By Mikkael A. Sekeres, MD, MS
|Please note the following clarification to the
7th paragraph in this article: Among 23 evaluable patients with myelofibrosis who received 15 mg of the study
drug twice a day and stayed on the study for at least six months, 11 (48 percent)
experienced a ≥35 percent reduction in spleen volume by MRI.
The Roman god Janus was associated with doorways, beginnings,
and transitions. Janus was often depicted as being two-faced, looking both
backward and forward — to the past and toward the future. The transition month
January owes its name to Janus — as do janitors, those guardians of clean who
were once considered ushers, or doorkeepers. But unlike his more famous Pantheon
counterparts, Mars and Venus, Janus was virtually forgotten after the fall of Rome, except by scholars
of Classical antiquity.
In early 2005, the god was awakened when four groups of
investigators reported a recurrent mutation in Janus kinase 2 (originally “just
another kinase”), the JAK2 V617F mutation, associated with myeloproliferative
neoplasms. As a consequence of this mutation, JAK2 — a cytoplasmic tyrosine
kinase that transduces signals, particularly those initiated by hematopoietic
growth factors — is rendered constitutively active, “opening the door” to
cytokine-independent cell proliferation. The phenotype most commonly associated
with JAK2 V617F is polycythemia vera, for which detection of a JAK2 mutation
has become almost a sine qua non. JAK2 mutations are also present in
approximately half of the cases of essential thrombocythemia and chronic
idiopathic myelofibrosis, and less commonly in other myeloid neoplasms.
Identifying a single lesion responsible for disease
initiation and potentiation is the goal of personalized therapy. How close have
we come to again quieting the god Janus? This question will be addressed this
afternoon at 4:30 p.m. in rooms 393-396 by a series of investigators exploring
the relationship between the mutation, disease status, and targeted therapy.
Dr. Francesco Passamonti, from Pavia, Italy,
will report results from a study of the relationship between JAK2 mutant allele
burden and progression to myelofibrosis in 320 polycythemia vera patients
(abstract #751). Dr. Passamonti and his colleagues found that patients with
more than 50 percent mutant alleles have a significantly worse hematologic
transformation-free survival than those with a lower mutant allele burden. When
considered as a continuous variable, allele burden is also related to
myelofibrosis-free survival, though not to AML transformation.
Providing provocative pre-clinical data on the potential
for combination therapies, Dr. Min Lu and colleagues from New York will report
on in vitro data using a combination of a Bcl-xL inhibitor (ABT-737) and
a JAK2 inhibitor (either erlotinib or INCB018424) to selectively eliminate JAK2
V617F progenitors (abstract #752). When ABT-737 was used in combination with
either of the JAK2 inhibitors, approximately 40 percent of JAK2 V617F CD34+
cells underwent apoptosis, compared to approximately 5 percent of cells treated
with each agent alone. We can anticipate future studies of combination
therapies with JAK2 inhibitors in myeloproliferative neoplasms.
Two presenters will discuss the use of lestaurtinib (CEP
701), an oral multikinase inhibitor, in myeloproliferative neoplasms associated
with the JAK2 (V617F) mutation. The first, by Dr. Alison Moliterno from Johns
Hopkins and her colleagues, is an open-label study of lestaurtinib in 39
patients with polycythemia vera or essential thombocythemia associated with the
JAK2 abnormality, with a primary endpoint of reduction in the JAK2 V617F
neutrophil allele burden (abstract #753). The second trial, presented by Dr.
Elizabeth Hexner on behalf of the Myeloproliferative Disorders Research
Consortium, is a phase I/II study of lestaurtinib in 19 patients with
myelofibrosis associated with JAK2 V617F (abstract #754). Both studies show the
drug to generally be safe and well tolerated, with no maximum tolerated dose
(MTD) reached on the phase I portion of the latter study. In both studies,
lestaurtinib caused at least modest reductions in allele burden and reduction
in spleen size.
Two other studies also focus on myelofibrosis associated
with the JAK2 mutation. The first is a phase I study of TG101348, a
JAK2-selective small molecule inhibitor, in 59 patients, which will be
discussed by Dr. Animesh Pardanani from Mayo Clinic. In this study, 67 percent
of patients experienced reduction in spleen size, and 48 percent had a
reduction in allele burden (abstract #755). The second myelofibrosis clinical
result, presented by Dr. Srdan Verstovsek from M. D. Anderson Cancer Center and
his colleagues, describes long-term follow-up of 155 patients with myelofibrosis
treated with INCB018424 (abstract #756). Optimization of dosing predicated on
baseline platelet count resulted in enhanced drug tolerability, with 15 percent
of patients experiencing reduction in spleen size and general improvement in
exercise capacity and symptoms.
In an interview in 1995 with Rolling Stone
magazine, Mick Jagger explained that the song, “Jumpin’ Jack Flash” is “… about
having a hard time and getting out.” With so many new therapies coming down the
road for patients with myeloproliferative neoplasms, getting JAK2 out may be an
apt metaphor for the future.
Dr. Sekeres indicated no relevant conflicts of
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