FEATURES
Is Chemoimmunotherapy
for Upfront CLL on Life
Support?
For years, standard of care first-line treatment for chronic
lymphocytic leukemia (CLL) included the FCR (fludarabine,
cyclophosphamide, rituximab) chemoimmunotherapy regimen.
However, the past decade has brought tremendous innovation
in the treatment of CLL. With seven new drug approvals in the
past 5 years alone, patients with CLL now have more options
then ever – as do the hematologists who treat them.
This dilemma was the subject of a debate session at
the 2019 ASH Annual Meeting, where two leading CLL
experts discussed whether the old standby FCR regimen
still has a role in upfront treatment of patients with
CLL, or whether clinicians should “pull the plug” on
chemoimmunotherapy.
Susan M. O’Brien, MD, Associate Director for Clinical
Science at the Chao Family Comprehensive Cancer Center
at the University of California, Irvine, and Stephan
Stilgenbauer, MD, Deputy Chair of the Department of
Internal Medicine at the University of Ulm in Germany,
tackled this question through a discussion of several
patient scenarios, supporting their viewpoints with data
on the use of novel treatments such as ibrutinib and
venetoclax.
Case #1: Previously Untreated CLL
To start the discussion, Drs. O’Brien and Stilgenbauer were
presented with the following scenario: A patient was diag-
nosed with CLL at age 57 and was followed with watchful
waiting. After 5 years, the patient, now 62, has a white
blood cell count of 102,000/µL, an absolute neutrophil
count of 1,000, a platelet count of 90×10 9 /L, and hemoglo-
bin level of 10.4 g/dL. The patient had a 4 cm right axillary
node, 3 cm left axillary node, bilateral 2 cm cervical nodes,
and palpable spleen. Serum chemistry was normal.
With no change in the patient’s FISH or TP53 status,
Dr. O’Brien opted to treat with FCR, based on results from
a randomized phase III trial published by Shanafelt et al.
in The New England Journal of Medicine in 2019. 1 Patients
with previously untreated CLL who were ≤70 years were
randomized 2:1 to receive either ibrutinib + rituximab for
6 cycles followed by ibrutinib alone until progression, or 6
cycles of FCR. Patients with del17p were excluded.
While ibrutinib + rituximab was associated with
8
Focus on Lymphoid & Plasma Cell Malignancies
significantly higher rates of 3-year progression-free
survival (PFS; 89.4% vs. 72.9%; hazard ratio [HR] = 0.35;
95% CI 0.22-0.56; p<0.001) and 3-year overall surviv-
al (OS; 98.8% vs. 91.5%; HR=0.17; 95% CI 0.05-0.54;
p<0.001) in the overall population, Dr. O’Brien noted
that “[the subset of] IGHV-unmutated patients is really
where we see all of the benefit.” In a subgroup analysis
of patients with and without IGHV-mutated disease,
those without the mutation had a 3-year PFS of 90.7%
with ibrutinib + rituximab, compared with 62.5% with
FCR (HR=0.26; 95% CI 0.14-0.50). However, in those with
the IGHV mutation, the 3-year PFS rates were similar
between arms: 87.7% for ibrutinib + rituximab versus
88.0% for FCR (HR=0.44; 95% CI 0.14-1.36).
“This is not that surprising, because we know that
patients with an unmutated immunoglobulin gene have
much shorter PFS with any chemotherapy that you give
them [compared with those with mutated IGHV],” Dr.
O’Brien said. “The relevant point is that, so far, we don’t
have any difference based on mutation status.”
In response, Dr. Stilgenbauer noted that this trial was
not powered for retrospective subgroup analysis based on
IGHV status. “Patients with mutated IGHV status derived
benefit from ibrutinib + rituximab over FCR simply based
on group size,” he said. “More important, there was a dif-
ference in OS. It was a 2:1 randomization, therefore, it is
not 4 deaths versus 10 deaths, but 4 deaths with ibrutinib
versus 20 with FCR, or a 1% versus 6% death rate within
a relatively short follow-up time. To me, this is the key
argument that ibrutinib + rituximab or ibrutinib alone is
the better treatment.”
Along with efficacy, tolerability is a crucial component
of treatment consideration, Dr. Stilgenbauer added. Given
available evidence, novel agents are preferable over stan-
dard chemoimmunotherapies.
“Of note, even in young CLL patients fit to withstand
FCR, [rates of] neutropenia, anemia, and thrombocytope-
nia are several-fold higher with FCR treatment,” he said.
He added that “[incidence of] infection and neutropenic
fever were much higher.”
In response to the argument that clinicians may give
ibrutinib + rituximab to avoid dealing with myelosuppression,
Dr. O’Brien said she still supported use of FCR because she