Management of myelodysplastic syndromes after failure of response to hypomethylating agents

Abstract

Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.

Long-Lasting Remission in De Novo Breast Myeloid Sarcoma Treated with Decitabine and Radiotherapy

“…Although the majority of MS occur in patients younger than 50 years [4,5], its onset at older age makes the therapeutic approach challenging due to the impaired fitness and comorbidities limiting the administration of intensive chemotherapy. This is a very rare case of bilateral breast involvement, efficiently detected by 18 F-FDG-PET/CT and confirmed by a bilateral biopsy. Some other reports have documented the sensitivity of the 18 F-FDG-PET/CT in the detection of extramedullary AML, with particular regards to breast localization.…”

“…But MS was more enriched with mutations of the RTK-RAS pathway genes [16,17]. At the moment, there are no standardized genetic or epigenetic alterations able to predict the response to decitabine and further studies are warranted [18,19].…”

“…Pneumonia recovered in one week. After three months from the end of radiotherapy (July 2017), the patient underwent to 18 F-FDG-PET/CT evaluation, which documented a complete metabolic response ( Figure 2D-F). Currently, the patient has completed her 22nd cycle of decitabine and maintains the disease remission at 27 months, confirmed by 18 F-FDG-PET/CT and BM evaluation.…”

“…The most common sites of MS localization are soft tissues, bones, central nervous system, skin, small intestine, and lymph nodes [2], whereas about 6% of MS involves the breast [3][4][5][6]. The emerging employment of 18 F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography ( 18 F-FDG-PET/CT) has significantly improved the staging of disease as well as the assessment of treatment response [2,7]. While the younger and fitter patients can be candidate for AML-like chemotherapy, for elderly patients a standard therapeutic approach is still lacking [2,8].…”

Dendritic Cells of Leukemic Origin: Specialized Antigen-Presenting Cells as Potential Treatment Tools for Patients with Myeloid Leukemia

“…The prognosis of AML patients, especially among the elderly (age > 65 years), is unsatisfactory, with 5-year overall survival rates of 5-15% in older cohorts and 30% in younger cohorts. The outcomes of (most of the time elderly) MDS patients, characterized by hematopoietic failure and increasing blasts, are even worse [2][3][4].…”