For patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for acute myeloid leukemia (AML), disease relapse remains the most common reason for transplant failure and patient death. ...Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-transplant maintenance therapy.
We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with observation or placebo in patients with AML after allogeneic HSCT. We searched Cochrane Library, PubMed and conference proceedings up to Febuary 2021.
Our search yielded five trials including 736 patients. Maintenance therapy consisted of tyrosine kinase inhibitors (TKIs) in 3 studies (sorafenib 2 studies; midostaurin 1 study) and hypomethylating agents (HMAs) in 2 studies (decitabine and azacytidine 1 study each). Maintenance therapy was associated with an improved overall survival (OS), HR = 0.61 (95% CI 0.47-0.80). Subgroup analysis revealed advantage in OS with either TKI or HMA maintenance. Relapse free survival (RFS) was also improved in the maintenance arm compared with the control arm HR = 0.51(95% CI 0.40 − 0.66). There was no difference between the two arms in overall grade 3/4 adverse events or overall infections, in grade 3/4 infections, or in acute and chronic graft versus host disease.
Our meta-analysis shows that post-transplant maintenance therapy in AML patients is effective in improving RFS and OS, with a satisfactory safety profile.
The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for ...curative–intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (
n
= 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.
Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific ...monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.
We report our “real-world” experience with blinatumomab in patients with relapsed/refractory B-ALL.
Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (
n
= 17), MRD positivity (
n
= 2), inability to continue intensive chemotherapy (
n
= 1), and bridging to a second alloSCT (
n
= 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.
Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.
Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).
In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.
Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias predisposing to leukemia require a timely and accurate diagnosis to ensure ...appropriate medical management, including adequate monitoring and stem-cell transplantation prior to the development of leukemia. We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. The study comprises children with persistent cytopenias, myelodysplastic syndrome, aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used Sanger sequencing of commonly mutated genes and a custommade targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias; the minority subsequently underwent whole exome sequencing. In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, 9 (19.1%) had inherited thrombocytopenia predisposing to leukemia, and 3 each (6.4%) had predisposition to myelodysplastic syndrome or congenital neutropenia. Twelve patients had cytopenias with no known leukemia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia. In summary, almost one-third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.
Disease overview
Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, ...anemia, and bleeding. An improved understanding of pathophysiology, improvements in measurement technology and at least 10 recently approved therapies have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML.
Diagnosis
One updated and one new classification system were published in 2022, both emphasizing the integration of molecular analysis into daily practice. Differences between the International Consensus Classification and major revisions from the previous 2016 WHO system provide both challenges and opportunities for care and clinical research.
Risk assessment and monitoring
The European Leukemia Net 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizing dynamic risk based on serial measurable residual disease assessment. However, how to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells into therapeutic decision making is controversial.
Risk adapted therapy
The diagnostic and therapeutic complexity plus the availability of newly approved agents requires a nuanced therapeutic algorithm which should integrate patient goals of care, comorbidities, and disease characteristics including the specific mutational profile of the patient's AML. The framework we suggest only represents the beginning of the discussion.
We hypothesized that via extracellular vesicles (EVs), chronic lymphocytic leukemia (CLL) cells turn endothelial cells into CLL-supportive cells. To test this, we treated vein-derived (HUVECs) and ...artery-derived (HAOECs) endothelial cells with EVs isolated from the peripheral blood of 45 treatment-naïve patients. Endothelial cells took up CLL-EVs in a dose- and time-dependent manner. To test whether CLL-EVs turn endothelial cells into IL-6-producing cells, we exposed them to CLL-EVs and found a 50% increase in IL-6 levels. Subsequently, we filtered out the endothelial cells and added CLL cells to this IL-6-enriched medium. After 15 min, STAT3 became phosphorylated, and there was a 40% decrease in apoptosis rate, indicating that IL-6 activated the STAT3-dependent anti-apoptotic pathway. Phospho-proteomics analysis of CLL-EV-exposed endothelial cells revealed 23 phospho-proteins that were upregulated, and network analysis unraveled the central role of phospho-β-catenin. We transfected HUVECs with a β-catenin-containing plasmid and found by ELISA a 30% increase in the levels of IL-6 in the culture medium. By chromatin immunoprecipitation assay, we observed an increased binding of three transcription factors to the IL-6 promoter. Importantly, patients with CLL possess significantly higher levels of peripheral blood IL-6 compared to normal individuals, suggesting that the inducers of endothelial IL-6 are the neoplastic EVs derived from the CLL cells versus those of healthy people. Taken together, we found that CLL cells communicate with endothelial cells through EVs that they release. Once they are taken up by endothelial cells, they turn them into IL-6-producing cells.
Lam et al. compared trisomy acute myeloid leukaemia (AML) patients (inclusive of single trisomy, double trisomy or tetrasomy cases) with cytogenetically normal AML to uncover distinguishing molecular ...and prognostic features of trisomy AML. The study contributes to our understanding of trisomy AML, but the heterogeneity of trisomy subtypes remains a barrier to its study. Commentary on: Lam et al. Distinct karyotypic and mutational landscape in trisomy AML. Br J Haematol 2024;204:939-944.
Venetoclax is a BCL-2 inhibitor that was approved in combination therapy with hypomethylating agents or low dose cytarabine for newly diagnosed acute myeloid leukemia (AML). The purpose of this ...review is to outline the most recent venetoclax-based combination therapies in newly diagnosed or relapsed myelodysplastic syndrome (MDS) and AML patients.
Venetoclax has been incorporated in various therapeutic regimens - either with chemotherapy, immunotherapy or targeted therapies. These combinations achieve high remission rates with deep molecular responses, as suggested by measurable residual disease measurements. There are concerns regarding the incomplete count recovery, prolonged cytopenia and infection rates, especially when combined with chemotherapy. There is also limited data concerning durability of these remissions, and the effectiveness in high-risk population (i.e. p53-mutated AML patients).
Venetoclax-based combination therapies encompass novel therapeutic possibilities in MDS and AML with encouraging initial results. However, the exact role of each combination therapy and the long-term effects on patients' outcome are yet to be defined.
