New Treatments for Myelodysplastic Syndromes

In the last decade, significant advances have been made in the treatment of patients with Myelodysplastic Syndromes (MDS). Although best supportive care continues to have an important role in the management of MDS, to date the therapeutic approach is diversified according to the IPSS risk group, karyotype, patient’s age, comorbidities, and compliance. Hematopoietic growth factors play a major role in lower risk MDS patients, and include high dose erithropoiesis stimulating agents and thrombopoietic receptor agonists. Standard supportive care should also include iron chelating therapy to reduce organ damage related to iron overload in transfusion-dependent patients. Biologic therapies have been introduced in MDS, as lenalidomide, which has been shown to induce transfusion independence in most lower risk MDS patients with del5q. Hypomethylating agents have shown efficacy in INT-2/high risk MDS patients, reducing the risk of leukemic transformation and increasing survival. Other agents under development for the treatment of MDS include histone deacetylase inhibitors, farnesyltransferase inhibitors, clofarabine and ezatiostat

Epigenetic Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemias

Epigenetic mechanisms affecting chromatin structure contribute to regulate gene expression and assure the inheritance of information, which are essential for the proper expression of key regulatory genes in healthy cells, tissues and organs. In the medical field, an increasing body of evidence indicates that altered gene expression or de-regulated gene function lead to disease. Cancer cells also suffer a profound change in the genomic methylation patterns and chromatin status. Aberrant DNA methylation patterns, changes in chromatin structure and in gene expression are common in all kind of tumor types. However, studies on leukemias have provided paradigmatic examples for the functional implications of the epigenetic alterations in cancer development and progression as well as their relevance for therapeutical targeting

Diagnostic Workup of Acute Myeloid Leukemia: What Is Really Necessary? An Italian Survey

Acute myeloid leukemia (AML) is a heterogeneous disease with a wide variety of clinical presentations, morphological features, and immunophenotypes. The diagnostic approaches to AML that are adopted in Italy have been explored using an online Delphi-based process to expand the global discussion on mandatory tests for the correct diagnosis and, consequently, for optimal management of AML in clinical practice. The final results of the panel of Italian hematologists involved in this work highlight the importance of genetic evaluation for classification and risk stratification and firmly establish that karyotyping, fluorescence in situ hybridization in cases with nonevaluable karyotype, and molecular tests must be performed in every case of AML, regardless of age. Obtaining clinically relevant genetic data at diagnosis is the basis for the success of patient-tailored therapy. The Italian specialists also confirm the role of multidisciplinary diagnostics for AML, now mandatory and expected to become more important in the future context of “precision” medicine

Case report: A Saprochaete clavata (Magnusiomyces clavatus) severe infection effectively treated with granulocyte transfusion in a young patient with myeloid sarcoma

Myeloid sarcoma is a hematologic malignancy consisting of extramedullary tissue involvement by myeloid blasts, usually considered as acute myeloid leukemia and treated accordingly. The disease itself, together with chemotherapy and disease-associated factors, may have an impact in increasing the risk of developing severe and frequently life-threatening infections. Herein, we describe the case of a patient with a right breast skin lesion, histologically diagnosed myeloid sarcoma, who developed a severe disseminated fungal infection by Saprochaete clavata (Magnusiomyces clavatus), during the first consolidation course of chemotherapy. Despite maximum antifungal therapy, the infection progressed and the fungus continued to be isolated until granulocyte transfusion therapy was initiated. Our experience suggests that patients with profound and long-lasting neutropenia could benefit from granulocyte transfusions as additional therapy in severe fungal infections resistant to broad-spectrum antimicrobial therapy

Clinical relevance of an objective - limit of detection - limit of quantification - based flow cytometry approach for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial

Using a multiparametric flow cytometry (MFC) assay, we assessed the predictive power of a threshold calculated applying the criteria of limit of detection (LOD) and limit of quantitation (LOQ) in adult patients affected with Acute Myeloid Leukemia (AML). This was a post-hoc analysis of 261 patients enrolled in the GIMEMA AML1310 prospective trial. According to the protocol design, using the predefined MRD threshold of 0.035% bone marrow residual leukemic cell (RLC) calculated on mononuclear cells, 154 (59%) were negative (MRD<0.035%) and 107 (41%) were positive (MRD≥0.035%). Using LOD and LOQ, we selected the following categories of patients: 1) LODneg if RLC were below LOD (74; 28.4%); 2) LODpos-LOQneg if RLC were between LOD and LOQ (43; 16.5%); and 3) LOQpos if RLC were above LOQ (144; 54.4%). Two-year overall survival (OS) of these 3 categories was 75.4% vs. 79.8% vs. 66.4%, respectively (p=0.1197). Due to superimposable outcome, LODneg and LODpos-LOQneg categories were combined. Two-year OS of LODneg/LODpos- LOQneg patients was 77.0% versus 66.4% of LOQpos individuals (P=0.043). Such a figure was challenged in multivariate analysis (p=0.048, HR 0.628, 95% CI 0.396-0.997) that confirmed the independent role of LOD-LOQ approach in influencing OS. In the AML1310 protocol, using the threshold of 0.035%, 2-year OS of MRD<0.035% and MRD≥0.035% patients was 74.5% vs. 66.4%, respectively (p=0.3521). In conclusion, the use of LOD-LOQ method results in a more sensitive detection of MRD that, in turn, translates in a more accurate recognition of patients with different outcome

A population-based study on myelodysplastic syndromes in the Lazio Region (Italy), medical miscoding and 11-year mortality follow-up. The Gruppo Romano-Laziale Mielodisplasie experience of retrospective multicentric registry

Data on Myelodysplastic Syndromes (MDS) are difficult to collect by cancer registries because of the lack of reporting and the use of different classifications of the disease. In the Lazio Region, data from patients with a confirmed diagnosis of MDS, treated by a hematology center, have been collected since 2002 by the Gruppo Romano-Laziale Mielodisplasie (GROM-L) registry, the second MDS registry existing in Italy. This study aimed at evaluating MDS medical miscoding during hospitalizations, and patients' survival. For these purposes, we selected 644 MDS patients enrolled in the GROM-L registry. This cohort was linked with two regional health information systems: the Hospital Information System (HIS) and the Mortality Information System (MIS) in the 2002-2012 period. Of the 442 patients who were hospitalized at least once during the study period, 92% had up to 12 hospitalizations. 28.5% of patients had no hospitalization episodes scored like MDS, code 238.7 of the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). The rate of death during a median follow-up of 46 months (range 0.9-130) was 45.5%. Acute myeloid leukemia (AML) was the first cause of mortality, interestingly a relevant portion of deaths is due to cerebro-cardiovascular events and second tumors. This study highlights that MDS diagnosis and treatment, which require considerable healthcare resources, tend to be under-documented in the HIS archive. Thus we need to improve the HIS to better identify information on MDS hospitalizations and outcome. Moreover, we underline the importance of comorbidity in MDS patients' survival

P499: APPLICABILITY OF 2022 CLASSIFICATIONS OF ACUTE MYELOID LEUKEMIA IN THE REAL-WORLD SETTING

Background: The increasing knowledge of molecular characterization in acute myeloid leukemia (AML) led to the necessity to fully evaluate the genetic profile also for clinical purposes. These efforts resulted in the release of 2022 new editions of AML classification and prognostication systems, including the 5th edition of The World Health Organization (WHO) classification, the International Consensus Classification (ICC), and the European LeukemiaNet (ELN) recommendations for AML prognosis. Aims: We aimed to provide a real-world application of the WHO 2022, ICC and ELN 2022 classifications in the real-world setting, to unravel differences and similarities, and to test their implementation in clinical AML diagnosis. We particularly focused on secondary AML, myelodysplasia (MDS) related. Methods: We selected a cohort of 1001 cases diagnosed with AML according to the WHO 2016 and the ELN 2017 classifications. Where available (44.9% of cases), information concerning a previous history of an antecedent MDS or MDS/Myeloproliferative neoplasm (MPN), as well as a previous exposure to cytotoxic therapies were considered for defining secondary AML (s-AML) and therapy-related AML (t-AML), respectively. Survival outcome was available for 84.4% patients. Results: The overall diagnostic changes between the WHO 2016, compared to WHO 2022 and ICC classifications were 22.8% and 23.7% respectively, with a 13.1% difference in patients’ distribution between ICC and WHO 2022. The “not otherwise specified” (NOS) by ICC and “defined by differentiation” by WHO 2022 categories shrank compared to WHO 2016 (24.1% and 26.8% respectively, vs 38.7%), particularly due to an expansion of MDS-related categories. The 92.7% and the 74.4% of RUNX1-mutated AML were re-classified respectively by the ICC into AML with MDS-related gene mutations and by WHO 2022 into the AML myelodysplasia related (MR) category, although the latter considers RUNX1 mutations lacking of sufficient unifying characteristics. Of 397 cases with a MDS-related AML according to ICC, 55.9% were definable by the presence of a MDS-related karyotype. More than 75.0% of s-AML and t-AML cases presented a MDS-related genetic profile according to both new 2022 diagnostic classifications. The overall re-stratification between ELN 2017 and 2022 accounted for 12.9% (4.0% favorable to intermediate and 8.1% intermediate to adverse risk). The majority of s-AML and t-AML (83.1%) fell into the ELN 2022 adverse risk group. Stratifying the 213 AML classified as favorable risk by ELN 2017, the difference in OS between ELN 2022-defined favorable and intermediate risk groups was statistically significant (p<0.01). We also focused on the heterogeneous group of patients with normal karyotype and adverse risk mutations according to the ELN 2022: the survival outcome was significantly inferior in patients with multiple versus single MDS-related gene mutations (p<0.05). Summary/Conclusion: The 2022 revisions of AML classification led to a significant improvement of diagnostic schemes. In the real-world setting, conventional cytogenetics, usually easily available and less expensive than molecular characterization, correctly stratified 56% of AML MDS-related, thereby maintaining a diriment diagnostic role. Although the secondary nature of AML (prior MDS or MDS/MPN and therapy-related) is now applied as “diagnostic qualifiers”, it maintains a predictive role for defining an adverse outcome according to the ELN 2022. Considering the similarities between WHO and ICC diagnostic schemes, a tentative to generate a unified model taking into account practical and socio-economic issues is desirable

Use of Measurable Residual Disease to Evolve Transplant Policy in Acute Myeloid Leukemia: A 20-Year Monocentric Observation

Measurable residual disease (MRD) is increasingly employed as a biomarker of quality of complete remission (CR) in intensively treated acute myeloid leukemia (AML) patients. We evaluated if a MRD-driven transplant policy improved outcome as compared to a policy solely relying on a familiar donor availability. High-risk patients (adverse karyotype, FLT3-ITD) received allogeneic hematopoietic cell transplant (alloHCT) whereas for intermediate and low risk ones (CBF-AML and NPM1-mutated), alloHCT or autologous SCT was delivered depending on the post-consolidation measurable residual disease (MRD) status, as assessed by flow cytometry. For comparison, we analyzed a matched historical cohort of patients in whom alloHCT was delivered based on the sole availability of a matched sibling donor. Ten-years overall and disease-free survival were longer in the MRD-driven cohort as compared to the historical cohort (47.7% vs. 28.7%, p = 0.012 and 42.0% vs. 19.5%, p = 0.0003). The favorable impact of this MRD-driven strategy was evident for the intermediate-risk category, particularly for MRD positive patients. In the low-risk category, the significantly lower CIR of the MRD-driven cohort did not translate into a survival advantage. In conclusion, a MRD-driven transplant allocation may play a better role than the one based on the simple donor availability. This approach determines a superior outcome of intermediate-risk patients whereat in low-risk ones a careful evaluation is needed for transplant allocation

Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status

Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged >= 55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (>= 0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline.Peer reviewe