Bone Marrow Transplantation (2010) 45, 622–626 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00
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ORIGINAL ARTICLE
Successful SCT for Nijmegen breakage syndrome MH Albert1, AR Gennery2, J Greil3, CM Cale4, K Kalwak5, I Kondratenko6, W Mlynarski7, G Notheis1, M Fu¨hrer1, I Schmid1 and BH Belohradsky1 1
Departments of Pediatric Hematology/Oncology and Infection/Immunity, Dr von Haunersches Kinderspital der LMU, Munich, Germany; 2Institute of Cellular Medicine, Department of Pediatric Immunology, University of Newcastle upon, Tyne, UK; 3 Department of Pediatric Hematology and Oncology, University Hospital, Heidelberg, Germany; 4Department of Immunology, Great Ormond Street Hospital, London, UK; 5Department of Pediatric Hematology/Oncology/BMT, Wroclaw, Poland; 6 Department of Immunology, Russian Children’s Clinical Hospital, Moscow, Russia and 7Department of Pediatrics, Oncology, Hematology & Diabetology, Medical University of Lodz, Lodz, Poland
Nijmegen breakage syndrome (NBS) is characterized by chromosomal instability, radiation hypersensitivity, characteristic facial appearance, immunodeficiency and strong predisposition to lymphoid malignancy. Traditionally, NBS patients have not undergone hematopoietic SCT (HSCT) owing to concerns about increased toxicity. We therefore report on the HSCT experience in NBS patients in Europe. Six patients were transplanted either for resistant or secondary malignancy (four patients) or severe immunodeficiency (two patients). Five patients received reducedintensity conditioning regimens. After a median follow-up of 2.2 years, five patients are alive and well. One patient who received myeloablative conditioning died from sepsis before engraftment. Acute GVHD grades I–II occurred in three of five patients, mild chronic GVHD in one. All five surviving patients exhibit restored T-cell immunity. The experience in these six patients suggests that HSCT in NBS is feasible, can correct the immunodeficiency and effectively treat malignancy. Acute toxicity seems to be reasonable with reduced-intensity conditioning regimens. Bone Marrow Transplantation (2010) 45, 622–626; doi:10.1038/bmt.2009.207; published online 17 August 2009 Keywords: NBS; SCT; chromosomal breakage; reducedintensity conditioning
Introduction Nijmegen breakage syndrome (NBS) was first described in patients living in the city of Nijmegen in the Netherlands.1 Patients with this autosomal-recessive primary immunodeficiency display characteristic clinical features, including microcephaly, growth retardation, bird-like facial features, humoral and cellular immune deficiency and a strong predisposition to develop lymphoid malignancies.2,3 NBS
belongs to the group of disorders with defective DNA repair leading to increased chromosomal breakage, such as Fanconi anemia (FA) or ataxia teleangiectasia. These disorders overlap in their clinical presentation but are genetically heterogeneous. The responsible gene, NBS1, encodes for the protein Nibrin, which is a part of the double-strand DNA break repair machine, and was first cloned on chromosome 8q21 in 1998.4,5 In an international survey of NBS, 22 of 55 patients developed malignant disease, predominantly of lymphoid origin (19 of 22), before the age of 22 years.2 The long-term outcome in NBS patients with malignancies is poor.2,6,7 Theoretically, replacement of defective hematopoietic stem cells in NBS by allogeneic hematopoietic SCT (HSCT) should be able to correct the immunodeficiency and the predisposition to malignancies of hematopoietic origin. Previously, HSCT has not been recommended in these patients, mainly because of concerns about toxicity of the conditioning regimens with DNA-damaging substances or irradiation. In this study, we summarized the HSCT experience in individual patients with NBS in Europe and analyzed their outcome.
Patients and methods The patients analyzed retrospectively in this study were identified by carrying out a Medline search using the terms ‘Nijmegen breakage syndrome’ and ‘transplantation’ and by scanning abstracts presented at the meetings of the European Group for Blood and Marrow Transplantation, the European Society for Immunodeficiencies and the German Paediatric SCT working party (PAED-AG KBT) from 2000 onwards. Data were reported by the treating physicians based on an anonymized questionnaire and after informed consent according to institutional guidelines.
Results Correspondence: Dr MH Albert, Department of Pediatric Hematology/ Oncology, Dr von Haunersches Kinderspital der LMU, Lindwurmstr. 4, 80337 Munich, Germany. E-mail:
[email protected] Received 11 May 2009; revised 24 June 2009; accepted 12 July 2009; published online 17 August 2009
Patient characteristics In this retrospective review, six patients (five male, one female) with NBS, who had undergone allogeneic HSCT, could be identified.
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Two have been previously reported.8–10 The ethnic origin of the patients was Eastern Europe (n ¼ 2), Pakistan (n ¼ 2) and Germany (n ¼ 2). The common founder mutation g.657_671delACAAA was present homozygously in all patients from Europe, whereas the Pakistani children harbored a homozygous g.C1089A mutation in NBS1. All displayed characteristic clinical features of NBS, most notably microcephaly and the typical facial appearance found in six of six and five of six patients, respectively. Immunodeficiency was characterized by reduced absolute T-cell numbers and T-cell proliferative response in all individuals tested. Humoral immunity was impaired in five of six patients. Four of the patients developed lymphoid malignancy at a median age of 12 years (range 5–19). One patient experienced a second, different lymphoid malignancy 8 years after chemotherapy for his first malignancy. Secondary malignancies are a common finding in NBS.11 All patient characteristics are detailed in Table 1. The patients reported here represent a typical group of NBS patients with the expected high incidence of lymphoid malignancy.
Transplantation The transplantation characteristics of these patients were analyzed (Table 2). Median age at transplantation was 14.5
Table 1
years (range 2.3–20.3). Two patients were transplanted for immunodeficiency. One of them was presumed to have FA at the time of transplantation.10 These two patients were transplanted at a younger age than the other patients who were transplanted for refractory, recurring or secondary malignancy. A wide range of different donors, conditioning regimens, GVHD prophylaxis and stem cell sources were used. It can be noted that five of the six patients received a reduced-intensity conditioning (RIC) regimen12 based on either fludarabine (four of five) or low-dose thoracoabdominal irradiation (one of five), combined with T-cell depleting antibodies. The remaining patient had a fully myeloablative, BU-based conditioning regimen. GVHD prophylaxis was CYA-based, with the exception of one patient who received a T-cell-depleted graft from a haploidentical parental donor.
Outcome At a median of 2.4 years (1.7–8.1) of follow-up, five of six patients are alive and well. Acute transplant-related toxicity differed widely but was manageable in the RIC recipients. Mucositis was not observed in three of five patients after RIC. Three patients had infectious complications. One patient who had received myeloablative conditioning died from bacterial sepsis before engraftment. GVHD was minor with acute GVHD
Patient characteristics
UPN Ethnic origin
Sex NBS1 mutationa
Age at Clinical Dx features (years)
1
Pakistan F
g.C1089A
1
2
Pakistan M
g.C1089A
5
3
Germany M
g.657_671 delACAAA
10
4
Russia
M
g.657_671 delACAAA
14
5
Poland
M
g.657_671 delACAAA
5
6
Germany M
g.657_671 delACAAA
18
Microcephaly, facial features, growth retardation Microcephaly, pigmented skin lesions Microcephaly, facial features
Immunodeficiency Humoral T-cell T-cell numbers proliferative immunity response
Age at Pre-transplant Reference Dx of morbidity malignancy (years)
Reduced Reduced
Reduced No
NA
RSV pneumonitis
Gennery et al.8 and Gennery et al.9
Reduced Reduced
Normal No
NA
—
New et al.10
Reduced ND
Reduced T-ALL, late responder
14
Reduced T-ALL, relapse
10
Reduced B-NHL
5
Reduced Reduced Microcephaly, facial features, growth retardation, mild mental retardation Microcephaly, Reduced ND facial features
Microcephaly, facial features, mild mental retardation
Malignancy
Reduced Reduced
T-ALLb Reduced HD, refractory disease
13b 19
Pansinusitis, bronchiectasis, decreased pulmonary function —
Renal insufficiency after MTX Decreased pulmonary function
Abbreviations: B-NHL ¼ B-cell non-Hodgkin’s lymphoma; Dx ¼ diagnosis; F ¼ female; HD ¼ Hodgkin’s disease; M ¼ male; NA ¼ not applicable; ND ¼ not done; RSV ¼ respiratory syncytial virus; UPN ¼ unique patient no.; T-ALL ¼ T-cell ALL; — ¼ none. a All patients were homozygous for their respective mutation. b The T-ALL was a secondary malignancy after successful treatment for B-NHL.
Bone Marrow Transplantation
SCT in NBS MH Albert et al
624 Transplant characteristics and conditioning
Table 2 UPN
Reason for Tx
Age at Tx (years)
Donor
HLA match
1
Immunodeficiency
2.3
MSD
12/12
2
Immunodeficiency
3.6
MFD
10/10
3
Malignancy
14.5
MMFD
4
Malignancy
16.0
MSD
12/12
5
Malignancy
14.5
MUD
9/10
6
Malignancy
20.3
MUD
9/10
4/8
Conditioning
Stem cell source
GVHD prophylaxis
Fludarabine 30 mg/m2 5 d CY 5 mg/kg 4 d Campath 0.2 mg/kg 5 d Thoracoabdominal irradiation 5 Gy 1 d CY 5 mg/kg 4 d Campath 0.2 mg/kg 5 d Fludarabine 40 mg/m2 4 d Thiotepa 10 mg/kg 1 d Melphalan 70 mg/m2 2 d OKT3 0.1 mg/kg 21 d BU 5 mg/kg p.o. 2 d CY 60 mg/kg 2 d Thiotepa 750 mg/m2 1 d BU 1 mg/kg p.o. 2 d Fludarabine 30 mg/m2 5 d ATG 20 mg/kg 3 d OKT3 0.1 mg/kg 20 d Fludarabine 25 mg/m2 5 d Melphalan 140 mg/m2 1 d ATG 20 mg/kg 3 d
BM
CsA
BM
CsA, MTX
PB
T-cell depletion, MMF
PB
CsA, MTX
PB
CsA
PB
CsA, MTX
Abbreviations: ATG ¼ rabbit anti thymocyte globulin; MFD ¼ matched family donor; MMF ¼ mycophenolate mofetil; MMFD ¼ mismatched family donor; MSD ¼ matched sibling donor; MUD ¼ matched unrelated donor; OKT3 ¼ muromonab; PB ¼ peripheral blood; p.o. ¼ per os; Tx ¼ transplantation.
Table 3
Transplant outcome
UPN Status Follow-up Toxicity after Tx (years)
Infections
1
A&W
4.7
—
—
2
A&W
8.1
3
A&W
4
aGVHD cGVHD Donor chimerism (overall grade)
—
—
Mucositis ADV CMV
—
—
2.0
Mucositis Sepsis ADV ITP cryptosporidiosis
—
—
DD
NA
NA
NA
5
A&W
2.4
Mucositis Fatal sepsis (d+5 after TX) — —
II
6
A&W
1.7
—
Mild (skin) —
—
I
Immune status T-cell T-cell Humoral numbers proliferative immunity response
Normal Normal 5% CD15 70% CD19 100% CD3 Normal Normal 80% mononuclear cells 10% neutrophils Complete Normal Normal
NA
Normal
Post-transplant morbidity/ development
Normal
Thyroidectomy for hyperthyroidism —
Reduced (postrituximab) NA
Pulmonary function normalized NA
NA
NA
Complete
Normal Normal
Normal
—
Complete
Normal Normal
Normal
Pulmonary function normalized
Abbreviations: ADV ¼ adenovirus; A&W ¼ alive and well; aGVHD ¼ acute GVHD; cGVHD ¼ chronic GVHD; DD ¼ died; ITP ¼ idiopathic thrombocytopenic purpura; NA ¼ not applicable; Tx ¼ transplantation.
grades I–II in two of five and mild chronic GVHD in one of five patients. All evaluable patients were either complete donor chimeras (three of five) or were predominantly of donor origin within the lymphocyte compartment (two of five). The underlying immunodeficiency was corrected in the five surviving patients with disappearance of frequent pulmonary infections and T-cell numbers restored back to normal levels. T-cell proliferation was normal in all five patients. One patient remains on i.v. Ig replacement after rituximab treatment for immune-mediated thrombocytoBone Marrow Transplantation
penia, the others have normal Ig levels and Ab responses to vaccine Ags (Table 3). Taken together, these data suggest that SCT in NBS is feasible without excessive toxicity and can correct the underlying immunodeficiency.
Discussion Primary immunodeficiency diseases and BM failure syndromes characterized by increased chromosomal instability
SCT in NBS MH Albert et al
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or radiosensitivity pose a significant therapeutic challenge. Not only do these disorders harbor a greatly increased risk for the development of malignancy, but also affected patients are more sensitive to chemotherapy and radiationinduced side effects. Early attempts to cure FA by allogeneic HSCT using standard myeloablative conditioning regimens showed extensive regimen-associated morbidity and mortality.13 Development of specialized conditioning regimens using very low dose CY, radiation and the introduction of fludarabine have helped to establish HSCT from an HLA-matched sibling as a standard treatment for BM failure in FA.14–16 In contrast, HSCT has traditionally not been attempted in NBS because of concerns about excessive chemo- or radiotherapy-induced toxicity. This is a valid concern as DNA-damaging antineoplastic chemotherapy or ionizing radiation can have pronounced acute and long-term toxicity in these DNA-repair disorders. In addition, transplant-related toxicity such as GVHD and the secondary immunodeficiency that accompanies it could further increase the risk for secondary malignancy. This is illustrated by the fact that in FA HSCT accelerates the occurrence of epithelial tumors, such as squamous cell carcinoma.17 This may also hold true for other DNA-repair disorders such as NBS, although, in contrast to FA, the vast majority of malignancies in NBS are of hematopoietic origin, which makes an increased risk for other solid tumors less likely. To date, no secondary malignancy has been observed in the transplanted NBS patients studied here, but careful long-term follow-up of these patients will be needed to recognize such sequelae. Recent reports have indicated that lymphoid malignancies occurring in NBS patients can be successfully brought into remission with standard chemotherapy regimens with minor dose modifications.6,7,18,19 However, a high rate of treatment failures and secondary lymphoid malignancies has been observed. In a study by Dembowska-Baginska et al.6 2 of 17 NBS patients with lymphoma experienced a different secondary lymphoid malignancy and 9 of 17 died from their malignant disease. In our study, all four patients with malignant diseases had either resistant, relapsing or secondary malignant disease. Thus, HSCT will often present as a last treatment option in NBS patients in whom standard chemotherapy regimens have failed. Longterm follow-up will need to show whether the risk of lymphoid malignancy in these patients is abolished after HSCT, but it is encouraging that HSCT might offer a viable treatment option. Furthermore, we show that the cellular and humoral immunodeficiency in NBS can be corrected by HSCT. Before real long-term safety data are available, this procedure should not be recommended as a standard treatment approach for NBS patients in whom the immunodeficiency can be controlled with conservative measures, but should be considered in select cases with malignancy or severe immunodeficiency where an HLAidentical donor is available. This report summarizes the experience of allogeneic HSCT in six NBS patients. It shows the feasibility of the procedure in these patients and that RIC can reduce regimen-related toxicity. These data should be used to
design prospective studies using standardized transplant regimens and evaluating the long-term outcome of HSCT in NBS.
Conflict of interest The authors declare no conflict of interest.
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