mutation analysis and treatment of concomitant diseases

During the LXVI National Congress of the Spanish Society of Hematology and Hemotherapy (SEHH) and the XL National Congress of the Spanish Society of Thrombosis and Hemostasis (SETH), Hemato2024, myelodysplastic syndromes (MDS) played a leading role. In this direction, the “Cyril Roseman Conference: Towards a Cure for Myelodysplastic Syndromes” was held by Guillermo Garcia-Manero, a leukemia specialist, professor of medicine and head of the MDS department at MD Anderson Cancer Center in Texas, USA. was responsible for focusing on the entire history of research related to these blood diseases.

The Spanish Group of Myelodysplastic Syndromes (GESMD) estimates that in Europe the incidence of MDS is between 3 and 5 cases per 100,000 inhabitants per year. Thus, European data are similar to those collected by Spanish hospitals, so it is assumed that In Spain, about 1,500 cases of the disease are diagnosed annually.. However, the incidence of this disease increases with age: the average age of diagnosis is 65 years and exceeds 50 cases per 100,000 inhabitants/year from 75 years.

In this context, Garcia-Manero began his presentation by saying that “there have been significant advances in the treatment of these patients over the last couple of years.” The specialist explained the situation that existed in 1999, when nothing was known either about the cytogenetic structure of the disease or at the molecular level. However, that scenario began to change in the early 2000s with the approval of the drug azacitidine, which “has shown very good results in patients with high-risk myelodysplasia,” he said.

MDS is a group clonal disorders of hematopoietic stem cells characterized by peripheral cytopenia, bone marrow hypercellularity, hematopoietic precursors and a high risk of conversion to acute myeloid leukemia. According to Garcia-Manero, “In the 90s, there was a concept that these patients were dying from acute myeloid leukemia, but this is not true,” the specialist said. “These patients die from causes inherent in myelodysplasia.”

Effect of azacitidine

Azacitidine works by eliminating abnormal cells produced by the bone marrow by inhibiting DNA methylation, which is necessary for cell proliferation. Therefore, since these abnormal cells cannot reproduce, they die.

This compound is mainly indicated for the treatment of patients not considered suitable for hematopoietic stem cell transplantation and those suffering from intermediate and high risk MDS according to the International Prognostic Scoring System (IPSS), as well as those suffering from chronic myelomonocytic leukemia with 10-29% bone marrow blasts without myeloproliferative disorders, suffering from acute myeloid leukemia with 20-30% blasts and multilineage dysplasia according to the WHO classification and in the same group are those with >30% medullary blasts.

“We first started to test that this compound in patients with high-risk myelodysplasia was associated with improved survival, but unfortunately, so far we have not been able to improve this prognosis,” the expert said.

Striving to improve prognosis

The specialist provided a historical review of studies and trials over approximately the last 30 years that have provided useful data and benefits for these patients.

Various studies have been conducted to find pharmacological treatments that will have a survival benefit for patients. One of them, published in The Lancet in 2009, analyzed Effect of azacitidine on overall survival compared with three conventional treatment regimens more common. In this study, patients with high-risk MDS were randomized to receive azacitidine (75 mg/m2 daily for seven days every 28 days) or usual care, including best supportive care, low-dose cytarabine, or intensive chemotherapy, as chosen by the investigators. before randomization. The primary endpoint of this study was overall survival. The conclusions were that azacitidine prolonged overall survival in these patients compared with those receiving conventional care.

Thus, in 2020, a study was published in The New England Journal of Medicine that analyzed the results of the use of azacitidine and venetoclax in previously untreated acute myeloid leukemia. The results showed that in treatment-naive patients who were not eligible for intensive chemotherapy, the overall survival rate was longer and remission rates were higher among patients receiving azacitidine in combination with venetoclax than among those receiving azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacytidine group than in the control group.

On the other hand, DNA methyltransferase inhibitors such as azacitidine and decitabine are currently administered parenterally to people with MDS or chronic myelomonocytic leukemia. In the same spirit, another ASCERTAIN study was published in early 2024, which compared Safety and pharmacokinetics of oral decitabine in combination with the cytidine deaminase inhibitor cedazuridine compared with intravenous decitabine..

According to their results, the oral combination of decitabine-cedazuridine demonstrated pharmacological and pharmacodynamic equivalence intravenous administration of decitabine. Thus, these results support its use as a safe and effective alternative for the treatment of patients with MDS or chronic myelomonocytic leukemia, offering greater convenience without compromising therapeutic efficacy.

Concomitant diseases

Another key point to highlight at this conference was the analysis of comorbidities associated with MDS. Garcia-Manero highlighted a 2017 study that analyzed the correlation between Clonal hematopoiesis and increased risk of atherosclerotic cardiovascular diseases. In this study, using atherosclerosis-prone and low-density lipoprotein receptor-deficient (Ldlr -/-) mice, they examined the expansion effects of Tet2 mutant cells.

The results showed that partial restoration of the bone marrow by TET2-deficient cells caused their clonal expansion, leading to significant increase in the size of atherosclerotic plaques. TET2-deficient macrophages showed increased secretion of interleukin-1β through the NLRP3 inflammasome. In addition, the NLRP3 inhibitor demonstrated superior atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells compared with non-chimeric mice. In summary, these data support the hypothesis that somatic TET2 mutations in blood cells causally contribute to the development of atherosclerosis.

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