Case report Discrepancy between serological complete ... - Nature

3 downloads 110 Views 33KB Size Report
new bone lytic lesions after infusion of escalating low doses of donor lymphocytes in ... tumor alloimmune effect may also be obtained in other hematologic and ...
Bone Marrow Transplantation, (1999) 24, 685–687  1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt

Case report Discrepancy between serological complete remission and concomitant new bone lytic lesions after infusion of escalating low doses of donor lymphocytes in multiple myeloma: a case report D Rondelli, G Bandini, M Cavo, F Re, MR Motta, B Senese, G Leopardi, M Stanzani and S Tura Institute of Hematology and Medical Oncology ‘Sera`gnoli’, University of Bologna, Italy

Summary: A graft-versus-myeloma effect has been previously induced by infusing high numbers of donor lymphocytes after allogeneic stem cell transplantation in relapsed/refractory multiple myeloma (MM) patients. A 43-year-old patient with MM refractory to standard chemotherapy and autologous transplantation received an allogeneic HLA-matched T cell-depleted marrow transplant from his sister after conditioning with single dose total-body irradiation, melphalan and cyclophosphamide. Twenty-four months after transplant neither a significant reduction of serum M protein nor evidence of acute or chronic graft-versus-host disease (GVHD) were observed. The patient was then treated with four escalating low doses of donor lymphocyte infusions (DLI) (0.1, 1.0, 5.0 and 5.0 × 106 CD3+ T cells/kg, respectively) over a 13 month period. Following the second infusion a mild liver acute GVHD and a partial, but transient, response occurred. After the last DLI the patient achieved a complete remission and developed extensive chronic GVHD. However, concomitant with the disappearance of clonal plasma cells from the marrow and of serum M protein, two new bone lytic lesions appeared requiring treatment with radiotherapy. In conclusion, escalating low doses of DLI may be effective in MM and may prevent severe acute but not chronic GVHD. However, the efficacy of DLI in extramedullary MM lesions is still unclear. Keywords: MM; BMT; GVM; DLI

Allogeneic bone marrow transplantation may cure many hematologic malignancies, but is often complicated by severe, and even lethal adverse immunological effects such as acute graft-versus-host disease (GVHD). In particular, initial studies of allogeneic stem cell transplant in multiple myeloma showed high morbidity and mortality,1 although molecular disappearance of the disease was also obtained Correspondence: Dr D Rondelli, Institute of Hematology and Medical Oncology ‘Sera`gnoli’, University of Bologna, Policl S Orsola, via Massarenti, 9–40138 Bologna, Italy Received 18 March 1999; accepted 19 April 1999

in a limited number of cases.2 However, better selection of patients as well as the use of different conditioning regimens are likely to contribute to reduced transplant-related mortality in more recent reports.3 Nonetheless, because of frequent relapses after allotransplant, induction of a graftversus-myeloma effect may be attempted by donor lymphocyte infusion (DLI). DLI, in fact, has been demonstrated to represent the most effective salvage therapy for chronic myeloid leukemia (CML) patients relapsed in chronic phase after allogeneic BMT,4 and it is conceivable that an antitumor alloimmune effect may also be obtained in other hematologic and non-hematologic disorders. At this time more data are needed to establish the role and the doses of DLI in multiple myeloma, which has been successful in a recent series of patients receiving high numbers of donor lymphocytes.5 Case report A 43-year-old man (UPN 207) underwent an allogeneic BMT in September 1994. He had been diagnosed with IgG/k multiple myeloma, stage IIIA in October 1993 and after seven cycles of the CMVP chemotherapy regimen (including vincistine, cyclophosphamide, BCNU, melphalan, doxorubicin and prednisone), radiotherapy on T6– T7 and intermediate-dose intensive chemotherapy with autologous rescue the disease was unresponsive. Pre-transplant monoclonal IgG was 3.116 g/dl, there were 12 lytic bone lesions and the plasma cell infiltration of bone marrow was 40%. He received marrow from his fully HLA-identical sister after preparation with 10 Gy single dose TBI, 120 mg/kg cyclophosphamide, and 100 mg/m2 melphalan. GVHD prophylaxis consisted of T cell depletion with the Campath 1-G monoclonal antibody. The number of T lymphocytes infused was 0.5 × 106/kg. The post-transplant course was totally uneventful with complete engraftment achieved on day 33 and without any sign of acute or chronic graft-versus-host disease (GVHD). However, the serum M protein evaluated 6, 12 and 24 months after transplantation was stable over 2.0 g/dl, the plasma cell bone marrow infiltration was 10% and no further bone lytic lesions were documented by radiological investigation. Chimerism analysis evaluated by karyotypic examination of marrow cells 24 months after transplant showed 50%

Partial effect of DLI in MM D Rondelli et al

Serum M comp (mg/dl)

686 3500

UPN 207: Effect of DLI after BMT in MM

DLI 3000 DLI 1 X 105 1 X 106 2500

DLI 5 X 106

DLI 5 X 106 RXT

2000

RXT

1500 1000 50% donor 100% donor bone lesion bone lesion cGVHD (skin++, oral++, liver+) 500 cGVHD (liver+/-) 0 Pre- 1 2 3 4 6 9 10 11 12 13 14 15 15,5 16 17 18 19

Months Figure 1 Modification of serum M protein after escalating doses of DLI. Correlation between levels of serum M protein and time and doses of DLI infusions, cytogenetic evaluation of chimerism, cGVHD development and observation of new lytic bone lesions, as well as radiotherapy treatment (RXT), is indicated.

donor female cells. The patient was then treated with escalating doses of DLI starting from 105 CD3+ T cells/kg 25 months after BMT, which neither induced aGVHD nor affected the serum M protein, followed 1 month later by 106 CD3+ T cells/kg which induced a mild liver aGVHD not requiring immunosuppressive therapy and resulted in a ⬎50% rapid decrease of the M component. At this time full donor chimerism in the marrow and a four-fold increase of circulating CD8+ T cells with NK phenotype (CD57+) were detected. The post-DLI course is shown in Figure 1. Nine months later, when a significant new increase of serum M protein occurred, 5 × 106 CD3+ T cells/kg were infused obtaining again a slight reduction of the serum protein. Three months later the same T cell dose was infused but at the same time a new bone lytic lesion appeared. Two months later, while the M component was progressively disappearing another bone lesion was documented. Concomitantly, signs of chronic GVHD involving the eyes, the mouth and the liver were observed and progressed to extensive scleroderma-like skin involvement, heart and pleural effusion requiring hospitalization and multiple treatment. Now, 12 months after the last DLI, the lytic lesions have been treated with radiotherapy, no monoclonal plasma cells are present in bone marrow biopsy and serum M component is undetectable by immunofixation analysis. The patient has a Karnofsky score of 70% and is receiving azathioprine and steroid treatment for cGVHD. Discussion The role of an anti-tumor immune effect by DLI in disorders other than CML is still a matter for discussion considering the high risk of severe complications such as GVHD or marrow aplasia reported in different series of transplanted patients affected by hematological neoplasia including MM. In fact, in this latter disease it has not yet been shown what might be the best dose of allogeneic lymphocytes to be infused in order to obtain a graft-versusmyeloma effect with no or limited GVHD.6–8 It has recently been reported5 that eight out of 13 MM patients obtained a clinical response after DLI, where four patients who received doses ⬎1 × 108 T cells/kg and four doses ⭐1 × 108 T cells/kg achieved a complete or a partial

remission. In six cases, there was acute GVHD grade II– III, with two deaths due to concomitant marrow aplasia, and six patients developed chronic GVHD. The clinical efficacy of DLI was mostly associated with concomitant acute and/or chronic GVHD although the majority of responding patients were shown to be ‘fully donor’ by analysis of chimerism before DLI. In the case that we report here escalating doses of DLI allowed us to obtain the complete disappearance of the serum M component by infusing four doses of donor T cells ⭐0.5 × 107/kg, with a total of 1.11 × 107 T cells/kg infused over a 13-month period. Since the potential immunogenicity of malignant mature B cells is likely to be due to minor histocompatibility antigens of the host and to the presence of the idiotype as a tumor-specific, and even a patient-specific antigen potentially triggering T cells,9 it is conceivable that these latter cells are important anti-MM effectors. Therefore, the small immune effect against MM cells after T cell-depleted allogeneic transplant could be overcome by several small doses of DLI. The appearance of a progressive cGVHD and GVM suggests that escalating doses of DLI may be very effective in MM and may prevent severe acute GVHD, but they do not prevent extensive cGVHD development. Another issue concerns the development of new bone lytic lesions while observing a dramatic reduction of the serum M component. Although a biopsy of new lesions was not performed, it is conceivable that they might be related to a progression of the disease since they were successfully treated with radiotherapy and neither the occurrence of a systemic relapse nor signs of another cancer have been observed 1 year after treatment. Therefore, it can be hypothesized that circulating allo-T cells may not reach or may not bind to plasma cells in the bone efficiently, or that bone microenviroment may secrete cytokines, such as TGF-␤, suppressing T cell function.10 Finally, it is not known whether small doses of DLI allow a sufficiently high frequency of cytotoxic T cells to exert an anti-tumor effect in extramedullary lesions.

Acknowledgements This work was supported by MURST, project 60%.

References 1 Tura S, Cavo M, Baccarani M et al. Bone marrow transplantation in multiple myeloma. Scand J Haematol 1986; 36: 176–179. 2 Bird JM, Russel NH, Samson D. Minimal residual disease after bone marrow transplantation for multiple myeloma: evidence for cure in long-term survivors. Bone Marrow Transplant 1993; 12: 651–654. 3 Cavo M, Bandini G, Benni M et al. High-dose busulfan and cyclophosphamide are an effective conditioning regimen for allogeneic bone marrow transplantation in chemosensitive multiple myeloma. Bone Marrow Transplant 1998; 22: 27–32. 4 Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.

Partial effect of DLI in MM D Rondelli et al

5 Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997; 90: 4206–4211. 6 Verdonck LF, Lokhorst HM, Dekker AW et al. Graft-versusmyeloma effect in two cases. Lancet 1996; 347: 800–801. 7 Tricot G, Vesole DH, Jagannath S et al. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.

8 Metha J, Singhal S. Graft-versus-myeloma. Bone Marrow Transplant 1998; 22: 835–843. 9 Kwak LW, Taub DD, Duffey PL et al. Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor. Lancet 1995; 345: 1016–1020. 10 Bright JJ, Sriram S. TGF-beta inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes. J Immunol 1998; 161: 1772–1777.

687