NcXHF

THERAPIES AND INDICATIONS FOR PH-NEGATIVE MPNs
Current Therapies and Their Indications for the Philadelphia-
Negative Myeloproliferative Neoplasms
Jean-Jacques Kiladjian, MD, PhD
OVERVIEW
The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented
intensive basic and clinical research in Philadelphia-negative myeloproliferative neoplasms (MPNs). During these years, many new
potential targets for therapy were identified that opened the era of targeted therapy for these diseases. However, only one new drug
(ruxolitinib) has been approved during the past 40 years, and, although promising new therapies are evaluated, the armamentarium
to treat MPN still relies on conventional drugs, like cytotoxic agents and anagrelide. The exact role of interferon (IFN) alfa still needs
to be clarified in randomized studies, although it has been shown to be effective in MPNs for more than 25 years. The current
therapeutic strategy for MPNs is based on the risk of vascular complication, which is the main cause of mortality and mortality in the
medium term. However, the long-term outcome may be different, with an increasing risk of transformation to myelodysplastic syndrome
or acute leukemia during follow-up times. Medicines able to change this natural history have not been clearly identified yet, and
allogeneic stem cell transplantation currently remains the unique curative approach, which is only justified for patients with high-risk
myelofibrosis or for patients with MPNs that have transformed to myelodysplasia or acute leukemia.
For decades, the armamentarium to treat Philadelphianegative
myeloproliferative neoplasms (MPNs), including
polycythemia vera (PV), essential thrombocythemia
(ET), and primary myelofıbrosis (PMF), was reduced to a
small handful of cytotoxic drugs like hydroxyurea (HU);
busulfan; and, in some countries, pipobroman. 1 Since the
discovery of the JAK2 V617F mutation 10 years ago followed
by the discovery of many other genetic alterations, 2 our
knowledge of the pathophysiology of these disorders has dramatically
changed, with the identifıcation of deregulated crucial
signaling pathways like the JAK-STAT (signal transducer
and activator of transcription) pathway or mutations affecting
the epigenome. With these major advances, MPNs have
entered into a new era of targeted therapy, inaugurated with
the approval of ruxolitinib, a JAK1/JAK2 inhibitor to treat
myelofıbrosis (MF) 3,4 and PV. 5
With conventional therapies, the treatment of MPNs
mainly aims at reducing the risk of vascular events (including
thrombosis and hemorrhage), which are the main causes of
mortality and morbidity over short and medium time periods.
6,7 However, the outcome of patients with these chronic
malignancies is different over the long-term evaluations (i.e.,
after 15 to 20 years of evolution), when transformation to myelodysplastic
syndrome (MDS) or acute myeloid leukemia
(AML) becomes a major concern, as demonstrated by the longterm
analyses of a randomized study in patients with PV after
more than 16 years of median follow-up time. 8 The development
of new therapies raises the hope of new objectives, including
reduction of the long-term risk of transformation to MDS or
AML; achievement of molecular or histopathologic complete
remissions; and, possibly, cure. However, to date, only allogeneic
hematopoietic stem-cell transplantation (ASCT) can cure
selected high-risk patients with MF.
VASCULAR RISK ASSESSMENT
The evaluation of the risk of vascular complications is a cornerstone
of current MPN management, especially in PV and
ET. Risk stratifıcation is reviewed in detail in a companion
article in this volume (Moliterno and Pemmaraju), and this
paragraph will focus on a few elements useful for decision
making in MPN therapy. Indeed, in the absence of curative
therapy, the aim of this risk-based classifıcation is to avoid
the use of cytoreductive therapy in patients who are at low
risk of developing thrombosis or hemorrhage. Although
many risk factors have been assessed and have had some relevance
in retrospective studies, the most reliable parameters
remain very easy to collect: age and history of vascular events.
Patients younger than age 60 and without any previous
thrombosis or bleeding related to their MPN are at low risk of
developing vascular complications. In contrast, patients with
one or both these features are at high vascular risk and will
benefıt from cytoreductive therapy.
From the Clinical Investigations Center, Hôpital Saint-Louis, Paris, France.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Jean-Jacques Kiladjian, MD, PhD, Clinical Investigations Center, Hôpital Saint-Louis, 1 Ave. Claude Vellefaux, Paris 75010, France; email: jean-jacques.kiladjian@sls.aphp.fr.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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