FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

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Temporal trends in critical care utilization and outcomes in allogeneic hematopoietic stem cell transplant recipients.

Historically, the prognosis of allogeneic hematopoietic stem cell transplant (allo-HCT) recipients who require intensive care unit (ICU) admission has been poor. We aimed to describe the epidemiological trends of ICU utilization and outcomes in allo-HCT patients. We conducted a retrospective cohort study including adults (≥ 18) undergoing allo-HCT between 01/01/2005 and 31/12/2020 at Mayo Clinic, Rochester. Temporal trends in outcomes were assessed by robust linear regression modelling. Risk factors for hospital mortality were chosen a priori and assessed with multivariable logistic regression modelling. Of 1,249 subjects, there were 486 ICU admissions among 287 individuals. Although older patients underwent allo-HCT (1.64 [95% CI: 1.11 to 2.45] years per year; P = 0.025), there was no change in ICU utilization over time (P = 0.91). The ICU and hospital mortality rates were 19.2% (55/287) and 28.2% (81/287), respectively. There was a decline in ICU mortality (-0.38% [95% CI: -0.70 to -0.06%] per year; P = 0.035). The 1-year post-HCT mortality for those requiring ICU admission was 56.1% (161/287), with no significant difference over time, versus 15.8% (141/891, 71 missing) among those who did not. The frequency and duration of invasive mechanical ventilation (IMV) declined. In multivariable analyses, higher serum lactate, higher sequential organ failure assessment (SOFA) scores, acute respiratory distress (ARDS), and need for IMV were associated with greater odds of hospital mortality. Over time, rates of ICU utilization have remained stable, despite increasing patient age. Several trends suggest improvement in outcomes, notably lower ICU mortality and frequency of IMV. However, long-term survival remains unchanged. Further work is needed to improve long-term outcomes in this population.

Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.

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.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).

Adjusting diffusing capacity for anemia in patients undergoing allogeneic HCT: a comparison of two methodologies.

BACKGROUND: Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. STUDY DESIGN: This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. RESULTS: Patients had normal spirometry (FEV1 99.7% [IQR: 89.4-109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9-94.1%) while Dinakara-DLCO 111.0% (97.3-124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV1, Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). CONCLUSION: The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT.

Pulmonary function as a continuum of risk: critical care utilization and survival after allogeneic hematopoietic stem cell transplantation - a multicenter cohort study.

Abnormal pre-transplant pulmonary function tests (PFTs) are associated with reduced survival after allogeneic HCT. Existing scoring systems consider risk dichotomously, attributing risk only to those with abnormal lung function. In a multicenter cohort of 1717 allo-HCT recipients, we examined the association between pre-transplant PFT measures and need for ICU admission (120d), frequency of mechanical ventilation (120d) and overall survival (5 y). Predictive models were developed and validated using Cox proportional hazards, incorporating age, FEV1 (forced expiratory volume in 1-second) and diffusing capacity (DLCO). In univariate analysis, hazard ratios for each outcome (95% CI) were: mechanical ventilation (FEV1: 0.60 [0.52-0.69], DLCO: 0.69 [0.61-0.77], p < 0.001), ICU admission (FEV1: 0.74 [0.67-0.82], DLCO: 0.79 [0.72-0.86], p < 0.001) and overall survival (FEV1: HR 0.87 [0.81-0.94], DLCO: 0.83 [0.77-0.89], p < 0.001). A multivariable Cox model was developed and compared to the HCT-CI Pulmonary score in a validation cohort. This model was better at predicting need for ICU admission and mechanical ventilation, while both models predicted overall survival (p < 0.001). In conclusion, the risk conferred by pre-transplant pulmonary function should be considered in a continuous rather than dichotomous manner. A more granular prognostication system can better inform risk of critical care utilization in the early post-HCT period.

Prognostic Significance of Early Declines in Pulmonary Function After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Pulmonary function test (PFT) impairments are common after allogeneic hematopoietic stem cell transplantation. The prognostic significance of these declines on outcomes is not well understood.The objectives were to determine the frequency of declines in pulmonary function (FVC, FEV1, and diffusing capacity for carbon monoxide [DLCO]) in the early post-transplantation period; and to determine the prognostic significance of these declines on mortality or development of bronchiolitis obliterans syndrome. METHODS: This was a retrospective cohort study conducted at Mayo Clinic, Rochester, Minnesota. PFTs were obtained at baseline and at day +100. Competing risk survival models were developed, which accounted for pre-transplantation pulmonary function and relapse status. RESULTS: Between January 1, 2005, and December 31, 2020, 1,145 subjects underwent allogeneic hematopoietic stem cell transplantation and had a pre-transplantation PFT performed. Of these, 900 (78.6%) survived to day 100 and had post-transplantation PFTs performed (median [interquartile range] 97 [94-103] d). A decline of ≥10% in FEV1, FVC, or DLCO was seen in 401 of 900 subjects (44.5%). Declines of ≥20% in FEV1 (hazard ratio 1.65, 95% CI 1.07-2.56; P = .02), FVC (hazard ratio 1.72, 95% CI [1.11-2.67]; P = .02), and DLCO (hazard ratio 1.46, 95% CI 1.04-2.07; P = .028) were all associated with reduced survival when compared with those with < 10% decline in PFT measures. These findings were independent of pre-transplantation pulmonary function or relapse status. Bronchiolitis obliterans syndrome was diagnosed in 118 subjects (10.3%), and there was no relationship between early PFT decline and a subsequent diagnosis of bronchiolitis obliterans syndrome. The subjects who received myeloablative conditioning with cyclophosphamide plus total body irradiation or cyclophosphamide plus fludarabine plus total body irradiation were more likely to have lower spirometry values after hematopoietic stem cell transplantation. The subjects who received reduced intensity conditioning or nonmyeloablative conditioning with fludarabine plus total body irradiation were more likely to have higher post-hematopoietic stem cell transplantation FEV1, FVC, and DLCO. CONCLUSIONS: An absolute decline of ≥20% in FEV1, FVC, or DLCO were associated with reduced survival independent of pre-transplantation pulmonary function or relapse status. In contrast to previous work, early declines in PFT measures were not associated with future development of bronchiolitis obliterans syndrome.