ABSTRACT
BACKGROUND: Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. OBJECTIVE: We evaluate the prognostic ability of the HCT-CI and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy based GVHD prophylaxis. STUDY DESIGN: Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥ 2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. RESULTS: A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 years after alloHCT (34.5% vs. 12.3%, Pâ¯=â¯0.003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 - 6.17, Pâ¯=â¯0.005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 - 4.36, Pâ¯=â¯0.034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 - 4.33, Pâ¯=â¯0.005) and high risk (HR 5.77, 95% CI 2.31 - 14.39, P < 0.001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. CONCLUSION: Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.
Subject(s)
Immunotherapy, Adoptive , Lymphohistiocytosis, Hemophagocytic , Receptors, Chimeric Antigen , Humans , Lymphohistiocytosis, Hemophagocytic/therapy , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Female , Receptors, Chimeric Antigen/immunology , Immunotherapy, Adoptive/adverse effects , Treatment Outcome , Child , Adult , Adolescent , Child, Preschool , Disease Management , Infant , Middle AgedABSTRACT
Not available.
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Not available.
ABSTRACT
ABSTRACT: Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.
Subject(s)
Disease Progression , Humans , Male , Female , Middle Aged , Aged , Adult , Aged, 80 and over , Mutation , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Pancytopenia/etiology , CytopeniaSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Cladribine , Cytarabine , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Cladribine/therapeutic use , Cladribine/administration & dosage , Male , Female , Middle Aged , Aged , Adult , Recurrence , Drug Resistance, Neoplasm/drug effects , Treatment OutcomeABSTRACT
The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.
Subject(s)
Leukemia, Myeloid, Acute , Mutation , Myelodysplastic Syndromes , Proto-Oncogene Proteins , Repressor Proteins , Humans , Male , Female , Repressor Proteins/genetics , Middle Aged , Aged , Adult , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/diagnosis , Proto-Oncogene Proteins/genetics , Aged, 80 and over , Core Binding Factor Alpha 2 Subunit/genetics , Prognosis , Young Adult , Hematopoietic Stem Cell Transplantation , AdolescentABSTRACT
Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.
Subject(s)
Cardiomyopathies , Leukemia, Myeloid, Acute , Sulfonamides , Male , Humans , Female , Retrospective Studies , Treatment Outcome , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Cardiomyopathies/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: Invasive aspergillosis is associated with significant morbidity and mortality in patients with haematologic malignancies and haematopoietic cell transplant recipients. The prognosis is worse among patients who have failed primary antifungal treatment. OBJECTIVES: We aim to provide guidance on the diagnosis and management of refractory invasive pulmonary aspergillosis. SOURCES: Using PubMed, we performed a review of original articles, meta-analyses, and systematic reviews. CONTENT: We discuss the diagnostic criteria for invasive pulmonary aspergillosis and the evidence on the treatment of primary infection. We outline our diagnostic approach to refractory disease. We propose a treatment algorithm for refractory disease and discuss the role of experimental antifungal agents. IMPLICATIONS: For patients with worsening disease while on antifungal therapy, a thorough diagnostic evaluation is required to confirm the diagnosis of aspergillosis and exclude another concomitant infection. Treatment should be individualized. Current options include switching to another triazole, transitioning to a lipid formulation of amphotericin B, or using combination antifungal therapy.
Subject(s)
Antifungal Agents , Invasive Pulmonary Aspergillosis , Humans , Invasive Pulmonary Aspergillosis/drug therapy , Invasive Pulmonary Aspergillosis/diagnosis , Antifungal Agents/therapeutic use , Disease Management , Amphotericin B/therapeutic useSubject(s)
Leukemia, Mast-Cell , Humans , Leukemia, Mast-Cell/therapy , Mast Cells , Treatment OutcomeABSTRACT
Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.
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Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/chemically induced , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/chemically induced , Bridged Bicyclo Compounds, Heterocyclic , Sulfonamides , Antineoplastic Combined Chemotherapy Protocols/adverse effects , DEAD-box RNA HelicasesABSTRACT
Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Leukemia, Myeloid, Acute , Sulfonamides , Adult , Humans , Aged , Disease-Free Survival , Retrospective Studies , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Genotype , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Rationale: Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives: To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods: Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results: Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870-0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828-0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782-0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831-0.914). Conclusions: A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure.