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Pharmacology and Therapeutics

000
41
Blackwell
Oxford,
International
IJD
0011-9059
1
UK
Science,
Journal
Ltd
2002
of Dermatology

Treatment of late-stage Szary syndrome with


2-Chlorodeoxyadenosine
2-Chlorodeoxyadenosine
Bouwhuis
et al.
for late-stage Szary syndrome

Saskia A. Bouwhuis, MD, Rokea A. el-Azhary, MD, Marian T. McEvoy, MD, Lawrence E. Gibson,
MD, Thomas M. Habermann, MD, Thomas E. Witzig, MD, and Mark R. Pittelkow, MD

From the Department of Dermatology and the


Division of Hematology and Internal Medicine,
Mayo Clinic, Rochester, MN, USA
Correspondence
R. A. el-Azhary, MD, Department of
Dermatology, Mayo Clinic, 200 First Street
SW, Rochester, 55905, USA
E-mail: elazhary.rokea2@mayo.edu

Abstract
Background 2-Chlorodeoxyadenosine (2-CdA), a purine adenosine analog, is safe and effective
chemotherapy for patients with hairy cell leukemia and low-grade lymphomas. Adverse effects
include neutropenia, lymphocytopenia, and infectious complications. Our objective was to
evaluate the efficacy of 2-CdA (2 6 seven-day cycles) in the treatment of late-stage, recalcitrant
Szary syndrome.
Methods Retrospective review of medical records of six patients with Szary syndrome who
had received 2-CdA cycles at Mayo Clinic, Rochester between March 1995 and March 2000.
Variables assessed from the records included improvement in global appearance, extent of
erythroderma, size of lymph nodes, pruritus, and leukocyte, lymphocyte, and absolute Szary
cell counts.
Results Two patients, both with stage III Szary syndrome, whose previous treatment consisted
of only two modalities, responded well to the treatment, with moderate to total clearing of
erythroderma and pruritus associated with a significant decrease in Szary cell counts. The other
four patients had only a partial response (one patient) or no response (three patients) to 2-CdA.
The mortality rate was 50%. All three patients died of Staphylococcus aureus sepsis. However,
only one patient was receiving 2-CdA treatment when he died. The other two patients died 8 and
9 weeks after the last 2-CdA cycle. This high mortality rate is attributed to infectious complications
after 2-CdA treatment in patients with recalcitrant disease.
Conclusion 2-Chlorodeoxyadenosine shows efficacy in stage III Szary syndrome, but it also
carries a substantial risk of septic complications and mortality. It can be used if no other suitable
alternatives are available. Caution should be exercised in all these patients regarding skin care and
avoidance of infections or sepsis.

Introduction

352

Szary syndrome, the leukemic form of primary cutaneous


T-cell lymphoma, is an aggressive disease, with a reported
median survival of 40 months, the lowest survival reported
for all cutaneous lymphomas.1 The clinical features of this
syndrome are severe pruritus, exfoliative erythroderma,
generalized lymphadenopathy, alopecia, onychodystrophy,
palmoplantar hyperkeratosis, and ectropion.2 Available treatment
options include extracorporeal photopheresis (ECP), interferon alpha, psoralen plus ultraviolet A (PUVA), prednisone,
methotrexate, total body electron beam therapy, retinoids,
topical and systemic corticosteroids, and topical and systemic
chemotherapy.3 None of these treatment options is curative,
and at best they are palliative.
An adenosine purine analog, 2-chlorodeoxyadenosine (2CdA), has demonstrated potent activity in hairy cell leukemia,
chronic lymphocytic leukemia, and low-grade lymphoma.46
International Journal of Dermatology 2002, 41, 352 356

The major adverse effects of 2-CdA are myelosuppression


with leukopenia, thrombocytopenia, infections, fever, nausea,
headache, fatigue, skin rashes, and tumor lysis syndrome.4
In a phase II trial in 1996 for the treatment of cutaneous
T-cell lymphoma (both Szary syndrome and mycosis
fungoides) with 2-CdA, Kuzel et al.4 reported an overall
response rate of 28% and a complete response rate of 14%,
with a median duration of 4.5 months. In 1997, Zaucha
et al.7 reported that 2-CdA treatment was without any
apparent benefit in four patients with Szary syndrome.
Herein, we report our experience with six patients with
Szary syndrome treated with 2-CdA.
Methods
We retrospectively reviewed the results of six patients with Szary
syndrome treated with 2-CdA between March 1995 and March
2000. Disease was staged according to the TNM classification.
2002 The International Society of Dermatology

2002 The International Society of Dermatology

2-CdA, 2-Chlorodeoxyadenosine; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ECP, extracorporeal photopheresis; PUVA, psoralen plus ultraviolet A.
*Died while receiving methotrexate therapy.

3
4
ECP, interferon alpha, PUVA, methotrexate
etretinate
4a
82 /F
6

3 year 6 month

2
3
ECP, PUVA, interferon alpha, systemic
corticosteroids
4b
77/M
5*

4 year 5 month
4b
60/M
4

1 year

1
2

6
12
3
3
6
3

ECP, interferon alpha


ECP, interferon alpha
ECP, PUVA, interferon alpha, retinoids,
CHOP methotrexate, systemic corticosteroids,
total body electron beam therapy
ECP, systemic chemotherapy, total body
electron beam therapy, methotrexate
2 year
2 year 7 month
7 year 5 month
3
3
4a
76/F
77 /F
65 /M

No. of 2-CdA
cycles
Previous treatments
Duration
of disease
Stage
of disease

The characteristics of our six patients (three males and three


females) are listed in Table 1. All the patients were white. The
age range was 60 82 years. Two patients had stage 3 disease,
two had stage 4a, and two had stage 4b. The average duration
of disease after Szary syndrome was diagnosed was 2.9
years (range, 1 7 years). Patients 1 and 2 each received two
different therapeutic regimens (ECP and interferon alpha)
before the initiation of 2-CdA therapy. The other four patients
received from four to seven therapeutic modalities before
2-CdA. Patients 1, 2, and 6 were alive and well at 3, 6, and
12 months after 2-CdA treatment, respectively. Patients 3, 4,
and 5 died of Staphylococcus aureus sepsis 1 3 months after
treatment.
The responses to 2-CdA treatment are summarized in Table 2.
Patient 1, with stage 3 disease, had complete remission after
three cycles of 2-CdA treatment (Fig. 1a and b). Her absolute
Szary cell count decreased from an average of 10 9650. Her
erythroderma and pruritus resolved entirely. At 6 months

Age
(years)/sex

Results

Table 1 Characteristics of patients with Szary syndrome treated with 2-Chlorodeoxyadenosine

Szary cell counts are known to fluctuate widely, this has not been
a problem at our institution. Serial Szary cell counts have been
found to be fairly consistent from day to day, particularly in the high
range (greater than 1000). Absolute Szary cell counts greater
than 500 are considered suspicious, and any count greater than
1000 is considered diagnostic for Szary syndrome. Szary cell
counts were recorded as an average of two different samples
taken on two consecutive days.

Follow up after
2-CdA (months)

For all patients, the disease had been recalcitrant to several


other treatments, including ECP (six patients), interferon alpha
(five patients), PUVA (three patients), prednisone (two patients),
methotrexate (three patients), total body electron beam therapy
(two patients), systemic chemotherapy (two patients), bexarotene
(Targretin; one patient), and etretinate (Tegison; one patient).
Follow up ranged from 1 to 12 months. Response to treatment was
evaluated according to improvement in global appearance, extent
of erythroderma, and size of the lymph nodes according to the
4-point scale given in Table 2. Pruritus was assessed subjectively
by the same scale. The absolute leukocyte count, lymphocyte
count, and Szary cell count, performed manually and by flow
cytometry, were recorded. Szary cells are typically large, although
small cell variants have been described. The nucleus has a
swirled chromatin pattern that has a notched, folded, or cleft-like
appearance, at times being compared with the convolutions of the
surface of the human brain. The cytoplasm is usually scanty and
clear, although occasional cells appear to be vacuolated, and
when stained specifically with periodic acid-Schiff, it has a
bending appearance that surrounds the nucleus.8 Although

1
2
3

Patient status

The drug was given as an intermittent infusion of 5 mg / m2 over 2 h.


The average time between two cycles was 6 weeks. Patients 1, 3,
and 5 received three cycles; patient 2, six cycles; patient 4, two
cycles, and patient 6, four cycles ( Table 1).

Alive
Alive
Dead
S. aureus sepsis, 8 weeks
after 3rd 2-CdA cycle
Dead
S. aureus sepsis, 4 weeks
after 2nd 2-CdA cycle
Dead
S. aureus sepsis, 9 weeks
after 3rd 2-CdA cycle
Alive

2-Chlorodeoxyadenosine for late-stage Szary syndorome Pharmacology and Therapeutics

Patient

Bouwhuis et al.

International Journal of Dermatology 2002, 41, 352 356

353

354

Pharmacology and Therapeutics 2-Chlorodeoxyadenosine for late-stage Szary syndrome

Bouwhuis et al.

Table 2 Response of Szary syndrome to 2-Chlorodeoxyadenosine treatment

Patient

Global
response*

Erythroderma*

Pruritus*

Lymph
node size*

Leukocyte count,
total average 109 / l

Absolute neutrophil
count at nadir, 109 / l

Szary count
before 2-CdA

Latest absolute
Szary count

1
2
3
4
5
6

++++
++
++

++++
+
++

++++
+
++

++

NA
NA
++

8.7
7.5
8.5
7.3
15.6
10.3

1200
1400
600
800
1200
NA

10 965
1 824
8 870
7 350
13 578
7 239

0
41
2 965
7 950
14 616
5 979

2-CdA, 2-Chlorodeoxyadenosine; NA, not available.


*+, mild (025%) improvement; ++, moderate (25 50%) improvement; +++, significant (50 75%) improvement; ++++, total
clearance (100%) improvement; , no change.

Figure 1 Patient 1: (a) stage 3 Szary syndrome before 2-Chlorodeoxyadenosine treatment. (b) remission of Szary syndrome after

3 cycles of 2-Chlorodeoxyadenosine.

after her last 2-CdA cycle, the patient was still in remission. Patient 2, with stage 3 disease, had partial remission
(50%) after six cycles of 2-CdA. Her erythroderma and pruritus
improved moderately, and her absolute Szary cell count
decreased from 1824 to 41. Follow up at 1 year showed that
International Journal of Dermatology 2002, 41, 352 356

the absolute Szary count was still low at 100; her skin continued to show only mild erythroderma associated with mild
pruritus.
Patient 3, with stage 4a disease, had marked relief from severe
pruritus and severe erythroderma after the second of three
2002 The International Society of Dermatology

Bouwhuis et al.

2-Chlorodeoxyadenosine for late-stage Szary syndorome Pharmacology and Therapeutics

cycles of 2-CdA. The previously detected inguinal (2 1 cm)


and axillary (1.5 1 cm) lymph nodes were substantially
decreased in size on physical examination. The absolute Szary
cell count decreased from 8870 to 2965. During the 3rd cycle
of 2-CdA, he complained of weakness and depression, and
in spite of improvement the treatment was discontinued.
The patient died 8 weeks later of S. aureus pneumonia. His
leukocyte count was adequate and reached a nadir, from
15.9 109/ l to 6.1 109 / l, after the 3rd cycle of 2-CdA.
Patients 4 and 5, both with stage 4b disease, did not
respond to 2-CdA. Their total Szary cell counts remained
high, and the severe erythrodermic skin involvement and
pruritus did not change. Inguinal and axillary lymphadenopathy as well as hepatomegaly were approximately the same as
before treatment. Both patients died of S. aureus sepsis. Patient
4 died within 4 weeks after his last 2-CdA cycle, and patient
5 died 9 weeks later while receiving methotrexate treatment.
Patient 6, with stage 4a disease, had a mild decrease in
erythroderma and a moderate decrease in pruritus after four
cycles of 2-CdA. His absolute Szary cell count was unchanged
or mildly decreased from 7239 to 5979.
Transient mild to moderate neutropenia occurred in all
six patients during 2-CdA treatment. The individual absolute
neutrophil counts at nadir are shown in Table 2. The lowest
count, 600 neutrophils, was seen in patient 3. Patient 6 had an
average lymphocyte count of 5.6 109/l and an average
leukocyte count of 5600. This patient received treatment
elsewhere, and the neutrophil count was not available.
Comment
Szary syndrome is a chronic debilitating disease with no
specific treatment. Average survival after the syndrome has
been diagnosed has been reported to be 40 months.9 The
approach to treatment is mainly palliative. For a newly diagnosed case of Szary syndrome, we generally start treatment
with ECP in conjunction with topical corticosteroids and wet
dressings. Our unpublished data for ECP are quite favorable,
and the patients who have a response to this treatment
continue to receive it as long as the symptoms are controlled.
Subsequently, interferon alpha is added, depending on the
response to ECP. If the disease does not respond to ECP or
interferon alpha (or both), other therapeutic options are
considered, including retinoids, particularly the new retinoid
bexarotene (patient 3), chemotherapy, or total body electron
beam therapy. In our experience, none of these options have
had effects as long lasting as ECP.
Kuzel et al.4 and Kong et al.5 showed that 2-CdA as monotherapy has therapeutic value in some cases of late-stage
Szary syndrome. In two of our patients, Szary syndrome
responded well to 2-CdA treatment, with moderate to total
clearing of the patients erythroderma and pruritus and a
marked decrease in the Szary cell count. Both of these
2002 The International Society of Dermatology

patients had stage 3 disease, which had been diagnosed


approximately 2 years earlier. They previously had received
treatment with two modalities only (ECP and interferon
alpha). All the other patients had either long-standing or
recalcitrant disease requiring numerous treatment modalities
before 2-CdA. Our results showed an overall response rate of
66%, a complete response rate of 13%, and a partial response
rate of 50%. These are in agreement with those of Kuzel et al.4
who also reported a complete response rate of 14%. The
mortality rate was 50% and was the result of infectious complications associated with chemotherapy. In addition, the high
mortality rate was observed in patients with recalcitrant
disease, as previously noted by Kuzel et al.4
Treatment with 2-CdA may be more beneficial when given
early in the disease process. When the disease becomes
recalcitrant, 2-CdA may not be the best treatment option.
Increased immunosuppression and associated life-threatening
S. aureus sepsis, also noted by Kuzel et al.4 and Kong et al.5,
are the major problems associated with late-stage Szary
syndrome treatment with 2-CdA. This is particularly true
with the Szary patient population because diseased skin
is a good carrier of S. aureus.
In patients with previously untreated mantle cell lymphoma,
Rummel et al.6 administered 2-CdA in combination with
mitoxantrone on day 1 and reduced the 2-CdA cycles to
3 days. No associated sepsis was reported in their cohort of
66 patients. Whether the combination of mitoxantrone and a
lower total dose of 2-CdA is effective in reducing sepsis has to
be shown in future trials.
In conclusion, 2-CdA may be effective treatment for stage
3 Szary syndrome, particularly if given early in the disease
process or before various other treatment modalities are used.
However, 2-CdA carries a substantial risk of septic complications and mortality and may not be the best treatment for
late-stage Szary syndrome. In all these patients, caution in
skin care and avoidance of infections and sepsis, particularly
from S. aureus, should be exercised.

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2002 The International Society of Dermatology