ARTICLE
Auteur(s) : Umit Barbaros Ure1, Muhlis Cem Ar1, Ayse
Salihoglu1, Sebnem Izmir Guner1, Ahmet
Baran1, Oya Oguz2, Burhan
Ferhanoglu1
1Istanbul University Cerrahpasa Medical Faculty,
Department of Internal Medicine, Division of Hematology, Istanbul
University Cerrahpasa Medical Faculty, 34300 Istanbul, Turkey
2Department of Dermatology, Istanbul, Turkey
accepté le 21 Juin 2007
Cutaneous T-cell lymphomas (CTCLs) comprise a group of disorders
characterized by the accumulation of malignant T cells within the
skin. Mycosis fungoides (MF), the most common form of CTCL, is a
rare, indolent, extranodal lymphoma, in which the skin is variably
affected by flat patches, thin plaques or tumours. Sézary syndrome
(SS), an erythrodermic variant of MF, is a more aggressive form
associated with the presence of circulatory tumour cells in the
peripheral blood [1]. Although MF is easily managed with a range of
topical therapies during its early phases, advanced stage MF/SS is
usually difficult to treat and it often becomes refractory to
chemotherapy [2]. New therapeutic approaches are needed to improve
the outcome of patients with advanced/symptomatic MF/SS.
Alemtuzumab (Campath-1H) is a humanized immunoglobulin G1
monoclonal antibody with a kappa chain that binds to CD52, a
glycosylated peptide cell surface antigen expressed on the surface
of essentially all (normal and malignant) B and T lymphocytes, a
majority of monocytes, macrophages, and NK cells, and a
subpopulation of granulocytes (< 5%) but not on
hematopoietic progenitor cells. The mechanism of action of
alemtuzumab is not completely understood but involves
antibody-dependent cellular cytotoxicity, complement-mediated cell
lysis and apoptosis [3]. Alemtuzumab is approved for the treatment
of chemotherapy-refractory B cell chronic lymphocytic leukemia [4].
It has also been successfully used in the treatment of T cell
prolymphocytic leukemia and for the prevention of graft versus host
disease in allogeneic stem cell transplant recipients [5].
Recently, promising case-based results have been reported with
alemtuzumab in the treatment of advanced stage MF/SS [6-9].
Prolonged pancytopenia and severe infectious complications seem to
be the major restrictions in the clinical utility of this drug
[10]. We herein describe a case of Sézary syndrome treated
successfully with alemtuzumab but who died of treatment-related
infection.
Case report
A 52-year-old male patient was diagnosed with MF in April 1999.
Treatment with a variety of topical agents induced transient
responses of limited duration. In 2003 the patient developed
pruritic erythroderma with hyperkeratosis of the palms and soles.
On physical examination his axillary and inguinal lymph nodes were
enlarged. The spleen was palpable beyond the costal margin. He had
a white blood cell count of 24,000/μL with 80% of lymphocytes
showing the morphological features of Sézary cells (SC). The
Immunophenotype of the lymphocytes on flow cytometric analysis was
as follows: CD3: 86.8%, CD4: 86.2%, CD8: 0.64%, CD3/CD56: 1.82%,
CD20: 1.24%, CD22: 11.9%, HLA-DR: 8.46%. The CD4/CD8 ratio was
>10. The patient was diagnosed as SS according to the EORTC
criteria [11]. Interferon alpha at 9 MU/3 times a week for 2
months, methotrexate at 40 mg/week for six weeks, chlorambucil
and multi-drug chemotherapy regimens including 4 cycles of COP
(cyclophosphamide, vincristine, prednisone) and 6 cycles of CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone) were tried
sequentially but all failed to produce a reasonable response.
In April 2004 the patient was admitted with stage 4B SS. His
performance status was poor (ECOG 3). On physical examination he
was found to have a heavily itching erythroderma, with many
cutaneous tumours all over the body, axillary and inguinal
lymphadenopathies of about 3 cm in diameter and
hepatosplenomegaly in addition to a “lion face” appearance (figure 1). Laboratory
tests revealed WBC: 51,600/μL (differential: neutrophils 11,400/μl,
lymphocytes: 36.500/μL), haemoglobin: 14.2 g/dL, platelet:
298,000/μL. The bone marrow biopsy showed interstitial CD4+
lymphocyte infiltration. Flow cytometric analysis of the bone
marrow aspirate disclosed a clonal expansion of CD3+, CD4+ T cells
(CD3: 95.7%, CD7: 12.3%, CD4: 92.5%, CD8: 28%, CD16/CD56: 1.86%,
CD5: 65.7%, CD19: 0.69%). Blood chemical analysis was unremarkable
except slightly elevated lactate dehydrogenase. Computed tomography
(CT) scan of the abdomen showed hepatosplenomegaly with enlarged
external iliac and inguinal lymph nodes. Chest CT was unremarkable
except for enlarged axillary lymph nodes.
Relying on the recently published data on
chemotherapy-refractory SS we decided to treat our patient with
alemtuzumab. It was given at a dose of 30 mg three times a
week. A few mild infusion-related adverse effects such as fever,
rigors, urticaria and fatigue were observed during the first week
of the treatment. The patient concomitantly received
co-trimoxazole, acyclovir and fluconazole prophylaxis. His CMV
viral load at the beginning of the treatment was not known. After
the first week of treatment, itching resolved. After 2 weeks of
alemtuzumab a marked improvement was noted in skin lesions (figure 2). His
lymphadenopathies and hepatosplenomegaly began to regress. But then
the treatment had to be withheld at the 3rd week of
alemtuzumab (after a total dose of 223 mg) due to infectious
complications.
On the 17th day of therapy the patient presented with
fever. On chest examination there were rales on the left upper lung
area and on the right lung base. His leukocyte counts were 6,900/μL
with 6,600/μL neutrophils and 100/μL lymphocytes (table 1). A computed tomography scan of the chest
revealed consolidations with air bronchograms in the associated
areas. Bacterial pneumonia was suspected and appropriate
antibiotherapy including piperacillin-tazobactam and teikoplanin
was started. After three days of antibiotherapy, fever persisted;
so empirical antifungal therapy with amphotericin B was initiated.
Blood and sputum cultures for typical as well as for atypical
bacteria, including mycobacterium species and Nocardia asteroids,
remained negative. Pneumocystis carinii was excluded appropriately.
Serologic tests for Legionella pneumophilia, Chlamydia pneumoniae
and Mycoplasma pneumoniae were also found negative. The patient’s
fever did not resolve despite broad-spectrum antibiotics and
antifungal treatment. His general status worsened. A mild
progression in the skin lesions was noted. Lymphadenopathies and
hepatosplenomegaly persisted. A bronchoalveolar-lavage (BAL) was
performed on 13th day of fever, but it was
non-diagnostic. Cytomegalovirus (CMV) infection was suspected. The
quantitative CMV-DNA assessment revealed a viral load of 100,000
copies/mL. Ganciclovir was commenced at a dose of 2 × 5 mg/kg.
He was still lymphopenic at that time (table
1). His blood chemical analysis was within normal limits.
The patient became afebrile on the 3rd day of
ganciclovir. CMV was successfully treated with a resultant clinical
and radiological improvement. Ganciclovir was continued for a month
until two negative CMV-DNA results were obtained.
The patient remained well for a few weeks but then he developed
fever again. Skin lesions exacerbated with ulcerating tumours and
increasing erythroderma two months after discontinuation of
alemtuzumab. Hepatosplenomegaly persisted. Minimal oedema was noted
in the lower extremities. His white blood cell count was 10,000/μL
with 7,200/μL neutrophils and 500/μL lymphocytes. Blood cultures
were found to be positive for methicillin resistant coagulase
negative staphylococcus. Meanwhile a second bronchoalveolar-lavage
was performed, revealing pseudomonas aeruginosa. The fever did not
respond to appropriate antibiotherapy. CMV reactivation was then
diagnosed with a viral load of 8350 CMV-DNA copies/ml. Ganciclovir
was added to the treatment. Unfortunately he developed a
progressive pneumonia and died of severe respiratory failure with
massive haemoptysis six months after administration of alemtuzumab.
Necropsy could not be done. The clinical and laboratory findings of
the patient during the follow-up period are summarized in table 1.
Table 1 Clinical and laboratory findings of the
patient
|
On admission
|
After alemtuzumab
|
CMV infection
|
CMV reactivation
|
Before death
|
|
Cutaneous lesions
|
Tumours, erythroderma
|
Regressed
|
Progressed
|
Ulcerating, bleeding
|
Ulcerating, bleeding
|
|
Haemoglobin (g/dL)
|
14
|
10
|
8
|
8
|
7.6
|
|
Lymphocyte count (/μL)
|
36,500
|
100
|
900
|
700
|
700
|
|
Neutrophil count (/μL)
|
11,400
|
7,800
|
4,400
|
5,700
|
23,700
|
|
Platelet count (/μL)
|
298,000
|
180,000
|
116,000
|
180,000
|
310,000
|
|
LDH (N:225-450 U/L)
|
633
|
849
|
598
|
395
|
181
|
|
CMV-DNA (copies/mL)
|
|
|
100,000
|
8,350
|
|
|
CRP (0-5 mg/L)
|
5
|
272
|
356
|
121
|
203
|
|
ESR (mm/h)
|
12
|
57
|
55
|
81
|
80
|
|
Thorax CT findings
|
|
|
Consolidations with air bronchograms
|
Regression in lesions
|
Pleural effusion, consolidation
|
Discussion
MF/SS is the most common form of cutaneous T-cell lymphomas [12].
Its treatment involves local and systemic therapies but cures are
usually difficult to attain with known standard regimens [13].
Although early stage MF can easily be managed with topical
treatment strategies, advanced stage MF and SS continue to be a
serious medical problem, with more than 3/4 of the patients either
becoming refractory to treatment or being lost due to infections
[2]. Recently, encouraging results have been published with
alemtuzumab in advanced stage refractory MF/SS patients [6-9].
These data are mainly derived from case reports and phase II
studies. Since there are no randomised large-scale multicenter
studies these results should be cautiously evaluated. With this
case report we hope to contribute to the knowledge on utilisation
of alemtuzumab in CTCL. This drug seems to be highly effective in
treatment of refractory patients but long lasting pancytopenia and
infectious complications limit its usage.
Hematotoxicity is one of the major complications. Cytopenias of
variable grades have been reported in more than 3/4 of the patients
using alemtuzumab [7, 14]. Cytopenias are less frequent and severe
in previously untreated patients [15]. Profound and sustained T and
B cell lymphopenia, a direct consequence of the pharmacological
action of the drug, is the most significant and consistent
side-effect of alemtuzumab. Lymphopenia reaches a nadir by the end
of first month and persists for months after the completion of
therapy, with full recovery taking up to 2 years [16-18]. In our
patient, marked lymphopenia ensued following the second dose of the
drug and persisted until the patient died, despite discontinuation
of the therapy for approximately 5 months. This long-lasting
immunosuppressive period provided a background for persevering
infections.
It also causes neutropenia and, to a lesser extent, a decline in
monocytes and NK cells [19]. Anaemia and thrombocytopenia are not
infrequent. The exact mechanism of these cytopenias is unclear
because myeloid stem cells and precursors usually do not express
CD52. Sequestration or autoimmune destruction may be the underlying
cause [20]. Concomitant viral infections, such as CMV, herpes
simplex virus or parvovirus may also contribute to the development
or persistence of cytopenias with different mechanisms of action.
But none of these factors is likely to explain the severe
cytopenias. Recently, Monteiro et al. postulated that activated CD4
(+) T cells are required for normal haematopoiesis, which may be
the cause underlying the cytopenias associated with alemtuzumab
[21]. Neutropenia and thrombocytopenia are reported to appear
usually following the second or third week of alemtuzumab therapy.
The median durations of neutropenia and thrombocytopenia are 28 and
21 days, respectively [15]. In our patient, however, severe
neutropenia never developed and thrombocytopenia was only mild.
This was probably due to the premature discontinuation of
alemtuzumab treatment. Most of the alemtuzumab-related cytopenias
reported in the literature were of transient nature but a few cases
with prolonged pancytopenia have also been described [22].
The mechanism of action of alemtuzumab and the associated
pattern of immune reconstitution together with the immune
abnormalities seen in MF/SS give the clue to the spectrum of
opportunistic infections seen. As described in detail by Rook and
Heald, there is a decrease in cell-mediated cytotoxicity and T cell
response to antigens in patients with MF/SS [23]. Besides this,
disrupted integrity of the skin by the infiltrating tumour causes
an increased risk of infection by providing a site of entry for
bacteria [24]. The infection risk also increases with advanced
disease, as combination chemotherapies (methotrexate/alkylating
agents) are used [25]. Alemtuzumab, by causing lymphopenia, further
increases the risk of infectious complications.
The overall infection rate has been reported to be around 60% in
CTCL patients treated with alemtuzumab. The infections usually
occur in the first 3 months of therapy when the CD4 (+) T cell
counts are lowest. Bacterial infection accounts for more than one
third of all infectious episodes. Bacterial infections are followed
by viral and fungal infections. As in our case, the most frequent
form of viral disease in CTCL patients treated with alemtuzumab is
CMV reactivation [26]. Regular monitoring for CMV reactivation and
pre-emptive treatment should therefore always be kept in mind when
treating patients with alemtuzumab. Table
2 outlines the infectious complications of alemtuzumab
reported in patients with CTCL and MF/SS. Prophylactic antibiotic,
antiviral, and antifungal treatments and potential support with
G-CSF are usually given for cytopenias and prolonged
immunosuppression, although evidence-based data related to this
issue are lacking.
Our patient probably suffered from recurrent bacterial
infections facilitated by the disturbed skin integrity and
suppressed cellular immunity. The picture was then complicated by
CMV infection/reactivation. Persisting infections made it
practically impossible to continue with alemtuzumab. But despite
the early discontinuation of alemtuzumab we noticed a significant
regression of the itchy erythroderma and cutaneous tumours, which
clearly demonstrates the potency of alemtuzumab. Unfortunately, the
response was very short lived, lasting only one month. Clinical
responses of up to 55% of CTCL patients treated with alemtuzumab
have been reported [27]. Alemtuzumab is particularly effective in
CTCL patients with pruritis. The response to alemtuzumab in
patients with cutaneous tumours or visceral involvement is not so
dramatic like that of erythrodermic and/or itching patients. This
monoclonal antibody seems to be more useful in patients with
relatively early MF/SS, who are not heavily pre-treated. In heavily
pre-treated advanced stage MF/SS patients, as in our case, however,
the results were less promising and usually of short duration [7,
8] (table 2).
Although alemtuzumab increases the risk of infectious
complications it certainly merits further investigation in the
setting of CTCL treatment alone or in combination with cytotoxic
agents, biological response modifiers and cytokines. Prospective
studies using these combinations may yield informative results to
help patients with this ‘difficult-to-treat’ disease.
Table 2 Alemtuzumab in the treatment of MF/SS – A
review of the literature
|
Studies
|
Kennedy GA et al., 2003[7]
|
Ferrajoli A et al., 2003[28]
|
Lundin J et al., 1998[29]
|
Gautschi O et al., 2004[9]
|
Capalbo S et al., 2003[6]
|
Lundin J et al., 2003[8]
|
Lenihan DJ et al., 2004[30]
|
|
Number of patients
|
7 MF/SS, 1 large cell transformation of MF
|
6 CTCL
|
8 MF
|
1 SS
|
3 MF/SS
|
22 MF/SS
|
8; 5 SS, 3 MF
|
|
Age (Median, range)
|
48, (30-62)
|
|
|
32
|
42, 68, 80
|
61 (38-77)
|
39-74
|
|
Sex
|
4F, 4M
|
|
|
M
|
|
|
4M, 4F
|
|
Disease stage
|
Advanced (IIB-IV)
|
Advanced
|
|
Advanced
|
Advanced
|
Stage II-IV
|
Stage IIB-IVB
|
|
No. of previous treatments (Median/range)
|
1-17
|
|
|
6
|
|
3 (1-5)
|
2-15
|
|
Previous therapy
|
PUVA, EBT, CT
|
Multiple CT
|
|
PUVA and multiple CT
|
Multiple CT in case 1 and 2 with autologous Tx in case 2
|
PUVA, RT and CT
|
EBT, RT, CT
|
|
No. of Alemtuzumab doses/cumulative dose, mg
|
2-13 weeks
|
Minimum 360 mg
|
|
30/900 mg
|
1080 mg, 223 mg, 480 mg
|
900 mg (360 mg-1080 mg)
|
43-553 mg
|
|
Clinical response
|
OR rate: 38%, 3PR, 2SD, 3PD
|
2 PR
|
OR in 4 patients, 2 CR
|
CR
|
PR, death, CR
|
OR rate: 55%, 7 CR, 5 PR, 3 SD, 7 PD
|
2 SD, 3 PR, 3 PD
|
|
Infectious Complications
|
MRSA skin infection, oral HSV1, viral bronchitis, Staphylococcus
skin infection, Cutaneous VZV, MRSA line sepsis, CMV infection,
Pseudomonas osteomyelitis, Parvovirus infection, Klebsiella
sepsis
|
Unknown
|
|
No infection was observed
|
No infection was observed
|
CMV reactivation in 4, FUO in 2, generalized herpes simplex
infection in 1, fatal pulmonary aspergillosis in 1, fatal
mycobacterium pneumonia in 1, and febrile neutropenia in 1 patient.
Infectious complications occurred in 50% (11) of patients
|
Infectious complications developed in 3 patients, one patient had
Legionella pneumonia
|
|
Outcome
|
All patients suffered from PD within 3 months of starting
alemtuzumab. 6 patients dying (one patient died from sepsis) a
median of 4 months. 1 patient is receiving palliative RT, one
underwent allogeneic SCT
|
|
Median time to progression: 10 months among patients who
responded
|
One year event free survival
|
Case 2 died because of a myocardial infarction
|
Median time to treatment failure in responding patients : 12 months
(5-32)
|
2 patients died of unspecified infectious complications
|
Acknowledgements
Financial support: none. Conflict of interest: none.
References
1 Girardi M, Heald PW, Wilson LD. The pathogenesis
of mycosis fungoides. N Engl J Med 2004; 350: 1978-88.
2 De Coninck EC, Kim YH, Varghese A,
Hoppe RT. Clinical characteristics and outcome of patients
with extracutaneous mycosis fungoides. J Clin Oncol 2001; 9:
779-84.
3 Lake DF, Briggs AD, Akporiaye ET.
Immunopharmacology. In: Katzung BG, ed. Basic and clinical
pharmacology. 9th ed. Mc Graw Hill, 2004: 948.
4 Flynn JM, Byrd JC. Campath-1H monoclonal antibody
therapy. Curr Opin Oncol 2000; 12: 574-81.
5 Ravandi F, O’Brien S. Expert Rev Anticancer Ther
2005; 5(1): 39-51.
6 Capalbo S, Delia M, Dargenio M, Liso A,
Diomede D, Garofalo G, Liso V. MF/SS: a report of
three cases treated with Campath-1H as salvage treatment. Med Oncol
2003; 20(4): 389-96.
7 Kennedy GA, Seymour JF, Wolf M,
Januszewicz H, Davison J, McCormack C, Ryan G,
Prince HM. Treatment of patients with advanced MF and SS with
alemtuzumab. Eur J Haematol 2003; 71: 250-6.
8 Lundin J, Hagberg H, Repp R,
Cavallin-Stahl E, Freden S, Juliusson G,
Rosenblad E, Tjonnfjord G, Wiklund T,
Osterborg A. Phase 2 study of alemtuzumab in patients with
advanced MF/SS. Blood 2003; 101: 4267-72.
9 Gautschi O, Blumenthal N, Streit M,
Solenthaler M, Hunziker T, Zenhäusern R. Successful
treatment of chemotherapy-refractory SS with alemtuzumab. Eur J
Haematol 2004; 72: 61-3.
10 Martin SI, Marty FM, Fiumara K, et al.
Infectious complications associated with alemtuzumab use for
lymphoproliferative disorders. Clin Infect Dis 2006; 43: 16-24.
11 Willemze R, Jaffe ES, Burg G, et al.
WHO-EORTC Classification for cutaneous lymphomas. Blood 2005; 105:
3768-85.
12 Siegel RS, Pandolfino T, Guitart J,
et al. Primary Cutaneous T-Cell Lymphomas: Review and Current
Concepts. J Clin Oncol 2000; 18: 2908-25.
13 Apisarnthanarax N, Talpur R, Duvic M.
Treatment of Cutaneous T-cell Lymphoma: current status and future
directions. Am J Dermatol 2002; 3: 193-215.
14 Enblad G, Hagberg H, Erlanson M, et al. A
pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy
for patients with relapsed or chemotherapy-refractory peripheral
Tcell lymphomas. Blood 2004; 103: 2920-4.
15 Lundin J, Kimby E, Mellstedt H, et al.
Haematological recovery after administration of subcutaneous
alemtuzumab in previously untreated versus refractory B-CLL. Blood
2002; 100(Pt1): 805a.
16 Mavromatis B, Cheson BD. Monoclonal antibody
therapy of chronic lymphocytic leukemia. J Clin Oncol 2003; 21:
1874-81.
17 Osterborg A, Werner A, Halapi E, et al.
Clonal CD8+ and CD52- T cells are induced in responding B cell
lymphoma patients treated with Campath-1H (anti-CD52). Eur J
Haematol 1997; 58: 5-13.
18 Frampton JE, Wagstaff AJ. Alemtuzumab. Drugs 2003;
63(12): 1229-43.
19 Lundin J, Porwit-MacDonald A, Rossmann ED,
et al. Cellular immune reconstitution after subcutaneous
alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment
as first-line therapy for B-cell chronic lymphocytic leukaemia.
Leukemia 2004; 18: 484-90.
20 Zent CS, Kay NE. Update on Monoclonal Antibody
Therapy in Chronic Lymphocytic Leukemia. Clin Adv Hematol Oncol
2004; 2: 107-13.
21 Monteiro JP, Benjamin A, Costa ES, et al.
Normal hematopoiesis is maintained by activated bone marrow CD4+ T
cells. Blood 2005; 105: 1484-91.
22 Gibbs SDJ, Westerman DA, McCormack C,
et al. Severe and prolonged myeloid haematopoietic toxicity
with myelodysplastic features following alemtuzumab therapy in
patients with peripheral T-cell lymphoproliferative disorders. Br J
Haematol 2005; 130: 87-91.
23 Rook AH, Heald P. The immunopathogenesis of T-cell
lymphoma. Hematol Oncol Clin North Am 1995; 9: 997-1010.
24 Tsambiras PE, Patel S, Greene JN, et al.
Infectious complications of cutaneous T-cell lymphoma. Cancer
Control 2001; 8: 185-8.
25 Akpek G, Koh HK, Bogen S, et al.
Chemotherapy with etoposide, vincristine, doxorubicin, bolus
cyclophosphamide, and oral prednisone in patients with refractory
cutaneous T-cell lymphoma. Cancer 1999; 86: 1368-76.
26 Thursky KA, Worth LJ, Seymour JF. Spectrum of
infection, risk and recommendations for prophylaxis and screening
among patients with lymphoproliferative disorders treated with
alemtuzumab. Br J Haematol 2005; 132: 3-12.
27 Dearden CE, Matutes E, Catovsky D. Alemtuzumab
in T-cell malignancies. Med Oncol 2002; 19(Suppl): S27-S32.
28 Ferrajoli A, O’Brien SM, Cortes JE,
et al. Phase 2 study of alemtuzumab in chronic
lymphoproliferative disorders. Cancer 2003; 98(4): 773-8.
29 Lundin J, Österborg A, Brittinger G,
et al. The European Study Group of Campath-1H treatment in
low-grade non-Hodgkin’s lymphoma. J Clin Oncol 1998; 16(10):
3257-63.
30 Lenihan DJ, Alencar AJ, Yang D, et al.
Cardiac toxicity of alemtuzumab in patients with mycosis
fungoides/Sézary syndrome. Blood 2004; 104(3): 655-8.
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