Consensus Recommendations for the Clinical Management of Hematological Malignancies in Patients with DNA Double Stranded Break Disorders

SIMPLE SUMMARY: Ataxia Telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are the most common DNA repair disorders (DNARDs), characterized by an exceedingly high risk for developing hematological malignancies and poor outcomes. Clinical management of lymphoproliferative diseases in AT and NBS is complicated due to the competing challenges of delivery of optimal cancer treatment and management of excessive toxicities. AT and NBS are rare genetic entities in the general population, thus gaining extensive experience in treatment of these patients is difficult. Additionally, no treatment guidelines for lymphoproliferative diseases have been specifically designed for this group of patients as yet. In this review we formulate clinical recommendations, considering the most critical aspects related to the management of lymphoproliferative disorders in AT and NBS and we concisely present the current state of knowledge about the biology and outcomes of leukemia and lymphoma in these DNARDs. ABSTRACT: Patients with double stranded DNA repair disorders (DNARDs) (Ataxia Telangiectasia (AT) and Nijmegen Breakage syndrome (NBS)) are at a very high risk for developing hematological malignancies in the first two decades of life. The most common neoplasms are T-cell lymphoblastic malignancies (T-cell ALL and T-cell LBL) and diffuse large B cell lymphoma (DLBCL). Treatment of these patients is challenging due to severe complications of the repair disorder itself (e.g., congenital defects, progressive movement disorders, immunological disturbances and progressive lung disease) and excessive toxicity resulting from chemotherapeutic treatment. Frequent complications during treatment for malignancies are deterioration of pre-existing lung disease, neurological complications, severe mucositis, life threating infections and feeding difficulties leading to significant malnutrition. These complications make modifications to commonly used treatment protocols necessary in almost all patients. Considering the rarity of DNARDs it is difficult for individual physicians to obtain sufficient experience in treating these vulnerable patients. Therefore, a team of experts assembled all available knowledge and translated this information into best available evidence-based treatment recommendations.