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Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count.

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

Abstract Background In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question. Methods In the present study, we tested the impact on survival of disease‐ and patient‐related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs). Results In 131 patients with a median age of 76 years, we confirmed that early response (

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

It has now been ascertained that acute myeloid leukemias—as in most type of cancers—are mixtures of various subclones, evolving by acquiring additional somatic mutations over the course of the disease. The complexity of leukemia clone architecture and the phenotypic and/or genotypic drifts that can occur during treatment explain why more than 50% of patients—in hematological remission—could relapse. Moreover, the complexity and heterogeneity of clone architecture represent a hindrance for monitoring measurable residual disease, as not all minimal residual disease monitoring methods are able to detect genetic mutations arising during treatment. Unlike with chemotherapy, which imparts a relatively short duration of selective pressure on acute myeloid leukemia clonal architecture, the immunological effect related to allogeneic hematopoietic stem cell transplant is prolonged over time and must be overcome for relapse to occur. This means that not all molecular abnormalities detected after transplant always imply inevitable relapse. Therefore, transplant represents a critical setting where a measurable residual disease-based strategy, performed during post-transplant follow-up by highly sensitive methods such as next-generation sequencing, could optimize and improve treatment outcome. The purpose of our review is to provide an overview of the role of next-generation sequencing in monitoring both measurable residual disease and clonal evolution in acute myeloid leukemia patients during the entire course of the disease, with special focus on the transplant phase.

The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML.

Introduction: The NPM1mut identification by RQ-PCR at diagnosis is important for AML risk stratification and represents a reliable marker to track minimal residual disease (MRD) and to early detect relapse. We retrospectively analyzed clinical and biological features of NPM1mut AML pts consecutively treated with intensive therapy in our Institution to evaluate the role of MRD monitoring in relation to overall survival (OS) and disease free survival (DFS). Methods: We analyzed 104 NPM1mut AML pts eligible for intensive therapy, diagnosed between 2008 and 2018. Median age was 52 years (y) (range, 8-75). NPM1mut was detected in the bone marrow (BM) by RQ-PCR at diagnosis and at different time points. MRD levels were expressed as a percentage (ratio of the NPM1 copies-cp to the housekeeping gene ABL cp × 100); MRD positivity was defined as any level above 0.01%. FLT3mut was detected in 50 pts (48.1%) (7 FLT3-TKD; 43 FLT3-ITD). All pts received intensive treatment according to local institutional standard. After induction and consolidation, pts received either high-dose (HD) chemotherapy followed by autologous stem cell transplantation (ASCT) or 2/3 further cycles of HDAra-C if not eligible for ASCT. Results: Eighty-nine pts achieved a complete remission (CR) (85.6%), 7 proved refractory (6.7%), while 8 died during induction (7.7%). After induction, MRD was available for 50 pts (61.7%): 8 (16%) were MRD negative (-) (7 FLT3wt; 1 FLT3mut) and 42 (84%) were MRD positive (+) (18 FLT3wt; 24 FLT3mut); MRD evaluation after I consolidation was performed in 52 pts (64.2%): 16 (30.8%) were MRD- (9 FLT3wt; 7 FLT3mut), 36 (69.2%) were MRD+ (16 FLT3wt; 20 FLT3mut). For the whole cohort, the 5y-OS was 40.8% (95% CI, 31.5-52.9%) and 5y-DFS was 38.2% (95% CI, 28.8-50.7%). Achieving an MRD- after induction or I consolidation, identified pts with better 5y-DFS than pts with persisting MRD+ (85.6% and 65.5% vs 40% and 26%; p= 0.015, p= 0.032). This also translated into significant differences in 5y-OS (100% and 75.8% vs 44% and 30.5%; p= 0.009, p= 0.045); 5y-cumulative incidence of relapse (CIR) was 43.7% (95% CI: 30.2-54.6%). No statistically significant differences were observed in OS (p= 0.535) and DFS (p= 0.224) according to FLT3 status. However, the CIR was higher in FLT3mut pts (p= 0.063). In the whole cohort, ASCT were 24, allogenic (allo)SCT were 26. Reasons for alloSCT in CR1 were: 1) FLT3-ITDmut; 2) secondary-AML; 3) raising MRD levels, 4) slow clearance of MRD reduction; 5) primary refractory pts. MRD- pts before alloSCT showed a trend towards better OS (p= 0.074) and DFS (p= 0.065) than MRD+ pts. Conclusions: Our study underlines the clinical relevance of achieving an early molecular response in NPM1mut AML. MRD monitoring is a valuable tool for the early identification of pts who might benefit from alloSCT/new drugs and pts with molecular relapse. The most relevant time points for collecting samples and the prognostic MRD thresholds remain to be defined.