Remission Induction Treatment Research Articles

Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p=0.08; I2=4%, p=0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

Predictive Factors of Renal Recovery and Progression to End-Stage Kidney Disease in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis With Severe Kidney Disease

IntroductionA significant number of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, eGFR<15mL/min/1.73m2) despite advances in remission-induction treatment. MethodsA retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and eGFR<15 ml/min/1.73 m2 or ESKD at presentation. Renal recovery, dialysis discontinuation and persistence of end-stage kidney disease (ESKD) after standard remission-induction, with or without the use of PLEX were analyzed. ResultsWe analyzed 166 patients with biopsy proven active AAV-GN and eGFR <15mL/min/1.73m2 at the time of diagnosis. Patients received glucocorticoids with CYC (n=84) or with RTX (n=72) for remission-induction, and 49 also received PLEX. The predictors for renal recovery were erythrocyte sedimentation rate, serum creatinine (SCr) at diagnosis and minimal or mild chronicity changes. We further analyzed 71 patients who started dialysis with or without PLEX within 4 weeks of AAV-GN diagnosis. The predictors for dialysis discontinuation were minimal chronicity changes in kidney biopsy at diagnosis (OR=6.138,[95%CI,1.389-27.118],p=0.017). Predictors for persistence of ESKD within 12 months included higher serum creatinine (SCr) at diagnosis (IRR=1.086,[95%CI,1.005-1.173],p=0.037), and moderate (IRR=3.797,[95%CI,1.090-13.225],p=0.036), or severe chronicity changes in kidney biopsy (IRR=5.883,[95%CI,1.542–22.439],p=0.009). ConclusionIn our cohort, kidney recovery, dialysis discontinuation, and persistence of ESKD in patients with AAV-GN and eGFR<15mL/min/1.73m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

P909 Proactive therapeutic drug monitoring and pharmacogenomics in mercaptopurine therapy for ulcerative colitis

Abstract Background OPTIC was a prospective placebo-controlled trial investigating therapeutic drug monitoring (TDM)-based mercaptopurine (MP) therapy in ulcerative colitis (UC). Although the primary endpoint (corticosteroid-free clinical remission and endoscopic improvement at week 52) favoured patients with TDM-based MP therapy over placebo, drug-related adverse events were frequent and drop-out rates high. This post-hoc analysis was carried out to show the therapeutic implications of proactive TDM of MP. Methods UC patients with active disease, despite ≥2 g/day mesalamine, underwent remission induction treatment with corticosteroids and initiated weight-based MP therapy (1-1.5 mg/kg). TDM based optimisations were performed at week 6, 12, 18, 24, 36 and 52 using the Dervieux method, unblinded non-including thiopurine expert physicians (DA, MD and AB) provided dosing advice according to a predefined algorithm, aiming for 6-TGN levels of 600-1200 pmol/8×108 RBC and 6-MMP of &amp;lt;5700 pmol/8×108 RBC. Associations between 6-TGN and 6-MMP levels, MP dose and thiopurine S-methyltransferase (TPMT) polymorphisms were explored. Results In total, 29 patients initiated MP treatment (41% female, median age 46 yrs [IQR 26-58], median disease duration 6 yrs [IQR 1-14]). TPMT heterozygosity was found in 4/29 patients (3/4 TPMT*3A, 1/4 TPMT*3C). TDM dose adjustments were required in 22/29 patients: 14/29 started allopurinol and decreased MP dose, 5/29 discontinued MP before the first TDM assessment, 2/29 continued MP at the initial dose up until week 52 and the remaining underwent MP dose adjustments. Most adjustments (71%) were made at week 6, thereafter 6-MMP levels stabilised, while 6-TGN concentrations remained stable (Figure 1). TPMT variant carriers had a higher median 6-TGN concentration compared to non-carriers (1700 [IQR 1625-1850] vs 539 pmol/8×108 RBC [IQR 355-953], P&amp;lt;0.001) and more likely to have leukopenia (P=0.025). Two TPMT heterozygous patients achieved the primary endpoint with dose reductions, two discontinued due to myelotoxicity or hepatotoxicity. Until week 52, 16/29 patients completed the trial, 14/29 reached the endpoint with a median 6-TGN of 585 pmol/8×108 RBC (IQR 428-745) and 6-MMP of 268 pmol/8×108 RBC (IQR 110-1257). MP dose correlated with 6-MMP but not with 6-TGN levels. Independently of allopurinol co-prescription, the initial median weight-based MP dose of 100 mg (IQR 75-125) decreased significantly to 50 mg (IQR 25-100, P=0.041). Conclusion Most patients underwent TDM optimisation of MP, half of the patients initiated allopurinol with decreased MP dose. TPMT heterozygosity led to supratherapeutic 6-TGN concentrations and adverse events. Weight-based initial MP dose may need reconsideration.

Association of long non-coding RNAs and ABO blood groups with acute lymphoblastic leukemia in Egyptian children

Acute lymphoblastic leukemia (ALL) is the most prevailing cancer among children. Despite extensive studies, ALL etiology is still an unsolved puzzle. Long non-coding RNAs (lncRNAs) emerged as key mediators in cancer etiology. Several lncRNAs are dysregulated in ALL, leading to oncogenic or tumor-suppressive activities. Additionally, a relation between ABO blood groups and hematological malignancies was proposed. The current study intended to explore the association of lncRNAs, ANRIL and LINC-PINT, and their downstream targets, CDKN2A and heme oxygenase-1 (HMOX1), with the incidence of ALL and treatment response, and to determine the distribution of blood groups across different childhood ALL phenotypes. Blood samples were taken from 66 ALL patients (at diagnosis and at the end of remission induction phase) and 39 healthy children. Whole blood was used for blood group typing. Expression of ANRIL, LINC-PINT and CDKN2A was analyzed in plasma by qRT-PCR. Serum HMOX1 was measured using ELISA. ANRIL and CDKN2A were upregulated, while LINC-PINT and HMOX1 were downregulated in newly diagnosed patients. All of which showed remarkable diagnostic performance, where HMOX1 was superior. HMOX1 was independent predictor of ALL as well. LINC-PINT and HMOX1 were significantly upregulated after treatment. Notably, ANRIL and LINC-PINT were associated with poor outcome. No significant difference in the distribution of ABO blood groups was observed between patients and controls. In conclusion, our results suggested an association of ANRIL and LINC-PINT with childhood ALL predisposition, at least in part, through altering CDKN2A and HMOX1 production. Furthermore, the impact of remission induction treatment was newly revealed.

Monitoring Changes in Plasma Proteome in AML Patients Receiving Blood Transfusion Products

Background: Hemato-oncological patients, and in particular patients with acute myeloid leukemia (AML) in the remission induction treatment phase frequently receive transfusion products. These products include platelet- and red blood cell- concentrates and are administered in order to prevent and treat bleeding complications and anemia. During this treatment, patients are constantly monitored by clinical laboratory tests, however, additional studies could add nuanced information about the patients' status. Different studies have shown that plasma proteins change and their patterns' characteristics could be key to illustrate the patients' healthy and/or disease status. Importantly, changes in the plasma proteome in AML patients receiving transfusion products have not yet been studied. Thus, defining protein profiles during this phase is vital to use as a point of reference prior to tracing patients' treatments and their responses. Aim: In light of this, we aim to delineate the baseline plasma proteome in AML patients during their treatment phase. Methods: We employed unbiased mass spectrometry (MS)-based proteomics to gain insight in treatment-induced changes of the plasma proteome (Figure 1A). We included samples derived from 11 healthy donors and 11 AML patients who received chemotherapy and platelet, and red blood cell transfusions. AML patients without a previous transplant or platelet transfusion were included in this study. Results: We identified over 400 proteins in each plasma sample and found associations between proteins and clinical laboratory data, exemplified by a high correlation between Pro-Platelet Basic Protein (PPBP) and platelet incounts (r = 0.7, p-value &amp;lt; 0.001). We observed 169 significantly different proteins between AML patients and healthy controls, amongst the most significant changes we captured a strong signature of inflammation with an increased abundance of proteins involved in the acute-phase response pathway (i.e. SAA1 and CRP) and a decreased abundance of proteins involved in innate immune response (i.e. DEF1 and CAMP). Interestingly, we also found an increased abundance of proteins from the complement pathway (i.e. C9 and CFHR) and decreased abundance in proteins enriching for plasma lipoprotein particle remodeling (i.e. APOA1 and PON1) (Figure 1B). Furthermore, by building correlation networks we analyzed differences in the dynamics of plasma proteins in AML patients compared to healthy controls. This analysis showed several changes in associations between proteins, including alterations in known interactions such as the gain of correlation between APOA1 and GPLD1 as well as a loss of correlation between PLG and KNG1. Conclusion: These results highlight an imbalance in lipid metabolism and innate defense mechanisms, such as the coagulation pathway and complement system, in AML patients during their transfusion-dependent window. The plasma proteome studied in this pilot can serve as the basis to further explore changes induced in specific subgroups of patients, for example patients with and without bleeding complications. Follow up studies to analyze the changes observed here in larger cohorts are currently running (ALPHABET, trial registration NL9204) and they would be key to explore their potential association with clinical outcome in AML patients receiving transfusion products. Figure 1.- Exploring proteome changes in AML patients during their transfusion treatment phase. A) Graphical summary of the study, and B) Proteins with contrasting dynamics when comparing AML patients in treatment phase to healthy controls. Box plots depict median with its upper and lower limits representing the first (25th) and third (75th) percentiles, respectively. Box plot whiskers extend up to the highest or lowest value within 1.5 x IQR.

IgG4-related uveitis. A French cohort and literature review

IntroductionIgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder that can affect almost any organ. IgG4-related ophthalmic disease is a protean condition involving the orbit and ocular adnexa. Although a few cases of uveitis have been reported, the exact pattern of IgG4-related intraocular manifestations remains unclear. Here, we report on a nationwide French multicenter cohort of patients with IgG4-RD and uveitis and conducted a literature review. MethodsPatients with uveitis and a concomitant definite diagnosis of IgG4-RD (Revised Comprehensive Diagnostic criteria, American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, International Consensus Diagnostic Criteria for auto-immune pancreatitis, or diagnostic criteria for IgG4-related hypophysitis), were screened from our national IgG4-RD and systemic fibrosis database. Concomitantly, we conducted a PubMed literature review and selected cases of definite IgG4-RD with uveitis. ResultsWe reported on 16 patients (8 from our database and 8 from the literature) and a total of 30 episodes of uveitis. Uveitis cases represented 3 % of total IgG4-RD patients in the national database on IgG4-RD and systemic fibrosis. Uveitis was inaugural in IgG4-RD in 4/16 cases (25 %) (appearing before any other IgG4-related symptom, at a median of 9 months), occurred concurrently to other IgG4-related symptoms in 9/16 cases (56 %) (at a median of 15 months before IgG4-RD diagnosis), and appeared during follow up in 3/16 patients (19 %) (at a median of 57 months after first IgG4-related symptoms). When uveitis occurred during follow up, it was associated with IgG4-RD manifestations in other organs in 6/9 patients (67 %). Uveitis was bilateral in 8/16 cases (50 %) and granulomatous in 5/10 cases (50 %). It was anterior in 8/13 (62 %), intermediate in 3/13 (23 %), and global (panuveitis) in 4/13 patients (31 %). Median serum IgG4 at diagnosis was 3.2 g/L. Median follow up time was of 6 years, during which 8/16 patients (50 %) experienced at least one relapse of uveitis. Treatment data was available for 29/30 uveitis flares. Steroids were used in 28/29 episodes of uveitis (97 %), leading to remission of uveitis in 16/28 cases (57 %). Methotrexate and rituximab (in combination with systemic steroids) were administered as second- or third-line therapy in 6/29 (21 %) and 5/29 (17 %) episodes of uveitis, respectively, and led to remission of uveitis in 4/6 cases (67 %) and 4/5 cases (80 %), respectively. One third of uveitides required at least two different lines of treatment for remission induction (mainly a combination of both systemic steroids and methotrexate or rituximab). Discussion and conclusionsUveitis may be one of the initial symptoms of IgG4-RD, and IgG4-RD should be considered in the diagnostic workup of uveitis. Its early onset in IgG4-RD may help with early diagnosis and treatment of the disease. Steroid monotherapy may be sufficient to treat IgG4-related uveitis, yet relapses were frequent (50 %) and ultimately a third of patients required at least two lines of treatment. Hence, steroid-sparing agents can be considered at early stages of the disease, particularly for patients with a high risk of relapse or steroid-related complications.

Sarcopenia in patients with rheumatic musculoskeletal diseases.

To investigate the impact of high-dose glucocorticoid therapy on sarcopenia in hospitalized patients with rheumatic musculoskeletal diseases (RMDs). We included patients with RMDs who were hospitalized between 2020 and 2022 for remission induction treatment and collected information on skeletal mass index (SMI) before high-dose glucocorticoid therapy and 1 month later. We divided the patients into 2 groups according to the progression of sarcopenia, defined as a >10% decrease in SMI, and compared their clinical characteristics. Forty-nine patients were included in this analysis. The mean age was 53.3 years, 73.5% were female, and the mean SMI was 5.3 kg/m2 . Before treatment, 83.7% had already met the definition of sarcopenia, and 57.1% experienced further sarcopenia progression after 1 month of high-dose glucocorticoid treatment. Patients with sarcopenia progression were predominantly male (P = 0.025), had a higher body weight (P = 0.048), and showed a higher SMI than those without sarcopenia at baseline (P = 0.008). Multivariable analysis revealed that body weight increase from 0 to week 1 of high-dose glucocorticoid treatment was associated with sarcopenia progression (odds ratio: 0.22, 95% CI: 0.04-0.61, P = 0.007) with a cut-off of -1.8 kg. During a mean observation period of 30.2 days, the incidence of infection was significantly higher in patients with progressive sarcopenia (P = 0.042). One-month hospitalization with high-dose glucocorticoid therapy is associated with sarcopenia progression in patients with RMDs. An early decrease in body weight can be used to predict muscle volume loss.

Medical nutrition therapy during intensive remission-induction treatment and hematopoietic stem cell transplantation in acute myeloid leukemia patients: Hematologists’ experiences and perspectives

The European Societies for Clinical Nutrition and Metabolism (ESPEN) and Blood and Marrow Transplantation (EBMT) recommend enteral nutrition (EN) as the first-choice medical nutrition therapy in acute myeloid leukemia (AML) patients undergoing intensive treatments, including high-dose remission-induction chemotherapy and hematopoietic stem cell transplantation (HSCT). However, parenteral nutrition (PN) remains the preferred method of nutrition support in current clinical practice. The aim of this qualitative study was to gain insight into hematologists' experiences and perspectives regarding the choice and ESPEN/EBMT recommendations on EN versus PN. Online semi-structured interviews were conducted with one hematologist from each of the 21 hospitals offering intensive AML treatments in the Netherlands, using Microsoft Teams. Interviews were audio-recorded, transcribed verbatim and thematically analyzed using Atlas. ti. One hundred nineteen hematologists working in the same hospitals were invited to complete a short online questionnaire survey (SurveyMonkey®) regarding their knowledge and opinion on the ESPEN/EBMT guidelines recommending EN over PN during intensive AML treatments. The results of this survey are presented in a descriptive way. Fifty-nine hematologists participated in this study (42% overall response rate), of which 21 in the semi-structured interviews (response rate 100%) and 38 in the online survey (response rate 32%). Hematologists considered medical nutrition therapy important for prevention and treatment of malnutrition and associated adverse outcomes in AML patients undergoing intensive remission-induction treatment and HSCT. However, opposed to the ESPEN/EBMT guidelines, the vast majority of hematologists were hesitant or reluctant to use EN instead of PN as the first-choice medical nutrition therapy in these patients. The most frequently cited barriers to use EN were the expected low feasibility and tolerance of EN, feeding tube-related discomfort and bleeding risk, and patient refusal. Other barriers to follow the guidelines on EN were related to personal factors, including hematologists' knowledge (lack of awareness and familiarity) and attitude (lack of agreement, outcome expectancy, experience, success, motivation, and learning culture), guideline-related factors (lack of evidence and applicability), and external factors (lack of collaboration and resources). Facilitators included strategies for nutrition education and dissemination of nutritional guidelines, interprofessional and patient collaboration, availability of feeding tubes that can be inserted without endoscopy and stronger scientific evidence. Hematologists recognized the importance of medical nutrition therapy for reducing malnutrition and related negative outcomes during intensive AML treatments. However, contrary to the ESPEN/EBMT guidelines, they preferred PN instead of EN as the medical nutrition therapy of first choice. To reduce compliance barriers, interventions should focus on improving hematologists' knowledge of medical nutrition therapy and dietary guidelines, enhancing success rates of EN by adequately triaging patients eligible for EN and inserting duodenal feeding tubes using an electromagnetic sensing device without endoscopy, developing decision aids and multidisciplinary guidelines and care pathways. Furthermore, future trials should focus on the feasibility and benefits of EN versus PN both during remission-induction treatment and HSCT.

#5128 PREDICTIVE FACTORS OF RENAL RECOVERY AND END-STAGE KIDNEY DISEASE IN PATIENTS WITH SEVERE ANCA-ASSOCIATED VASCULITIS WITH GLOMERULONEPHRITIS

Abstract Background and Aims A significant number of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, eGFR&amp;lt;15mL/min/1.73m2) despite advances in remission-induction treatment. Method A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and ESKD at presentation. Renal recovery, dialysis discontinuation and maintenance in ESKD after standard remission-induction, with or without the use of PLEX were compared. Results We analyzed 166 patients with biopsy proven active kidney involvement and eGFR &amp;lt;15mL/min/1.73m2 at the time of AAV-GN diagnosis. Patients received glucocorticoids with CYC (n = 84) or with RTX (n = 72) for remission-induction, and 49 also received PLEX. The predictors for renal recovery were erythrocyte sedimentation rate, SCr at diagnosis and minimal or mild chronicity changes. We analyzed 71 patients who started dialysis with or without PLEX within 4 weeks from AAV-GN diagnosis. The predictors for dialysis discontinuation were minimal chronicity changes in kidney biopsy at the time of diagnosis (OR 6.138, [95%CI 1.389-27.118],p = 0.017) and focal glomerular involvement (OR 5.017,[95%CI 1.287-19.567],p = 0.020). Predictors for maintenance in ESKD at 12 months included higher serum creatinine (SCr) at the time of diagnosis (IRR 1.086, [95%CI 1.005-1.173],p = 0.037), moderate (IRR 3.797,[95%CI 1.090-13.225],p = 0.036), or severe chronicity changes in kidney biopsy (IRR 5.883,[95%CI 1.542–22.439],p = 0.009). Conclusion In our cohort, kidney recovery, dialysis discontinuation, and maintenance of ESKD in patients with AAV-GN and eGFR&amp;lt;15mL/min/1.73m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

Sex Differences in Clinical Manifestations of Hospitalized Patients With Eosinophilic Granulomatosis With Polyangiitis: A Retrospective Cohort Study.

To investigate the effect of sex on the clinical characteristics, prognoses, and therapeutic selection of eosinophilic granulomatosis with polyangiitis (EGPA). We retrospectively enrolled 170 hospitalized patients with EGPA who were managed at our hospital between 2007 and 2020. Detailed clinical data were reviewed. Manifestations, prognoses, treatments, and outcomes were compared between female and male patients. Cumulative survival rates were calculated using Kaplan-Meier curves. In this cohort, the male to female ratio was 1.4:1. Renal involvement was more frequent in male patients, including serum creatinine elevation, and proteinuria > 1 g/24 h. Severe gastrointestinal (GI) involvement occurred more commonly in male patients. Female patients had longer allergy duration and higher ratios of allergic rhinitis and asthma. Sex differences in proteinuria > 1 g/24 h, serum creatinine > 150 mmol/L, severe GI involvement, and weight loss were more significant in patients aged ≤ 55 years than those in patients aged > 55 years. Overall, male patients had a higher Birmingham Vasculitis Activity Score and a worse prognosis assessed at diagnosis, with a lower proportion of 1996 Five Factor Score = 0 than females. Regarding treatment selection, methylprednisolone pulse and cyclophosphamide were administered more frequently to male patients. All-cause mortality and cumulative survival rates were comparable between the sexes. In this Chinese EGPA cohort, male and female patients showed distinct disease phenotypes. Male patients with EGPA had a higher disease activity at diagnosis and required more aggressive treatment for remission induction.

Management of anti-neutrophil cytoplasmic antibody associated vasculitis with glomerulonephritis as proposed by the ACR 2021, EULAR 2022 and KDIGO 2021 Guidelines/Recommendations.

Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past ten years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids, avacopan and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Economic burden of acute myeloid leukemia on patients in a resource-limited tertiary hospital in the Philippines

IntroductionThe remission induction treatment for acute myeloid leukemia (AML) has remained unchanged in the resource-limited setting in the Philippines. AML treatment consists of induction chemotherapy followed by high dose consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. In the Philippines, the Filipino household bears the burden of health care cost of hospitalization expenditure. Insights into the treatment costs becomes an essential requirement as these guides the allocation of resources to scheme health programs. MethodThis study involved a retrospective cohort analysis of AML patients who underwent treatment for AML. Review of the statements of account per admission per patient during treatment for remission induction, consolidation, relapsed and refractory disease and best supportive care from 2017 to 2019. Of the 251 eligible patients, 190 patients were included. ResultThe mean healthcare expenditure for remission induction chemotherapy (Phase 1) was US $2, 504.78 (Php 125,239.29). While 3 to 4 cycles of consolidation chemotherapy cost an average of US $3,222.72 (Php 162,103.20). For patients who had relapsed and refractory disease, an additional mean cost of US $3,163.32 (Php 159,115.28) and US $2, 914.72 (Php 146,610.55) were incurred, respectively. The average cost of palliative care was US $1,687.00 (Php 84,856.59). ConclusionThe cost of chemotherapy and other therapeutics bear most of the weight of the direct healthcare cost. The cost of AML treatment represents a significant economic burden for patients and the institution. The cost increases as patients proceed through subsequent lines of treatment for induction failure. Existing subsidy for health insurance benefits could still be improved for appropriate source allocation of resources.

Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.

The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry. In 161 patients with de novo FLT3-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS). NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P < .001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry. NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

PLEX in AAV-GN: insights from the meta-analysis results and impact on remission induction treatment recommendations.

The risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5years of follow-up, 14-25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX. A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12months of 16.0% for those at high risk or with a serum creatinine >5.7mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations. However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed.

S890 A Diet High in Fruits and Vegetables During Biologic Induction May Improve Response to Biologics in Patients With Inflammatory Bowel Disease

Introduction: Several biologics now exist as treatment for inflammatory bowel disease (IBD) but effective induction of remission still ranges between 20-40% for most. Studies suggest that diet may modify intestinal inflammation. In this study, we sought to examine the effect of diet on biochemical response to biologic induction therapies. Methods: We conducted a single-center retrospective analysis of patients with IBD seen at a tertiary referral center from 2019 to 2021. A validated 26-item diet questionnaire, the Dietary Screener Questionnaire (DSQ), was completed as part of a pre-check-in process before each clinic visit. IBD patients who completed a DSQ within three months of induction of a biologic (anti-TNFs, vedolizumab, ustekinumab) and who had markers of inflammation available pre and post-induction (C-Reactive Protein (CRP)) were included. Follow up period was 3 months post-induction. Using linear and average mixed-effects models, we examined the contribution of food items in the DSQ (i.e., processed meats, red meats, fruits, vegeTables) to a reduction in CRP following induction. We used pre-induction biochemical markers as a baseline reference. Current steroid use, prior biologic exposure, age, gender, body mass index (BMI), smoking status, IBD type (ulcerative colitis (UC) or Crohn’s disease (CD)), and class of biologic were added as covariates in the models. Results: A total of 105 patients were included in this study (62.9% had CD and 32.4% had UC). The most common biologic was anti-TNFs (52.4%). The mean CRP value pre-induction was 13.4 (SD 20.2) and post-induction was 6.63 (SD 12.4). On multivariable analyses adjusting for covariates mentioned, we found an independent effect of high daily intake of fruits and vegeTables on reduction in CRP. For every 1 unit increase in daily fruits and vegeTables, there was a reduction in CRP value by 1.82 post-induction of biologics (p=0.04), Table. Red meat intake, processed meats, fiber from whole grains, and dairy were not associated with CRP reduction (Table). Conclusion: In this preliminary analysis, we find that a diet high in fruits and vegeTables during induction of biologics may independently improve biochemical response. Future clinical drug trials should consider dietary assessment and the influence of diet on response to medication treatment. Table 1. - Average Marginal Effects (AME) Assessing the Contribution of Each Variable on the Reduction of CRP Level During Induction Factor Average Mixed Effects (AME) Standard Error (SE) p-value Age 0.1253 0.07186 0.862 Gender (Male) 0.30313 0.23377 0.1977 BMI 0.08005 0.07203 0.2701 IBD- Ulcerative Colitis -0.33136 0.14984 0.0304 Previous biologic use -0.03417 0.14799 0.818 anti-TNF biologic induced (ref) 1.29018 0.94172 0.1734 Ustekinumab induced 0.10442 0.15699 0.5082 Vedolizumab induced 0.1059 0.17734 0.5525 Steroids on induction 0.23593 0.14915 0.1181 Diet Factors Red Meat -0.01567 0.17881 0.9303 Processed Meat -0.32794 0.34438 0.343 Fiber 0.5546 0.05404 0.3071 Calcium 0.15903 0.19979 0.4277 Whole grain (cups) -0.40034 0.26105 0.1279 Added sugar (teaspoons) -0.01585 0.0235 0.5014 Dairy (cups) 0.0488 0.32823 0.8821 Fruit (cups) 0.62825 0.76457 0.413 Fruits and Vegetables daily (cups) -1.8186 0.87858 0.0406

Optimizing MATRix as remission induction in PCNSL: de-escalated induction treatment in newly diagnosed primary CNS lymphoma

BackgroundPrimary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT.MethodsThis is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months.DiscussionCurrent treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy.Trial registrationGerman clinical trials registry DRKS00022768 registered June 10th, 2021.

Challenges and outcomes of treating acute myeloid leukemia (AML) in resource-constrained settings.

7014 Background: Acute myeloid leukemia (AML) is a heterogeneous disease. Improvement in supportive care, has considerably improved AML induction outcomes, decreasing induction deaths to &lt;5% in recent studies. However, induction deaths during AML treatment in resource constraint settings remains as high as 25% in young adults. In this study we explore various challenges encountered in treating AML patients in one of the largest public sector teaching hospitals in India. Methods: Consecutive patients diagnosed with AML and registered in our clinic from January 1, 2018 to December 31, 2019, were included. Results: Of 316 patients diagnosed with AML, only 181 (57%) were able to get admitted to our institute for remission induction treatment. Median time from diagnosis to treatment initiation was 9.5 days (range, 0-232 days). Almost half (N=88; 49%) of admitted patients had infections at the time of admission. Among these, 31 (35%) had invasive fungal infection; 14 possible, 15 probable, and 2 proven. Fifty-two (29%) patients died prior to starting their remission induction therapy. Induction mortality in our cohort is 40%. Primary induction failure and primary refractory disease were noted in twenty (18%), and 5 (4%) patients respectively. Only 1 patient was able to get all three high dose cytarabine (HIDAC) consolidations on time. Median time to first HIDAC was 39.5 days (range, 28-91). Of 83 patients who were candidates for consolidative allogeneic hematopoietic cell transplantation (HCT), only ten (12%) patients were able to get transplanted. Median time to HCT from CR1 was 3.8 months (range, 1.89-12.8). The median event free survival (EFS) was 1.7 months (95%CI, 1.03-2.5) and median overall survival was 2.5 months (95%CI, 1.6-3.6). The median EFS in favourable risk, intermediate risk and adverse risk AML was 3.6 months, 3.7 months, and 3.4 months respectively. Likewise the median OS was 8.8 months, 11.8 months and 7.4 months in the three risk strata respectively. Conclusions: Outcomes of AML treatment in our cohort are discordant with that reported from the West. Our study identifies various challenges in treating AML in resource-constraint setting. Strategies need to be formulated to overcome these challenges. [Table: see text]

POS1424 RISK FACTORS FOR ADVERSE EVENTS OF SULFAMETHOXAZOLE-TRIMETHOPRIM PROPHYLAXIS IN PATIENTS WITH SYSTEMIC RHEUMATIC DISEASES

BackgroundThe prophylactic use of sulfamethoxazole-trimethoprim (SMX/TMP) can reduce the risk for developing pneumocystis pneumonia in immunosuppressed patients with systemic rheumatic diseases, whereas discontinuation of SMX/TMP prophylaxis is frequent due to adverse events (AEs) with this drug.ObjectivesThe purpose of this study was to identify risk factors for AEs of SMX/TMP in patients with systemic rheumatic diseases.MethodsAll consecutive patients who were admitted in our hospital for induction treatment between 2012 and 2019 and newly received prophylactic SMX/TMP were included in the study. We divided them into two groups according to the presence or absence of AEs of SMX/TMP leading to discontinuation of the drug and compared clinical characteristics between the AE and non-AE groups. Multivariable analysis was performed to identify risk factors for AEs of SMX/TMP prophylaxis.ResultsA total of 438 patients were included in the study. Rheumatic diseases of the patients were systemic lupus erythematosus (25.3%), anti-neutrophil cytoplasmic antibody associated vasculitis (15.5%), rheumatoid arthritis (11.6%), polymyositis/dermatomyositis (10.7%), IgG4-related disease (8.5%), large vessel vasculitis (7.1%), adult-onset Still’s disease (AOSD; 4.1%), and others (17.2%). Among them, 82 patients (18.7%) stopped SMX/TMP due to AEs. Most frequent AEs were skin rash (36.6%), followed by liver dysfunction (29.3%), thrombocytopenia (19.5%), elevation in serum creatinine levels (15.9%), hyperkalemia (14.6%), hyponatremia (11%), leukopenia (6.1%), and fever (6.1%). Baseline age (61.4±16.4 vs 56.3±16.9 years, p=0.014) and prednisolone dose for remission induction treatment (0.97 vs 0.91 mg/kg/day, p=0.03) were significantly higher in the AE group than in the non-AE group, respectively. In terms of disease type, significantly higher rates of AEs were observed in patients with AOSD than in those with the other diseases (66.7% vs 16.7%, p&lt;0.001; Figure 1). Blood tests at SMX/TMP initiation demonstrated lower lymphocyte counts (10.1 vs 10.8 x102/μl, p=0.049), lower platelet counts (20.9 vs 25.8 x104/μl, p=0.045), lower albumin levels (3.2 vs 3.4 g/dl, p=0.007), higher AST levels (26 vs 23 U/L, p=0.04), higher creatinine levels (0.71 vs 0.67 mg/dl, p=0.047), and higher ferritin levels (167 vs 154 ng/ml, p=0.047) in the AEs group compared with the non-AEs group, respectively. Multivariable analysis identified an older age (OR 1.03, p=0.002) and AOSD (OR 9.72, p&lt;0.001) as independent risk factors for AEs leading to SMX/TMP withdrawal (Table 1).ConclusionOld age and AOSD were associated with AEs of SMX/TMP prophylaxis in patients with systemic rheumatic diseases.Disclosure of InterestsNone declared

POS0246 SEQUENTIAL RITUXIMAB AND MEPOLIZUMAB IN EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS

BackgroundRituximab (RTX) is an effective remission-induction treatment in ANCA-associated vasculitides (AAVs). Some reports have suggested that it might be effective also in Eosinophilic Granulomatosis with Polyangiitis (EGPA), to induce and maintain remission of vasculitic manifestations [1,2]. However, its effects for preventing respiratory relapses seem to be poor. Mepolizumab (Mepo) (both 100 and 300mg/month) is effective in improving respiratory manifestations and lung function, while partially controlling also systemic activity [3,4]. Isolated case reports further indicate that the sequential therapy with RTX and Mepo might be effective [5-7].ObjectivesThe study aimed to investigate the efficacy and safety of a therapeutic regimen based on sequential RTX and Mepo for the control of EGPA.MethodsA multicenter, retrospective, cohort study was conducted on adult patients diagnosed with EGPA according to the ACR classification criteria [8] or MIRRA trial criteria [3]. Only patients who received induction therapy with RTX (any dosage), and subsequent treatment with Mepo (100-300 mg/4 weeks) within 12 months from last RTX administration were included. Patients receiving other induction therapies between RTX and Mepo were excluded. The effectiveness of sequential RTX and Mepo was assessed in terms of disease activity (by the Birmingham Vasculitis Activity Score, BVAS) and daily corticosteroid dosage. Safety data were also collected.ResultsThirty-four EGPA patients treated with sequential RTX and Mepo were included (59% females, median age of 51 years (IQR 40-58); 41% ANCA positive).In most cases (26/34; 76%), RTX was started at the dosage of 1g q2w, and all except two patients had active disease at time of RTX beginning [median BVAS of 9 (IQR 6-14)]. Specifically, most patients started RTX for the control of systemic manifestations (19/34; 56%), or of both systemic and respiratory symptoms (11/34; 32%). All except one patient were receiving oral corticosteroids, at a median dosage of 25 mg/day (10-38).Mepo was started after a median of 14 months (6-23) from RTX initiation and after a median of 5 months (IQR 3-11) from the last RTX administration. Mepo was used at the dosage of 100mg/4 weeks in 32/34 (94%), mostly for the control of respiratory manifestations (25/34, 74%). At the time of starting Mepo, the median BVAS was 4 (2-8), and median prednisolone dose 10 mg/day (7-15). After a median follow-up of 28 months (IQR 23-33) from starting Mepo, the median BVAS decreased to 1.5 (IQR 0-4) and the median corticosteroid dosage to 5 mg/day (2.5-5), with 7/34 (21%) patients being off steroids. At last follow-up, most patients were off-RTX (28/34), typically due to stable disease remission (20/34; 59%).Both RTX and Mepo were well-tolerated; 5 patients had adverse events on RTX (none serious), and 5 on Mepo (including one serious infection).ConclusionSequential use of RTX and Mepo seems to be effective for remission induction and maintenance in EGPA.