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

16 th Congress of the European Hematology Association
the first of these agents entering clinical phase I testing
a little over 2 years from the discovery of JAK2-V617F
(Figure 1).
The agent that is farthest along in development is
INCB018424 (JAK1/2 inhibitor), which was tested in
153 patients with PMF and post-PV/ET myelofibrosis in
a Phase I/II study. 20 Substantial clinical benefit and
improvement in symptoms were observed, such as a
reduction in pruritus, and patients gained weight and
increased their walking distance. In addition, serial
administration of the MF-SAF throughout this trial
demonstrated a significant improvement in MF associated
symptoms. 21 The greatest improvements in MF-SAF
scores were reported by patients experiencing abdominal
discomfort, night sweats, pruritus, and fever.
Responses were equivalent regardless of subtype of MF
(i.e., PMF vs. post-ET or post-PV MF) or JAK2 mutation
status, and responses appear durable (median duration
of response >1 year). Reduction in splenomegaly (>50%
decrease in size according to criteria of the IWG-MRT)
was seen in 52% of patients at the 15 mg BID dose and
across all dose levels for 44%.
TG101348 is a selective JAK2 inhibitor s active
against FLT3 and RET. 22 In a phase I study in 59 high- or
intermediate-risk primary or post-PV/ET and PMF
patients, 47% achieved a spleen response (IWG-MRT)
at 12 months, with a mean response duration of 315
days. 23 Leukocytosis and thrombocytosis normalized in
57% and 90%, respectively. In patients with symptoms
at baseline, early satiety resolved in 56%, night sweats
in 89%, cough in 67%, pruritus resolved in 50%, and
fatigue improved in 63% of patients. JAK2V617F allele
burden was significantly reduced. 23
SB1518 is a selective JAK2 inhibitor active at low
nanomolar concentrations against both wild-type and
mutant (V671F) JAK2, as well as FLT3. 24 In a Phase I/II
study of 33 with previously treated PMF and
splenomegaly at enrollment, activity was demonstrated
with 17 of 30 patients (57%) achieving a 25% or greater
reduction in spleen volume by MRI. Side effects were of
GI nature (diarrhea, nausea, vomiting, abdominal pain)
and fatigue with little myelosuppression. 24
CYT387 inhibits Jak1/2 and TYK2, as well as other
kinases (CDK2/cyclin A, MAPK8, PRKCN, PRKD1,
ROCK2, and TBK1). 25 The overall response rate (ORR)
by IWG-MRT in the Phase I/II study was 62%. Anemia
response was 50% overall and higher in transfusion
dependent patients with 57% and 69% at 150 mg and
300 mg, respectively. Interestingly responses were seen
in 5 of 9 patients previously treated with other JAK2
inhibitors and 5 of 12 patients treated with pomalidomide.
Splenomegaly was reduced in 47%, and constitutional
disease symptoms were controlled in more than
80% of patients, including night sweats (88%), bone
pain (80%), pruritus (92%), and fever (100%).
Hyperlipasemia, transaminitis, headache, and a firstdose
effect (lightheadedness, hypotension) were DLTs
or side effects. Greater than or equal to grade 3 thrombocytopenia,
anemia, and neutropenia were seen in
27%, 7%, and 5% of patients, respectively. These
results and especially anemia results are early, need confirmation,
and a full manuscript is awaited.
MF Scenario 3: the intermediate I risk patient
Patients who are intermediate risk are probably the
most heterogeneous group amongst those with
myelofibrosis (Table 1). Individuals in this group may
have survivals that could range anywhere from as low
as 3 years to as much as 8 or 9 years. Individuals by current
prognostic scores fall into either Intermediate 1 or
Intermediate 2 group (Table 1). Given that individuals
who are intermediate 2 have survivals that range from
35–48 months, their management is best, though
amongst similar strategies as those used for high risk
patients (see next section). When deciding individualized
therapy in the heterogeneous intermediate I risk
group, one needs to try to delineate where amongst this
group an individual may lie with perhaps the current
DIPSS-Plus criteria being the most helpful to sub-stratify
an individual’s prognosis. Initially, an individual has to
be mindful of a patient’s goals, wishes, age, comorbidities,
and philosophy. Therapeutic options really fall into
two categories, one, those which would be disease
altering and potentially have higher risks, but higher
reward in terms of survival (allogeneic stem cell transplant
– Table 2) or therapies that may be disease altering;
but we do not have definitive proof of these agents
at this point in time, including JAK2 inhibition, interferon
alpha 2a, or hypomethylation therapy, such as azacitidine26
(Table 4). The next group of options would
revolve around medicines that are helpful amongst palliative
goals and finally clinical trials, which as an
umbrella term incorporates medicines of a targeted and
non-targeted nature, including JAK2 inhibitors, which
remain on clinical trials and other agents, which are efficacious
against myelofibrosis.
Goal of disease altering therapy
Now amongst these patients, if the goal is disease
course alteration, where an individual lies in that spectrum
of prognosis from 3 years to 8 years, this becomes
very important. Allogeneic stem cell transplant could
either be considered frontline therapy in this group for
individuals in the higher end of the intermediate risk
category who are appropriate stem cell candidates
based on their comorbidities and a suitable donor (Table
2). Likewise, for individuals at the longer end of the
spectrum, transplant may remain a more reasonable
backup option if other lines of therapy fail or risks
increase. Outside of stem cell transplantation, JAK2
inhibition is probably our most interesting group of
agents in this group of patients (Table 3). It may be a disease-altering
therapy, but there is no definitive proof at
this time, and randomized clinical trials are expected
with anticipation.
Allogeneic stem cell transplant (ASCT) offers the possibility
of cure to patients with MF. However, the risk of
graft versus host disease (GVHD), transplant related
mortality (TRM), and post-transplant relapse of the MF
itself make it essential to use this form of therapy only
in the most appropriate candidates. So who are the optimal
candidates for ASCT in MF? This is a highly controversial
question. We have no randomized prospective
data from which to draw conclusions. As with all decisions
in medicine, the choice and timing of ASCT in MF
is based on weighing of the risk-to-benefit ratio, as well
| 268 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)