Weeks Of Treatment Initiation Research Articles

P0801 Real-world Effectiveness and Tolerability of Etrasimod in Active Ulcerative Colitis: A 26-week Observational Study

Abstract Background Etrasimod, a selective sphingosine-1-phosphate receptor modulator, has demonstrated efficacy in controlled trials for moderately to severely active ulcerative colitis (UC). However, real-world data on its effectiveness and tolerability have not been reported. This 26-week observational study evaluates clinical response and remission in UC. Methods Patient demographics, disease characteristics, prior therapies, and SCCAI scores were recorded at baseline and at weeks 2, 4, 8, 12, and 26. Clinical response (SCCAI reduction ≥3) and remission (SCCAI ≤2) were assessed, with statistical differences between time points determined by paired T-tests. Side effects and laboratory findings were collected at each time point. Results We treated 22 patients with etrasimod: median age 38.5 years (Q1-Q3: 33.5–45.8), median disease duration 5.5 years (Q1-Q3: 4–11.3). 82% of patients (n=18) had prior 5-ASA exposure, and 23% (n=5) had received advanced therapies. 82% of the patients (n=18) were started due to active inflammation confirmed by symptomatic, biochemical, or endoscopic findings, a subset (59%, n=13) had clinical symptoms (SCCAI ≥3) at etrasimod commencement. The mean SCCAI dropped from 3.4 at baseline to 2.0 at week 2 (p=0.04), 1.5 at week 4 (p=0.01), 1.3 at week 8 (p=0.05), 1.0 at week 12 (p=0.04) and 3.0 (p=0.07) among all patients (Figure 1A). At week 12, 64% had achieved clinical remission, however this dropped to 18% at week 26 in an intention-to-treat (ITT) analysis (Figure 1B). This was primarily driven by high rates of discontinuation during this period (10 patients by week 26). Similar trends were observed in the 13 patients with clinical symptoms at baseline (SCCAI≥3), where 62% achieved clinical remission at week 12 followed by a drop to 23% at week 26 (Figure 1C,D). As expected, the absolute lymphocyte count reduced over the initial weeks of treatment (Figure 1E); there were no infections reported. Only 1 patient received oral steroids at etrasimod start, and 3 received steroids by week 2; 3 of these 4 stopped etrasimod due to lack of efficacy. One patient remained on 5-ASA throughout, and 2 patients had 5-ASA added before week 12 due to symptom recurrence. Of the 5 patients with prior advanced therapies, none achieved remission at week 26. One patient reported transient light-headedness on etrasimod initiation, without arrhythmia. Conclusion We demonstrate the first real-world effectiveness of etrasimod in a tertiary population of UC, with the majority achieving remission within the first 12 weeks and about half maintaining it through week 26. Those who lost response were more often patients with prior advanced therapy treatment or those who needed steroids in the first 12 weeks. Etrasimod was safe and overall well-tolerated.

Parathyroid Hormone-Related Protein Levels and Treatment Outcomes in Hypercalcemia of Malignancy: A Retrospective Cohort Study

Abstract The challenge of managing acute hypercalcemia in patients diagnosed with hypercalcemia of malignancy (HCM) merits further attention. Elevated levels of parathyroid hormone-related protein (PTHrP) may be a risk factor for treatment resistance in acute hypercalcemia; however, few studies have tested this hypothesis. This study aimed to investigate whether high PTHrP levels represent an independent risk factor that impedes the treatment of acute hypercalcemia. This retrospective cohort study recruited 159 patients aged 20–80 years with diagnosed malignancies who had been hospitalized for hypercalcemia with PTHrP levels above the reference value (1.1 pmol/L). The median (25–75%) patient age was 69 (61–76) years, and the median PTHrP level was 6.3 (3.3–11.1) pmol/L. The corrected calcium levels decreased from 12.8 mg/dL (11.9–14.1 mg/dL) to 10.6 mg/dL (9.8–11.7 mg/dL) following treatments, such as bisphosphonates and saline solution. Multivariate linear regression analysis showed less significant decreases in the corrected calcium levels as natural logarithm-transformed PTHrP levels increased (β coefficient [95% confidence interval]: 0.569 [0.225–0.914]; P=.001 for Model 3). Multivariate logistic regression analysis showed an association between high natural logarithm-transformed PTHrP levels and lack of treatment response, defined as a corrected calcium level of ≤10.4 mg/dL in the last blood test conducted within 2 weeks of treatment initiation (odds ratio [95% confidence interval]: 0.504 [0.312–0.814]; P=.005). Therefore, elevated PTHrP levels are a potential risk factor for treatment resistance in hypercalcemia in HCM patients, complicating management regardless of calcium levels.

Brain Age Gap as a Predictor of Early Treatment Response and Functional Outcomes in First-Episode Schizophrenia: A Longitudinal Study: L'écart d'âge cérébral comme prédicteur de la réponse en début de traitement et des résultats fonctionnels dans un premier épisode de schizophrénie : une étude longitudinale.

Accelerated brain aging, i.e., the age-related structural changes in the brain appearing earlier than expected from one's chronological age, is a feature that is now well established in schizophrenia. Often interpreted as a feature of a progressive pathophysiological process that typifies schizophrenia, its prognostic relevance is still unclear. We investigate its role in response to antipsychotic treatment in first-episode schizophrenia. We recruited 49 drug-naive patients with schizophrenia who were then treated with risperidone at a standard dose range of 2-6 mg/day. We followed them up for 3 months to categorize their response status. We acquired T1-weighted anatomical images and used the XGboost method to evaluate individual brain age. The brain age gap (BAG) is the difference between the predicted brain age and chronological age. Patients with FES had more pronounced BAG compared to healthy subjects, and this difference was primarily driven by those who did not respond adequately after 12 weeks of treatment. BAG did not worsen significantly over the 12-week period, indicating a lack of prominent brain-ageing effect induced by the early antipsychotic exposure per se. However, highly symptomatic patients had a more prominent increase in BAG, while patients with higher BAG when initiating treatment later showed lower gains in global functioning upon treatment, highlighting the prognostic value of BAG measures in FES. Accelerated brain aging is a feature of first-episode schizophrenia that is more likely to be seen among those who will not respond adequately to first-line antipsychotic use. Given that early poor response indicates later treatment resistance, measuring BAG using structural MRI in the first 12 weeks of treatment initiation may provide useful prognostic information when considering second-line treatments in schizophrenia.

Association between Immune-Related Adverse Events and Atezolizumab in Previously Treated Patients with Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs. We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study. Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively. In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders. Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab.

Mortality and Associated Risk Factors Among People Living With HIV With Kaposi Sarcoma: A5263/AMC066 and A5264/AMC067.

AIDS-related Kaposi sarcoma (AIDS-KS) remains a leading cause of morbidity and mortality among people living with HIV in Africa. Mortality among people with AIDS-KS on antiretroviral therapy remains high compared with people on antiretroviral therapy who do not have AIDS-KS. People living with HIV with Kaposi sarcoma (KS) who participated in 2 randomized trials (A5263/AMC066 [advanced stage] and A5264/AMC067 [mild-to-moderate stage]) conducted by AIDS Clinical Trials Group/AIDS Malignancy Consortium in low- and middle-income countries. We estimated mortality rates over the trial period. Cox proportional hazards regressions were used to identify baseline characteristics associated with mortality and compared mortality rates between participants who had KS progression within 12 weeks of treatment initiation (early progression of KS [KS-PD]) and those who did not. Of the 329 and 189 eligible participants in A5263/AMC066 and A5264/AMC067, 71 (21.6%) and 24 (12.7%) died, respectively. In both trials, hypoalbuminemia was associated with increased hazards of death compared with normal albumin; A5263/AMC066: mild hypoalbuminemia (adjusted hazard ratio [aHR] = 3.01; 95% CI: 1.42 to 6.29), moderate hypoalbuminemia (aHR = 5.11; 95% CI: 2.54 to 10.29), and severe hypoalbuminemia (aHR = 14.58; 95% CI: 6.32 to 35.60), and A5264/AMC067: mild hypoalbuminemia (aHR = 5.66; 95% CI: 1.90 to 16.93) and moderate hypoalbuminemia (aHR = 7.02; 95% CI: 2.57 to 19.15). The rate of death was higher among participants who had early KS-PD than those without early KS-PD in A5263/AMC066 (HR = 5.09; 95% CI: 1.71 to 15.19) but not in A5264/AMC067 (HR = 1.74; 95% CI: 0.66 to 4.62). Albumin measurements may be used to identify individuals at higher risk of death after initiating KS treatment and for evaluation of interventions that can reduce AIDS-KS mortality.

Efficacy of macozinone in mice with genetically diverse susceptibility to Mycobacterium tuberculosis infection

Host heterogeneity in pulmonary tuberculosis leads to varied responses to infection and drug treatment. The present portfolio of anti-TB drugs needs to be boosted with new drugs and drug regimens. Macozinone, a clinical-stage molecule targeting the essential enzyme, DprE1, represents an attractive option. Mice (I/St, B6, (AKRxI/St)F1, B6.I-100 and B6.I-139) genetically diverse susceptibility to Mycobacterium tuberculosis (Mtb) H37Rv infection were subjected to aerosol- or intravenous infection to determine the efficacy of macozinone (MCZ). They were treated with macozinone or reference drugs (isoniazid, rifampicin). Lung and spleen bacterial burdens were measured at four and eight weeks post-infection. Lung histology was evaluated at four weeks of treatment. Treatment with macozinone resulted in a statistically significant reduction in the bacterial load in the lungs and spleen as early as four weeks after treatment initiation in mice susceptible or resistant to Mtb infection. In the TB hypoxic granuloma model, macozinone was more potent than rifampicin in reducing the CFU counts. However, histopathological analysis revealed significant lung changes in I/St mice after eight weeks of treatment initiation. Macozinone demonstrated efficacy to varying degrees across all mouse models of Mtb infection used. These results should facilitate its further development and potential introduction into clinical practice.

Rapid decrease in IL-1Ra and IP-10 plasma levels following tuberculosis treatment initiation

ObjectivesMonitoring tools that could provide quick predictions of tuberculosis (TB) treatment outcomes are urgently needed. Here, we assessed whether the evolution of selected biomarkers of innate immunity may help monitoring TB treatment response within 2 weeks of treatment initiation. MethodsANRS12394-LILAC-TB was a proof-of-concept prospective study: adults with a rifampicin-susceptible TB who are HIV-negative and HIV-infected documented by a positive Xpert MTB/RIF test were enrolled in Cambodia and Côte d'Ivoire. Plasma concentrations of interleukin-1 receptor antagonist (IL-1Ra), interferon-γ–induced protein-10 and clusters of differentiation (CD) (scavenging CD163) were measured by commercial enzyme-linked immunosorbent assay kits. A Wilcoxon test for paired data was used for longitudinal comparisons. ResultsA total of 55 patients were enrolled (women: 31%, median age: 37 years; median CD4 count in the 10 of 13 participants with HIV: 53 cells/mm3). Overall, 83% were considered in TB treatment success. Compared with baseline, the IL-1Ra plasma levels significantly decreased as soon as week (W) 1, independent of HIV status (−71% in HIV-positive vs −33% in HIV-negative; P <0.001). The IP-10 plasma levels significantly decreased at W1 and W2 compared with baseline (P <0.0001); however, that decrease was less marked in participants with HIV. ConclusionsOur findings suggest that measuring IL-1Ra plasma levels with a standard enzyme-linked immunosorbent assay technique at baseline and then 1 week after TB treatment onset could help clinicians to quickly assess TB treatment response.

Highly variable timing renders immunotherapy efficacy and toxicity impractical biomarkers of one another in clinical practice.

A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

Early and Sustained Response to Benralizumab in Severe, Eosinophilic Asthma: A Real-World Observational Study.

Although studies have evaluated benralizumab, a monoclonal IL-5 receptor α antibody in severe eosinophilic asthma (SEA), in real-world settings, additional evidence is needed to further characterize its effectiveness in specific patient populations. Our study aimed to evaluate asthma control over 56weeks in patients treated with benralizumab in Swiss real-world settings. Conducted across 13 centres, this prospective, observational, non-interventional study involved 73 adults with physician confirmed SEA. Benralizumab 30 mg was administered according to the Swiss label at baseline and up to week 56. Primary outcome was the change in Asthma Control Questionnaire (ACQ-5) scores at week 8 compared to baseline. Exacerbations, use of oral corticosteroids (OCS), and lung function were assessed descriptively. At baseline, the mean ACQ-5 score was 2.76 (SD 1.26), with 82.2% of patients showing not well-controlled asthma (ACQ-5 > 1.5). At week 8, the mean change in ACQ-5 compared to baseline was -0.95 (95% CI: -1.25, -0.66; p < 0.001). More than half of patients (59.1%) reached a clinically relevant improvement (MCID ≥ 0.5) at week 8, with 40.9% of patients doing so at week 1 and 87.2% at week 56. The annualized exacerbation rate (AER) of 3.65 (95% CI: 3.18, 4.18) at baseline was reduced to 0.68 (95% CI: 0.39, 1.19) at week 56. The relative reduction in AER from baseline to week 56 was 81.3%. Maintenance usage of OCS at baseline (median 25.0 mg/day) decreased over the study leading to a median change of 17.50 mg/day (95% CI: 10.0; 40.0) from baseline compared to week 56. The mean pre-bronchodilator FEV1 change from baseline to week 56 was 0.23 L (95% CI: 0.08; 0.38, p = 0.003). Benralizumab demonstrated significant, rapid improvements in asthma control within one week of treatment initiation, with sustained benefits over 56weeks.

Advancements in autism: exploring innovative therapies and targeted approaches to management and reversal of neurodevelopmental disorders

This article explores effective treatment strategies for Autism Spectrum Disorders (ASD), focusing on innovative targeted therapies within the field of regenerative medicine. We reviewed and assessed the use of advanced regenerative techniques in treating ASD, highlighting new therapeutic modalities that address key pathological pathways associated with autism. The discussion includes cellular therapies, neuropeptide interventions, and treatments involving neuromediator precursors. Clinical outcomes were measured by improvements in behavioral, cognitive, and social functions. Patients with autism who received comprehensive biological therapy showed noticeable improvements in self-regulation and behavior within the initial weeks of treatment. By 2-3 months, significant progress was observed in eye contact, attention span, verbal responsiveness, and speech development. Follow-ups at six months indicated better communication skills and self-management. The addition of neuropeptides during the maintenance phase led to marked reductions in anxiety and aggression, and improved social skills and communication. Long-term therapy demonstrated sustained enhancements in conversational abilities, decreased repetitive behaviors, and improved social and emotional interactions. The combination of novel biological therapies and nutraceuticals appears to offer a promising approach to managing ASD, with significant gains in behavioral and cognitive outcomes. These results suggest the potential of regenerative medicine in improving ASD treatment and highlight the need for further research to refine treatment protocols and confirm long-term benefits.

The Effect of Oral Administration of Hypericum Perforatum on Serum Glucose and Lipids, Hepatic Enzymes and Lipid Peroxidation in Streptozotocin-Induced Diabetic Rats

Background: In this research, the beneficial effects of oral administration of Hypericum perfo­ratum (HP) on serum glucose and lipids, hepatic enzymes and the amount of malondialdehyde in Streptozotocin-induced diabetic rats are studied. Materials and Methods: In this experi­mental study, 32 male rats where randomly divided into 4 groups of control, treatment-control, diabetic and treatment-diabetic. HP was orally administered to treatment groups over a period of 6 weeks. Serum glucose levels, triglyceride, total cholesterol along with HDL and LDL were all evaluated prior to initiation of the treatment, and at 3rd and 6th (last) week of treatment initiation, and in the end of the treatment, malondialdehyde and aminotransferase enzymes of the liver were evaluated. Results: regarding serum glucose levels and body weight measured in the 3rd and 6th week, the treatment-diabetic group didn’t show a significant change compared to the diabetic group, regarding serum total cholesterol and LDL levels, a significant decrease was observed and regarding serum HDL, a significant increase was documented. Furthermore, treating the treatment-diabetic group with HP did not result in any significant decrease in serum triglyceride, malondialdehyde or alanine aminotransferase but, in fact, did cause a significant decrease in aspartate aminotransferase. Conclusions: Oral administration of HP did in fact have a beneficial effect on lowering serum levels of total cholesterol, LDL and the hepatic enzyme as­partate aminotransferase and on raising the levels of HDL in diabetized rats with Streptozotocin. [GMJ.2017;6(4):319-29] DOI: 10.22086/gmj.v6i4.889

Determinants of catastrophic costs among households affected by multi-drug resistant tuberculosis in Ho Chi Minh City, Viet Nam: a prospective cohort study

Background Globally, most people with multidrug-resistant tuberculosis (MDR-TB) and their households experience catastrophic costs of illness, diagnosis, and care. However, the factors associated with experiencing catastrophic costs are poorly understood. This study aimed to identify risk factors associated with catastrophic costs incurrence among MDR-TB-affected households in Ho Chi Minh City (HCMC), Viet Nam.Methods Between October 2020 and April 2022, data were collected using a locally-adapted, longitudinal WHO TB Patient Cost Survey in ten districts of HCMC. Ninety-four people with MDR-TB being treated with a nine-month TB regimen were surveyed at three time points: after two weeks of treatment initiation, completion of the intensive phase and the end of the treatment (approximately five and 10 months post-treatment initiation respectively). The catastrophic costs threshold was defined as total TB-related costs exceeding 20% of annual pre-TB household income. Logistic regression was used to identify variables associated with experiencing catastrophic costs. A sensitivity analysis examined the prevalence of catastrophic costs using alternative thresholds and cost estimation approaches.Results Most participants (81/93 [87%]) experienced catastrophic costs despite the majority 86/93 (93%) receiving economic support through existing social protection schemes. Among participant households experiencing and not experiencing catastrophic costs, median household income was similar before MDR-TB treatment. However, by the end of MDR-TB treatment, median household income was lower (258 [IQR: 0–516] USD vs. 656 [IQR: 462–989] USD; p = 0.003), and median income loss was higher (2838 [IQR: 1548–5418] USD vs. 301 [IQR: 0–824] USD; p < 0.001) amongst the participant households who experienced catastrophic costs. Being the household’s primary income earner before MDR-TB treatment (aOR = 11.2 [95% CI: 1.6–80.5]), having a lower educational level (aOR = 22.3 [95% CI: 1.5–344.1]) and becoming unemployed at the beginning of MDR-TB treatment (aOR = 35.6 [95% CI: 2.7–470.3]) were associated with experiencing catastrophic costs.ConclusionDespite good social protection coverage, most people with MDR-TB in HCMC experienced catastrophic costs. Incurrence of catastrophic costs was independently associated with being the household’s primary income earner or being unemployed. Revision and expansion of strategies to mitigate TB-related catastrophic costs, in particular avoiding unemployment and income loss, are urgently required.

Teclistamab Induces Rapid Responses in Patients with Relapsed/Refractory AL Amyloidosis

Introduction Systemic light chain (AL) amyloidosis is a rare disorder characterized by tissue deposition of amyloid fibrils derived from immunoglobulin free light chains. While daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) is the standard for upfront treatment of AL, management of relapsed/refractory (R/R) disease is often challenging, particularly in context of multiorgan dysfunction. Teclistamab was recently approved for treatment of R/R multiple myeloma (MM) and showed an overall response rate (ORR) of 63% (N Engl J Med 2022;387:495). Notable adverse effects (AEs) included cytokine release syndrome (CRS), neurologic, renal and hematologic toxicities, and infections. Efficacy of teclistamab in AL has not been previously reported. Here, we present a series of three patients who received treatment with teclistamab for R/R AL and MM. Methods In this retrospective study, we included all patients with R/R AL and MM who received teclistamab at two US academic centers between October 2022 and July 2023. We recorded all standard metrics, including serologic and biomarker data. Hematologic and organ responses were evaluated based on standard consensus criteria. Toxicity assessment was performed in accordance with the NCI CTCAE v5.0, except for CRS and neurotoxicity, which were graded according to the 2019 ASTCT criteria (BBMT 2019;25:625). Results We identified 3 patients; baseline characteristics are provided in Table 1 and treatment data in Table 2. Median age was 67 years (range, 54-70). All patients were male, and 2 had AL λ-type. At the time of teclistamab initiation, the median number of prior therapies was 7 (5-10), with all patients being refractory to a bortezomib, lenalidomide and daratumumab. Median iFLC was 228 mg/L (45.5-1272) with 10% median bone marrow (BM) plasmacytosis. In one patient with rapidly progressive multiple myeloma, BM FISH showed high-risk cytogenetic changes, including gain 1q, del 1p and del 17p. All patients were hospitalized for treatment initiation and received escalating doses of 0.06 mg/kg, 0.3 mg/kg and 1.5 mg/kg during the ramp-up phase. Subsequent treatment with target dose of 1.5 mg/kg was continued in the outpatient setting on a weekly basis. Monitoring for cytokine release syndrome (CRS) and neurologic toxicity was performed in accordance with institutional protocols. At a median follow-up of 49 days (44-58), 2 patients achieved hematologic responses (HR), with 1 complete hematologic response (CR) and 1 low dFLC PR. Both hematologic responses occurred promptly within 3 weeks of treatment initiation, were deep with iFLC &amp;lt;10 mg/L, and were ongoing at the last follow-up. One patient with rapid renal progression prior to teclistamab also enjoyed a renal response by day 42. The most common toxicity was hematologic, with 1 patient experiencing grade 4 lymphopenia, grade 2 thrombocytopenia and hypogammaglobulinemia. There were no infectious complications or instances of febrile neutropenia, CRS or neurologic AEs. All patients received routine prophylaxis against VZV and PJP, as well as prophylactic IVIg. One patient with heavily pre-treated, high-risk MM had an aggressive clinical relapse with widespread osseous involvement within 6 months of an autologous stem cell transplant (ASCT) and experienced progressive disease as best response to teclistamab, necessitating discontinuation after 29 days in favor of cytotoxic chemotherapy. Conclusion In this series of 3 patients with heavily pre-treated, R/R AL and MM, teclistamab showed an impressive hematologic response rate of 67%. These responses were deep and occurred rapidly within 3 weeks of treatment initiation. One patient also enjoyed a renal response, whereas cardiac responses were non-evaluable in 2 patients. While the most common treatment-related toxicity was hematologic in nature, infections or febrile neutropenia were not observed, likely due to the institution of aggressive prophylactic measures. Importantly, no new safety signals were identified in AL patients. To our knowledge, this is the first report providing preliminary evidence for efficacy of teclistamab in R/R AL, highlighting the need to investigate this strategy in clinical trials.

CTIM-03. LONG TERM FOLLOW-UP OF A PROSPECTIVE SAFETY AND TOXICITY STUDY OF IMMUNE CHECKPOINT INHIBITOR THERAPY INITIATED 8 DAYS PRIOR TO RADIOSURGERY FOR MELANOMA BRAIN OR SPINE METASTASIS

Abstract We conducted a pilot study of checkpoint inhibitor (ICI) therapy followed in eight days(+/- 2) by initiation of SRS for brain or spine metastasis based on murine experiments of pre-SRS initiation of ICI. Alternative time intervals would be tested If there was &amp;gt;33% dose limiting toxicity(DLT) &amp;gt;Gr3 by CTCAE 4.0 within 12 weeks of treatment initiation (excluding Gr3 tumor flare, rash, immune reaction resolving to gr1 in &amp;lt;28 days). Initially ipilimumab was used, with protocol change to nivolumab as standard of care evolved. Treatment continued until DLT, progression, or clinical decision to end therapy. Dosing and timing of subsequent cycles were by institutional preference. Eligibility included melanoma with newly diagnosed unirradiated brain or spine metastasis, at least one &amp;gt;3 mm, no autoimmune diseases. Twenty-one patients enrolled, 17(81%) treated with nivolumab, 20(95%) had brain metastasis. The median baseline number of brain metastasis was 2(1-9). 7 subjects (33%) had only one brain met. Seven subjects(33%) were free of extra-CNS metastasis at baseline; 5(23%) had 1-5 systemic metastasis (oligometaststic), and 9 subjects(43%) had 6 or more systemic metastasis. Median number of cycles of checkpoint inhibitor therapy was 3 (1-37). The grade 3 toxicities (no grade 4 and 5) with possible, probable, or definite attribution to ipilimumab were colitis(4.8%), diarrhea(9.5%), fatigue(4.8%), muscle weakness (4.8%), and headache(4.8%). One subject had colitis as a DLT. No toxicity &amp;gt;3 or above was associated with nivolumab. Estimated median overall survival was 37.4 months, within minimum f/u of 8 surviving patients of 40 months (40-68). Three-year OS rate was 52%. Checkpoint inhibitor therapy initiated 8 days prior to SRS was safe and survival outcome is favorable. Peripheral blood Immune correlative studies are pending. Prospective data is needed to define optimal safety, timing, and outcome of concurrent checkpoint inhibitor therapy and radiosurgery for melanoma metastatic to the brain.

Two non-familial cases of Galloway-Mowat syndrome carrying the homozygous mutations of WDR73 and TP53RK

Galloway–Mowat syndrome (GAMOS) is a rare hereditary disease manifested as a combination of nephrotic syndrome and central nervous system impairment. To date, many GAMOS cases attributed to various gene mutations have been reported such as WHAMM, NUP107, WDR73, OSGEP, and TP53RK. We detected two novel homozygous mutations of WDR73 ‘’NM_032856:c.G287A:p.R96K‘’ and TP53RK ‘’NM_033550:c.A193O:p.K65Q‘’ in two female kids of the consanguineous parents from different families using whole exome sequencing. Both patients almost manifested similar neurodegenerative phenotypes, including developmental delay, microcephaly, hypotonia, and brain atrophy on magnetic resonance imaging during infancy. WDR73-positive GAMOS case manifested a late-onset minimal nephrotic syndrome at the age 4 years while TP53RK-positive case presented nephrotic syndrome at the age 1 which progressed to steroid-resistant nephrotic syndrome due to lack of remission after 4-6 weeks of initial treatment with prednisone. Despite the brain abnormalities and the onset time difference of renal abnormalities, both patients are still alive. Given the heterogeneity of the renal phenotype among GAMOS types, accurate recognition of expanding spectrum of phenotype findings and regular renal function screening are necessary for an early diagnosis and timely treatment.

Neoadjuvant nivolumab + palbociclib + anastrozole for oestrogen receptor-positive/human epidermal growth factor receptor 2-negative primary breast cancer: Results from CheckMate 7A8

BackgroundPreclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2–) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2− breast cancer. Here, we report outcomes from the safety run-in phase. MethodsPatients with histologically confirmed, untreated ER+/HER2− breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation. ResultsAt safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [n = 6], grade 3 febrile neutropaenia [n = 1], grade 1 pneumonitis [n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [n = 1]). Consequently, the study was closed early. ConclusionsNeoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2− breast cancer.

Evaluating the Necessity of Adaptive RT and the Role of Deformable Image Registration in Lung Cancer with Different Pathologic Classifications.

This study aimed to analyze differential radiotherapy (RT) responses according to the pathological type of lung cancer to see the possibility of applying adaptive radiotherapy (ART). ART planning with resampled-computed tomography was conducted for a total of 30 patients (20 non-small-cell lung cancer patients and 10 small-cell lung cancer patients) using a deformable image registration technique to reveal gross tumor volume (GTV) changes according to the duration of RT. The small-cell lung cancer group demonstrated an average GTV reduction of 20.95% after the first week of initial treatment (p = 0.001), whereas the adenocarcinoma and squamous cell carcinoma groups showed an average volume reduction of 20.47% (p = 0.015) and 12.68% in the second week. The application of ART according to the timing of GTV reduction has been shown to affect changes in radiation dose irradiated to normal tissues. This suggests that ART applications may have to be different depending on pathological differences in lung cancer. Through these results, the present study proposes the possibility of personalized treatment options for individual patients by individualizing ART based on specific radiation responses by pathologic types of lung cancer.

Changes in ctDNA levels as an early indicator of outcomes in advanced NSCLC treated with TKI: Initial findings from a retrospective aggregate analysis of 8 clinical trials.

3030 Background: To determine whether changes in circulating tumor DNA (ctDNA) levels reflect treatment outcome, Friends of Cancer Research created the ctDNA to Monitor Treatment Response (ctMoniTR) Project with collaborators from industry, government, academia, and advocacy. A prior ctMoniTR effort analyzing 5 clinical trials (CT) showed an association between decreases in ctDNA levels and improved outcomes in patients with advanced non-small cell lung cancer (aNSCLC) treated with an anti-PD-(L)1. The current study expands that work and focuses on CT investigating tyrosine kinase inhibitors (TKI) treatment in oncogene-driven aNSCLC. Methods: We performed a retrospective analysis of patient-level clinical and ctDNA data across 8 CT representing 1,015 patients with aNSCLC treated with TKI (i.e., anti-EGFR, ALK, RET, or MET). Patients included in the analysis had a baseline ctDNA measurement (T0), an on treatment ctDNA measurement within 10 weeks of treatment initiation (for those with multiple ctDNA measurements within 10 weeks, we used the lowest measurement within 10 weeks) (T1), and overall survival (OS) data (n=749). CT used different ctDNA collection timepoints and assays. We randomly divided the dataset into training (2/3 of the data) and validation (1/3 of the data) datasets stratified by CT cohort (i.e., arm), age, tumor stage, and prior lines of therapy, then ran initial analyses on the training dataset (n=501; reported herein). ctDNA change was calculated as the percent change in maximum variant allele frequency (VAF) between T0 and T1 using tumor-derived variants provided by sponsors for each unique patient sample. CT used either ddPCR or an NGS assay. ctDNA limits of detection were assay specific and varied across CT. Multivariate analyses are ongoing and validation dataset analyses will be conducted. Results: At T0, 141 patients had non-detected (ND) ctDNA and 360 patients had detected (D) ctDNA. Of these, 27% (n=136) had ND ctDNA at both T0 and T1 (“ND/ND”), 52% (n=260) had changes from D at T0 to ND at T1 (“D/ND”), 12% (n=60) had at least a 50% decrease from T0 to T1 (“decrease”) and 9% (n=45) had an increase or a less pronounced decrease in ctDNA. In a univariate analysis, patients with ND/ND and D/ND were associated with improved OS compared to the decrease group. In addition to other characteristics, patients with max VAF ≤0.5% or ND at T0 (n=214, 43%) had improved OS (HR=0.44, P&lt;0.001) compared to those with max VAF &gt;0.5% at T0 (n=287, 57%). Conclusions: In a retrospective aggregate analysis of 8 CT, ND ctDNA at T1 was associated with improved OS in patients with aNSCLC treated with TKI. Changes in ctDNA levels, particularly from D to ND, may provide an early indication of treatment benefit and predict long-term outcomes in this population. Additional ctMoniTR analyses are ongoing to validate the potential use of ctDNA as an early endpoint.

Pitfalls in the diagnosis of glioblastoma

Glioblastoma (GBM) is one of the most dreadful human cancers having a literature-reported median of life of 14 months with maximal treatment. The correct diagnosis is of crucial importance for the best chances of treatment. Misdiagnosis is uncommon, but seen in daily practice, and leads to important delays for patients. This paper will discuss the delays found in glioblastoma diagnosis in a series of 60 newly diagnosed patients. Four out of 60 patients had a delay of more than 6 weeks of treatment initiation, as at first imaging, GBM was not suspected as a diagnosis.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial

Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. Amgen.