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GVL effect in plasmacytoid DC leukemia/lymphoma ARTICLE in BONE MARROW TRANSPLANTATION · OCTOBER 2009 Impact Factor: 3.57 · DOI: 10.1038/bmt.2009.270 · Source: PubMed
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Bone Marrow Transplantation (2010) 45, 961–962 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00
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LETTER TO THE EDITOR
GVL effect in plasmacytoid DC leukemia/lymphoma Bone Marrow Transplantation (2010) 45, 961–962; doi:10.1038/bmt.2009.270; published online 5 October 2009 According to the WHO–EORTC classification, plasmacytoid DC (pDC) leukemia/lymphoma represents a discrete entity with characteristic biological and clinical features.1–2 Despite high response rates with intensified induction therapy, relapse is frequent, allo-SCT increases the chance of long-term survival.3–4 A 57-year-old male presented with a 10-day history of pyrexia, malaise and multiple tender red–purple skin nodules over the head and trunk. He had mild painless hepatomegaly and pancytopenia. BM showed 85% agranular blasts with the following immunophenotype: DR þ þ , CD123 þ þ , CD4 þ , CD56 þ , CD45RA þ , NG2 þ , CD68 þ , BDCA-2 þ , BDCA-4 þ , CD7 þ , MPO, Tdt, CD19, CD10, CD64, cCD3. Biopsy of a skin lesion revealed infiltration of the deep dermis and skin appendices by immature cells with an identical immunophenotype. Cytogenetic analysis showed trisomy 21q22 and del13q14. The diagnosis of pDCL was made. Hyper-C-VAD chemotherapy regimen resulted in prompt hematologic,
immunophenotypic and cytogenetic CR. To consolidate the remission, he underwent reduced-intensity allo-SCT from his brother with fludarabine 150 mg/m2, BU 8 mg/kg and ATG 10 mg/kg. The blood cell graft had 2.4 106/kg CD34 þ cells. CYA and mycophenolate mofetil were administered as GVHD prophylaxis. Full donor-type chimerism was documented early after allo-SCT. Four months later he developed de novo extensive chronic GVHD which was refractory to immunosuppression. Twenty-six months post-allo-SCT, while on immunosuppression, he developed a cutaneous nodule on his back reminiscent of the lesions at presentation. Marrow showed 70% infiltration of blast cells. Skin biopsy showed infiltration with malignant cells (Figure 1). Immunosuppression was withdrawn and subcutaneous. IL-2 and IFN-a were administered on an alternate day scheme to evoke GVL effect. No response was seen. He then received two donor leukocyte infusions (DLI) consisting of 1 107/kg and 4.9 107/kg CD3 þ cells 20 days apart, in addition to the cytokines. One month later, he attained CR with full donor-type chimerism. IL-2 and IFN-a were continued for 4 months, the treatment was then discontinued because of lack of compliance.
Figure 1 Skin biopsy: Diffuse infiltration of monomorphous blastoid cells in the dermis, leaving the epidermis intact (H-E, magnification 200). Blast cells were positive for CD68 (a, magnification 200), vimentin (b, magnification 400), CD 56 (c, magnification 400), CD4 (d, magnification 400) and CD38 (e, magnification 400).
Letter to the Editor
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Furthermore, Hanabuchi et al.8 reported that the addition of IL-2 and IFN-a in human pDCs enhances NK cytotoxicity through the GITR (glucocorticoid-induced TNF receptor) ligand, which is preferentially expressed in activated pDCs. Finally, Naranjo-Gomez et al.9 showed that exogenous IL-2 increases the activation of human pDCs. We postulate that the addition of IL-2 and IFN-a to the DLIs resulted in a strong GVL effect in our case by enhancing T- and NK-alloreactivity, and activating pDC blasts and augmenting their Ag-presenting properties.
Conflict of interest The authors declare no conflict of interest.
Figure 2
Bone marrow aspirate: Diffuse infiltration of large, monocytoid, agranular blasts. The immunophenotype revealed the plasmacytoid dendritic cell origin.
A progressive reversion to mixed chimerism ensued and immunotherapy was reinitiated. Nevertheless, overt relapse with two skin lesions and marrow infiltration with 80% blasts (Figure 2) developed over the next few days. The patient did not respond to the increased doses of IL-2 and IFN-a. Two more DLIs were infused a month apart; 1 107/kg and 4.0 107/kg CD3 þ cells, respectively, and the skin lesions were irradiated. CR with full donor-type chimerism was attained once again, and has been maintained for more than 7 months now with repeated DLIs every 2 months and IL-2/IFN-a administration every alternate day. Reimer et al.4 reported that allo-SCT resulted in lower relapse rate compared with autotransplantation, but this benefit was offset by the high mortality rate of the allo-SCT procedure. A reduced-intensity allograft represents a safe and effective approach for patients not eligible for myeloablative conditioning, but its success is dependent upon GVL. Our patient attained CR lasting over 2 years after a reduced-intensity allo-SCT, but the heavy, prolonged immunosuppressive therapy probably predisposed to recurrence. However, the clinical course of the disease after relapse provides evidence for powerful donor T-cell alloreactivity against the malignant cells. A retrospective study of EBMT evaluated the outcome of DLIs for relapse management following allo-SCT. Blast counts o35% and the achievement of hematological CR before DLI administration emerged as favorable factors for response.5 Our patient relapsed twice after allo-SCT with high tumor burden and responded promptly to DLIs plus immunotherapy without receiving any previous chemotherapy. This may be related to the particular biological properties of malignant pDC cells, which make them more efficient Ag presenters compared with other leukemic cells. Chaperot et al.6,7 showed that pDC blasts have a spontaneous capacity to stimulate naive allogeneic T-lymphocytes, and induce a powerful T-cell proliferation upon IL-3 exposure.
Bone Marrow Transplantation
P Kaloyannidis1, A Zomas2, G Paterakis3, C Vadikoliou1, D Mallouri1, L Sakkas1 and I Sakellari1 1 Department of Hematology–BMT Unit, George Papanicolaou Hospital, Thessaloniki, Greece; 2 ‘Attikon’ University Hospital, Athens, Greece and 3 Department of Immunology, ‘G.Gennimatas’ Hospital, Athens, Greece E-mails:
[email protected] or
[email protected]
References 1 Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneus lymphomas. Blood 2005; 105: 3678–3685. 2 Garnache-Ottou F, Feuillard J, Saas P. Plasmacytoid dendritic cell leukaemia/lymphoma: towards a well defined entity? Br J Haematol 2007; 136: 539–548. 3 Feuillard J, Jacob MC, Valenci F, Maynadie` M, Gressin R, Chaperot L et al. Clinical and biologic features of CD4+ CD 56+ malignancies. Blood 2002; 99: 1556–1563. 4 Reimer P, Ru¨diger T, Kraemer D, Kunzmann V, Weissinger F, Zettl A et al. What is CD4+ CD56+ malignancy and how should it be treated? Bone Marrow Transplant 2003; 32: 637–646. 5 Schmid C, Labopin M, Nagler A, Bornha¨user M, Finke J, Fassas A et al. Donor lymphocyte Infusion in the treatment of first haematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukaemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 2007; 25: 4938–4945. 6 Ghaperot L, Bendriss N, Manches O, Gressin R, Maynadie M, Trimoreau F et al. Identification of a leukemic counterpart of the plasmacytoid dendritic cells. Blood 2001; 97: 3210–3217. 7 Chaperot L, Perrot I, Jacob MC, Blanchard D, Salaun V, Deneys V et al. Leukemic plasmacytoid dendritic cells share phenotypic and functional features with their normal counterparts. Eur J Immunol 2004; 34: 418–426. 8 Hanabuchi S, Watanabe N, Wang YH, Wang YH, Ito T, Shaw J et al. Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptorligand (GITRL). Blood 2006; 107: 3617–3623. 9 Naranjo-Go´mez M, Oliva H, Climent N, Ferna`ndez MA, RuizRiol M, Bofill M et al. Expression and function of IL-2 receptor in activated human plasmatoid dendritic cells. Eur J Immunol 2007; 37: 1764–1772.
