DOI: 10.1002/hon.

2594

SUPPLEMENT ARTICLE

New treatment options in hairy cell leukemia with focus on

BRAF inhibitors

Brunangelo Falini | Enrico Tiacci

Institute of Hematology and CREO (Center for

Hemato‐Oncological Research), Ospedale S.
Maria della Misericordia, University of Perugia,
Perugia, Italy
Correspondence
Brunangelo Falini, Institute of Hematology and
CREO (Center for Hemato‐Oncological
Research), Ospedale S. Maria della
Misericordia, University of Perugia, Perugia,
Italy.
Email: brunangelo.falini@unipg.it
Abstract
Hairy cell leukemia (HCL) responds initially very well to chemotherapy with purine
analogues. However, up to 50% of patients relapse, often multiple times, and
become progressively less sensitive to these myelotoxic and immune‐suppressive
drugs. At progression, viable therapeutic strategies include addition of rituximab to
purine analogues, and treatment with the anti‐CD22 immunotoxin moxetumomab
pasudotox, which has been recently approved by the FDA in HCL patients after at
least two prior therapies. Identification of the BRAF‐V600E kinase mutation as the

Funding information
Leukemia and Lymphoma Society, Grant/
Award Number: Translational Research
Program 6557‐18 to E.T.; Hairy Cell Leukemia
Foundation; European Research Council,
Grant/Award Number: Hairy Cell Leukemia‐
617471 to E.T.; Italian Association for Cancer
Research—AIRC, Grant/Award Number: “5 per
mille 2010” Molecular Clinical Oncology
10007 to B.F.; IG 19143 to E.T.
genetic cause of HCL has opened the way, in the relapsed/refractory experimental
setting, to targeted and non‐myelotoxic effective strategies that are based on
inhibition of BRAF with vemurafenib, co‐inhibition of BRAF and its target MEK with
dabrafenib and trametinib, and BRAF inhibition with vemurafenib combined with
anti‐CD20 immunotherapy. In particular, vemurafenib plus rituximab is emerging
as a short, safe, chemotherapy‐free regimen able to induce deep complete
remissions in most HCL patients refractory to, or relapsed multiple times, after
chemo(immuno)therapy.

1 | I N T RO D U CT I O N
Hairy cell leukemia (HCL) is an uncommon mature B‐cell neoplasm
that usually occurs at a median age of 55 to 60 years, shows a male
predominance (M:F ratio = 4‐5:1), and most frequently presents with
cytopenias, low percentage of leukemic circulating cells with typical
1
hairy morphology, and monocytopenia, associated with splenomegaly
and no or little lymphadenopathy.2 The HCL cells characteristically
co‐express B‐cell–associated antigens (CD19, CD20, and CD22)
and the CD103, CD25, and CD11c molecules.2 HCL responds well
to therapy with purine analogues (cladribin or pentostatin).2
The genetic lesion causing HCL has remained unknown for over
50 years since the original description of this pathological condition
in 1958 under the term of leukemic reticuloendotheliosis.3
Cygenetic/FISH did not reveal consistently recurring genetic abnor-
malities. Both gene expression4 and microRNA5 profiles unraveled a
unique molecular signature, potentially explaining some characteristic
Brunangelo Falini and Enrico Tiacci contributed equally to this work.
functional features of HCL cells like the hairy morphology and the
selective homing of leukemic cells to particular anatomical sites.6
High‐density genome‐wide single‐nucleotide polymorphism (SNP)
genotyping showed that HCL has a much more stable genome7 than
other B cell neoplasms. However, none of the above techniques could
detect any recurrent genetic lesion responsible for the disease. Using a
whole‐exome sequencing approach, we discovered in 2011 the
BRAF‐V600E mutation as the causal genetic event of HCL8
(Figure 1). This finding opened new perspectives on the biology,
diagnosis, and therapy of HCL.9,10
2 | CONVENTIONAL AND MOLECULAR
DIAGNOSTIC ASSAYS FOR HCL
HCL is usually diagnosed based upon clinico‐laboratory features (ie,
splenomegaly and cytopenias including monocytopenia), presence of
a usually low percentage of circulating HCL cells, a typical “fried‐egg”
histological pattern at bone marrow biopsy, and a characteristic

30 © 2019 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/hon Hematological Oncology. 2019;37(S1):30–37.
FALINI AND TIACCI 31

FIGURE 1 The RAS‐RAF‐MEK‐ERK

signaling pathway in hairy cell leukemia (HCL).
A, The RAS‐RAF‐MEK‐ERK signaling pathway
is physiologically triggered by the binding of a
surface receptor tyrosine kinase (RTK) to its
ligand. This activates RAS and, in turn, RAFs
(BRAF and, not shown, CRAF). BRAF‐CRAF
heterodimers phosphorylate the MEK1 and
MEK2 kinases (pMEK), which in turn
phosphorylate ERK1 and ERK2 (pERK). Then
active ERKs phosphorylate several substrates
in the cytoplasm (not shown) as well as in the
nucleus, where they initiate a transcriptional
response (eg, through the activator protein 1
transcription complex) that includes cyclin‐D1
upregulation and that promotes cell survival
and proliferation, as well as feedback inhibitory
mechanisms (not shown) to counterregulate
pathway activity. The latter, if uncontrolled,
can result in neoplastic transformation. Indeed,
the BRAF‐V600E mutation renders BRAF
constitutively active independent from
upstream regulatory signals and from
heterodimerization with CRAF. B, In vivo
activation of the BRAF‐MEK‐ERK pathway in
HCL patients is illustrated by the expression of
pERK (red) and cyclin‐D1 (nuclear, brown) by
bone marrow leukemic hairy cells
(counterstained with hematoxylin in the top
panel and double stained for the surface B‐cell
marker CD20 in blue in the bottom panel). This
figure was originally published in Blood. Falini B,
Martelli MP, Tiacci E. BRAF V600E mutation in
hairy cell leukemia: From bench to bedside.
Blood 2016;128:1918‐27. The American
Society of Hematology

immunophenotype of HCL cells (Ig+, CD20+, CD22+, CD11+, CD25+, 2.2 | Detection of BRAF‐V600E by molecular assays
11-13
CD103+, and CD123+). Highly specific diagnostic assays, inspired and immunohistochemistry
by genomic studies, such immunostaining for Annexin‐A1 or search for
the BRAF‐V600E mutation, can help to solve difficult cases.9 The BRAF‐V600E mutation can be detected by Sanger sequencing or
more sensitive techniques,17-20 including allele‐specific PCR (with a
threshold of 0.01%, ie, 10−4, using an improved version of our
2.1 | Immunostaining for Annexin‐A1 (ANXA1)
published method17). Molecular studies are also applicable to fixed‐
decalcified/paraffin‐embedded bone marrow biopsies.21 Alternatively,
ANXA1 was identified as a potential HCL‐specific diagnostic marker
routine bone marrow paraffin sections can be immunostained with a
by gene expression profiling.4 Immunostaining of paraffin sections
monoclonal antibody (VE1) specifically directed against BRAF‐
from bone marrow biopsies with a monoclonal antibody against
V600E.22,23 This antibody has the potential to represent a reliable sur-
ANXA1 (when evaluated in parallel with CD20) is highly specific for
rogate for molecular PCR assays,24 but further studies are required to
HCL at first diagnosis.13 However, it is not suitable for monitoring
validate these findings.
minimal residual disease (MRD) after therapy since ANXA1, although
a specific marker for HCL among normal and neoplastic B cells, is also
expressed in myeloid elements, macrophages, and T cells, thus making 2.3 | Differential diagnosis between HCL and
the interpretation of the results very difficult,4,14-16 unless a double HCL‐like disorders
staining with CD20 or CD79a is performed in the same section.
Molecular studies (see below) are more informative when monitoring HCL is treated differently from its mimickers. Therefore, this condition
of MRD is required. must be clearly distinguished from HCL‐like disorders, including HCL
32
variant (HCLv),25 splenic marginal zone lymphoma (SMZL), and splenic
diffuse red pulp small B‐cell lymphoma (SDRPSBCL),25 which also
present with cytopenias and splenomegaly without significant
lymphadenopathy.
SMZL differs from HCL because of the frequent intrasinusoidal infil-
tration of the bone marrow by neoplastic B cells (clearly highlighted by
immunohistochemistry for CD20). In addition, compared with HCL, the
circulating SMZL cells show shorter and usually polarized villous projec-
tions. Finally, SMZL cells are negative for several characteristic HCL
markers, ie, CD103, CD25, and annexin A1, lack the BRAF‐V600E
mutation17,18 and frequently harbor NOTCH2 mutations.26,27
More problematic is the distinction between HCL and HCLv.
Useful criteria for HCLv diagnosis include (1) frequent lymphocytosis
(as compared with only 10%‐15% of HCL cases), (2) lack of
monocytopenia (usually found in HCL), (3) presence of one single
prominent nucleolus (absent in HCL cells), (4) negativity for CD25,
ANXA1, and BRAF‐V600E, and (5) presence of MAP2K1 mutations28
in a fraction of cases.
The features of circulating cells in SDRPSBCL tend to overlap with
25,29
those of SMZL. A diagnosis of SDRPSBCL may be proposed in
cases with purely intrasinusoidal bone marrow involvement and villous
lymphocytes in the blood, but the differential diagnosis with SMZL
may require a splenectomy (rarely done nowadays). Similarly to SMZL
and HCLv, this tumor is negative for CD25, ANXA1, and the
BRAF‐V600E mutation.
3 | T HE R A P Y O F H CL
Despite its rarity, during the past 60 years, HCL has served as a paradigm
for the development of new therapies. Initially, the only available thera-
peutic approach was splenectomy that usually resulted only in a transient
improvement of blood cell counts. The first milestone in the therapy of
HCL occurred in the early 1980s with the introduction of interferon30
that induced partial responses, sometimes durable, in 40% to 80% of
patients.31,32 The introduction in the 1990s of the nucleoside analogues,
cladribine and pentostatin, was the second milestone as both drugs led to
very high rates of long‐lasting complete remission (CR) in the majority of
patients.33,34 Moreover, a randomized trial clearly demonstrated the
superiority of pentostain over interferon.32 Thus, cladribine or
pentostatin currently represent the frontline standard of care, with the
possible addition of rituximab proposed by some investigators.35
3.1 | Definition of criteria for starting treatment and
evaluation of response
According to current consensus guidelines,36 indications for starting
treatment in HCL patients are the presence of at least one of the fol-
lowings: hemoglobin < 11 g/dL, platelet count < 100 000/μL, or abso-
lute neuthrophil count < 1000/μL. Other indications to start therapy
include malignant lymphocytosis (greater than 5‐20/nL), increased
susceptibility to infections, symptomatic splenomegaly, and significant
lymphadenopathy.
FALINI AND TIACCI
Complete remission (CR) requires resolution of splenomegaly and
cytopenias (neutrophils ≥ 1500 μL, hemoglobin ≥ 11 g/dL, and plate-
lets ≥ 100 000 μL), as well as absence of HCL cells in Wright‐stained
blood and marrow smears and in hematoxylin/eosin‐stained marrow
biopsy sections.36 Partial remission (PR) requires resolution of cytope-
nias and 50% or more reduction of splenomegaly and of leukemic infil-
tration in the bone marrow biopsy.36 PR is consistently associated
with a shorter time to relapse compared with CR.36 Noteworthy, the
bone marrow biopsy can still show significant HCL infiltration 3 months
after purine analogue therapy while a CR is eventually achieved by
6 months without intervening treatment.37 Thus, early bone marrow
biopsy assessment (before 4‐6 mo) should be discouraged.
Modern combination treatments (see below) have the potential to
induce negativity of minimal residual disease (MRD) in HCL patients
who achieve CR. MRD can be evaluated using immunohistochemistry,
flow cytometry, or molecular techniques. Immunohistochemistry is based
on the use of antibodies against BRAF‐V600E, CD20 (in patients who
have not previously received rituximab), or CD79a (in patients previously
treated with rituximab). In marrow aspirates, MRD can be detected with
multicolor flow cytometry, conventional allele‐specific PCR for the
BRAF‐V600E mutation or for the patient‐specific immunoglobulin
rearrangement, and next‐generation sequencing or digital PCR for
BRAF‐V600E,10 with a range of sensitivities down to 10−6. MRD analysis
in the blood underestimates the disease burden, which is largely located
in the bone marrow and the spleen.
3.2 | Conventional chemotherapy and
chemo‐immunotherapy strategies in HCL
Cladribine is administered as a single 5‐ or 7‐day course while
pentostatin is usually given every other week until hematologic
parameters have nearly normalized and splenomegaly has disappeared
on physical examination.36 These two purine analogues have similar
clinical activity and overlapping toxicities that include fever (particu-
larly during the first weeks of treatment), neutropenia, and decrease
in the number of CD4‐positive T cells (lasting up to 50 months).2 In
spite of the substantial equivalence of the two drugs, cladribine is
more commonly used because of its more convenient schedule of
administration.37 CR rate with these agents is 85% to 90%.
Rituximab alone shows in HCL an overall response rate of about
40%, including a fraction of CRs. Therefore, HCL patients have been
also treated using a combination of a purine analogue with rituximab.
Ravandi et al38 conducted a prospective trial in which HCL patients
received as first‐line treatment five daily doses of cladribine
(0.15 mg/kg) intravenously followed, 1 month later, by eight weekly
doses of rituximab (375 mg/m2) intravenously. An update of this
study35 showed that all 59 patients with newly diagnosed disease
achieved CR. After a median follow‐up of 50 months (range, 3‐128),
only one patient had relapsed, and one patient had died of a second
neoplasm. This regimen was also very effective in eradicating MRD
that remained detectable in only 21% and 30% of patients by flow
cytometry and PCR, respectively. A randomized phase‐2 trial is
FALINI AND TIACCI
ongoing (NCT00923013) that tests rituximab given concurrently with
cladribine versus sequentially after cladribine only if MRD persists
after cladribine.39
In the relapsed/refractory setting, addition of rituximab to a purine
analogue produces remissions of longer duration than previously
obtained by the purine analogue alone in the same patients. 40
Further-
more, the combination of bendamustine at the dose of either 70 or
90 mg/m2 on days 1 and 2 (for six cycles of 28 days) with rituximab
2
(375 mg/m , on days 1 and 15) has been investigated in 12 HCL
patients with relapsed/refractory disease.41 The overall response rate
was 100%, with CRs in four of six patients treated with bendamustine
at 90 mg/m2 vs three of six patients who received bendamustine at
2
the dosage of 70 mg/m . Both absence of MRD (67% vs 33%) and
time to CR (111 vs 223 days) seemed to favor the higher dose of
bendamustine.37 This trial is currently randomizing patients to
bendamustine 90 mg/m2 plus rituximab versus pentostatin plus ritux-
imab. 37
Also, fludarabine plus rituximab has been tested in 15
relapsed/refractory HCL patients, with all 13 evaluable patients
responding to this treatment and 14 of 15 being progression‐free after
a median of almost 3 years.42
4 | NEW TREATMENT OPTIONS
Despite these progresses, 40% to 50% of patients still experience
relapses during the course of the disease, and these events usually
associate with a progressively worse response to purine analogues.43,44
Moreover, over time, repeated therapy with cladribine or pentostatin
can lead to cumulative myelotoxicity and long‐lasting severe immune
suppression. More recently, the availability of anti‐CD22 immunotoxins
and BRAF and MEK inhibitors (originally developed for treating BRAF‐
mutated metastatic melanoma45,46) offers new therapeutic options
for HCL patients with refractory or relapsed disease.
5 | MOXETUMOMAB PASUDOTOX
This is a recombinant immunotoxin containing an antibody with high
affinity and selectivity for the CD22 molecule conjugated to a trun-
cated Pseudomonas exotoxin. This immunotoxin, originally called
HA22 for “higher affinity for CD22,” was renamed CAT‐8015 and,
more recently, Moxetumomab Pasudotox (moxe).37 A global single‐
arm phase‐3 registration trial was recently completed in 77
relapsed/refractory HCL patients (median of three previous therapies),
who received moxe 40 μg/kg intravenously on days 1‐3‐5 every
28 days for a median of six cycles. The overall response rate was
75%, including 43% CRs and 31% CRs lasting 6 months or more. Nota-
bly, most CRs were MRD‐negative (82%),47 and at a median follow‐up
of 16.7 months, the median cytopenia‐free survival post‐CR was not
reached. Treatment was generally well tolerated, although 10% of
patients discontinued the drug due to toxin‐induced hemolytic‐uremic
syndrome (HUS) or capillary‐leak syndrome (CLS). Based on these
data, moxe (Lumoxiti) was recently approved by the US FDA in
relapsed/refractory HCL after two or more prior therapies (including
33
a purine analog), with a boxed warning for HUS and CLS including
life‐threatening cases.
6 | M O L E C U L A R TA R G E T ED TH E R A P Y
WITH BRAF INHI BIT ORS
6.1 | Preclinical studies with BRAF inhibitors
The lack of true human HCL cell lines48,49 and animal models of the
disease6 makes preclinical studies of HCL difficult to perform due to
the typically little number of HCL cells circulating in the blood. How-
ever, we were able to test in vitro the activity of BRAF inhibitors
(vemurafenib and dabrafenib) and a MEK inhibitor (trametinib) directly
on primary HCL cells purified from patients.50 Notably, all these
agents led to the MEK and ERK dephosphorylation, silencing of the
RAS‐RAF‐MEK‐ERK pathway transcriptional output, abrogation of
the HCL‐specific gene expression signature, loss of hairy morphology,
and apoptosis.50 Apoptosis occurred after the loss of hairy morphol-
ogy and was associated with upregulation of the pro‐apoptotic genes
BIM/BCL2L11 and CDKN1C/p57‐KIP2.50 This is consistent with the
concept that the growth of HCL is mostly sustained by inhibition of
apoptosis50 and with the observation that the proliferative index of
HCL (less than 1%) is one of the lowest among B‐cell malignancies.51
Notably, BRAF inhibitors induced the above effects specifically in
HCL but not in BRAF wild‐type HCL‐like cells. These in vitro results,
together with the ubiquitous MEK‐ERK pathway activation shown
by HCL cells in vivo (Figure 1),52 strongly supported the use of BRAF
and MEK inhibitors for the targeted therapy of HCL.
6.2 | Therapy of relapsed/refractory HCL with BRAF
inhibitors
The first descriptions of the clinical activity of BRAF inhibitors referred
to anecdotal cases of refractory/relapsed HCL,53-60 usually treated
with low doses of vemurafenib (mostly 240 mg to 480 mg × 2/die)61
compared with the standard dose used in BRAF‐mutated melanoma
(960 mg ×2/die). In 2015, we and others reported the results of two
multicenter phase‐2 clinical trials (one performed Italy and the other
in United States) using vemurafenib in a total of 54 patients with
refractory/relapsed HCL.62 The drug was administered at the dose of
960 mg × 2/die for a median of 16 weeks in the Italian study and
18 weeks in the US study.62 In 49 evaluable patients, the ORRs were
96% (CR = 35%) and 100% (CR = 42%) in the Italian trial (n = 25
patients) and the US study (n = 24 patients), respectively, with all CRs
being MRD‐positive. Cytopenias resolved usually within 4 weeks, and
formal response to the drug occurred in a median of 2 to 3 months.62
At a median follow‐up of 23 months, the median relapse‐free sur-
vival in the Italian trial was 19 months in patients who had achieved
CR and 6 months in those who had obtained PR62; the median
treatment‐free survival in these cases was 25 and 18 months, respec-
tively. In the US study, the progression‐free survival and the overall
survival at 1 year were 73% and 91%, respectively.62
34
Vemurafenib was generally well tolerated, with a toxicity profile
similar to that reported in patients with metastatic melanoma.63-65
Adverse drug reactions were reversible, largely grade 1‐2 and mostly
affecting the skin (rash, photosensitivity, palmar/plantar fibrosis, and
warts) and the joints (arthralgia, arthritis; usually responsive to low
doses of steroids). Dose reduction was required in 50% to 58% of
patients in the two trials.62
Similarly to what observed in patients with metastatic melanoma,
skin tumors with little malignant potential developed in six HCL
patients: two basal cell carcinoma and one superficial melanoma
(in three patients from the Italian trial) and three squamous cell
62
carcinomas (in three patients of the US study). All tumors were
managed by simple excision, without requiring dose interruption or
reduction. They are known to be caused by a paradoxic effect of
vemurafenib in skin cells harboring a pre‐existing RAS mutation
66
(especially affecting HRAS).
Notably, vemurafenib showed no myelotoxicity. This supports its
use not only in the setting of refractory/relapsed HCL but also as
front‐line therapy in HCL patients who, at the time of initial diagnosis,
present with a severe opportunistic infection, that precludes the use
of myelotoxic agents.67,68
6.3 | Mechanisms of resistance to BRAF inhibitors in
HCL
The dramatic responses achieved with vemurafenib in refractory/
relapsed HCL were frequently followed by relapse, due to persistence,
FIGURE 2 Proposed treatment algorithm of hairy cell leukemia (investigational agents in italic)
FALINI AND TIACCI
at the end of treatment, of vemurafenib‐resistant cells, even in
complete responders.62 Several mechanisms of resistance to BRAF
inhibitors have been described in BRAF‐mutated melanoma patients
treated with vemurafenib until progression,69-78 including mutations
of RAS or MAP2K1/MEK1 (but not BRAF). Conversely, knowledge is
scarce in HCL patients relapsing months (often several) after the end
of treatment.
Interestingly, one patient of the American HCL trial acquired at
relapse two independent subclonal activating KRAS mutations.62 Also,
six of 13 evaluable cases in the Italian trial showed the persistence of
ERK phosphorylation in bone marrow HCL cells at the end of
treatment, despite ongoing prolonged exposure (16 to 20 weeks) to
vemurafenib. This observation suggests that, in at least some HCL
patients, the growth of HCL cells is still dependent on MEK‐ERK
signaling, which is likely reactivated through mechanisms bypassing
BRAF inhibition by vemurafenib. Functional and genetic studies of
leukemic cells, before and after therapy with BRAF inhibitors, are
required to further clarify the mechanisms of resistance to this drug
in HCL.
6.4 | Future perspectives
BCR signaling inhibition with ibrutinib has demonstrated some activity
in a phase‐2 trial of 17 relapsed/refractory HCL, with an ORR of 59%
(including four CRs, 24%, and six PRs, 35%) after prolonged drug
administration (median > 22 months).79
FALINI AND TIACCI
Based on previous studies in melanoma,46 dual inhibition of BRAF
and MEK should address the MEK/ERK‐dependent mechanisms of
resistance to BRAF inhibition alone and is expected also to decrease
the incidence of secondary skin tumors. In a phase‐2 multicenter trial,
the BRAF inhibitor dabrafenib combined with the MEK inhibitor
trametinib was given at their standard doses for a median of
17 months to 43 relapsed/refractory HCL patients. ORR was 78%
with 49% of CRs,80 which does not appear considerably different from
the efficacy of a BRAF inhibitor alone given for a defined and signifi-
cantly shorter duration.62 However, the CRs achieved with dabrafenib
plus trametinib were MRD‐negative in 30% of cases.80 Although grade
3‐4 adverse events were reported in 49% of cases, only 12% of
patients permanently discontinued the treatment (including two due
to pancreatic adenocarcinoma and Hodgkin lymphoma).80 We are
testing, in the relapsed/refractory setting, an alternative combination
of BRAF and MEK inhibitors, vemurafenib and cobimetinib, respec-
tively, through a multicenter phase‐2 trial (EudraCT 2017‐001836‐
20) close to full patient accrual.
Combination therapy of a BRAF inhibitor plus immunotherapy with
rituximab might eliminate the residual BRAF inhibitor‐resistant HCL
cells whether or not depending on MEK‐ERK signaling. Indeed, in
our ongoing phase‐2 single center trial of such combination given at
standard doses for 8 weeks to 31 relapsed/refractory HCL patients,81
we strikingly observed a CR rate of 100% (25 of 25 evaluable cases),
including MRD‐negative CRs in 14 of 23 (61%) evaluable patients.
Among the latter, 10 underwent follow‐up bone marrow evaluations,
and nine of them (90%) maintained an MRD‐negative status after a
median of 14.5 months (range, 3‐18.5); in the remaining patient,
MRD reappeared 12.5 months later without cytopenias. Toxicity was
mostly of grade 1‐2 and was consistent with that of either drug when
used alone; one patient with lung aspergillosis was safely and effec-
tively treated with this drug combination. Therefore, vemurafenib plus
rituximab represents a short, safe, and non‐myelotoxic regimen that
produces a high rate of deep and durable responses
relapsed/refractory HCL patients. It is clearly superior to historical
results of vemurafenib or rituximab alone and has the potential not
only of becoming the most attractive treatment in
relapsed/refractory setting (Figure 2) but also of challenging chemo-
therapy in the front‐line setting.
ACKNOWLEDGEMEN TS
The authors' work was supported by grants from the Italian
Association for Cancer Research—AIRC (“5 per mille 2010” Molecular
Clinical Oncology 10007 to B.F.; Investigator Grant 19143 to E.T.), the
European Research Council (FP7/2007‐2013 Consolidator Grant
“Hairy Cell Leukemia,” 617471 to E.T.), the Hairy Cell Leukemia
Foundation (to B.F. and E.T.), and the Leukemia and Lymphoma
Society (Translational Research Program 6557‐18 to E.T.).
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How to cite this article: Falini B, Tiacci E. New treatment
options in hairy cell leukemia with focus on BRAF inhibitors.
Hematological Oncology. 2019;37(S1):30–37. https://doi.org/
10.1002/hon.2594