open access: Nature Reviews: Key Advances in Medicine

in CLL. Four cases were analyzed and 46
somatic mutations were identified. 2 Four
genes with recurrent mutations were confirmed
in 363 patients with CLL: NOTCH1,
XPO1, MYD88 and KLHL6. Mutations in
MYD88 and KLHL6 were predominantly
found in patients with CLL who had a high
number of somatic hypermutations in the
variable region of IGHV, whereas mutations
in NOTCH1 and XPO1 were mostly
detected in patients who did not have IGHV
mutations. These findings indicate a role
for mutations in NOTCH1, MYD88 and
XPO1 in the clinical evolution of CLL.
In a similar study on 91 patients with
CLL, Wang et al. 3 performed massively parallel
sequencing of 88 whole exomes and
genomes. They found nine genes that are
mutated at significant frequencies, including
four with established roles (TP53 in 15%
of patients, ATM in 9%, MYD88 in 10%, and
NOTCH1 in 4%) and five genes without
established roles (SF3B1, ZMYM3, MAPK1,
FBXW7, and DDX3X). SF3B1, which functions
at the catalytic core of the spliceosome,
was the second most frequently mutated
gene (15% of patients). SF3B1 mutations
occurred primarily in tumors with deletions
in chromosome 11q, which are associated
with a poor prognosis. The authors also
showed that mutations in SF3B1 induced
alterations in pre–mRNA splicing.
All three studies have considerable clinical
implications for CLL. Firstly, the stem
cell origin of CLL offers a plausible explanation
for the fact that conventional chemoimmunotherapies
regularly fail to cure CLL.
This type of therapy may not effectively
eradi cate the HSC pool that regenerates CLL
cells. Secondly, our understanding of the
genetic basis of CLL has improved. These
advances will facilitate the development of
better-targeted therapies for this disease.
In the past 10 years, a remarkable improvement
in overall survival was achieved for
several types of B-cell lymphomas. This
improvement was largely a result of the use
of rituximab, an antibody targeting CD20.
In follicular lymphoma, several randomized
trials have demonstrated that addition
of rituximab to different chemotherapeutic
regimens can prolong survival; therefore,
rituximab-based chemoimmuno therapy is
the current standard first-line treatment.
Disease progression usually occurs 3–5 years
after initial therapy and rituximab maintenance
therapy was previously shown to have
a clinical benefit in patients with relapsed
disease. The PRIMA study 4 evaluated the
benefit of rituximab maintenance therapy
after first-line treatment for follicular lymphoma.
In this study, 1,019 patients who
achieved a response after different chemoimmunotherapies
(rituximab plus cyclophosphamide,
vincristine, doxo rubicin
and prednisone [R-CHOP]; rituximab plus
cyclophosphamide, vincristine and prednisone;
or rituximab plus fludarabine,
cyclo phosphamide and mitoxantrone) were
randomly assigned to receive 2 years of maintenance
therapy with rituximab (375 mg/m²
every 8 weeks) or no further therapy (observation).
The maintenance treatment was
well tolerated. Infectious events were more
common in the maintenance arm than the
observation arm, but were mostly mild or
moderate and only a few patients withdrew
from the study because of toxicity. No significant
decrease in immunoglobulin levels was
observed and patient quality of life was not
affected by the repeated rituximab infusions.
Maintenance therapy improved the
quality of response and prolonged progression-free
survival and event-free survival.
No effect on overall survival was shown
for rituximab maintenance therapy, which
might be explained by a short follow-up
period and the efficacy of salvage therapies.
However, rituximab should be considered as
maintenance therapy after first-line chemoimmunotherapy
in follicular lymphoma, as
the duration of response to first-line therapy
has prognostic value. 5
The outstanding outcome observed in
patients with Hodgkin lymphoma allowed
researchers to consider a reduction in
treatment intensity to reduce both acute
and long-term adverse events, such as
infertility and secondary neoplasias. The
Key advances
■ Genomic analyses of patients with
chronic lymphocytic leukemia identified
mutations in genes such as Notch1 and
SF3B1 that have prognostic impact 2,3
■ Rituximab maintenance therapy after
first-line treatment with rituximab-based
chemoimmunotherapy significantly
improves the quality of response and
prolongs progression-free survival in
patients with follicular lymphoma 4
■ In advanced-stage, high-risk Hodgkin
lymphoma, reduction in treatment
intensity has not improved outcome and
further analyses are needed to define the
optimal treatment intensity 7
■ Patients with diffuse large B-cell
lymphoma, in particular, those with a
non-germinal center B-cell-like subtype,
benefit from the addition of bortezomib
to first-line chemoimmunotherapy 9
CLINICAL ONCOLOGY
HD10 trial of the German Hodgkin Study
Group (GHSG) 6 showed that two cycles of
ABVD (doxo rubicin, bleomycin, vinblastine
and dacarbazine) therapy followed
by 20 Gy of involved–field radio therapy
was as efficacious as four cycles of ABVD
and 30 Gy of involved-field radiotherapy
in patients with stage I or II disease and
favorable risk factors. Reduced treatment
intensity may be considered as the new
standard treatment for early-stage, lowrisk
Hodgkin lymphoma. By contrast, the
reduction of treatment intensity is debated
in advanced-stage Hodgkin lymphoma
(stage II–IV or IIB with extranodal lesions
or mediastinal mass).
The results of the HD12 trial by Borchmann
et al. 7 were slightly disappointing, because
the reduction of the intensity of chemotherapy
from eight cycles of high-dose
BEACOPP (bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine,
procarbazine and prednisolone) to four
cycles of high-dose BEACOPP followed
by four cycles of BEACOPP at the baseline
dose did not reduce the severity of toxicity or
treatment-related mortality, but could possibly
reduce efficacy. Thus, the GHSG considers
eight cycles of high-dose BEACOPP
as the standard treatment for advancedstage
Hodgkin lymphoma and is evaluating
other individualized, PET-controlled dose
reduction strategies in ongoing trials.
Viviani et al. 8 compared BEACOPP and
ABVD in advanced-stage Hodgkin lymphoma.
In this trial, 331 patients received
either four cycles of high-dose BEACOPP
plus four cycles of BEACOPP at baseline
dose or six to eight cycles of ABVD; each
treatment was followed by involved-field
radiotherapy. The estimated 7-year rate of
freedom from first progression was 85% in
patients treated with BEACOPP and 73%
in patients treated with ABVD. However,
all patients with a relapse or less than complete
response after initial therapy were
treated with multiple cycles of ifosfamidecontaining
chemotherapy followed by
KEY ADVANCES IN MEDICINE JANUARY 2012 | S15
© Eraxion | Dreamstime.com