Bone Marrow Transplantation (2007) 40, 401–403 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
www.nature.com/bmt
LETTER TO THE EDITOR
Graft versus lymphoma effect after early relapse following reduced-intensity sibling allogeneic stem cell transplantation for relapsed cytotoxic variant of mycosis fungoides
Bone Marrow Transplantation (2007) 40, 401–403; doi:10.1038/sj.bmt.1705741; published online 25 June 2007 A 45-year-old man was diagnosed with a cytotoxic (CD8 þ ve CD56 þ ve TIA-1 þ ve) variant of mycosis fungoides (MF) stage IB, in 2002. He presented with patches and plaques involving the face, trunk and lower limbs. His disease rapidly progressed to tumour stage over the course of the following 4 months, with cutaneous tumours, cervical and axillary lymphadenopathy, pulmonary nodules and gingival ulceration, which upon biopsy proved to be involved with lymphoma. At diagnosis, T-cell receptor rearrangement analysis of the skin lesions demonstrated the presence of a T-cell clone; however, peripheral blood PCR was polyclonal and no Sezary cells were seen. He was treated with CHOP chemotherapy achieving only a transient and partial remission. He then underwent total skin electron beam therapy before progressing to a BEM (BCNU, etoposide and melphalan) conditioned autologous peripheral blood stem cell transplant (SCT). T-cell depletion of the graft was performed in vitro (CD34 þ ve immunoselection) and in vivo (intravenous Campath 1H). The patient was planned for elective allogeneic SCT within 6 months following his autograft, as previously published evidence from our centre suggests that a majority of patients suffer early relapse.1 On day þ 64, he developed a lesion on his leg, which preceded a rapid relapse with multiple cutaneous plaques and patches. Biopsy confirmed disease relapse. The neoplastic cells upon relapse were found to have an aberrant phenotype with loss of expression of CD2, CD4 and TIA-1. Six months after the autologous SCT, in the context of relapsed disease with multiple skin and pulmonary lesions, he underwent an allogeneic SCT using unmanipulated peripheral blood stem cells (PBSC) from his HLA-identical sibling. Conditioning utilized Campath 1H (10 mg days 10 to 6), fludarabine (25 mg/m2 days 8 to 4) and cyclophosphamide (60 mg/m2 days 3 to 2). Graft versus host disease (GVHD) prophylaxis consisted of cyclosporine 2.5 mg/kg from day –1. A high-resolution CT scan of the chest was performed on day þ 12, which showed that his multiple lung lesions had resolved in addition to regression of his skin lesions. Neutrophil engraftment was at day 14 and platelet engraftment at day 18. Interphase FISH analysis at day 30 revealed near-complete (97% (95/98) XX) whole blood full donor chimaerism.
However, by day þ 18, his cutaneous disease had reappeared on his arm, and over the course of the next 2 weeks, extended to involve trunk, limbs and face with pulmonary disease seen on CT. On day þ 30, his cyclosporine was stopped and rapid regression of his lesions was seen over the next 7 days. By day þ 71, lymphoma was no longer clinically evident, and had been replaced by suberythroderma with widespread xerosis and some asteatotic change suggestive of GVHD. Biopsy confirmed GVHD grade II, which was managed with topical steroid therapy. His post transplant period was complicated by episodes of sepsis. The patient died at day þ 265 from progressive multifocal leucoencephalopathy (PML) in complete remission (CR) from cutaneous T-cell lymphoma (CTCL) (Figures 1 and 2). Prognosis for advanced tumour stage MF and Sezary’s syndrome (SS) is poor with a median survival of approximately 5 and 2.5 years in those patients with visceral involvement or node effacement.2 Transformation also confers a poor prognosis.3 Treatment for advanced disease currently is largely palliative and allogeneic transplantation with the potential of a graft versus lymphoma (GVL) effect offers the only hope of long-term CR. The experience of allogeneic haematopoietic transplantation in this setting is limited. However, there have been a number of previous case reports suggesting a graft versus tumour effect. Burt et al.4 described relapse of advanced MF 9 months after a myeloablative sibling transplant. Withdrawal of immunosuppression led to regression of active disease concomitant with the development of GVHD. This patient remained in remission for further 8 months, although no subsequent data is available. Further supportive evidence comes from Soligo et al.,5 who reported on the feasibility of non-myeloablative transplants in advanced MF with full donor engraftment occurring in all three cases. All patients achieved remission from their CTCL and all of them developed acute skin GVHD. However, in this small series, viral complications were substantial with EBV-related lymphoproliferative disease, CMV reactivation and BK virus infection. One patient died of bacterial sepsis, an established problem in patients with MF. The other patients remained in CR at 18 and 24 months from transplantation. More recently, Herbert et al.6 reported on three cases of MF who relapsed after a reduced-intensity allograft procedure where reduction of immune suppression resulted in enhanced response accompanied by GVHD. All subsequently had relapse of disease despite
Letter to the Editor
402
Figure 1
Pre-transplant – patient before SCT.
Figure 2 Post transplant – patient after relapse following the withdrawal of immunosuppression and onset of GVHD.
an initial putative GVL effect. Two of these patients went on to receive donor lymphocyte infusions (DLI), which resulted in regression of relapsed disease; however, these regressions have not been sustained and the patients experienced considerable GVHD, with one dying from pneumonitis complicating progressive chronic GVHD. The largest series of allogeneic transplantation in MF comes from the experience of the Californian group,7 which also included follow-up of an individual case previously reported in the literature. In this series, eight patients (four of tumour stage MF and four of SS) were allografted using a number of different regimes including both myeloablative and reduced intensity, different donor sources (four sibling transplant and four volunteer unrelated grafts) and different stem cell sources (BM and PBSC). All patients have achieved disease remission, with long-term CR (range 24–98 months) in those alive (6/8) with concurrent GVHD, thereby providing further evidence supporting a possible GVL effect; however, there are no data as to whether these patients relapsed post transplant and subsequently went into a further remission with reduced immunosuppression as in the cases described above. In our case, the patient showed an early relapse of his disease as early as at the time of donor engraftment. He previously had aggressive disease, which was likely to be evolving as evidenced by a change to an aberrant phenotype. His post transplant relapse was rapidly progressive. The subsequent swift regression of this relapse by removal of cyclosporine-mediated immunosuppression illustrates in our opinion a clear graft versus tumour effect and supports the limited published data. The evidence suggests that this GVL effect can achieve remission after relapse of MF/SS and if sustained, a potential long-term Bone Marrow Transplantation
remission, and is likely to hold the key to curing advanced stages of CTCL. The use of DLI after transplant requires further evaluation, ideally within a multicentre randomized controlled trial. Viral infection seems to be increased in those patients who have received SCT for MF. Interestingly, our patient died from PML, which is classically associated with JC virus. The only other patient in the literature known to have received Campath 1H (pretransplant) died from respiratory syncytial virus infection. Therefore, the role of in vivo T-cell depletion in this group of patients requires careful consideration. IH Gabriel1, E Olavarria1, RR Jones2, S Whittaker2, A Chaidos1 and JF Apperley1 1 Department of Clinical Haematology, Hammersmith Hospital, London, UK and 2 Skin Tumour Unit, St Johns Institute of Dermatology, St Thomas’ Hospital, London, UK E-mail:
[email protected]
References 1 Olavarria E, Child F, Woolford A, Whittaker S, Davis J, MacDonald C et al. T-cell depletion and autologous stem cell transplantation in the management of tumour stage mycosis fungoides with peripheral blood involvement. Br J Haematol 2001; 114: 624–631. 2 Sausville EA, Eddy JL, Makuch RW, Fischmann AB, Schechter GP, Matthews M et al. Histopathologic staging at initial diagnosis of mycosis fungoides and the Sezary syndrome. Ann Intern Med 1998; 109: 372–382. 3 Diamandidou E, Colome-Grimmer M, Fayad L, Duvic M, Kurzrock R. Transformation of mycosis fungoides/Sezary
Letter to the Editor
403 syndrome: clinical characteristics and prognosis. Blood 1998; 92: 1150–1159. 4 Burt RK, Guitart J, Traynor A, Link C, Rosen S, Pandolfino T et al. Allogeneic haematopoietic stem cell transplantation for advanced mycosis fungoides: evidence of a graft-versus-tumour effect. Bone Marrow Transplant 2000; 25: 111–113. 5 Soligo D, Ibatici A, Berti E, Morandi P, Longhi E, Venegoni L et al. Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant 2003; 31: 663–666.
6 Herbert KE, Spencer A, Grigg A, Ryan G, McCormack C, Prince HM. Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 521–525. 7 Molino A, Zain J, Arber D, Angelopolou M, O’Donnell M, Murata-Collins J et al. Durable clinical, cytogenetic, and molecular remissions after allogeneic haematopoietic cell transplantation for refractory sezary syndrome and mycosis fungoides. J Clin Oncol 2005; 25: 6163–6171.
Bone Marrow Transplantation
