Population studies have shown that patients with sickle cell disease (SCD) who have undergone an unsuccessful allogeneic hematopoietic cell transplantation (alloHCT) have an increased incidence of leukemia, but the underlying etiology of this association is unknown. In a small study recently published in Blood, investigators report that high-risk TP53 clonal mutations present before alloHCT expand after transplant and contribute to this risk.
“Our study suggests that patients with SCD can get leukemia after successful and unsuccessful transplant,” corresponding study author Courtney D. Fitzhugh, MD, from the National Heart, Lung, and Blood Institute (NHLBI), told ASH Clinical News. “We were not sure, however, whether the transplant conditioning, such as chemotherapy and/or total body irradiation, led to the somatic mutations discovered at the time of leukemia diagnosis or if the patients were predisposed [to leukemia] due to a lifetime of SCD, erythropoietic stress, and inflammation.”
In this report, Dr. Fitzhugh and colleagues analyzed bone marrow samples from 2 of 3 patients with homozygous SCD (HbSS) who developed myeloid malignancy after transplantation – from a cohort of 76 adult patients with SCD who received alloHCT between September 2004 and April 2018 while on NHLBI Review Board–approved clinical trials. All patients had received a nonmyeloablative mobilized peripheral blood alloHCT.
The first patient was a man who, at 37 years of age, had received non-myeloablative conditioning with alemtuzumab and 400 cGy total body irradiation, and cyclophosphamide 100 mg/kg after alloHCT. His SCD had been complicated by:
- chronic renal insufficiency with a baseline creatinine of 5 g/dL
- recurrent vaso-occlusive crises
Initially, the patient engrafted, but the graft failed 73 days after transplant and the patient’s hematopoiesis recovered. Clinicians also observed severe neutropenia 2 years after transplant, at which point bone marrow findings revealed a hypercellular marrow with megakaryocytic and myeloid lineage dysplasia featuring increased marrow fibrosis, <5% myeloid blasts, and complex cytogenetics. The researchers also found a TP53 mutation with variant allele frequency (VAF) of 72.4% in the patient’s bone marrow. Retrospectively, the mutation was observed prior to alloHCT at a low VAF, and the VAF consistently increased following transplant. He received 3 cycles of decitabine followed by 1 cycle of azacitidine but did not respond. At 3 years post-transplant, the patient died from severe pulmonary hypertension.
The second patient included in this study presented with HbSS complicated by frequent vaso-occlusive crises and chronic pain. At 37 years old, he also underwent alloHCT with non-myeloablative conditioning, with alemtuzumab and 300 cGy total body irradiation and a human leukocyte antigen–matched sibling transplant.
Similar to the first patient, this patient also initially engrafted but rejected the graft 6 months after alloHCT. By 2.5 years post-transplant, the patient developed worsening anemia and thrombocytopenia. Researchers observed hyperplasia without evidence of increased blasts at a repeat bone marrow evaluation. Dyserythropoiesis was observed on blood smear, and investigators identified a TP53 mutation at a VAF of 4.5% on next-generation sequencing. A myeloablative haploidentical alloHCT was performed 3 years following the first transplant, but the patient died 47 days after due to intracranial hemorrhage.
Myeloid malignancy was observed in only those patients who had rejected grafts, while none of the patients who successfully engrafted developed MDS or AML.
Researchers also identified a third patient with HbSS whose bone marrow evaluation demonstrated a hypercellular diffusely fibrotic marrow featuring dysplastic megakaryocytic hyperplasia and 10 to 15% blasts 5 years after an unsuccessful alloHCT with alemtuzumab-total body irradiation conditioning, consistent with therapy-related myeloid neoplasm. Cytogenetic analysis showed that this patient also had del7q, which is often observed in myeloid neoplasms with TP53 mutation, but next-generation sequencing was not performed in this patient.
The authors stressed that myeloid malignancy was observed in only those patients who had rejected grafts, while none of the patients who successfully engrafted developed myelodysplastic syndromes/acute myeloid leukemia. They added that, although there have been anecdotes of myeloid malignancy arising during prolonged hydroxyurea treatment in patients with SCD, the current study showed no such association.
One of the primary limitations of this study is the small number of participants, which may reduce the generalizability of the findings across the broader patient population with SCD. “This report is just a start because we performed extensive analyses over time in 2 of the 3 patients from baseline to the time of leukemia development,” added Dr. Fitzhugh. “Our analyses should be repeated in a larger population of patients with SCD who undergo transplantation.”
Replication of the findings in a larger cohort also may be needed to determine these findings’ implications for clinical care, Dr. Fitzhugh noted. “This is an important question, but it is too early to conclude that patients with TP53 mutations at baseline are more likely to develop leukemia after transplant because the study was so small,” she said. “However, a larger study is currently being planned to address this question.”
The authors report no relevant conflicts of interest.
Ghannam JY, Xu X, Maric I, et al. Baseline TP53 mutations in adults with SCD developing myeloid malignancy following hematopoietic cell transplantation. Blood. 2020 February 14. [Epub ahead of print]