Allogeneic Hematopoietic SCT for Primary Cutaneous T Cell Lymphomas

ORIGINAL ARTICLE Allogeneic hematopoietic SCT for primary cutaneous T cell lymphomas

VR Paralkar1, SD Nasta1, K Morrissey2, J Smith1, P Vassilev1, ME Martin3, SC Goldstein1, A Loren1, AH Rook2, EJ Kim2 and DL Porter1

1Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA and 3Division of Bone Marrow Transplantation, Temple University School of Medicine, Philadelphia, PA, USA

Cutaneous T-cell lymphomas (CTCL) are a hetero- disease has progressed beyond early stages, it can behave in geneous group of non-Hodgkin lymphomas that are a highly aggressive manner. SS (circulating lymphoma cells considered incurable. The role of allogeneic hematopoietic greater than 1000/mm3 and greater than 10% of peripheral SCT (HSCT) in the treatment of CTCL is not well blood leukocytes) has a median survival time of 31 defined but may provide potent graft-vs-lymphoma (GVL) months.2 Although there are numerous therapies available activity independent of the conditioning therapy. We to treat CTCL, including newer biological therapies, present outcomes of 12 extensively-pretreated patients CTCL is highly responsive to immune manipulation.3,4–7 with CTCL who underwent allogeneic HSCT using, most Responses to IFN a, IFN g and IL-12 highlight the fact commonly, a reduced intensity conditioning regimen. that CTCL is influenced by host immune status.8,9 Median age at diagnosis of CTCL was 49 years, and Conventional treatments are at best temporizing with median time to transplantation from diagnosis was 3.3 aggressive disease,10 and high-dose chemotherapy with years. Transplantation induced and maintained CR in six autologous hematopoietic SCT (HSCT) for MF and SS patients with active disease, supporting the presence of a has had disappointing results.11 GVL effect. TRM was low, and 42% of patients were For many diseases, allogeneic HSCT is an ideal form alive and disease-free a median duration of 22 months of immunotherapy; however, the role for allogeneic HSCT after transplant. Two patients showed strong and direct in CTCL is not well defined. Allogeneic transplant is evidence of a GVL-effect with a direct response to successful in part because of the graft-vs-lymphoma (GVL) withdrawal of immunosuppression or to donor leukocyte effect of the donor graft, independent of the conditioning infusion. Our data show that HSCT can provide long- regimen.12 Several small series describe durable remissions term disease control in patients with advanced CTCL, during allogeneic HSCT after both reduced intensity which otherwise was refractory to immunotherapy and conditioning (RIC) and myeloablative conditioning.13–15 chemotherapy. Donor leukocyte infusion (DLI) has also been reported to Bone Marrow Transplantation (2012) 47, 940–945; be effective in producing a GVL effect, but only when doi:10.1038/bmt.2011.201; published online 24 October 2011 combined with several other modalities of therapy includ- Keywords: CTCL; GVL; allogeneic; HSCT; DLI ing chemotherapy.14 Nevertheless, long-term remissions, particularly in the setting of RIC allogeneic transplant, and the observation of responses with withdrawal of immunosuppression support the presence of a potent GVL 14,15 Introduction effect. We showed the outcomes of 12 consecutive patients who Cutaneous T-cell lymphomas (CTCL) are a heterogeneous underwent allogeneic HSCT using, most commonly, a RIC group of non-Hodgkin lymphomas; the majority of cases regimen for this rare lymphoid malignancy at our institu- are Mycosis fungoides (MF) and/or Sezary syndrome (SS); tion. The high response rate, durable remissions and direct the remainder include a variety of subtypes which vary GVL induction with DLI, all support a potent GVL-effect greatly in clinical behavior. All forms of CTCL are in patients with MF and SS from allogeneic HSCT. generally considered to be incurable. Although mycosis fungoides may have a relatively indolent course,1 once the Materials and methods

A retrospective review was performed using the University Correspondence: Dr VR Paralkar, Division of Hematology/Oncology, of Pennsylvania BM transplant database to identify all the University of Pennsylvania, 34th and Spruce Sts., 16 Penn Tower, patients who underwent allogeneic HSCT for cutaneous Philadelphia, PA 19104, USA. E-mail: [email protected] T cell lymphoma. In all, 12 patients were identified who Received 18 April 2011; revised 1 September 2011; accepted 2 September underwent transplantation between 2004–2010. A chart 2011; published online 24 October 2011 review was performed to obtain data about diagnosis, Allogeneic transplantation in cutaneous T cell lymphoma VR Paralkar et al 941 staging, treatment, transplantation and outcomes. This RIC with fludarabine (120 mg/m2 over 4 days) and BU study was reviewed and approved by the institutional (6.4 mg/kg over 2 days), or fludarabine (same dose) and CY review board at the University of Pennsylvania. (3 g/m2) was used in 10 cases. Conventional myeloablative conditioning with CY (120 mg/kg over 2 days) and TBI (1200 cGy fractionated) in six doses over 3 days was used in Patient selection two young patients with excellent performance status and Patients were referred for transplantation because of poor active disease prior to transplantation (see Table 1). GVHD prognosis or progression after conventional therapy. They prophylaxis consisted of a calcineurin inhibitor and MTX were generally heavily pretreated, having received a median in all patients. of eight non-chemotherapy and two chemotherapy-based treatment modalities before being transplanted. Treatments are listed in Table 1. Only three patients were in CR at the Statistics time of transplant, whereas one had minimal residual OS was measured as time from HSCT to death from any disease detectable by flow cytometry in the BM, four had cause. EFS was measured as time from HSCT to relapse, chemo-responsive active disease and four had progressive progression or death from any cause, whichever occurred active disease. first. Probabilities of OS and EFS, and survival curves, were generated using Kaplan–Meier estimates.16 Statistical analysis was performed using Statview. Transplantation Seven of the patients (Patient no. 1–no. 7) had HLA- identical sibling donors, whereas unrelated donors were Results identified for the rest. Of these, donors for four patients (Patient no. 8, Patient no. 10–no. 12) were well-matched by Patient characteristics high resolution molecular typing at HLA- A, B, C, DR and Patient characteristics, diagnosis and stage are shown in DQ, whereas patient no. 9 had a single Ag mismatch. Table 1. Patients were staged using the ISCL/EORTC TNM

Table 1 Patient characteristics (sorted chronologically according to date of transplant)

Patient Sex/age Time Dx to Diagnosis Prior treatment Prior treatment Highest stage Disease status Conditioning SCT (years) (non-chemotherapy) (chemotherapy) prior to prior to HSCT regimen HSCT

1 F/57 2.8 SS w/o B, C, EB, ECP, INF, Alemtuzumab IVA1 Active disease, Flu/Cy LCT Me, PUVA, S, Sar, progressive Tacrolimus, TSEB 2 M/52 1.1 MF w/o — CHOP, HyperCVAD IIB CR Flu/Bu LCT 3 M/41 1.6 GDTL B, Hydroxychloroquine, Denileukin Diftitox, T3b Active disease, Flu/Mel S, TSEB HyperCVAD, MTX chemo-responsive 4 F/43 0.8 MF w/o S, INF, TSEB — IIB MRD (marrow) Cy/TBI LCT 5 F/48 0.8 GDTL B, S Alemtuzumab, T3b Active disease, Cy/TBI Cytarabine, chemo-responsive CY, MTX 6 M/56 5.9 MF with B, C, EB, Imiquimod, Alemtuzumab, IVA2 Active disease, Flu/Bu LCT INF, M, S, TSEB, Denileukin progressive PUVA Diftitox, ICE, Zanolimumab 7 F/52 7.0 MF with C, INF, Me, S, CHOP IVB CR Flu/Bu LCT Tazarotene, TSEB, V 8 M/61 3.7 MF w/o B, C, INF, PUVA, S, Alemtuzumab IIIB CR Flu/Bu LCT Sar, Tretinoin, TSEB, UVB 9 F/44 3.9 GDTL B, EB, S, V CY, Denileukin T3b Active disease, Flu/Bu Diftitox progressive 10 M/61 0.5 SS with S, TSEB, UVB CHOP, HyperCVAD, IVA2 Active disease, Flu/Bu LCT Alemtuzumab progressive 11 F/61 6.8 SS w/o B, ECP, INF, M, Alemtuzumab IVA2 Active disease, Flu/Bu LCT PUVA, S, Sar, chemo-responsive TSEB, V 12 F/54 6.8 SS w/o B, ECP, Forodesine, INF, Alemtuzumab IVA2 Active disease, Flu/Bu LCT Pegﬁlgastrim, PUVA, chemo-responsive Romidepsin, S, Tretinoin

Abbreviations: B ¼ Bexarotene; C ¼ Carmustine (topical); EB ¼ localized electron beam radiotherapy; ECP ¼ extracorporeal photopheresis; GDTL ¼ gamma–delta T-cell lymphoma; ICE ¼ Ifosfamide, Carboplatin, Etoposide; IFN ¼ IFN-alpha/gamma; LCT ¼ large-cell transformation; Me ¼ Mechlorethamine (topical); MF ¼ mycosis fungoides; PUVA ¼ Psoralen + UV light A photochemotherapy; S ¼ steroids; Sar ¼ Sargramostim; SS ¼ Se´zary Syndrome; TSEB ¼ total skin electron beam radiation treatment; UVB ¼ UV light B phototherapy; V ¼ Vorinostat.

Bone Marrow Transplantation Allogeneic transplantation in cutaneous T cell lymphoma VR Paralkar et al 942 Table 2 Post transplant donor chimerism (for patients surviving to 100 days)

No. Day 100 6 months 1 year 2 years

1 15 NE (lost graft) NE (lost graft) NE (lost graft) 2 90 (BM) NE (died month 7) NE (died month 7) NE (died month 7) 3 100 100 100 100 4 93 (BM) 85 88 (BM) 100 6 100 (Day 60) NE (died month 5) NE (died month 5) NE (died month 5) 7 85 99 100 100 8 97 (BM) 98 94 NE (F/U not reached) 9 100 NE (died month 6) NE (died month 6) NE (died month 6) 11 97 97 95 NE (F/U not reached) 12 97 (BM) 97 100 NE (F/U not reached)

Abbreviation: NE ¼ not evaluable. Listed chimerism is whole blood chimerism unless mentioned otherwise.

12 patients transplanted 1.0

2 died within 100 days 8 achieved/ 0.8 maintained CR 2 did not at 100 days achieve CR 0.6

0.4 3 alive in 1 died in 4 1 alive with 1 died from continuous CR CR relapsed active progression

(GVHD) Event free survival disease 0.2

2 alive in CR after tapering 2 died from 0.0 immunosuppression/DLI progression. Could not 0 10 20 30 40 50 receive DLI Time (months) from transplant Figure 1 Flowchart showing patient outcomes. 1.0

0.8 staging system.17 There were ﬁve male and seven female patients with a median age of 49 years at diagnosis of CTCL 0.6 (range 40–61 years). Of the 12 patients, ﬁve had MF (stages IIB, IIB, IIIB, IVA2, IVB; two with nodal transformation), 0.4

four had SS (one stage IVA1, three IVA2; one with nodal Overall survival transformation) and three had Gamma-delta T-cell lympho- 0.2 ma (all T3b). Median time to transplantation from diagnosis was 3.3 years (range 0.5–7 years), with a median age of 53 0.0 years (range 41–61 years) at transplantation. 01020 30 40 50 The median follow-up is 15 months (range 1–45 months) Time (months) from transplant for all patients and 24 months (range 13–45 months) for patients who are currently alive. Figure 2 (a and b) Kaplan–Meier curves of patient outcomes. (a) EFS (relapse/progression/death). Median EFS was 5.3 months. Achievement of CR is underestimated by this curve, as two patients with relapse re-achieved and maintained CR after withdrawal of immunosuppression/ DLI. (b) OS. The 2-year estimated OS was 58% and estimated median Engraftment survival was 37 months. Neutrophil engraftment occurred with an ANC 4500 at a median of 13 days (range 10–34 days) after HSCT. At day 100 after HSCT in 10 evaluated patients, median whole Response and survival outcomes blood chimerism was 97%. Patient no. 1 was diagnosed The outcomes of all patients are shown in Figure 1. Two with CNS PTLD within 100 days of HSCT and lost her patients (one with RIC and the other with myeloablative graft after rapid tapering of immunosuppression. Patient conditioning) died within the ﬁrst 100 days from sepsis with no. 8 had decreasing donor chimerism 15 months after active disease. At day 100, 8 of 10 evaluated patients were in HSCT, and received DLI with subsequent achievement of CR; transplant had induced and maintained CR in six points 100% donor chimerism. Individual chimerism trends are with active disease. Three patients remained alive in described in Table 2. continuous CR 16, 22 and 45 months after transplant. Four

Bone Marrow Transplantation Table 3 Posttransplant outcomes

Patient Non-relapse/ Acute GVHD (grade, Chronic GVHD Disease status Relapse Treatment (s) Current status Time SCT to last non-GVHD toxicity organ and stage) at 100 days (Y/N) since relapse follow-up (months)

1 CNS PTLD (responded — — CR Y Denileukin Diftitox, Expired (progression) 37 to Rituximab), CMV Alemtuzumab antigenemia, pneumonitis 2 Widely metastatic melanomaa Grade II — CR Y — Expired (progression and 7 (gut stage 1) metastatic melanoma)a 3 Sinusitis, osteoporosis, Grade III Severe chronic GVHD of CR N — Alive, CR (continuous) 45 herniated disk, hearing loss, (gut stage 3) mouth, musculoskeletal steroid-induced glaucoma system and lungs (bronchiolitis obliterans) 4 Steroid-induced DM Grade II (skin — CR Y DLI with Alive, CR 39 stage 3, gut stage 1, re-achievement liver stage 0) of CR 5 Bacterial sepsis — — Expired Y — Expired (early TRM) 2 6 — Grade III (skin — Progression Y Tapering of immuno- Expired (progression) 5 stage 3, liver suppression stage 2) (not effective), nodal XRT, CY 7 — Grade I — Relapse Y Tapering of immuno- Alive, active disease 27 (skin stage 1) suppression, DLI (chemo-responsive) lymphoma cell Paralkar T VR cutaneous in transplantation Allogeneic (ineffective), Vorinostat, topical carmustine, TSEB, IFN gamma-1b, ICE al et 8 PICC-associated UE DVT, Grade III — CR N — Alive, CR (continuous) 22 hypothyroidism, Herpes (skin stage 3, zoster liver stage 0) 9 Cholecystitis, bacterial Grade IV — CR N — Expired in CR (GVHD) 6 sepsis (gut stage 4, liver stage 4—VOD) 10 Bacterial sepsis Grade I — Expired Y — Expired (early TRM) 1 (skin stage 2) 11 Hypothyroidism — — CR N — Alive, CR (continuous) 16 12 — Grade I — CR Y Tapering of immuno- Alive, CR 13 (skin stage 2) suppression with re-achievement of CR

oeMro Transplantation Marrow Bone Abbreviations: DVT ¼ deep venous thrombosis; ICE ¼ Ifosfamide, Carboplatin, Etoposide; PTLD ¼ post-transplant lymphoproliferative disease; VOD ¼ veno-occlusive disease. aPatient no. 2 had a remote history of localized, resected melanoma, which resurfaced as widely metastatic disease after HSCT. Death was due to rapid progression of both CTCL and melanoma. 943 Allogeneic transplantation in cutaneous T cell lymphoma VR Paralkar et al 944 patients relapsed after achieving CR between 4–13 months transplant, with 11 patients achieving sustained remissions, after HSCT, but two of them re-achieved and maintained CR, and several achieving stable disease after a combination one after tapering immunosuppression and the other after of DLI, immunosuppression withdrawal and/or chemo- receiving DLI (without additional chemotherapy). Thus, of therapy. Delioukina et al.15 also showed similarly encoura- the 10 patients who survived to 100 days, five are alive in CR ging results for RIC:SCT in 11 patients with CTCL, and at last contact and one is alive with active disease. observed no further relapses/deaths after the first 18 The median EFS for all points was 5.3 months (Figure 2a). months of HSCT. This underestimates achievement of CR, because two We report our experience using, most commonly, a RIC patients were able to relapse and maintain CR as mentioned regimen followed by allo-SCT in 12 consecutive patients above. Kaplan–Meier estimated that 2-year OS was 58%, with extensively pretreated advanced CTCL. Response and estimated median OS was 37 months (Figure 2b). rates were high. Treatment-related mortality was low. Two patients who did not respond died from infectious GVHD complications within 100 days of transplant. GVHD In all, 9 of 12 patients developed acute GVHD, with four accounted for death in one patient. The most common developing Grade III and IV GVHD. GVHD was the cause cause of death was disease progression in five patients. of death in one patient. Acute and chronic GVHD are In all, 42% of our patients were alive and disease-free detailed in Table 3. with median duration of 22 months after transplant. Although this percentage seems lower than that of other reports, it is difficult to compare patients across different GVL activity retrospective studies. Furthermore, our outcomes provide Patient no. 4 received DLI (2.2 Â 108 nucleated cells/kg) at strong and direct support for the presence of a GVL effect the time of relapse (after tapering off immunosuppression) in CTCL; one patient achieved CR after DLI alone for 13 months after HSCT, and achieved CR that is persistent relapse and a second achieved sustained remission after for 26 months after DLI. Patient no. 12 was on Tacrolimus withdrawal of immunosuppression. at the time of relapse, and achieved CR with discontinua- Despite the limitations associated with this retrospective tion of immunesuppression. The patient remains in CR 8 review of small numbers of patients, our outcomes support months later. This provides clear evidence for a GVL effect, the presence of a meaningful GVL effect associated with as none of these patients received any accompanying RIC allo-SCT. With small numbers of patients it was not chemo/systemic therapy that might explain achievement possible to associate the occurrence of GVHD. and maintenance of CR. Our experience shows that RIC HSCT can provide long- Of note, patient no. 7 received DLI (1.5 Â 108 nucleated term disease control in patients with advanced CTCL who cells/kg) 6 months after HSCT, with minimal effect on are otherwise refractory to immunotherapy and chemother- disease progression. Patient no. 8 received DLI (107 apy. Ideally, prospective studies will further define the role nucleated cells/kg) 15 months after HSCT for decreasing of allogeneic HSCT in this disease. However, given the donor chimerism (no evidence of relapse), with a subsequent limited TRM, consideration for earlier transplant should be achievement of 100% donor chimerism and continued CR. given, with a focus on the use of newer agents for achieving minimal residual disease prior to transplant. Interventions to decrease the risk of relapse should be considered, Discussion including the possibility of maintenance immunotherapy and/or planned DLI. Although CTCL is often an indolent lymphoma, with numerous effective treatment options, it is generally incurable, and most patients eventually fail chemotherapy Conflict of interest and biological therapies and will die of their disease.18 The prognosis is especially poor for patients with transformed Alain H Rook is on the Speaker’s bureau of Therakos, and CTCL and for patients who fail conventional therapy.19 is a consultant for HY Biopharma. Ellen J Kim has Newer treatments like denileukin diftitox,20 vorinostat3 and obtained research funding from TenX, Biocryst, Genmab, romidepsin7 have recently shown promising results. Glouchester, Celgene, and is a consultant for Eisai. Other High-dose therapy and autologous HSCT has been authors declare no conflict of interest. disappointing, and early relapses are common.11 The role of allogeneic HSCT in CTCL is unclear. A recent retro- Acknowledgements spective study from the EBMT included a heterogeneous group of patients who received both myeloablative and This work was supported in part by grants from The Leukemia & RIC regimens with estimated 3-year survival of 54%.21 Lymphoma Society (7000-02) and NIH (K24 CA11787901) (DLP). Three other small reports further support the role of allogeneic HSCT in CTCL. Molina et al.13 described eight patients with MF/SS who were treated with RIC:SCT and References six patients remained alive without disease 33–108 months 1 van Doorn R, Van Haselen CW, van Voorst Vader PC, Geerts 14 after transplant. Duvic et al. described outcomes in 19 M-L, Heule F, de Rie M et al. Mycosis fungoides: disease recipients of an intensive though RIC that included total evolution and prognosis of 309 Dutch patients. Arch Dermatol skin electron beam irradiation followed by allogeneic 2000; 136: 504–510.

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