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Long-term Remission After Allogeneic Hematopoietic Stem Cell Transplantation for Refractory Cutaneous T-Cell Lymphoma
Joan Guitart, MD;
Scott C. Wickless, DO;
Yu Oyama, MD;
Timothy M. Kuzel, MD;
Steve T. Rosen, MD;
Ann Traynor, MD;
Richard Burt, MD
Arch Dermatol. 2002;138:1359-1365.
ABSTRACT
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Background Allogeneic hematopoietic stem cell transplantation has proved to be
an effective therapeutic option in various hematologic neoplastic disorders.
Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis,
with minimal possibilities of sustained remission, we studied the therapeutic
potential of hematopoietic stem cell transplantation.
Observations Three young patients with refractory tumor stage mycosis fungoides underwent
allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched
peripheral blood stem cell transplantation after cytoreductive chemotherapy
and total-body irradiation. Complete and sustained clinical and histologic
remission was achieved in 2 patients, and both remain disease free 4
years and 15 months later. One patient was in complete remission for 9 months,
followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor
effect have contained the recurring disease as a low-grade process.
Conclusions Allogeneic hematopoietic stem cell transplantation has the potential
for sustained remission and the possibility of cure for young patients with
advanced and recalcitrant cutaneous T-cell lymphoma. Even in the absence of
complete remission, an allogeneic graft-vs-tumor effect may provide an immune
mechanism to control the malignant T-cell process and alter the natural history
of disease.
INTRODUCTION
CUTANEOUS T-CELL lymphoma (CTCL) is a malignant proliferation of T lymphocytes
with homing features to the skin. In general, mycosis fungoides (MF) is an
indolent process with slow progression from patches and plaques to tumors,
although some patients experience a more aggressive course.1-3 In
the early stages, the malignant lymphocytes are mostly confined to the upper
dermis, with prominent extension into the epidermis (epidermotropism). However,
with time, CTCL cells may grow in the dermis, resulting in dermal tumors and
eventually nodal and systemic involvement.4 The
most common immunophenotype expressed in CTCL is the CD4+ CD45RO+ memory-helper phenotype, with absence of CD7 expression.5 Although
the prognosis is good for the early stages, advanced CTCL tends to become
refractory to treatment and has a poor prognosis. Sézary syndrome is
the leukemic variant characterized by circulating clonal T lymphocytes with
cerebriform nuclei and generalized erythroderma.
Although there are multiple successful treatment modalities for the
early stages, advanced CTCL tends to respond poorly to therapy. Interferon
alfa, extracorporeal photopheresis, single-agent and multiagent chemotherapy,
radiation therapy, retinoids, and recombinant fusion proteins can provide
significant and sustained palliation, but, in general, the period of remission
tends to be short. There is no current therapy that can reliably provide long-term
remission or cure for patients with advanced stage MF.3
Allogeneic and autologous hematopoietic stem cell transplantation (HSCT)
is a well-established treatment option for various hematologic diseases and
lymphoproliferative disorders. However, the type of graft significantly affects
the rate of relapse. In patients with previously treated low-grade lymphoma,
the allogeneic relapse rate was 18%, which represents a significant (P = .02) improvement compared with the relapse rate of
46% for those with autologous grafts. This higher effectiveness of allogeneic
transplants is most likely due to an immunologic graft-vs-lymphoma (GVL) effect.6
To our knowledge, we report the first series of successful allogeneic
HSCT therapy in advanced CTCL. Reinduction of clinical and histologic remission
after withdrawal of immunosuppressive medication provides evidence of a GVL-mediated
remission in CTCL.
PATIENTS AND METHODS
PATIENT SELECTION
Patients with histologically confirmed MF who did not respond to psoralen–UV-A
(PUVA) irradiation and at least 1 systemic therapy were candidates if an HLA-matched
potential donor sibling existed. If criteria for the primary bone marrow transplantation
protocol were fulfilled, including being younger than 55 years, Eastern Cooperative
Oncology Group performance status of 0 or 1, and no major end organ dysfunction,
candidates were offered an adjunct protocol to augment donor bone marrow with
CD34-enriched peripheral blood stem cells. The secondary protocol for CD34-enriched
peripheral blood stem cells is approved by the US Food and Drug Administration
under investigational device exception number BB-IDE 6991.
SUPPORTIVE CARE
Patients were treated on a HEPA (high-efficiency particle arresting)–filtered
unit to prevent infections. A low-microbial diet and treatment with fluconazole
(400 mg/d, oral or intravenous), valacyclovir hydrochloride (500 mg 3 times
daily, oral or intravenous), and ursodiol (300 mg 3 times daily, by mouth)
were started on hospital admission and were discontinued when the absolute
neutrophil count (ANC) rebounded to 500 cells/µL. Oral ciprofloxacin
(750 mg twice daily, oral) was started on hospital admission, and switched
to intravenous piperacillin sodium and tazobactam when the ANC declined below
500 cells/µL. During neutropenia, patients were confined to their rooms.
Hand washing and glove use were required for all personnel entering a patient's
room. Subcutaneous granulocyte colony-stimulating factor therapy (5 µg/kg)
was started the day of hematopoietic stem cell infusion and continued until
the ANC was greater than 1000/µL for 3 consecutive days.
STEM CELL COLLECTION
Donor marrow was harvested with the patient under general anesthesia.
A mononuclear product was obtained using the Ficoll gradient technique and
were cryopreserved in the vapor phase of liquid nitrogen. The following day,
10 µg/kg per day of granulocyte colony-stimulating factor (Amgen, Inc,
Thousand Oaks, Calif) was given subcutaneously. A 10- to 15-L leukapheresis
was performed on day 5 of granulocyte colony-stimulating factor therapy. If
a minimum of 2.0 x 106 CD34 cells/kg was not available after
enrichment, a second leukapheresis was performed on day 6.
CD34 ENRICHMENT
To diminish the risk of increasing graft-vs-host disease (GVHD), the
peripheral blood stem cell harvest was lymphocyte depleted by CD34+ selection
using an immunoabsorption column (Ceprate; CellPro, Inc, Bothell, Wash). The
enriched stem cell fraction was cryopreserved in the vapor phase of liquid
nitrogen.
STEM CELL INFUSION
After completing the conditioning regimen with chemotherapy or chemoradiotherapy,
the donor's hematopoietic stem cells are infused intravenously. By definition,
the day of stem cell infusion is day 0. Engraftment is defined as an ANC greater
than 500 cells/µL and a platelet count greater than 20 x 103/µL without transfusions.
GVHD PROPHYLAXIS
To prevent GVHD, patients received prophylaxis with cyclosporine, corticosteroids,
and, in some cases, mycophenolate mofetil. Cyclosporine administration was
started on day -1 at 5 mg/kg per day infused intravenously across 24
hours. Cyclosporine was switched to oral twice-daily dosing when the ANC was
greater than 500 cells/µL. Cyclosporine administration is slowly tapered
and discontinued, usually within 6 months of transplantation. Corticosteroid
therapy was started on day 7 as either an intravenous methylprednisolone or
an equivalent oral prednisone dose of 0.5 mg/kg per day. Corticosteroid dosages
were increased to 1.0 mg/kg per day on day 15 and then tapered weekly until
discontinuation on day 56.
REPORT OF CASES
CASE 1
A 36-year-old white man presented with a 5-year history of pruritic
patches and plaques. Hyperpigmented plaques were present on 70% to 80% of
the body surface area (T2), with thick hyperkeratotic palms and soles. The
skin biopsy specimen was diagnostic for MF, and the patient was diagnosed
as having MF stage IB. After 3 years of therapy with PUVA, interferon alfa,
PUVA with interferon alfa, and spot radiation, the patient developed tumor
lesions (T3). Sézary cells, lymphadenopathy, and hepatosplenomegaly
were not detected at any time. After conditioning with cyclophosphamide (120
mg/kg) with mesna, total-body irradiation (1200 rad [12 Gy]), and allogeneic
HLA-matched sibling transplantation, the posttransplantation course was complicated
by mild and transient acute GVHD of the gastrointestinal tract (grade 3) and
asymptomatic cytomegaloviremia that resolved with ganciclovir therapy. Cyclosporine
use was discontinued 6 months after transplantation. Skin biopsy samples of
residual hyperpigmented patches showed postinflammatory hyperpigmentation
and no evidence of MF. The patient has been in complete remission for more
than 4 years without treatment or any signs of GVHD.
CASE 2
A 39-year-old African American woman presented with a 5-year history
of a pruritic cutaneous eruption. Widespread reddish brown indurated patches
and thick plaques were present on approximately 10% (T2) of the body, most
notably on the face and trunk. The skin biopsy specimen showed MF large cell
type with a CD4+ CD7- immunophenotype. A T-cell
clone was not detected by gamma T-cell receptor polymerase chain reaction
(PCR). Her condition progressively worsened despite partial and temporary
improvements with various treatment modalities, including topical mechlorethamine
hydrochloride, PUVA with interferon alfa, temozolomide, and interleukin 2.
Eventually, she developed lymphadenopathy, erythroderma, and thick lichenified
plaques covering 40% of her body surface area (Figure 1). The serum lactate dehydrogenase level was elevated, and
Sézary cells were detected in her blood (20% of total lymphocytes and
an absolute count of 980 cells/mL). Lymph node biopsy findings were positive
for T-cell lymphoma (histologic grade LN3), reaching stage IVA. After conditioning
with cyclophosphamide (120 mg/kg) with mesna, total-body irradiation (1200
rad [12 Gy]), and etoposide therapy (30 mg/kg), she received an allogeneic
HLA-matched unmanipulated sibling bone marrow with CD34-enriched peripheral
blood stem cell transplant from her sister. She developed mild gastrointestinal
tract (grade 1) and skin (grade 2) GVHD that resolved with use of mycophenolate
mofetil, a corticosteroid, and cyclosporine (Figure 2). Skin biopsy findings at that time were positive for GVHD
(histologic grade 2), with no evidence of MF. Mild and transient hypertension
with subclinical heart failure resolved with appropriate management. The patient
has been in complete remission, free of skin lesions, Sézary cells,
or signs of GVHD, since transplantation more than 15 months ago (Figure 3).
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Figure 1. A, Extensive plaques and tumors
involving the face, neck, and chest before allogeneic hematopoietic stem cell
transplantation in patient 2. B, Extensive plaques and tumors involving the
neck and back before treatment in patient 2.
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Figure 2. After allogeneic hematopoietic
stem cell transplantation, patient 2 developed an acute episode of patches
of graft-vs-host disease. The slide shows an interface infiltrate with occasional
necrotic keratinocytes (arrow) but no evidence of atypia (hematoxylin-eosin,
original magnification x100).
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Figure 3. Patient 2 had complete resolution
of the lesions after chemoablation, radiation therapy, and allogeneic hematopoietic
stem cell transplantation.
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CASE 3
A 27-year-old African American woman presented with widespread patches,
plaques, and tumors involving approximately 35% (T3) of her body surface area
(stage IIB). Skin biopsy samples showed MF large cell type, and a clone was
identified by gamma T-cell receptor gene PCR (Figure 4). Rare Sézary cells (<5%) were noted in peripheral
blood. She soon developed lymphadenopathy, and a nodal biopsy specimen was
positive for T-cell lymphoma (stage IVA). With time, the patient became refractory
to multiple treatments, including PUVA with interferon alfa, 6 cycles of CHOP
(cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone)
and 2 cycles of 9-aminocamptothecin. Conditioning with cyclophosphamide (200
mg/kg) and total-body irradiation (1200 rad) was followed by allogeneic HLA
sibling transplantation. The posttransplantation course was complicated by
GVHD of the gastrointestinal tract and liver (grade 2), which resolved with
prednisone treatment. Asymptomatic cytomegaloviremia responded to ganciclovir
administration. The patient was in complete remission for 9 months when new
small papules and plaques on the chest and right thigh were noted. The skin
biopsy specimen confirmed the recurrence of MF large cell type, and the T-cell
clone was again detected by PCR and Southern blot analysis. Because there
was no evidence of GVHD, prophylactic immunosuppression with cyclosporine
was discontinued. Within 1 month, the MF plaques resolved and were replaced
by lichenoid scaly patches (Figure 5). Repeated skin biopsy specimens obtained from the site of previous MF relapse
showed lichenoid changes of chronic GVHD without evidence of T-cell atypia
or T-cell receptor clonality by PCR. Subsequently, a new onset of small plaques
and papules improved with the reinfusion of donor lymphocytes. Resolution
of one of the lesions was also corroborated by a negative skin biopsy result.
Five years after the allogeneic HSCT, the patient continues to develop occasional
small papules and small patches of MF, which respond to topical treatments
with mechlorethamine hydrochloride ointment, imiquimod gel, or spot electron
beam radiation (Figure 6). Surveillance
visits with routine computed tomographic scans and blood examination have
been negative.
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Figure 4. Skin biopsy sample of a tumor
from patient 3 showing a dense infiltrate of large and atypical cells (hematoxylin-eosin,
original magnification x400).
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Figure 5. Patient 3 is shown with a large
patch of chronic graft-vs-host disease, lichenoid type, involving the thigh.
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Figure 6. Patient 3 is shown with few recurrent
papules (arrows) of mycosis fungoides involving both hands and the right thigh.
The lesions resolved with topical treatments.
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COMMENT
In the past decade, major advances have occurred in the treatment of
CTCL. Despite the encouraging results obtained with use of immune-modulating
agents and targeted chemotherapy, most patients with advanced CTCL eventually
become refractory to treatment and die of complications of the disease, such
as infection, as a consequence of the relentless deterioration of the immune
status.
Bone marrow transplantation after ablative chemotherapy and irradiation
has proved to be an effective curative therapy in various lymphoproliferative
and myeloproliferative disorders. However, only a few case reports and small
series have been published on the effect of HSCT in CTCL.
Autologous bone marrow transplantation has the advantage of being a
safe procedure with low treatment-related morbidity and mortality rates, but
the results in CTCL have been disappointing. Complete clinical remission was
achieved in most cases, but the benefit was short-lived, with rapid relapse
(Table 1). Hence, although MF
is responsive to dose-intense chemotherapy, it is not curable by autologous
HSCT. The relapse may be attributed to reinfusion of tumor cells contaminating
the autologous graft or failure of high-dose chemotherapy to totally eradicate
residual disease. The quick relapse emphasizes a critical factor: the inability
of the reinfused and deteriorated host immune system to fight the malignant
T-cell process. The high relapse rate of CTCL after chemotherapy and autologous
transplantation is consistent with the rates noted in other low-grade lymphomas.6
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Table 1. Autologous Hematopoietic Stem Cell Transplantation in Patients
With Cutaneous T-Cell Lymphoma (CTCL)*
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Because allogeneic transplantation is capable of inducing long remissions
in low-grade lymphomas with a lower relapse rate than autologous transplantation,
we reasoned that CTCL could respond similarly. 13-14 Allogeneic
transplantation from a healthy donor not only eliminates the potential of
graft contamination by tumor cells but also provides an immunologic antitumor
effect owing to adoptive transfer of donor leukocytes with the allograft.
The reconstruction of an effective immune system is therefore pivotal for
the treatment's success. An allogeneic graft-vs-tumor effect is best documented
in leukemias and is often referred to as a GVL effect. A GVL effect has also
been documented in other hematologic conditions. Indeed, chronic myelogenous
leukemia, myeloma, and low-grade lymphomas are curable by allogeneic, but
not autologous, transplantation. Evidence supporting the potent immunologic
effect of GVL in preventing relapse includes (1) lower relapse rates with
increasing severity of GVHD, (2) increased relapse rates with T-lymphocyte
depletion of the donor graft,15 (3) increased
relapse rates in identical twin donor transplantations with a perfect match
but without GVHD,16 and (4) remission after
successful reinduction with donor lymphocyte infusion when the initial allogeneic
HSCT had failed.17 Patient 3 demonstrates that
even when relapse occurs after allogeneic transplantation, withdrawal of immunosuppressive
therapy or even donor lymphocyte infusion could be an acceptable therapeutic
option to treat residual or recurring disease.
The efficacy of donor lymphocyte infusion varies according to the type
of leukemia. For example, chronic myelogenous leukemia relapse in the chronic
phase responds better than acute leukemia. Whether this difference in remission
rates is due to intrinsic immunologic variability between leukemias or differences
in growth rates, with faster-growing leukemias not responding as well, is
unknown. Nevertheless, the ability of the donor cytotoxic T cells to recognize
host and tumor antigens resulting in reinduction underscores the importance
of donor immunity in disease remission.18
If the major advantage of allogeneic transplants is the high response
rate achieved by the GVL effect, the major disadvantage is also attributed
to the same cell-mediated immune system acquired with the graft, which results
in the damage of some of the host epithelial organs (ie, skin, liver, and
gastrointestinal tract). Allogeneic transplant patients have a higher risk
of treatment-related mortality, particularly when the donor is unrelated.
Graft-vs-host disease in allotransplants results in mortality nearing 20%.1 Although there are some reports of patients developing
GVL without GVHD,19 there seems to be a direct
relationship between GVHD and GVL. All patients in our study had mild forms
of GVHD. In addition to patient 3 in the present study, who has been described
in a previous publication,20 there have been
2 single case reports of allogeneic HSCT in CTCL (Table 2). Koeppel et al22 described
a 21-year-old woman with CTCL stage IVA; 6 years after transplantation, the
patient was in remission. However, during the 6 years of follow-up, she had
2 episodes of localized cutaneous recurrence, which resolved with localized
irradiation and topical corticosteroid treatment.22 Because
chimerism was proved by cytogenetics, this case confirms our impression that
even in the event of partial remission, the downgrading of CTCL with myeloablative
therapy followed by allogeneic HSCT and the powerful GVL effect can prevent
the malignant T-cell process from tumor progression. The other case report21 was a young woman with refractory Sézary syndrome
who was disease free 3 years after allogeneic transplantation.
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Table 2. Allogeneic Hematopoietic Stem Cell Transplantation in Patients
With Cutaneous T-Cell Lymphoma (CTCL)*
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For young patients with advanced CTCL (tumor or large cell transformation
or stage III and IV) who have not responded to standard treatment options
and who have a suitable donor, the potential benefits of matched sibling allogeneic
HSCT, in our opinion, outweigh the serious potential complications of the
procedure. Furthermore, significant advances in the management of acute and
chronic GVHD with modalities such as extracorporeal photopheresis, anti–tumor
necrosis factor  therapies, and mycophenolate mofetil treatement may
increase the appeal of allotransplants in CTCL.23 An
alternative approach in the future treatment of lymphoproliferative disorders
with allogeneic HSCT may be the use of low-dose, nonmyeloablative protocols,
also known as minitransplants. This strategy spares the high morbidity and
mortality of allotransplants. Although this treatment approach without chemoablation
is not designed to eradicate the lymphoma, the hematopoietic graft creates
a chimeric marrow with a powerful GVL effect. The results of minitransplants
in patients who initially were not eligible for a standard allotransplant
protocol have been encouraging, with reported complete remission of 67% in
patients with chronic lymphocytic leukemia.24 The
minitransplant strategy may eventually offer some hope for the many patients
with CTCL who are presently ineligible for allogeneic HSCT because of their
advanced age (>60 years) or suboptimal renal or cardiac performance. Furthermore,
Molina et al25 recently presented an abstract
that included a patient with advanced CTCL who achieved complete remission
after a "reduced-intensity" regimen of fludarabine phosphate and melphalan
with allogeneic HSCT. That case further supports the potential benefit of
the GVL effect in the treatment of CTCL. Similar to patient 1 in the present
study, other studies of patients with durable complete remissions after allogeneic
HSCT are encouraging and show the potential for cure in advanced CTCL.25 The advantages of allogeneic transplantation include
low relapse rates, improved disease-free survival, and GVL with the option
of donor lymphocyte infusion therapy in case of recurrence.22, 26-28
The patients described herein demonstrate the important role of an effective
immune system capable of fighting the tumor cells during the treatment of
CTCL. Allogeneic HSCT provides hope for a curative treatment modality for
patients with advanced and refractory CTCL.
AUTHOR INFORMATION
Accepted for publication April 16, 2002.
Corresponding author and reprints: Joan Guitart, MD, Department of
Dermatology, Northwestern University Medical School, 675 N St Clair St, Suite
19-150, Chicago, IL 60611 (e-mail: j-guitart{at}northwestern.edu).
From the Department of Dermatology (Drs Guitart and Wickless) and the
Divisions of Hematology/Oncology (Drs Oyama, Kuzel, and Rosen) and Immunotherapy
(Drs Traynor and Burt), Department of Internal Medicine, Robert H. Lurie Comprehensive
Cancer Center, Northwestern University Medical School, Chicago, Ill.
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