Standard Induction Regimen Research Articles

Alfentanil versus fentanyl for emergency department rapid sequence induction with ketamine: A-FAKT, a pilot randomized trial

BackgroundFentanyl is often administered during rapid sequence induction of anesthesia (RSI) in the emergency department (ED) to ameliorate the hypertensive response that may occur. Due to its more rapid onset, the use of alfentanil may be more consistent with both the onset time of the sedative and the commencement of laryngoscopy. As such, we compared the effect of alfentanil and fentanyl on post-induction hemodynamic changes when administered as part of a standardized induction regimen including ketamine and rocuronium in ED RSI. MethodsThis was a double-blind pilot randomized controlled trial of adult patients requiring RSI in the ED of three urban Australian hospitals. Patients were randomized to receive either alfentanil or fentanyl in addition to ketamine and rocuronium for RSI. Non-invasive blood pressure and heart rate were measured immediately before and at two, four, and six minutes after induction. The primary outcome was the occurrence of at least one post-induction systolic blood pressure outside the pre-specified range of 100-160mmHg (with adjustment for patients with baseline hypertension). Secondary outcomes included hypertension, hypotension, hypoxia, first-pass intubation success, 30-day mortality, and the pattern of hemodynamic changes. ResultsA total of 61 patients were included in the final analysis (31 in the alfentanil group and 30 in the fentanyl group). The primary outcome was met in 58% of the alfentanil group and 50% of the fentanyl group (difference 8%, 95% confidence interval: -17% to 33%). The 30-day mortality rate, first-pass success rate, and incidences of hypertension, hypotension, and hypoxia were similar between the groups. There were no significant differences in systolic blood pressure or heart rate between the groups at any of the measured time-points. ConclusionAlfentanil and fentanyl produced comparable post-induction hemodynamic changes when used as adjuncts to ketamine in ED RSI. Future studies could consider comparing different dosages of these opioids.

Treatment discontinuation due to toxicity for patients with acute myeloid leukemia (AML) treated on SWOG S1203.

6529 Background: Curative-intent therapy for patients with newly diagnosed AML centers on the use of cytarabine as part of an intensive multi-drug induction regimen. Treatment-related toxicity may lead to patients stopping treatment, despite the considerable risk of inadequately treated AML. We compared rates of protocol therapy discontinuation due to adverse events (AEs) in either of two standard induction regimens (7+3 or high dose cytarabine + idarubicin, IA) on the S1203 study (Garcia-Manero; Leukemia 2023). Methods: S1203 was a randomized study of patients <60 years old with newly diagnosed AML. Patients were required to have performance status (PS) <3, ejection fraction >45%, and no prolonged QTc interval or known cardiac disease. There were no exclusion criteria for kidney or liver function. On the 7+3 induction arm, subjects received daunorubicin 90 mg/m2 IV daily days 1-3 with continuous infusion cytarabine 100 mg/m2 daily days 1-7. On the IA arm, subjects received idarubicin 12 mg/m2 daily days 1-3 with continuous infusion cytarabine 1.5 g/m2 daily days 1-4. Toxicities were assessed per the Common Terminology Criteria for Adverse Events version 4.0. Rates of discontinuation were compared using Fisher’s exact test. Results: From 4/2013-11/2015, 522 subjects were randomized (261 to each arm). Treatment discontinuation due to either death or toxicity occurred in 8 vs 22 patients on 7+3 vs IA respectively (p=0.014). During induction, 0 patients on the 7+3 arm discontinued treatment due to toxicity versus 4 patients on the IA arm (0% vs 2%; p=0.12). Toxicities leading to treatment discontinuation on the IA arm included congestive heart failure (n=2, one with concurrent arrhythmia), acute kidney injury (n=1), and hypotension complicated by stroke and cardiac arrest (n=1). Two of the 4 patients who discontinued treatment due to toxicity on IA achieved a complete remission after their first cycle. For patients with PS 2-3 (n=40 on 7+3, n=27 on IA), rates of grade 3-5 AEs were 85% vs 86% and rates of grade 5 AEs were 0% vs 11% (p=0.065). Conclusions: 7+3 was well tolerated. Excluding patients from S1203 with PS 2-3 or decreased hepatic/renal function would not have prevented treatment-related toxicity. The low rate of protocol therapy discontinuation due to toxicity suggests that eligibility criteria for clinical trials could be further broadened to improve patient access. Clinical trial information: NCT0180233 . [Table: see text]

Incidence of thromboses and secondary cancers in patients with multiple myeloma after lenalidomide-based induction followed by maintenance as first-line therapy: A systematic review and meta-analysis.

e19510 Background: Lenalidomide, an immunomodulatory drug (IMiD) is one of the backbones of standard first-line induction regimen for multiple myeloma (MM). Lenalidomide maintenance is associated with improved progression-free survival, especially after bone marrow transplantation. The optimal duration of maintenance therapy is unknown. In our study, we evaluated the incidence of any thrombosis, venous thrombosis (VTh) and arterial thrombosis (ATh) as well as any secondary cancers, secondary solid and hematologic cancers in patients with MM who received lenalidomide-based first-line induction followed by lenalidomide maintenance for at least 6 months. Methods: This systematic review identified pertinent clinical trials from MEDLINE, Embase, and CENTRAL databases from inception to December 31, 2023. After two rounds of review by 4 authors independently, 25 clinical trials in patients with MM met the above eligibility criteria. The number of cases with any thrombosis, VTh, ATh, any secondary cancers, secondary solid and hematologic cancers along with the total number of patients in the arms with lenalidomide-based therapy were extracted from each trial. The incidence meta-analysis was performed using the “meta” package version 6.2-0 of R version 4.2.2 via a random-effects model. Pooled incidence and its associated 95% confidence interval (CI) were reported for each outcome. I² statistic was used to determine the heterogeneity of the studies. Results: 10743 patients were reviewed from 25 clinical trials. The pooled incidence rate of any thrombosis was 4% (0.04; 95% CI: 0.03 to 0.06, I2=91%). The pooled incidence rate of arterial thrombosis and venous thrombosis was 1% (0.01; 95% CI: 0.00 to 0.02, I2=77%) and 4% (0.04; 95% CI: 0.02-0.09, I2=94%) respectively. The pooled incidence rate of any secondary cancer was 5% (0.05; 95% CI, 0.04 to 0.07, I2=93%). The pooled incidence rate of secondary hematological malignancies was 2% (0.02; 95% CI, 0.01 to 0.03, I2=90%) and secondary solid cancers was 4% (0.04; 95% CI, 0.03 to 0.06, I2=76%). Conclusions: IMiDs are one of the backbones of the MM regimen. Our meta-analysis showed lenalidomide-based regimen increased the risk for thromboses – higher for VTh (4%) and slightly higher for ATh (1%). It also showed a higher rate of secondary cancers – both solid (4%) and hematologic cancers (2%). However, our study showed considerable heterogeneity. These events become clinically important as patients with MM live longer. MM patients on lenalidomide maintenance could benefit from an active surveillance, monitoring and early treatment program for these long-term adverse effects. VTh prophylaxis based on the type of regimen is already standard. Secondary cancer surveillance may need to be individualized for MM patients in remission.

Quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma (TENDMM): A systematic review and meta-analysis.

e19534 Background: Immunomodulatory drugs, proteasome inhibitors plus dexamethasone are the standard triplet induction regimen for TENDMM. We analyzed the efficacy of adding either anti-CD38 monoclonal antibodies (mAbs) or anti-SLAMF7 antibody to the triplet therapy. Methods: Ovid MEDLINE, EMBASE and published abstracts were systematically searched from each database’s inception through 01-31-2024 to identify II/III trials assessing quadruplet therapy versus triplet therapy in TENDMM patients. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), odds ratios (OR) for overall response rates (ORR), measurable residual disease (MRD) negativity rate (with sensitivity of 10 -5) and grade 3 or higher treatment-related adverse events (G≥3 TRAE) were summarized using random effects meta-analysis via inverse variance approach. Additional subgroup analyses based on the cytogenetic risk were performed. P-value of interaction (Pint ) < 0.1 was pre-specified as statistically significant for the difference between the two groups. Results: 3806 studies were screened and seven trials were included with a total of 3546 patients. Four trials (2303 patients) assessed the addition of anti-CD-38 mAbs and three (1243 patients) assessed anti-SLAMF7 mAb, elotuzumab to the triplet regimen. Quadruplet therapy significantly improved PFS as compared to triplet (HR: 0.63; 95% CI: 0.43-0.92), and the PFS benefit was also observed in standard risk group (HR 0.5; 95% CI 0.2-0.9); however, results were insignificant for high-risk group (HR 0.8; 95% CI 0.62-1.93). No significant OS benefit was observed (HR: 0.79; 95% CI 0.49–1.26); however, data for three trials (CASSIOPEIA, DSMM XVII, PERSEUS) is immature, with longer-term follow-up ongoing. Quadruplet therapy showed significant results for very good partial response or better (OR: 1.7; 95% CI 1.2-2.36), stringent complete response (OR: 1.74; 95% CI 1.27-2.07) and complete response or better (OR: 1.91; 95% CI 1.19-3.06). MRD rate shows benefit with quadruplet therapy (OR: 2.59; 95% CI 2.22-3.01). Improved MRD rate was also observed for high-risk (OR 2.13; 95% CI 1.4-3.2) and standard-risk group (OR 2.58; 95% CI 1.68-3.94). Secondary analysis for efficacy of anti-CD38 mAbs showed benefit for PFS (HR: 0.44; 95% CI: 0.35-0.56), ORR (OR: 1.77;95% CI: 1.02-3.06), and MRD (OR: 2.98; 95% CI 1.8-4.8). G ≥3 TRAE did not significantly differ between the groups (OR: 1.05; 95% CI 0.97-1.12). However, quadruplet therapy showed significant risk of infection (OR: 1.2; 95% 1.05-1.35) and thrombocytopenia (OR: 1.41; 95% CI 1.24-1.59). Conclusions: Quadruplet therapy improved PFS, ORR, and MRD rates compared to triplet regimen and has demonstrated promising benefits to be considered the new standard of care for TENDMM patients.

Maintenance Therapy for CD20+ Indolent Lymphoma: Who Should Receive Maintenance?

Maintenance rituximab (MR) has been a mainstay of treatment in Canada for CD20‑positive indolent lymphoma for two decades. The adoption of MR into clinical practice occurred after the publication of the EORTC 20981 trial. This trial showed a significant improvement in progression free survival (PFS) with two years of MR versus observation after induction therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed follicular lymphoma (FL). The use of MR was broadly extended to include its use in the front‑line setting, following any R-containing inductions and including all CD20-positive indolent lymphoma histologies. Automatic recommendations for MR became the standard practice for most patients. Given the recent changes to standard induction regimens in some indications, and with heightened concerns about infectious complications during B-cell depleting therapy, the recommendation for the use of MR should no longer be considered automatic. This review offers a balanced perspective of the evidence for MR.

P782 Comparison of accelerated and standard infliximab induction regimens in Acute Severe Ulcerative Colitis using propensity score: A retrospective multicenter study in a Chinese cohort

Abstract Background The optimal regimen of infliximab salvage in acute severe ulcerative colitis (ASUC) patients remains controversial. This retrospective multicenter study aimed to compare accelerated and standard infliximab induction in a Chinese cohort of ASUC patients, and to explore risk factors associated with poor prognosis. Methods Data were collected retrospectively from steroid-refractory ASUC patients who received infliximab induction as rescue therapy at seven tertiary centers across China. Accelerated infliximab induction was defined as receiving two doses of infliximab on or before day 13 and/or receiving intensified doses of ≥ 7.5 mg/kg. Outcomes including colectomy and clinical remission (Mayo score ≤ 2 and every subscore ≤ 1 at day 14) rates were compared using propensity score adjustment for potential confounders. The variables in propensity score model was determined by logistic regression analysis for accelerated induction. Results A total of 76 patients were included: 29 received standard induction and 47 received accelerated induction. The overall disease severity was significantly higher in patients of accelerated group (Table). The 30-day colectomy rates did not differ between two groups (4.3% vs. 0%, P=0.522). However, the accelerated group had a higher 90-day colectomy rate (17.8% vs. 0%, P=0.019) and lower clinical remission rate (27.7% vs. 65.5%, P=0.001). (Figure. A) After adjusting with propensity score and institution, there was no significant difference in colectomy (P=0.20) or no clinical remission (P=0.48) hazards. Dose-effect curves plotted by restricted cubic splines (adjusted for propensity score and institution) showed decreased colectomy hazard with higher cumulative infliximab dosage within 5 days, while no improvement was observed for increasing cumulative infliximab dosage within 28 days. (Figure. B) Multivariate logistic regression analyses revealed female gender (OR=7.69, 95%CI: 1.96-33.33) and C-reactive protein (CRP) >10 mg/L at infliximab initiation (OR=5.00, 95%CI: 1.27-24.34) as independent risk factors for no clinical remission. (Figure. C) Conclusion After adjusting for confounders, there were no significant differences in colectomy or clinical remission rates between accelerated and standard infliximab induction among steroid-refractory ASUC patients. Elevated CRP at infliximab initiation indicated more intensive treatment or earlier surgery to be considered. And it would be better to give early intensified dosage within 5 days if needed.

Challenges to achieving BMT in the treatment of AML in Brazil

Introduction: Acute myeloid leukemia is a heterogeneous aggressive leukemia with a poor prognosis. The standard remission induction regimen for medically eligible patients consists of a backbone of cytarabine & anthracycline. Objective: This study assessed the efficacy and safety of cytarabine and anthracycline in a public health center in Salvador, Brazil. Methods: It is a retrospective analysis of 45 non-promyelocytic AML patients diagnosed between 2018 and 2022. Subgroups analyzed included patients having FTL3 and NPM1 mutations, leukocyte count (>10,000 or <10,000), platelets count (>20,000 or <20,000), and transplanted patients. Kaplan-Meier methods were used to determine overall survival (OS) and progression-free survival (PFS). Results: The median age at diagnosis was 43 years (16-69 years), and 62% were females. FLT3-ITD and NPM1 mutations were found for 17.8% and 13.3% of patients, respectively. 85% of the patients had a normal karyotype. For efficacy, 52% of patients were eligible for the next treatment after complete remission. Refractory patients were 20%. Early mortality was 28.8%. Median values of PFS and OS were 3.6 and 8.2 months, respectively. Patients presenting FLT3 mutation and stem cell transplantation had PFS and OS of 20 and 43 months, respectively. Conclusion: The outcomes were consistent with the literature. Waiting time was not critical for treatment outcomes.

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China

Comparison of accelerated and standard infliximab induction regimens in acute severe ulcerative colitis using propensity score analysis: a retrospective multicenter study in China

The approach of HMA plus VEN with or without BMT for all patients with AML.

Treatment options for acute myeloid leukemia (AML) have expanded over the last 5 years. New regimens are increasing the options for patients who previously may not have been offered any antineoplastic therapy. The use of the hypomethylating agent (HMA) decitabine or azacitidine combined with the BCL2 inhibitor venetoclax (HMA-VEN) has improved overall survival in an older and unfit population compared to HMA therapy alone. Delivering these regimens outside academic centers allows more patients with AML to be treated, though support and collaboration with allogeneic stem cell transplant (SCT) centers should still be considered to determine eligibility and promptly initiate a donor search for potential transplant candidates. Expanding the use of HMA-VEN to younger and fit patients who are also candidates for intensive chemotherapy (IC) is being studied prospectively and is not recommended at this time outside of a clinical trial. Retrospective studies suggest populations that may benefit from HMA-VEN over IC, but this is not yet confirmed prospectively. Utilizing HMA-VEN prior to allogeneic SCT is also under investigation, and some retrospective data show feasibility and the ability to achieve measurable residual disease negativity pretransplant. Upcoming prospective randomized clinical trials aim to answer the comparability or superiority of HMA-VEN vs IC in fit populations and its potential use as a standard pretransplant induction regimen.

Venetoclax Combining with Homoharringtonine，Daunorubicin and Cytarabine (HAD) As Induction Treatment in Newly Diagnosed Adult Acute Myeloid Leukemia Patients

INTRODUCTION Venetoclax (Ven), a potent oral inhibitor of BCL-2, has improved clinical outcomes in acute myeloid leukemia. For chemotherapy-fit patients, Ven combined with intensive chemotherapy (IA, CLIA, FLAG-IDA and DA) achieves high complete response (CR) rate and measurable residual disease (MRD)-negative rates in de novo AML after one cycle of induction therapy. Homoharringtonine (HHT, omacetaxine mepesuccinate) is an alkaloid derived from trees of the genus Cephalotaxus. HHT, cytarabine (Ara-C) and daunorubicin (DNR) regimen (HAD) have been used as standard remission induction regimen in China. Here, we reported the data of 25 patients with newly diagnosed AML who were administered with Venetoclax combining with dose-reduced HAD as induction treatment in our hospital. The purpose of this study was to observe the efficacy and safety of the regimen. METHODS Between May 2022 and February 2023, twenty-five newly diagnosed AML who fulfilled the criteria of AML according to the 2016 World Health Organization (WHO) classification were treated with Ven combined with HAD as induction treatment. The induction regimen consisted of oral Ven (100mg Day -1; 200mg Day 0; 400 mg, Days 1-7), intravenous HHT (2mg/m 2/d, Days 2-6), DNR (45 mg/m²/d, Days 4-5), and Ara-c (100 mg/m 2/d, Days 2-6). After achieving CR, allogeneic hematopoietic stem-cell transplantation (allo-HSCT) were recommended according to ELN guidelines. Patients who could not or did not need allo-HSCT received consolidation ± maintenance therapy. The consolidation therapy included two cycles of Ven combining with intermediate-dose Ara-C (Ven 400 mg on Days 1-7, Ara-C 1 g/m 2/q12 h Days 2-4), two cycles dose-reduced DA (DNR 45 mg/m², Days 1-2 and Ara-C 100 mg/m², Days 1-5) chemotherapy and one cycle HA (HHT 2 mg/m², Days 1-5 and Ara-C 100 mg/m², Days 1-5). After completing consolidation treatment, patients (intermediate and adverse risk) entered maintenance therapy with AZA (100 mg/d, Days 1-5) every month for at least four cycles. The primary endpoints were the overall response rate (ORR), included of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints were overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. RESULTS Between May 2022 and February 2023, 25 patients who were enrolled in this study. Baseline characteristics of the twenty-five patients are shown in Table 1. After one cycle of induction therapy, twenty-one patients achieved CR, CR rate was 84.0% (21/25 95% CI, 68.6-99.4); one patient achieved PR. The ORR (CR+PR) was 88.0% (22/25 patients; 95% CI, 74.3-100). Three NR patients and one PR patient achieved remission after salvage therapy. For patients who achieved CR after one cycle of induction therapy, MRD was evaluated in 21 patients by flow cytometry and 17 patients attained MRD negative (81.0%; 95% CI, 61.6-96.7). None patient died before response evaluation . To June 20, 2023, with a median follow-up of 10.0 (4-13) months, 9 (36.0%) patients underwent allo-HSCT. The median OS, EFS, and DFS were not reached, and the estimated 1-year OS, EFS, and DFS rates were 100%, 94.7% (95% CI, 89.6-99.8%), and 94.7% (95% CI, 89.6-99.8%), respectively (Figure 1). The most frequent hematological adverse events were Grade 3 to 4 anemia, thrombocytopenia, and neutropenia during the induction treatment and occurred in all patients (25/25 100%). The most frequent grades 3-4 non-hematological adverse events were febrile neutropenia (25/25 patients, 100%). None of patients died during the induction therapy. Conclusion: Ven combined with HAD is an effective and safe induction regimen in de novo AML patients. It is worth and necessary to enroll more patients to further verify this regimen. 【Keywords】Venetoclax; HAD; AML; induction treatment

ACS10- Cytarabine Pharmacogenomics Score Impacts Survival in Pediatric AML Patients Treated on AAML1031 Trial and Associates with Outcome Differences in Black AML Patients

Cytarabine (ara-C) has been used to treat acute myeloid leukemia (AML) for decades. While ara-C based regimens successfully induce remission in the majority of patients, significant number of patients experience relapse. Although advances in hematopoietic stem cell transplantation (HSCT) and supportive care regimens have improved over the years, it is imperative that personalized methods to optimize pharmacological intervention and improve outcomes are needed. To identify genetic predictors of ara-C response, we recently reported an ara-C pharmacogenomics score (ACS10) consisting of 10 SNPs in nine ara-C pathway genes (PMID: 34990262). In pediatric patients treated on AML02 and AAML0531 trials, low ACS10 score (<0) was associated with poor survival as compared to patients with high score (>0). Given these promising results, we sought to investigate the ACS10 score in a large cohort of children treated on Children's Oncology Group clinical trial AAML1031 (NCT01371981). AAML1031 trial enrolled 1,097 newly diagnosed patients from 0 to 29.5 years of age that received either conventional AML treatment (ara-C, daunorubicin and etoposide (ADE): arm A) or conventional treatment with the addition of bortezomib (ADE+bortezomib: arm B). Overall, no benefit for adding bortezomib was observed (PMID: 32029509). The current study included 717 patients with both DNA specimens and clinical outcome data available. ACS10 SNPs were genotyped using Taqman assays and ACS10 score was calculated for each patient as per previous report (PMID: 34990262). Overall, for the 717 patients included in this study, 249 patients had low ACS10score (< 0) and 468 patients had a high ACS10 score (>0). When combining patients treated on arm A and arm B, ACS10 score was not associated with overall survival (OS). However, patients with low ACS10 scores had poorer event-free survival (EFS) than those with high ACS10 scores, although this difference was not statistically significant (HR: 0.827, 95% CI (0.669-1.022), P=0.078). Patients with high ACS10 scores in arm A had improved EFS (HR: 0.689, 95% CI (0.50-0.94), P=0.023, Fig1), while OS did not show significant differences (P=0.378). Excluding the patients who received HSCT, showed increased EFS for patients with high ACS10 scores as compared to low ACS10 scores when treated with standard chemotherapy (HR: 0.628, 95% CI (0.445-0.887), P=0.008 Fig 1). In contrast, a significant difference was not observed within the standard ADE+bortezomib arm (arm B). At the whole cohort level, black patients (N=84) had reduced OS (HR: 1.47, 95% CI (1.02-2.13), P=0.041) as compared to white patients, while there was no significant decrease in EFS (HR: 1.22, 95% CI (0.89-1.66), P=0.206) (N=522). Within arm A, black patients had significantly poorer outcome as compared to white patients (EFS, HR: 1.718, 95% CI (1.099-2.686), P=0.018 Fig1; OS HR: 1.80, 95% CI (1.05-3.10), P=0.032). Difference in outcome by race in arm B was not significant implying addition of bortezomib might have some benefit to black patients. Subsequent comparison by treatment arm showed a non-significant but better outcome in black patients when treated on arm B (Black patients: EFS, arm A vs. arm B: HR:0.66, 95% CI (0.37-1.17), P=0.154). Consistent with our previous investigation, low ACS10 score group was more abundant in black patients as compared to white patients (69% of black patients vs. 28% of white patients had low ACS10 score, P<0.001). These results are particularly salient given trends showing poor outcome in black as compared to white AML patients. Despite AAML1031 being one of the largest pediatric AML cohorts, the small number of black patients limited our ability to do further subset analyses by scores and arms (only 10 of 39 black patients treated on arm A had high ACS10 score). In conclusion, we demonstrate the utility of the PGx-based ACS10 score in a large cohort of newly diagnosed pediatric AML patients when treated with standard ADE induction regimen. Consistent with previous observation, black patients with low ACS10 score had inferior outcome in standard arm, however such an association was not observed for the bortezomib arm. Higher abundance of the low ACS10 SNP scores in black patients warrants further in-depth evaluation. Our future and ongoing studies include compiling data from multiple clinical trials to increase the sample size as well as expanding investigations within Hispanic/Latino AML patients

The Impact of Induction Regimens on Clinical Outcomes in Double and Triple-Hit Lymphoma: A Meta-Analysis of Comparative Studies

Background: Double and triple hit lymphomas (DTHL) are aggressive high-grade lymphomas that harbor translocations of MYC and BCL2 and/or BCL6. They constitute 6-14% of all aggressive B-cell lymphoma and have been associated with poor clinical outcomes. Though there is no established standard therapy for DTHL, induction chemotherapy vacillates between R-CHOP-like regimens, R-EPOCH, or more dose-intense regimens (DI) such as R-hyperCVAD/MA and CODOX-M/IVAC with or without consolidation with stem cell transplant. Currently, there are no randomized trials establishing a standard induction regimen. Furthermore, several retrospective studies reported conflicting results regarding the comparative benefits of these various induction approaches. Therefore, we conducted this meta-analysis to evaluate the impact of induction chemotherapy regimens on the clinical outcomes of DTHL. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of DTHL, comparative studies of induction chemotherapy regimens, and studies that reported overall (OS) and progression-free (PFS) survival. Studies that reported the aggregate outcome of mixed samples of DTHL and other lymphomas were excluded. A meta-analysis using the fixed effects and random effects models was conducted. Results: Seven retrospective comparative studies with a total of 1433 patients were included. The median age was 62 years, and the median follow-up was 27.5 months. DI regimens were associated with better PFS than R-CHOP-like regimens (HR = 0.81, 95%CI 0.66-0.99, p = 0.039) but without improved OS. R-EPOCH, including R-DA-EPOCH, regimens were associated with better PFS than R-CHOP-like regimens (HR = 0.62, 95%CI 0.43-0.91, p = 0.013) but without improved OS. R-HyperCVAD/MA regimen was associated with better PFS compared to R-CHOP-like regimens (HR = 0.64, 95%CI 0.47-0.87, p = 0.005) but without improved OS. Conclusions: This is the first and largest meta-analysis to show that induction DI regimens, in general, and R-EPOCH and R-HyperCVAD/MA regimens, in particular, are associated with better PFS than R-CHOP-like regimens in patients with DTHL. However, this advantage did not translate into a survival benefit.

Five-Year Real World Data on AML Retrospective Study from Public Health Center in Brazil

Introduction: Acute myeloid leukemia (AML) is a heterogeneous aggressive leukemia with poor prognosis. The standard remission induction regimen for medically eligible patients with AML consists of a backbone of cytarabine & an anthracycline (“7+3” therapy). Brazil is a large country with striking differences in in climate, ethnic heterogeneity and socioeconomic factors. Objectives: To assess effectiveness (Eligible to the Next Treatment-ENT CR and suficient performance status to the next treatment, PFS and OS) and security (Early Mortality) of cytarabine and anthracycline in a public health center in Salvador, Brazil. Subgroups analyzed were about FTL3 and NPM1 mutations, leukocytes (>10,000 or <10,000), platelets (>20,000 or <20,000), and transplanted or non-transplanted. Methods: It was a retrospective analysis of all the cases of non-promyelocytic AML diagnosed between 2018 and 2022 in the University Hospital Professor Edgar Santos of Federal University of Bahia, after being approved by the Ethics Committee of the hospital. Kaplan-Meier methods were used to determine the median of the time to OS and PFS. Results: A total of 45 patients were analyzed. Median age at diagnosis was 43 years (range, 16-69 years) with 62% females. There were 21% and 11% patients with FLT3-ITD and NPM1 mutations, respectively. Only 14 patients had karyotype test (85% with normal karyotype). Regarding effectiveness, 52% of patients were eligible for the next therapy after complete remission (consolidation or stem cell transplantation). Refractory patients were 20%. Early (4 weeks) mortality was 28% (19% in <40a, 27% in 40-55a and 40% in >55a). The median of PFS and OS were 3.6 and 8.2 months respectively. Patients with FLT3 mutation, platelet < 20.000 and leukocytes < 10.000 had poor outcomes. In AML patients after stem cell transplantation, PFS and OS were, respectively 20 and 43 months. Average waiting time for start induction therapy was 12 days. Conclusion: The outcomes were consistent with the literature, adjusted for the population in question. Even with access to diagnostic tests (not common in Brazilian's health public centers), patients did not have access to targeted therapies, with the 7+3 regimen being the only treatment for fit patients. To achieve complete remission followed consolidation/transplantation is still the BEST scenarios in AML eligible patients, but the improvement of access to diagnostic and treatment is still an unmet need.

Infliximab Redosing During Massive GI Bleeding Resulting from Severe Crohn’s Disease

In moderate-to-severe Crohn’s disease (CD), early introduction of biologics is indicated. However, a standard frequency induction regimen may be insufficient for disease activity control in patients with significant ongoing hematochezia. We present a previously healthy 21-year-old man who was found to have severe-fulminant CD with involvement of the esophagus, stomach, small intestine, and colon. Since his disease remained refractory despite an accelerated high-dose infliximab initiation regimen, an infliximab level was checked and returned undetectable. In patients with Crohn’s disease who present with large volume gastrointestinal hemorrhage, it is imperative to proactively assess infliximab levels and aggressively re-dose if needed.

Clinical Outcome and Treatment-Related Mortality in Patients with Acute Myeloid Leukemia Treated at the Uganda Cancer Institute

Background Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults, accounting for about 80% of cases, and accounts for 20% of childhood leukemias. Treatment of AML is similar in both high-income and low- and middle-income countries (LMICs), and utilizes an anthracycline and cytarabine backbone. Treatment-related mortality (TRM) for AML in high-income countries is significantly lower than in LMICs. Understanding the factors associated with TRM in LMICs is critical to improving AML outcomes. Here we describe the response rate to induction therapy and TRM in patients with AML treated at a tertiary cancer facility in Uganda. Methods A retrospective study of all patients treated for AML at the Uganda Cancer Institute (UCI) in the years 2015-2020 was performed. The diagnosis of AML was based on bone marrow or peripheral blood morphology or flow cytometry. The regimen for remission induction of adult patients with AML at the UCI includes daunorubicin 60mg/m2 given intravenously on days 1-3 and cytarabine 200mg/m2 given intravenously on days 1-7 ("3+7"), while the paediatric regimen (termed "AD") consists of daunorubicin 50mg/m2 given intravenously on days 1, 3, and 5 and cytarabine 100mg/m2 given intravenously twice daily on days 1-10, followed by a second course. Consolidation therapy is given to all patients who achieve complete remission after up to 2 courses of induction. Complete remission was defined as <5% blasts in the marrow identified by morphology or flow cytometry. The study was approved by the UCI Research Ethics Committee (Ref. UCI-2020-9) and the Uganda National Council for Science and Technology (Ref. HS946ES). All patients’ information was anonymized. Results. Medical records were reviewed for 290 patients with a diagnosis of AML, of whom 186 were further analyzed after excluding patients diagnosed with acute promyelocytic leukemia (n=33), those who did not receive induction therapy (n=66), and those who received low dose chemotherapy (n=5). The median age was 20 (IQR, 10-35) years. Patient characteristics are reported in Table 1. One hundred fourteen (61.3%) adult and adolescent patients received a standard "3+7” induction regimen, 65 (34.9%) children were treated with "AD,” and 7 (3.8%) patients received other regimens. Seventy four (39.8%) patients received a second course of induction. Treatment response assessment showed that 86 (46.2%) patients achieved complete remission (CR). Of these, 62 (72%) achieved CR after the first induction, with the remaining 24 (28%) after the second induction. Forty five (24.2 %) patients with evaluable response data at the end of induction did not achieve remission. A total of 55 (29.6%) patients died, all in the first induction course. The overall 30-day induction TRM rate was 31.5% (95% CI, 25.2 - 38.8) with 3-month, 6-month and one-year survival of 52.9% (95% CI, 45.3 - 60), 43.3% (95% CI, 35.8 - 50.6) and 30.8% (95% CI, 23.6 - 30.4) respectively (Figure 1). A pre-treatment HCT - CI score of >2 HR 3.37 (1.084 - 10.461), p=0.04 was associated with increased 30-day TRM. Conclusion This study of 186 patients with AML treated at the UCI with standard induction regimens over a 5-year period demonstrates a CR rate of 46.2% and an overall 30-day induction TRM rate of 31.5%. A pre-treatment HCT-CI score of >2 was associated with increased TRM. Our study demonstrates the urgent need for interventions that can reduce TRM and improve the outcome for patients with AML in LMICs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Induction Related Mortality Score in Acute Myeloid Leukemia: Prospective Validation Study (pRISM) of the Hematology Cancer Consortium (HCC)

Treatment of Acute Myeloid Leukemia (AML) should be initiated at the earliest to improve outcomes. The standard induction regimen (3+7) is associated with significant risk of induction mortality, especially in resource limited settings. Hence there is a need to develop risk prediction model for our patient cohorts. Treatment related mortality (TRM) scoring systems developed and used in developed country, mostly for the elderly, may not be directly applicable to population of young adults in developing countries, many of whom have poor general condition and infections at baseline. We developed a multivariate model of induction mortality score in 2019, from a retrospective AML cohort of the Indian acute leukemia research database [INwARD] established by the Hematology Cancer Consortium (HCC). In the present study we have validated the approach and recalibrated the induction mortality score on a multicenter prospective cohort. Prospective data for adult AML, for a period of 20 months, starting July 2020 to February 2022, was received from 17 member institutions in a central online data management system. Potential variables that would predict mortality were selected based on clinical and statistical significance. Eleven variables relating to baseline patient and disease characteristics (age, ECOG performance status, duration of symptoms in days, albumin, creatinine, bilirubin, white cell count, platelet, hemoglobin, peripheral blood blast percentage, and presence of infection requiring intravenous antibiotic within one week prior of starting induction), were considered for the predictive model using machine learning (ML) algorithms: Logistic regression (LR), Support Vector Machine (SVM) and eXtreme Gradient Boosting (XGB). Of the various ML algorithms, the best model was chosen based on area under curve (AUC) from the training dataset and validity statistics from the test dataset. We also used the same approach to predict intensive care unit (ICU) admission. R software was used to analyze the data. Of the 779 treated cases during the study period, 438 received intensive induction, '3+7' being the most common regimen in 80%. The median age of this cohort was 37 years (IQR 28, 46), male to female ratio 1.2. European Leukemia Net (ELN) risk group was good in 31.3 % (n= 137), intermediate in 44% (n=192), high in 13.7% (n=60), and unknown in 11% (n=48). Complete remission was attained in 56.3%. Overall induction mortality was 13.0%, ranging from 7.1% to 40% across different centers. Infection was the most common cause of death in 52%. For predicting induction mortality using 11 covariates, SVM provided the best threshold as 0.126, with an AUC of 94.71%, sensitivity (92.50%), and specificity (96.11%). A comparison of the ML algorithms is shown in Fig 1 and statistics for the SVM model in Table 1. ICU admission was observed in 22.8%; a cut-off threshold of 0.231, with an AUC of 93.3% in the SVM model predicted ICU admission with sensitivity of 93.15% and specificity of 89.7%. Induction mortality prediction score developed in a retrospective cohort was effectively applied to contemporary prospective data from major centers across the country, with diverse resources and patient profiles. Thus, we have validated the machine learning approach of predicting induction mortality with variables relevant to regional clinical settings including baseline infection. The SVM model predicted the risk of both induction mortality as well as morbidity with high accuracy. An online calculator is being developed to help clinicians use this score in regular practice for guiding treatment intensity as per an individual patient's risk and in directing appropriate resource utilization. Further, the approach of risk-adapted induction intensity, especially for young adult AML, based on the score adjusted to center-specific prevalence of mortality rates, is under consideration for a prospective clinical trial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low Intensity Salvage Therapy after Failure of Standard (7 +3) Induction Regimen in Acute Myeloid Leukemia (AML). a Single Center Experience from United Arab Emirates

Hypomethylating agent (HMA) and venetoclaxR as salvage therapy for Acute Myeloid Leukemia (AML) failing intensive induction therapy. A single center experience from United Arab Emirates. Introduction: Patients with AML who are younger and fit for therapy are treated with intensive chemotherapy. Complete remissions (CRs) range from 40-80% (Kantarjian, Blood vol. 116,22 (2010): 4422-9). Non-CR patients can be treated with salvage therapy as a bridge to Allogeneic hematopoietic cell transplant (AlloHCT). Salvage regimens have included high dose cytarabine based therapies (FLAG, MEC, HAM) which can be more toxic limiting the use of AlloHCT. Lower intensity and more targeted therapy could decrease toxicity with improved responses. We describe our experience with a low intensity regimen as salvage treatment after failure of intensive induction therapy and bridge to AlloHCT. Methods: This is a retrospective analysis of AML patients treated at Tawam Hospital, UAE from 01/2019 to 06/2022. Patient data was collected from the medical records including: demographics, hemogram at presentation, bone marrow biopsies, karyotyping, treatment and response. Results: Eighty patients were diagnosed with AML during this period. The median age was 45 years (range 16-95 years). Fifty-seven patients received therapy while twenty-three patients refused or were not eligible due to comorbidities and / or performance status. Intensive chemotherapy (infusional cytarabine and idarubicin 7+3 or FLAG) was used for thirty-three patients. The median age was 35 years (range 16 - 63 years). Cytogenetics (Metaphase Karyotyping and FISH): normal, n=7; good risk n=6 (inv 16 or t (8;21), growth failure n=5, poor risk n=10 (Complex = 3, Del 7 = 3, 11q abnormalities = 3, trans 6;9 =1) other n=5. Molecular testing for NPMI, FLT3, IDH1 and IDH2 was not available. Three patients died during induction and are excluded from analysis. Fifteen patients attained CR after 1 cycle of induction (50%). Twelve patients not in CR received outpatient, low intensity salvage therapy with HMA (5 azacitidine 75 mg/m2 daily x 7 days subcutaneously with Venetoclax 100 mg orally daily x 21 days along with antimicrobial prophylaxis with azoles in 28 days cycles). Bone marrow was repeated after the second cycle. The median number of cycles is 3 (range 1-9). Eight (67 %) achieved CR1. There were no treatment related deaths. This is comparable to our report of FLAG salvage therapy (Hassan IB. Int J Hematol. 2018 Oct;108(4):390-401). Four of the eight patients who achieved remission went for AlloHCT while one is awaiting AlloHCT. One patient is unable to go for HCT and is in remission after 9 cycles of therapy. Two patients after achieving CR relapsed and died of disease progression. With a median follow up of 123 days (range 33 -1107 days) five patients are alive and in remission, one has been lost to follow-up while the other six have died from progressive disease and complications. Conclusion. Low Intensity therapy with HMA and Venetoclax is a reasonable and effective alternative to intensive chemotherapy as first line salvage with minimal morbidity and zero treatment related mortality. Treatment was well tolerated and no patients required hospitalization for complications. This regimen is easily administered as an outpatient, serving as a bridge to AlloHCT

Carfilzomib, Lenalidomide and Dexamethasone (KRd) Vs Bortezomib, Lenalidomide, and Dexamethasone (VRd) As Induction Therapy in Newly Diagnosed High-Risk Multiple Myeloma

Background: Bortezomib, lenalidomide, dexamethasone (VRd) and carfilzomib, lenalidomide, dexamethasone (KRd) are standard induction regimens for the treatment of newly diagnosed multiple myeloma (NDMM). The phase III ENDURANCE trial excluded patients with high-risk NDMM (HR-NDMM) and included patients with no intention for immediate autologous stem cell transplant (ASCT) (Kumar SK, et al. Lancet Oncol 2020). Herein, we examined outcomes associated with KRd and VRd induction in the management of HR-NDMM. Methods: We conducted a retrospective chart review study with 154 consecutive HR-NDMM patients treated with VRd and KRd at MSKCC between 1/1/2015 to 12/31/2019. Only patients with high-risk (HR) cytogenetics defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p) were included. The cutoff date for analysis was 8/18/21. Early transplant was defined as ASCT within 6 months of completing induction. Primary endpoint was progression-free survival (PFS). Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (IQR). PFS and overall survival (OS) were evaluated by Kaplan-Meier method. Multivariable Cox models were fitted with pre-specified clinical parameters including age, cardiac history, R-ISS stage, best response to induction, early ASCT (both time dependent covariates), and induction regimen. Results: Baseline characteristics of the 67 VRd and 87 KRd treated patients are summarized in table 1. There were 51 (76%) patients in the VRd group and 63 (72%) patients in the KRd group with 1 HR cytogenetic abnormality. Sixteen (24%) and 24 (28%) patients in the VRd and KRd groups, respectively, had ≥2 HR cytogenetic abnormalities. Among the HR-NDMM patients, 32 VRd- and 48 KRd-treated patients received early ASCT. Overall response rate by the end of induction was 93% and 98% for VRd and KRd, respectively, including 66% with ≥VGPR in the VRd group and 80% in the KRd group. Median follow-up for the entire patient population was 42.5 (IQR, 37.5-50) months with 47.9 (42.5-53.9) months for the VRd group and 37.6 (35-50) months for the KRd group. The median PFS for HR-NDMM patients treated with VRd induction was 42.6 months (95%CI, 32.8-62) and was NR (95%CI, 45.5-NR) for the KRd group (HR=1.84; 95%CI, 1.11-3.06; P=0.02) (Fig. 1). We conducted a multivariate analysis for important clinical variables that may affect survival outcomes. Multivariable analysis for PFS showed that KRd induction (HR=1.80; 95%CI, 1.05-3.10; P=0.033) and R-ISS Stage I compared to R-ISS Stage II (HR=2.67; 95%CI, 1.33-5.38; P=0.006) and R-ISS Stage III (HR=3.51; 95%CI, 1.02-12.07; P=0.046) were associated with better PFS. Early ASCT was not associated with improvement of PFS on multivariable analysis (P=0.30). Age, cardiac history, and achieving CR/sCR or VGPR/PR compared to <PR as the best response to induction did not have a statistically significant effect on PFS. We conducted a subgroup analysis of HR-NDMM patients who received early ASCT (N=79). At median follow-up since time of transplant of 43.5 months for VRd and 28.4 months for KRd, the estimated 3-year PFS since the time of transplant was 55% (95%CI, 38-79) and 67% (95%CI, 52-85) for VRd and KRd-treated patients, respectively (HR=1.65; 95%CI, 0.78-3.50; P=0.20). The estimated 3-year OS from the time of transplant was 80% (95%CI, 66-81) for the VRd group and 91% (95%CI, 81-100) for the KRd group, respectively (HR=2.45; 95%CI, 0.60-10.0; P=0.20). Conclusion: There was a significant improvement in PFS among HR-NDMM patients who received KRd compared to VRd induction. In patients who received early ASCT, we did not observe a statistically significant difference in PFS or OS between the two induction regimens, but this analysis is subject to inherent selection bias. Until results from prospective randomized studies are available for HR-NDMM patients, the use of various induction regimens in transplant-eligible patients opting for early transplant should be tailored to each patient. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Managing ANCA-associated vasculitis during COVID-19 pandemic: a single-center cross-sectional study.

The objective of the study is to report the outcomes of COVID-19 in ANCA-associated vasculitis (AAV) patients. This was a registry-based observational study conducted at a tertiary care center in north India. AAV patients with at least one follow-up visit between March 2020 and September 2021 were included. Demographic features, clinical manifestations, disease activity, and treatment details of underlying AAV were noted in all patients. Details of COVID-19 infection including severity, treatment, and outcomes were noted. Predictors of COVID-19 severity were determined using univariate analysis. A total of 33 (18.3%) out of 180 AAV patients contracted COVID-19 infection. Moderate COVID-19 infection was seen in 33.3% and severe or critical infection was seen in 36.3% of patients. Seventeen patients (51.5%) required supplemental oxygen therapy. Nine patients had active disease at the time of COVID-19 infection and three of them died due to COVID-19 infection. The risk of COVID-19 infection and its severity did not differ between patients receiving different immunosuppressants including rituximab induction. Hypothyroidism (p = 0.046) and ocular (p = 0.038) involvement due to AAV predicted the development of moderate to severe/critical COVID-19. Three (9.1%) patients died from COVID-19 and the rate of AAV flare after COVID-19 was similar to that in non-COVID-19 patients (15.3/100 person-year vs. 15.6/100 person-year, p = 0.95). Majority of the patients with AAV had moderate to severe or critical COVID-19 infection. The rate of death due to COVID-19 in AAV is higher than in general population. Use of standard remission induction regimens did not lead to increased risk of COVID-19 infection in our AAV cohort.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00296-022-05177-2.

P526: REAL-WORLD COMPARISON OF DIFFERENT TREATMENT MODALITIES FOR FAVORABLE RISK ACUTE MYELOID LEUKEMIA: STANDARD DOSE ANTHRACYCLINE VS HIGH DOSE ANTHRACYCLINE VS ADDITION OF GEMTUZUMAB OZOGAMICIN

Background: The standard remission induction regimen for medically fit patients with acute myeloid leukemia (AML) consists of a backbone of cytarabine & an anthracycline (“7 + 3” therapy). However, the choice & dose of the anthracycline varies between institutions & practitioner preference, particularly in AML with favorable risk cytogenetics. Gemtuzumab ozogamicin (GO) may improve outcomes in this patient population but is associated with increased toxicities. Aims: We aimed to compare the outcomes of 3 cohorts of newly diagnosed AML with favorable cytogenetics who received induction 7 + 3 induction therapy: 1. Standard dose (45 or 60 mg/m2 daunorubicin) (SD); 2. Higher dose (90 mg/m2 daunorubicin or 12 mg/m2 idarubicin) (HD) of anthracycline, 3. 7 + 3 with fractionated GO. Methods: We performed a multicenter retrospective analysis of medically fit patients ≥ 18 yo with favorable risk AML determined using ELN 2017 guidelines from 2015-2020 treated across 6 US academic institutions. Categorical variables were summarized using means and standard deviations. The former was compared using Fisher’s exact test; the latter was compared using either the Wilcoxon text or the Kruskal-Wallis as appropriate. One way ANOVA test was used to compare continuous variables. Kaplan-Meier curves were generated to provide visual summaries of survival and time-to-event data. Results: Our study included 189 treated patients who met eligibility criteria with a median follow up of 2 years. Patients’ characteristics and outcomes are summarized in Table 1. Sixty-nine (37%) received induction with SD, 100 (53%) received HD, and 20 (11%) received GO. Patients in the SD and HD group were younger (median age 50 and 52 yo, respectively) and the majority (>94%) had de novo AML. The rates of composite complete remission in the SD, HD, and GO groups were 66.7%, 70% and 75%, respectively (p=0.761). RFS and OS were similar between all groups (p=0.4 and 0.3, respectively). The rate and duration of cytopenias at day 40 after induction, major bleeding, infections, admission to the intensive care unit, new onset cardiomyopathy (ejection fraction<50%), liver dysfunction and acute renal injury were similar among all groups. No patients developed veno-occlusive disease. Table 1: - Participant Characteristics and Outcomes by Treatment Regimen GON = 20 HDN = 100 SDN = 69 P-value Age in years (standard deviation) 57.75 (9.32) 49.68 (13.67) 51.55 (13.83) 0.038 de novo AML, N (%) 19 (95.0) 94 (94.0) 65 (94.2) 1.000 Disease status after induction 0.812 CR, N (%) 14 (70.0) 66 (66.0) 40 (58.0) CRi, N (%) 0 (0.0) 2 (2.0) 2 (2.9) Persistent, N (%) 1 (5.0) 4 (4.0) 2 (2.9) Composite CR, N (%) 15 (75.0) 70 (70.0) 46 (66.7) 0.761 Admission to ICU, N (%) 4 (20.0) 17 (17.0) 11 (15.9) 0.969 Infections, N (%) 17 (85.0) 74 (74.0) 62 (89.9) 0.082 Major bleeding, N (%) 3 (15.0) 6 (6.0) 4 (5.8) 0.299 VOD, N (%) 0 (0.0) 0 (0.0) 0 (0.0) Transaminitis, N (%) 4 (20.0) 19 (19.0) 19 (27.5) 0.538 Acute renal injury, N (%) 3 (15.0) 19 (19.0) 15 (21.7) 0.962 Cardiomyopathy, N (%) 4 (20.0) 8 (8.0) 5 (7.2) 0.523 Cytopenias at D40 after induction, N (%) 0 (0.0) 7 (7.0) 6 (8.7) 0.542 Image:Summary/Conclusion: Our analysis demonstrated no differences in RFS and OS in patients with AML treated with either GO, HD or SD. In addition, the rates of complications secondary to chemotherapy were similar among all groups. However, a measurable residual disease analysis is ongoing for further characterization of disease response.