Acalabrutinib-Based Regimens in Frontline or Relapsed/Refractory Higher-Risk CLL
Acalabrutinib-based regimens achieve long-term efficacy in patients with higher-risk CLL, across all lines of therapy. Safety profile of acalabrutinib in patients with higher-risk CLL was similar to the overall safety profile of acalabrutinib.
Summary
Pooled Analysis of 5 Clinical Trials
[Posted 13/Jul/2024]
AUDIENCE: Hematology, Family Medicine
KEY FINDINGS: The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. The analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.
BACKGROUND: Before targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy.
DETAILS: Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, authors pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. A total of 808 patients were included (TN cohort, n = 320; R/R cohort, n = 488). Median follow-up was 59.1 months (TN cohort) and 44.3 months (R/R cohort); 51.3% and 26.8% of patients in the TN and R/R cohorts, respectively, remained on treatment at last follow-up. In the del(17p)/TP53m, uIGHV, and CK subgroups in the TN cohort, median progression-free survival (PFS) and median overall survival (OS) were not reached (NR). In the del(17p)/TP53m, uIGHV, and CK subgroups in the R/R cohort, median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and median OS was 60.6 months, NR, and NR, respectively.
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Source: Davids, M. S., Sharman, J. P., Ghia, P., et al. (2024). Acalabrutinib-Based Regimens in Frontline or Relapsed/Refractory Higher-Risk CLL: Pooled Analysis of 5 Clinical Trials. Blood Advances. 2024; 8(13): 3345-3359. Published: July, 2024. DOI: 10.1182/bloodadvances.2023011307.
Obesity, Rather Than High Body Surface Area Alone, Predicts Clinically Significant Asparaginase Toxicity During Induction Therapy for Acute Lymphoblastic Leukemia
Among 4,925 children and young adults with ALL, obesitynot high BSA alonewas the strongest predictor of clinically significant asparaginase toxicity. Patients with obesity and high BSA had the highest risk of hepatic toxicity and thromboembolism, whereas induction toxicities were not associated with increased end-of-induction MRD positivity.
KEY FINDINGS: This large multicenter analysis demonstrates that obesity-not elevated BSA alone-is the principal patient-related risk factor for clinically significant asparaginase toxicity during induction therapy for ALL. The greatest excess risk occurred in patients with both obesity and high BSA, particularly for hepatic toxicity and thromboembolic events, while pancreatitis risk was unaffected. Older age independently increased toxicity risk, especially hyperbilirubinemia. Notably, induction-phase AAT did not compromise early treatment response, as measured by EOI MRD. These findings suggest that obesity should be prioritized when identifying patients for enhanced toxicity surveillance and future preventive strategies, whereas high BSA in the absence of obesity does not appear to justify dose modification based solely on body size.
BACKGROUND: Asparaginase remains a cornerstone of induction therapy for acute lymphoblastic leukemia (ALL), but treatment-limiting toxicities frequently interrupt therapy and may compromise long-term outcomes. Previous studies have produced conflicting evidence regarding whether older age, obesity, or high body surface area (BSA) independently increase the risk of asparaginase-associated toxicities (AAT). This large Children’s Oncology Group analysis evaluated the relative contributions of these risk factors and examined whether induction-phase AAT affected early treatment response measured by end-of-induction (EOI) minimal residual disease (MRD).
DETAILS: This retrospective analysis included 4,925 patients aged 1-30 years enrolled in the Children’s Oncology Group trials AALL0232 and AALL0434. All patients received a single induction dose of pegaspargase 2500 IU/m² without dose capping. Investigators assessed grade >=3 hyperbilirubinemia, grade >=4 alanine aminotransferase (ALT) elevation, grade >=2 thromboembolism, and grade >=3 acute pancreatitis. Multivariable analyses evaluated the independent effects of age, obesity, and BSA, while EOI MRD positivity (>=0.01%) was analyzed to determine whether AAT adversely influenced early leukemia response. Among 4,925 patients, 290 (6%) experienced at least one clinically significant AAT during induction. Toxicity rates increased with advancing age and obesity. After adjustment for confounding variables, obesity independently increased the likelihood of AAT (OR 2.5; 95% CI 1.88-3.24), whereas high BSA alone was not an independent predictor. Patients with both obesity and high BSA had the greatest risk of overall AAT (OR 3.3; 95% CI 2.22-4.77), while high BSA without obesity was not associated with increased risk (OR 1.4; 95% CI 0.94-2.04). Older patients (>=10 years) demonstrated more than a twofold increase in AAT risk compared with younger children.
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Obesity combined with high BSA significantly increased the risk of hyperbilirubinemia (OR 3.5; 95% CI 2.2-5.7), severe ALT elevation (OR 3.3; 95% CI 1.7-6.6), and thromboembolism (OR 3.1; 95% CI 1.5-6.5). Acute pancreatitis showed no significant association with obesity or BSA. Importantly, development of AAT did not increase the likelihood of EOI MRD positivity (36.6% vs 33.5%; Ps= .318), suggesting that induction toxicities did not adversely affect early disease response.
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Source: Orgel, E., Maese, L. D., Devidas, M., et al. Toxicity From Asparaginase During Acute Lymphoblastic Leukemia Induction: A Report From the Children's Oncology Group. Blood Advances. 2026; 10(14):4923-4930. Published: July 28, 2026. DOI: 10.1182/bloodadvances.2026019870
Single-Encounter Augmented Reality-Guided Localization for Resection of Suspected Early-Stage Lung Cancer
Single-encounter augmented reality (AR)-guided localization demonstrated noninferiority to conventional CT-guided localization for successful sublobar resection in patients with suspected early-stage lung cancer. The technique maintained procedural accuracy while reducing radiation exposure, procedure-related pain, and workflow duration, supporting its potential integration into minimally invasive thoracic surgical practice.
KEY FINDINGS: This randomized clinical trial demonstrated that single-encounter AR-guided localization was noninferior to conventional CT-guided localization for achieving successful sublobar resection of suspected early-stage lung cancer. In addition to maintaining localization accuracy, the AR-guided approach reduced radiation exposure, procedural pain, and workflow time, supporting its potential as an alternative localization strategy for minimally invasive lung surgery.
BACKGROUND: Accurate preoperative localization is critical for successful sublobar resection of small pulmonary nodules suspicious for early-stage lung cancer. Conventional computed tomography (CT)-guided localization typically requires multiple encounters, including localization in the CT suite followed by transfer to the operating room, increasing patient discomfort, radiation exposure, and procedural complexity. This randomized clinical trial evaluated whether a single-encounter augmented reality (AR)-guided localization strategy could achieve surgical outcomes comparable to standard CT-guided localization while improving procedural efficiency and patient experience.
DETAILS: This multicenter, randomized, noninferiority trial was conducted at 5 centers in China between August 8, 2024, and September 30, 2025. Among 296 randomized patients, 270 were included in the modified intention-to-treat analysis, with 134 assigned to single-encounter AR-guided localization and 136 to conventional multiple-encounter CT-guided localization. Eligible participants had CT-detected pulmonary nodules suspicious for early-stage lung cancer requiring preoperative localization before sublobar resection. The primary endpoint was successful sublobar resection, defined as R0 resection with protocol-specified adequate surgical margins. Secondary outcomes included localization accuracy, radiation exposure, localization-related complications, patient-reported pain, and procedural efficiency. The median (IQR) patient age was 59 (50-67) years, and 172 participants (63.7%) were women. Successful sublobar resection was achieved in 132 of 134 AR-guided procedures (98.5%) and 135 of 136 CT-guided procedures (99.3%), yielding a risk difference of -0.8 percentage points (95% CI, -2.7 to 3.9) and meeting the prespecified criterion for noninferiority. Localization accuracy was similar between groups, with a median (IQR) localization error of 3.0 (0.0-5.0) in the AR group and 3.0 (2.0-6.0) in the CT group. Compared with CT guidance, AR-guided localization significantly reduced radiation exposure (456.50 [378.75-631.85] vs 1260.11 [1026.48-1544.53] mGy·cm; P<.001), preoperative pain (0 [0-0] vs 5 [4-6]; P<.001), puncture time (0.63 [0.50-0.83] vs 6.50 [5.00-8.75] minutes; P<.001), and localization-to-incision interval (2.00 [1.50-2.00] vs 33.50 [18.00-63.00] minutes; P<.001). Pneumothorax occurred in 40 of 136 CT-guided cases (29.4%), whereas no clinically significant complications associated with AR-guided localization were reported.
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Gadolinium-Based Contrast Agents: Reassessing Safety Beyond Nephrogenic Systemic Fibrosis
This review highlights that gadolinium-based contrast agents continue to play a critical role in diagnostic MRI, but their use should be guided by careful patient selection and individualized risk assessment. Although the risk of nephrogenic systemic fibrosis has declined considerably, further research is needed to clarify the clinical significance of gadolinium retention and its long-term safety.
KEY FINDINGS: This review emphasizes that GBCAs remain indispensable for diagnostic MRI but should be used following an individualized benefit-risk assessment, particularly in patients with chronic kidney disease or acute kidney injury. Although modern practice has substantially reduced the incidence of NSF, uncertainties remain regarding gadolinium retention, long-term toxicity, and persistent symptoms after exposure. Continued research into the mechanisms of gadolinium-associated injury, along with transparent patient counseling and evidence-based imaging policies, will be essential to optimize both patient safety and diagnostic care.
BACKGROUND: Gadolinium-based contrast agents (GBCAs) have been widely used to enhance magnetic resonance imaging (MRI) since the 1980s because of their favorable diagnostic performance and generally low incidence of acute adverse reactions. However, concerns regarding nephrogenic systemic fibrosis (NSF), gadolinium retention, and potential long-term toxicity have prompted ongoing debate about their safety, particularly in patients with kidney disease. This review examines current evidence on GBCA-associated complications, mechanisms of toxicity, and considerations for balancing diagnostic benefits with potential risks.
DETAILS: This narrative review synthesizes published evidence on the clinical safety of GBCAs, including acute hypersensitivity reactions, nephrotoxicity, NSF, gadolinium retention, and emerging concepts such as gadolinium-associated symptoms. The authors discuss differences between linear and macrocyclic GBCAs, proposed mechanisms of tissue deposition and fibrosis, the role of kidney dysfunction in gadolinium elimination, current American College of Radiology (ACR) recommendations, and unresolved questions regarding long-term toxicity. Experimental and clinical data addressing tissue retention, dialysis, and mechanistic pathways underlying gadolinium-induced injury are also reviewed. The review highlights that the incidence of NSF has declined substantially following the adoption of risk-based prescribing practices and updated clinical guidelines. Nevertheless, available evidence indicates that gadolinium retention can occur in multiple tissues, including the brain, even in individuals without severe renal impairment. The authors emphasize that tissue retention and toxicity are not fully explained by current GBCA classifications and that macrocyclic agents, although generally considered more stable, do not completely eliminate potential risk. Evidence reviewed also suggests that gadolinium may contribute to acute kidney injury, persistent tissue deposition, rare cases of encephalopathy, and symptoms associated with gadolinium exposure. Current data do not establish a definitive exposure threshold for toxicity, and the benefit of prophylactic hemodialysis after GBCA administration remains uncertain. While observational studies have estimated the risk of NSF with group II agents to be below 0.07%, the review notes that the true absolute risk remains difficult to define because of limitations in available evidence and confounding factors.
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Optical Coherence Tomography Enables Optical Biopsy of Endometrial Tissue for Early Cancer Detection
Catheter-based 3D optical coherence tomography demonstrated high accuracy for distinguishing benign endometrium from endometrial intraepithelial neoplasia and endometrial cancer in this ex vivo study. The findings support its potential as a rapid, minimally invasive optical biopsy technique, although prospective in vivo validation is needed before clinical implementation.
KEY FINDINGS: This proof-of-concept study demonstrates that catheter-based 3D OCT, integrated with quantitative functional, structural, and radiomic image analysis, can differentiate normal and benign endometrium from EIN and endometrial cancer with high diagnostic performance in ex vivo specimens. The ability to image the entire endometrial cavity within minutes and provide automated tissue characterization supports the potential of OCT as a minimally invasive optical biopsy technique. Further prospective in vivo clinical studies are required to validate its diagnostic accuracy and facilitate translation into routine gynecologic practice.
BACKGROUND: Early diagnosis of endometrial cancer (EC) is essential for improving outcomes and preserving fertility in selected patients with endometrial intraepithelial neoplasia (EIN). Current diagnostic approaches rely on invasive endometrial biopsy, which has an estimated 10% false-negative rate and may be limited by sampling variability. Although hysteroscopy permits direct visualization of the uterine cavity, it does not provide subsurface tissue characterization. This study evaluated whether catheter-based three-dimensional (3D) optical coherence tomography (OCT), combined with functional, structural, and radiomic feature analysis, could serve as a noninvasive optical biopsy technique for detecting EIN and EC.
DETAILS: This ex vivo imaging study enrolled patients undergoing hysterectomy at Barnes-Jewish Hospital between December 2024 and June 2025. Of 69 uterine specimens initially imaged, 57 were included in the final analysis after exclusion of the first 12 cases used for workflow optimization. The cohort comprised 16 premenopausal and 41 postmenopausal women, including 23 grade 1 EC, 6 grade 2 EC, 5 EIN, 1 hyperplasia without atypia, 7 cystic atrophy with benign polyps, and 15 normal specimens. A custom 3.1-mm catheter-based OCT system generated volumetric 3D images of the endometrial cavity within 3–5 minutes. Functional, structural, and radiomic features were extracted from OCT images, with 26 statistically significant imaging features selected to construct a cosine similarity matrix and network graph. A leave-one-out cross-validated logistic regression classifier was then developed to distinguish normal or benign tissue from EIN or EC. OCT imaging demonstrated distinct architectural differences between benign and malignant endometrial tissues. Compared with normal endometrium and benign hyperplasia, EIN and EC exhibited greater heterogeneity in optical scattering, increased structural entropy, distorted glandular architecture, and reduced tissue homogeneity. The cosine similarity network correctly classified 32 of 34 EIN/EC specimens and 20 of 23 normal or benign specimens, corresponding to an exploratory sensitivity of 94% and specificity of 87%. The logistic regression classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.957, with 91.2% sensitivity and 82.6% specificity using leave-one-out cross-validation. Misclassifications were primarily attributed to focal fundal lesions, mixed benign and malignant pathology, or very thin inactive endometrium.
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Promising Drug Candidates and Emerging Therapeutic Strategies Against Candida auris
Emerging therapies for Candida auris extend beyond conventional antifungal agents and include repurposed drugs, novel antifungal compounds, vaccines, antimicrobial peptides, and nanotechnology-based approaches. While further clinical validation is needed, these strategies may help address the growing challenge of multidrug-resistant C. auris infections.
KEY FINDINGS: This review underscores the expanding pipeline of therapeutic strategies targeting Candida auris, ranging from repurposed medications and next-generation antifungal agents to vaccines, antimicrobial peptides, nanoparticle formulations, and innovative environmental control measures. Although no single therapy has emerged as a definitive solution, compounds such as ibrexafungerp (SCY-078), ATI-2307, and fosmanogepix, together with drug repurposing and bioinspired approaches, represent promising avenues for addressing multidrug-resistant C. auris infections. Continued translational research and clinical evaluation remain essential to establish safe and effective treatment options for this increasingly important fungal pathogen.
BACKGROUND: Candida auris has rapidly emerged as a multidrug-resistant fungal pathogen of global concern since its first identification in 2009. The organism is associated with healthcare-associated outbreaks, high transmissibility, frequent misidentification, and severe invasive infections, with reported mortality rates ranging from 35% to 72%. Resistance to currently available antifungal agents further complicates treatment, with approximately 90% of isolates resistant to fluconazole, around 30% resistant to amphotericin B, and fewer than 5% resistant to echinocandins. These challenges have accelerated efforts to identify novel antifungal therapies and alternative treatment strategies.
DETAILS: This publication is a comprehensive narrative review that summarizes advances in antifungal research targeting C. auris over the preceding decade. The authors evaluated emerging therapeutic approaches from a medicinal chemistry perspective, including drug repurposing, combination therapy, novel antifungal agents, natural products, metal-based compounds, nanoparticles, vaccines, antimicrobial peptides, and environmental decontamination strategies. The review also examined chemical and physicochemical characteristics of promising compounds, including lipophilicity and topological polar surface area, to identify structural features that may facilitate future antifungal drug development. The review highlights several promising therapeutic candidates with activity against multidrug-resistant C. auris. Drug repurposing identified multiple agents with antifungal or antibiofilm activity, including sertraline, miltefosine, iodoquinol, octenidine dihydrochloride, taurolidine, and bensulfuron methyl. Miltefosine demonstrated fungicidal and antibiofilm activity, while encapsulation within alginate nanoparticles reduced toxicity and improved survival in an infected Galleria mellonella model. The NDV-3A vaccine generated cross-reactive antibodies against C. auris and protected neutropenic mice, with additive efficacy when combined with micafungin.
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Among novel antifungal agents, SCY-078 (ibrexafungerp), an orally available 1,3-ß-D-glucan synthesis inhibitor, demonstrated potent activity against C. auris, with an MIC90 of 1 mg/L and MIC50 and MIC90 values of 0.5 µg/mL and 1 µg/mL, respectively, across 100 isolates representing the four major clades. More than 150 strains with diverse resistance profiles were subsequently shown to be uniformly susceptible to SCY-078, and the agent remained active against pan-resistant isolates while also exhibiting antibiofilm activity.
Additional investigational therapies also demonstrated encouraging preclinical activity. The arylamidine T-2307 (ATI-2307) exhibited in vitro MIC values ranging from 0.125 to 4 µg/mL and improved survival while reducing kidney fungal burden in murine infection models following 3 mg/kg once-daily subcutaneous treatment. Other experimental approaches included antimicrobial peptides, ceragenins, fluorinated hydrazone derivatives, and novel chemical scaffolds designed to overcome existing resistance mechanisms.
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Source: Billamboz, M., Fatima, Z., Hameed, S., et al. Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris. Microorganisms. 2021; 9(3): 634. Published: March 18, 2021. DOI: 10.3390/microorganisms9030634.
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