Progress in Understanding of Hairy Cell Leukemia and Hairy Cell Leukemia-Like Disorders
Nahla AM Hamed*
Faculty of Medicine, Alexandria University, Egypt
Submission: October 18, 2018;Published: November 05, 2018
*Corresponding Address: Nahla AM Hamed, Professor of Hematology, Faculty of Medicine, Alexandria University, Egypt
How to cite this article: Nahla AM Hamed. Progress in Understanding of Hairy Cell Leukemia and Hairy Cell Leukemia-Like Disorders. Canc Therapy & Oncol Int J. 2018; 12(4): 555844. DOI:10.19080/CTOIJ.2018.12.555844
HCL is a well-recognized clinicopathological entity. BRAF-V600E mutation is present in many patients with cHCL and is absent in vHCL. Despite the remarkable progress that has been made with purine nucleoside analogs as the initial treatment of HCL patients, yet relapse and eventual development of refractory disease occurs. An appropriate approach to retreatment represents continuing areas for research. FDA has recently approved immunotoxin conjugates moxetumomab pasudotoxfor the treatment of HCL patients who have already undergone at least two lines of standard therapy. The development of internationally accepted, reproducible criteria on definitions of response, relapse, and methods of determining MRD is of paramount importance in comparing clinical trials.
HCL is a rare subtype of B-cell chronic lymphoid leukemia that accounts for 2% of all leukemia .Males are affected more frequently than females (ratio 4:1), usually over the age of 60 years . It is characterized by progressive pancytopenia, splenomegaly  (approximately 90%)  and infiltrations of the bone marrow, liver, and spleen, with B lymphocytes possessing cytoplasmic projections that appear as fine hair-like microvilli.  Some patients present with profound pancytopenia accompanied by massive splenomegaly. Others have moderate asymptomatic pancytopenia that may remain progression-free for many years without therapy . Monocytopenia is a relatively sensitive and specific manifestation of cHCL. There are numerous case reports of atypical manifestations of HCL. For example, HCL may atypically present with cutaneous, visceral, bone, pleural, and meningeal involvement .
HCL can mimic or coexist with other clonal hematologic disorders and has been associated with autoimmune disorders .It may coexist with other B-lymphoid malignancies. Polyclonal and monoclonal gammopathy have been reported in 3%–20% of patients and may be related to an associated plasma cell dyscrasia, lymphoma, or autoimmune disorder. HCL may be associated with a variety of autoimmune disorders, most commonly vasculitis . HCL must be differentiated from other HCL-like disorders, including vHCL and splenic diffuse red pulp lymphoma.
vHCL should be suspected in cases presented with splenomegaly associated with cytopenias, a normal monocyte count, and lymphocytosis characterized by hairy cells with prominent nucleoli. Despite morphologic similarities, vHCL is not biologically related to cHCL. cHCL and vHCL differ in prognosis, with vHCL responding poorly to PAs, with a median survival less than half that of cHCL.
A subset and a new variant of HCL that is associated with poor prognosis, which includes higher disease burden at diagnosis, poor response to standard therapy, shorter overall survival and absence of the BRAF-V600E mutation .Forty percent of vHCL and ten percent of HCL patients have an IGHV4–34 immunoglobulin variable heavy chain rearrangement .
Gene-expression profile data strongly suggest that hairy cells arise or are related to memory B cells .The mutations present in each HCL subtype are distinct . BRAF-V600E mutations are identified in up to 80–90% of HCL cases . The mutation in B-raf proto-oncogene (BRAF gene) (7q34) occurs in exon 15 at position 1799, in which thymine and adenine are exchanged, leading to valine (V) substitution by glutamate (E) at codon 600 (V600E) of the BRAF protein. BRAF-V600E mutation constitutively activates
BRAF by autophosphorylation of the protein and downstream
MEK-ERK signaling pathway, leading to increased expression of
genes involved in survival and proliferation . In BRAF-V600Enegative
HCL cases, the possibility of 2 novel mutation in exon 11
(F468C, D449E) must be excluded. (1)BRAF-V600E mutation is
not detected in vHCL , IGHV4-34 variants of HCL  or other
small B-cell lymphoid neoplasms .
The most common genetic alteration in cHCL apart from BRAFV600E
was heterozygous loss of chromosome7q, the minimally
deleted region of which targeted wild-type BRAF, subdividing
cHCL into those hemizygous versus heterozygous for the BRAFV600E
mutation . Additional alterations are frequently
required for tumor initiation and/ or progression as suggested by
studies of BRAF-V600E-mutant cells in diverse cancers marked
by BRAF-V600E mutation . The two mutations most frequently
identified after BRAF mutations were histone methyltransferase
KMT2C (MLL3) and CDKN1B mutations, which occur in 15% and
11% of patients, respectively .
The CDKN1B gene encodes the cyclin dependent kinase
inhibitory protein p27, which inactivates the cyclin E-CDK2
complex. The p27 protein is a known tumor suppressor that exerts
either stimulatory or inhibitory effects on cell proliferation, cell
motility, or apoptosis. Moreover, p27 upregulation can participate
in chemotherapy resistance. At high levels, p27 binds to the cyclin
E-CDK2 complex, inhibiting its activity and allowing cell cycle
arrest. In contrast, lower levels of p27 protein stabilize cyclin
D-CDK4/6 complexes and facilitate cell cycle progression .
Mutation in MAP2K1which encodes MEK1 (downstream
of BRAF) have been reported in almost half of vHCL and in the
majority of HCL that use IGHV4-34 . Activating mutations in
CCND3 and a change-of-function mutation in the splicing factor
U2AF1 were present in 13% for any in vHCLs. Recurrent
inactivating mutations in KMT2C (MLL3) were identified in 25%
of vHCLs. These data identify numerous novel drivers of HCL
and additional shared cooperating alterations, as well as diseasespecific
alterations targeting BRAF, KMT2C, and CDKN1B in cHCL
and MAP2K1, CCND3, U2AF1, TP53, and KMT2C in vHCL .
Diagnosis of HCL is based on morphological evidence of
hairy cells, an HCL immunologic score based on the four markers
CD11C, CD103, CD123, and CD25 expression. A score of 3 or 4 is
observed in 98% of HCL cases, whereas the score in other HCL-like
disorders is usually 0 or 1 . cHCL and vHCL share expression of
CD11c and CD103, only cHCL expresses CD25, CD123, CD200, and
annexin A1 .The immunophenotype CD103pos/CD11cbright/
CD123neg/CD25neg supports the diagnosis of vHCL .
A trephine bone marrow biopsy and aspirate are important
at diagnosis. A dry bone marrow tap is often attainable because
of extensive fibrosis. Approximately 10% of patients will have
a hypocellular bone marrow biopsy at diagnosis reflecting a
decrease in normal hematopoiesis . IHC stains for CD20, CD76,
annexin A1, and VE1 (a BRAF-V600E stain) will establish the
diagnosis and provide an accurate assessment of the degree of
leukemic bone marrow infiltration. In patients treated with anti-
CD20 monoclonal antibody apply pan B-cell markers, other than
CD20, such as CD79a and/or HCL-specific markers (e.g., VE1) or
DBA.44 to avoid unpredictable results.
Bone marrow biopsy should be delayed 4 to 6 months after
cladribine administration and performed after a clinical response
with pentostatin therapy to document a complete remission.
Highly sensitive techniques (e.g., allele-specific polymerase chain
reaction or next-generation sequencing) should be preferred to
avoid false-negative results when few leukemic cells (<10%)
are present in the peripheral blood or in diluted bone marrow
aspirates. If leukemic cells are insufficient or highly sensitive
molecular techniques for genomic profiling are inaccessible, IHC
stain (eg, VE1) to the bone marrow biopsy may enable detection
of BRAF-V600E mutation .Demonstration of BRAF-V600E
mutation could be important for those who do not respond to
standard therapy or have multiple relapses .Flow cytometry,
using an 8-color panel (CD103/CD305/CD19/CD123/CD25/
CD3/CD45/CD20), can be a tool for detecting blood MRD .
Treatment should be started in symptomatic patients (e.g.,
symptomatic splenomegaly) or if the hematologic parameters are
declining. At least one of the following hematologic parameters
indicates a need for treatment: hemoglobin <11 g/dL, platelet
count <100.000/mL or absolute neutrophil count <1000/mL .
Primary induction therapy for HCL involves either cladribine
or pentostatin . They are associated with profound and
prolonged myelosuppression and immunosuppression.
Attempts to control infection should be pursued prior to
starting the PAs . Resistance and relapses occur with PAs.
Splenomegaly (> 3cm), leukocytosis (>10X109/L), hairy cells
in the blood (> 5 X 109/L), and high beta2-microglobulin (>
2N) are associated with a poor prognosis and resistance to PAs.
CD38 expression drives poor prognosis.Patients with unmutated
IGHV have shorter overall survival durations than those with the
mutated gene . Resistance is a major problem with vHCL.
Activation of signaling pathways parallel to the MAPK pathway
may be responsible for RAF inhibitor resistance . Relapses in
HCL are in the range of 20%–30% at 5 years and up to 48% at 10
Complete Response: It is defined by normalization of
peripheral blood counts (without transfusion), resolution of
palpable splenomegaly and disappearance of hairy cells from the
bone marrow .Minimal residual disease (MRD) is defined as
HCL infiltrates recognizable by IHC stains, but not by conventional
stains . A single report grouped the risk of relapse predicted by
MRD into: group I, <1% positive cells, low risk for relapse; group
II, 1% to 5% positive cells by IHC, intermediate risk for relapse;
and group III, >5% positive cells by IHC, higher risk for relapse.
Future studies are needed to validate the clinical value of these
predictive groups .
Partial Response is defined by near normalization of the
peripheral blood counts with a minimum of 50% improvement
in both organomegaly and bone marrow biopsy infiltration with
hairy cells .
Relapse retreatment is based upon recurrence of diseaserelated
symptoms or deterioration in hematologic parameters
equivalent to initial values used for beginning treatment .
Therapeutic options will depend on the duration of first remission
. Relapse after over 60 months remission should be re-treated
with the same or an alternative PAs. For remissions >24 months,
use PAs followed by rituximab. Response to either humanized,
glycoengineered Type II (obinutuzumab) or the second-generation
anti-CD20 monoclonal antibodies (ofatumumab) is not yet known.
Patients with relapse before 24 months should be considered as
relapsed/refractory HCL patients. The presence of a BRAF-V600E
mutation must be checked. Specific BRAF inhibitors represent the
best option for mutated BRAF cases.In unmutated BRAF cases,
immunotoxins, BCR inhibitors, combination of bendamustine
with rituximab or investigational agents and regimens should be
a. FDA has recently approved immunotoxin conjugates
moxetumomab pasudotox (lumoxiti), a bacterial toxin-based
drug for the treatment of HCL patients who have undergone
at least two lines of standard therapy. It binds CD22 receptors
on the surface of cancerous B cells where it is internalized and
processed to release its toxic payload. However, there is a risk
of capillary leak syndrome .
b. Ibrutinib, a Bruton tyrosine kinase inhibitor that is
currently under study for HCL patients who have not achieved
optimal response to standard therapies .
c. BRAF inhibitor (Vemurafenib, dabrafenib): Vemurafenib
is an ATP-competitive BRAF inhibitor that has potent
antitumor activity in BRAF-V600E-mutated HCL patients.
Its administration has improved peripheral blood counts.
Vemurafenib has been used successfully in a neutropenic
patient with an active infection. After the associated infection
of the underlying leukemia has been resolved, consolidation
with standard therapy could be approached. Genomic analysis
of de novo vemurafenib-resistant cHCL identified a novel
gain-of-function mutation in IRS1 and losses of NF1 and
NF2. Adverse effects from the BRAF inhibitors may include
skin rash, arthralgias, arthritis, or secondary skin tumors .
Rarely, vemurafenib has caused abnormal renal function and
some fewer common toxicities.
d. Consider investigational approaches if poor-risk
features were identified (e.g., severe anemia, spleen >10 cm
below the left costal margin, atypical immunophenotypic
profile, p53 mutation, IGHV4-34 rearrangement, unmutated
IGHV, absence of BRAF-V600E mutation, identification of an
underlying explanation for a less-than desired initial response.