Significant disagreement between conventional parameters and 3D echocardiography-derived ejection fraction in the detection of right ventricular systolic dysfunction and its association with outcomes.

AIMS: Conventional echocardiographic parameters such as tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strain (FWLS) offer limited insights into the complexity of right ventricular (RV) systolic function, while 3D echocardiography-derived RV ejection fraction (RVEF) enables a comprehensive assessment. We investigated the discordance between TAPSE, FAC, FWLS, and RVEF in RV systolic function grading and associated outcomes. METHODS: We analyzed 2D and 3D echocardiography data from two centers including 750 patients followed up for all-cause mortality. RV dysfunction was defined as RVEF<45%, with guideline-recommended thresholds (TAPSE<17 mm, FAC<35%, FWLS>-20%) considered. RESULTS: Among patients with normal RVEF, significant proportions exhibited impaired TAPSE (21%), FAC (33%), or FWLS (8%). Conversely, numerous patients with reduced RVEF had normal TAPSE (46%), FAC (26%), or FWLS (41%). Using ROC analysis FWLS exhibited the highest AUC of discrimination for RV dysfunction (RVEF<45%) with 59% sensitivity and 92% specificity. Over a median 3.7-year follow-up, 15% of patients died. Univariable Cox regression identified TAPSE, FAC, FWLS, and RVEF as significant mortality predictors. Combining impaired conventional parameters showed that outcomes are the worst if at least two parameters are impaired and gradually better if only one or none of them (log-rank p<0.005). CONCLUSION: Guideline-recommended cut-off values of conventional echocardiographic parameters of RV systolic function are only modestly associated with RVEF-based assessment. Impaired values of FWLS showed the closest association with the RVEF cut-off. Our results emphasize a multiparametric approach in the assessment of RV function, especially, if 3D echocardiography is not available.

Multi-assay approach shows species-associated personality patterns in two socially distinct gerbil species.

We aimed to investigate whether two closely related but socially distinct species of gerbils differ in personality patterns. Using a suit of multivariate repeated assays (docility test, dark-light emergence test, startle test, novel object test, elevated platform test, and stranger test), we assessed contextual and temporal consistency of docility, boldness, exploration, anxiety, and sociability in the solitary midday gerbil, Meriones meridianus, and social Mongolian gerbil, M. unguiculatus. We revealed contextually consistent and highly repeatable sex-independent but species-specific personality traits. Species differed in temporal repeatability of different behaviours, and contextual consistency was more pronounced in solitary M. meridianus than in social M. unguiculatus. This finding contradicts the social niche specialization hypothesis, which suggests that personality traits should be more consistent in more social species. Instead, we hypothesize that social complexity should favour more flexible and less consistent behavioural traits. The habituation effect indicative of learning abilities was weak in both species yet stronger in social M. unguiculatus, supporting the relationship between the sociality level and cognitive skills. In both species, only a few different behavioural traits covaried, and the sets of correlated behaviours were species-specific such that the two species did not share any pair of correlated traits. Between-species differences in personality traits, habituation, and behavioural syndromes may be linked to differences in sociality. The lack of prominent behavioural syndromes is consistent with the idea that context-specific individual behavioural traits might be favoured to allow more flexible and adequate responses to changing environments than syndromes of correlated functionally different behaviours.

Role and application of three-dimensional transthoracic echocardiography in the assessment of left and right ventricular volumes and ejection fraction: a UK nationwide survey.

Three-dimensional echocardiography (3DE) imaging has permitted advancements in the quantification of left ventricular (LV) and right ventricular (RV) volumes and ejection fraction. We evaluated the availability of 3DE equipment / analysis software, the integration of 3DE assessment of the LV and RV in routine clinical practice, current training provisions in 3DE, and aimed to ascertain barriers preventing the routine use of 3DE for volumetric analysis. Through the British Society of Echocardiography (BSE) regional representatives' network, echocardiographers were invited to participate in an open online survey. A total of 181 participants from echocardiography departments in the United Kingdom (UK), the majority from tertiary centres (61%), completed the 28-question survey. For 3DE quantification, 3DE-LV was adopted more frequently than 3DE-RV (48% vs 11%, respectively). Imaging feasibility was a recognised factor in 3DE RV and LV adoption. Many respondents had access to 3D probes (93%). The largest observed barriers to 3DE routine use were training deficiencies, with 83% reporting they would benefit from additional training opportunities and the duration of time permitted for the scan, with 68% of responders reporting allowances of less than the BSE standard of 45-60 min per patient (8% < 30-min). Furthermore, of those respondents who had undertaken professional accreditation, competence in 3DE was not formally assessed in 89%. This UK survey also reported good accessibility to magnetic resonance imaging (72%), which was related to overall 3DE adoption. In summary, although 3DE is now readily available, it remains underutilised. Further training opportunities, integrated formal assessment, improved adoption of BSE minimum recommended scanning times, alongside industry and societal support, may increase 3DE utilisation in routine practice.

Myocardial work of the systemic right ventricle and its association with outcomes.

We aimed to evaluate clinical and prognostic significance of myocardial work parameters of the systemic right ventricle (SRV). Thirty-eight patients with the SRV underwent echocardiographic assessment of the SRV systolic function including 3D-echocardiography derived ejection fraction, 2D longitudinal strain and myocardial work analysis. The study endpoint was the combination of all-cause mortality and heart transplantation. Global constructive work (GCW) and global work index (GWI) demonstrated moderate correlation with the 3DE-derived SRV ejection fraction (EF) (Rho 0.64, p < 0.0001 and Rho 0.63, p < 0.0001, respectively). GCW showed the strongest correlation with the BNP level (Rho - 0.77, p < 0.0001), closely followed by GWI, 4-chamber longitudinal strain and 3DE EF (all Rho - 0.73, p < 0.0001). GCW and GWI were significantly lower in patients with moderate or severe tricuspid regurgitation compared with less than moderate regurgitation (1226 ± 439 vs 1509 ± 264 mmHg%, p = 0.02, and 984 ± 348 vs 1259 ± 278 mmHg%, p = 0.01, respectively). During a follow-up of 3.5 (2.8-3.9) years, seven patients (18%) died and one received transplantation (3%). They had significantly lower GCW and GWI compared with patients who did not reach the study endpoint (908 ± 255 vs 1433 ± %, p < 0.001 and 721 ± 210 vs 1173 ± 315 mmHg%, p < 0.001, respectively). In Cox regression analysis, GCW, GWI, 3DE SRV volumes and EF were the best-fit models based on the Akaike Information Criterion, outperforming longitudinal strain parameters. GWI and GCW, novel echocardiographic parameters of myocardial work, provided reliable quantification of the SRV systolic function. GWI, GCW and 3DE-derived SRV parameters were closely associated with all-cause mortality and heart transplantation in patients with the SRV.

The Role of Multimodality Imaging in Patients with Congenital Heart Disease and Infective Endocarditis.

Infective endocarditis (IE) represents an important medical challenge, particularly in patients with congenital heart diseases (CHD). Its early and accurate diagnosis is crucial for effective management to improve patient outcomes. Multimodality imaging is emerging as a powerful tool in the diagnosis and management of IE in CHD patients, offering a comprehensive and integrated approach that enhances diagnostic accuracy and guides therapeutic strategies. This review illustrates the utilities of each single multimodality imaging, including transthoracic and transoesophageal echocardiography, cardiac computed tomography (CCT), cardiovascular magnetic resonance imaging (CMR), and nuclear imaging modalities, in the diagnosis of IE in CHD patients. These imaging techniques provide crucial information about valvular and intracardiac structures, vegetation size and location, abscess formation, and associated complications, helping clinicians make timely and informed decisions. However, each one does have limitations that influence its applicability.

Multimodality Imaging Assessment of Tetralogy of Fallot: From Diagnosis to Long-Term Follow-Up.

Tetralogy of Fallot (TOF) is the most common complex congenital heart disease with long-term survivors, demanding serial monitoring of the possible complications that can be encountered from the diagnosis to long-term follow-up. Cardiovascular imaging is key in the diagnosis and serial assessment of TOF patients, guiding patients' management and providing prognostic information. Thorough knowledge of the pathophysiology and expected sequalae in TOF, as well as the advantages and limitations of different non-invasive imaging modalities that can be used for diagnosis and follow-up, is the key to ensuring optimal management of patients with TOF. The aim of this manuscript is to provide a comprehensive overview of the role of each modality and common protocols used in clinical practice in the assessment of TOF patients.

Prognostic significance of subpulmonary left ventricular size and function in patients with a systemic right ventricle.

AIMS: To assess the additional prognostic significance of echocardiographic parameters of subpulmonary left ventricular (LV) size and function in patients with a systemic right ventricle (SRV). METHODS AND RESULTS: All adults with an SRV who underwent transthoracic echocardiography in 2010-18 at a large tertiary centre were identified. Biventricular size and function were assessed at the most recent examination. The study endpoint was all-cause mortality or heart/heart-lung transplantation. We included 180 patients, with 100 (55.6%) males, with a mean age of 42.4 ± 12.3 years, of whom 103 (57.2%) had undergone Mustard/Senning operations and 77 (42.8%) had congenitally corrected transposition of great arteries. Over 4.9 (3.8-5.7) years, 28 (15.6%) patients died and 4 (2.2%) underwent heart or heart-lung transplantation. Univariable predictors of the study endpoint included age, New York Heart Association functional Class III or IV, history of atrial arrhythmias, presence of a pacemaker or cardioverter defibrillator, high B-type natriuretic peptide, and echocardiographic markers of SRV and subpulmonary LV size and function. On multivariable Cox analysis of echocardiographic variables, indexed LV end-systolic diameter [ESDi; hazard ratio (HR) 2.77 (95% confidence interval, CI) 1.35-5.68, P = 0.01], LV fractional area change [FAC; HR 0.7 (95% CI 0.57-0.85), P = 0.002), SRV basal diameter [HR 1.66 (95% CI 1.21-2.29), P = 0.005], and SRV FAC [HR 0.65 (95% CI 0.49-0.87), P = 0.008] remained predictive of mortality or transplantation. On receiver-operating characteristic analysis, subpulmonary LV parameters performed better than SRV markers in predicting adverse events. CONCLUSION: SRV basal diameter, SRV FAC, LV ESDi, and LV FAC are significantly and independently associated with mortality and transplantation in adults with an SRV. Accurate echocardiographic assessment of both SRV and subpulmonary LV is, therefore, essential to inform risk stratification and management.

A Systematic Review on the Safety of Mycobacterium tuberculosis-Specific Antigen-Based Skin Tests for Tuberculosis Infection Compared With Tuberculin Skin Tests.

Background: A systematic review showed that the accuracy of Mycobacterium tuberculosis antigen-based skin tests (TBSTs) for tuberculosis is similar to that of interferon γ release assay, but the safety of TBSTs has not been systematically reviewed. Methods: We searched for studies reporting injection site reactions (ISRs) and systemic adverse events associated with TBSTs. We searched Medline, Embase, e-library, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure database for studies through 30 July 2021, and the database search was updated until 22 November 2022. Results: We identified 7 studies for Cy-Tb (Serum Institute of India), 7 (including 2 found through the updated search) for C-TST (Anhui Zhifei Longcom), and 11 for Diaskintest (Generium). The pooled risk of any injection site reactions (ISRs) due to Cy-Tb (n = 2931; 5 studies) did not differ significantly from that for tuberculin skin tests (TSTs; risk ratio, 1.05 [95% confidence interval, .70-1.58]). More than 95% of ISRs were reported as mild or moderate; common ISRs included pain, itching, and rash. In 1 randomized controlled study, 49 of 153 participants (37.6%) given Cy-Tb experience any systemic adverse event (eg, fever and headache), compared with 56 of 149 participants (37.6%) given TST (risk ratio, 0.85 [95% confidence interval, .6-1.2]). In a randomized controlled study in China (n = 14 579), the frequency of systemic adverse events in participants given C-TST was similar to that for TST, and the frequency of ISRs was similar to or lower than that for TST. Reporting of the safety data on Diaskintest was not standardized, precluding meta-analysis. Conclusion: The safety profile of TBSTs appears similar to that of TSTs and is associated with mostly mild ISRs.

Association of Right Ventricular Functional Parameters With Adverse Cardiopulmonary Outcomes: A Meta-analysis.

AIMS: We aimed to confirm that three-dimensional echocardiography-derived right ventricular ejection fraction (RVEF) is better associated with adverse cardiopulmonary outcomes than the conventional echocardiographic parameters. METHODS: We performed a meta-analysis of studies reporting the impact of unit change of RVEF, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strain (FWLS) on clinical outcomes (all-cause mortality and/or adverse cardiopulmonary outcomes). Hazard ratios (HRs) were rescaled by the within-study SDs to represent standardized changes. Within each study, we calculated the ratio of HRs related to a 1 SD reduction in RVEF versus TAPSE, or FAC, or FWLS, to quantify the association of RVEF with adverse outcomes relative to the other metrics. These ratios of HRs were pooled using random-effects models. RESULTS: Ten independent studies were identified as suitable, including data on 1,928 patients with various cardiopulmonary conditions. Overall, a 1 SD reduction in RVEF was robustly associated with adverse outcomes (HR = 2.64 [95% CI, 2.18-3.20], P < .001; heterogeneity: I2 = 65%, P = .002). In studies reporting HRs for RVEF and TAPSE, or RVEF and FAC, or RVEF and FWLS in the same cohort, head-to-head comparison revealed that RVEF showed significantly stronger association with adverse outcomes per SD reduction versus the other 3 parameters (vs TAPSE, HR = 1.54 [95% CI, 1.04-2.28], P = .031; vs FAC, HR = 1.45 [95% CI, 1.15-1.81], P = .001; vs FWLS, HR = 1.44 [95% CI, 1.07-1.95], P = .018). CONCLUSION: Reduction in three-dimensional echocardiography-derived RVEF shows stronger association with adverse clinical outcomes than conventional right ventricular functional indices; therefore, it might further refine the risk stratification of patients with cardiopulmonary diseases.

Latitudinal gradients in body size and sexual size dimorphism in fleas: males drive Bergmann's pattern.

We tested for the effects of latitude and geographic range size (GRS) on body size, leg length, and sexual size dimorphism (SSD) across 103 species of fleas, taking into account phylogenetic between-species relationships. When the data on body size were combined for males and females, the positive correlation between body size and latitude, but not GRS, was revealed. When the analysis was restricted to one sex only, the effect of latitude appeared to be non-significant for females, whereas male body size increased with an increase in latitude. Intraspecific body size variation was not associated with either the latitude or the latitudinal span of the geographic range, independently of which data subset was analyzed. No evidence of association between size-independent tibia length and latitude was found for either females, males, or both sexes combined. The degree of SSD decreased with a decrease in latitude but was not affected by GRS. We conclude that macroecological patterns might be manifested differently in males and females. This should be kept in mind while searching for these patterns.

Non-Invasive Imaging Assessment in Patients with Aortic Coarctation: A Contemporary Review.

Coarctation of the aorta (CoA) is a congenital abnormality characterized by a narrowing of the aortic lumen, which can lead to significant morbidity and mortality if left untreated. Even after repair and despite significant advances in therapeutic management, these patients have overall reduced long-term survival due to the consequences of chronic afterload increase. Cardiovascular imaging is key from the first diagnosis to serial follow-up. In recent years, novel imaging techniques have emerged, increasing accessibility to advanced imaging modalities and enabling early and non-invasive identification of complications after repair. The aim of this paper is to provide a comprehensive review of the role of different imaging techniques in the evaluation and management of patients with native or repaired CoA, highlighting their unique strengths and limitations.

The dysfunctional right ventricle: the importance of multi-modality imaging.

Assessment of right ventricular (RV) function is crucial for the evaluation of the dyspnoeic patient and/or with systemic venous congestion and provides powerful prognostic insights. It can be performed using different imaging modalities including standard and advanced echocardiographic techniques, cardiac magnetic resonance imaging, computed tomography, and radionuclide techniques, which should be used in a complementary fashion. Each modality has strengths and weaknesses based on which the choice of their use and in which combination may vary according to the different clinical scenarios as will be detailed in this review. The conclusions from multiple studies using different imaging techniques are concordant: RV function can be reliably assessed and is a critical predictor of clinical outcomes.

Contraction patterns of the systemic right ventricle: a three-dimensional echocardiography study.

AIMS: To investigate contraction patterns of the systemic right ventricle (SRV) in patients with transposition of great arteries (TGA) post-atrial switch operation and with congenitally corrected transposition of great arteries (ccTGA). METHODS AND RESULTS: Right ventricular (RV) volumes and ejection fraction (EF) were measured by three-dimensional echocardiography in 38 patients with the SRV (24 TGA and 14 ccTGA; mean age 45 ± 12 years, 63% male), and in 38 healthy volunteers. The RV contraction was decomposed along the longitudinal, radial, and anteroposterior directions providing longitudinal, radial, and anteroposterior EF (LEF, REF, and AEF, respectively) and their contributions to total right ventricular ejection fraction (LEFi, REFi, and AEFi, respectvely). SRV was significantly larger with lower systolic function compared with healthy controls. SRV EF and four-chamber longitudinal strain strongly correlated with B-type natriuretic peptide (BNP) level (Rho -0.73, P < 0.0001 and 0.70, P < 0.0001, respectively). In patients with TGA, anteroposterior component was significantly higher than longitudinal and radial components (AEF 17 ± 4.5% vs. REF 13 ± 4.9% vs. LEF 10 ± 3.3%, P < 0.0001; AEFi 0.48 ± 0.09 vs. REFi 0.38 ± 0.1 vs. LEFi 0.29 ± 0.08, P < 0.0001). In patients with ccTGA, there was no significant difference between three SRV components. AEFi was significantly higher in TGA subgroup compared with ccTGA (0.48 ± 0.09 vs. 0.36 ± 0.08, P = 0.0002). CONCLUSION: Contraction patterns of the SRV are different in TGA and ccTGA. Anteroposterior component is dominant in TGA providing compensation for impaired longitudinal and radial components, while in ccTGA all components contribute equally to the total EF. SRV EF and longitudinal strain demonstrate strong correlation with BNP level and should be a part of routine echocardiographic assessment of the SRV.

Contraction Patterns of the Right Ventricle Associated with Different Degrees of Left Ventricular Systolic Dysfunction.

BACKGROUND: The functional adaptation of the right ventricle (RV) to the different degrees of left ventricular (LV) dysfunction remains to be clarified. We sought to (1) assess the changes in RV contraction pattern associated with the reduction of LV ejection fraction (EF) and (2) analyze whether the assessment of RV longitudinal, radial, and anteroposterior motion components of total RVEF adds prognostic value. METHODS: Consecutive patients with left-sided heart disease who underwent clinically indicated transthoracic echocardiography were enrolled in a single-center prospective observational study. Adverse outcome was defined as heart failure hospitalization or cardiac death. Cross-sectional analysis using the baseline 3-dimensional echocardiography studies was performed to quantify the relative contribution of the longitudinal, radial, and anteroposterior motion components to total RVEF. RESULTS: We studied 292 patients and followed them for 6.7±2.2 years. In patients with mildly and moderately reduced LVEF, the longitudinal and the anteroposterior components of RVEF decreased significantly, while the radial component increased resulting in preserved total RVEF (RVEF: 50% [46%-54%] versus 47% [44%-52%] versus 46% [42%-49%] in patients with no, mild, or moderate LV dysfunction, respectively; data presented as median and interquartile range). In patients with severe LV systolic dysfunction (n=34), a reduction in all 3 RV motion components led to a significant drop in RVEF (30% [25%-39%], P<0.001). In patients with normal RVEF (>45%), the anteroposterior component of total RVEF was a significant and independent predictor of outcome (hazard ratio, 0.960 [CI, 0.925-0.997], P<0.001). CONCLUSIONS: In patients with left-sided heart disease, there is a significant remodeling of the RV associated with preservation of the RVEF in patients with mild or moderate LV dysfunction. In patients with normal RVEF, the measurement of the anteroposterior component of RV motion provided independent prognostic value.

Global and regional right ventricular mechanics in repaired tetralogy of Fallot with chronic severe pulmonary regurgitation: a three-dimensional echocardiography study.

BACKGROUND: Data about the right ventricular (RV) mechanics adaptation to volume overload in patients with repaired tetralogy of Fallot (rToF) are limited. Accordingly, we sought to assess the mechanics of the functional remodeling occurring in the RV of rToF with severe pulmonary regurgitation. METHODS: We used three-dimensional transthoracic echocardiography (3DTE) to obtain RV data sets from 33 rToF patients and 30 age- and sex- matched controls. A 3D mesh model of the RV was generated, and RV global and regional longitudinal (LS) and circumferential (CS) strain components, and the relative contribution of longitudinal (LEF), radial (REF) and anteroposterior (AEF) wall motion to global RV ejection fraction (RVEF) were computed using the ReVISION method. RESULTS: Corresponding to decreased global RVEF (45 ± 6% vs 55 ± 5%, p < 0.0001), rToF patients demonstrated lower absolute values of LEF (17 ± 4 vs 28 ± 4), REF (20 ± 5 vs 25 ± 4) and AEF (17 ± 5 vs 21 ± 4) than controls (p < 0.01). However, only the relative contribution of LEF to global RVEF (0.39 ± 0.09 vs 0.52 ± 0.05, p < 0.0001) was significantly decreased in rToF, whereas the contribution of REF (0.45 ± 0.08 vs 0.46 ± 0.04, p > 0.05) and AEF (0.38 ± 0.09 vs 0.39 ± 0.04, p > 0.05) to global RVEF was similar to controls. Accordingly, rToF patients showed lower 3D RV global LS (-16.94 ± 2.9 vs -23.22 ± 2.9, p < 0.0001) and CS (-19.79 ± 3.3 vs -22.81 ± 3.5, p < 0.01) than controls. However, looking at the regional RV deformation, the 3D CS was lower in rToF than in controls only in the basal RV free-wall segment (p < 0.01). 3D RV LS was reduced in all RV free-wall segments in rToF (p < 0.0001), but similar to controls in the septum (p > 0.05). CONCLUSIONS: 3DTE allows a quantitative evaluation of the mechanics of global RVEF. In rToF with chronic volume overload, the relative contribution of the longitudinal shortening to global RVEF is affected more than either the radial or the anteroposterior components.

Lifestyle modification program, LIFE is LIGHT, in patients with type 2 diabetes mellitus and obesity: Results from a 48-week, multicenter, non-randomized, parallel-group, open-label study.

BACKGROUND: Obesity is a potential risk factor for development of type 2 diabetes mellitus (T2DM). To achieve long-term weight reduction in patients with T2DM and obesity using comprehensive lifestyle management program (LMP). MATERIALS AND METHODS: This 48-week interventional, multicenter, parallel-group, open-label study included patients aged ≥18 years with T2DM and a body mass index (BMI) of 27-40 kg/m2. The primary objective was to demonstrate a clinically significant weight reduction (≥5%) from baseline in intensive lifestyle modification (ILM) and standard treatment (ST) groups. RESULTS: The ILM group (N = 100) received recommendations for dietary and physical activity, and behavioral counseling. The ST group (N = 30) was managed in accordance with routine T2DM clinical practice. The patients in ST group were older (60.6 ± 8.9 vs. 54.6 ± 10.2 years in ILM group); overall more than 60% were women. At Week 48, the mean reduction in body weight was 5.8% (95% confidence interval [CI]: -6.9, -4.6) and 1.2% (95% CI: -2.6, 0.2) (p < 0.001) in the ILM and ST group, respectively. At Week 48, a weight loss of ≥5% was achieved by 50% of patients in the ILM group versus 13.3% in the ST group (p = 0.002). The decreases in BMI, waist-to-hip ratio and glycated hemoglobin (HbA1c) was significantly greater in the ILM versus ST group with between-group differences of -1.63 (p ≤ 0.001), -0.03 (р ≤ 0.001) and -0.69% (p = 0.002), respectively. CONCLUSION: A clinically significant weight reduction (≥5%) was demonstrated in patients with obesity and T2DM with use of a comprehensive LMP, along with improvements in BMI, waist-to-hip ratio, and HbA1c.

Anteroposterior Contraction of the Systemic Right Ventricle: Underrecognized Component of the Global Systolic Function.

Accurate echocardiographic evaluation of the systemic right ventricle is challenging because of its specific morphology and contraction patterns. We present a detailed multimodality assessment of the systemic right ventricle, analyze the relative contribution of the longitudinal, radial, and anteroposterior components of systolic function, and identify reasons for a potential discrepancy among imaging modalities. (Level of Difficulty: Intermediate.).

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study.

The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10% to 15% of patients are cured by the procedure. Preclinical studies indicate that substitution of post-transplantation cyclophosphamide with bendamustine (PTB) in a prophylaxis regimen may be associated with an augmented graft-versus-leukemia (GVL) reaction. The aim of this study was to establish the optimal dose of PTB and evaluate the antileukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. In the prospective trial (NCT02799147), PTB was administered in doses of 140, 100, and 70 mg/m2 on days +3 and +4. Myeloablative conditioning with fludarabine and oral busulfan was provided to all patients. The first 12 patients received single-agent PTB, and subsequent patients received combination therapy with tacrolimus and mycophenolate mofetil (MMF). Inclusion criteria were acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and ≥5% clonal blasts in the bone marrow. The study cohort comprised 22 patients with AML and 5 with ALL. Seven patients were enrolled in the 140 mg/m2 group (due to a stopping rule), and 10 each were enrolled in the 100 mg/m2 and 70 mg/m2 groups. Primary refractory disease was documented in 41% of the patients, and secondary refractory was documented in 59%. The median blast count in the bone marrow at the start of the conditioning was 18% (range, 6% to 97%). Transplantation was performed with a matched sibling donor in 5 patients, a matched or mismatched unrelated donor in 15, and a haploidentical donor in 7. Engraftment was documented in 93% of the patients, including 89% with complete remission and 63% without measurable residual disease. After PTB prophylaxis, we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3 to 5 CRS in 44%. The most frequent clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation in 37%, and central nervous system toxicity in 26%. The development of CRS was associated with use of an HLA-mismatched donor (75% versus 20%; P = .0043). Classic acute GVHD was documented in 44% of the patients. Grade II-IV acute GVHD was associated with grade 3 to 5 CRS (67% versus 25%; P = .031). Moderate and severe chronic GVHD in the 100-day survivors were more often observed after single-agent PTB than after the combination immunosuppression (100% versus 18%; P = .002). A relatively low relapse rate was observed for this patient population. Three-year overall survival was 28% (95% confidence interval [CI], 13% to 46%), and event-free survival was 29% (95% CI, 13% to 46%). Nonrelapse mortality was 46% (95% CI, 25% to 64%), and the cumulative incidence of relapse was 26% (95% CI, 11% to 44%). No relapses were documented after day +100. There were no statistically significant differences among the dose groups (P = .3481); however, survival was higher in the 100 mg/kg group. Survival was higher in patients with AML compared with those with ALL (35% versus 0%; P = .0157). PTB represents a promising option to augment the GVL effect in refractory AML; however, the high CRS-associated mortality necessitates additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications, at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.