Written in Blood
• the m7-FLIPI (which includes the mutation status of seven genes:
EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11)
• the Eastern Cooperative Oncology Group performance status at the
time of treatment initiation (ECOG-PS)
Researchers used clinical and molecular data from two independent
cohorts of patients with symptomatic, advanced stage or bulky FL who
were in need of first-line immunochemotherapy, but who were considered ineligible for curative radiotherapy:
• German Low-Grade Lymphoma Study Group (GLSG) trial (n=151)
• British Columbia Cancer Agency (BCCA; n=107)
In the randomized GLSG study, patients with advanced, bulky disease
received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and interferon maintenance therapy. The median
patient age was 57 years (range = 27-77 years), and 51 percent (n=77)
had high-risk disease, according to FLIPI score. After a median follow-up
of 7.7 years, the five-year failure-free survival (FFS) was 66 percent and
the five-year OS was 83 percent.
The BCCA group included patients from the population-based
BCCA registry who received R-CVP (rituximab, cyclophosphamide,
vincristine, and prednisone), followed by rituximab maintenance
therapy by intention to treat in 87 percent of patients (n=93). The
median patient age was 62 years (range = 37-83 years), and 50 percent
(n=53) had high-risk disease, according to FLIPI score. After a median
follow-up of 6.7 years, the five-year FFS and OS rates were 58 percent
and 74 percent, respectively.
Dr. Jurinovic and colleagues calculated two risk models that specifically predict POD24 using data from the GLSG cohort: In the first model,
coefficients for high-risk FLIPI and ECOG-PS >1 were not penalized
(forcing these variables into the model). In the second model, all coefficients were penalized.
The BCCA cohort was used as an independent validation cohort.
Nineteen patients (13%) from GLSG and five (5%) from BCCA
were not evaluable for POD24. Among the remaining patients, POD24
occurred in 17 percent of the GLSG group (n=23) and 23 percent of the
BCCA group (n=23).
OS differed significantly between patients with and without POD24,
with six patients in the GLSG group and four patients in the BCCA
group alive at five years. The five-year OS rates for GLSG patients with
and without POD24 were 41 percent versus 91 percent (hazard ratio
[HR] = 9.72; 95% CI 4.51-20.96; p<0.001) and 26 percent versus 86 percent for the BCCA cohort (HR=11.93; 95% CI 5.31-26.76; p<0.001).
These results confirmed the predictive utility of POD24. “[POD24]
very closely reflects either the aggressiveness of the disease and/or
treatment-specific resistance,” the authors noted. ”POD24 will be useful immediately in clinical
practice to select high-risk
patients for experimental
salvage treatments.”
First, the researchers
evaluated FLIPI risk in
patients with and without
POD24, finding that those
with high-risk FLIPI and no
POD24 did not have inferior
FFS compared with those
with low-risk FLIPI and
no POD24. “FLIPI, which
uses only clinical factors
and classifies 51 percent of
GLSG and 50 percent of
BCCA patients as high-risk,
overestimates the number of
patients with poor outcome,”
they reported.
Next, using the m7—VINDI JURINOVIC, MD
FLIPI model, the researchers
“Disease
progression
within 24
months will be
useful to select
high-risk patients
for experimental
salvage
treatments.”
38
ASH Clinical News
found that 28 percent of GLSG patients (n=43) and 22 percent of BCCA
patients (n=24) were classified as high-risk. These patients were significantly more likely to develop POD24 (OR=5.82 in the GLSG group;
p=0.00031 and OR=4.76 in the BCCA group; p=0.0052).
For those with POD24, the five-year OS was 65 percent in the GLSG
group and 90 percent in the BCCA group, compared with 42 percent and
84 percent, respectively, for those without POD24 (HR=3.4 in the GLSG
group and 4.9 in the BCCA group; p<0.0001 for both).
Compared with FLIPI, the m7-FLIPI model had greater specificity for
predicting POD24 (56% vs. 79% in the GLSG group and 58% vs. 86% in
the BCCA group). However, 21 percent of GLSG patients and 14 percent
of BCCA patients who did not experience POD24 were assigned as
high-risk patients per m7-FLIPI measures; six percent and 12 percent of
patients, respectively, were classified as low-risk m7-FLIPI but developed
POD24. In both cohorts, though, high-risk m7-FLIPI was associated
with a shorter FFS and OS among patients without POD24. There also
was a subset of patients with POD24 who were not detected by any of the
risk models, which presents the need for improvements and integration
of additional biomarkers, they added.
“The m7-FLIPI has the highest accuracy and positive predictive value
for POD24 among all pre-treatment risk models,” Dr. Jurinovic and colleagues concluded. “Also, high-risk m7-FLIPI is associated with inferior
outcome in patients who do not fail treatment within 24 months, a subset
currently missed by the POD24 classifier.”
“The m7-FLIPI establishes solid grounds for upfront patient stratification by actual risk, however several challenges still need to be addressed before it can be applied in clinical trials and practice,” the authors
cautioned, including standardization of molecular technologies and
analysis pipelines to ensure widely reproducible results.
The study’s results are limited because it analyzed a specific patient
population that might not be reflective of patients seen in real-world
clinical practice. The authors recommend a larger coh ort and longer
follow-up to further understand these results.
REFERENCE
Jurinovic V, Kridel R, Staiger AM, et al. Prospective clinicogenetic risk models to predict early progression of follicular
lymphoma after first-line immunochemotherapy. Blood. 2016. [Epub ahead of print]
Lenalidomide Plus Bendamustine
and Rituximab Led to Increased
Activity, Increased Toxicity in Older
Patients With Untreated Mantle
Cell Lymphoma
Mantle cell lymphoma (MCL) is
associated with a median overall
survival (OS) of five years, and for
elderly patients – who comprise a
majority of the MCL population
– standard therapy is not defined.
In a phase I/II trial by the Nordic
Lymphoma Group, researchers
found that adding the immunomodulatory agent lenalidomide
to bendamustine and rituximab
(L+BR) increased response rates
and extended progression-free
survival (PFS) compared with
rates seen with BR alone in earlier
clinical trials, but this combination
also led to higher-than-expected
rates of infections and second
primary malignancies (SPMs).
“For older patients, who
constitute the majority of the MCL
population, there is no defined
standard therapy,” the authors, led
by Alexandra AlbertssonLindblad, MD, from Skåne University Hospital in Lund, Sweden,
explained. “The German STiL
group compared BR and R-CHOP
(rituximab, cyclophosphamide,
doxorubicin, vincristine, and
prednisone) in a randomized trial,
with the conclusion that BR was
associated with higher PFS and
less toxicity, making this regimen
preferable.”
Given that lenalidomide has
demonstrated activity as firstline treatment for MCL, as well
as relapsed/refractory MCL, Dr.
Albertsson-Lindblad and investigators examined the safety and
efficacy of L+BR as first-line treat-
September 2016