Outcome of patients with Fanconi anemia developing myelodysplasia and acute leukemia who received allogeneic hematopoietic stem cell transplantation: A retrospective analysis on behalf of EBMT group

Abstract

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo‐HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre‐HSCT cytoreductive therapies and related toxicities, disease status pre‐HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5‐year OS and EFS were 42% (30‐53%) and 39% (27‐51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48‐95] vs 37% [24‐50],P = .04), while none of the other variables considered had an impact. Twenty‐two patients received pre‐HSCT cytoreduction and 9/22 showed a grade 3‐4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre‐HSCT 48% [20‐75%] vs no‐toxicity 51% [25‐78%],P = .98). The cumulative incidence of day‐100 grade II‐IV a‐GvHD and of 5‐year c‐GvHD were 38% (26‐50%) and 40% (28‐52%). Non‐relapse‐related mortality and incidence of relapse at 5‐years were 40% (29‐52%) and 21% (11‐30%) respectively, without any significant impact of the tested variables. Causes of death were transplant‐related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre‐HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre‐HSCT should be considered if a donor have been secured.

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

“…Successful hema to poi etic stem cell trans plant (HSCT) can cure bone mar row fail ure (BMF) and pre vent leu ke mic trans for ma tion; how ever, trans plant out come is poor in patients who have already devel oped malig nant clones before HSCT. 2,3 Besides, HSCT comes with a price of poten tial end organ dam age and accel er ated solid tumor i gen e sis. Therefore, the major goal of sur veil lance is to detect early signs of malig nant trans for ma tion and deter mine the ideal tim ing for trans plant.…”

Genetic screening of children with marrow failure. The role of primary Immunodeficiencies

“…tailored conditioning regimen when Stem Cell Transplantation (SCT) is indicated. [4][5][6][7] Constitutional marrow failure syndromes (CMFs), such as Fanconi Anemia (FA) and telomere diseases (TD), are genetic disorders in which MF is associated with specific clinical issues related to the underlying impaired molecular and biochemical pathways, such as DNArepair and telomere length maintenance, respectively. 8,9 However, the clinical phenotype of both disorders can be atypical and, in some cases, patients may present only with marrow failure (MF) without other signs or symptoms, thus mimicking the diagnosis of acquired idiopathic aplastic anemia.…”

Bone marrow transplant using fludarabine‐based reduced intensity conditioning regimen with in vivo T cell depletion in patients with Fanconi anemia

“…Sibling #1 did not have any myelodysplasia or clonal evolution in his pre‐transplant bone marrow; however, his platelet requirements had increased in preceding 3–4 months pre‐transplant; thus, due to concern of developing clonal abnormality and graft stability with unrelated graft, busulfan was added to his preparative regimen. Both siblings are doing well and were transplanted prior to developing dysplastic or leukemic bone marrow changes, suggesting a potential role for early transplant to improve overall survival 20 …”