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A Single Cycle of 2-Chlorodeoxyadenosine Results in Complete Remission in the
Majority of Patients With Hairy Cell Leukemia
By Martin S.Tallman, David Hakimian, Daina Variakojis, Denise Koslow, Gale A. Sisney, Alfred W. Rademaker,
Esther Rose, and Karen Kaul
Twenty-six patients with hairy cell leukemia (HCL) were
treated with 2-chlorodeoxyadenosine (2-CdA), a purine analogue resistant t o adenosine deaminase, at 0.1 mg/kg/d for
7 days by continuous intravenous infusion. Fifteen patients
were previously untreated, while 11 patients had received
prior treatment with splenectomy alone (three patients),
interferon alpha alone (four), splenectomy, then interferon
alpha (two), or splenectomy, interferon alpha, then 2-deoxycoformycin (2-DCF) (two). Sixteen (80%) of 20 patients
evaluable at 3 months achieved complete remission (CR),
and four (20%) achieved partial remission (PR) following a
single cycle of therapy. All four patients in PR had complete
recovery of their peripheral blood counts (except one patient
whose platelet count remained 84,OOO/pL), but had residual
HCL in the bone marrow (three patients) or residual spleno-
megaly (one). Patients with bulky adenopathy, massive splenomegaly, and severe pancytopenia responded as well as
those with only modest marrow involvement. The three
patients with residual marrow disease received a second
cycle of 2-CdA, and two have attained CR. Therefore, 18 of 20
(90%) achieved CR with either one or two cycles of therapy.
No patient achieving CR has relapsed at a median follow-up
of 12 (k2.1) months. Toxicities included myelosuppression
and culture-negative fever. A community-acquired pneumonia was the only infectious complication. Since a single cycle
of 2-CdA induces sustained CR in the vast majority of
patients with minimal toxicity, this agent is emerging as the
treatment of choice for all patients with HCL.
o 1992by The American Society of Hematology.
H
AIRY CELL LEUKEMIA (HCL) is an uncommon
2-CdA and complete pathologic remission was achieved in
chronic lymphoproliferative disorder initially de11patients with minimal toxicity. We report the results of a
phase I1 trial of 2-CdA in patients with HCL and confirm
scribed by Bouroncle and Wiseman in 1958.’ The disease is
that CR is achieved in the majority of both previously
characterized by splenomegaly, pancytopenia, and infiltratreated and untreated patients.
tion of the bone marrow with lymphoid-appearing mononuclear cells that have irregular cytoplasmic projections when
MATERIALS AND METHODS
identified in the peripheral b l o ~ d .HCL
~ , ~ is recognized as a
Between February 1991 and January 1992,26patients with HCL
clonal B-cell malignancy with surface antigens reflecting
were treated with 2-CdA at the Robert H. Lurie Cancer Center of
differentiation between the mature B cell of chronic lymphoNorthwestern University. Eligibility criteria included the following:
cytic leukemia and the plasma cell of m y e l ~ m a . ~
Most
,~
(1) pathologically confirmed diagnosis of HCL based on the bone
patients have an indolent course with a median survival of 4
marrow aspirate,core biopsy, and peripheral blood smear obtained
years; however, others have life-threatening pancytopenia,
within 2 weeks of study entry; (2) evidence of active disease,
painful splenomegaly, or constitutional symptom^.^,^ For
including any of the following: neutropenia (neutrophils < 1,5001
many years, the treatment of choice has been splenectomy,
pL), anemia (hemoglobin < 12 g/dL), thrombocytopenia (platewhich results in normalization of peripheral blood counts in
lets < 150,000/pL), symptomatic splenomegaly, or adenopathy;
40% to 70% of cases, but complete pathologic remissions
(3) no active infection; (4) no prior treatment for the disease within
4 weeks of study entry; and ( 5 ) normal hepatic and renal function.
do not occur.8-12Interferon alpha was first reported to be
There were 22 men and four women (Table 1). Patients ranged
effective in 1984 by Quesada et a1.13 Although interferon
in
age from 34 to 85 years, with a median of 47.5 years. Eleven
alpha is associated with a high response rate, the majority of
patients had received prior treatment, while 15 were previously
responses are partial, and relapse is common when interuntreated. Prior treatment included interferon alpha alone in four
feron is discontinued.13-17Toxicities include flu-like symppatients, splenectomy alone in three patients, splenectomy then
toms, fatigue, peripheral neuropathies, and depression, as
interferon alpha in two patients, and splenectomy, interferon
well as myelosuppression and elevated hepatic transamialpha, then 2-DCF in two patients. All patients gave voluntary
nases. 2-Deoxycoformycin (2-DCF, pentostatin) was the
informed consent according to procedures approved by the Institutional Review Board of Northwestern University.
first agent to induce a significant number of complete
remissions (CR) and does so in 60% to 89% of patient~.l8-~3
This agent inhibits adenosine deaminase, an enzyme inFrom the Robert H. Lurie Cancer Center of Northwestem University;
volved in purine metabolism found in all lymphoid cells.
the Northwestem University Medical School, Department of Medicine,
Deoxyadenosine metabolites accumulate and are believed
Division of HematologylOncology; the Departments of Pathology and
to be responsible for cytotoxicity in HCL. Toxicities include
Radiology; Cancer Center Biometry Section, Chicago, IL; and the
nausea, vomiting, skin rash, conjunctivitis, neurologic dysR K Johnson Pharmaceutical Research Institute, Raritan, NJ.
function, myelosuppression, and i m m u n o s u p p r e s s i ~ n . ~ ~ ~ ~ Submitted March 26,1992; accepted June 30, 1992.
Address reprint requests to Martin S. Tallman, MD, Robert H. Lurie
2-Chlorodeoxyadenosine (2-CdA) is a purine analogue
Cancer Center of Northwestem University, Division of Hematology/
resistant to adenosine deaminase. The drug accumulates in
Oncology, 233 E Erie St, Suite 700, Chicago, IL 60611.
cells rich in deoxycytidine kinase, but low in S’-nucIeotidase
The publication costs of this article were defrayed in part by page
activity. The triphosphate metabolite does not readily exit
charge payment. This article must therefore be hereby marked
the cell and induces DNA double-strand breaks in both
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
dividing and nondividing human lymphocytes.26-282-CdA
indicate this fact.
was first reported to be effective for HCL by Piro et a1 in
0 1992 by The American Society of Hematology.
1990.29Twelve patients were treated with a single course of
0006-4971/92/8009-0032$3.00/0
Blood, Vol80, No 9 (November 1). 1992:pp 2203-2209
2203
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2204
TALLMAN ET AL
Table 1. Patient Characteristics
No. of
Patients
Characteristics
26
47.5 (34-85)
No. of patients
Mean age in years (range)
Sex
Male
Female
Previous treatment
None
Splenectomy
Interferon alpha
Splenectomy, interferon
Splenectomy, interferon, pentostatin
22
4
15
3
4
2
2
Treatment plan. Patients were treated with 2-CdA provided by
The R.W. Johnson Pharmaceutical Research Institute (Raritan,
NJ). All patients received 2-CdA at a dose of 0.1 mg/kg/d by
continuous intravenous infusion for 7 days either as an inpatient
(10 patients) or as an outpatient by portable pump (16 patients).
Patients received a single 7-day cycle and were then evaluated at 3
months. If they achieved a partial remission (PR), they were
eligible to receive a second 7-day cycle. Neutropenic patients who
developed fever greater than 101°F were hospitalized, cultured,
and given empiric broad-spectrum antibiotics. Packed red blood
cells were transfused if patients developed symptomatic anemia or
a hemoglobin less than 7.0 g/dL. Platelets were given if the platelet
count was less than 15,0OO/kL.
Initial evaluation and serial studies. At the time of study entry,
all patients had a complete history and physical examination;
complete blood cell count (CBC) with differential count and
platelet count; SMA-20 biochemical profile; reticulocyte count;
direct and indirect Coombs test; urinalysis; electrocardiogram;
chest radiograph; serum protein electrophoresis and quantitative
immunoglobulins; computerized tomographic (CT)scans of the
chest, abdomen, and pelvis; unilateral marrow aspirate and bone
core biopsy with tartrate-resistant acid phosphatase (TRAP) and
reticulin stain when necessary; and immunophenotyping and gene
rearrangement studies, if a sufficient number of cells were available. During the 7 days of treatment, all patients had a daily CBC
and an SMA-20 biochemical profile on days 1 and 4. Thereafter, a
CBC, differential count, and platelet count were performed weekly
for 8 weeks and a SMA-20 biochemical profile was obtained
monthly for 3 months. Patients received daily allopurinol for 2
weeks beginning on the first day of treatment as prophylaxis against
potential tumor lysis.
Bone marrow findings. Bone marrow biopsies from all patients
were evaluated before therapy. The median cellularity was 75%
(range, 25% to 90%). Hairy cells comprised a median of 70% of the
total marrow elements (range, 25% to 95%). Hairy cells were
detected in the peripheral blood in all but one patient.
Response criteria. Patients were evaluable for response 3 months
after the initiation of 2-CdA. All studies performed at entry were
repeated. A CR required all of the following: (1) complete absence
of hairy cells in the peripheral blood and bone marrow; (2)
normalization of peripheral blood counts (hemoglobin 2 12 g/dL,
white blood cell count 2 3,OOO/kL, neutrophils 2 1,5OO/kL, and
platelet count 2 lOO,OOO/kL); (3) absence of all palpable adenopathy and hepatosplenomegaly; (4) absence of constitutional symptoms; and ( 5 ) disappearance of all abnormal adenopathy and
hepatosplenomegaly by CT scans. Patients with mild residual
splenomegaly ( > 12 cm, but 5 14 cm in craniocaudal dimension) or
minimal soft tissue abnormality ( s 2 cm in diameter) were considered in CR.
A partial remission (PR) required all of the following: (1)
reduction of greater than 50% of hairy cells in the bone marrow
core biopsy; (2) increase of greater than 50% of all abnormally low
peripheral blood counts; and (3) reduction of greater than 50% in
abnormal adenopathy or hepatosplenomegaly.
Patients who did not fulfill the criteria for CR or PR were
classified as nonresponders.
Relapse was defined as the reappearance of hairy cells in the
bone marrow core biopsy after achieving a CR or an increase in
greater than 50% of hairy cells in the bone marrow core biopsy
after achieving a PR.
Toxicity was graded according to standard criteria?O
Statistical analysis. Median blood counts and follow-up times
were calculated using the BMDP package, program 2D.31
RESULTS
Accrual. Results were analyzed as of June 1, 1992.
Twenty-six consecutive patients have been treated and
complete follow-up data are presented on the first 20
patients.
patients are evaluable for toxicity.
Response. Sixteen patients (80%) achieved CR and four
patients (20%) achieved PR with a single cycle of 2-CdA.
The overall response rate (CR + PR) was 100%. All four
patients achieving PR had marked improvement in the
peripheral blood counts (Table 2). Each patient demonstrated normalization of the absolute neutrophil count,
hemoglobin, and platelet count, except one patient whose
platelet count remained 84,OOO/pL. Three of the four
patients achieving PR received a second course of 2-CdA
because of residual HCL in the marrow. Two of these three
patients achieved a CR with the second cycle and one has
had no further response. The fourth patient was categorized as a PR because of residual splenomegaly measuring
16 cm. He was not retreated because his peripheral blood
counts had normalized and his bone marrow was free of
hairy cells. Four patients achieving CR had minimal residual splenomegaly, while one had minimal residual soft
Table 2. Characteristics of Patients Achieving PR After a Single Cycle of 2-CdA
Pt.No.
It
2
3
4t
Prior
Therapy
ANC
Hgb
Posttherapy (Cycle 2)
Posttherapy (Cycle 1)
Pretherapy
Plt
None
54 6.9 25
Splenectomy 2,150 9.8 37
1,064 12.3 41
None
468 13.5 63
None
ANC
Hgb
Plt
2,144 14.9 84
4,095 12.9 252
2,747 14.6 123
1,725 15.1 129
Marrow
Spleen'
ANC
Hgb
Pit
Marrow
Spleen
13 cm
Residual HCL(40%) 16cm (pre29cm) 2,442 14.9 123 Normal
Residual HCL (35%)
3,508 12.9 114 Residual HCL 16cm(pre27cm) Normal
10 cm
Residual HCL(33%) 13cm (pre21 cm) 1,924 16.3 170 Normal
Abbreviations: ANC, absolute neutrophil count (per pL); Hgb, hemoglobin (g/dL);Plt, platelets ( x 109/L).
*Length in craniocaudal dimension.
tPatient achieved CR after second cycle.
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2205
2-CHLORODEOXYADENOSINE IN HAIRY CELL LEUKEMIA
Table 3. ResponsesAccording to Prior Treatment
Prior Treatments
No. of
Patients
None
Splenectomy
Interferon
Splenectomy, interferon
Splenectomy, interferon, pentostatin
Total
PLTS ANC
Response
CR
PR
12
1
3
2
2
11’
It
1
20
18 (90%)
150
W
f
m
-
100
!
0
3
2
2
7
50
o!
2 (10%)
*Two of these patients required two cycles to achieve CR.
t o n e patient was categorized as PR on the basis of persistent
splenomegaly (16 cm), although peripheral blood and marrow normalized.
tissue abnormality at sites of previous massive adenopathy.
The latter patient showed continued resolution of the soft
tissue abnormality at 6 months. Therefore, 18 patients
(90%) achieved CR with either one or two cycles of therapy
(Table 3). No patient achieving CR has relapsed at a
median follow-up (2SE) of 12 (22.1) months. One of the
patients achieving PR has relapsed with recurrent thrombocytopenia and 85% hairy cells in the marrow.
Peripheral blood. The platelet count began to increase
almost immediately after therapy and generally recovered
by 1 month (Table 4, Fig 1). In contrast, the absolute
neutrophil count (ANC) recovered slowly, changing little
during the first month. Thereafter, the ANC increased
steadily and normalized by 2 months. Similarly, the improvement in the hemoglobin was delayed and paralleled that of
the ANC. Eight patients required transfusion of packed red
blood cells after the initiation of treatment. However, no
patient required transfusion more than 2 weeks after
completion of 2-CdA. Platelet transfusions were given to
three patients during treatment.
Bone marrow findings. The median bone marrow cellularity 3 months after treatment was 35% (range, 10% to
65%). An 85-year-old patient with pretreatment marrow
cellularity of 25% achieved 65% cellularity after one cycle.
The three patients achieving PR with residual disease in the
marrow had an approximately 50% decrease in the percentage of hairy cells.
Toxic& The most common toxicities were myelosuppression and culture-negative fever. Myelosuppression was
defined as the development of a neutrophil count less than
1,000/ pL or a greater than 50% decrease from baseline, or
Table 4. Hematologic Parameters Before Therapy and at a Minimum
of 3 Months’ Follow-up
Median
(+ SE)
Pretreatment (n = 20)
Neutrophils (/JLL)
Hemoglobin (g/dL)
Platelets ( x lO9/L)
3-Month
Neutrophils (/pL)
Hemoglobin (g/L)
Platelets ( x lO9/L)
HGB
200
Minimum
Maximum
948.0 ( 2 313)
11.9 (* 0.7)
61.0 (211.0)
54.0
6.2
11.0
5,106.0
13.6
466.0
3,748.0 (k 628)
13.6 (e 0.4)
182.0 (217.3)
1,240.0
10.7
84.0
6,532.0
15.1
483.0
0
PRE
1
2
3
MONTH
Fig 1. Change in median peripheralblood counts following a single
cycle of 2-CdA.
a platelet count less than lOO,OOO/~L,or a greater than
50% decrease from baseline. Sixteen patients (66%) developed myelosuppression with treatment; however, 10 of
these 16 patients (63%) were neutropenic before therapy.
Only one of these 16 patients developed thrombocytopenia.
Three patients (12%) developed peripheral vein chemical phlebitis, but did not require therapy other than a
change in intravenous sites. Fever greater than 101°F
occurred after the initiation of 2-CdA in 12 patients (48%),
most often toward the end of the 7-day cycle. In general,
fever lasted 2 to 10 days; however, one patient had
persistent fever for 40 days. The only confirmed infection
was a community-acquired pneumonia occurring 2 weeks
after treatment in a 75-year-old man whose neutrophil
count was 1,350/ pL. Noninfectious hepatitis developed 2
weeks after the initiation of therapy in the patient who
experienced prolonged fever. One patient developed a
diffuse maculopapular skin rash 4 days after treatment,
which was attributed to allopurinol. Tumor lysis syndrome
did not occur. Eleven patients required admission for fever.
One patient developed pain in all four extremities 4 months
after receiving a second cycle of therapy. Nerve conduction
velocity studies showed a mild sensory neuropathy. He died
7 months after the second cycle of a presumed cardiac
event, although no autopsy was performed.
Splenic volume measurement. Splenic volume was estimated from CT scans by calculating the splenic index
(product of the length x width x thickness) on all nonsplenectomized patients pretherapy and posttherapy. The splenic
index returned to normal in only one patient posttherapy
(Table 5).
Gene rearrangement studies. Gene rearrangement studies of peripheral blood were completed in 15 of the 20
patients before therapy (Table 6). Four patients showed
rearrangements in both the immunoglobulin heavy chain
and K light chain, and three patients in both the heavy chain
and h light chain, while four patients showed rearrangements in only the heavy chain. In five patients, gene
rearrangement studies were not completed due to insufficient numbers of peripheral lymphocytes. At 3 months’
follow-up, two patients had persistent gene rearrangements
in the peripheral blood. One such patient had circulating
hairy cells and residual marrow disease (PR), while the
other has remained in a CR for 13 months. However, it
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TALLMAN ET AL
2206
Table 5. Calculation of Splenic Index in Nonsplenectomized HCL Patientsand Controls
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pretherapy
1 0 x 1 2
19 X 15 X
13 X 16 X
16 X 14 X
22 X 18 X
21 X 17 X
13 X 17 x
1 2 X 11 X
18 X 16 X
16 X 18 X
29 x 18 X
20 X 16 X
17 X 15 X
27 X 24 X
~6 = 660
8 = 2,066
6 = 1,248
8 = 1,792
9 = 3,564
10 = 3,570
10 = 2,210
6 = 745
7 = 2,016
9 = 2,592
11 = 5,742
8 = 2,560
9 = 2,295
11 = 7,128
Controls*
Posttherapy
6 ~ 1 1 ~
9 X 15 X 8 =
12 X 13 X 5 =
12 X 11 X 6 =
14 X 14 X 6 =
13 X 13 x 8 =
1 4 X 11 X 5 =
11X11X6=
14 x 13 x 6 =
13 X 14 X 7 =
16 X 12 X 6 =
10 X 12 X 5 =
12 X 13 X 7 =
16 X 18 X 6 =
4264
=
1,080
780
792
1,245
1,352
770
726
1,092
1,274
1,152
600
1,092
1,728
~
6~ 9 X 4 = 2 1 6
7 X 11 X 5 = 3 8 5
8 ~ 1 0 ~ 5 = 4 0 0
6 x 1 1 X7=462
8X11~5=440
10~11~4=440
7X 8 ~ 4 = 2 2 4
9 x 1 1 X5=485
4 X 3 X 7 = 84
6 ~ 1 0 ~ 4 = 2 4 0
~~
Splenic Index in cm3 = length (measured craniocaudal) x width (measured anterior-posterior) x thickness (measured at splenic hilum
medial-lateral).Normal range, 120 to 480 cm3.
*Ten randomly selected CT scans with normal spleens.
should be noted that posttreatment gene rearrangement
studies were not completed in 14 patients due to an
insufficient number of cells.
Immunophenotyping studies. Immunophenotyping studies on the peripheral blood were performed in 17 of the 20
patients before therapy (Table 6). Clonality was determined based on an excess of C D l l c to CD15 staining, and
an abnormal K to A ratio. There was evidence of an
abnormal clone expressing the K light chain in seven cases
and the A light chain in four cases. The remaining six cases
had no abnormalities. At 3 months’ follow-up, 17 patients
had sufficient cells to be analyzed and immunophenotypic
abnormalities persisted in three cases. Two of these patients achieved PR, while one has remained in CR for ll
months.
DISCUSSION
Our results demonstrate that 2-CdA is highly effective
treatment for patients with HCL. The CR rate of 90% in
consecutive and nonselected patients is far superior to most
other effective therapies including splenectomy, intensive
chemotherapy, and interferon alpha. Every patient in our
series, whether untreated or heavily pretreated, responded
extremely well. Patients with bulky adenopathy and profound pancytopenia associated with replacement of the
marrow responded as well as those with only modest
marrow involvement. Furthermore, although follow-up is
short, none of our patients achieving CR has relapsed.
Only a limited number of patients with HCL have been
treated with 2-CdA.29,32-34
Our results support the observations by Piro et al, that 2-CdA induces an extremely high
percentage of CRs after a single cycle of treatment with
minimal t o x i ~ i t y .Estey
~ ~ , ~et~ a1 have also recently reported
CR in 36 of 46 (78%)
and in a smaller study from
Sweden, Juliusson and Liliemark reported CR in 12 of 16
(75%) ~atients.3~
We applied stricter criteria for CR than
either of the latter two studies in that we required resolution of organomegaly by CT scan, rather than by physical
examination alone.
Our study permits several new observations. First, despite resolution of splenomegaly by physical examination
and conventional radiographic criteria, persistent splenomegaly was evident by measuring the splenic index, which
may more accurately assess spleen ~ i z e . 3Although
~
the
craniocaudal dimension of the spleen frequently returned
to normal, the splenic index did so in only one patient,
indicating that posttreatment splenomegaly may be more
common than previously recognized. The single patient
achieving a PR on the basis of persistent splenomegaly (16
cm) had a posttreatment splenic index less than other
patients, whose spleen size was normal by craniocaudal
dimension. Whether persistent splenomegaly reflects a
sanctuary of residual disease is not known. Indeed, Pangalis
et a1 describe six patients in whom splenectomy was
performed after achieving apparent CR with interferon
alpha.36 Despite resolution of splenomegaly by physical
examination, persistent infiltration of the red pulp by hairy
cells was present in all patients. Patients will need to be
followed prospectively to determine if the posttreatment
splenic index correlates with relapse. Furthermore, we
suggest that a uniformly acceptable definition of CR is
needed. Second, two patients relapsing after 2-DCF
achieved CR with 2-CdA. Following treatment with 2-DCF,
one patient’s peripheral blood counts completely recovered, but residual hairy cells remained in the marrow. The
second patient achieved a CR in the marrow with 2-DCF,
but had a residual bulky abdominal mass. Both patients
achieved a sustained CR with 2-CdA, suggesting a lack of
cross-resistance between these two purine analogues. Further studies will be needed to determine if patients who fail
2-DCF will routinely respond to 2-CdA. Third, two of our
patients had evidence of a persistent abnormal clone by
either gene rearrangement or immunophenotyping studies
after achieving a CR. Only a limited number of gene
rearrangement studies in patients with HCL are available.37.38
The paucity of data may reflect the low number of
circulating hairy cells at presentation, as well as the
frequent difficulty in aspirating marrow. The importance of
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2207
2-CHLORODEOXYADENOSINE IN HAIRY CELL LEUKEMIA
Table 6. lmmunophenotype and Gene Rearrangement Studies
Before and After Treatment With 2-CdA
lg Gene Configuration
lmmunophenotype
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Heavy
Chain
K
A
Response
Sample
Clonal
Pre
Post
No
No
G
NS
NS
NS
NS
NS
CR
Pre
Post
No
No
G
NS
G
NS
G
NS
CR
Pre
Post
Yes
No
R
G
NS
G
NS
CR
Pre
Post
No
No
G
NS
R
NS
G
CR
Pre
Post
No
Yes
R
NS
G
NS
G
NS
PR
Pre
Post
Yes
No
K
R
NS
R
NS
G
NS
CR
Pre
Post
Yes
No
K
R
NS
R
NS
G
NS
CR
Pre
Post
NS
No
NS
G
NS
G
NS
G
PR
Pre
Post
Yes
No
h
G
G
G
G
G
G
CR
Pre
Post
Yes
No
A
R
NS
G
NS
R
NS
PR
Pre
Post
Yes
K
K
R
R
R
R
G
Yes
G
PR
Pre
Post
No
No
NS
NS
NS
NS
NS
NS
CR
Pre
Post
Yes
No
K
R
NS
R
NS
G
NS
CR
Pre
Post
Yes
No
A
R
NS
G
NS
R
NS
CR
Pre
Post
Yes
No
K
R
G
G
G
G
G
CR
Pre
Post
No
No
NS
NS
NS
NS
NS
NS
CR
Pre
Post
Yes
NS
R
NS
G
NS
R
NS
CR
Pre
Post
NS
Yes
NS
G
NS
G
NS
G
CR
Pre
Post
Yes
NS
R
NS
G
NS
G
NS
PR*
Pre
Post
NS
NS
NS
NS
NS
NS
NS
NS
CR
Light Chain
K
NS
G
A
h
A
K
Abbreviations: lg, immunoglobulin; G, germline; R, rearranged; NS,
not sufficient cells for analysis.
*Patient classified as PR on basis of residual splenomegaly measuring 16 cm in craniocaudal dimension.
identifying a persistent abnormal clone by these sophisticated techniques is not known. Longer follow-up will be
needed to determine whether these patients have a higher
incidence of relapse. Fourth, patients achieving a PR with a
single cycle may achieve a CR with a second cycle. Three
patients in the present series have received a second cycle
of 2-CdA because of residual HCL in the marrow (Table 2).
Two patients converted from a PR to a CR. In Piro's series,
patients whose peripheral blood counts had completely
recovered were not given a second cycle even if the marrow
contained residual disease. More patients achieving PR will
need to be treated with a second cycle of 2-CdA to permit
definitive conclusions regarding efficacy. It is unclear
whether patients with normal blood counts, but residual
hairy cells in the marrow, benefit from further treatment. It
is possible that their survival may be as lengthy as patients
achieving CR. This question may never be resolved, because the CR rate with a single cycle is so high.
2-CdA appears to be more effective than interferon for
HCL. A number of studies have confirmed a high overall
response rate of 80% for interferon; however, the CR rate
is only 5% to 40%.13J4,39340
Furthermore, clinical, as well as
hematologic, improvement requires prolonged treatment.
Compared with 2-CdA, recovery of peripheral counts is
long (4 to 5 months), infections are common, and toxicity is
significant. Although maintenance therapy may prolong
remission,4l relapse is common when the treatment is
st~pped.l~-l~,~~
Our results appear superior to those obtained with
2-DCF in several respects. Most remarkable is the fact that
results reported here were achieved with a single cycle of
therapy in almost all patients, whereas remission with
2-DCF requires multiple cycles. In addition, although
comparable CR rates may be achieved with both agents,
toxicity is less with 2-CdA. Myelosuppression was seen in
two thirds of our patients, yet only one patient developed an
infection. A similar incidence of myelosuppression and
infection was reported by Piro et alZ9and Estey et al.33In
contrast to these studies, Juliusson and Liliemark reported
opportunistic infections in five of 16 patients (31%) (three
fungal and two cytomegalovirus), of which two were
The reason(s) for the high incidence of infection in this
series is not completely clear. However, three patients were
treated with either 2-DCF or interferon immediately prior
to 2-CdA and as a result may have been profoundly
immunosuppressed. In a study of 50 patients treated with
2-DCF, Cassileth et a1 reported a 50% incidence of infection and a 6% infectious death rate. Severe neurologic and
hepatic toxicity each occurred in 4% of patients.22 In this
study, 2-DCF was administered at a dose of 5 mg/m2 on 2
consecutive days every 2 weeks (40 mg/m2 every 2 months).
Kraut et a1 studied a lower dose, 4 mg/m2 every other week
(16 mg/m2 every 2 months), and reported less toxicity with
equal efficacy.19 In this study, although four of 23 patients
(17%) had systemic infections, none were fatal. Johnston et
a1 evaluated yet a lower dose of 2-DCF, 4 mg/m2/wk for 3
weeks every 8 weeks (12 mg/m2 every 2 months), and
reported two episodes of septicemia, two episodes of
herpes simplex, and two cases of cellulitis among 31
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2208
TALLMAN ET AL
patients treated.21Although the incidence of infection has
decreased as the dose has been reduced, it is still significant. This may be attributable to the more severe immunosuppression with 2-DCF compared with 2-CdA.43Similarly,
noninfectious toxicities with 2-DCF remain substantial
despite dose reduction. In Johnston’s series, 76% of patients experienced nausea and vomiting, 62% lethargy, 41%
skin rash, 6% altered taste, and 10% paresthesias. In
contrast, the only definitive noninfectious toxicity observed
with 2-CdA in the present study was fever. Since our one
patient who developed a painful peripheral neuropathy
received a second cycle of 2-CdA, we cannot exclude the
possibility that the neuropathy represented cumulative
drug toxicity. However, neurologic toxicity is extremely
uncommon at this dose, and other patients in our series
received a second cycle without incident.
Fludarabine is another adenosine nucleoside analogue
with activity in HCL.44,45In two brief reports, three of four
patients achieved a PR. It remains to be determined
whether fludarabine will have any role in the treatment of
patients with HCL given the success of 2-DCF and 2-CdA.
Our data and those previously published suggest that
splenectomy and interferon should no longer be considered
first-line treatments for HCL, because sustained CRs rarely
occur. 2-DCF may be as effective as 2-CdA, since both
produce high CR rates. However, with its ease of administration and minimal toxicity, 2-CdA is emerging as the
treatment of choice for all patients with HCL.
ACKNOWLEDGMENT
The authors thank Marla Murray for her assistance in manuscript preparation.
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A single cycle of 2-chlorodeoxyadenosine results in complete
remission in the majority of patients with hairy cell leukemia
MS Tallman, D Hakimian, D Variakojis, D Koslow, GA Sisney, AW Rademaker, E Rose and K Kaul
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