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Real-world treatment patterns and outcomes in patients with CLL and cardiovascular comorbidities: Interim analysis of the multicenter study conducted by eric.
No full textIntroduction: Management of chronic lymphocytic leukemia (CLL) has advanced significantly over the past decade with the introduction of targeted therapies (TT). Despite that, important challenges persist in optimizing treatment, especially for patients (pts) with concurrent cardiovascular comorbidities (CVC). We examined real-world treatment patterns and outcomes among pts with CLL and CVC, aiming to better understand therapeutic approaches and effectiveness in this complex population.
Methods: This retrospective multicenter longitudinal study included pts diagnosed with CLL between 2010 and 2020 (index period), who had at least one CVC at diagnosis or prior to first-line treatment (1L) initiation. Demographic and clinical variables were collected from physician-reported records. Pts were followed from the index date until the last follow-up (f/u), end of study (September 2024), or death, whichever came first. Clinical outcomes were assessed following 1L initiation and were described for both the overall study population and pts who received only TT.
Results: A total of 1393 pts from 20 centers in 7 countries were included. Most pts were male (898/1393, 64.5%) and had received at least 1 line of CLL-directed treatment (857/1393, 61.6%). The median f/u from diagnosis and 1L initiation were 8.4 years (yrs) [IQR=8-9] and 4 yrs [IQR=1.9-6.9], respectively. The median age (mAge) at diagnosis and 1L was 69 (IQR=62-76) and 71 (IQR=64-78) yrs, respectively. Most pts were diagnosed with arterial hypertension (1112/1393, 79.8%), followed by atrial fibrillation/flutter (AF) (180, 12.9%). Ischemic heart disease [excluding myocardial infarction (MI)], stroke, cardiomyopathy, MI, heart failure, other cardiac arrythmias (excluding AF), and cardiac valve disease were present in 139 (10%), 85 (6.1%), 61 (4.4%), 59 (4.2%), 52 (3.7%), 41 (2.9 %), 31 (2.2%), respectively.
At the time of 1L initiation, most pts had unmutated IGHV genes (316/547, 57.8%), while 94/641 (14.7%) had TP53 aberrations. The most common 1L treatments were chlorambucil-based (CHL) regimens [295/857 (34.4%), CHL monotherapy: 117 (13.7%) and CHL plus anti-CD20 monoclonal antibody: 178 (20.1%)] and BTK inhibitors (BTKis) [141/857 (16.5%), ibrutinib (I): 92 (10.7%), acalabrutinib (A): 45 (5.3%), zanubrutinib (Z): 4 (0.5%)]. Fludarabine-cyclophosphamide-rituximab (FCR) and bendamustine-rituximab (BR) were used in 133 (15.6%) and 53 (6.2%), respectively. Venetoclax-based (ven) regimens were used in 55 [6.4%, 50 (5.8%) received ven-obinutuzumab] pts. I plus ven was used in 7 (0.8%) pts.
After 2020, the use of BTKis [86/234 (36.7%), A: 43 (18.8%), I: 39 (16.7%), Z: 4 (1.7%)] and ven regimens (48, 20.5%) increased markedly, while chemoimmunotherapy use declined [CHL regimens: 43 (18.4%), BR: 12 (5.1%) and FCR: 5 (2.1%)].
The overall survival (mOS) and time to next treatment or death (mTTNTD) from 1L initiation were 8.4 yrs (95%CI=7.7-9.4) and 3.6 yrs (95%CI=3.2-4), respectively. Of the pts who received TT only, the mOS was not reached [95%CI=5.6 yrs, not estimable (NE)], and mTTNTD was 5.6 yrs (95%CI=4.5-NE).
The 3-year-TTNTD for BTKis [mAge: 73yrs], ven regimens (mAge: 69yrs), FCR (mAge: 61), and CHL regimens (mAge: 75yrs) was 71% (95%CI=62-80), 87.1% (95%CI=74-100), 67.5% (95%CI=60-76) and 44.2% (95%CI=39-51), respectively. Overall, 54/141 (38.3%) pts discontinued BTKis in 1L. The reasons were toxicity (tox) (20, 14.2%, CV tox: 9/20 and non-CV tox: 11/20), disease progression (PD) (15, 10.6%), CLL-unrelated (CLL-u) deaths (13, 9.2%) and other reasons (6, 4.2%). Of the 55 pts who received ven regimens, 6 (10.9%) discontinued treatment earlier than scheduled [non-CV tox: 3 (5.5%), other reasons: 2 (3.6%), and CLL-u death: 1 (1.8%)]. FCR (n=133) was discontinued earlier than scheduled in 15 (11.3%) pts [non-CV tox: 12 (9%), PD: 1 (0.8%), other reasons: 2 (1.5%)]. Finally, CHL regimens (n=295) were discontinued in 36 (12.2%) pts [non-CV tox: 14 (4.7%), PD: 12 (4.1%), other reasons: 9 (0.8%), CLL-u death: 1 (0.3%)].
Conclusion: We highlight a shift toward the use of TT in pts with CLL and CVC and illustrate differential patterns in TTNTD and discontinuation according to regimen. Differences in pts age and treatment duration across regimens may have contributed to the varying incidence of CV tox leading to discontinuation, especially in pts receiving BTKi. The study's retrospective nature, age and f/u differences preclude any comparison of TTNTD between treatments
AML-1196: The molecular and clinicopathological landscape of core-binding factor acute myeloid leukemia: a retrospective study
No full textContext:
Acute myeloid leukemia (AML) with core-binding factor (CBF) rearrangements, encompassing t(8;21)(q22;q22) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22), represents a distinct biological and clinical subset of AML.
Objective:
Comprehensively characterize the molecular and clinicopathological features of CBFAML through retrospective analysis, with the aim of identifying prognostic markers.
Design/Methods:
We retrospectively analyzed diagnosed cases of CBF-AML. Clinical features, hematological parameters, immunophenotypic profiles, cytogenetic and molecular findings, minimal residual disease (MRD) status, and survival outcomes were analyzed. Survival outcomes were analyzed using Kaplan–Meier survival analysis.
Results:
Among 192 CBF-AML patients (pediatric: 112; adult: 80), 165 had AML1-ETO/t(8;21), and 29 had CBFB-MYH11/inv(16). The median age was 14.5 (range 1–59) years, with a male:female ratio of 2.4:1. At presentation, the median hemoglobin was 7.3 g/dL, white blood cell count 17 × 109/L, platelets 28 × 109/L, and LDH 638 IU/L. Median peripheral blood and bone marrow blast percentages were 55% and 65%, respectively. Immunophenotypic analysis showed frequent co-expression of CD34, CD13, CD33, and HLA-DR across CBF-AML cases. Aberrant expression of CD56 (76% vs 28%) and CD19 (57.6% vs 7.7%) was more prevalent in cases with AML1-ETO, whereas aberrant expression of CD36 (28% vs 12.2%) and CD14 (20.8% vs 8%) was more common in cases with CBFB-MYH11. FLT3 mutation was observed in 9.1% of cases; NPM1 mutation was very rare, in 0.5% of cases. Additional cytogenetic abnormalities and complex karyotypes were detected in 52.6% and 10.3% of all cases, respectively, and were more prevalent in cases with AML1-ETO than in cases with CBF-MYH11. All patients received intensive induction chemotherapy, primarily the “7+3” regimen. Complete remission after induction was achieved in 77.8% of cases, and MRD negativity was observed in 64.3% of evaluable patients and was associated with significantly improved relapse-free survival (P < 0.001) and overall survival (P < 0.001). Patients with CBFB-MYH11 (inv(16)) demonstrated higher rates of complete remission and MRD negativity than those with AML1-ETO (t(8;21)).
Conclusions:
This study highlights the molecular and immunophenotypic differences between CBF-AML subtypes, with AML1-ETO linked to CD56/CD19 expression and complex karyotypes, and CBFB-MYH11 associated with CD14/CD36 expression and better responses. MRD negativity post induction strongly predicted improved survival
Altered dynamics of T cell subsets in peripheral blood impacts disease progression in newly diagnosed multiple myeloma
No full textT cells are essential for tumor immunosurveillance and disease regulation in Multiple Myeloma (MM), but their role in disease pathogenesis is not well understood. To investigate this, we analyzed T cell subsets for activation status, relative distribution of naïve and memory T cell populations, regulatory T cells (Tregs), and circulating follicular helper T cells (cTFH) in the peripheral blood of 40 newly diagnosed MM (NDMM) patients. We also assessed inhibitory receptor expression CD160, ICOS/CD278, CD152/CTLA-4, and PD-1/CD279 on T cells in peripheral blood. Our results showed reduced T cell numbers, an imbalance between naïve and effector CD4+ T cells, and decreased memory Tregs in newly diagnosed MM patients compared to healthy controls. Furthermore, plasma cells in the bone marrow correlated with percentage of activated cTFH cells and inhibitory receptor expressing T cells in peripheral blood indicating that disrupted T cell homeostasis and immune-mediated processes may drive disease progression in NDMM
Multi‐Day Extreme Precipitation Caused Major Floods in India During Summer Monsoon of 2024
No full textThe risk of extreme precipitation and flooding has increased in India due to climate change. During the 2024 summer monsoon season, three major extreme precipitation events occurred across the western, southern, and northern states of India, leading to widespread flooding in these regions. We examine the causes and impacts of extreme precipitation and flood events using a combination of observational data, reanalysis data sets, and hydrological models. In all the three regions, extreme rainfall occurred immediately after multiday continuous precipitation, resulting in catastrophic flooding. The 3-day extreme precipitation that caused flooding in the three regions had return periods of more than 75 years, 100 years, and 200 years, respectively. The primary moisture sources for the Gujarat floods were the Arabian Sea and the Indian Ocean, while the floods in Andhra Pradesh and Telangana were mainly sourced by the Bay of Bengal. For the floods in northern India, the dominant moisture sources were recycled land moisture and moisture transport from the Bay of Bengal. These moisture inflows, coupled with favorable atmospheric conditions, resulted in multiday extreme precipitation in the three regions. Saturated soil moisture conditions before the extreme precipitation contributed to high runoff, triggering extensive flooding in all the three regions. Our findings highlight the growing challenge of managing such extreme events as their frequency and intensity are projected to increase under a warming climate
High-impact and Low-likelihood compound hot and dry extremes in India
No full textCompound hot and dry extremes (CHDEs) in India have lasting impacts on agriculture, water resources, and energy sectors, which are likely to increase under the warming climate. However, the occurrence and implications of high-impact and low-likelihood (HILL) CHDEs under the observed and projected future climate remain underexplored. We identified that India witnessed HILL-CHDEs in 1987 and 2015 during the summer monsoon (June-September) and non-monsoon (October-May) seasons, respectively, between 1979 and 2024. The two CHDEs during the observed climate had high impacts, as these severely affected agriculture and water availability and covered about half of the country. Using 100 ensemble simulations from the Community Earth System Model (CESM2-LENS2), we find that HILL-CHDEs are projected to rise significantly in frequency, duration, spatial extent, and intensity, especially during the summer monsoon. This increase is primarily driven by climate warming and further intensified by El Niño events. The growing occurrence of HILL-CHDEs may severely impact food production, water supplies, groundwater use, and hydropower generation in the future
On the Utility of Soil Moisture for Monitoring and Prediction of Compound Hot and Dry Extremes in India
No full textThe increasing frequency of compound hot and dry extremes (CHDEs) across India poses serious risks to agriculture and ecosystems. However, real-time monitoring and prediction of CHDEs in India have been lacking. Here, we examine the effectiveness of soil moisture (SM) and evaporative stress ratio (ESR) in capturing dry extremes during the summer monsoon (June–September) and non-monsoon (October–May) seasons. Indicators solely based on soil moisture or ESR fail to capture dry extremes across the seasons and regions in India. However, a joint indicator based on soil moisture and (ESR) effectively captures dry extremes during the monsoon and non-monsoon seasons. We developed a catalog of CHDEs in India using the Standardized Hot and Drought Index (SHDI) for the 1979–2020 period. Most CHDEs in India occur during the summer monsoon season, driven by precipitation deficit and increased vapor pressure deficit (VPD). CHDEs cause vegetation stress as captured by solar-induced fluorescence (SIF) and the normalized difference vegetation index (NDVI). However, SIF responds more quickly to CHDEs than NDVI during the summer monsoon and non-monsoon seasons. We used SHDI and NDVI to examine their utility for near-real-time monitoring and predicting CHDEs in India. CHDEs in India can be predicted 2 weeks in advance using soil moisture, ESR, and temperature based on the Extended Range Forecasting System (ERFS), highlighting the potential of integrating observations and forecasts for monitoring and prediction
Weak coupling of observed surface PM2.5 in Delhi-NCR with rice crop residue burning in Punjab and Haryana
No full textAir pollution impacts on human health are of serious concern in northern India, and over the Delhi National Capital Region (NCR) in particular. The Kharif crop residue burning (CRB) is often blamed for degradation of Delhi-NCR’s seasonal air quality. However, the concentration of fine particulate matter (PM2.5) remained stable in Delhi, while the fire detection counts (FDCs) from satellites over Punjab and Haryana declined by 50% or more during 2015–2023. We measured PM2.5, carbon monoxide (CO) and related parameters over Delhi-NCR, Haryana and Punjab from a network of 30 low-cost sensors (CUPI-Gs) in a selected period (September–November) of 2022 and 2023. Measured PM2.5 showed lower concentration in 2023 compared to 2022 at Punjab and Haryana sites, in compliance with FDC reductions. Using the CUPI-G measurements, airmass trajectories, particle dispersion and chemical-transport model simulations, we show that the CRB emissions over Punjab contributed only a meagre ~14% to the overall PM2.5 over Delhi-NCR during October-November 2022. This indicates that there exists only a very weak coupling between PM2.5 mass over Delhi-NCR and the CRB over Punjab, highlighting the effectiveness of the Graded Response Action Plan (GRAP) in controlling air pollution in the region
Non-finite type étale sites over fields
No full textWe consider the notion of finite type-ness of a site introduced by Morel and Voevodsky, for the étale site of a field. For a given field k, we conjecture that the étale site of Sm / k is of finite type if and only if the field k admits a finite extension of finite cohomological dimension. We prove this conjecture in some cases, e.g. in the case when k is countable, or in the case when the p-cohomological dimension cdp (k) is infinite for infinitely many primes p
East Antarctic ice core record reveals a dramatic rise in anthropogenic copper emissions since ~ 1985
No full textAntarctic ice cores provide past atmospheric composition beyond the timeframe of the instrumental records. Here, we examine the record of copper (Cu), a trace metal contaminant, from an ice core record spanning the past ~ 200 years (1809–2012 CE) from the coastal Dronning Maud Land (cDML), East Antarctica (71.5° S, 10.25° E). We observed two-phase variability in Cu flux, first with no discernible trend (slope = − 0.0001, p = 0.27), and marked by a few high flux periods related to El Niño Southern Oscillations (ENSO) events during 1809–1942 (average = 0.05 µg cm−2 a−1), and second phase with an exponentially increasing trend that started around 1943 (R2 = 0.424, average = 0.09 µg cm−2 a−1), resulting in the doubling of Cu deposition after 1985 (average = 0.14 µg cm−2 a−1). Our study reveals that the dramatic increase of Cu deposition since ~ 1985 can be attributed to the combined role of 42-fold increase in Cu production from Chilean Cu mines and favorable atmospheric transport by a deepened low-pressure anomaly and stronger westerlies associated with the positive phase of the Southern Annular Mode (SAM). A comparable trend was observed for antimony (Sb), a trace element often associated with primary copper minerals, further supporting the attribution of elevated Cu deposition at the core site to historical mining activities. Our investigation on the Cu flux record revealed strong linkages with climate modes such as SAM and ENSO in controlling the variability of the Cu deposition flux. Further, examining the specific peaks and dips in the Cu flux record during 1985–2012, peak years showed an average wind intensification of 0.45–1.05 ms−1 compared to dip years, which contributed to the doubling of Cu deposition over the region. Considering this increasing trend in Cu deposition in this region, elevated copper levels may pose a long-term risk to phytoplankton growth and primary productivity in the Southern Ocean due to potential Cu toxicity
Constraining binary mergers in active galactic nuclei disks using the nonobservation of lensed gravitational waves
No full textThe dense and dynamic environments within active galactic nuclei (AGN) accretion disks may serve as prolific birthplaces for binary black holes (BBHs) and one possible origin for some of the BBHs detected by gravitational-wave (GW) observatories. We show that a considerable fraction of the BBH in AGN disks will be strongly lensed by the central supermassive black hole (SMBH). Thus, the nonobservation of lensed GW signals can be used to constrain the fraction of BBH binaries residing in AGN disks. The nondetection of lensing with current Ο(100) detections will be sufficient to start placing constraints on the fraction of BBHs living within accretion disks near the SMBH. In the next-generation detectors era, with Ο(105) BBH observations and no lensed events, we will be able to rule out most migration traps as dominant birthplaces of BBH mergers; moreover, we will be able to constrain the minimum size of the accretion disk. On the other hand, should AGNs constitute a major formation channel, lensed events from AGNs will become prominent in the future