrutinib
+ obinutuzumab led to longer median PFS, compared
with chlorambucil + obinutuzumab (not reached vs. 19.0
months; HR=0.23; 95% CI 0.15-0.37; p<0.0001). 5
“In a high-risk population, defined as patients with
del17p, TP53 mutation, or del11q, [the benefit was] even
more marked because those features are predictive of
worse outcomes with chemotherapy,” Dr. O’Brien said.
For many patients, data from the ALLIANCE A041202
trial may be more relevant, she noted. The A041202 trial
randomized untreated patients ≥65 years to bendamustine
+ rituximab (BR), ibrutinib + rituximab, or ibrutinib alone. 6
A greater percentage of patients assigned to the two ibru-
tinib regimens were progression-free at 2 years (88% and
87%, compared with those who were treated with BR (74%).
“If you look at patients with IGHV-mutated disease, we
see this same trend,” she added.
As expected, patients assigned to BR had greater rates
of myelosuppression, while those assigned to an ibrutinib-
containing arm had higher rates of atrial fibrillation and
hypertension.
Ultimately, the decision comes down to the treating
hematologist’s judgment on whether it is appropriate to
treat a healthy, fit, 74-year-old patient with BR. “Personally
I never use BR, as there is no plateau on the curve,” Dr.
O’Brien said. “The main reason I’m still interested in FCR
is because I do think there is a cure fraction. If there is no
cure fraction with BR, I would rather give the regimen that
doesn’t have myelosuppression.”
Dr. Stilgenbauer further supported the role of novel
therapies in the treatment of this older patient, citing
data on acalabrutinib, a recently FDA-approved, second-
generation Bruton tyrosine kinase inhibitor. In the
ELEVATE TN study, treatment-naïve patients were ran-
domly assigned 1:1:1 to acalabrutinib alone, acalabruti-
nib + obinutuzumab, or obinutuzumab + chlorambucil. 7
Patients in both acalabrutinib arms had significantly
higher PFS rates (HR=0.10 with acalabrutinib alone and
HR=0.20 with acalabrutinib + obinutuzumab; p<0.0001
for both comparisons). Subgroup analyses also revealed
that patients with IGHV-mutated disease derived greater
benefit from acalabrutinib therapy than chlorambucil-
based therapy.
The OS results were particularly impressive, he added.
“Despite the opportunity for patients to cross over, re-
searchers observed at least a trend in favor of a survival
advantage with novel therapy compared with chemother-
apy,” he explained. The findings suggest that, “not only
for young patients, but for the vast majority of elderly
patients, it is better to have a chemotherapy-free option
in the frontline setting.”
The CLL14 trial, which tested chlorambucil + obinutu-
zumab against venetoclax + obinutuzumab in previously
untreated older patients or those considered unfit for
standard chemoimmunotherapy, also supported use of a
chemotherapy-free option in this population. 8 The novel
therapy combination led to a significant improvement
in PFS, compared with the chlorambucil-based regimen
(88.2% vs. 64.1%). The survival benefit was seen in pa-
tients with or without mutated disease.
Adverse events were balanced between the treatment
arms, Dr. Stilgenbauer noted. Patients treated with the
venetoclax combination had slightly more neutropenia,
but this did not translate into more infections.
Case #3: CLL With Del17p
Finally, both CLL experts revisited the original patient
scenario to discuss how their treatment approach would
change if the patient had been found to have del17p.
“Until recently, there was a simple straightforward an-
swer to this question – ibrutinib – because these patients
[have poor responses] to chemotherapy,” Dr. O’Brien said.
“Del17p is such a poor prognostic factor that it renders
mutation status irrelevant.”
For example, in the CLL8 trial, which compared FCR with
fludarabine + cyclophosphamide, patients with del17p had
far worse survival than the overall population, whether they
had IGHV-mutated disease or not. “The median survival was
about 1 year, so these patients had very poor survival with
FCR – arguably the best chemotherapy that we have.”
Dr. O’Brien noted that, thankfully, del17p incidence is
quite low in upfront treatment of CLL. Still, that also makes
it difficult to collect data on treatment. In data reported
by the National Institutes of Health, older patients with
CLL with del17p or TP53 mutation had 5-year PFS rates of
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