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•tCMML has lower incidence of high-risk genomic features characteristic of other therapy-related myeloid neoplasms.•tCMML does not exhibit the poor outcomes of therapy-related myeloid neoplasms.

Patients with acute myeloid leukaemia have high rates of relapse, especially if they are unable to complete standard consolidation strategies or allogeneic haematopoietic stem-cell transplantation (HSCT). The phase 3 QUAZAR AML-001 study showed an overall survival benefit with oral azacitidine maintenance. The BCL2 inhibitor venetoclax is highly active in acute myeloid leukaemia and synergistic with azacitidine. We aimed to evaluate the efficacy and safety of low dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia.

Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax.

•The mPRS can accurately segregate 3 groups of patients with AML with different outcomes with HMA and Ven.•Patients with FLT3-ITD and NRAS/KRAS mutations have a relatively unfavorable outcome with HMA and Ven, for which new strategies are needed.

Graphic abstract:

•Early flow-based MRD dynamics are independently associated with RFS in patients with AML undergoing frontline therapy.•Patients with intermediate-risk AML who achieved early MRD negativity still benefit from allogeneic SCT.

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and postremission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, whereas it recommends allogeneic stem cell transplantation (alloSCT) as a postremission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%), and 245 (36%) patients allocated to the favorable-, intermediate-, and adverse-risk group, respectively. The 2- and 5-year overall survival (OS) rates were 77% and 70% for favorable-risk patients, 52% and 46% for intermediate-risk patients, and 33% and 23% for adverse-risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype, and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol based on alloSCT after remission for nonfavorable ELN subgroups and identifies a genetic subset with a very poor outcome that warrants investigation of novel strategies.

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and postremission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, whereas it recommends allogeneic stem cell transplantation (alloSCT) as a postremission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%), and 245 (36%) patients allocated to the favorable-, intermediate-, and adverse-risk group, respectively. The 2- and 5-year overall survival (OS) rates were 77% and 70% for favorable-risk patients, 52% and 46% for intermediate-risk patients, and 33% and 23% for adverse-risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype, and/or TP53mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol based on alloSCT after remission for nonfavorable ELN subgroups and identifies a genetic subset with a very poor outcome that warrants investigation of novel strategies.

The negative prognostic impact of internal tandem duplication of FLT3(FLT3-ITD) in patients with acute myeloid leukemia with mutated NPM1(AML-NPM1) is restricted to those with a higher FLT3-ITD allelic ratio (FLT3high; ≥0.5) and considered negligible in those with a wild-type (FLT3WT)/low ITD ratio (FLT3low). Because the comutation of DNMT3A(DNMT3Amut) has been suggested to negatively influence prognosis in AML-NPM1, we analyzed the impact of DNMT3Amutin FLT3-ITD subsets (absent, low, and high ratios). A total of 164 patients diagnosed with AML-NPM1included in 2 consecutive CETLAM protocols and with DNMT3Aand FLT3status available were studied. Overall, DNMT3Amutstatus did not have a prognostic impact, with comparable overall survival (P= .2). Prognostic stratification established by FLT3-ITD (FLT3WT= FLT3low>FLT3high) was independent of DNMT3Amutstatus. Measurable residual disease (MRD) based on NPM1quantitative polymerase chain reaction was available for 94 patients. DNMT3Amutwas associated with a higher number of mutated NPM1transcripts after induction (P= .012) and first consolidation (C1; P< .001). All DNMT3Amutpatients were MRD+after C1 (P< .001) and exhibited significant MRD persistence after C2 and C3 (MRD+vs MRD−; P= .027 and P= .001, respectively). Finally, DNMT3Amutpatients exhibited a trend toward greater risk of molecular relapse (P= .054). In conclusion, DNMT3Amutdid not modify the overall prognosis exerted by FLT3-ITD in AML-NPM1despite delayed MRD clearance, possibly because of MRD-driven preemptive intervention.

CD19-directed chimeric antigen receptor (CAR) T cells have yielded impressive response rates in refractory/relapse B cell acute lymphoblastic leukemia (B-ALL); however, most patients ultimately relapse due to poor CAR T cell persistence or resistance of either CD19+or CD19−B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+and CD19−relapses. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T cells showed similar in vitroexpansion to CD19-CAR T cells with no increase in tonic signaling. CRISPR-Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitroand in vivousing B-ALL cell lines, patient samples, and patient-derived xenografts (PDXs). Strikingly, the robust antileukemic activity of the Tan-CAR was slightly more effective in controlling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.

The negative prognostic impact of internal tandem duplication of FLT3 (FLT3-ITD) in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to those with a higher FLT3-ITD allelic ratio (FLT3high; ≥0.5) and considered negligible in those with a wild-type (FLT3WT)/low ITD ratio (FLT3low). Because the comutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence prognosis in AML-NPM1, we analyzed the impact of DNMT3Amut in FLT3-ITD subsets (absent, low, and high ratios). A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Overall, DNMT3Amut status did not have a prognostic impact, with comparable overall survival (P = .2). Prognostic stratification established by FLT3-ITD (FLT3WT = FLT3low > FLT3high) was independent of DNMT3Amut status. Measurable residual disease (MRD) based on NPM1 quantitative polymerase chain reaction was available for 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts after induction (P = .012) and first consolidation (C1; P < .001). All DNMT3Amut patients were MRD+ after C1 (P < .001) and exhibited significant MRD persistence after C2 and C3 (MRD+ vs MRD−; P = .027 and P = .001, respectively). Finally, DNMT3Amut patients exhibited a trend toward greater risk of molecular relapse (P = .054). In conclusion, DNMT3Amut did not modify the overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly because of MRD-driven preemptive intervention.

Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative option for relapsed/refractory acute myeloid leukemia and other high-risk myeloid malignancies. To improve alloHCT results in this setting, sequential regimens were designed as a strategy to lower tumor burden and quickly induce the graft-versus-leukemia effect. We analyzed long-term outcomes of a sequential regimen based on IDA-FLAG and high-dose melphalan, as set forth by the CETLAM cooperative group. This protocol yielded a high complete response rate (89%) and a lower cumulative relapse incidence (30% at five years) compared to other regimens. Five-year non-relapse mortality, however, reached 45%, with grade 3–4 acute graft-versus-host disease being the most frequent adverse event (a 100-day incidence of 29%). Altogether, 5-year overall survival was 25% in this group of patients with otherwise dismal prognosis. Long-term survivors enjoyed a good quality of life after a median follow-up of 68 months.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration of patient-matched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD34− leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.

Autologous stem cell transplant (ASCT) has demonstrated to be an effective treatment for patients with light-chain (AL) amyloidosis. However, a high transplant-related mortality (TRM) rate was reported in previous series of patients and questioned the role of transplant in this disease. Recently, experienced groups have shown a significant TRM decrease that has been attributed to an accurate selection of patients. Moreover, application of several supportive measures has decreased toxicity over amyloid-involved organs. We analyzed a series of 66 patients with AL amyloidosis, who underwent ASCT at a single institution and evaluated the impact of these measures beyond patient selection. Four temporary groups were established: group-A (non-selection plus post-transplant G-CSF use) with 29 patients, group-B (selection) with 13, group-C (selection and G-CSF avoidance) with 14, and group-D (selection, G-CSF avoidance and corticosteroid’s prophylaxis) with 10. A decreasing TRM was observed over time from group-A (38%), to group-D (0%); p= 0.02. We also observed a progressive increase of three-year OS from 62% in group-A to 100% in group-D; p= 0.049. On the multivariate analysis, cardiac involvement was the only independent predictor of survival. Therefore, tailored selection policy together with transplant supportive measures have allowed ASCT to be a safe procedure in AL amyloidosis.

The role of transforming growth factor-β (TGFβ) signaling in embryological development and tissue homeostasis has been thoroughly characterized. Its canonical downstream cascade is well known, even though its true complexity and other non-canonical pathways are still being explored. TGFβ signaling has been described as an important pathway involved in carcinogenesis and cancer progression. In the hematopoietic compartment, the TGFβ pathway is an important regulator of proliferation and differentiation of different cell types and has been implicated in the pathogenesis of a diverse variety of bone marrow disorders. Due to its importance in hematological diseases, novel inhibitors of this pathway are being developed against a number of hematopoietic disorders, including myelodysplastic syndromes (MDS). In this review, we provide an overview of the TGFβ pathway, focusing on its role in hematopoiesis and impact on myeloid disorders. We will discuss therapeutic interventions with promising results against MDS.

CD19-directed immunotherapies have revolutionized the treatment of advanced B-ALL. Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. B-ALL patients successfully treated with CD19-directed T-cells eventually relapse, which coupled with the early onset of CD22 expression during B-cell development suggests that pre-existing CD34+CD22+CD19-(pre)-leukemic cells could represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19-CD22+cells are found in diagnostic and relapsed BM samples of ~70% B-ALL patients, and their frequency increases 2-fold in B-ALL patients in CR after CD19-CAR T-cell therapy. The median of CD34+CD19-CD22+cells before treatment was 3-fold higher in B-ALL patients who relapse after CD19-directed immunotherapy (median follow-up of 24 months). FISH analysis in flow-sorted populations and xenograft modeling revealed that CD34+CD19-CD22+cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that pre-leukemic CD34+CD19-CD22+progenitors may underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual-targeting as a strategy to reduce CD19- relapses. The implementation of such CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of B-ALL patients during CD19-targeted therapy is encouraged.

Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.

Introduction:Hypomethylating agents (HMA) with Venetoclax (Ven) is the standard of care for patients with acute myeloid leukemia (AML) ≥ 75 yrs of age or not candidates to intensive treatment. Döhner, et al. (ASH 2022) demonstrated that the European LeukemiaNet (ELN) risk classifications do not accurately predict prognosis in HMA-Ven treated patients. A prognostic risk signature classification (PRSc) was proposed, stratifying patients by RAS, FLT3and TP53mutations alone. We report a validation of this PRSc in a large cohort of patients treated with HMA-Ven.

Background:

AML arising from HMA-treated myeloid disorders, also known as “treated-secondary AML” (ts-AML) is associated with an adverse prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-10 months). E-selectin, a marker of cell survival and resistance to chemotherapy, is highly expressed in the leukemic microenvironment. Exposure of leukemic blasts to HMAs has been shown to increase its expression. Uproleselan is an e-selectin antagonist that has demonstrated antileukemic activity in AML. We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance.

Background:The most recent World Health Organization (WHO) classification has stablished NPM1-mutated myeloid neoplasms (MNs) to be acute myeloid leukemia (AML) regardless of bone marrow (BM) blast percentage. In contrast, the new International Consensus Classification (ICC) considers NPM1-mutant MNs as AML only in the presence of ≥10% BM blasts. Previous studies from our group and others have reported favorable outcomes of NPM1-mutant MNs with <20% blasts when treated with intensive chemotherapy. Here we seek to further evaluate clinical outcomes of this group of pts.

Background:Hypomethylating agents (HMA), such as decitabine, azacitidine, and oral decitabine/cedazuridine, are standard-of-care therapies for patients with myelodysplastic syndromes (MDS). Though they improve peripheral blood cytopenia and delay disease progression, most patients eventually lose response to these agents, a phenomenon known as HMA failure (HMA-F). Survival outcomes are poor with no Federal Drug Administration-approved treatment options in the HMA-F setting. Here, we assess MDS patients treated with HMA for potential clinical and pathological predictors of HMA-F.

Hypomorphic DDX41mutations are prototypic lesions for germline predisposition to late onset myeloid neoplasia (MN), chiefly MDS. In a recent study 1, we demonstrated that germline mutations in this gene are found in up to 5% of MDS cases and explain nearly 80% of the etiologic fraction of known MN inherited predisposition. DDX41mutation carriers have a ~50% lifetime risk of developing MN, which commonly accompanies the acquisition of a secondary somatic DDX41mutation in the contralateral allele (most commonly p.R525H) with a strong male predominance. Because of these peculiarities, risk classification assigned by currently available schemes such as the revised/molecular international prognostic scoring system (IPSS-R/M) has also been questioned, differentiating DDX41-mutant MDS as a distinct nosologic subentity, whereby current prognostic tools are not able to capture invariant biologic features crucial for outcome prediction. Particularly, the impact of somatic DDX41mutations on disease progression has not been evaluated.

Introduction:Cytogenetic and molecular aberrations are common at diagnosis in patients with acute myeloid leukemia (AML) and may have significant prognostic impact. Relapse after prior response is associated with a poor outcome. The dynamics of cytogenetic and molecular abnormalities at relapse and their impact on outcome is less well studied.

Introduction:Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival. The standard of care for HR-MDS are hypomethylating agents (HMA). The addition of venetoclax (Ven) to HMA has been shown to improve outcomes in acute myeloid leukemia (AML) and potentially in HR-MDS. The combination of oral decitabine/cedazurridine (DEC-C) with Ven has been shown to induce high response rates in patients with HR-MDS. Herein we analyze the responses of patients treated with DEC-C with Ven according to different response criteria. Additionally, we analyze the cytogenetic responses and mutation dynamics.

Introduction:Therapy-related myeloid neoplasms are associated with a previous exposure to cytotoxic agents or ionizing radiation, and account for 10-20% of all myeloid neoplasms. They are associated with a worse outcome, usually with high risk genetic abnormalities and poor response to therapies. Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm with persistent monocytosis, bone marrow dysplasia and an inherent risk of acute myeloid leukemia (AML) transformation. Due to its rarity, it is difficult to establish the specific impact of previous therapy in CMML. We previously reported the characteristics and outcomes of patients with therapy-related CMML (tCMML). Herein we report an update, including molecular characteristics, being the largest tCMML cohort reported to date.

Background:Patients with myelodysplastic syndromes (MDS) undergo risk stratification with various prognostication tools, such as the International Prognostic Scoring System (IPSS) and Revised IPSS (IPSS-R). Recently, the Molecular IPSS (IPSS-M) was developed incorporating genomic data in addition to clinical and cytogenetic characteristics. Though IPSS-M has been shown to improve prognostication in all MDS patients at baseline, its utility in specifically patients undergoing hypomethylating agent (HMA) therapy remains unknown. Here, we assess the efficacy of IPSS-M in HMA-treated patients with MDS.

Introduction

Introduction:The incorporation of novel targeted agents into combination regimens used in the treatment of patients with acute myeloid leukemia (AML) has improved their outcomes. However, disease relapse is still challenging and associated with a poor response rate, limited therapeutic options and poor outcome. Predictors of outcome for patients in first relapse include the duration of first remission, cytogenetic risk at diagnosis, age and whether they underwent an allogeneic stem cell transplantation (alloSCT) in first remission. The incorporation of genetic aberrations detectable at diagnosis has been useful in further stratifying prognosis, but their predictive value at the time of relapse is not well established. Herein we analyze a large cohort of frontline-treated AML patients, focusing on the outcomes of patients presenting a first disease relapse.

Background

Introduction:Relapsed/refractory acute myeloid leukemia (rAML) remains a significant challenge, with low response to therapy and poor long-term survival. Treatments focusing on achieving a response and, in eligible patients (pts), proceeding with an allogeneic stem cell transplantation (alloSCT) offer the best prospect for improved survival. CPX-351 is a liposomal fixed-ratio formulation of cytarabine and daunorubicin, which has demonstrated higher response rates and reduced early mortality in some subsets of AML and has also been shown to be active in rAML. The BCL2 inhibitor venetoclax (Ven) has demonstrated efficacy in AML in combination with other agents, such as hypomethylating agents, low dose cytarabine, and intensive chemotherapy. We conducted a Phase Ib/II dose-finding study to evaluate the combination of CPX-351 with Ven in AML. Herein we present the results of CPX-351 plus Ven in the cohort of rAML pts treated on study (NCT03629171).

Introduction:Hypomethylating agents (HMA) with Venetoclax (Ven) is the standard of care for patients (pts) with acute myeloid leukemia (AML) ≥ 75 yrs of age or not candidates to intensive treatment. Döhner, et al. (ASH 2022) demonstrated that the European LeukemiaNet (ELN) risk classifications do not accurately predict prognosis in HMA-Ven treated pts. A prognostic risk signature classification (PRSc) was proposed, stratifying pts by RAS, FLT3and TP53mutations alone. This classification has not been validated in low intensity treatments combining Ven with cladribine (CLAD) and cytarabine. Moreover, RASmutations are common mechanisms of resistance to HMA-Ven, whilst it has been proposed that cytarabine and recently cladribine-based regimens could be effective in AML with this mutation. We report an update of pts treated with CLAD, low dose cytarabine (LDAC) and Ven, focusing on outcomes and risk group stratification.

Background:

Background:Venetoclax (Ven) in combination with hypomethylating agents is approved for treatment in patients (pts) with newly diagnosed (ND) acute myeloid leukemia (AML) who are ≥75 years old or unfit for intensive chemotherapy (IC), based on the longer median overall survival (OS) with Ven+azacitidine (Aza) compared with Aza in combination with placebo in the Phase III VIALE-A study (NCT02993523). Several studies are now evaluating Ven-based regimens in pts eligible for IC, for example Ven+Aza compared with IC (NCT04801797). Additionally, Ven in combination with cladribine (CLAD) and low-dose cytarabine (LDAC) is currently under investigation in a Phase II single-arm study (NCT03586609) amongst older pts (aged ≥60 years) with ND AML. An interim analysis of this trial evaluated 60 pts where complete remission (CR) and CR with incomplete count recovery (CRi) was observed in 93% of pts, and the median OS, overall and by transplant status, was not reached; 1-year OS was 72.9% and 2-year OS was 63.5% (Kadia et al. J Clin Oncol 2022). The aim of this study is to better understand treatment outcomes amongst older pts (aged ≥60 years) with ND AML receiving IC in a routine clinical care setting in the United States (US).

Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro-inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids’ prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid’s prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P< 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P= 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P= 0.001). The most important variables related to ES were HCT-CI >2 (p< 0.0001; HR 8.5) and risk groups (p< 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid’s prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs.

•Cancer-predisposing GVs are present in patients with AML without suspicion of hereditary hematologic malignancy syndrome.•ATMnonsense mutations were found in 6.4% of patients of our cohort, warranting further studies to clarify their role in AML predisposition.

Tormo: MSD: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Salamero:Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction