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Review article
The renaissance of interferon therapy for the treatment of myeloid malignancies
Jean-Jacques Kiladjian,1-3 Ruben A. Mesa,4 and Ronald Hoffman5
Centre d’Investigations Cliniques, Hôpital Saint-Louis, Assistance Publique–Hôpitaux de Paris, Paris, France; 2Université Paris Diderot–Paris 7, Paris, France;
3Inserm, CIC 9504, Paris, France; 4Mayo Clinic, Scottsdale, AZ; and 5Tisch Cancer Institute Mount Sinai School of Medicine, New York, NY
IFN␣ has been used to treat malignant and
viral disorders for more than 25 years. Its
efficacy is likely the consequence of its
broad range of biologic activities, including
direct effects on malignant cells, enhancement of anti-tumor immune responses, induction of proapoptotic genes, inhibition of
angiogenesis, and promotion of the cycling
of dormant malignant stem cells. Because
of the recent development of “targeted”
therapies, the use of IFN has been dramatically reduced over the last decade. The
increasing awareness of the multistep
pathogenesis of many malignancies has
suggested, however, that such an approach using target-specific agents is not
universally effective. These observations
have resulted in a number of recent clinical trials utilizing IFN␣ in patients with
chronic myeloid leukemia (CML), systemic mast cell disease, hypereosinophilic syndrome and the Philadelphia
chromosome-negative myeloproliferative
neoplasms (MPN) with promising out-
comes. These reports provide evidence
that IFN␣, alone or in combination with
other agents, can induce surprisingly robust molecular response rates and possibly improve survival. Although IFN␣ at
present remains an experimental form of
therapy for patients with myeloid malignancies, these promising results suggest
that it may become again an important
component of the therapeutic arsenal for
this group of hematologic malignancies.
(Blood. 2011;117(18):4706-4715)
Introduction
Almost 25 years after the approval of interferon-␣ (IFN␣) for the
treatment of patients with hairy cell leukemia, its use remains
limited to a small numbers of patients with hematologic malignancies, a practice that is in contrast to its widespread use for the
treatment of patients with a number of viral diseases. This restricted
role of IFN␣ in the treatment of patients with hematologic
malignancies can in part be attributed to limited patient tolerability
and the recent availability of more effective chemotherapeutic
agents such as the purine nucleoside analogs with which to treat
patients with hairy cell leukemia, and tyrosine kinase inhibitors
(TKI) to treat patients with chronic myeloid leukemia (CML).1-3
Furthermore, the promise of additional targeted small-molecule
therapies for other forms of blood cancer has further dampened the
enthusiasm for the use of IFN␣.4 Recently, the potential limitations
of relying solely on a single small molecule targeting a specific
acquired genetic abnormality for the treatment of a number of
cancers has become increasingly apparent.5,6 This change in
strategy can be attributed to the development of resistance to TKIs
and the growing understanding that the origins and progression of
an increasing number of myeloid malignancies are likely the
consequence not of a single but multiple genetic and epigenetic
events acting in concert with a disordered tumor microenvironment.7-11 The administration of IFN␣, which is associated with a
broad range of therapeutic effects influencing multiple events
affecting the biology of tumors, might, therefore, be valuable for
use alone or in combination with other active drugs to effectively
treat patients with several myeloid malignancies.1,12-14 Furthermore, the more recent availability of pegylated (peg) forms of
IFN␣ with a more favorable toxicity and pharmacokinetic profiles
has created renewed interest in the use of IFN␣-containing
regimens to treat patients with CML, the Philadelphia chromosome–
Submitted August 11, 2010; accepted February 22, 2011. Prepublished online
as Blood First Edition paper, March 9, 2011; DOI: 10.1182/blood-201008-258772.
4706
negative myeloproliferative neoplasms (MPN), systemic mastocytosis, and the hypereosinophilic syndrome.
Mechanisms of Action of IFN
The mechanisms by which IFN therapy achieves therapeutic
responses in patients with myeloid malignancies remains the
subject of active investigation. The discovery of IFN more than
50 years ago was based on observations made concerning its role in
antiviral innate immunity.1,15 IFN proteins are traditionally categorized as type1 (␣, ␤) or viral IFN and type 2 (␥) or immune IFN.
Both type 1 and type 2 IFN exert their actions through cognate
receptor complexes, IFNAR and IFNGR1 (CD119), respectively,
which are present on the surface of cells belonging to numerous
tissues.1,15,16 The genes that encode the type 1 IFNs are located on
human chromosome 9, and the gene that encodes the single type 2
IFN is located on human chromosome 12. In addition, another
family of IFNs, the type 3 IFNs, have been recognized and include
3 proteins, IFN␭1, IFN␭2, and IFN␭3. Type 3 IFNs signal through
the IFN␭ receptor, which has a specific ligand binding chain
(IL-28R) and an IL-10R chain.17 The type 1 and type 3 IFNs have
similar biologic activities and are illustrative of biologic redundancy among the members of the IFN system.15,18 The IFN␭
receptors are, however, not highly expressed by hematopoietic cells
but act predominately at epithelial surfaces.17 In this report, the
type 1 INFs will be discussed in greatest detail because recombinant forms of IFN␣2 are exclusively approved to treat patients with
myeloid malignancies.
The production of the type 1 IFNs is induced by viral infections
whereas type 2 IFN production occurs in response to mitogenic or
antigenic stimuli.17 Most types of virally infected cells are capable
The online version of this article contains a data supplement.
© 2011 by The American Society of Hematology
BLOOD, 5 MAY 2011 䡠 VOLUME 117, NUMBER 18
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BLOOD, 5 MAY 2011 䡠 VOLUME 117, NUMBER 18
of producing type 1 IFN, whereas type 2 IFN is synthesized
exclusively by immune cells including natural killer cells, CD4⫹
T cells, and CD8⫹ T cells.1,15-17 A cell specialized for the production of large amounts of type 1 IFN, which is also necessary for
NK cell–mediated killing of virally infected cells, has been recognized.19 These naturally occurring IFN-producing cells are characterized by their round appearance, eccentric nucleus, and abundant
endoplasmic reticulum and are referred to as plasmacytoid dendritic cells (pDCs).19 These cells constitutively express IFN
regulatory factors 7 and 8, which, once phosphorylated, drive the
expression of the type I family of IFN genes, permitting the
amplification of type 1 IFN production in response to singlestranded RNA and DNA viruses.17
IFNs are normally present at low levels in plasma, which
presumably plays a role in antiviral and antitumor surveillance.17,20
The type 1 IFNs induce cell-autonomous antiviral immunity,
whereas IFN␥ acts predominately on macrophages to induce a
microbicidal state against intracellular nonviral pathogens.17 The
levels of the type 1 IFNs dramatically increase in response to viral
infections.20 IFN inhibits several steps involved in viral multiplication by altering the synthesis of viral polypeptides.1,20 These
antiviral effects have led to the successful use of IFN for the
treatment of chronic hepatitis B and C, Kaposi sarcoma (human
herpes virus 8), and genital warts (human papillomavirus).20
Although IFN␥ has some antiviral activity, its structure differs
from the type 1 INFs.1,15-17 Patients with chronic granulomatous
disease, a rare genetic disorder of superoxide generation, respond
to therapy with IFN␥ with increased superoxide generation resulting in fewer bacterial infections.21 Patients with severe congenital
osteopetrosis have decreased bone resorption associated with
defective leukocyte superoxide generation.22 IFN␥ therapy in these
patients also results in a reduced incidence of infections as well as a
reduction in trabecular bone mass.22 IFN␥-1b is currently approved
for the treatment of patients with these 2 genetic disorders.21,22
IFN␣ binds to a cell-surface complex consisting of 2 transmembrane type 1 IFN receptor subunits, IFNAR1 and IFNAR2, which
are members of the class II cytokine receptor superfamily.16,17,23
The genes for these receptors are clustered on chromosome 21.
IFNAR2 along with IFNAR1 form a high-affinity receptor complex that mediates the activities of the IFN␣.16,17 IFNAR2 has a
1000-fold greater affinity for type I IFNs than IFNAR1. IFNAR1
appears to be primarily a signal-transducing unit whereas IFNAR2
mediates both ligand binding and signaling.1,15,17 There are
3 isoforms of IFNAR2: IFNAR2a, a soluble receptor; IFNAR2b, a
short transmembrane form; and IFNAR2c, a long transmembrane
form. IFNAR2b is usually expressed at lower levels than IFNAR2c
and may exert a dominant negative effect on IFN␣ signaling by
binding ligand but not transducing signal.16,17 IFN receptors lack
tyrosine kinase activity and rely on Janus kinases (JAK) for their
phosphorylation, and signal-transducing molecules such as STATs
for the transmission of intracellular messages.17 IFNAR1 is constitutively associated with tyrosine kinase 2 (Tyk2) and IFNAR2c is
associated with JAK1.17 The interaction of IFN␣ with these
receptors results in their rearrangement, dimerization of their
subunits followed by autophosphorylation, and activation of JAK
proteins forming 2 transcriptional complexes. One complex is a
homodimer of activated STAT1 that binds a distinct promoter
sequence, the ␥ IFN–activated sites (GAS).16,17 The importance of
GAS for IFNGR signaling is well established, whereas its importance for IFN␣ responses remains obscure.24 The other transcriptional complex results in the recruitment of STAT1 to receptorbound STAT2 and the formation of STAT1-STAT2 heterodimers.16,17
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These STAT1-STAT2 heterodimers associate with the IFN regulatory factor 9 (IRF9, p48) to form a heterotrimeric complex termed
IFN stimulated gene (ISG) factor 3 (ISGF3).16,17 ISGF3 complexes
migrate into the nucleus and bind to specific elements, termed IFN
stimulated response elements (ISRE), which are located along the
promoter region of the IFN-regulated genes leading to their
transcription.16,17 Expression of the antiproliferative and proapoptotic genes associated with IFN␣ signaling are mainly under the
control of the ISGF3 complex (STAT2 and IRF9).24,25 Further
diversity of IFNAR signaling is achieved by activation of other
pathways including other STAT and non-STAT proteins. Such
alternative signaling pathways include CrkL, Rap1, MAP kinases,
VAV, and PI3-kinases.16,25,26 IFN␣ can elicit multiple biologic
functions depending on its binding affinity to receptors, the
receptor composition, and the accessory molecules expressed by
different cell types.27
Several biologic processes affected by IFN␣ have been shown
to contribute to the therapeutic effectiveness of IFN␣ against a
number of hematologic malignancies. These processes are discussed below.
The effects of IFN␣ on immune modulatory cells
A role for immune effector cells in mediating the antitumor
responses associated with the IFNs was first suggested based on
studies using a number of mouse models.1,15,28,29 IFN␣ augments
the functional activity of T cells, macrophages, and natural killer
cells, which may cooperate to target a number of malignancies
including CML.29-31 IFN␣ induces dendritic cell differentiation of
CML mononuclear cells both in vitro and in vivo. These dendritic
cells serve as antigen-presenting cells for CML-specific peptides.30-33 This is in contrast to imatinib, which inhibits T-cell and
dendritic cell activation providing evidence that these 2 drugs
likely act against CML cells by different yet possibly complementary mechanisms.34 The dendritic cells that are favored by the IFNs
are endowed with an ability to capture apoptotic bodies and
promote CD8⫹ T-cell cross-priming, which may provide a possible
explanation for the autoimmune reactions and antitumor effects
associated with IFN therapy.31
IFN therapy also increases the expression of tumor-associated
antigens and major histocompatibility complex antigens.28,31,35
Some of these gene products have been thought to be candidates for
eliciting therapeutic immune responses. Major histocompatibility
class I antigens present peptides to T cells. Proteinase 3 (P3) or
myeloblastin is a myeloid tissue restricted serine protease that is
abundantly expressed in the azurophilic granules of normal and
leukemic myeloid cells.32,36-38 IFN␣ induces P3 expression by
mononuclear cells, and increased P3 expression levels in CML
cells has been shown to be associated with a favorable patient
prognosis.33 Imatinib, by contrast, down-regulates the expression
of P3.33 IFN␣ also promotes the maturation of monocytes to
antigen-presenting cells with T-cell costimulatory potential, which
likely contribute to the generation of PR1 cytotoxic T lymphocytes
(CTL).33,36-38 CTLs specific for PR1, an HLA2.1-restricted peptide
that is derived from P3 and neutrophil elastase, have been observed
in virtually all CML patients who respond to IFN␣ therapy,
although such CTLs are not detected in nonresponders and in most
patients in remission following imatinib therapy.33,36-38 PR1-CTLs
are capable of killing CML hematopoietic progenitor cells (HPCs).36
Burchert et al have demonstrated that these antileukemic PR1CTLs persist in CML patients who continue to receive maintenance
IFN␣ therapy after imatinib therapy is interrupted.32 Furthermore,
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KILADJIAN et al
Kanodia and coworkers have reported that the numbers of PR1CTLs are increased in CML patients who remain in complete
cytogenetic remission after IFN␣ therapy is discontinued.33 This
functional immunity can be eliminated by CML cells, which
overexpress P3 by inducing deletion of high-avidity PR1-CTLs.37
IFN␣ treatment leads to continued proliferation of central memory
T cells resulting in the expansion of the PR1-CTL compartment,
which produces IFN␥ following stimulation with PR1 peptide.
Relapse in CML patients has been reported to be associated with
the inability of PR1-CTLs to continue to produce IFN␥.33 Because
imatinib and IFN␣ appear to affect CML cells by different
mechanisms, regimens employing concurrent or sequential therapy
of these agents have been evaluated to determine whether combination therapy might eliminate CML hematopoietic stem cells (HSC)
by both cytotoxic and immunologic mechanisms.7,14,39-41
The importance of immune effects associated with the therapeutic effectiveness of IFN␣ has also been reported in polycythemia
vera (PV) patients who have achieved clinical and molecular
responses following IFN␣ therapy. Expression of novel antigens by
PV cells that are capable of eliciting a potent humoral immune
response has been associated with the achievement of molecular
remissions.42,43 IFN␣ therapy has been reported to up-regulate a
putative tumor antigen termed MPD6, which is encoded by a
cryptic open reading frame located in the 3⬘-untranslated region of
myotrophin mRNA by a novel internal ribosome entry site
upstream of the MPD6 reading frame.43 Furthermore, type 1 IFNs
also enhance antibody responses to soluble antigens and promote
immunoglobulin class switching.44 These data suggest that IFN
may act in PV by regulating self-antigen repertoires, which elicit
antitumor immune reactions. The role of CTLs in the achievement
of molecular remissions in PV patients45,46 has yet to be explored.
IFN induces the expression of proapoptotic genes
IFN␣ promotes apoptosis of a variety of tumor cell types.25,47 The
induction of apoptosis by IFN␣ is frequently delayed (by 48 hours),
indicating that this effect involves the activation of a number of
ISGs that mediate this response.25,47 Gene-expression studies have
identified more than 15 ISGs with proapoptotic functions.25,47
Although these ISGs alone are probably not sufficient to induce
apoptosis, their cumulative effects likely result in apoptosis. These
mediators of apoptosis include caspase 4, caspase 8, tumor
necrosis–related apoptosis-inducing ligand (TRAIL), Fas/CD95,
the X-linked inhibitor of apoptosis (XIAP), death-activating protein kinases, IFN regulatory factors, dsRNA-activated protein
kinase, and PML (acute promyelocytic leukemia gene).25 The
induction of caspase 8 and caspase 4 by IFN may sensitize tumor
cells to death receptor (TRAIL and Fas L)–mediated apoptosis. The
ability of IFN to induce apoptosis is independent of cell-cycle
arrest, the presence of wild-type p53, or expression of Bcl-2 family
members but appears to always involve the FAS-associated death
domain (FADD)/caspase 8 signaling, activation of the caspase
cascade, which leads to disruption of mitochondrial potential and
eventual DNA fragmentation.25,47 Crosstalk between IFN activation of the PI3K/mTOR pathway and the JAK/STAT pathways
have been shown to play a role in IFN␣-induced apoptosis.25,47
Furthermore, there has been conflicting evidence as to the role that
STAT1 and STAT2 play in IFN-induced apoptosis. It appears most
likely that the PI3K and JAK-STAT pathways act independently of
each other in mediating IFN␣-induced apoptosis, and that the
particular pathway operating is dependent on the target cell
type.25,47 Several of these pathways may actually act together to
contribute to IFN␣-induced apoptosis of tumor cells.
BLOOD, 5 MAY 2011 䡠 VOLUME 117, NUMBER 18
Interferon is an inhibitor of angiogenesis
The anti-angiogenic properties of type 1 IFN has been attributed, in
part, to inhibition of basic fibroblast growth factor, IL-8, or
vascular endothelial cell growth factor gene expression.1,12,13,48 In
addition, IFN␣ directly impairs endothelial cell proliferation and
migration.1,12,13,48 Furthermore, IFN␣ can also act by up-regulating
the production of the angiostatic chemokines, CXCL9, CXCL10,
and CXCLl1.48 Whether these properties contribute to the effects of
the IFNs against human hematologic malignancies has yet to be
determined. Collectively, these studies suggest that IFN␣ therapy
may also be altering the microenvironment of tumors, thereby
contributing to the achievement of therapeutic responses.
Interferon suppresses the proliferation of hematopoietic
progenitor cells and promotes the cycling of hematopoietic
stem cells
Type 1 IFNs suppress the ability of normal human HPCs to form
colonies in vitro in the presence of a variety of cytokine combinations or conditioned media.49-51 IFN␣ acts directly against HPCs, as
this inhibitory activity has been documented using CD34⫹ cell
populations.49,50 This inhibitory role of IFN␣ has been shown to
synergize with the inhibitory activities of IFN␥, which is likely
produced by marrow auxiliary cells in response to IFN␣.51 CML
and PV CD34⫹ cells are more sensitive to the inhibitory effects of
IFN␣ than normal HPCs.49,52 CML CD34⫹ cells are characterized
by greater expression of IFNAR2 but lower expression of IFNAR1.52
The greater degree of expression of IFNAR2 by CML CD34⫹ cells
has been shown to correlate with a clinical response to IFN␣.52
Peschel and coworkers have also reported that the myelosuppressive effects of IFN␣ could also be in part attributed to the inhibition
of the paracrine production of several stimulatory hematopoietic
growth factors including GM-CSF and IL-11 and inhibition of the
production of IL-1 receptor antagonist by marrow stromal cells.53,54
IFN␣ therapy of hepatitis patients is frequently complicated by
dose-limiting thrombocytopenia.55 This has led to a more careful
examination of the effects of IFN␣ on normal megakaryocyte
development. IFN␣ directly inhibits colony forming unitmegakaryocyte proliferation and differentiation by blunting the
JAK/STAT signaling responses that occur in response to thrombopoietin (TPO), and impairs TPO-induced intracellular signaling by
up-regulating SOCS-1 expression. IFN␣ reduces TPO-induced
activation of the TPO receptor, MPL, as well as phosphorylation of
JAK2, JAK3, and STAT5.56,57 Furthermore, IFN␣ directly inhibits
cytoplasmic maturation and platelet production by megakaryocytes
but not the proliferation of megakaryocyte progenitor cells or
endomitosis of human megakaryocytes.58 These dramatic effects
of IFN␣ on thrombopoiesis likely account for the effectiveness of
IFN␣ in treating patients with MPN with extreme degrees of
thrombocytosis.46,59
The ability of type 1 IFNs to inhibit HPC proliferation and
maturation has been documented to occur independently of the
STAT pathway.16,49,50,60-65 Type 1 IFNs activate the p38 MAPK, a
proline-directed serine/threonine kinase that is required for ISG
transcription through IRSE.63 The pharmacologic blockade of p38
in IFN-treated CML and PV HPCs reverses the inhibitory effects of
IFN␣.49,50 The inhibitory activities of type 1 IFN against normal
and malignant HPCs involve several additional downstream signaling pathways including the Crkl adaptor protein, the MAPKinteracting kinase 1 (Mnk), a MAPK-regulated kinase that phosphorylates the eukaryotic initiation factor 4e, and the Schlafen family of
proteins that include several members which regulate cell-cycle
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BLOOD, 5 MAY 2011 䡠 VOLUME 117, NUMBER 18
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Table 1. Uses of interferon-␣ (alone or in combination) for myeloid malignancies in 2011
Disease
Chronic myeloid leukemia
Interferon use
(ⴙ combination)
Situation
Reference
Chronic phase:
1. Combined with imatinib as front line therapy
1. Imatinib
1. Preudhomme et al41
2. Maintenance after imatinib plus interferon
2. Interferon-␣ alone
2. Burchert et al32
Systemic mast cell disease
Aggressive systemic mast cell disease (ASM)
Single agent
Kluin-Nelemans et al,75 Lim et al76
Myeloproliferative neoplasms
Polycythemia vera and essential thrombocythemia
Single agent
Quintas-Cardama et al,46 Kiladjian et al78
Hypereosinophilic syndrome
Resistance to steroids, hydroxyurea, and TKI-insensitive
Single agent
Butterfield and Gleich,95 Ceretelli et al96
progression and growth arrest.61,62 The relative contribution of each
of these pathways to the antiproliferative effects of IFN␣ on HPC
requires further investigation. P38 MAP kinase activation by IFN␣
has been reported to promote apoptosis of PV CD34⫹ cells.49
Activation of p38 MAP kinase results in mitochondrial translocation of the proapoptotic protein Bax, leading to the induction of
apoptosis.63
Recently 2 groups have independently reported that IFN␣ has a
surprising effect on murine marrow HSCs.66,67 High levels of IFN␣
induce murine HSCs to exit from a normally quiescent state and to
transiently proliferate.66,67 In these studies, the HSC proliferative
response was not observed in HSCs that lacked IFNAR or STAT1.
However, HSCs that lacked the IFNAR did respond to IFN␣ if they
were mixed with wild-type cells, suggesting that other cytokines
such as IFN␥ that are elaborated by marrow auxiliary cells may be
responsible for this biologic activity. In support of this hypothesis
is the recent report that IFN␥ is also capable of inducing HSC
cycling.68 The effect of IFNs on HSC cycling appears to occur by a
pathway that is distinct, from which mediates their antiproliferative
effect on HPC. Essers et al reported that STAT1 was required for
the IFN␣-mediated exit of HSC from dormancy, suggesting that
this effect is mediated by canonical type 1 IFN signaling.66 It
remains uncertain whether human HSCs respond in a similar
fashion to IFN␣, and clonal stem cells from MPN patients cycle at
a higher rate than the small reservoir of normal HSCs that persist in
such patients. If MPN HSCs are characterized by such a proliferative advantage, this might serve as an additional rationale for the
use of combined modality therapy with IFN␣ and a TKI to treat
patients with MPNs.69 These effects of IFN␣ on MPN HSCs are of
potential importance because imatinib therapy alone does not affect
the fate of CML stem cells, which likely accounts for the
persistence and relapse that frequently occur following the cessation of TKI therapy.70
Current uses of interferon in the treatment of
myeloid malignancies
IFN␣ has been shown to have therapeutic activity against a broad
variety of both myeloid and lymphoid neoplasms. As previously
mentioned, the availability of several effective treatment options
(such as imatinib in CML–chronic phase71) has relegated the uses
of IFN␣ to being mainly that of a second-line therapeutic option.
Disorders in which IFN␣ has been found to be therapeutically
active but where its use has been dramatically curtailed include
patients with multiple myeloma72,73 and hairy cell leukemia.74
However, it is particularly in myeloid neoplasms where the greatest
activity is being demonstrated.
The experience with targeted therapies has, however, demonstrated that (1) targeted therapeutics are sometimes active but not
always capable of inducing complete eradication of malignant
clone and that (2) there remains a subset of patients in whom such
therapy is not sufficiently effective. Given the historical knowledge
of IFN␣ therapeutic activity in many of these disorders, clinical
investigators are now re-evaluating its use in conjunction with
targeted agents or as maintenance therapy after remission has been
obtained. Areas of potential benefit showing incremental benefits
are CML, systemic mast cell disease, hypereosinophilic syndromes, and finally classic MPN (PV and essential thrombocythemia [ET]; Table 1).32,41,46,75-79
The role of interferon therapy in CML
The therapy of CML has evolved significantly over the past
2 decades. IFN␣ treatment had a significant impact on the outcome
of patients with CML.80 Before the availability of imatinib, IFN␣
was used in high doses and was associated with the achievement of
hematologic and even molecular remissions in individuals with
CML; however, significant toxicities were frequently encountered
including depression and neurologic disturbances. The development of targeted therapy with imatinib was a watershed moment in
the history of cancer treatment, and imatinib was found to be
superior for achieving cytogenetic and molecular responses and
prolonging event-free survival as compared with IFN␣ (in combination with low-dose Ara-C).81 The subsequent development of
additional TKIs including dasatinib82 and nilotinib83 has further
impacted the utilization of IFN␣. However, the long-term followup of participants in the IRIS study continue to show that not all
patients remain in long-term molecular remissions with imatinib
therapy and that as many as one-quarter to one-third of patients
become resistant or intolerant.84 Given these findings, there has
been increased interest in reincorporating IFN␣ into treatment
strategies for CML patients based on the rationale previously
discussed and the clinical outcomes of patients treated with
combined modality therapy. Utilization of IFN␣ is now being
investigated in 3 clinical settings in patients with chronic phase
(CP) CML: combination therapy including a TKI and IFN␣, as
maintenance after TKI therapy, and during pregnancy.
Combination therapy with IFN␣ and imatinib in CML
A seminal phase 3 randomized multicenter clinical trial of
636 patients was recently completed in France using 2 different
forms of combination therapy in CML patients.41 The outcomes of
imatinib mesylate alone at doses of 400 mg/d or 600 mg/d were
compared with a combination regimen of imatinib plus cytarabine
(20 mg/m2/d, days 15-28) or a second combination regimen of
imatinib plus pegylated (peg)–IFN␣-2a (90 ␮g weekly). The end
points of this study were based on data that showed that CML
patients receiving imatinib therapy who underwent monitoring of
the BCR-ABL transcript burden by real-time quantitative polymerase chain reaction and had a reduction of 3log10 or more of
BCR-ABL transcripts had a negligible risk of disease progression.
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KILADJIAN et al
This degree of reduction in BCR-ABL transcripts was considered
to be a major molecular response. A superior molecular response
was defined as a 4log10 reduction in BCR-ABL transcripts. The
independent safety and monitoring board for this study recommended that patient enrollment in the groups receiving 600 mg of
imatinib alone and imatinib plus cytarabine be stopped because of
the superiority of the imatinib plus peg-IFN␣-2a therapy and the
toxicity associated with the administration of cytarabine. Compared with imatinib alone at the 2 doses tested or imatinib in
combination with cytarabine, treatment with imatinib plus pegIFN␣-2a was associated with a significantly higher rate of major
and complete molecular responses. To achieve these rates of
molecular responses, combination therapy for more than 12 months
was required, which was frequently difficult because of toxicity of
peg-IFN␣-2a, leading these investigators to reduce the dose of
peg-IFN␣-2a. More impressive was the doubling of the number of
patients with undetectable residual disease in the group of patients
receiving the combination of imatinib and peg-IFN␣-2a compared
with patients randomized in the other treatment arms. By contrast,
the use of second-generation TKIs (nilotinib and dasatinib)83,85 has
been associated with lower rates of major molecular remissions
after 12 months of therapy than those reported with imatinib plus
peg-IFN␣-2a. Whether these superior molecular responses achieved
with the combination of imatinib plus peg-IFN␣-2a will significantly improve long-term survival or reduce the rate of evolution to
blast crisis will require further study.
Interferon as maintenance therapy in CML-CP
Although cessation of imatinib does not necessarily results in
relapse in patients with CP CML,86 recent studies suggest that
likely up to 61% of patients will relapse even after achieving an
initial complete molecular response. A pilot study performed in
Germany focusing individuals who had received combination
imatinib and IFN␣-2a therapy for a median of 2.4 years and then
received IFN␣-2a as maintenance therapy32 showed that 75%
(15 of 20) of patients remained on complete molecular remission
on IFN␣-2a alone after discontinuing imatinib. In addition, the
number of individuals with a complete molecular response increased from 2 to 5 after 2 years of IFN␣-2a maintenance therapy.
The 5 individuals who relapsed off imatinib restarted imatinib and
were able to again achieve a molecular remission. The response
observed with IFN␣ has been attributed to the induction of a
proteinase-3–specific CTL response as previously discussed.33
However, because second-generation TKIs may be superior to
imatinib for front-line therapy,87 the next step of evaluating IFN␣ in
CML may require combinations with second-generation TKIs.88
Interferon use during pregnancy in CML-CP and other MPNs
The uses of TKIs are believed to be relatively contraindicated
during pregnancy89 because of a small but real risk of teratogenicity. IFN␣ has never been tested in randomized trials, nor approved
by the Food and Drug Administration for use during pregnancy.
With those reservations aside, pregnant women with CML, particularly after the first trimester, have successfully been managed by an
approach of selective leukapheresis and IFN␣.90
In Philadelphia chromosome–negative MPNs, current guidelines recommend the use of IFN␣ when cytoreductive therapy is
indicated during pregnancy.91 Although the drug is not approved
for this indication, many case reports have shown that its use is safe
for both the mother and the fetus.92
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Systemic mast cell disease and hypereosinophilic syndrome
Aggressive systemic mast cell disease represents an MPN where
the degranulation of mast cells leads to damage to a variety of end
organs.93 IFN␣ has been shown to be quite effective in individuals
with imatinib-insensitive disease (53% overall response rate, 18%
complete responses),94 improving symptoms because of mast cell
degranulation, bone marrow mast cell infiltration and ameliorating
mastocytosis-related ascites and hepatosplenomegaly, cytopenias,
skin changes, and osteoporosis.76 The use of IFN␣ for systemic
mast cell disease should, however, be restricted to individuals with
aggressive disease, lacking an imatinib-sensitive target, and likely
having failed therapies such as corticosteroids.94
Similarly, IFN␣ has been shown to be effective in suppressing
the aberrant proliferation of eosinophils observed in patients with
hypereosinophilic syndromes. However, the published literature
includes the experience with a limited number of patients.95,96
Presently, IFN␣ therapy in this setting should likely be limited to
patients refractory to steroids and hydroxyurea and who are not
responsive to TKI therapy.79
Myeloproliferative neoplasms: PV, ET, and PMF
In the United States, the pioneering study of Silver in 1988
documented the clinical effectiveness of IFN␣ in controlling
erythrocytosis as well as pruritus and other constitutional symptoms in PV patients,97 while Austrian and French groups reported
during the same period evidence that IFN␣ was also effective in
reducing thrombocytosis in ET patients.59,98 A number of clinical
trials have been performed subsequently, using several different
commercial preparations of IFN which are summarized in Tables
2-4. Recent reviews of the literature found more than 400 PV and
ET patients and more than 100 primary myelofibrosis (PMF)
patients reported who participated in clinical trials.92,99 A metaanalysis of these studies has proven problematic. First, various
forms of IFN were used, and one cannot exclude the possibility that
each of these preparations of IFN might have different effects that
might influence response rates and/or disease evolution. Furthermore, heterogeneous response criteria were used to evaluate
efficacy. The recently proposed response criteria for use in MPNs
clinical trials provided by the European LeukemiaNet might be
helpful to avoid such dilemma in the future.100
In almost all PV and ET trials, IFN␣ therapy rapidly normalized
platelet numbers and corrected the degree of leukocytosis and
erythrocytosis, allowing reduction in the requirement for phlebotomies within a few months (Tables 2-3). In both diseases, an
objective hematologic response was observed in about 80% of
patients, including complete freedom from phlebotomies in PV in
60% of patients. In addition, IFN␣ was also able to reduce
PV-associated pruritus in a significant number of cases, and appears
to be an effective drug for this purpose. However, toxicity
associated with IFN␣ therapy was not trivial, leading to the
discontinuation of treatment in almost one-quarter of patients.
In contrast to trials of PV and ET, the clinical trials of IFN␣
therapy in PMF have been disappointing,101 although in vitro data
suggested that IFN␣ might be effective in correcting bone marrow
fibrosis (PMF clinical trials that included more than 10 patients are
listed in Table 4). Virtually no objective response were observed,
and toxicity in these studies was much higher than that recorded in
PV or ET patients, leading to the rapid discontinuation of treatment
(usually after 3-6 months) in more than 50% of the patients. One of
the major limiting toxicities of IFN␣ therapy in PMF was the
worsening of cytopenias. However, the French Intergroup of MPN
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RENAISSANCE OF INTERFERON THERAPY
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Table 2. Clinical trials of interferon in polycythemia vera
First author, year
No. of
patients
Reduction of
PHL, n (%)
Freedom from
PHL, n (%)
Discontinuations,
1st year, n (%)
Discontinuations,
total
Type of
IFN
Cacciola, 1991
11
9 (82)
5 (45)
0
NA
Cimino, 1993
13
10 (77)
4 (31)
0
NA
␣2b
Finelli, 1993
13
11 (85)
11 (85)
3 (23)
NA
NA
0
␣2a
Turri, 1991
11
7 (64)
4 (36)
Papineschi, 1994
11
9 (82)
8 (73)
Sacchi, 1994
22
21 (95)
21 (95)
Muller, 1995
15
7 (47)
Taylor, 1996
17
14 (82)
0
NA
NA
␣2a
0
0
hl-IFN
NA
4 (27)
6 (40)
␣2b
9 (53)
2 (12)
6 (35)
NA
␣2a
NA
Foa, 1998
38
19 (50)
11 (29)
11 (29)
16 (42)
Gilbert, 1998
31
NA
NA
NA
7 (23)
␣2b
Stasi, 1998
18
17 (94)
11 (61)
NA
hl-IFN
Heis, 1999
32
28 (87)
2 (6)
4 (12)
Radin, 2003
12
5 (42)
1 (8)
NA
NA
Silver, 2006
55
55 (100)
53 (96)
NA
8 (14)
␣2a, ␣2b
Samuelsson, 2006
21
7/9 (78)
4/9 (44)
NA
7/23 (30)
peg-␣2b
0
10 (31)
NA
NA
Kiladjian, 2008
37
37 (100)
36 (97)
3 (8)
13 (35)
peg-␣2a
Quintas-Cardama, 2009
40
32 (80)
28 (70)
10%
22%
peg-␣2a
For complete references, see supplemental Table 2 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article).
PHL indicates phlebotomy; IFN, interferon; NA, data not available; and hl-IFN, human leukocyte interferon.
(FIM) recently reported promising results with an acceptable
degree of toxicity in PMF using peg-IFN␣-2a.102 This retrospective
study requires confirmation in a larger cohort of patients. Such
results with peg-IFN␣-2a confirm the earlier findings with lowdose standard IFN, suggesting that IFN␣ therapy should be
considered as an effective therapy of PMF in the hypercellular
phase of the disease (reviewed in Hasselbalch et al99).
Recently, investigators have performed 2 independent phase
2 studies using peg-IFN␣-2a in PV and ET46,78 and showed
similarly impressive hematologic response rates compared with
standard IFN␣, but with less associated toxicity (less than 10% of
patients discontinued therapy during the first year of therapy). In
addition, these studies showed for the first time evidence of
significant molecular responses as documented by a clear reduction
in the JAK2V617F allele burden following IFN␣ treatment.45 A
specific effect of IFN␣ against the MPN clone had previously been
suggested by occasional studies showing reversion from monoclonal to polyclonal patterns of hematopoiesis (based on
X-chromosome inactivation pattern studies) or disappearance of a
marker chromosomal abnormality present before treatment.103-106
The discovery of the JAK2V617F mutation provides a tool with
which to measure molecular response to a variety of therapeutic
approaches in MPN, an end point not available before the
discovery of this mutation in 2005. Overall, the 2 clinical trials with
peg-IFN␣-2a46,78 showed a meaningful and progressive reduction
in the JAK2V617F allele burden in about 70% of PV and 40% of
ET patients. Importantly, the JAK2V617F mutation became undetectable (with 1% sensitivity PCR assays) in 24% of PV patients in
the French “PVN-1” study after about 3 years’ median follow-up,
and in 14% and 6% of PV and ET patients, respectively, in the US
Table 3. Clinical trials of interferon in essential thrombocythemia
No. of
patients
Response
rate, %
Giles, 1988
18
100%
Bellucci, 1988
12
NA
Gugliotta, 1989
10
100
NA
␣2a
Lazzarino, 1989
26
86
9 (35)
␣2b
First author, year
Discontinuation,
n (%)
Type of IFN
0
␣2a and ␣2b
4 (33)
␣2a
Giralt, 1991
13
69
NA
␣2b
Gisslinger, 1991
20
85
10 (50)
␣2c
Sacchi, 1991
35
85
4 (11)
␣2b
Turri, 1991
10
70
1 (10)
␣2a
Seewann, 1991
19
80
6 (30)
␣2b
Kasparu, 1992
14
86
0
␣2b
Rametta, 1994
25
92
NA
␣2b
Berte, 1996
12
83
NA
␣2a and ␣2b
Sacchi, 1998
11
100
1 (9)
Radin, 2003
17
88
NA
Alvarado, 2003
11
100
2 (18)
␣
␣2
peg-␣2b
␣2a
Saba, 2005
20
75
3 (15)
Langer, 2005
36
75
13 (36)
peg-␣2b
Samuelsson, 2006
21
70
11 (55)
peg-␣2b
Jabbour, 2007
13
70
NA
peg-␣2b
Quintas-Cardama, 2009
39
81
NA
peg-␣2a
For complete references, see supplemental Table 3.
IFN indicates interferon; and NA, data not available.
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4712
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KILADJIAN et al
Table 4. Clinical trials of interferon in myelofibrosis
First author, year
No. of
patients
Response
rate, %
Spleen size reduction,
% of patients
Discontinuation,
%
Hasselbalch, 1988
Barosi, 1989
Type of
IFN
10
0
10
NA
␣2b
10
25
0
25
␣2b
Gilbert, 1998
22
NA
58
46
␣2b
Tefferi, 2001
11
0
18
64
␣2
Radin, 2003
31
3
33
NA
␣2
Jabbour, 2007
11
9
NA
26
peg-␣2b
Ianotto, 2009
18
44
11
11
peg-␣2a
Silver, 2009
13
38
38
8
␣2b
For complete references, see supplemental Table 4.
IFN indicates interferon; and NA, data not available.
study after about 2 years’ median follow-up. Combining both
studies, 12/64 (19%) of PV patients achieved a molecular complete
response (MCR). Of note, each of these MCRs occurred after the
12th month of treatment whereas hematologic responses occurred
within a few weeks. Prolonged exposure (⬎ 12 months) to pegIFN␣-2a seems to be an important factor in achieving MCR. The
reduction in the JAK2V617F allele burden was not influenced by
the cumulative dose of peg-IFN␣-2a in the PVN-1 study, but
toxicity was clearly dose-dependent in the US study. Taken
together, these results indicate that peg-IFN␣-2a therapy is best
initiated at very low doses that are gradually increased until
hematologic response is achieved; this strategy avoids cessation of
therapy and allows sufficient exposure to the drug to occur to allow
for the achievement of a molecular response. These results are in
agreement with studies from Denmark showing major molecular
responses in PV after long-term treatment with IFN␣-2b, that could
persist after IFN␣ was discontinued.107 Finally, 5/7 patients who
achieved MCR in the PVN-1 study have maintained this response
after peg-IFN␣-2a was discontinued (up to 30 months after discontinuation), with none experiencing hematologic relapse (J.-J.K.,
personal unpublished data). Such long-term clinical and molecular
responses after the discontinuation of treatment have previously
been reported after IFN␣ therapy in MPN patients,107,108 an effect
that has not been reported with other currently available therapies.
It is important to emphasize that the elimination of JAK2V617F
in this setting is not necessarily indicative of cure of the MPN, and
that clinical implications of these molecular responses remain
uncertain and require validation. It has been shown that molecular
relapse can rapidly occur after IFN␣ discontinuation in some
cases.109 In one patient with a biclonal JAK2V617F/TET2-mutated
PV, peg-IFN␣-2a treatment did not affect the TET2-mutated cells
while the JAK2V617F clone was eradicated.110 Nevertheless,
prolonged periods of time (up to 40 months, personal unpublished
data) during which the patient remained in complete hematologic
remission without any cytoreductive therapy after peg-IFN␣-2a
withdrawal was observed in several patients of the PVN-1 study,
even though low levels of the JAK2V617F allele (around 5%) were
still detected. Such results suggests that despite the disease not
being eradicated, long-term exposure to peg-IFN␣-2a was sufficient to modify the clinical expression of the MPN for a sustained
period of time.99
In addition to clinical, hematologic, and molecular complete
responses achieved in a significant proportion of PV and ET
patients, IFN␣ therapy has also been shown recently to reverse
bone marrow histopathologic abnormalities in selected cases of
both PV107 and PMF.111 Thus, IFN␣ seems to be the uniquely
available drug able to induce complete resolution of all clinical,
biologic, and morphologic abnormalities in selected MPN patients,
raising the hope that a curative outcome might be possible in a
subset of such patients.99 These observations lead one to question
the validity of the current therapeutic strategies for PV and ET
patients in which myelosuppressive therapy is exclusively used in
subpopulations of patients at high risk for developing additional
thrombotic events. If IFN␣ is shown in a large prospective trial to
eliminate clinical, histologic, cytogenetic, and molecular evidence
of disease with acceptable toxicity, one might also consider early
treatment of low-risk patients, when the tumor burden is still low.99
Interestingly, the incidence of new thrombotic events in IFN␣treated MPN patients was consistently lower than that expected in
patients receiving the standard of care.112,113 In the PVN-1 study, no
vascular events were observed in a cohort of 37 PV patients after a
median follow-up of 55 months (J.-J.K., personal unpublished
data), although about 8 cases would have been expected, given the
cumulative rate of 5.5 events per 100 patients per year reported in
the literature.114 Silver also reported an absence of vascular events
in 55 PV patients treated with standard IFN␣, with an average
follow-up of 53 months.113
Finally, it is of note that currently published national guidelines
for PV115 (British Society of Hematology) and ET116 (Italian
Society of Hematology) recommend the off-label use of IFN␣ as
first-line therapy in younger patients, arguing that this drug is not
leukemogenic. The updated MPN management recommendations
recently published by international experts on behalf of the
European LeukemiaNet even propose IFN␣ as first-line therapy in
PV patients regardless of their age.117 Evolution to myelofibrosis,
myelodysplastic syndrome, or acute leukemia is indeed a matter of
concern in such patients who are expected to live for several
decades, although the exact incidence of such transitions is still
debated.118,119 If IFN␣ has an impact on the disease natural history
as suggested by the decrease of JAK2V617F allele burden,
reversion to normal features of the bone marrow histopathology, or
the reduced incidence of vascular events on IFN␣ therapy, a delay
or actual elimination in the evolution to myelofibrosis or leukemia
might be anticipated.
Conclusions
The novel use of IFN␣ as a therapeutic option (eg, lower doses, in
combination with other active agents, pegylated forms) have led to
promising results in the treatment of various myeloid malignancies
including CML and Philadelphia chromosome–negative MPN. We
conclude that IFN␣ represents an important component of the
therapeutic arsenal that has the potential to improve not only
response rates but also the number of patients with these disorders
achieving sustained molecular remissions. As opposed to targeted
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BLOOD, 5 MAY 2011 䡠 VOLUME 117, NUMBER 18
RENAISSANCE OF INTERFERON THERAPY
therapies, the broad range of biologic properties of this drug
(including direct toxic effects on transformed cells, enhancement of
immune response against malignant cells, induction of proapoptotic genes, inhibition of angiogenesis, ability to cycle dormant
malignant stem cells) may paradoxically render IFN␣ a candidate
agent with which to treat a number of these malignancies. Recent
clinical trials have, however, included limited numbers of patients,
and the poor patient tolerability of IFN␣ may still be a limiting
factor when used by clinicians not familiar with the use of this
drug. A large, randomized, multicenter trial (Myeloproliferative
Disorders Research Consortium Clinical Trial -112), which is being
performed jointly in Europe and the United States, will compare
treatment with peg-IFN␣-2a to the standard of care (hydroxyurea)
in high-risk patients with ET and PV. This study will document
whether the recently proposed low-dose sustained utilization
strategies of peg-IFN␣-2a are truly more tolerable and effective
therapies resulting in a favorable change in the natural history of
patients with MPNs. At present, IFN␣, despite the promising trials
summarized here, remains an experimental therapy in most my-
4713
eloid malignancies, thereby emphasizing the importance of completing such large clinical trials in this setting. IFN␣ has previously
been used as a single agent, which is at odds with the manner in
which most hematologic malignancies are treated with combinations of drugs. It is hoped that future clinical trials with IFN␣ in
MPN patients will involve combinations of this cytokine with
chromatin-modifying agents, JAK2 inhibitors, or inhibitors of
antiapoptotic proteins to improve tolerability and increase efficacy.
Authorship
Contribution: All authors equally contributed to the article.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Jean-Jacques Kiladjian, Hôpital Saint-Louis,
Centre d’Investigations Cliniques, 1 avenue Claude Vellefaux,
75010 Paris, France; e-mail: [email protected].
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2011 117: 4706-4715
doi:10.1182/blood-2010-08-258772 originally published
online March 9, 2011
The renaissance of interferon therapy for the treatment of myeloid
malignancies
Jean-Jacques Kiladjian, Ruben A. Mesa and Ronald Hoffman
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