Primary myelofibrosis in untreated sickle cell disease: Are adult patients at higher risk for developing hematological myeloid neoplasms?
Authors: Jean‐Antoine Ribeil
Journal: American Journal of Hematology (2021)

In this issue of the American Journal of Hematology, Green, Singh, and Baer report an interesting case of a 76-year-old patient with Beta 0/S sickle cell disease (SCD) diagnosed with primary myelofibrosis (PMF).1 This patient had mild SCD, most likely due to concomitant hereditary persistence of fetal hemoglobin and PMF, which was an unexpected finding in a routine complete blood count. Hemoglobin values, white blood cell count and differential were not uncommon for a homozygous SS or Beta 0/S patient. Even the platelet count values above 1000 ×106/μL that led to the diagnosis are sometimes observed in patients with hemoglobinopathies who have had a surgical or functional splenectomy. This case highlights the importance of comparing biological abnormalities with previous results to avoid failing to diagnose hematological neoplasms that can occur in SCD patients. This case seems to be the first in which primitive myelofibrosis was reported in an adult patient with SCD. However, several myeloid malignancies had been previously reported in SCD, leading to the hypothesis that SCD may lead to the development of hematologic malignancies, even in the absence of disease-modifying treatments. An international survey of 16 613 SCD patients at 52 institutions conducted by the International Association of Sickle Cell Nurses and Physician Assistants (IASCNAPA) identified one patient with acute myeloid leukemia (AML) and another with chronic myeloid leukemia (CML).2 Two recent epidemiology reports from California and the United Kingdom have suggested that patients with SCD have a higher risk of hematologic malignancies than the general population.3, 4 A review of 27 years of population-based data from California (with a median follow-up of 22 person-years data) showed that SCD patients had a risk of leukemia more than twice as high as that of the general population. Patients with severe SCD (defined by those who had an average of ≥ 3 hospital or emergency department visits per year) had a risk nearly four times higher than the general population. The risk factor for SCD patients developing AML was 3.59.3 A review of linked hospital and mortality records from the United Kingdom found that the rate of myeloid leukemia in the SCD population was 10 times higher than that observed in a control population.4 Neither of these two large studies provides data on the etiology of leukemia, nor does either consider the use of disease-modifying treatments or hematopoietic stem cell (HSC) transplant. A recently published review from Li et al. reported 15 SCD patients with myeloid neoplasms. Of these, 4 cases were reported by the authors and 11 were found in a review of the literature. Seven patients had a myelodysplastic syndrome (MDS) with an excess of blast or transformed to acute leukemia, three had AML with no myelodysplasia mentioned, and four with CML.5 Improvements in treatment and care in the last 50 years have extended the life expectancy in SCD, to the extent that many patients now survive to an age at which they are at an increased risk for cancer.6 Aging is associated with a functional decline of HSC as well as an increased risk of myeloid malignancies.7 An association between hydroxyurea (HU) exposure in SCD patients and leukemia is unproven and large studies did not show a significant increased risk of leukemia.8, 9 The study from California conducted from 1988 to 1999 and from 2000 to 2014 did not show an increased risk of leukemia after the approval of HU by the FDA in 1997.3 Moreover, the study of SCD patients treated with HU suggest that HU could decrease hematopoietic stress and slow down the rapid aging of these patients' HSC.10 Recently, the largest lentiviral vector-mediated β-globin replacement gene therapy trial in SCD reported two cases of adult patients diagnosed with myeloid neoplasms. One patient was diagnosed 3 years after transplant, the other 5 years after transplant.11-13 Both patients had been treated with bone marrow (BM) HSC and the original lentiviral transduction process, which likely accounted for their unsatisfactory responses. The less effective original process did not produce a sufficient percentage of modified HSC, and this process also failed to produce sufficient response at the peripheral red cell level; these deficiencies likely accounted for the unsatisfactory clinical outcomes of the earliest stage of the trial. These two patients' myeloid neoplasms shared cytogenetic and molecular similarities, with monosomy 7 and mutations in the oncogenes RUNX1 and PTPN11, which are typically associated with the development of AML. These cytogenetic and molecular abnormalities were not found in first patient's pre-conditioning BM samples. It was concluded that both these events were likely not related to the gene therapy procedure. The first case was considered to be a secondary myeloid neoplasm related to busulfan conditioning.13 In the second case, the myeloid neoplasm clone developed from genetically modified HSC, which was not affected by busulfan conditioning, because the transgene had been found in the genome of the blast cells of this patient. It was concluded that this AML was likely not related to gene therapy, because the vector insertion in the AML cells took place in the VAMP4 gene, which has no known role in any cellular process related to cancer and because no disruption of gene expression was found in nearby genes.14 The Center for International Blood and Marrow Transplant Research (CIBMTR) reported that four patients developed a myeloid neoplasm (2 AML, 2 MDS) out of 910 patients with SCD transplanted from January 2008 to December 2017.15 For three cases, it happened after a haplo-identical transplant and an HLA-matched sibling one for the last one. These four patients rejected the transplant after receiving a nonmyeloablative conditioning regimen. An NIH study on 76 SCD adult patients, transplanted from 2004 to 2018 with nonmyeloablative conditioning, showed that of the 19 patients who rejected their grafts, 3 patients developed MDS/AML within 5 years after transplant. For two of these patients, the pathological clone showed p53 pathogenic mutations, which were present before transplant.16 This progression from baseline high-risk p53 clonal abnormalities to myeloid malignancy occurred only in patients who did not engraft or rejected the graft. By contrast, none of the 57 patients who engrafted developed MDS/AML. It is important to note that there were no reports of post-transplant malignant neoplasms in patients treated with myeloablative regimens, neither in the CIBMTR study nor in the French study of 234 geno-identical allotransplants performed between 1988 and 2012.15, 17 If myeloid leukemia cases were simply coincidental with SCD, their cytogenetics and molecular characteristics should be similar to de novo myeloid neoplasms observed in the general population. However, the study by Li et al. showed cytogenetic profiles with complex abnormalities in all the 10 non-CML cases for which cytogenetic information was available. Cytogenetic abnormalities –5/5q– and/or –7/7q– were component in 9 of these cases. Molecular diagnostic tests were available for four patients and mutations in the p53 gene were found in three of them.5 These morphologic features and this cytogenetic profile are often associated with alkylating agents and/or ionizing radiation; this association prompts consideration of these therapies as causes of myeloid neoplasm in this patient population.18 However, of the 10 patients with complex cytogenetic abnormalities, only 2 had had a previous HSC transplantation and HU, 4 had been treated with HU, and the remaining 4 received only transfusion and supportive care. The p53 mutations were found in one who received HU and then an HSC transplant, one patient treated with HU, and one treated with transfusion and supportive care only. These non-CMLs with complex karyotypic abnormalities, which are not secondary myeloid neoplasms suggest other causes than those of SCD pathophysiology.5 Aging HSC acquires mutations that sometimes provide a selective advantage. Next-generation DNA sequencing can be used to detect expanded peripheral blood progeny of a mutant clone and clonal hematopoiesis of indeterminate potential (CHIP), which is a risk factor for subsequent hematologic malignancy.19 Hematopoiesis in patients with SCD is associated with erythroid hyperplasia, reticulocytosis, and ineffective erythropoiesis starting at the immature erythroblast stage in the BM.20 The effects of SCD on the stem and progenitor cells have not been fully determined.10 Because of chronic hemolysis, vaso-occlusive crises, hematopoietic stress, ischemia–reperfusion, endothelial damage, tissular hypoxia inflammation, and compromised apoptosis, SCD may promote accelerated aging of hematopoiesis and potentially oncogenic somatic mutations.21-24 These mutations are extremely rare in children, and therefore, pose a very low risk of cancer, but they increase substantially in adult patients and appear to present a significant cancer risk.5, 7, 25 An increase in the prevalence of clonal hematopoiesis in SCD patients after 40 years old, was recently described by whole-genome sequencing studies.26, 27 Real-world evidence studies will be needed to confirm that while patients with SCD have a higher risk of hematologic malignancies than the general population, the absolute risk is low. Studies that assess the incidence of CHIP throughout the lifetimes of SCD patients treated with disease modifier therapies or various transplant modalities will be critical in assessing the impacts of those treatments on hematopoiesis, and in determining, which therapeutic strategy offers the most benefit to patients with severe SCD.