Should allogeneic hematopoietic stem cell transplantation be a treatment option for patients with Nijmegen breakage syndrome? Belarusian experience

Abstract

Introduction: Nijmegen breakage syndrome (NBS) is characterized by chromosome instability, combined immunodeficiency, radiosensitivity and high predisposition to lymphoid malignancy. A specific therapy is not available, however, hematopoietic stem cell transplantation (HSCT) is considered for NBS patients with refractory or recurrent leukemia or lymphoma. Purpose: We aimed to present Belarusian data in NBS diagnosis and management and to discuss indications for allo-HSCT treatment. Patients and Methods: A total of 238 patients were registered with primary immune deficiency (PID), including 19 cases of NBS. DNA was analyzed for mutation in NBN gene by direct sequencing of exon 6. Histological classification of lymphoid neoplasms was performed according to World Health Organization classification (2008). The patients were treated according to modified pediatric regimens or individually. Results: NBS accounted for 8.0% of all PID cases and was diagnosed at the age from 0.3 to 21.6 years (median 7.1). Mutation 657-661delACAAA in NBN gene and combined immunodeficiency of various degrees was confirmed in all patients. Lymphoid malignancy developed in 9 (47.4%) NBS patients ageing from 4.3 to 21.6 years (median 10.7). Acute leukemia was diagnosed in 4 patients, and stage III non-Hodgkin’s lymphoma in 5. Lymphoma/leukemia were in 7 out of 9 cases of T-cell origin. Complete remission (CR) was achieved in 66.7% of the patients.. Events were: death from infections in induction or in CR1 in 3 patients, progression/relapse in 3, second lymphoma in 1. Totally 7 NBS patients died, all after the development of malignancies. Two patients with T-mature lymphoma/leukemia did not respond to induction chemotherapy, were treated with unrelated HSCT in the 1CT and alive disease free within 6 and 13 months after transplantation. HSCT from a sibling donor was performed 9.8 years ago in a boy without malignancy but with infectious and autoimmune complications. They all received reduced-intensity conditioning regimens, which were well tolerated. Conclusions: NBS needs to be diagnosed early. With respect to progressive immunodeficiency and high risk of lymphoid malignancies with uncertain curative prospective, an allo-HSCT approach with reduced-intensity conditioning could be proposed as a treatment option for NBS patients with severe defects of immune function, and for all NBS patients with lymphoid malignancy in 1st complete remission.