Giuseppe Leone

Acute myeloid leukemia, myelodysplasia-related (AML-MR), represents a genetically defined and clinically heterogeneous entity characterized by myelodysplasia-related gene (MRG) mutations, specific cytogenetic abnormalities, and frequently a previous history of myelodysplastic syndromes (MDS) or MDS/myeloproliferative neoplasm (MDS-MPN). The transition from the World Health Organization (WHO) 2016 classification to the 2022 WHO and International Consensus Classification (ICC) systems reflects a paradigm shift from morphology-based definitions toward genomics-driven disease entities. However, while diagnostic precision has improved, translation of these classifications into clinically actionable strategies remains incomplete. This review critically examines the biological and prognostic implications of MRG mutations, their interaction with key molecular subgroups such as NPM1- and FLT3-mutated AML, and their impact on therapeutic decision-making. We highlight unresolved issues, including the context-dependent prognostic value of MRG mutations, limitations of static risk stratification, and the need to integrate measurable residual disease (MRD), genomics, and patient fitness into therapeutic algorithms. At the clinical level, many studies have explored the sensitivity of AML-MR to various induction treatments in both younger and older AML patients, with significant improvements in survival. The main objective of these different induction therapy strategies is to achieve a complete remission with minimal toxicity, particularly in older patients, allowing patients to proceed to allogeneic hematopoietic stem cell transplantation, the only curative option so far.

Plasma cell leukemia (PCL) is a rare and aggressive form of multiple myeloma (MM), characterized by the presence of malignant plasma cells in the peripheral blood. Until 2021, PCL was defined by having plasmacytosis making up at least 20% of the differential white blood cell count . PCL was found in 2-4% of newly diagnosed MM cases (primary PCL). It can also develop from a preexisting, usually end-stage, MM, known as secondary PCL (sPCL), which exhibits distinct biological and clinical features. Both primary plasma cell leukemia (pPCL) and secondary plasma cell leukemia (sPCL) are very rare presentations of MM. However, the rate of MM transforming into sPCL is increasing as patients are living longer. According to the International Myeloma Working Group, plasma cell leukemia is generally diagnosed when the percentage of CPCs in peripheral blood exceeds 5%. PCL has a more aggressive clinical presentation than MM, involving more severe cytopenia, hypercalcemia, and renal failure. Higher tumor burden and proliferation activity in PCL are reflected by elevated levels of B2-microglobulin and lactate dehydrogenase (LDH). Extramedullary localization at diagnosis is more common in pPCL and sPCL than in MM. Conversely, osteolytic lesions are less frequent in pPCL. The immunophenotype of PCL expresses the common MM markers, CD38 and CD138. Still, it exhibits a more immature phenotype than MM. Molecularly, PCL lacks a specific marker but shows a markedly lower frequency of hyperploidy, gains of chromosome 1, and translocations t(14;16) or t(14;20). The recent therapy of PCL is similar to that of other high-grade myelomas, taking advantage of anti-proteasome, like bortezomib, an immunomodulator, like lenalidomide, and dexamethasone triplet + anti-CD38 antibody and/or cyclophosphamide, and hematopoietic stem cell transplantation. However, the results are not as good as in the other forms of myeloma.

Multiple myeloma is a disease related to the proliferation of malignant plasma cells; in the large majority of patients the disease is confined at the level of bone marrow. However, in a minority of patients the malignant plasma cells are localized also outside bone marrow, either at the level of peripheral blood (plasma cell leukemia) or at the level of soft tissues (extramedullary multiple myeloma). These two rare forms of aggressive MM (ultrahigh-risk (uHR) MM as MM leading to death within 24-36 months) are both associated with some molecular features and with a limited response to current treatments.

The aim of our review has been to give an appropriate idea of analogies and differences between primitive MDS (p-MDS) and t-MDS throughout an accurate reviewing of English peer-reviewed literature focusing on clinical, cytogenetic, epigenetic, and somatic mutation features of these two groups of diseases. Therapy-related MDS (t-MDS) are classified by WHO together with therapy-related acute myeloid leukemia (t-AML) in the same group, named therapy-related myeloid neoplasm. However, in clinical practice, the diagnosis of t-MDS is made with the same criteria as for primitive MDS (p-MDS), and the only difference is a previous non-myeloid neoplasm. The prognosis and the consequent therapy can be established following the same criteria as for p-MDS, and the therapy is generally decided using the same criteria. We stress the possible difference in cytogenetics, mutations, and epigenetics to distinguish the two forms. Actually, there is no marker specific for t-MDS either in cytogenetics, epigenetics, or mutations; however, some alterations are also frequent in t-MDS and, in general, they induce a poorer prognosis. So, the high-risk forms in t-MDS are prevalent. The present literature data suggest classifying the t-MDS as a subgroup of MDS and introducing some parameters to evaluate the probability of previous therapy in inducing MDS. An important issue remains the patient’s fitness, which strongly influences the outcome. Keywords: MDS, t-MDS- Cytogenetics, Mutation, Epigenetics.

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p < 0.001): 7.7% (95% CI: 1.3–21.7%) for patients treated before 1990 (period 1: n = 26), 23.3% (95% CI: 17.1–30.0%) for those treated between 1990 and 2000 (period 2: n = 188) and 36.5% (95% CI: 28.7–44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; p = 0.01), WBC ≥ 25 × 10⁹/L (HR = 2.00; p < 0.0001), age 46-60 years (HR = 1.65; p < 0.001) and poor-risk cytogenetics (HR = 2.17; p < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, p = 0.003) or period 3 (HR = 0.43; p = 0.0008). Having received high-dose cytarabine (HD-AraC) (n = 48) in the induction chemotherapy (HR = 0.54, p = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age (n = 502), the OS was dismal, and there was no improvement over time.

Infections remain a significant problem in myelodysplastic syndromes in treated as well in non-treated patients and assume a particular complexity. The susceptibility to infections is due, in the absence of intensive chemotherapies, mainly to functional defects in the myeloid lineage with or without neutropenia. Furthermore, MDS include a heterogeneous group of patients with very different prognosis, different therapy and various risk factors regarding survival and infections. You should distinguish risk factors related to the disease, like as neutrophils function impairment, neutropenia, unfavorable cytogenetics and bone marrow insufficiency; factors related to the patient, like as age and comorbidities, and factors related to the therapy. When the patients with MDS are submitted to intensive chemotherapy with and without HSCT, they have a risk factor for infection very similar to that of patients with AML, and mostly related to neutropenia. Patients with MDS treated with supportive therapy only or with demethylating agent or lenalidomide or immunosuppressive drugs should have a tailored approach. Most of the infections in MDS originate from bacteria, and the major risk factors are represented by neutropenia, thrombocytopenia, and unfavorable cytogenetics. Thus it is reasonable to give antibacterial prophylaxis in patients who start the therapy with demethylating agents with a number of neutrophils <500, or with thrombocytopenia and unfavorable cytogenetics. The antifungal prophylaxis is not considered cost/benefit adequate and should be taken into consideration only when there is an antecedent fungal infection or presence of filamentous fungi in the surveillance cultures. Subjects submitted to immunosuppression with ATG+CSA have a high number of infections, and when severely neutropenic should ideally be nursed in isolation, should be given prophylactic antibiotics and antifungals, regular mouth care including an antiseptic mouthwash.

Book of Fifth International Symposium on Secondary Leukemia and Leukemogenesis