Case report Matched unrelated allogeneic bone marrow ... - Nature

Bone Marrow Transplantation, (1998) 22, 603–604  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt

Case report Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP) T Hoffmann1, C Heilmann2, HO Madsen3, L Vindeløv1 and K Schmiegelow2 1

Hematologic Clinic II, The Finsen Center; 2Pediatric Clinic II, The Juliane Marie Center; and 3Department of Clinical Immunology, The Laboratory Centre, National University Hospital, Copenhagen, Denmark

Summary: A 14-year-old male and a maternally related cousin were diagnosed with X-linked lymphoproliferative disease (XLP) after developing recurrent B-NHL, characterized by long disease-free intervals and absence of an increased chemoresistance of the recurrent lymphomas. The demonstration of different clonal IgH gene rearrangements in two of the lymphomas from one of the patients further supports that the lymphomas were clonally unrelated. The cousin underwent matched related BMT, whereas the proband received a deliberately delayed MUD BMT in third CR. Both are in CR 68 months and 21 months, respectively, post-BMT. Delaying BMT probably contributes to reducing treatment-related morbidity. We suggest MUD BMT as a feasible curative strategy for XLP patients with B-NHL lacking matched related donors. Keywords: XLP; lymphoma; matched unrelated donor; bone marrow transplantation

XLP or Duncan’s syndrome is a heterogeneous immune deficiency syndrome presenting in childhood or adolescence with one or more of several clinical manifestations: malignant lymphoma, fulminant infectious mononucleosis, dysgammaglobulinaemia or aplastic anemia.1,2 The molecular basis for this X-linked immune deficiency is a mutation at the long arm of the X chromosome. In affected individuals, the immune response to primary Epstein–Barr virus (EBV) infection is reduced and, as a consequence, EBV surveillance in these patients is impaired, leading to an increased risk of severe or fatal EBV infection.2 The majority of patients die before the age of 20 years, and 75% of patients die before the age of 10 years.3 Most conservative treatment modalities have been unsuccessful, including chemotherapy, antiviral agents, high-dose intravenous immunoglobulins and interferon Correspondence: Dr T Hoffmann, Bone Marrow Transplantation Unit, Department of Hematology L 4042, Rigshospitalet-9-Blegdamsvej, DK2100 Copenhagen, Denmark Received 23 February 1998; accepted 7 May 1998

(alpha and gamma).4 Allogeneic bone marrow transplantation (BMT) is the only therapy available with a curative potential, although the reported transplantation-related mortality has been high.5–7 Recognition of a family with XLP is possible only when two maternally related males are diagnosed with one or more of the above mentioned manifestations. Following identification, screening of family members for carrier status by restriction fragment length polymorphism (RFLP) is possible and relevant.8 Since the majority of patients do not have a matched related bone marrow donor, an alternative is to use a matched unrelated donor (MUD), however, this may increase the risk of treatment-related mortality. We report the successful treatment of a 14-year-old boy (patient 1) with XLP in complete remission (CR) after his third B cell non-Hodgkin lymphoma (B-NHL) by BMT with a MUD. Following chemotherapy for an intestinal EBV genome negative B-NHL with bone marrow involvement an 11year-old male maternal cousin (patient 2) achieved CR. Four years later he again received chemotherapy for a localized second intestinal EBV genome negative B-NHL. CR was obtained and he had an uncomplicated BMT 4 months later with an HLA-identical maternal sibling donor (previously published5). At 5 years old, the proband (patient 1), an EBV sero-negative Caucasian boy with no previous history of immune deficiency, was diagnosed with a surface IgM lambda-positive localized intestinal B cell diffuse large cell lymphoma. The treatment consisted of 15 series of chemotherapy according to the NCI 7704 NHL (Burkitt type) protocol. CR was obtained without undue delay or complications. Four years later, the patient presented with a second intestinal B cell diffuse large cell lymphoma, again without other organ involvement. Therapy consisted of hemicolectomy and six series of chemotherapy according to the BFM90 protocol. The patient responded well, and a second CR was induced. Two and a half years later, a third localized intestinal B cell lymphoma was diagnosed, and chemotherapy according to the BFM90 protocol was repeated (four series). Again, CR was obtained without major complications. IgH gene rearrangement analysis of the tumors demonstrated a difference between the clonal gene rearrangement of the first tumor and that of the third tumor. Because of possible DNA contamination the ques-

MUD BMT for XLP T Hoffmann et al

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tion of clonal identity between the first tumor and the second tumor as well as between the second tumor and the third tumor is uncertain. No EBV genome was detected in any of the tumors by in situ hybridization.9 Although this patient probably had a good prognosis with respect to his third B-NHL, a MUD BMT was performed to cure the underlying immune deficiency and prevent further malignancies. The BMT was performed 7 months after cessation of chemotherapy. The conditioning regimen consisted of TBI (12 Gy), 4 Gy testis radiation, ATG, and 120 mg cyclophosphamide per kg body weight. The infused marrow was HES sedimentated due to ABO incompatibility. It contained 1.3 × 108 leukocytes per kg recipient body weight. Cyclosporine and MTX were given as GVHD prophylaxis. The initial transplantation course was without complications except for grade 1–2 GVHD (skin only), manageable with low-dose steroids. An absolute neutrophil count of 0.5 × 109/l was reached 30 days post transplant. Full donor engraftment was documented 93 days post transplant by the demonstration of 100% donor cells in a bone marrow aspirate. However, due to poor marrow function with persistent low platelet counts (⬍10 × 109/l), a supplementary T cell-depleted marrow infusion from the original donor was given on day 106 after transplantation. T cell depletion was performed with the Supermax system using CDXX antibody. The patient received 0.95 × 108 nucleated cells per kg, of which a total of 1.2 × 106 were CD34 positive. No T cell content was detectable by flow cytometry analysis. No preparatory therapy was given. The hematological parameters responded satisfactorily, and no GVHD was observed. Twenty-one months after BMT and 17 months after the second marrow infusion the patient is well and remains free of lymphoma. Discussion This is the first report of a successful BMT for XLP with a MUD. BMT has emerged as the treatment of choice for XLP. Treatment objective is not only to eradicate malignant lymphoma, but also to cure the underlying immune deficiency. The diagnosis of XLP in the reported cases is based on the occurrence of a total of five intestinal B-NHL in two maternally related cousins. The long interval between each recurrence of lymphoma (patient 1: 4 years and 2. years; patient 2: 4 years), suggested that they all were clonally separate tumors, as relapse more than 18 months from diagnosis is extremely rare in childhood BNHL.10 This was further substantiated by the demonstration of a difference between a clonal IgH gene rearrangement of the first and third tumor in patient 1. Finally, the chemosensitivity of the recurrent lymphomas indicated new malignancies. The favorable responses in all our three cases of recurrent B-NHL suggest that in members of a family with XLP, late recurrence of the disease should be regarded as a new lymphoma, with a sensitivity to chemotherapy that

may not differ from the primary B-NHL. Relapse of BNHL in childhood is generally associated with an extremely poor prognosis as a lasting remission is very difficult to obtain with second-line chemotherapy.10 The recognition of recurrent B-NHL as a manifestation of XLP and hence as new malignancies with no expected reduction in the probability of achieving lasting remissions allowed delaying transplantation for 7 months. This would normally be associated with a high risk of recurrence in a child with relapsed non-XLP B-NHL in second or third CR.10 In XLP-associated second B-NHL, however, the likelihood of achieving a stable CR justifies a longer interval between remission and transplant. We believe that postponing BMT for 7 months contributed to reducing the transplant-related morbidity. As patient 2 remains disease-free 5. years after transplantation, and since the disease course in the two patients is very similar, it seems likely that patient 1 is also cured, both with respect to the recurrent lymphoma and to XLP. We suggest MUD BMT as a feasible curative strategy for XLPpatients with B-NHL lacking matched related donors. References 1 Purtilo DT, Cassel CK, Yang JPS et al. X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet 1975; 1: 935–941. 2 Seemayer TA, Gross TG, Egeler RM et al. X-linked lymphoproliferative disease: twenty-five years after the discovery. Pediatr Res 1995; 38: 471–478. 3 Purtilo DT, Grierson HL, Davis JR, Okano M. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975–1990. Pediatr Pathol 1991; 11: 685–710. 4 Okano M, Pirruccello SJ, Grierson HL et al. Immunovirological studies of fatal infectious mononucleosis in a patient with X-linked lymphoproliferative syndrome treated with intravenous immunoglobulin and ␣-interferon. Clin Immunol Immunopathol 1990; 54: 410–418. 5 Gross TG, Filipovich AH, Conley ME et al. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant 1996; 17: 741–744. 6 Williams LL, Rooney CM, Conley ME et al. Correction of Duncan’s syndrome by allogeneic bone marrow transplantation. Lancet 1993; 2: 587–588. 7 Pracher E, Panzer-Gru¨mayer ER, Zoubeck A et al. Successful bone marrow transplantation in a boy with X-linked lymphoproliferative syndrome and acute severe infectious mononucleosis. Bone Marrow Transplant 1994; 13: 655–658. 8 Purtilo DT, Grierson HL. Methods of detection of new families with X-linked lymphoproliferative disease. Cancer Genet Cytogenet 1991; 51: 143–153. 9 D’Amore F, Johansen P, Houmand A et al. Epstein–Barr virus genome in non-Hodgkin’s lymphomas occurring in immunocompetent patients: highest prevalence in nonlymphoblastic Tcell lymphoma and correlation with a poor prognosis. Blood 1996; 87: 1045–1055. 10 Sandlund JT, Downing JR, Crist WM. Non-Hodgkin’s lymphoma in childhood. New Engl J Med 1996; 334: 1238–1248.