Time Of Study Entry Research Articles

Initial Patient Characteristics of TSOG 102: A Multicenter Prospective Registry of Active Surveillance in Patients with Multiple Ground Glass Opacities

ObjectivePresentation with multiple ground glass opacities (GGOs) is an increasingly common occurrence, and the optimal management of these lesions is unclear. Active surveillance has been increasingly adopted as a management strategy for other low-grade malignancies. We hypothesized that active surveillance could be a feasible and safe option for patients with multiple GGOs. MethodsPatients with ≥2 GGOs (ground glass predominant, <50% solid, ≤3 cm) were enrolled in a multi-institutional registry and prospectively followed up on active surveillance with computed tomography scans every 6 to 12 months. Each GGO was catalogued and measured individually at each follow-up visit. ResultsTarget accrual was met, with 337 patients from 23 institutions. The mean age was 70 years (interquartile range, 65-77 years), and 74% were women. Most were former (70%) or current (9%) smokers, with a mean exposure of 30 pack-years (interquartile range [IQR], 15-44 pack-years). Half of the patients (51%) had a previous lung cancer, and the majority (86%) were already under surveillance at the time of study entry. The median number of GGOs per patient was 3 (IQR, 2-5), with a total of 1467 GGOs under surveillance. The median GGO size was 0.9 cm (IQR, 0.7-1.3 cm). Most GGOs were 0.5 to 1 cm in size. ConclusionsActive surveillance, rather than immediate intervention, was an acceptable option to patients, and accrual to this registry trial was feasible. Safety endpoints and long-term outcomes will be assessed in the planned 5-year follow-up in accordance with the protocol.

Abstract PO5-19-05: A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer

Abstract Background: The term oligoprogression (OP) refers to a clinical scenario in which patients with diffuse metastatic disease on systemic therapy have a limited number of metastases that have progressed or are new whereas the majority of metastases are stable or improved. OP disease is increasingly being encountered in clinical practice due to improvements in systemic therapy. Treating OP disease with local ablative therapies may therefore prolong the time to more diffuse progression necessitating a change in systemic therapy and may therefore lead to improved overall survival in these patients. Only one study has evaluated the role of SBRT in patients with OP MBC. This trial accrued 47 patients with OP MBC, with 2/3 having triple negative disease. There was no difference in PFS between patients that received SBRT versus those that did not (4.2 months vs. 4.4 months, p=0.2). Whether ablative therapies are beneficial in subtypes of breast cancer that have many effective systemic therapies available, such as ER+ breast cancer, remains an open question and an unmet clinical need. Design: Phase II study for patients with OP ER+ MBC (1-4 new and/or progressing metastatic lesions). Eligible patients will receive stereotactic body radiation therapy (SBRT) to the OP lesions. SBRT will be delivered to each lesion in 3-5 fractions. Each patient’s systemic therapy regimen will be held during study therapy and will resume upon completion of study therapy. Patients will then be restaged at 12 weeks post-SBSRT. Patients that have at least stable disease at that time point will continue on their systemic therapy and then be re-staged 12 weeks later (24 weeks after SBRT). This study will also study the role of ER-targeted positron emission tomography (PET) imaging with 16α-18F-Fluoro-17β-Fluroestradiol (FES) in the OP ER+ patient population with FES PET scans obtained at baseline, and at each of the 2 follow-up imaging timepoints. A key secondary hypothesis is that the use of FES PET in addition to standard imaging at baseline and in follow-up will help confirm patients have OP disease and will help assess for new lesions on subsequent restaging. Eligibility: Key inclusion criteria: age≥18 yo; histologically confirmed ER+/HER2- metastatic breast cancer; the presence of metastatic breast cancer at the time of study entry with progression in 1-4 lesions (including new lesions); SBRT must be feasible for all progressing lesions. Key Exclusion Criteria: &amp;gt;2 lines of systemic therapy for metastatic disease; intracranial disease progression Objective: To determine whether using SBRT to treat OP lesions allows ER+ breast cancer patients to continue on their current systemic therapy for at least 24 weeks post SBRT. Objective: To assess whether FES-PET increases the number of lesions found prior to SBRT; To determine the impact of SBRT on patient quality of life; time to next line systemic therapy; PFS Statistical Methods Simon 2 stage optimal design with α=0.05 and 1-β=0.80. The null hypothesis is that the proportion of patients that remain on their original systemic therapy ≥24 weeks (2 restaging scans) post-treatment is 20%. The alternative hypothesis is that the proportion of patients that remain on their original systemic therapy after 2 restaging scans is 50%. In stage 1, 8 patients that proceed to SBRT will be enrolled. The study will be terminated if only 0 or 1 subjects remain on original systemic therapy after 2 restaging scans. However, if ≥2 patients remain on original systemic therapy after 2 restaging, then an additional 10 patients would be enrolled for a total of 18 patients. The null hypothesis will be rejected if ≥6 patients remain on their original systemic therapy after 2 restaging scans. Contact Information: Jose G. Bazan (jbazan@coh.org) Funding Source: City of Hope Comprehensive Cancer Center Citation Format: Jose Bazan, Joanne Mortimer, Yun-Rose Li. A Phase II Trial of Stereotactic Body Radiation Therapy and Fluoroestradiol Positron Emission Tomography in Patients with Oligoprogressive Estrogen Receptor Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-05.

Oropharyngeal Microbiome Analysis in Patients with Varying SARS-CoV-2 Infection Severity: A Prospective Cohort Study.

Patients with COVID-19 infection have distinct oropharyngeal microbiota composition and diversity metrics according to disease severity. However, these findings are not consistent across the literature. We conducted a multicenter, prospective study in patients with COVID-19 requiring outpatient versus inpatient management to explore the microbial abundance of taxa at the phylum, family, genus, and species level, and we utilized alpha and beta diversity indices to further describe our findings. We collected oropharyngeal washing specimens at the time of study entry, which coincided with the COVID-19 diagnosis, to conduct all analyses. We included 43 patients in the study, of whom 16 were managed as outpatients and 27 required hospitalization. Proteobacteria, Actinobacteria, Bacteroidetes, Saccharibacteria TM7, Fusobacteria, and Spirochaetes were the most abundant phyla among patients, while 61 different families were detected, of which the Streptococcaceae and Staphylococcaceae families were the most predominant. A total of 132 microbial genera were detected, with Streptococcus being the predominant genus in outpatients, in contrast to hospitalized patients, in whom the Staphylococcus genus was predominant. LeFSe analysis identified 57 microbial species in the oropharyngeal washings of study participants that could discriminate the severity of symptoms of COVID-19 infections. Alpha diversity analysis did not reveal a difference in the abundance of bacterial species between the groups, but beta diversity analysis established distinct microbial communities between inpatients and outpatients. Our study provides information on the complex association between the oropharyngeal microbiota and SARS-CoV-2 infection. Although our study cannot establish causation, knowledge of specific taxonomic changes with increasing SARS-CoV-2 infection severity can provide us with novel clues for the prognostic classification of COVID-19 patients.

Abstract B084: Association between race and ethnicity, area deprivation, and exposure to environmental toxins in the WISDOM clinical trial population

Abstract Background: Women Informed to Screen Depending on Measures of risk (WISDOM) is a preference-tolerant, pragmatic clinical trial comparing the safety and morbidity of personalized risk-based and annual breast cancer screening. Environmental risk factors are not considered in WISDOM’s risk assessment. Geocoded residential addresses were used to understand whether a relationship between area deprivation, exposure to environmental toxins, and race and ethnicity exists within the cohort. Methods: The residential addresses at time of study entry of consented WISDOM participants were geocoded to latitude/longitude coordinates and assigned census tract and/or Zip Code Tabulation Area IDs from the US Census Bureau. Each census tract was assigned an Area Deprivation Index (ADI). The ADI comprises 17 indicators of poverty, housing, education, and employment which classifies a census tract on a scale from 1 (least deprived) to 10 (most deprived). ADI was grouped into highest deprivation (ADIs 8-10), middle deprivation (ADIs 4-7), and least deprivation (ADIs 1-3). Census tracts were also mapped to data from the Environmental Protection Agency Environmental Justice Screen (EJS) on the national percentile rank of 12 toxic exposures such as proximity to hazardous waste sites, air particulate matter and ozone concentrations. Each EJS exposure variable was categorized into quartiles. The cohort was limited to self-reported White, Asian, Black African American, and Mixed participants. The Kruskal-Wallis rank sum test and the Dunn’s test of multiple comparison using Bonferroni adjustment were used to test the association between race and ethnicity, ADI, and EJS variables. Results: The analysis cohort had 42,388 women. Most WISDOM participants were White (85%), followed by Asian (5%), Black or African American (5%), and Mixed (5%) race and ethnicity. Most lived in the least deprivation areas (57%) while a minority lived in the highest deprivation areas (12%). Black or African American women were significantly more likely to live in the highest deprivation areas compared to all other races and ethnicities (p&amp;lt;0.001). The highest deprivation areas where more likely to rank in the highest quartile of exposure to ozone (p&amp;lt;0.001), proximity to hazadous waste sites (p&amp;lt;0.001), and concentration of cancer risk air toxins (p=0.017) compared to the middle and least deprivation areas. White and Asian women were more likely to live in the least deprived areas that were more likely to rank in the highest quartile of exposure to particulate matter 2.5 compared to the most deprived areas (p&amp;lt;0.001). Conclusions: Black and African American women in the WISDOM study were more likely to live in the most deprived areas which have higher exposure to several environmental toxins. Given that exposure to some environmental toxins are known to increase breast cancer risk, investigation on how environmental factors can be encorporated in risk estimation is warranted. WISDOM should also direct targeted recruitment efforts to women who live in the most deprived areas. Citation Format: Katherine E Leggat-Barr, Kimberly Badal, Allison Stover-Fiscalini, Dan Meltzer, Mindy Hebert-DeRouen, Laura Van 'T Veer, Laura Esserman. Association between race and ethnicity, area deprivation, and exposure to environmental toxins in the WISDOM clinical trial population [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B084.

The clinical course of acute, subacute and persistent low back pain: a systematic review and meta-analysis.

Understanding the clinical course of low back pain is essential to informing treatment recommendations and patient stratification. Our aim was to update our previous systematic review and meta-analysis to gain a better understanding of the clinical course of acute, subacute and persistent low back pain. To update our 2012 systematic review and meta-analysis, we searched the Embase, MEDLINE and CINAHL databases from 2011 until January 2023, using our previous search strategy. We included prospective inception cohort studies if they reported on participants with acute (< 6 wk), subacute (6 to less than 12 wk) or persistent (12 to less than 52 wk) nonspecific low back pain at study entry. Primary outcome measures included pain and disability (0-100 scale). We assessed risk of bias of included studies using a modified tool and assessed the level of confidence in pooled estimates using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool. We used a mixed model design to calculate pooled estimates (mean, 95% confidence interval [CI]) of pain and disability at 0, 6, 12, 26 and 52 weeks. We treated time in 2 ways: time since study entry (inception time uncorrected) and time since pain onset (inception time corrected). We transformed the latter by adding the mean inception time to the time of study entry. We included 95 studies, with 60 separate cohorts in the systematic review (n = 17 974) and 47 cohorts (n = 9224) in the meta-analysis. Risk of bias of included studies was variable, with poor study attrition and follow-up, and most studies did not select participants as consecutive cases. For the acute pain cohort, the estimated mean pain score with inception time uncorrected was 56 (95% CI 49-62) at baseline, 26 (95% CI 21-31) at 6 weeks, 22 (95% CI 18-26) at 26 weeks and 21 (95% CI 17-25) at 52 weeks (moderate-certainty evidence). For the subacute pain cohort, the mean pain score was 63 (95% CI 55-71) at baseline, 29 (95% CI 22-37) at 6 weeks, 29 (95% CI 22-36) at 26 weeks and 31 (95% 23-39) at 52 weeks (moderate-certainty evidence). For the persistent pain cohort, the mean pain score was 56 (95% CI 37-74) at baseline, 48 (95% CI 32-64) at 6 weeks, 43 (95% CI 29-57) at 26 weeks and 40 (95% CI 27-54) at 52 weeks (very low-certainty evidence). The clinical course of disability was slightly more favourable than the clinical course of pain. Participants with acute and subacute low back pain had substantial improvements in levels of pain and disability within the first 6 weeks ( moderate-certainty evidence); however, participants with persistent low back pain had high levels of pain and disability with minimal improvements over time (very low-certainty evidence). Identifying and escalating care in individuals with subacute low back pain who are recovering slowly could be a focus of intervention to reduce the likelihood of transition into persistent low back pain. PROSPERO - CRD42020207442.

Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

Ongoing impacts of childhood-onset glomerular diseases during young adulthood.

Childhood-onset glomerular disease often requires ongoing treatment and follow-up into adulthood. However, few studies have analyzed the associated impact and distress experienced by patients with this condition during the transition from childhood to adolescence and adulthood. At three facilities, we recruited patients who developed idiopathic nephrotic syndrome or IgA nephropathy during childhood and were at least 18years old at the time of study entry. Among them, a questionnaire-based survey was administered to patients who consented to participate, and the results were analyzed in conjunction with clinical information. Data from a total of 38 patients were analyzed. Of these patients, 15 had idiopathic nephrotic syndrome and 23 had IgA nephropathy. The age of transition from pediatrics to the adult medicine department was correlated with the number of recurrences. Many patients also reported being significantly affected by exercise restrictions and physical decline associated with their diseases and medications. Various impacts, including distress, affected decision-making regarding higher education, with patients engaging in higher education at a significantly higher rate compared with the regional average (66.7% vs. 46.9%, p = 0.028). We analyzed the impact of childhood-onset glomerular disease and distress during the transition period from pediatric to adult care. This study highlighted the significant impact of medications and exercise restrictions on patients' decisions regarding higher education. Future prospective studies will be needed to examine patients' distress in more detail and establish management approaches to enhance patient quality of life.

Long Term Durable Responses in Relapsed/Refractory (r/r) ALL, DLBCL, and FL Patients Treated with Tisagenlecleucel and Its Association with Persistence of CAR T-Cells

Introduction: Monitoring of chimeric antigen receptor (CAR) transgene levels in peripheral blood post tisagenlecleucel (tisa-cel) infusion provides information on expansion and persistence of CAR T-cells. In adult diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) patients (pts), the expansion of CAR T-cells was similar between responding and non-responding pts, while in pediatric and young adult acute lymphoblastic leukemia (ALL) pts, higher expansion in responding pts was observed. Based on long term follow up data from tisa-cel treated pts, analyses were performed to delineate the impact of CAR persistence and B cell aplasia on duration of remission (DOR). Methods: Transgene levels in blood measured by quantitative polymerase chain reaction were available from pivotal phase II studies in pts with r/r ALL (ELIANA [N=79], ENSIGN [N=64], NCT03123939 [N=69], NCT01626495 [N=60]), r/r DLBCL (JULIET [N=115]), and r/r FL (ELARA [N=97]), along with the long term follow up study (NCT02445222). The time related to loss of persistence of CAR T-cells (T loss) was defined as the time at which transgene levels first dropped below 50 transgene copies/µg DNA (approximates to lower limit of quantification (LLOQ) of the assay) after maximal expansion. Kaplan Meier analysis was performed to investigate the impact of duration of T loss and time corresponding to last quantifiable level (T last) on DOR/relapse. The impact of time to B cell recovery (&amp;gt;1% CD19+ B cells/WBCs or &amp;gt;3% CD19+ B cells/lymphocytes for ALL, and 80-616 cells/µL for DLBCL and FL), on DOR/relapse was also investigated. Results: Long term CAR persistence in tisa-cel treated pts has been observed for up to 9, 6, and 2.5 years for ALL, DLBCL, and FL pts, respectively, reflecting differing length of follow up based on initiation of trials in respective indications. Across indications, pts who lost transgene within 6 months or between 6-12 months had shorter DOR relative to pts with persistent transgene (Fig 1, ALL pts). In ALL, the median T loss was 27.4, 18.2, 9.7, and 18.0 months for ongoing complete response (CR) &amp;gt; 12 months, CR pts between 6-12 months, relapsed pts &amp;lt; 12 months, and relapsed pts &amp;gt; 12 months, respectively. However, of the pts who lost transgene within first 6 months, some pts maintained durable responses for ≥12 months (29%, 15%, and 50% in ALL, DLBCL, and FL, respectively). Among ALL relapsed pts, majority (17/26, 65%) of the pts with T loss &amp;lt; 6 months showed B cell recovery, however 6 pts had T loss at &amp;lt; 6 months as well as B-cell recovery but maintained response for ≥ 12 months. In ALL, Pulsipher et al.,(Blood Cancer Discov. 2022)have shown that NGS MRD within the first 6 months to 1 year post infusion may be a more reliable predictor of potential relapse than B cell recovery. The median time to B-cell recovery was 266 days in pts who relapsed/censored within 12 months but was not reached for pts with ongoing response at 12 months. On the contrary, B cell recovery seems to have no association with relapse in DLBCL or FL pts. Of the ALL pts with CAR persistence, pts with &amp;lt;50% morphologic blasts at any time prior to infusion of tisa-cel had longer DOR compared to pts with ≥50% blasts. This may also reflect a more resistant high risk ALL at the time of study entry or greater potential for stochastic loss of CD19 in pts with the higher disease burden. Conclusions: Long term sustained remission/response was observed in tisa-cel treated pts in the pivotal trials. The analyses demonstrate a positive association between CAR persistence and durable clinical responses across indications, however, some pts maintained durable responses despite early loss of transgene and/or early B cell recovery (&amp;lt; 6 months post infusion; Myers et al., J Clin Oncol. 2021). To note, in DLBCL and FL, the transgene levels in blood may not represent the levels at target sites including lymph nodes, moreover, T last and T loss are dependent on the duration of follow up, LLOQ etc. Of note, these analyses represent data from pivotal tisa-cel clinical studies with a heavily treated pt population post multiple lines of therapy including prior HSCT, and may not represent pts treated with commercial product, at earlier times post diagnosis in current studies with fewer lines of prior treatment, lower pre-infusion disease burden, and/or other CAR product. In pts with early loss of transgene, further research is needed to identify potential factors or patient characteristics resulting in durable responses.

Emapalumab, a Fully Human Anti-Interferon Gamma Monoclonal Antibody, in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis: Long-Term Follow-up of a Phase 2/3 Study

Background: Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening genetically heterogeneous, autosomal recessive disorder, characterized by immune dysregulation and hyperinflammation. Acute treatment of pHLH has traditionally involved immunochemotherapy with glucocorticoids and etoposide to suppress hyperinflammation and facilitate the patient undergoing allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Emapalumab, a fully human immunoglobulin G1 anti-interferon-γ (IFNγ) monoclonal antibody, binds free and receptor-bound IFNγ, neutralizing its biologic activity. Emapalumab has demonstrated efficacy in patients with pHLH and has a favorable safety profile with no increase in the risk of adverse events (AEs), including infections, with increasing drug exposure prior to patients undergoing HSCT. Objective: To monitor the long-term safety and efficacy of emapalumab in patients with pHLH, including the period after undergoing HSCT. Methods: Long-term follow-up study (NCT02069899) of patients with pHLH who had received ≥1 dose of emapalumab in a multicenter, single-arm, open-label phase 2/3 clinical trial who were followed for 1 year after HSCT or last administration of emapalumab in the parent study (NCT01818492). Patients received emapalumab for 4 to 8 weeks in the parent study, which included a 4-week short-term follow-up period, during which patients could have undergone HSCT. Treatment with emapalumab could continue according to the parent study protocol during follow-up, if a favorable benefit/risk assessment was established. Any concomitant treatment ongoing at the time of study entry was continued as considered necessary by the investigators. Endpoints included safety, 1-year survival, and HSCT outcomes. Results: Overall, 37/45 patients who participated in the phase 2/3 study entered long-term follow-up, with 24 patients (64.9%) completing the study; 13 patients (35.1%) withdrew from the study, most commonly because of AEs (6 patients [46.2%]) and withdrawal of informed consent (2 patients [15.4%]). All patients had ≥1 concomitant medications including systemic corticosteroids and ≥1 systemic antimicrobial. Emapalumab treatment continued during long-term follow-up for 22 patients (59.5%). All patients experienced at least one AE during follow-up ( Table), most commonly infections or infestations (27 patients [73.0%] reported an infection AE). Most AEs were mild or moderate in intensity. Four patients (10.8%) had study drug-related AEs. Overall, 56.8% of patients experienced at least one severe AE. 28 patients (75.7%) experienced at least 1 serious AE (SAE), but only 1 patient (2.7%) had a treatment-related SAE (Coombs positive hemolytic anemia). Infusion-related reactions of rash were observed in 2 patients (5.4%), but these reactions were temporary and resolved without treatment. No patients experienced AEs leading to study drug discontinuation. Nine patients died during the study (4 prior to HSCT conditioning and 5 during the post-conditioning period). No study drug-related deaths were reported. 28 (75.7%) patients were alive at last observation or 1 year after last emapalumab dose and 33 (89.2%) survived to undergo HSCT or until 1 year after last emapalumab dose (whichever came first). 29 patients (78.4%) underwent HSCT, including 18 during long-term follow-up. 24 of the 29 (82.8%) patients who underwent HSCT were alive at last observation or 1 year after last emapalumab dose. Sustained engraftment was achieved in 23 patients (79.3%; 95% confidence interval, 61.6-90.2%). During the follow-up period, 6 patients (20.7%; 95% confidence interval [CI], 9.8-38.4%) experienced primary or secondary graft failure after undergoing HSCT and 7 patients (24.1%; 95% CI, 1.2-42.1%) had acute or chronic graft-versus-host disease. At the 12-months post-transplant visit, 25/26 (96.2%) patients maintained a complete response, while 1 (3.8%) patient was reported to have maintained a partial response. No pHLH reactivation was reported during the study. Conclusions: The long-term outcomes for patients with pHLH treated with emapalumab are consistent with observations made during a phase 2/3 study. A favorable safety profile was maintained, and a high proportion of patients received HSCT and achieved long-term survival.

Plasma Proteomic Signature Predicts Risk of Myeloid Neoplasm

Introduction The presence of clonally expanded mutant hematopoietic stem cells, clonal hematopoiesis (CH) is known to predispose to hematologic malignancy, particularly myeloid neoplasms (MN). However, the overall risk of developing MNs among individuals with CH is low (&amp;lt;1% per year). Limitations in our ability to predict who with CH will progress to MN is a barrier to prevention strategies. The human proteome reflects the downstream impact of complex interactions between genetic and epigenetic regulation of biologic systems. We hypothesized that plasma proteomic markers might be associated with MN risk and if so could inform our understanding of the mechanisms promoting the progression of CH to MN. Methods Among 46,237 individuals in the UK Biobank (UKB) with whole exome sequencing data and single nucleotide polymorphism (SNP) array profiling of the blood and plasma proteomic profiling using the Olink Explore platform (1,463 unique proteins), we jointly characterized CH and plasma proteomic profile. Cox proportional hazard models were used to assess the association between the level of each plasma protein and risk of MN; while controlling for age, sex, genetic ancestry, smoking status, blood counts, and sample collection year. The relative contribution of clinical, CH, and proteomics features in prediction of incident MN was assessed using lasso regression with 100-fold cross validation. We performed protein quantitative trait loci (pQTL) mapping to identify independent germline autosomal genetic loci that significantly regulate plasma proteomic levels (p &amp;lt;5x10 -8). We calculated genetically predicted risk scores for plasma protein levels as the as the sum of the effect estimates from linear regression analysis with additive genetic effect, multiplied by the number of risk alleles for each locus. As a validation cohort, we used an independent set of 427,614 individuals in the UKB to test for an association between genetically predicted levels of proteomic markers and MN risk. Results A total of 115 participants developed MN at least 3 months after study entry (median 83 months). As expected, participants who developed MN (cases) had a higher frequency of CH at the time of study entry compared to those free of hematologic malignancy (controls); 42 versus 6% for SNV/Indels and 23 versus 3% for mosaic copy number events in cases compared to controls respectively. We identified 115 proteins significantly associated (qFDR &amp;lt;0.05) with incident MN (Figure 1). These include known regulators of the adaptive immune system, innate immune system, leukocyte trafficking, hematopoietic stem cell self-renewal, and platelet activation. Given that CH is a genetic precursor to MN, we assessed the relationship between plasma proteomic markers of MN and CH. Among the 115 plasma proteins that were significantly associated with MN, 35 were significantly (qFDR &amp;lt;0.05) and 59 nominally (p &amp;lt;0.05) associated with CH. After adjusting for CH, the strength of the association between plasma protein markers and MN risk was generally reduced (mean 7%), but remained significant for many (N=44). We identified a total of 79 plasma proteins that were associated with the presence of CH at the time of study entry, 34 of which overlapped with MN risk proteins. Inclusion of proteomics features in a lasso regression model (AUC = 0.85) improved prediction of incident MN beyond clinical factors and CH (AUC = 0.80; Figure 2). There were 1,282 independent genetic loci that were significantly associated with 115 proteomic markers of MN risk. On average, genetic risk scores captured 12% of the total variance of plasma protein levels (range 0.1-64%). In an independent cohort of 427,614 UKB participants (1,099 of whom developed MN), we found that of the 110 plasma protein markers with a genetic risk score R 2 &amp;gt;1%, 12 were significantly associated with MN (p &amp;lt;0.05). Of the remaining, 63 were directionally consistent. Conclusions We show that plasma proteomic markers predict risk of MN. Some, but not all of the impact of plasma proteomic profile on MN risk is mediated by baseline CH. Inclusion of proteomic markers improves MN risk prediction beyond clinical and CH features. Genetic risk score analysis provides orthogonal validation of the plasma proteomic signature for MN risk. These data highlight the promise of protein and genetic biomarker integration for early diagnosis of MN and further support the role of immune cell regulation in early leukemogenesis.

Investigating Thrombosis Risk Factors in Sickle Cell Disease Utilizing Archetypal Analysis

Background: Thrombosis in sickle cell disease (SCD) affects both the arterial and venous vasculature with devastating consequences. Individuals with SCD have an increased risk of venous thromboembolism (VTE). The risks are multifactorial with prior studies identifying both VTE-specific and SCD-specific risk factors. Machine learning (ML) offers the potential to detect non-linear relationships in complex multifactorial diseases and has successfully predicted outcomes in deeply phenotyped patients. We investigated whether archetypal analysis (AA), a method of ML would identify clinical and laboratory factors associated with arteriovenous thrombosis in patients with SCD. Methods: We retrospectively analyzed a prospective longitudinal cohort of patients with SCD (NCT00011648) studied between 2000-2017. A prior history of VTE and/or stroke at the time of study entry as captured by the electronic medical record was used to define index “cases”. SCD patients without a history of thrombosis were “controls”. The demographic and clinical characteristics of cases and controls were compared using Wilcoxon rank-sum test for continuous and Fisher's exact test for categorical variables. Unsupervised AA was used to identify patterns of clinical and laboratory test characteristics within the entire cohort of patients including cases and controls. AA identifies patterns are on the convex hull that encloses all patients in the cohort in the high-dimensional feature space. Once specific archetypes were identified, the frequency of each archetype was determined within cases and controls. In addition, we describe the age and laboratory characteristics of the archetypes that were significantly more prevalent in cases as compared to controls. Results: The cohort consisted of 633 out of 862 patients that had their whole exome sequenced. A combined total of 160 arterial and venous thrombosis events was detected in 148/633 patients (24%) with half (n=79) attributable to arterial stroke and half (n=81) attributable to VTE [Table 1]. A small proportion of patients had both arterial and venous thrombosis (n=12). The median age (31 years, p=0.94) and sex were similar between the cases (n=148) and controls (n=485). The distribution of genotypes was similar between the two groups (p=0.09). A significantly higher proportion of patient with thrombosis had a prior history of blood transfusion (p&amp;lt;0.0001) and history of insertion of a central venous access device (p=&amp;lt;0.0001) [Table 1]. History of medical management with hydroxyurea was similar among the cases and controls (p=0.70). Compared to controls, the cases had elevated laboratory parameters including AST levels (p=0.02), and serum ferritin (p&amp;lt;0.0001), while HbS percentages were significantly lower (p&amp;lt;0.0001). Based on the minimum error in matrix factorization, a total of 15 archetypes were identified in the cohort [Figure 1]. Each patient was decomposed as a weighted combination of the 15 archetypes. The contributing archetypes for each patient were those archetypes that have non-zero weights. Among those 15 archetypes, archetypes 9, 14 and 15 were significantly more enriched among the cases compared to controls (p&amp;lt;0.02) [Figure 1]. We observed elevated serum ferritin levels and low levels of HbS across the three archetypes, which are consistent with the previously identified risk factors [Figure 1]. Conclusions: Machine-identified archetypes are objective and reproducible feature representations. Archetype analysis-based machine learning appears to hold promise to identify both traditional VTE and SCD-specific risks for clinical thrombosis. Future studies will utilize archetypal analysis to investigate associations between clinical, laboratory and genetic markers for thrombosis and assess their reproducibility using validation cohorts.

Type 1/like Calr Mutation in Momelotinib-Treated Patients with Myelofibrosis Is the Most Prominent Predictor of Drug Survival and Longevity without Transplant

Background: Non-transplant treatment options in myelofibrosis MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi). FDA-approved JAKi for the treatment of MF include ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is currently under review. We have previously reported long-term survival data on momelotinib and drug survival that was significantly longer, retrospectively compared to ruxolitinib ( AJH. 2022;97:E433). In the current study, we focused on molecular predictors of drug survival (i.e., drug retention) and longevity without allogeneic hematopoietic stem cell transplant AHSCT (transplant-censored survival). Methods : The current study included data from Mayo Clinic patients who participated in a phase-1/2 core study of momelotinib (NCT00935987). Study design, drug doses and schedule, and additional details on treatment effect and side effects have previously been published. Drug survival was calculated from time of initiation of momelotinib to time of treatment discontinuation. Survival analysis required censoring of patients at time of AHSCT. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA). Results : 79 JAKi-naïve patients with MF were considered: median age 67 years; males 54%; PMF 65%, post-PV MF 20%, post-ET MF 15%; JAK2 71%, type 1/like CALR ( CALR-1) 14%, CALR-2 3%, MPL 8%, triple-negative 5%. Risk category according to DIPSS was high/intermediate in 80% of the patients and unfavorable karyotype in 29%. Non-driver mutation information was available in a subset of patients and included ASXL1 22% and SRSF2 18%. Median time from diagnosis to study entry was 25.2 months; patients were enrolled between November 2009 and March 2011 with follow-up information updated through July 2023; during this period, 68 (86%) deaths, 13 (16%) leukemic transformations, and 7 (9%) AHSCTs were recorded. Median follow-up for alive patients was 12.5 years (range 11.3-13.1). Anemia response rate was 48% and spleen 47%. Median treatment duration was 25 months (range 0.1-157); the proportion of patients remaining on active therapy was 68% at 1 year, 30% at 3 years, 16% at 5 years, and 7% at 10 years (Figure 1a). At the time of this writing, 5 (6.3%) patients were still receiving momelotinib therapy with treatment durations of 152 to 157 months. In univariate analysis, molecular predictors of drug survival included CALR-1 (p=0.006) but not ASXL1 (p=0.6) or SRSF2 (p=0.3) mutation, or unfavorable karyotype (p=0.08). The 3-, 5-, and 10-year drug survival rates for CALR-1-mutated patients were 64%, 40%, and 18%, respectively, and for CALR-1 wild-type 25%, 11%, and 4% (p=0.01, Figure 1b). CALR-1 independent association with longer drug survival was also appreciated for younger age (p&amp;lt;0.01) and absence of baseline transfusion dependency at time of study entry (p=0.02); all three risk factors remained significant during multivariable analysis with HR (95% CI) rates of 0.4 (0.2-0.87) for CALR-1, 0.5 (0.3-0.89) for age &amp;lt;63 years, and 0.6 (0.3-0.9) for absence of transfusion-dependency. Spleen response (p&amp;lt;0.01) but not anemia response (p=0.23) was also associated with longer drug survival; in multivariable analysis all 4 risk factors retained significance. Multivariable analysis of genetic variables for transplant-censored survival identified absence of CALR-1 (HR 3.5, 95% CI 1.2-10.5; p=0.03) and presence of high molecular risk (HMR; ASXL1/ SRSF2) mutations (HR 2.3, 95% CI 1.1-4.6; p=02) to independently predict inferior survival. Among 11 patients with CALR-1 mutation, median transplant-censored survival was 125 months with 10-year survival rate of 60% (Figure 1c); by contrast, the corresponding figures were 37 months and 12%, in the 68 patients not harboring CALR-1 mutation (Figure 1c). In multivariable analysis, absence of CALR-1 (HR 2.9, 95% CI 1.02-8.1), age ≥63 years (HR 3.0, 95% CI 1.5-6.0), and absence of spleen response (HR 2.6, 95% CI 1.5-4.5) were identified as being most significant in predicting inferior transplant-censored survival. Conclusions : CALR-1 mutation is the most important risk factor for both drug survival and longevity without AHSCT, in momelotinib-treated patients with MF. Such information might help identify MF patients who might benefit from treatment with momelotinib and in whom AHSCT might be deferred or not.

Quality of Life in Emicizumab-Treated People with Hemophilia A in the ATHN 7 Hemophilia Natural History Study - an Assessment of Baseline PROMIS®-29 Scores

Background: People with hemophilia A (PwHA) experience frequent bleeding into joints, muscles and soft tissues due to a deficiency of factor (F)VIII, which has a substantial negative impact on their health-related quality of life (HRQoL). The American Thrombosis and Hemostasis Network (ATHN) ATHN 7 research study is: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment for People with Hemophilia (NCT03619863). ATHN 7 prospectively monitors the use of hemophilia A (HA) and B therapies, including emicizumab. The aim of this abstract is to contribute to the literature on disease burden in PwHA. We describe baseline scores for a subset of adult PwHA enrolled in ATHN 7 who were receiving emicizumab and completed the Patient-Reported Outcomes Measurement Information System (PROMIS®) Profile-29 measure at the time of study entry. Methods: ATHN 7 is a longitudinal, prospective observational cohort study conducted at 26 ATHN-affiliated sites in the United States (US). Clinical and demographic information was collected at baseline. Participants completed patient-reported outcome measures, including PROMIS-29, at baseline. The PROMIS-29 Profile is a disease-agnostic measure capturing data across physical, mental, and social health domains: physical function, fatigue, sleep disturbance, pain intensity, pain interference, depressive symptoms, anxiety, and ability to participate in social roles/activities. PROMIS measures are scored using a standardized T-score metric with a reference population mean of 50 and a standard deviation (SD) of 10, based on the US general population. Higher scores indicate the participant is experiencing more of the concept being measured (positive or negative). No statistical comparisons were performed in this analysis. A mean standardized T-score of 0.5-1.0 SD worse than the reference population mean is defined as mild symptoms/impairment, 1.0-2.0 SD worse than the mean as moderate symptoms/impairment, and ≥2.0 SD worse than the mean as severe symptoms/impairment (HealthMeasures, 2023). Results: Overall, 67 participants in ATHN 7 receiving emicizumab at study entry completed PROMIS-29 at baseline ( Table 1). Participants had a median (min, max) age of 30.0 (18.0, 75.0) years. Disease severity at diagnosis was mild or moderate for 14 (20.9%) participants and severe for 53 (79.1%) participants. There were 12 (17.9%) PwHA with FVIII inhibitors. At time of study entry, participants had been receiving emicizumab for a median (min, max) of 126 (13.1, 254.0) weeks. Mean PROMIS-29 domain T-scores for the ability to participate in social roles and activities, and symptoms of anxiety, sleep disturbance, depression and fatigue at baseline all fell within 0.5 SD of the mean of the reference population ( Figure 1). PwHA in this analysis did however, demonstrate mild symptoms of pain interference (mean baseline T-score: 55.62; [normal: &amp;lt;55]). Mean baseline PROMIS-29 domain T-scores were also analyzed according to presence of FVIII inhibitors, disease severity, and age. PwHA with FVIII inhibitors had mild impairment of physical function (42.17 [normal: &amp;gt;45]) and mild symptoms of pain interference (58.64; [normal: &amp;lt;55]), while those without inhibitors had physical function (45.96; [normal: &amp;gt;45]) and pain interference (55.00; [normal &amp;lt;55]) within or on the boundary of 0.5 SD of the reference population. Similarly, people with severe HA without FVIII inhibitors had mild impairment of physical function (44.76; [normal &amp;gt;45]) and mild symptoms of pain interference (55.49; [normal: &amp;lt;55]), while people with mild/moderate HA without inhibitors had physical function (49.85; [normal: &amp;gt;45]) and pain interference (53.46; [normal: &amp;lt;55]) within 0.5 SD of the reference population. Physical function decreased with age, from 51.71 in the group aged ≤24 years (normal: &amp;gt;45) to 36.18 (moderate impairment) in the group aged ≥50 years, while pain interference increased with age, from 51.18 in the group aged ≤24 years (normal: &amp;lt;55) to 59.80 (moderate symptoms) in the group aged ≥50 years. Conclusions: In this analysis, we observed that HRQoL in PwHA receiving emicizumab, as measured by PROMIS-29 domain T-scores, generally did not differ from that of the US reference population. PwHA did report mild symptoms of pain interference. Results should be interpreted with caution given that no statistical tests were performed, and subgroup numbers are small.

Evaluation of palbociclib in combination with topotecan and cyclophosphamide in pediatric patients with recurrent or refractory neuroblastoma.

TPS10069 Background: Palbociclib is an orally administered, highly selective, reversible, small molecule cyclin-dependent kinases 4/6 (CDK4/6) inhibitor. Inhibition of CDK4/6 reduced growth of neuroblastoma cell lines. The phase 1 portion of the study, conducted and funded by Pfizer in collaboration with the Children's Oncology Group, established the recommended phase 2 dose (RP2D) of palbociclib with topotecan and cyclophosphamide (TOPO/CTX) in children with solid tumors. Per study protocol, if 2 or more patients from the phase 1 study show a confirmed objective response (OR) in a specific tumor type, an open-label, non-randomized tumor-specific cohort (TSC) may be opened. Methods: A neuroblastoma TSC has been opened to evaluate the preliminary antitumor activity of palbociclib with TOPO/CTX in the treatment of patients with recurrent/refractory neuroblastoma using a modified Simon’s 2-stage optimal design. Up to 21 patients will be enrolled and receive palbociclib with TOPO/CTX. The primary endpoint is OR, as assessed by investigator using International Neuroblastoma Response Criteria (INRC). Secondary efficacy endpoints include duration of response, progression-free survival, and overall survival. Key eligibility criteria include: recurrent/refractory neuroblastoma, measurable disease as defined by INRC, aged ≥2 and &lt; 21 years at the time of study entry, adequate blood counts organ function, and performance status. Patients may have received prior TOPO and/or CTX, provided their disease did not progress on this regimen. Prior treatment with a CDK4/6 inhibitor is exclusionary. Patients will receive palbociclib at the RP2D of 75 mg/m2 orally once daily on days 1–14 of each 21-day treatment cycle. CTX (250 mg/m2) followed by TOPO (0.75 mg/m2) will be administered intravenously once daily on days 1–5. Concurrent radiotherapy or surgery for local control will be permitted. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity , or up to 24 months of treatment, whichever occurs first. Enrollment in the neuroblastoma TSC was initiated in December 2022 ( NCT03709680 ). Clinical trial information: NCT03709680 .

VELOCITY-Lung: A phase (Ph) 2 study evaluating safety and efficacy of domvanalimab (dom) + zimberelimab (zim) + sacituzumab govitecan (SG), or etrumadenant (etruma) + dom + zim, or etruma + zim in patients (pts) with treatment-naïve metastatic non-small cell lung cancer (mNSCLC).

TPS9155 Background: Current standard of care (SOC) for pts with mNSCLC lacking an actionable mutation includes checkpoint inhibitor (CPI), platinum (PT)-based therapy, or a combination of the two, but is associated with poor outcomes. SG is a Trop-2–directed antibody-drug conjugate. SG monotherapy resulted in a 17% objective response rate (ORR), with a manageable safety profile in pts with mNSCLC who had multiple prior therapies (Heist RS, et al. J Clin Oncol. 2017), and a Ph 2 study is currently ongoing assessing SG+CPI±PT-based therapy (NCT05186974) in treatment-naïve mNSCLC. Etruma (dual adenosine receptor antagonist), dom (anti-TIGIT), and zim (anti–PD-1) are under clinical investigation for antitumor activity. Substudy-01 is part of the VELOCITY-Lung Ph 2 platform study evaluating novel treatment combinations in pts with treatment-naïve mNSCLC. Methods: VELOCITY-Lung (NCT05633667) is an open-label, multicenter, randomized, Ph 2 platform study. Key eligibility criteria for substudy-01 include age ≥18 y; pathologically documented stage IV NSCLC at time of study entry without EGFR, ALK, or other actionable genomic alterations; no prior systemic treatment for mNSCLC; ECOG PS 0-1; any PD-L1 status. Pts previously treated in the (neo)adjuvant setting may be included if therapy was completed ≥12 mo before study drug initiation. Current treatment arms in the preliminary stage are Arm A: dom+zim+SG; Arm B: etruma+dom+zim; Arm C: etruma+zim. Dosing will be as follows: etruma 150 mg po once daily, dom 1200 mg IV q3wk, zim 360 mg IV q3wk, SG 10 mg/kg IV on D1 and D8 of a 21-D cycle. Randomization will be stratified by histology and baseline PD-L1 status (central testing; ≥50% vs &lt; 50%). Pts are randomized equally between treatment arms (arms can be added to evaluate additional novel combinations) in the preliminary stage. Once the expansion stage opens, pts will be randomized based on the number of experimental arms in the expansion stage, the comparator arm, and any newly added preliminary stage treatment arms. Pts will continue to receive treatment until progressive disease, death, unacceptable toxicity, or initiation of a subsequent anticancer therapy. The primary endpoint is ORR assessed by investigator per RECIST v1.1. Secondary endpoints include progression-free survival, duration of response, overall survival, and safety. During the preliminary stage, efficacy will be compared with historical SOC; during the expansion stage, efficacy will be compared with an active comparator arm within the study. Depending on the number of arms being tested in the expansion stage, this study plans to enroll ~69 to 289 patients globally and is open for recruitment. Clinical trial information: NCT05633667 .

Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: Analysis from the PENELOPE-B trial.

502 Background: The PENELOPE-B phase III trial investigated the addition of one year of palbociclib to endocrine therapy (ET), in patients with hormone receptor positive HER2 negative breast cancer with residual invasive disease after neoadjuvant chemotherapy. Prior research has demonstrated that detection of circulating tumor DNA (ctDNA) in the adjuvant setting is associated with a high risk of disease relapse. We assessed the potential of ctDNA analysis to predict future clinical relapse for patients enrolled in the PENELOPE-B trial. Methods: Patients who were endocrine naïve at the time of study entry were selected for ctDNA analysis. Plasma samples were collected at baseline (after completion of neoadjuvant chemotherapy and surgery), prior to cycle 7 (approximately 6 months into ET +- palbociclib), end of treatment (EOT), and progressive disease. A tumor sample was subjected to exome sequencing, and up to 50 tumor somatic mutations were tracked in plasma using error-corrected sequencing combined with a proprietary algorithm for ctDNA detection (RaDaR assay). Detection of ctDNA was associated with invasive disease-free survival (iDFS) and distant metastasis-free survival using Cox proportional hazard models. Results: Of 1250 patients enrolled in PENELOPE-B, 129 were endocrine naïve at trial entry, and 78 had a baseline ctDNA sample analyzed. The ctDNA analysis group was representative of the overall endocrine naïve group, with median follow-up of 42.9 months. Seven patients had baseline ctDNA detected, with detection strongly associated with iDFS (HR 8.8, 95% CI 3.3-23.4, p &lt; 0.0001). Detection of ctDNA at cycle 7 (4 patients) was also strongly associated with iDFS (HR 25.5, 95% CI 6.5-99.6, p &lt; 0.0001). Of the 7 patients with baseline ctDNA detection, 2 had undetectable ctDNA at cycle 7 and remained progression free at 30 months, although one later relapsed; the 3 patients with detectable ctDNA at cycle 7 all relapsed within 25 months. Of the 12 patients with a distant relapse within 24 months, only 4 had ctDNA detected at baseline and 3 first at cycle 7/EOT. Of the 8 patients with distant relapse after 24 months, 2 had ctDNA detected at baseline and none first at cycle 7/EOT. Conclusions: Detection of ctDNA following neoadjuvant chemotherapy, and surgery, is associated with a very high risk of early relapse suggesting limited efficacy of adjuvant ET. Clinical imaging and studies of experimental therapy are warranted in this patient population. Testing ctDNA after recent neoadjuvant chemotherapy in luminal-A like breast cancer has relatively low ‘sensitivity’ for predicting future relapse, in particular for later relapses, in part suggesting that response to neoadjuvant chemotherapy may reduce ctDNA detection. Clinical trial information: NCT01864746 .

Habits related to the use of insulin infusion set in patients with type 1 diabetes on pump therapy — the effect of the educational intervention

Proper use of insulin infusion sets (IIS) plays an important role in pump therapy of patients with type 1 diabetes mellitus (T1DM). We assessed the habits associated with the use of IIS in patients with T1DM treated with insulin pump.This study included 79 T1DM patients who were examined for the presence of lipohypertrophy (LH) and retrained for proper IIS use. They completed a standard questionnaire regarding IIS at the time of study entry and at the follow-up. R e s u l t s: At baseline, most of the patients declared to have been using a plastic cannula (n = 68; 86.1%), changing the infusion set regularly (n = 65; 82.3%), and placing the infusion sets on the abdomen wall (n = 68; 86.1%). The most common rotation habit was the "curve pattern" on both sides of the umbilicus (n = 16; 20.3%). After a median of 23 weeks (IQR 20-34), 58 patients were available for the follow-up. A rise in the proportion of patients who declared to change IIS regularly (n = 48; 82.8% vs. n = 57; 98.3%, p = 0.016), change IIS every 2 to 3 days (n = 27; 46.6% vs. n = 35; 60.3%, p = 0.043), use "crisscross" rotation (n = 5; 8.8% vs. n = 12; 21.4%, p = 0.027) was observed. There were less patients reporting not having repeatable rotation manner (n = 15; 26.3% vs. n = 2; 5.4%, p = 0.009). C o n c l u s i o n s: A substantial proportion of T1DM patients on pump therapy declare that they do not follow the recommended principles of IIS use. The intervention consisting of LH assessment and retrain- ing of proper use of IIS might be effective in improving patient compliance.

Habits related to the use of insulin infusion set in patients with type 1 diabetes on pump therapy - the effect of the educational intervention.

Proper use of insulin infusion sets (IIS) plays an important role in pump therapy of patients with type 1 diabetes mellitus (T1DM). We assessed the habits associated with the use of IIS in patients with T1DM treated with insulin pump. This study included 79 T1DM patients who were examined for the presence of lipohypertrophy (LH) and retrained for proper IIS use. They completed a standard questionnaire regarding IIS at the time of study entry and at the follow-up. R e s u l t s: At baseline, most of the patients declared to have been using a plastic cannula (n = 68; 86.1%), changing the infusion set regularly (n = 65; 82.3%), and placing the infusion sets on the abdomen wall (n = 68; 86.1%). The most common rotation habit was the "curve pattern" on both sides of the umbilicus (n = 16; 20.3%). After a median of 23 weeks (IQR 20-34), 58 patients were available for the follow-up. A rise in the proportion of patients who declared to change IIS regularly (n = 48; 82.8% vs. n = 57; 98.3%, p = 0.016), change IIS every 2 to 3 days (n = 27; 46.6% vs. n = 35; 60.3%, p = 0.043), use "crisscross" rotation (n = 5; 8.8% vs. n = 12; 21.4%, p = 0.027) was observed. There were less patients reporting not having repeatable rotation manner (n = 15; 26.3% vs. n = 2; 5.4%, p = 0.009). C o n c l u s i o n s: A substantial proportion of T1DM patients on pump therapy declare that they do not follow the recommended principles of IIS use. The intervention consisting of LH assessment and retrain- ing of proper use of IIS might be effective in improving patient compliance.

Venetoclax Consolidation Achieves Durable Off-Treatment Remissions in Patients with High Risk CLL Who Have Been on Ibrutinib More Than a Year

Background Patients (pts) receiving ibrutinib (ibr) for CLL rarely achieve complete remission (CR) with undetectable minimal residual disease (U-MRD). Therefore, indefinite ibr maintenance therapy (Rx) is standard of care. Long-term Rx with ibr results in a cumulative risk of Rx discontinuation due to progression or toxicity. The risk of progression is highest in pts with complex karyotype and/or del(17p); some series suggest increased risk in pts with del(11q) or persistently elevated β2-microglobulin. Venetoclax (ven) is synergistic with ibr. We hypothesized that adding ven to ibr in pts at high-risk for CLL progression, who had been on ibr for more than 12 months (mo) would achieve U-MRD and allow Rx discontinuation. Methods We designed a phase II, investigator-initiated, response-adapted clinical trial with the addition of ven to ibr in pts (pts) with one or more high-risk features for disease progression who had received at least 1y of ibr regardless of line of Rx. Pts had detectable disease at time of study entry without meeting IWCLL criteria for progression. High-risk was defined as presence of at least one of: del(17p) or TP53 mutation; complex karyotype; del(11q); or elevated β2-microglobulin. Ibr was continued at 140-420mg/d and standard initiation and escalation of ven was performed to the target dose of 400mg/d. Rx with combined ibr and ven continued for a maximum duration of 24, 28-day cycles (C). Pts had bone marrow (BM) evaluation for MRD by flow cytometry (sensitivity 10-4) and CT scan for re-staging every 6mo. Pts in CR with U-MRD on two consecutive evaluations, 6mo apart, stopped ven, but could continue ibr at physician discretion. Pts who were MRD+ post-C24 continued ibr maintenance. Results: We report the results of the first 45 pts enrolled. All patients have completed ven treatment. Median number of prior therapies was 1 (range 0-4). 22/45 patients were receiving ibr as initial Rx. 63% of pts had del(17p) and/or mutated TP53. On intent to treat analysis, 17/45 pts (38%) post-C6 and 26/45 (57%) post-C12 achieved U-MRD. Three patients stopped ven prior to C12 (ineligible, n=1, metastatic solid tumor, n=2). Six of 16 (38%) patients with MRD+ at C12, converted to U-MRD by the end of the study. Best cumulative rate of U-MRD in BM was 33/45 (73%), Figure 1A. There was no difference in U-MRD4 rates or PFS according in those with TP53 abnormalities vs those without. Three pts were in CR prior to ven. Of the remaining pts, 24/42 (57%) pts improved response to CR/CRi during ven treatment. Median follow-up is 37.5 mo for PFS and 40.3 mo for OS. Forty-one patients completed treatment per protocol. Of the 32 patients with U-MRD at the completion of Rx, 10 stopped ven prior to C24 per protocol (5 after C12 and 5 after C18) after achieving U-MRD CR on two consecutive response assessments. At completion of ven, 10/32 pts with U-MRD4 continued ibr at physician discretion (6/10 with del(17p)). Five patients have progressed (Figure 1B): 1 during combination therapy; 3 during ibr maintenance (2 of whom had U-MRD4 at completion of ven); 1 with Richter's Syndrome during observation after achieving U-MRD4 CR. No pt died during ven Rx. Two patients died after receiving treatment for other cancers (metastatic melanoma, AML) and one after coming off protocol to receive acalabrutinib. Blood MRD analysis was obtained q6 mo (Figure 1C) in pts with U-MRD at the EOT; 10/32 have had confirmed MRD re-emergence (8/22 who stopped ibrutinib and 2/10 who continued); 3 subsequently progressed. Treatment was well-tolerated. The most common AE was diarrhea in 47 pts, grade 1-2 in all but 1 pt. The most common grade 3-4 AE was neutropenia, seen in 20% pts (Grade 3 in 8 and grade 4 in 1 patient). No febrile neutropenia was seen. Three patients developed grade 3 infections (pneumonia, pyelonephritis, skin abscess). No patient stopped ven due to toxicity. Seventeen patients experienced at least one SAE, most commonly non-melanoma skin cancers (n=9). Conclusions: Consolidation ven added to ibr in pts with high-risk CLL was well-tolerated and achieved cumulative BM U-MRD4 rate of 73% ibr discontinuation in 49% of pts. Only 1/45 pts progressed during combination Rx. At a median of 12 mo post-ven follow up, most pts who attained BM U-MRD have ongoing U-MRD in blood. A second cohort restricted to 45 high-risk pts with TP53 abnormalities or complex karyotype is accruing and there are plans to also include patients treated with acalabrutinib. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Versus Late Treatment with Ruxolitinib in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease: A Post Hoc Analysis from the Randomized, Phase 3 REACH3 Study

Background: Chronic graft-versus-host-disease (cGVHD) occurs in a relevant proportion of long-term survivors after allogeneic hematopoietic stem cell transplantation and is a leading cause of morbidity and nonrelapse mortality. Standard first-line treatment for cGVHD is systemic corticosteroids; however, approximately 40%-60% of patients either do not respond or become refractory and require additional systemic therapy. Ruxolitinib is an oral, selective Janus kinase (JAK)1/JAK2 inhibitor approved for steroid-refractory (SR)-cGVHD in adult and pediatric patients aged ≥12 years after failure of ≤2 lines of systemic therapy. In the phase 3 pivotal REACH3 trial, compared with best available therapy (BAT), ruxolitinib significantly improved response rates and allowed for steroid tapering among patients with SR-cGVHD. The impact of timing of ruxolitinib initiation on treatment response and patient outcomes needs further investigation. Methods: REACH3 (NCT03112603) was a phase 3 randomized, open-label, multicenter study in which SR-cGVHD patients aged ≥12 years with moderate or severe SR or steroid-dependent cGVHD were randomized to receive either ruxolitinib 10 mg twice daily or investigator-selected BAT. This post hoc analysis examined overall response rate (ORR [complete response (CR) + partial response (PR)]) at Week 24, best overall response (BOR) at any time, and duration of response (DOR) between early (≤14 days from SR-cGVHD), late (>14-28 days), very late (>28 days), or late and very late (>14 days) study treatment initiation. Subgroups were defined based on time from SR-cGVHD to randomization. DOR was measured as the time from first documented CR or PR among those with response at Week 24. Odds ratio (OR) and 95% CI for ORR and BOR were calculated using stratified Cochran-Mantel-Haenszel test or Wald confidence limits. DOR was analyzed with the Kaplan-Meier method. Results: Overall, 165 patients were randomized to ruxolitinib (n=88, 77, 47 for early, late-and-very-late [>14 days], and very late, respectively) and 164 to BAT (n=85, 79, 46). Median age ranged from 47-51 years between subgroups, and most patients were male (range between subgroups, 52.9%-66.2%). Approximately half of patients had experienced prior acute GVHD (range between subgroups, 47.8%-55.8%). Patients had moderate (42.9%) or severe (56.8%) SR-cGVHD at time of study entry; mean time from cGVHD diagnosis to randomization ranged from 154.3-346.0 days between subgroups. Ruxolitinib was superior to BAT in all time-to-treatment subgroups for ORR (early: OR, 2.83 [95% CI: 1.49, 5.37]; late-and-very-late: OR, 3.10 [95% CI: 1.51, 6.34]; very late: OR, 3.41 [95% CI: 1.30, 8.95]; Table). There was a trend toward higher rate of CR for ruxolitinib treatment vs BAT regardless of treatment delay. DOR represented as probability of loss of response over time is presented in the Figure. Ruxolitinib was superior to BAT for BOR of CR or PR up to Week 24 in late-and-very-late (OR, 2.92 [95% CI: 1.46, 5.87]) and very late subgroups (OR, 2.72 [95% CI: 1.13, 6.52]) and numerically greater in the early treatment subgroup (OR, 1.59 [95% CI: 0.80, 3.15]; Table). No differences in ORR, BOR (Table), or DOR were observed between ruxolitinib time-to-treatment subgroups. Conclusions: These data demonstrate that ruxolitinib provides clinical benefit compared with BAT regardless of time elapsing between onset of SR-cGVHD and treatment start. These findings confirm ruxolitinib as an effective treatment option compared with BAT that leads to durable responses in patients with cGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal