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Durable Clinical, Cytogenetic, and Molecular Remissions After Allogeneic Hematopoietic Cell Transplantation for Refractory Sezary Syndrome and Mycosis Fungoides

From the Divisions of Hematology/Hematopoietic Cell Transplantation and Anatomic Pathology (Hematopathology and Cytogenetics), City of Hope National Medical Center, Duarte, CA

Address reprint requests to Arturo Molina, MD, MS, City of Hope Comprehensive Cancer Center, Division of Hematology and Hematopoietic Cell Transplantation, 1500 E Duarte Rd, Duarte, CA 94305; e-mail: arturo.molina{at}biogenidec.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: Sezary syndrome (SS) and tumor-stage mycosis fungoides (MF) are generally incurable with currently available treatments. We conducted a retrospective study to evaluate the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) in this patient population.

PATIENT AND METHODS: From August 1996 through October 2002, eight patients with advanced MF/SS underwent allogeneic HSCT at our institution. All patients were heavily pretreated, having failed a median number of seven prior therapies (range, five to 12). Clonal T-cell populations in peripheral blood or bone marrow were detectable by polymerase chain reaction analyses of T-cell receptor -chain gene rearrangements in six patients and cytogenetics in three patients. The conditioning regimen included total-body irradiation and cyclophosphamide (n = 3), busulfan and cyclophosphamide (n = 1), and the reduced-intensity regimen of fludarabine and melphalan (n = 4). Allogeneic hematopoietic stem cells were obtained from HLA-matched siblings (n = 4) and unrelated donors (n = 4).

RESULTS: All patients achieved complete clinical remission and resolution of molecular and cytogenetic markers of disease within 30 to 60 days after HSCT. Two patients died from transplantation-related complications; graft-versus-host disease (GVHD; n = 1) and respiratory syncytial virus pneumonia (n = 1). With a median follow-up of 56 months, six patients remain alive and without evidence of lymphoma.

CONCLUSION: Our results suggest that allogeneic HSCT from both HLA–matched sibling and unrelated donors can induce durable clinical, molecular, and cytogenetic remissions in patients with advanced cutaneous T-cell lymphoma that is refractory to standard therapies.

	INTRODUCTION

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Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma (CTCL) that usually presents with patch and plaque lesions that may progress to generalized erythroderma or tumor-stage disease. Some patients have advanced stages of disease at presentation. Sezary syndrome (SS) is a leukemic variant of CTCL associated with generalized erythroderma and circulating cells in the peripheral blood known as Sezary cells. Both of these advanced manifestations of CTCL are associated with severe signs and symptoms such as severe pruritis, painful skin lesions, and cosmetic disfigurement. Historically, the prognosis for patients with these types of advanced CTCL has been poor.^1-4

A variety of treatments is currently being utilized for CTCL, including topically directed therapies such as photochemotherapy (PUVA), total skin electron-beam radiation therapy (TSEB), and topical chemotherapy as well as systemic therapies such as single-agent and combination chemotherapy, interferon-, retinoids, extracorporeal photochemotherapy (photopheresis), and combined modality regimens.^1,2,5,6 The recent development of newer agents such as bexarotene (Targretin; Ligand Pharmaceuticals Inc, San Diego, CA), denileukin diftitox (ONTAK; Ligand Pharmaceuticals Inc, San Diego, CA), and alemtuzumab (Campath; Ilex Pharmaceuticals, San Antonio, TX) have provided new therapeutic options for these patients.^7-9 Most of these therapies are palliative and none are considered to have significant curative potential in patients with advanced disease.

There is limited experience with the use of allogeneic hematopoietic stem-cell transplantation (HSCT) for the treatment of MF/SS.^10-14 Herein, we report a retrospective study of eight patients with advanced refractory CTCL who underwent allogeneic HSCT at our institution (City of Hope Comprehensive Cancer Center [COHCCC], Duarte, CA). Prior transplantation, all eight patients were severely symptomatic and had relapsed multiple times or failed to respond adequately to a median of seven prior therapies. After HSCT, all eight patients achieved a complete clinical remission (CR) with resolution of skin lesions, lymphoma-related symptoms, and adenopathy and disappearance of all molecular, flow cytometric, and cytogenetic markers of disease. Six patients are alive and in remission, with two remissions lasting for more than 6 years. There have been no clinical relapses observed to date suggesting that a graft-versus-lymphoma (GVL) effect may play a role in inducing and maintaining remissions in this setting. Long-term follow-up shows that patients with advanced CTCL can achieve durable remissions after allogeneic HSCT.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Patients
Eight patients with MF/SS underwent HSCT at COHCCC between August 1996 and October 2002. Approximately 110 patients with MF/SS were evaluated at COHCCC during the study period (A. Molina and J. Zain, personal communication). Twenty-six patients were potentially eligible for allogeneic transplantation based on advanced disease stage and refractoriness to conventional therapy. The median age of these patients was 60.5 years (range, 21 to 86 years). Twelve patients were not considered transplantation candidates because of comorbid medical conditions or poor performance status resulting from uncontrolled disease and older age (range, 65 to 86 years). Many of these patients were evaluated before the initiation of clinical trials with the reduced-intensity conditioning regimen of fludarabine and melpahalan in 2000. Two patients (age, 60 years and 61 years) with tumor-stage disease and histologic transformation underwent autologous HSCT because an HLA–matched donor was unavailable, and both relapsed and died from progressive disease. One patient (age, 46 years) refused transplantation, and two patients (age, 41 years and 56 years) died while we were searching for an unrelated donor stem-cell product. One younger patient (age, 46 years) died from rapidly progressive transformed disease before transplantation evaluation.

The TNM staging criteria developed by the National Cancer Institute was used to stage patients before transplantation (Table 1). ¹⁵ The patient characteristics are listed in Table 2. Five patients had generalized erythroderma, including four patients with SS. The other three patients had tumor-stage MF with extensive skin involvement, one with transformation into a diffuse large cell histology documented in a lymph node biopsy. Patients with peripheral T-cell lymphoma were excluded from this analysis. The median age was 45.5 years (range, 21 to 59 years). There were five women and three men. The median time from onset of disease symptoms and skin lesions to transplantation was 7.5 years (range, 3.5 to 12 years). The median number of prior therapies, excluding systemic and topical corticosteroids, was seven (range, 5 to 12). Prior treatments included PUVA (n = 6), interferon- (n = 8), extracorporeal photochemotherapy (ECP; n = 7), cladarabine (n = 4), methotrexate (n = 6), oral etoposide chemotherapy (n = 4), local or total skin electron-beam radiation therapy (n = 4), local external-beam orthovoltage radiation (n = 2), topical nitrogen mustard (n = 2), bexarotene (n = 4), cyclosporine (n = 1), interferon- (n = 1), deoxycoformycin/pentostatin (n = 2), isotretinoin (n = 1), gemcitabine (n = 3), liposomal doxorubicin (n = 1), denileukin diftitox (n = 1), alemtuzumab (n = 1), oral cyclophosphamide ± etoposide (n = 2), polychemotherapy with Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and methotrexate/cytarabine (n = 1), and gemcitabine, navelbine, and liposomal doxorubicin (n = 1).

Conditioning Regimens
These patients were not treated on a uniform protocol specifically designed for MF/SS. The choice of conditioning regimen was made according to the practice pattern and available protocols at our institution at the time of allogeneic HSCT. Three patients received a conditioning regimen of fractionated total-body irradiation (FTBI) to a total dose of 13.20 Gy followed by cyclophosphamide (Cy) 60 mg/kg (ideal body weight) [FTBI/Cy] for 2 consecutive days. One patient received 16 doses of busulfan (Bu) 16 mg/kg intravenously every 6 hours followed by 2 days of cyclophosphamide 60 mg/kg (Bu/Cy). The other four patients were treated with a reduced-intensity conditioning regimen of fludarabine (Flu) 25 mg/m² daily for 5 consecutive days followed by melphalan (Mel) 140 mg/m² (Flu/Mel).^16,17

Donor Selection
Serologic typing was performed for class I HLA-A, HLA-B, and HLA-C loci. Molecular typing of class II HLA-DRB1 and HLA-DQ antigens was done by sequence-specific oligonucleotide probe hybridization as described previously.¹⁸ The donors and recipients were serologically matched at HLA-A and HLA-B loci and molecularly matched at HLA-DR loci.

Source of Stem Cells
Three patients received allogeneic bone marrow; two from matched unrelated donors and one from a sibling donor. Five patients received granulocyte colony-stimulating factor mobilized peripheral blood stem cells; three from a sibling donor and two from an unrelated donor.

Graft-Versus-Host Disease Prophylaxis
Graft-versus-host disease (GVHD) prophylaxis was provided as specified by institutional guidelines or protocols available at the time of allogeneic HSCT. The first two patients were treated with a triple regimen of cyclosporine, methotrexate, and methylpredinsolone,^18,19 and four patients received a combination of cyclosporine and mycophenylate mofetil as previously described.²⁰ Two patients who underwent an unrelated donor transplant with the Flu/Mel regimen received cyclosporine, mycophenylate mofetil 1,000 mg intravenously twice a day and low-dose methotrexate (10 mg/m² on day 1 and 5 mg/m² on days 3 and 6). GVHD prophylaxis was continued on an outpatient basis and doses of immunosuppressive medications were tapered or adjusted as defined by institutional practice guidelines.

Supportive Care
Supportive care, including prophylactic antibiotics, antifungal therapy, total parenteral nutrition, hematopoietic growth factors, immune globulin replacement, and treatment of mucositis and neutropenic fever was administered in accordance with institution standard operating procedures and practice guidelines.²¹ Surveillance blood cultures for cytomegalovirus were monitored twice weekly for the first 100 days post-transplantation and patients received pre-emptive therapy on development of cytomegalovirus viremia. Aggressive skin and wound care was administered to patients with ulcerated skin lesions.

Response Evaluation
Response to HSCT was evaluated by routine physical examination and computed tomography scans during follow-up care. Peripheral blood (PB) and bone marrow (BM) specimens were obtained from all patients before transplantation and at approximately 30 days, 100 days, 6 months, 1 year, 18 months, 24 months, and yearly thereafter on the patients who were transplanted more than 3 years ago. These specimens were sent for flow cytometry, cytogenetics, and molecular studies. Skin biopsies, and additional GVHD evaluation was done as clinically indicated.

Flow Cytometry
Immunophenotyping was performed by three-color flow cytometric analysis of bone marrow aspirates and peripheral blood with a Beckton Dickenson FACScan instrument (Mountain View, CA).²²

Cytogenetic Studies
Peripheral blood cytogenetic studies were obtained for patients with known or suspected Sezary syndrome.²³ Cytogenetic studies were also obtained on routine BM biopsy evaluations as part of pre- and post-transplant restaging procedures. Three or four separate cell cultures were initiated for each specimen using the following conditions: (1) 24 to 48 hours in RPMI-1640 (Irvine Scientific, Irvine, CA) media; (2) 72 hours in RPMI-1640 with phytohemmaglutinin and interleukin-2 (IL-2); (3) 72 hours in RPMI-1640 with lipopolysaccaride and pokeweed; and (4) 96 hours 4-phorbol 12-myristate 13-acetate (PMA)/IL-2 in RPMI-1640 or overnight RPMI-1640 with vinblastine. Chromosome slide preparation techniques including harvesting, fixation, and GTG-banding were performed using standard protocols. A minimum of 20 mitotic cells per specimen was fully analyzed by light microscopy. Karyotypes were described per International System for Human Cytogenetics Nomenclature guidelines.²⁴

T-Cell Receptor Gene Rearrangement Studies
Both peripheral blood and bone marrow samples were studied for T cell receptor -chain gene rearrangements (TCRGRs) using primers directed against the variable region TCR genes (V_1-8, V₉, V₁₀ and V₁₁) and a multiplex of joining region primers, as previously described.^25,26 Gene rearrangment studies were also carried out on skin biopsy samples.

	RESULTS

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Efficacy
HSCT resulted in clinical remission in all eight patients as listed in Table 3. All patients engrafted and demonstrated evidence of persistent complete donor chimerism using short tandem repeat analysis (data not shown). There was complete resolution of skin lesions, including tumors and ulcerated lesions and lymphoma-related symptoms (ie, pruritis and pain) within 30 to 60 days after HSCT. Computed tomography scans confirmed the resolution of prior adenopathy in all patients. Figure 1 shows the complete disappearance of generalized erythrodermatous hand lesions, including skin fissuring and onchodystrophy after HSCT in patient 4. Similar responses were observed in all patients with erythrodermic CTCL. In instances where skin biopsies were performed, there was no histologic or molecular evidence of persistent or recurrent disease. Follow-up examination of PB and BM in the four patients with Sezary syndrome showed morphologic and flow cytometric remission of Sezary cells (data not shown). Currently, the Karnofsky performance status on all surviving patients is 70% to 100%.

View larger version (130K): [in this window] [in a new window]   Fig 1. Patient 4 has Sezary syndrome with generalized erythroderma and circulating (Sezary) cells. (A and B) Before hematopoietic stem cell transplantation (HSCT), her hands are affected with fissuring, cracking, and nail destruction. (C and D) One year after HSCT, there was regression of skin involvement and normalization of nails.

Acute and Chronic GVHD
Myeloablative conditioning regimen (n = 4). Two patients developed acute GVHD of the skin and the other two developed a presumptive diagnoses of oral and gastrointestinal GVHD. Patient 1 remains on low-dose immunosuppressive therapy for chronic limited GVHD of the skin. Patient 3 developed extensive chronic GVHD of the skin and oral mucosal and subsequently died 16 months after transplantation from complications related to the treatment of chronic GVHD (renal failure and infection). Patient 4 is on very low-dose cyclosporine for mild GVHD of the skin. Patient 2 is off immunosuppressive therapy.

Reduced-intensity conditioning regimen (n = 4). Acute GVHD appeared to be less severe among the three assessable patients who received the Flu/Mel regimen. Although none of these patients developed acute GVHD greater than grade 2, all three patients subsequently developed limited chronic GVHD: oral mucosa (n = 1), mild liver dysfunction (n = 1), and skin (n = 1). All three of these patients responded to an adjustment of their immunosuppressive medication regimen. Evidence of skin GVHD developed in a patient who had immunosuppressive therapy discontinued because of suspected relapse of CTCL. The biopsy-proven GVHD lesion resolved on reinitiation of low-dose corticosteroids, and the patient remains without evidence of GVHD or CTCL at 33 months post-transplant.

Molecular Responses After HSCT
Before allogeneic HSCT, six patients had evidence of a clonal TCRGR in PB and/or BM detectable by PCR analysis, which disappeared within 30 to 60 days post-HSCT (Fig 2). Follow-up PCR studies demonstrate no evidence of recurrence of the original clonal T-cell population. However, new transient clonal T-cell populations were detected in two patients (patients 1 and 6) during the follow-up period. These TCRGRs were distinct from the original clonal rearrangement. Patient 6 developed a band in the V9 region 60 days post-transplant. This band was positioned differently than the pretransplant band, which was in the V10 region (data not shown). The patient remains free of disease at 45 months post-transplant. Patient 1 developed a faint band in the V gamma 2 region 1 year after transplantation that disappeared on subsequent analysis (data not shown). Similarly, this patient remains free of disease recurrence 108 months after HSCT. These bands may represent transient oligoclonal expansions of grafted T-cells detectable by TCRGR molecular analysis and may be associated with the onset GVHD and may not be indicative of active lymphoma.²⁷

View larger version (39K): [in this window] [in a new window]   Fig 2. Clonal T TCR gene rearrangements are eradicated after allogeneic hematopoietic stem cell transplantation. Pretherapy bone marrow (BM), peripheral blood (PB), and skin (patient 5) demonstrated TCR rearrangements while all post-therapy (Tx) specimens are negative. Arrows indicate the size of the expected positive polymerase chain reaction product. MW, molecular weight marker.

View larger version (29K): [in this window] [in a new window]   Fig 3. Abnormal peripheral blood karyotypes. (A) Structural abnormalities include a three-way translocation between chromosomes 3, 20, and 22, and a deletion in 10q. (B) Multiple numerical (ie, trisomy 4, trisomy 8, and trisomy 17) and structural abnormalities including deletions in 5q, 13q, and 17p.

	DISCUSSION

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In 1999, we reported a case study describing the 3-year follow-up results of allogeneic HSCT on the first CTCL patient in the current series.¹⁰ By the time she was referred to COHCCC in 1996, this patient had a 10-year history of poorly controlled SS that progressed after treatment with MTX, PUVA, photopheresis, hydroxyurea, interferon-, and cladarabine. Despite having end-stage, refractory SS, this patient achieved a durable clinical and molecular remission using a fully myeloablative conditioning regimen and unrelated-donor BM as a source of stem cells. With ongoing follow-up, this patient has been in remission for 98 months after transplantation and is presumably cured. Based on our early observation that allogeneic HSCT was effective in inducing a remission in patient 1, we subsequently offered allogeneic HSCT to patients with advanced stage refractory CTCL who were eligible for participation in our ongoing institutional transplant protocols.

Although the eight patients reported in this retrospective study had refractory, heavily pretreated, highly symptomatic, and otherwise incurable advanced MF/SS, all achieved a complete remission after HSCT and six patients remain in remission at 24, 35, 41, 50, 82, and 98 months post-HSCT. One patient died of respiratory syncytial virus pneumonia on day 34 after transplantation. This patient was heavily pretreated, having received 12 prior therapies, including alemtuzumab and other immunosuppressive agents. Seven patients developed chronic GVHD and one died 16 months after HSCT from complications related to treatment of extensive chronic GVHD. The six surviving patients remain without signs or symptoms of lymphoma and have KPS scores of 70% to 100%. Two patients are off immunosuppressive therapy.

Before HSCT, six patients had clonal TCRGRs in PB or BM that were detectable by PCR. All patients became PCR-negative after transplantation and remain without evidence of clinical or molecular relapse during the follow-up period. Two patients developed a new faint clonal TCRGR after HSCT that was distinct from the original TCRGR associated with clinically active disease. The clinical significance of these new TCRGR remains unclear, and may be associated with the presence of GVHD.²⁷ Clinically, these patients remain free of recurrent lymphoma. Four patients had clonal T-cell populations in PB detectable by flow cytometry and all of these disappeared after transplant. In a study reported by Thangavelu et al,²³ MF patients with clonal structural cytogenetic abnormalities had a median survival of 3 months compared with patients without structural chromosome abnormalities in whom the median survival had not been reached. In our study, three patients had clonal structural cytogenetic abnormalities detected in PB and/or BM before HSCT, including two with very aberrant karyotypes, and all achieved a sustained cytogenetic remission after HSCT.

The failure of the autologous HSCT to produce durable responses in this group of CTCLs suggests that a GVL effect seen with allogeneic HSCT is an important factor in mediating these durable responses.^31,32 The use of an allogeneic graft offers the advantage of providing stem cells that are not contaminated with malignant cells and at the same time provides an important adoptive immunotherapeutic or graft-versus-tumor effect that is most pronounced in chronic myeloid leukemia and certain types of indolent malignant lymphomas. Immune-mediated responses may be especially important in patients with CTCL because some patients with this disease may respond to immunomodulatory therapies such as ECP, interferon-, IL-2, IL-12, or withdrawal of immunosuppression after allogeneic HSCT.^12,33-35

Because GVHD frequently occurs in the skin, the most common site of involvement of MF/CTCL, it is also intriguing to consider whether this phenomenon may contribute to the efficacy of allogeneic HSCT in the treatment of these disorders. In the current study, there was no correlation between the distribution of cutaneous chronic GVHD and sites of previous skin involvement.

Reduced-intensity conditioning regimens have been developed in an attempt to reduce the upfront mortality of a traditional fully ablative transplantation while preserving the graft-versus-tumor effect in the allogeneic setting. The Flu/Mel–based regimen has been described as an effective reduced-intensity regimen for patients unable to undergo standard conditioning for allogeneic BMT due to comorbidities or advanced age.^16,17,36

With an average age of 60 years at presentation, advanced MF/SS tends to affect older individuals who have historically been excluded from allogeneic HSCT. The median age of the patients in our series is younger than that of the general MF/SS patient population, suggesting a potential for bias in the referral or selection of patients for allogeneic HSCT. At COHCCC, patients older than 50 to 55 years were excluded from participation in studies utilizing fully ablative transplantation regimens because of concerns over an increased risk of transplantation-related toxicity and mortality. As such, the first four patients in our study received a fully ablative transplantation regimen and were younger than 50 years. After the introduction of the Flu/Mel regimen at our institution in 2000, older MF/SS patients (ie, 50 years or older) have been evaluated for and treated with allogeneic transplant. Currently, patients up to age 65 years are considered potential candidates for allogeneic HSCT using the Flu/Mel regimen.

The optimal allogeneic HSCT conditioning regimen for this group of CTCL patients remains unknown. The use of a truly nonmyeloablative regimen can be explored in a situation where the patient has more clinical control of the disease. Because the patients reported in the current study were heavily pretreated and had a high tumor burden at the time they were referred to our institution, the reduced-intensity Flu/Mel regimen was chosen because these agents have a substantial antilymphoma effect and provide good disease control while the GVL becomes established.

Based on our experience and the results of allogeneic bone marrow transplantation in other types of low-grade lymphoma,^32,37-40 we suggest that patients with advanced and refractory CTCL be considered for allogeneic transplantation using sibling or unrelated donor hematopoietic stem cells. The use of the reduced-intensity Flu/Mel regimen appears to be less toxic and equally efficacious as the conventional FTBI-based transplantation regimens and may allow broader application of this procedure to older patients with advanced stage CTCL. The optimal timing of transplantation for this group of patients is unknown. Based on the poor long-term results obtained with purine analogs and other chemotherapies, we suggest that these patients be evaluated for allogeneic HSCT when they start to fail to respond to photopheresis, interferon-, bexarotene, or other biologic agents.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

	NOTES

 
Supported in part by United States Public Service Grants 30206 and 33572 from the National Cancer Institute. A.M. was supported in part by an American Cancer Society Clinical Oncology Career Development Award.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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40. Molina A, Nademanee A, Palmer JC, et al: Allogeneic hematopoietic stem cell transplantation (ALLO HSCT) for poor-risk non-Hodgkin’s lymphoma (NHL): The City of Hope (COH) experience. Proc Amer Soc Clin Oncol 19:19a, 2000 (abstr 65)

Submitted October 25, 2004; accepted April 11, 2005.

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