Complete Induction Research Articles

Dry Medical Thoracoscopy with Artificial Pneumothorax Induction Using Veress Needle.

In the absence of, or minimal-volume pleural effusion, conventional medical thoracoscopy (MT) is often precluded by the risk of lung injury. Dry medical thoracoscopy (dry MT) aims to ameliorate these dangers by inducing an artificial pneumothorax via needle insufflation or blunt dissection. Veress needle is a device used by surgeons to induce pneumoperitoneum before laparoscopic surgeries, but is not commonly reported in dry MT. We present data from a series of 31 patients in which dry MT with artificial pneumothorax induction using Veress needle were performed under thoracic ultrasonography (TUS) guidance. Procedures were deemed technically successful if all the following criteria were met: (i) successful pneumothorax induction, allowing smooth insertion of semi-rigid thoracoscope during the procedure; (ii) no immediate significant procedural-related complications; and (iii) no delayed complications such as persistent air leak, defined as leakage lasting more than 5 days necessitating prolonged chest tube placement. Complete pneumothorax induction was successful in 25 cases (80.6% technical success rate); nevertheless, biopsies were successfully performed in all cases. The most common histopathological diagnosis was malignancy (n=9, 29.0%), followed by inflammatory pleuritis (n=8, 25.8%) and tuberculosis (n=8, 25.8%). No complications were reported secondary to the procedure. These findings suggest that TUS-guided dry MT with a Veress needle is technically feasible and safe in the hands of experienced MT performers who are competent in TUS.

Delaying pegaspargase during induction in adults with acute lymphoblastic leukaemia is associated with lower risk of high-grade hepatotoxicity without adversely impacting outcomes.

Pegaspargase is a key drug for the treatment of younger adults with acute lymphoblastic leukaemia (ALL). Pegaspargase-associated hepatotoxicity is most common during induction, and its incidence increases with age and body mass index (BMI). We hypothesized that the delayed administration of pegaspargase during induction is associated with lower risk of hepatotoxicity while retaining efficacy. We retrospectively reviewed 141 adult patients with newly diagnosed ALL who received pegaspargase during induction from November 2013 to February 2024. There were 78 (55.3%) patients who received early pegaspargase (EP) on day 4 and 63 (44.7%) patients who received delayed pegaspargase (DP) on day 15. High-grade hepatotoxicity (grade ≥ 3 transaminitis and/or hyperbilirubinaemia) occurred more frequently in the EP group (p = 0.06). Rates of complete remission and negative minimal residual disease post induction were not different between cohorts. Univariate logistic regression analysis showed that BMI and age significantly predicted an increased risk of high-grade hepatotoxicity while DP was associated with a lower risk (odds ratio = 0.44; p = 0.04). Overall survival and event-free survival were not significantly different between cohorts. Delaying pegaspargase administration from day 4 to day 15 during induction cycle in adults with ALL might reduce the risk of high-grade hepatotoxicity without adversely impacting clinical efficacy outcomes.

Management of postpartum anoestrus in Vechur cows by hormonal methods

The study aimed to evaluate suitable hormonal treatment regimen for inducing oestrus in postpartum anoestrus Vechur cows and its reproductive outcome. The efficiency of Ovsynch and Ovsynch + progesterone protocols in 12 anoestrus cows was studied. Six anoestrus cows were kept as untreated control and they were observed for a period of 180 days postpartum. Both treatment protocols resulted in a complete oestrus induction response of 100 per cent. The interval from treatment to induced oestrus was significantly lower in the Ovsynch group (50.10 ± 1.44 h) than in the Ovsynch + progesterone (54.40 ± 0.48 h) group. In comparison to the control group, treatment group animals displayed a high intensity score for oestrus. The duration of oestrus in the Ovsynch group (26.41 ± 0.53 h) was significantly longer than the control (24.45 ± 0.46 h) group and the Ovsynch + progesterone group (24.13 ± 0.42 h). The overall conception rate for three consecutive AI in Ovsynch, Ovsynch + progesterone and control group were 66.67, 83.33 and 33.33 per cent, respectively. The calving to conception intervals were significantly (p<0.001) shorter in Ovsynch (118.33 ± 9.71 d) and Ovsynch + progesterone (106.67 ± 8.12 d) groups than the control (191.5 ± 5.36 d). It is concluded that hormonal treatment is effective in inducing postpartum oestrus and reducing the calving to conception interval in Vechur cows. Keywords: Ovsynch, postpartum anoestrus, progesterone, Vechur

Leucocytosis during all-trans retinoic acid and arsenic trioxide treatment in acute promyelocytic leukaemia.

In patients with acute promyelocytic leukaemia (APL), differentiation syndrome (DS) is a life-threatening complication caused by the differentiating effect of all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Leucocytosis is frequently observed during induction therapy for APL and is intimately associated with the development of DS and its severity. The management of DS is particularly important due to the high likelihood of excellent outcomes for APL patients who successfully complete induction therapy. Commentary on: Cicconi etal. Leukocytosis during induction therapy with all-trans-retinoic acid and arsenic trioxide in acute promyelocytic leukemia predicts for differentiation syndrome and treatment-related complications. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19759.

Myeloid sarcoma, spectrum of clinical characteristics, prognostic impact, and treatment outcome

BackgroundAcute leukemia may present with extramedullary (EM) tissues. Myeloid sarcoma (MS) and leukemia cutis (LC) are considered extramedullary diseases. This study aims to evaluate the incidence, clinical characteristics, and prognostic factors affecting the outcome of pediatric patients with myeloid sarcoma at the pediatric oncology center from July 2007 to December 2017. Radiological imaging was used to stage the tumor, biopsy was done for pathological diagnosis, and bone marrow aspirate for morphology, flow cytometry, cytogenetics, and molecular analysis. Patients received chemotherapy protocols based on those used by the Children's Cancer Group for acute myeloid leukemia (AML).ResultThe study included 91 (13.2%) of 687 pediatric patients with acute myeloid leukemia, with a male-to-female ratio of 1.9 to 1. Prognostic factors that improved the patient’s 5-year overall survival (OS) were age > 5 years old, molecular and cytogenetic detection of t (8; 21), inv 16, presence of a single and small size lesion < 5 cm, negative CNS lesion, and achieved radiological response in isolated disease or radiological and marrow complete remission in disseminated disease post induction 1 with significant P value. Relapse, particularly early relapse, worsens the OS and EFS by 10% and 7.7%, respectively.ConclusionPatients over five with low-risk disease based on cytogenetics, a small, single, negative CNS lesion, and a complete response post induction 1 had better outcomes, with no significant difference between those with isolated extramedullary disease and those with marrow dissemination. Early relapse harms the outcome. The study group’s 5-year OS and EFS rates are 51.4% and 49.4%, respectively.

Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis

AbstractThis phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease (PD) or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until PD, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled; 95.2% completed induction (6 AVR cycles) and 47.6% continued acalabrutinib maintenance. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs and 5 [23.8%] deaths, all among unvaccinated patients). There was no grade ≥3 atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) was 100% (95% CI, 83.9-100.0) with 71.4% complete response. With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI, 67.0-97.5) and 63.2% (95% CI, 34.7-82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI, 70.7-99.3) and 75.2% (95% CI, 50.3-88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10–6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity. The trial was registered at www.ClinicalTrials.gov as #NCT02717624.

Where George Spencer-Brown went wrong – re-entry recalculated

PurposeThe paper uncovers a mathematical error in George Spencer-Brown's genesis of re-entry. It distinguishes between the two interpretations of re-entry presented in “Laws of Form”: recursive versus sequential. The Indeterminacy inferred by George Spencer-Brown from his recursive genesis of re-entry is refuted in three different ways. The calculation of the Modulator from “Laws of Form” demonstrates that only the sequential interpretation of re-entry is reasonable. This contributes to the demystification of re-entry and enables a deeper understanding. Finally, six differences between the concept of form from “Laws of Form” and Niklas Luhmann's sociological systems theory are presented.Design/methodology/approachMethodologically, the paper uses the ternary logic of discrete mathematics, which extends {0, 1} by “don't care” to {0, 1, -}. George Spencer-Brown's Indeterminicy is refuted by using three different methods: complete induction, Theorems 14 and 15 and the software XBOOLE. For the calculation of the Modulator, the only practical application of re-entry in “Laws of Form”, techniques from automata theory are used.FindingsThe paper reveals a mathematical error in George Spencer-Brown's genesis of the re-entry of “Laws of Form” and refutes the assumption of Indeterminicy. The analysis of the only practical application of re-entry presented by George Spencer-Brown shows that the functioning of this Modulator can only be described correctly with the sequential interpretation of re-entry.Originality/valueThe paper emphasizes the interdisciplinary potential of sociology and information technology and provides methods and tools of discrete mathematics for use in the analysis of the works of George Spencer-Brown and Niklas Luhmann.

Treatment Patterns, Acute Healthcare Resource Use, and Costs of Patients with Treatment-Resistant Depression Completing Induction Phase of Esketamine in the United States.

This study aimed to understand treatment patterns, acute healthcare use, and cost patterns among adults with treatment-resistant depression (TRD) who completed induction treatment with esketamine nasal spray in the United States (US). Per label, induction is defined as administration twice a week for 4 weeks, after which maintenance is started on a weekly basis for 4 weeks, and thereafter, patients are treated weekly or bimonthly. Adults with one or more esketamine claim (index date) on or after March 5, 2019 were selected from Optum's de-identified Clinformatics® Data Mart Database (January 2016-June 2022). Before the index date, patients had evidence of TRD and ≥12 months of continuous insurance eligibility (baseline period). Patients with eight or more esketamine treatment sessions were included in the main cohort. A subgroup included patients with one or more baseline mental health (MH)-related inpatient (IP) admission or emergency department (ED) visit (i.e., prior acute healthcare users). Treatment patterns were described during the follow-up period (index date until earliest of end of insurance eligibility or data); acute healthcare (i.e., IP and ED) resource use and costs (2021 US dollars) were reported during the baseline and follow-up periods. Of the 322 patients in the main cohort, 111 comprised the subgroup of prior acute healthcare users. During the follow-up period, mean time from index date to eighth esketamine session was 73.2days in the main cohort and 78.8days in the subgroup (per label, 28days). Further, 75.2% of the main cohort and 73.9% of the subgroup completed four or more esketamine maintenance sessions following induction. In the main cohort, mean all-cause acute healthcare costs per patient per month (PPPM) decreased from baseline ($837) to follow-up ($770). Similar reductions were observed for mean MH-related acute healthcare costs PPPM (baseline $648, follow-up $577). In the subgroup, mean all-cause acute healthcare costs PPPM also decreased (baseline $2323, follow-up $1423), driven by mean MH-related acute healthcare costs PPPM (baseline $1880, follow-up $1139). Mean all-cause acute healthcare use per ten patients per month remained largely stable from baseline to follow-up in the main cohort (IP days: baseline 2.24, follow-up 2.13; ED visits: baseline 1.33, follow-up 1.45) and decreased in the subgroup (IP days: baseline 6.38, follow-up 4.56; ED visits: baseline 2.58, follow-up 2.41). Trends in mean MH-related acute healthcare use were similar. Patients generally required more time than label recommendation to complete esketamine induction treatment, and most went on to have 12 or more esketamine sessions. Completion of induction treatment correlated with reductions in mean all-cause and MH-related acute healthcare costs. Larger reductions were seen in the subgroup of prior acute healthcare users.

An Improved Zero-Flowrate Switching Control Method to Reduce Switching Losses in a Hydraulic Actuator

Hydraulic switching actuators are high-efficiency, fast response, and low-cost solutions for hydraulic control systems. One of the challenging problems is throttling losses during valve transitions. Previously, the authors proposed a zero-flowrate switching method to reduce the throttling energy loss of the switching valve, where a hydraulic resonator is applied to make the flowrates through the lines approaching zero before the valves are switched off. The major challenge of this approach is fast switching valves whose transition times are less than 2 ms. In this paper, an improved zero-flowrate switching method is presented. It utilizes the capacity with independent inlet/outlet ports to regulate flowrates through the lines. Models of capacity applied in a simple line with different pressure signals are developed to explore characteristics of the capacity, based on which a complete actuation system is developed. In the complete model, resistance and inductance are optimized to achieve the desired flowrate response. The improved zero-flowrate switching method reduces throttling energy losses by 99.945% compared to a hard switching system. The simulation results demonstrated that the improved zero-flowrate switching method performs as expected in the design condition. A capacity with proper volume is able to regulate flowrates through all the lines to zero, with the help of appropriate resistance and inductance. Compared to the previous zero-flowrate switching method, the novel strategy allows slower switching valves applied in hydraulic actuation systems and achieves better efficiency performance. This research paves a new avenue for reducing throttling energy losses and improves system efficiency in hydraulic switching actuators, as well as most of the hydraulic switch-mode circuits.

ALL induction outcome: Real-world data from a pediatric oncology center in an LMIC setup with rural predominance.

Acute lymphoblastic leukemia (ALL) has survival rates of greater than 90% in developed nations. However, various sociodemographic factors adversely affect outcome rates in low- and middle-income countries (LMICs). To study induction outcome of ALL and various factors affecting it. This was a prospective cohort study which enrolled 86 children up to the age of 18 years with newly diagnosed ALL registered in newly established pediatric hematology and oncology division over the duration of 3 years. Sociodemographic and clinical data was collected. Outcome was assessed using morphological remission, minimal residual disease (MRD) and mortality rate. Of the 170 children with malignancies registered, 86 were ALL. Mean age was 7.09 ± 4.07 years and the M: F ratio of 1.32:1. Sixteen (38.09%) of them had severe acute malnutrition and another 16 (38.09%) had moderate acute malnutrition. Thirty (68.18%) children over 5 years were undernourished. Seventy-four (86.05%) were B-ALL and 12 (13.95%) T-ALL. In total, 28.77% had WBC counts greater than 50 × 10 9 /L. t (12;21) was the most common cytogenetic abnormality. Majority (60.46%) of the patients belonged to lower socioeconomic status. Seventy-one (93.42%) patients completed induction of which 100% attained morphological remission and 64 (90.14%) were MRD negative. There were five mortalities, three (60%) due to sepsis and 2 (40%) due to hemophagocytic lymphohistiocytosis. Fifty (65.78%) children had morbidities during induction, febrile neutropenia being the commonest. Successful induction outcome rates at par with high-income countries can be achieved even in resource-limited settings of LMIC with support from government and NGOs. Decentralized cancer care centers can effectively pave the way in reducing cancer mortality in children of lower socioeconomic status residing in rural areas.

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

Novel Uses of Methadone Under the "72-Hour Rule" to Facilitate Transitions of Care and Low-Dose Buprenorphine Induction in an Outpatient Bridge Clinic.

Federal regulations restrict methadone for opioid use disorder (OUD) treatment to licensed opioid treatment programs (OTPs). However, providers in other settings can administer methadone for opioid withdrawal under the "72-hour rule" while linking to further care. Prior work has demonstrated that methadone initiation in a low-barrier bridge clinic is associated with high OTP linkage and 1-month retention rates. We describe 2 other novel applications of the 72-hour rule in which methadone withdrawal management facilitated linkage to inpatient hospitalization and outpatient buprenorphine induction. Patient 1 was a 46-year-old woman with OUD complicated by serious injection-related infections. Severe opioid withdrawal limited her ability to tolerate emergency department wait times and receive inpatient care. We administered methadone for opioid withdrawal in an outpatient bridge clinic immediately before emergency department referral; this enabled hospital admission for intravenous antibiotics and anticoagulation. Patient 2 was a 36-year-old man with OUD desiring buprenorphine treatment. He had been unable to complete traditional buprenorphine induction without experiencing precipitated withdrawal. Thus, we recommended a low-dose buprenorphine induction overlapping with a full opioid agonist. Given the patient's preference to stop using fentanyl immediately, he received 72 hours of methadone for withdrawal treatment during the induction phase and successfully transitioned to buprenorphine without significant concomitant fentanyl use. In addition to facilitating OTP linkage, on-demand 72-hour methadone administration for opioid withdrawal can reduce barriers to acute medical care and buprenorphine treatment.

P192 Personalizing treatment for predicting response to infliximab in children with Crohn’s disease using proteomic biomarkers

Abstract Background Identifying minimally invasive diagnostic biomarkers that predict and monitor response to TNF inhibitors would enable treatment to be personalized and increase knowledge of the biological pathways associated with response or lack thereof. Methods Children and adolescents with Crohn’s disease who started treatment with infliximab (IFX) were enrolled in a prospective, multi-center (n=6) trial to identify biomarkers that predict response to IFX. Electronic case report forms were prepared by Studytrax (Macon, GA). Subjects &amp;lt;18 years of age were diagnosed with Crohn’s disease using standard clinical/pathologic criteria. Clinical evaluation and serum samples were obtained prior to initiation of IFX, after induction (dose 4), at six months, and after one year or at the time of treatment withdrawal. There were 119 subjects enrolled and 102 subjects completed induction. Non-responders (n=15) were defined prior to the 4th infusion as having a PCDAI &amp;gt; 10, an elevated Physician Global Assessment (PGA) or requiring dose escalation or medication change. Responders at the 4th infusions were either in remission (PUCAI ≤ 10) or were described as quiescent by PGA. Using the 7k SomaScan (SomaLogic; Boulder, CO) proteomics platform, quantitative protein profiles were generated from banked pre-treatment (V1) and after the three-dose induction (V2) to identify candidate protein biomarkers predictive of therapeutic response. Associations between the 7,310 proteins detected with SomaScan and response to IFX were assessed using t test. Response predictor models were developed using linear regression with backward selection. We report our preliminary findings from a discovery cohort of 56 subjects who completed induction. Results There were 15/56 (27%) non-responders and 41/56 (73%) responders at V2 after IFX induction. SomaScan analysis of the 56 individuals identified sets of differentially expressed proteins discriminating between non-responders and responders at both V1 and V2 and also defined protein signatures that changed from V1 to V2 for responders and non-responders, respectively. Strikingly, only responders demonstrated significant decreases in pro-inflammatory pathways at V2 compared to V1, thereby correlating well with anticipated reduced inflammation in responders. A 6-protein linear regression model performed with an AUC of 0.99 for predicting IFX response at pre-treatment V1. Conclusion In a discovery cohort from a multicenter, prospective trial of children and adolescents treated with infliximab, a comprehensive proteomics platform was able to identify serum proteins that are highly associated with response to infliximab and accurately predict response prior to treatment.

P1014 Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response – Results from the FAVOUR study

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

Monocentric study of IL-5 monoclonal antibody induction therapy for eosinophilic granulomatosis with polyangiitis

ObjectiveAlthough sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan. MethodsHospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP. ResultsTwenty-seven EGPA patients aged 10–70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19–71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92∼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0–10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13–56 injections (41 ± 15) were prescribed with a follow-up period of 12∼52 months (38 ± 14). ConclusionIn this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients.

The Role of urinary kidney injury molecule 1 (KIM-1) in monitoring the treatment response in Egyptian Lupus Nephritis Patients

Lupus nephritis (LN) affects almost two-thirds of systemic lupus erythematosus (SLE) patients. Despite initial aggressive therapy, up to 25% of patients with LN will progress to permanent renal damage. Conventional serum markers for LN lack the sensitivity of an ideal biomarker. Urinary kidney injury molecule-1 (UKIM-1) is an excellent biomarker for early diagnosis of acute kidney injury and predicting renal outcomes. This study intended to determine the predictive performance of UKIM-1 among LN patients in response to induction therapy by assessing and correlating its levels with renal disease activity. The study included 60 SLE patients divided into 20 SLE patients with active lupus nephritis, 20 SLE patients with inactive lupus nephritis, and 20 lupus patients without nephritis as controls. The study was completed after six months from induction treatment. UKIM-1 was measured by an enzyme linked immunosorbent assay at baseline, three-month follow-up and after complete induction therapy. At baseline, the mean serum creatinine and mean UKIM-1 were 1.7 ±0.7 mg/dL and 10.3 ±1.2 ng/dL, respectively in active LN patients. The mean UKIM-1 levels of complete response and partial response groups were 9.8 ±0.9 ng/mL and 11.3 ±1.0 ng/mL respectively. Based on receiver operating characteristics curve analysis, we found a better diagnostic performance of UKIM-1 to predict response to induction treatment, outperforming conventional biomarkers. The sensitivity and specificity were 84.6% and 85.7 %, respectively at an area under the curve of 0.896 and the best cut-off level was ≤10.6 ng/mL. In conclusion, UKIM-1 performed better than conventional biomarkers in predicting response to treatment of active LN.

Retrospective Analysis of Adolescent Young Adult Patients with Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma Treated with the CALGB 10403 Regimen Since Completion of Trial Enrollment

INTRODUCTION The outcomes of adolescent and young adult (AYA) patients (ages 15-39 years) with acute lymphoblastic leukemia/lymphoma (ALL) have improved in part with the adoption of pediatric ALL regimens in the adult treatment setting. The Cancer and Leukemia Group B (CALGB) 10403 trial (C10403) was the largest prospective trial conducted in the United States (U.S.), demonstrating the safety and efficacy of delivering an intensive pediatric regimen utilizing asparaginase in the adult oncology treatment setting to AYAs with ALL, with 3-year event-free survival (EFS) and overall survival (OS) of 59% (95% CI, 54%-65%) and 73% (95% CI, 68%-78%), respectively (Stock et al., Blood 2019). Although this regimen is widely used in the U.S., outcomes for patients treated with C10403 outside of a clinical trial setting remain unknown. We thus conducted a multi-center retrospective study to examine the real-world, off-trial efficacy of the C10403 regimen delivered across U.S. cancer centers. METHODS AYAs ages 17-40 years with newly diagnosed Ph-neg B-ALL or T-ALL between October 1, 2012 and July 1, 2020 who received initial treatment with the C10403 regimen (off trial) across 5 U.S. centers were included. Patients were excluded if they had Ph+ or Burkitt-type ALL. Previously treated patients, except with hydroxyurea, steroids, or one dose of single-agent therapy were excluded; patients given rituximab for CD20+ B-ALL were included. Primary endpoints were induction response rate (IRR), 3-year EFS, and 3-year OS. Induction response was defined as achieving &amp;lt;5% blasts on bone marrow by end of induction or extended induction. Patients were censored for EFS at the time of change in regimen, the addition of another agent (eg blinatumomab) or if they proceeded to hematopoietic cell transplant (HCT). Patients with deviation from the C10403 regimen were included in the 3-year OS analysis. Events were defined as: 1) failure to achieve bone marrow response by the end of induction or extended induction, 2) failure to achieve metabolic response of lymphoma on PET-CT as determined by the clinician 3) death, 4) relapse at any site, or 5) development of second malignancy. RESULTS Among 101 included in the cohort, 54% were 20-29 years old, 69% were male, 55% were Caucasian and 31% identified as Hispanic. Of those with B-cell immunophenotype (70%), 49% had CD20 expression. The majority had normal karyotype (40%), while 3% were hypodiploid, 7% were KMT2a-rearranged, and 30% of the 27 patients assessed had Ph-like ALL. CNS involvement at diagnosis was documented in 20% (9% CNS2/11% CNS3) and 14% had a mediastinal mass. Of the B-ALL cohort (N=71), 16 (23%) received at least one dose of rituximab. Among the entire cohort, the IRR was 91% (54% MRD negative; threshold of at least 10 -4). Of the 101 patients who began induction with C10403, 72 (71%) completed induction and continued to consolidation; 51 (50%) continued beyond consolidation, and 31 (31%) completed the entire C10403 regimen through end of maintenance. Two patients (2%) died while in remission and still receiving treatment. Forty-four patients (44%) were taken off C10403 while in CR; 20 (20%) for allogeneic HCT, 23 (23%) for non-HCT alternative treatments including Hyper-CVAD or blinatumomab, and 1 (1%) for patient preference. The 3-year EFS and OS were 65% (95% CI, 53.8%-78.5%) and 82.7% (95% CI, 75.5%-90.5%), respectively (Figures 1 and 2). Conclusion In this multi-center, real world study of the C10403 regimen administered to newly diagnosed AYA ALL patients across adult U.S. centers, we demonstrate survival outcomes as favorable as the reported clinical trial results. While only 31% of patients completed the regimen through end of maintenance, a majority of patients who came off regimen either underwent consolidative HCT or alternative therapy while in CR. These data confirm the pediatric regimen as an excellent front-line option in AYA ALL.

Evaluation of the Effectiveness of Antifungal Prophylaxis in Adult Acute Lymphoblastic Leukemia during Induction Chemotherapy

Background and Objectives: Due to immune suppression, patients with hematological malignancies are at a high risk of invasive fungal disease (IFD) during chemotherapy. For patients with myeloid tumors, antifungal prophylaxis is generally recognized. However, there are evident interactions between agents used in acute lymphoblastic leukemia (ALL) remission-induction and antifungal agents, resulting in most clinical trials excluding ALL patients. The need for primary antifungal prophylaxis in ALL patients during chemotherapy is still under debate. This study analyzed the efficacy of primary antifungal prophylaxis (PAP) and the incidence of IFD during the first remission induction in the PDT-ALL-2016 cohort, as well as evaluated the impact of PAP on the outcomes of ALL patients. Methods: The PDT-ALL-2016 cohort consists of 408 newly diagnosed ALL patients aged ≥ 14 years, treated between January 2016 and December 2021. All patients were treated using the GRAALL-2003 backbone, a pediatric-like regimen. This study included 280 patients, with a total of 128 exclusions. Excluded patients consisted of 103 individuals who received initial induction treatment in other hospitals, 12 individuals who died without IFD during the induction period, 9 individuals who experienced fungal infection before induction treatment, 2 individuals who did not complete induction remission treatment and were discharged, and 2 individuals who had lost their cases. PAP was defined as the administration of any systemic antifungal agent for two or more consecutive days to a patient without any evidence or history of IFD during the neutropenic period. The diagnosis of IFD was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. Results: Among the 280 patients, 232 received PAP, with caspofungin (n=104), voriconazole (n=59), micafungin (n=44), and others being used as prophylaxis. The baseline characteristics of patients who did or did not receive PAP were similar, except for the age difference (prophylaxis group median age 28.7 versus without prophylaxis group 23.0, P&amp;lt;0.01). In the cohort, 11 proven/probable and 21 possible IFD cases were identified. The incidence of IFD in patients who did or did not receive PAP was 8.6% and 25.0%, respectively. The cumulative incidence of IFD was significantly lower in patients receiving PAP compared to those who did not (HR 0.3, 95% CI 0.1-0.6; P=0.001). In the cohort, the infections of IFD negatively affected overall survival (HR 1.6, 95% CI 0.9-2.7, P=0.093). Conclusions: Our study demonstrates, in a real-life setting, that IFD is a poor prognostic factor for adult ALL and that PAP significantly reduces the incidence of IFD during induction chemotherapy, thereby improving patient survival. Furthermore, compared to published studies (4.3%-18.3%), the incidence of IFD in the prophylaxis group within our cohort is relatively lower. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

CTNI-05. INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR: A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY (PMLM, NCT 05289908)

Abstract OBJECTIVES This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors. METHODS Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. RESULTS Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.

T-regulatory Cells in Acute Leukemia and their Relation with Induction Outcome

Abstract Background: The leukemic microenvironment has become an area of interest for researchers in recent times. Nonmalignant T and B lymphocytes form a significant part of leukemic microenvironment and are postulated to have an effect on its progression and behavior. These lymphocytes are constantly interacting with blasts and are actively involved in innate and acquired immune responses against these blasts. We decided to look at the role of T-regulatory lymphocytes in tumor surveillance and treatment outcome. Aim and Objectives: The aims and objectives of the study are to evaluate the role of T-regulatory lymphocytes in acute leukemia cases and its correlation with treatment outcome. Materials and Methods: We evaluated consecutive 55 acute leukemia cases to investigate the prognostic effect of T-regulatory cells (T-regs) in acute leukemia. The study period was between January 2021 and December 2021. All patients whose complete records were available till the completion of induction were included in the study. The immunophenotype used to characterize and evaluate T-regs was CD4+CD25+ T lymphocytes. For comparison, a total of 10 healthy controls were included in the study. Clinicohematological parameters including fever, lymphadenopathy, hepatosplenomegaly, extramedullary involvement, day 1 total leukocyte count, and blast percentage in peripheral blood and bone marrow were studied and documented to establish any possible correlation with T-regs percentage and treatment outcome. The treatment outcome evaluated in the study was complete remission postfirst induction. Results: As compared to those of healthy participants, the frequencies of CD4+CD25+ T-regs in the peripheral blood of acute leukemia patients were significantly increased (1.5% [range: 0.50%–4.3%] vs. 0.58% [range: 0.40%–1.05%], P = 0.0001). Furthermore, the frequencies of CD4+CD25+ T-regs in the peripheral blood of acute leukemia patients who did not achieve remission were significantly increased as compared to those who achieved remission (2.9% [range: 0.20%–4.3%] vs. 1.3% [range: 0.30%–2.9%], P = 0.002). No significant correlation was noted in the T-reg cells and parameters such as fever, lymphadenopathy, hepatosplenomegaly, extramedullary involvement, day 1 total leukocyte count, and blast percentage. Conclusion: This study suggests the possibility of using T-regs percentages as a prognostic indicator of acute leukemia and possible role of anti-T-regulatory immunomodulators in improving the outcome of disease.