H e m a t o lo g y E d u c a t io n - European Hematology Association

DLBCL that mostly occurs in young patients. 63 This subtype
is defined by a combination of clinical and pathological
features and some cases may have pathological
features reminiscent of Hodgkin’s lymphoma, all of
which can confound an accurate diagnosis. 7,64 Two
recent studies using GEP have confirmed the unique
biological identity of PMBL and have shown a strong
relationship between PMBL and Hodgkin’s lymphoma
(Figure 4A and 4B). 65,66 Cases of PMBL could be accurately
identified by a model using 35 genes that were more
highly expressed in PMBL and 11 genes that were more
highly expressed in DLBCL. 65 When this model was
applied to 46 patients with a diagnosis of PMBL, 76%
were classified as PMBL. Of the remaining 11 cases,
however, seven and four were classified as belonging to
the GCB and ABC DLBCL subtypes, respectively, indicating
that, although these latter cases predominantly
involved the mediastinum, they were not PMBL.
Clinically, cases identified as PMBL by gene expression
appeared to have a relatively favorable 5-year survival
of 64% compared to 59% and 30%, respectively, for the
GCB and ABC DLBCL subtypes.
Over half of PMBL cases and three Hodgkin’s lymphoma
cell lines had gains/amplifications in a region of
chromosome 9p. The amplicon on chromosome 9p
includes JAK2, which encodes a tyrosine kinase, and
SMARCA2, which encodes a putative chromatin regulator.
Functional studies are needed to assess the relative
contributions of each of these chromosome 9p genes to
the pathogenesis of PMBL. 65 To identify oncogenes in
this amplicon, an RNAi screen was performed targeting
amplicon genes and identified JAK2 and the histone
demethylase, JMJD2C, as essential genes. 67 Inhibition of
JAK2 and JMJD2C cooperated in killing these lymphomas
by decreasing tyrosine 41 phosphorylation and
increasing lysine 9 trimethylation of histone H3, promoting
heterochromatin formation. MYC, a major target
of JAK2-mediated histone phosphorylation, was
silenced after JAK2 and JMJD2C inhibition, with a corresponding
increase in repressive chromatin. Thus,
JAK2 and JMJD2C cooperative to remodel the PMBL
epigenome, and provides rationale for developing JAK2
and JMJD2C inhibitors.
Treatment strategies in primary mediastinal B
cell lymphoma
Currently, the treatment standard for PMBL entails
immunochemothearpy such as R-CHOP followed by
involved field radiation. 68 Unfortunately, the outcome is
suboptimal due to treatment failure in approximately
25% of patients despite the recommended use of radiation,
which has long-term side effects. This and other
studies have suggested that more dose-intense regimens
such as MACOP-B or VACOP-B yield a superior outcome
compared to CHOP, raising a question of the optimal
chemotherapy for PMBL. 68-72 Interestingly, the benefit
of dose intensity in PMBL is supported by molecular
evidence showing its close molecular relationship with
nodular sclerosis Hodgkin’s lymphoma, where the
value of dose intense regimens such as escalated BEA-
COPP is well-demonstrated. 73 Based on such evidence
that dose intensity is important in PMBL, Dunleavy et al.
assessed DA-EPOCH-R, a dose intense regimen, without
radiotherapy in PMBL. 74,75 In a recent update of 40
patients with untreated PMBL, the EFS and OS were
95% and 100%, respectively, at the median 4-year follow-up.
Importantly, only two patients required consolidation
radiation treatment and no patients have progressed
(Dunleavy et al., 2011, Abstract submitted at the
11 th International Conference on Malignant Lymphoma,
Lugano, Switzerland). These results suggest that DA-
EPOCH-R obviates the need for radiation in most
patients with PMBL, thus eliminating the risk of longterm
toxicities such as secondary malignancies and
heart disease. This is particularly important given that
patients afflicted with PMBL are typically young and
often women, and are at increased risk of breast and
other cancers as well as late term toxicities.
Although the outcome of PMBL is excellent with regimens
such as DA-EPOCH-R, it would be important to
further reduce the toxicity and length of treatment.
Hence, targeted agents will be important to test in
PMBL. In this regard, RNAi screens have identified JAK2
as a potentially important target for PMBL. Mutations of
JAK2 have been implicated in myeloproliferative disorders,
and the selective JAK 1/2 inhibitor, INCB18424
from Incyte corporation, has shown significant activity
in these diseases. 76,77 Presently trials are planned to assess
inhibitors of the JAK pathway in DLBCL including
PMBL, but no clinical data is available at this time.
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