1. health and fitness
2. disease

Published Ahead of Print on January 10, 2011 as 10.1200/JCO.2010.31.7016
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2010.31.7016
JOURNAL OF CLINICAL ONCOLOGY
R E V I E W
A R T I C L E
Modern Strategies for Hairy Cell Leukemia
Michael R. Grever and Gerard Lozanski
From The Ohio State University Medical Center, Columbus, OH.
Submitted July 16, 2010; accepted
October 19, 2010; published online
ahead of print at www.jco.org on
January 10, 2011.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Michael R.
Grever, MD, Division of Hematology,
395 W 12th Avenue, Columbus, OH
43210; e-mail:
michael.grever@osumc.edu.
© 2011 by American Society of Clinical
Oncology
0732-183X/10/2899-1/$20.00
DOI: 10.1200/JCO.2010.31.7016
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Enormous progress in the treatment of hairy cell leukemia over the last five decades has emerged
as a result of organized clinical investigations. Although interferon represented one of the initial
major therapeutic advances in the management of this disease in 1984, the subsequent
introduction of purine nucleoside analogs (pentostatin and cladribine) changed the natural history
of this rare disease by achieving a high rate of complete and durable remissions. The disease-free
survival after effective therapy has not reached a plateau, suggesting control but not cure of the
disease. Identification of minimal residual disease in patients achieving a complete hematologic
remission provides insight into the potential source for predicting eventual relapse. Modern
strategies of targeted therapies directed against immunophenotypic markers on the leukemic cells
provide hope that improved long-term control of the disease is possible. Combined chemoimmunotherapy may hold the highest promise for disease eradication, but the optimal strategy for using
this approach is under active investigation. Despite the perception by hematologists that this
disease has already been conquered, there are critically important unanswered questions that
remain. Investigation of the bone marrow microenvironment and its impact on minimal residual
disease may ultimately prevent relapse. Consideration of the median age of patients at diagnosis
combined with a substantial relapse rate mandates continued pursuit of improved therapy. The
ultimate goal will be to achieve cure rather than simple control of the disease.
J Clin Oncol 28. © 2011 by American Society of Clinical Oncology
ENORMOUS PROGRESS THROUGH
CLINICAL INVESTIGATION
Bouroncle et al1 published the initial description of
leukemic reticuloendotheliosis as a clinical entity
now known as hairy cell leukemia in 1958. There was
no effective or tolerable chemotherapy for this disease for the ensuing two decades, and splenectomy
remained the sole therapeutic approach affording
temporary improvement in hematologic parameters. This rare form of adult chronic leukemia now
serves as a model for clinical research. Although the
projected median survival for these patients was estimated to be between 4 and 6 years in the mid1980s, Quesada et al2 published the initial report of
the effectiveness of interferon alfa in treating this
disease in 1984. Although this initial study was small,
three patients achieved a complete remission, and the
other four patients achieved a partial remission. Subsequently, larger follow-up studies confirmed that
approximately 80% of patients had hematologic response, with approximately 5% to 11% achieving a
complete remission, showing that interferon alfa was
capable of inducing a therapeutic response.3,4
In 1984, Spiers et al5 published the initial report
showing that a purine nucleoside analog (pentostatin) was capable of inducing complete remissions in
a small number of patients. Kraut et al6,7 confirmed
in a larger series that low doses of pentostatin
achieved complete responses in 87% of previously
untreated patients with hairy cell leukemia. Additional investigators confirmed the extremely high
rate of durable complete remissions with pentostatin.4,8-11 A few studies reported lower rates of
complete remission in patients either resistant to
interferon or treated on a National Cancer Institute
(NCI) compassionate protocol.9,12 In 1995, Grever
et al3 reported the first randomized clinical trial
comparing pentostatin and interferon alfa in previously untreated patients with this leukemia. They
confirmed that approximately 76% of patients in a
multi-institutional study achieved a complete remission with pentostatin. Furthermore, patients
who initially were randomly assigned to interferon
were frequently crossed over to pentostatin, and
with this approach, the complete remission rate was
66% after cross over.
In 1990, Piro et al13 reported that cladribine,
another purine nucleoside analog, produced an extremely high complete response rate in 11 of 12
patients with hairy cell leukemia and that this could
be achieved with a single course of chemotherapy
involving 7 days of continuous intravenous drug
infusion. The ease of drug administration made this
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Grever and Lozanski
a highly attractive alternative to multiple treatments with pentostatin
delivered every other week over the course of months. In the
reports of cladribine, many studies excluded patients with an active
infection because there may be prolonged myelosuppression with
this therapy. Numerous reports confirmed the high rate of durable
complete remissions (eg, approximately 76% to 91%).8,14,15 With
two effective agents, the clinical practice over the next two decades
favored the use of either of these single agents in the initial management of this disease. Cladribine became the more frequently
used agent.
Although the longest follow-up data with cladribine resulted
from studies using a 7-day continuous intravenous infusion, more
recent studies have explored a variety of ways to administer the
drug.14,16 Many oncologists administer cladribine intravenously over
several hours each day for 5 days.4 Several investigators in Europe have
studied the subcutaneous route of administration on a variety of
schedules.17-19 In an effort to reduce the myelosuppression, an interrupted or weekly schedule was pursued.20-22 There is a lack of agreement on the optimal schedule or route for cladribine administration,
but the remarkable response rate has been confirmed. Interrupteddose administration of cladribine has not reduced the rate of infections compared with the daily dosing approach.18,20
Recent summaries of the initial and long-term follow-up studies
on both purine analogs conclude that these agents are equivalent as
induction therapy and in terms of long-term outcome.8,23 Although
the schedule of drug administration may be easier with cladribine, the
use of pentostatin in interrupted doses as an outpatient is well tolerated.3 Because pentostatin is administered as a short intravenous infusion in the clinic every 2 weeks, doses may be titrated by delaying
treatment for a week if unacceptable myelosuppression occurs.19 The
frequency of febrile neutropenia with cladribine is higher than that
observed with pentostatin.3 Both of these agents have markedly contributed to improving the natural history of this disease by achieving a
high rate of complete durable remission. Despite these encouraging
results, long-term follow-up studies over the last decade report that
approximately 30% to 40% of patients who achieve a complete remission will experience relapse and may require re-treatment within a
10-year period.8,11,14,15,23,24 The slope of the progression-free survival
curve does not plateau, suggesting that this disease is controlled but
not cured.
ESTABLISHING THE CORRECT DIAGNOSIS AND
INITIATING THERAPY
Remarkable improvement in long-term survival has been achieved in
patients with classic hairy cell leukemia who are accurately diagnosed
and managed. In the past, patients with hairy cell leukemia presented
with symptoms relating to pancytopenia with profound bone marrow
failure. Infections, weakness, and fatigue reflected that these individuals were often in an advanced stage of the disease at diagnosis.
Bouroncle et al1 found that splenic enlargement was present in 96% of
patients. Fifty-eight percent of patients had hepatomegaly, and many
patients presented with symptomatic advanced disease.1,25 In the
modern era, patients often present with abnormalities of their peripheral blood discovered on routine laboratory examination. An updated
assessment of presenting symptoms and signs would be useful in this
current era of earlier diagnosis. Infection at the time of presentation
2
© 2011 by American Society of Clinical Oncology
Fig 1. Characteristic hairy cell leukemia. This figure depicts the characteristic
malignant cell in the peripheral blood from a patient with hairy cell leukemia. The
serrated cytoplasmic border and the nuclear chromatin pattern are readily
appreciated on a Wright stain.
may occur in patients.26 An updated inventory of the types of infections and other disease manifestations would also be informative.
Patients may present with autoimmune complications, vasculitis, hemolysis, and lytic bone disease.
The outstanding responses in hairy cell leukemia expected with
purine analog monotherapy are not observed with the other chronic
B-cell malignancies.27,28 Therefore, it is important to distinguish classic hairy cell leukemia from the variants of this entity. The WHO has
determined that hairy cell leukemia variant is a completely distinct
clinical and pathologic entity from classic hairy cell leukemia. The
biology and clinical course, including response to therapy, of hairy cell
leukemia variant are different than those experienced with the classic
form of hairy cell leukemia.29
The hematologic parameters frequently encountered with hairy
cell leukemia include neutropenia and an absolute monocytopenia.1 Patients are often anemic and thrombocytopenic. In Figure 1,
the characteristic cell in hairy cell leukemia is observed with its
serrated border. Some of the other indolent lymphoid malignancies may be difficult to discern from this disease. The hair-like
projections in hairy cell leukemia tend to be circumferential in
contrast to those with marginal zone lymphoma, which may have
polar or noncircumferential features with the cytoplasmic border.30 Despite the distinctive morphologic features of this malignant cell, the accurate differentiation from other similar chronic
lymphoid malignancies requires flow cytometry for making the
correct diagnosis.27,28 In Figure A1 (online only), the typical flow
presentation of hairy cell leukemia is presented.
A monoclonal population of B cells with either ␬ or ␭ light
chain restriction will be demonstrable by flow cytometry. The
pattern of antigen expression on circulating leukemic cells in classic hairy cell leukemia includes CD20, CD11c, CD25, and CD103.
These cells have also been recently distinguished by expression of
CD123 and bright annexin A1-positive cells.27 From a clinical
perspective, patients with the variant of hairy cell leukemia often
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Modern Strategies for Hairy Cell Leukemia
A
B
Fig 2. Hairy cell leukemia presenting with hypocellular bone marrow. Hairy cell leukemia may substantially suppress normal hematopoiesis in the bone marrow. It is
critically important to realize that, in patients with pancytopenia, the presence of a severely hypocellular marrow may be associated with hairy cell leukemia and not
aplastic anemia. This figure presents two bone marrow photographs illustrating the severe degree of bone marrow hypoplasia with (A) a hematoxylin and eosin stain
and (B) an immunohistochemical stain revealing DBA.44 immunostain-positive cells consistent with hairy cell leukemia. The leukemic cell infiltration may be subtle and
requires this immunohistochemical technique to make a correct diagnosis.
have elevated numbers of circulating leukemic cells with their
distinctive antigenic pattern showing loss of CD25 positivity coupled with negative CD103.28 If the diagnosis of hairy cell variant is
made, a completely different therapeutic approach will be required. In fact, close inspection of the initial diagnostic data should
be considered for patients with hairy cell leukemia who do not
show an expected clinical response to therapy.
In addition to the examination of peripheral-blood morphology and flow cytometry, an initial diagnostic bone marrow biopsy
provides an estimate of bone marrow involvement and the extent
of fibrosis.30 The bone marrow aspirate is often not obtainable, so
that immunohistochemical stains of the bone marrow biopsy with
either DBA.44 or anti-CD20 will yield an accurate estimate of the
extent of bone marrow infiltration. In addition, it is important to
realize that occasional patients with hairy cell leukemia and pancytopenia present with a severely hypocellular bone marrow.30-32 In
Figure 2, the severely hypocellular bone marrow might be mistaken
for aplastic anemia. Thus, establishing an accurate diagnosis of this
highly treatable leukemia is critically important for successful patient management.
In Figure 3, the extensive bone marrow involvement with leukemia and fibrosis observed in a patient with this disease illustrates the
A
B
basis for poor tolerance of cytotoxic chemotherapy. Therefore, a careful assessment of the bone marrow is helpful in establishing the correct
diagnosis and in planning therapy.
MANAGEMENT DECISIONS
The data using either pentostatin or cladribine alone for hairy cell
leukemia suggest that these agents are equally effective in terms of
response rate and remission duration.8,23 Furthermore, the long-term
adverse effects are quite comparable. The concerns regarding increased risk for either late infections or secondary malignancies have
not been fully resolved.14,15,24,26,33-36 Patients have had a substantial
improvement in overall survival as a result of the initial use of either
analog. Although they will need to be closely observed for late
adverse effects of therapy, patients with hairy cell leukemia may
now live as long as they would have without this diagnosis. The
progress in treatment changed the natural history of this disease.
Although there is still not a recognized best way to initiate therapy,
there is a consensus that striving for a complete remission is important. In selecting appropriate chemotherapy, several clinical
features must be considered.
C
Fig 3. Hairy cell leukemia depicting extensive bone marrow disease and fibrosis. Patients presenting with pancytopenia and bone marrow failure do not tolerate
cytotoxic therapy well. This photograph of the bone marrow biopsy shows the extensive leukemic cell replacement coupled with extensive fibrosis. Hairy cells excrete
fibronectin and induce myelofibrosis. (A) The trichrome stain shows prominent collagen deposition. (B) Fibrosis is confirmed with a reticulin stain. (C) The anti-CD20
stain is consistent with hairy cell leukemia.
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Grever and Lozanski
Does the Patient Have Sufficient Evidence of Bone
Marrow Failure to Warrant Initiation of Therapy?
In patients with a diagnosis of hairy cell leukemia, the absence
of declining peripheral-blood counts may be used to select patients
who can be observed closely on a watch and wait program.19 An
international Hairy Cell Leukemia Consortium has been organized
to address important unanswered questions. There is no uniform
agreement on the exact counts required to justify therapy, but
select patients may benefit from close observation. The current
highly effective chemotherapy does entail some risk, and the occasional patient who is completely asymptomatic with a diagnosis of
hairy cell leukemia found on incidental blood work may not merit
immediate initiation of treatment.
Issues relating to patient management in hairy cell leukemia that
need more research are listed in Table 1. Recommendations are being
developed by the Hairy Cell Leukemia Consortium for the absolute
blood counts that usually merit initiation of therapy. The careful
follow-up of the patient who is being observed entails at least quarterly
blood counts and physical examination. If the patient develops a
sustained decline in the blood counts or becomes symptomatic with
generalized symptoms of fatigue or splenomegaly, then therapy is
started before the counts decline to dangerously low levels. The initiation of either cladribine or pentostatin may be associated with a
temporary worsening of the blood counts, so intervention should
definitely begin before these hematologic parameters have deteriorated to the levels requiring support. Because either of these agents is
highly effective as monotherapy, most clinicians will select the agent,
dose, and schedule that they have effectively used in the past.
Is There Evidence of Active, Untreated,
Ongoing Infection?
Although it is prudent to attempt to effectively treat an active
infection before administering a purine nucleoside analog to a patient
with hairy cell leukemia, the profound neutropenia and monocytopenia related to the disease may force the decision to start effective
therapy. Otherwise, the patient may succumb to the infection. However, purine analogs may temporarily worsen the hematologic parameters. Most of the initial reports of cladribine indicate that this agent
should not be administered to a patient with an ongoing infection.13,37,38 This cautionary statement relates to the prolonged my-
Table 1. Issues Requiring More Research in the Management of Hairy
Cell Leukemia
Issue
Develop consensus on when to initiate therapy based on symptoms and
hematologic parameters (eg, absolute granulocyte count ⬍ 1,000/␮L;
platelet count ⬍ 100,000/␮L, etc)
Develop evidence-based recommendation for initial therapy with either a
purine analog or combined chemoimmunotherapy (eg, What is optimal
agent, dose, and schedule for administration?)
Optimize therapy for patients with active infection
Define importance of and approach to minimal residual disease
Explore the biology of bone marrow microenvironment as it relates to
innovative therapeutic strategies (eg, novel agents targeting stroma)
Determine the best approach for patients in relapse with sensitive disease
(eg, when and how to retreat)
Determine the best approach for patients with unresponsive disease
4
© 2011 by American Society of Clinical Oncology
elosuppression that may be seen after an intense course of the drug.
Under these circumstances, one strategy involves treating the patient
with interferon alfa to obtain an improvement in the granulocyte
count that may enable the antibiotic or antifungal therapy to be more
effective in controlling the infection.39 Subsequently, the patient can
receive more definitive antileukemia therapy with a purine analog in
seeking to achieve a more durable complete remission.
Alternatively, pentostatin was used in a large study where patients
with active infections were not automatically excluded.3 Although the
complete remission rate was higher in the uninfected group, compared with patients with infection, with either pentostatin (78% v
68%, respectively) or interferon (11% v 5%, respectively), the effect of
infection at registration on the subsequent achievement of a complete
remission was not significant (two-tailed P ⫽ .17, logistic regression
analysis). In this multi-institutional study, the frequency of febrile
episodes requiring antibiotic therapy was 27% with pentostatin compared with 37% to 58% after a 7-day course of cladribine reported in
other studies.13,40,41 Again, it is recommended that the infection be
controlled if possible before using pentostatin.
Saven et al42 studied the effect of filgrastim on cladribineinduced neutropenic fever in hairy cell leukemia. This agent could
raise the absolute granulocyte count and shorten the period of
severe neutropenia in these patients. However, the investigators
found that there was no clinical advantage in patients who were not
initially infected at the time of entrance onto the study. These
findings were based on historical controls and did not constitute a
prospectively randomized trial. Filgrastim, however, may benefit
patients with severe neutropenia and active infection.43 Optimal
management of patients with hairy cell leukemia and infection
merits further investigation.
Does the Patient Have a Good Performance Status
and Adequate Renal Function?
Many studies have explored the optimal dose and route of
cladribine administration. The dose of cladribine most frequently
administered in the United States on the Scripps regimen involves a
continuous intravenous infusion with 0.1 mg/kg/d for 7 days.14 On
this regimen, the complete remission rate has been reported to be
95%, and the relapse rate has been reported as 37% with long-term
follow-up. If the agent is delivered at a dose of 0.14 mg/kg intravenously over 1 to 2 hours on a 5-day schedule, the results are reported to
be similar.4
If the decision is made to use pentostatin, the standard dose is
4 mg/m2 intravenously every 2 weeks until a complete remission is
achieved. This dose and schedule may be delayed if unanticipated
worsening myelosuppression is observed, but as the marrow function improves with therapy, the dose is returned to normal to
complete the therapy. Pentostatin is cleared through a renal route.
Thus, renal function must be carefully monitored during therapy.3
Patients were excluded from receiving this agent if the baseline
serum creatinine was ⱖ 1.5 mg/dL. The initial dose of the drug was
reduced to 2 mg/m2 if the patient’s performance status was impaired and subsequently escalated to full-dose therapy (4 mg/m2) if
no adverse reactions were encountered. In managing patients as
outpatients on pentostatin, patients received 1.5 L of fluid hydration with each dose. Serum creatinine was checked before each new
dose of pentostatin to ensure that renal function was adequate for
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Modern Strategies for Hairy Cell Leukemia
safe drug administration. Basically, this outpatient regimen is
well tolerated.3
The importance of continued participation in clinical trials is
paramount for further refining the excellent results that have already
been achieved to date. Many patients will not be able to participate in
ongoing clinical trials because of geographic considerations or because of
other comorbid illness. Therefore, we encourage physicians to consider
enrollingtheirpatientsontoongoingclinicaltrialwhenpossibletoaddress
some of the important remaining unanswered questions (Table 1).
IMPORTANCE OF MINIMAL RESIDUAL DISEASE
With immunohistochemical staining, it became apparent that minimal residual disease is present in many of the successfully treated
patients thought to be in complete remission by light microscopy.44-46
In general, the definition of a complete remission required normal
bone marrow histopathology with normalization of peripheral-blood
counts.3 The hemoglobin recovered to greater than 12 g/dL, the platelet count increased to more than 100,000/␮L, and the absolute granulocyte count exceeded 1,500/␮L. Patients with enlargement of the
spleen had disappearance of this abnormality on physical examination. In a complete remission, no visible hairy cells could be identified
on light microscopy. Although hematologic recovery was achieved in
these patients, specialized studies documented that residual disease
might predispose to relapse. In fact, the extent of minimal residual
disease remaining after initial therapy with a purine analog may predict for clinical relapse.44,47,48 However, there are long-term survivors
with minimal residual disease who have not experienced a hematologic relapse.49
Minimal residual disease is identified by immunophenotypic
analysis, immunohistochemical staining, or DNA polymerase chain
reaction in the absence of morphologic evidence of hairy cell leukemia.44 Although previous reports have characterized the posttreatment bone marrow as being either positive or negative for
minimal residual disease, future studies should quantitate these findings in a reproducible manner. In addition to quantifying the extent of
this phenomenon, the timing and uniformity of this assessment may
be important. In Figure 4, the immunohistochemical stains with
A
DBA.44 or anti-CD20 monoclonal antibody show the presence of
persistent hairy cell leukemia that may be unappreciated with either
Wright or Giemsa staining alone.44 Immunohistochemical staining of the bone marrow core biopsy using a combination of stains
that includes annexin A1, CD19, CD20, TRAP, and DBA.44 markedly enhances the sensitivity and accuracy of detecting minimal
residual disease in hairy cell leukemia that would be missed on
slides stained with hematoxylin and eosin alone. A current issue
that must be resolved is how to best approach the patient with
minimal residual disease.
The bright expression of CD20 on the leukemic cells from patients with hairy cell leukemia suggested that rituximab would be a
rational therapeutic approach to convert patients with residual disease
to a more complete remission.44,50-52 The results after rituximab have
been reported with a limited number of patients, and often there is a
mixture of previously treated and untreated patients. Some reports
include patients with purine-resistant disease, whereas others include
patients with relapse. The response to rituximab may vary depending
on the composition of the patients and the extent of bone marrow disease.53-57
HAIRY CELL LEUKEMIA IN RELAPSE AND
UNRESPONSIVE DISEASE
Many studies include patients either with disease in relapse requiring therapy or with unresponsive disease. Some of the patient
groups encompassed those with classic hairy cell leukemia and
others with a variant of the disease. It is important that studies
focus on specific clinical entities to enable accurate comparison
across trials. It is difficult to make comparative statements if patients with the classic form of the disease are reported along with
those who have the variant.
If patients with classic hairy cell leukemia achieve a complete
remission and then experience relapse requiring therapy less than 1 to
2 years after initial treatment, it is important to confirm that the
patient has a correct diagnosis.4,19 If the patient with classic hairy cell
leukemia experiences relapse within 2 years after monotherapy with a
purine analog, the patient should be considered for re-treatment with
B
Fig 4. Hairy cell leukemia: minimal residual disease comparison hematoxylin and eosin (HE) stain and anti-CD20 stain. In patients who achieve complete remission
according to light microscopy, there is no detectable disease through (A) HE stain. Furthermore, the peripheral blood and bone marrow aspirate will not reveal
discernible leukemic cells in those patients in complete remission. (B) Using immunohistochemical staining of the bone marrow core biopsy with a combination of stains
that include annexin A1, CD19, CD20, TRAP, and DBA.44 markedly enhances the sensitivity and accuracy of the detection of hairy cell leukemia minimal residual
disease that would be missed on HE-stained sections.
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Grever and Lozanski
the alternative purine analog or with combined chemoimmunotherapy.58 Investigators at several institutions are exploring the optimal utilization of combined chemoimmunotherapy.
Some investigators report results with rituximab alone, but
the responses have been less impressive than those achieved with
combined chemoimmunotherapy. Recent studies show that combined chemoimmunotherapy with a purine analog and a monoclonal antibody is effective in patients who experienced relapse
after initial therapy with chemotherapy alone.58,59 Considering the
limited number of patients with this disease, randomized clinical
studies to conclusively prove that combined chemoimmunotherapy would be more effective than monotherapy with a purine
analog have not been performed. In addition, there is no evidence
yet that simultaneous purine analog administration combined
with a monoclonal antibody is more effective than these agents
delivered in series. Some studies used four weekly courses of rituximab, whereas others have reported that eight courses were effective.48,53,54,60 The empiric approach to combination therapy may
be reasonably well tolerated, but the evidence to optimize the use of
these agents has not yet been rigorously defined. There is an ongoing protocol to determine whether simultaneous combined therapy is superior to these agents being administered in series, but this
NCI study has just recently been launched.58 On the basis of
published data in chronic lymphocytic leukemia, the simultaneous
administration of a purine analog (fludarabine) and rituximab was
superior to the agents delivered in series. In this prospective randomized trial, the outcome of simultaneous drug administration
resulted in higher complete remission rates.61,62 In contrast to
chronic lymphocytic leukemia, hairy cell leukemia is exquisitely
more sensitive to monotherapy with a purine analog. Therefore,
the conundrum exists as to whether combined chemoimmunotherapy should be used as initial therapy for hairy cell leukemia or
instead used at the time of relapsed disease requiring reinitiation
of therapy.
Novel therapies have been successful in treating patients with
truly refractory disease. The immunotoxin conjugates developed
by Drs Kreitman and Pastan at NCI have yielded impressive early
results.58,63,64 These agents link a potent toxin (eg, truncated
Pseudomonas exotoxin) to modified fragments of monoclonal antibodies that target a B-cell antigen expressed on the surface of
hairy cells. Although one of the initial promising agents was LMB-2
directed against CD25, this antigen is not expressed on leukemic
cells from many patients with the variant form of this leukemia.27
In contrast, CD22 is expressed on the leukemic cells from patients
with both classic hairy cell leukemia and the variant. BL22 is an
immune conjugate delivering Pseudomonas exotoxin to leukemic
cells expressing CD22. BL22 produced complete remissions in an
earlier phase I trial with highly resistant hairy cell leukemia. Although a reversible hemolytic uremic syndrome had been observed
in some of the earlier patients (13%), the subsequent phase II trial
had a lower rate of this complication (6%). HA22, the current
modified agent, has been well tolerated with impressive early results and is undergoing further evaluation by the group at NCI.58
Kreitman et al65 presented encouraging phase I data using HA22 in
26 patients with hairy cell leukemia who had extensive previous
treatment. The objective response rate was 73%, with a complete
remission rate of 34.6% and a partial response rate of 38.5%.
6
© 2011 by American Society of Clinical Oncology
Despite the preliminary nature of this report, the response durations and toxicity profile are encouraging.
POTENTIAL NEW AVENUES FOR THERAPEUTIC RESEARCH IN
HAIRY CELL LEUKEMIA
The importance of minimal residual disease as a predictor for relapse
is being investigated, and rational therapy based on combinations of
chemoimmunotherapy directed toward the residual, less responsive
hairy cells has been well described.44,48 A relatively new exciting area of
investigation will focus on the bone marrow microenvironment as a
potential source of resistance to effective therapy.66 Investigators have
described the biology underlying the unusual fibrosis encountered in
the bone marrow as a result of the presence of hairy cell leukemia.67
Elucidation of the cytokines and their receptors, as well as the adhesion
molecules, may yield novel therapeutic strategies unexplored to date.
Furthermore, the impairment in hematopoiesis and induction of
bone marrow fibrosis may be related to transforming growth factor ␤
produced by the hairy cells.68
After the remarkable improvement of hematologic parameters
with successful induction of a complete remission, the bone marrow
serves as a well-documented locus for minimal residual disease. Addressing the underlying biology associated with these residual leukemic cells with apparent resistance to initial induction therapy may
parallel the ongoing studies in another chronic B-cell leukemia—
chronic lymphocytic leukemia—where accessory stromal cells are
linked to drug resistance.69-71 The preliminary evidence suggests that
cross-talk between the leukemic cells and the microenvironment provides a potential novel strategy for seeking effective therapy.66 If indeed minimal residual disease in the bone marrow represents a source
for eventual relapse, pursuing the underlying role of the microenvironment in leukemic cell survival will open the way for introducing novel agents that may ultimately result in true long-term
control. In lieu of repeated therapy with purine analogs with each
successive relapse, considering targeted therapy with immunebased agents or novel agents that target the accessory stromal cells
will hold promise for continued therapeutic advances in this disease. The alternative of repeated courses of purine analog therapy
for each relapse carries the potential risk of bone marrow toxicity
(eg, potential myelodysplasia).72-75
Optimizing the treatment of hairy cell leukemia is needed because these patients, with a median age at diagnosis of 55 years, have a
substantial rate of relapse. Many patients ultimately will require retreatment. Although we view this disease as a model for therapeutic
advances, further defining the basis for relapse and developing novel
agents to circumvent drug resistance require an understanding of the
gaps in our current knowledge. Many hematologists consider hairy
cell leukemia as a conquered disease, but more work is needed to
address several important unanswered questions.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
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relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Michael R. Grever, International
Consortium on Hairy Cell Leukemia (U) Consultant or Advisory Role:
None Stock Ownership: None Honoraria: Michael R. Grever,
participant, educational session sponsored by Hospira in conjunction
with the annual European Haematology Association Meeting June 2010
Research Funding: None Expert Testimony: None Other
Remuneration: Michael R. Grever, Hospira (travel costs to European
Haematology Association Meeting June 2010), travel expenses for trip to
Chicago and the National Institutes of Health for Hairy Cell Leukemia
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Consortium. No honorarium, solely expenses covered. Reimbursements
made by Rockefeller Philanthropic for the Consortium
AUTHOR CONTRIBUTIONS
Conception and design: Michael R. Grever
Administrative support: Michael R. Grever
Provision of study materials or patients: Michael R. Grever,
Gerard Lozanski
Collection and assembly of data: Michael R. Grever, Gerard Lozanski
Data analysis and interpretation: Michael R. Grever
Manuscript writing: Michael R. Grever, Gerard Lozanski
Final approval of manuscript: Michael R. Grever, Gerard Lozanski
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■ ■ ■
8
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Modern Strategies for Hairy Cell Leukemia
Appendix
Q1
0.0%
B
Q2
92.7%
102
101
100 Q3
7.1%
Q4
0.2%
100
103
101
102
H1
48.0%
102
101
H3
103
100
E
L2
91.1%
102
101
100 L3
7.6%
103
101
102
J1
6.1%
J3
7.3%
101
102
103
L1
1.4%
J1
5.7%
J2
92.1%
102
CD103-FITC
103
102
103
J3
2.0%
J4
0.2%
101
103
100
101
102
103
102
103
CD19-ECD
I
L2
3.1%
103
102
P1
5.1%
P2
0.8%
102
101
L3
11.9%
101
101
102
100
100
M4
0.4%
100
100 7.8%
103
J4
4.1%
100
H
M2
90.1%
101
M3
7.4%
X4
12.7%
101
CD19-ECD
102
100
F
CD5-PC5
M1
2.1%
X3
102
100
101
103
CD27-PC5
CD19-ECD
103
X2
79.1%
Lambda-PE
J2
82.8%
CD19-ECD
G
X1
1.3%
103
102
100
L4
1.1%
100
102
CD11c-PE
L1
0.1%
101
103
Kappa-FITC
CD123-PE
CD25-PC5
103
H4
13.7%
100 6.5%
CD20-PE
D
C
H2
32.4%
CD19-PC5
103
CD19-PC5
CD19-PC5
A
100 P3
L4
83.8%
100
101
P4
75.9%
18.2%
101
CD19-ECD
102
103
100
101
CD19-FITC
Fig A1. Diagnostic flow cytometry for hairy cell leukemia. Flow cytometry is critically important to define the light chain–restricted monoclonal cells expressing the
diagnostic markers of this disease. The classic form of hairy cell leukemia expresses positive markers including (A-G) CD11c, CD25, CD103, CD19, CD20, and CD123.
In contrast, the hairy cell variant is often negative for CD25 and CD103. The negative (H) CD 27 and (I) CD5 are also consistent with hairy cell leukemia. Inclusion of
CD27 may help in distinguishing splenic lymphoma with villous lymphocytes from hairy cell leukemia. This flow analysis was performed on a bone marrow aspirate
sample, but it would have been identical if it had been performed on a peripheral-blood sample.
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9