Standard-risk Patients Research Articles

IMWG /ECOG Frailty Score Was a Good Indicator for ASCT Candidate Selection for NDMM in China from a Hcmmd Retrospective Study

Background Autologous hematopoietic stem cell transplantation (ASCT) has always been considered as the standard choice for newly diagnosed multiple myeloma (NDMM) patients less than 65 years old, or even older. At present, how to define the patients who is suitable for transplantation is still controversial in clinic in China. Rate of utility of ASCT in front line was as low as 10%. The screening of transplant patients mainly depends on the evaluation of the general condition of patients, the wishes of patients and their families, and the evaluation of organ function by physical examination. In this way, it is particularly difficult for doctors in non-transplant medical units to recommend stem cell transplantation for patients. Based on “HemaTank” Chinese multiple myeloma database(HCMMD), a retrospective study of construction of special disease cohort and prognostic model for multiple myeloma were conducted to explore the posibilities of utility of IMWG/ECOG frailty score to select transplantation candidate, and the prognostic significance of frailty score in all MM patients. Methods In this study, 322 NDMM in the first affiliated Hospital of Soochow University from August 2018 to October 2022 were analyzed retrospectively. All patients were valuated with IMWG/ECOG frailty score before each cycle of treatment, which included age, the ECOG score, and the Charlson Comorbidity Index. Patients with IMWG frailty score≥2 were defined as frail, with score <2 were unfrail. Transplant patients received 4 courses of induction of VRd regimen followed by ASCT, and 2 courses of VRD consolidation after transplantation. Non-transplant patients received 8 courses of induction with VRD regimen. Standard risk patients received lenalidomide as maintenance therapy until PD. High risk patients received V+R as maintenance treatment until PD. Results The median age of 322 patients was 58(29-79). 178(55.3%) patients were male. 170 (52.8%) patients were unfrail at diagnosis, with a mean age of 56.72±7.11. 77.8% of the unfrail patients were less than 65 years old. 152 patients were frail at diagnosis, with a mean age of 59.47±8.28. 68% of the patients were less than 65 years old. There were statistical differences in age, DS stage, ISS stage and R-ISS stage between the two groups. (P < 0.05). After induction therapy, 246 patients (76%) rescored IMWG/ECOG frailty score before ASCT. 46 patients changed from frail state at first diagnosis to nonfrail before transplantation, mainly because of the improvement of ECOG score and renal function. There is no change from a nonfrail state at the first diagnosis to a frail state when entering the ASCT program. After logistics regression analysis of IMWG/ECOG score, age, renal function and CCI, unfrailty is the best indicator of selection patients as ASCT candidate, OR=0.37, 95%CI 0.21-0.63 (P < 0.001). At the time of ASCT, there was no significant difference in the ORR of induction therapy between frail and unfrail patients. But the granulocyte and platelet reconstruction during ASCT in the frail group was slower than that in the unfrail group, P<0.0001. The transplantation-related mortality was 0. In this cohort, the PFS and OS of the NDMM patients accepted VRD+transplantation was all better than those received VRD only. Most importantly, the OS of the frail patients scored at the time of ASCT was much poorer (P<0.05) than that of the unfrail group with no significant difference in PFS between two groups. But there were no significant differences in PFS and OS of the patients who changed from frail to unfrail after induction therapy compared with those remained unfrail at diagnosis and after induction therapy. Conclusion IMWG/ECOG frailty score can be used to select ASCT candidate for NDMM patients. In the study 144 patients (84.7%) remained unfrail at diagnosis and before transplantation accepted ASCT. and 46 frail patients (30.2%) at diagnosis transferred from frail to unfrail after induction and accepted transplantation. It was suggested that the IMWG/ECOG frailty score evaluated before transplantation is more instructive for long-term overall survival. The OS of unfrail patients was better than that of frail patients even with no significant difference in PFS.

Asparaginase-Associated Toxicities and Hypersensitivity Reactions in Pediatric and Adolescent Down Syndrome Patients with Acute Lymphoblastic Leukemia or Lymphoma

Children with Down syndrome acute lymphoblastic leukemia (DS-ALL) have worse prognosis compared to those with non-DS-ALL, largely due to higher treatment related mortality. Pegaspargase (PEG) is integral in protocols for the treatment of pediatric ALL and lymphoblastic lymphoma (LBL), and full exposure to all doses of PEG can be limited by toxicities, including hypersensitivity reactions (HSR) due to the production of anti-asparaginase antibodies rendering PEG therapy ineffective. To date, minimal data has been reported on the use of PEG in children with DS-ALL/LBL. We conducted a prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent ALL/LBL patients receiving PEG with antihistamines-H1 and -H2 blockers with subsequent therapeutic drug monitoring (TDM) to better identify patients with true HSR versus those with non-antibody mediated infusion reactions. Here, we report on the incidence of HSRs and PEG-associated toxicities in the cohort of children with DS-ALL/LBL. Eligible patients from six centers received PEG, as per a Children's Oncology Group protocol, beginning in induction therapy. An H1 blocker (diphenhydramine) and H2 blocker (ranitidine, famotidine or cimetidine) were administered prior to PEG administration in consolidation and subsequent cycles. TDM was performed at 7 and 14 days post each PEG. PEG was administered at 2500 International units/m 2/dose that was capped for obesity or age > 22 years. Patients were monitored for HSR and other PEG-related toxicities using CTCAE version 5 criteria. Therapeutic asparaginase activity (AA) was defined as ≥ 0.1 IU/mL (≥100 IU/L) at 7 days post infusion and greater than the lower level of quantification at 14 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14 days without symptoms). Descriptive statistics summarized patient characteristics and mixed effects modeling procedure assessed mean AA levels at 7 and 14 days with specification of repeat measures and compound symmetry covariance structure. Out of 148 patients, 9 DS (8 B-ALL, 1 B-LBL) were enrolled between 10/2019 - 3/2022. The median age at diagnosis was 5.0 years [IQR: 4.3, 14.9], 4 were National Cancer Institute (NCI) High Risk (HR) at diagnosis, 4 were Hispanic and none were obese. ALL 9 DS patients received a total of 26 doses of PEG at the standard dose without dose capping required. The mean unadjusted AA levels at 7 and 14 days post PEG were 0.76 IU/ml (SE=0.11) and 0.54 IU/ml (SE=0.11), respectively, p<.001. None of the DS patients experienced HSR or silent inactivation. Accelerated clearance was observed in 1 patient. Nineteen episodes of grade >3 PEG-associated toxicity were observed in 5 DS-ALL patients (5/9; 55.6%). PEG-associated toxicity was observed more frequently in older patients whose mean age was 13 years (SD=6.2) versus 4.3 years in those without toxicity (SDE=0.9), p=.028. Four of the DS-ALL who experienced toxicities were NCI HR at diagnosis and > 10 years of age. For the 19 episodes of toxicities: 6 occurred during induction, 9 during consolidation, and 4 during delayed intensification. The most common toxicity observed was hepatoxicity (increased alanine transaminase) which was experienced by 3 DS-ALL patients. There were no grade > 3 hyperbilirubinemia. All 4 DS-ALL patients who experienced PEG toxicity during induction also had toxicity with subsequent cycles. One DS-ALL patient had a dose limiting toxicity (grade 3 pancreatic pseudocyst), requiring discontinuation of subsequent PEG therapy. There were no grade 4 or 5 toxicities observed. All 4 DS patients who did not experience toxicities were NCI Standard Risk patients. All DS patients had undetectable minimal residual disease (MRD) that was < 0.01 at the end of induction therapy. We noted that in this small DS-ALL/LBL cohort, none of the patients experienced HSR, and all achieved therapeutic AA at both time points of 7 and 10 days post PEG. Five (55.6%) of the DS-ALL patients experienced at least one grade > 3 asparaginase toxicity, and they were older than those without toxicity. Most toxicity occurred during the consolidation phase and no grade 4 or 5 toxicities were observed. Given the PEG-associated toxicity observed in DS ALL/LBL, we are conducting pharmacokinetic analysis to propose a lower dose of PEG which may minimize toxicity while maintaining therapeutic efficacy.

Age-Based Comparison of Dara-Rvd, Krd and Rvd Induction Therapies during the First Line of Therapy for Multiple Myeloma Patients

Background Since the development of proteasome inhibitors, the combination of lenalidomide (R), bortezomib (V), and dexamethasone (d) for induction has been the standard of care when treating patients with multiple myeloma. This combination has been shown to improve the clinical outcomes and quality of life of multiple myeloma patients. More recently, new generations of proteasome inhibitors, such as carfilzomib (K), and the development of monoclonal antibodies have created new opportunities for treatment that provide better outcomes with fewer side effects. The addition of daratumumab (Dara) to the RVd induction therapy has shown more potent results, increasing response rates and outcomes. However, there is a lack of evidence about the influence that age may have on the efficacy of these therapies. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1100 patients with multiple myeloma. Patients were categorized into two groups based on age (<65 and ≥65). We compared ‘Time to Next Treatment’ (TTNT) among patients who received DaraRVd, KRd, or RVd as induction therapy. The analysis was conducted using Kaplan-Meier curves in R. Age groups were also subclassified by high-risk cytogenetics according to mSMART staging by fluorescence in situ hybridization (FISH), and the Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1100 patients with MM, of which 718 patients (65.3%) were age <65 and 382 patients (34.7%) were age ≥65. The <65 group had a median age of 55±7, and the ≥65 group had a median age of 70±5. The majority of patients were female (n=586, 53.3%). The median year of diagnosis was 2018 (2009-2022). In the <65 group, the majority of patients were White (88%), and other big groups were Blacks (5.8%), and Hispanics or Latinos (2.6%). Similarly, in the ≥65 group, the majority of patients were White (93.0%), and other big groups were Blacks (3.3%), and Hispanics or Latinos (2%). In the <65 group, 55 patients had DRVd as induction therapy, 77 KRd, and 586 RVd. In the ≥65 group, 38 patients received DRVd as induction therapy, 39 KRd, and 305 RVd. R-ISS staging was available for 588 patients. In the <65 group, 139 patients (36.7%) were classified as R-ISS stage I, 170 patients (44.8%) stage II, and 70 patients (18.5%) stage III. In the ≥65 group, 75 patients (35.9%) were stage I, 104 patients (49.8%) were stage II, and 30 patients (14.3%) were stage III ( p=0.37). mSMART staging was available for 1035 patients, of whom patients with high-risk, double, and triple hit represented 16.2%, 5.0%, and 0.3%, respectively ( p = 0.35). Regarding stem cell transplant (SCT), 571 patients (51.9%) underwent SCT. In the <65 group, 404 patients (56.3%) received SCT; of those, 18 (32.7%) received DRVd, 21 (53.3%) KRd, and 345 (58.9%) RVd. In the ≥65 group, 167 patients (43.7%) received SCT; of those, 12 (31.6%) received DRVd, 23 (59%) KRd, and 132 (43.3%) RVd as induction therapy. For patients aged <65, the median TTNT was not yet reached for the DRVd group, 33 mo for the KRd group, and the RVd group was longer at 48 mo ( p=0.049). For patients aged ≥65, the median TTNT was not yet reached for the DRVd group, and 54 mo for the KRd group, which did not significantly differ from the RVd group, which had a median TTNT of 47 mo (p=0.52). Conclusion This study found that in the <65 age group, RVd induction therapy led to a longer TTNT compared to KRd, while in the ≥65 age group, KRd showed a longer TTNT than RVd. When considering the SCT usage rate, which increases TTNT by at least 12 months on average, KRd did not significantly improve outcomes over RVd in both age groups. However, when evaluating KRd induction, it's worth noting that KRd showed an improved outcome with a longer TTNT in the ≥65 age group compared to the <65 age group, despite toxicity concerns. These results align with the ENDURANCE trial, which also indicated that KRd did not significantly improve outcomes in standard-risk patients compared to VRd. Though the TTNT for the DRVd group is yet to be reached, the current trend suggests promising results for DRVd as a first-line therapy over KRd and RVd in both age groups. Nevertheless, further research is needed to validate and gain better insight into these observed trends.

Prommis Trial Prospectively Demonstrates the Efficacy of SKY92 Risk Stratification in Newly Diagnosed Multiple Myeloma Patients

Introduction: Multiple myeloma (MM) is a complex hematologic malignancy characterized by genetic instability, variable survival rates, and diverse treatment responses. SKY92 gene expression profiling (GEP) is a valuable tool in risk stratifying patients into high-risk and standard-risk groups for progression and survival. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) trial, a prospective US multicenter study, was designed to validate the prognostic performance of SKY92 through real-world data. Methods: The GEP of 251 newly diagnosed MM patients was assessed using the SKY92 assay (SkylineDx, San Diego), which involved analyzing RNA extracted from CD138-positive plasma cells (≥80% purity) isolated through immunomagnetic separation. The test was performed at the enrolling institute, or by sending the samples into a central lab. The standard method for risk stratification by R-ISS stage was integrated with SKY92 into three distinct groups: Low-Risk (LR), defined by SKY92 standard-risk (SR) combined with R-ISS I; Intermediate Risk (IR), as SKY92 SR with R-ISS II/III, or SKY92 high-risk with R-ISS I; and High-Risk as SKY92 high-risk with R-ISS II/III. Progression-free survival (PFS) and overall survival (OS) were available for 221 patients, measured from the date of diagnosis of the patients. The median follow-up at the time of analysis is 38 months. Survival analyses were performed using Cox proportional hazards model. Results: Upon analysis, 179 patients (71.3%) were classified as SKY92 standard-risk, and 72 patients (28.7%) as SKY92 high-risk. Notably, the percentage of high-risk patients in this study was slightly higher than that observed in previous retrospective analyses (15-25%). Furthermore, the survival analysis revealed significant differences in both PFS (HR: 2.1, 95%CI 1.4-3.1, p<0.001) and OS (HR: 3.7, 95%CI 1.8-7.6, p<0.001) between the two risk categories. The median PFS from the time of the diagnosis for SKY92 standard-risk patients was 50 months, whereas for SKY92 high-risk patients, it was 26 months. The median OS was not reached within the 60-month timeframe for both the standard- and high-risk groups. R-ISS could be determined for 204 patients (81%), of which 29.9% (n=61) were classified as stage I, 59.3% (n=121) as stage II, and 10.8% (n=22) as stage III. We integrated R-ISS staging with SKY92 classification for these patients. The combination of these two classification systems yielded the following stratification ( Figure 1): LR n=53 (27%), IR n=96 (47%), and High-Risk n=55 (26%). Consistent with previous studies, R-ISS and SKY92 hold independent prognostic value: in particular, we found that this combined classification method identified a higher number of patients as high-risk compared to the R-ISS annotation (55 [27%] vs. 22 [11%]). The high-risk group exhibited significantly shorter OS and PFS compared to the LR group (OS: HR:18.7, 95% CI 2.5-140, p=0.004 and PFS: HR:2.6, 95% CI 1.4-4.7, p=0.002). Conclusions: This study represents the first US-based multicenter prospective evaluation of the GEP SKY92 in a real-world clinical setting. The results obtained align with the retrospective validations of SKY92, further confirming its reliability as a prognostic marker for MM patients. In addition, we observed that the SKY92 is able to identify a higher number of high-risk patients, with significantly shorter PFS and OS, compared to the conventional R-ISS staging system. Figure 1: PFS and OS based on SKY92+R-ISS risk classification

A Single Dose of PEG-Asparaginase at the Beginning of Induction Not Only Accelerates MRD Clearance but Also Improves Long-Term Outcome in Children with B-Lineage ALL

This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m2 on day 3 of induction therapy in children with B-lineage ALL. Methods. Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG). Results. The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG− and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG− and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG− and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group). Conclusions. Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups.

NCOG-24. RISK-ADAPTED TREATMENT STRATEGIES WITH PRE-IRRADIATION CHEMOTHERAPY IN PEDIATRIC MEDULLOBLASTOMA: OUTCOMES FROM THE POLISH PEDIATRIC NEURO-ONCOLOGY GROUP

Abstract Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone of childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyze treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-oncology Group were included in the analysis. Median age at diagnosis was 8.0 years. Sixty-seven patients were classified as standard risk and 86 as high risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (± standard error) were 87 ± 4.3% and 84 ± 4.6% respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5% respectively. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.

Efficacy of D-RVD Vs RVD Among t(11;14) Patients with Newly Diagnosed Myeloma

Introduction: The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is highly effective for newly diagnosed myeloma (NDMM) patients including standard and high risk patients. The addition of daratumumab (dara) to RVD (D-RVD) has been shown to increase deep responses and improve PFS. Phase 3 studies are ongoing to confirm that benefit. We and others have previously demonstrated that patients with t(11;14) have a decreased PFS compared to other standard risk patients. It is unknown whether patients with t(11;14) derive similar benefit from the addition of daratumumab to RVD as part of induction. Here, we present a real-world comparison of consecutively treated patients with t(11;14) with either D-RVD or RVD induction therapy in terms of response and outcomes. Methods: Of the 1000 consecutive NDMM patients treated with RVD between January 2007- August 2016, and 326 NDMM patients treated with D-RVD induction therapy from April 2018 - August 2022, 185 had t(11;14). 121 were in the RVD cohort and 64 were in the D-RVD cohort. Demographic and clinical characteristics and outcomes data were obtained from our institutional review board approved myeloma database and with manual abstraction. Dara was administered as part of standard RVD induction prior to autologous transplant without planned dara during lenalidomide maintenance. Consolidation after transplant was not planned for either cohort. The responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. Results: Patient characteristics were similar between the two cohorts. The median age was 63 years old. There were 58.7% and 54.7% males in RVD and D-RVD respectively. There were 45.5% and 36.5% black patients in the RVD and D-RVD cohorts respectively. Patients had free light chain only disease in 27.4% and 32.3%. There were 5.3 and 4% R-ISS stage 3 patients. The VGPR rate or better after induction improved from 49.2 to 81.3 with the addition of dara. After transplant, the VGPR rate or better improved from 76.3 to 94.2% with the addition of dara as part of induction. Median PFS for the RVD cohort is 47.3 months (95% CI 35.9 - 58.8) and not reached in the D-RVD cohort (see Figure 1). The median OS for the RVD cohort is 115 months (95% CI 97-133.2) and not reached with 96.9% of the patients alive at last follow up in the D-RVD cohort. Conclusions: Patients with t(11;14) represent a unique set of myeloma patients with a distinct clinical presentation, biology and response to treatment. These patients have a decreased PFS when compared to other standard risk patient when treated with RVD. Overall survival is similar possibly due to advances in the management of relapsed disease in t(11;14) patients. In this cohort of patients, the addition of dara to RVD improved VGPR rates and PFS. Whether dara is able to completely overcome the PFS disadvantage to t(11;14) will be evaluated with longer follow up.

An Entirely Oral Regimen of Oral-Arsenic Trioxide/All-Trans Retinoic Acid/Ascorbic Acid in Newly-Diagnosed Acute Promyelocytic Leukaemia (APL): Updated Results of an Ongoing Multicentre Trial

Background: Pure oral arsenic trioxide (oral-ATO) solution (Arsenol ®) was first formulated in Hong Kong. It achieves a bioavailability comparable with that of intravenous ATO (i.v.-ATO). Oral-ATO combined with all-trans retinoic acid (ATRA) and ascorbic acid (the AAA regimen) combined with chemotherapy is highly efficacious in relapsed and newly-diagnosed APL. To reduce treatment-related toxicities and long-term risks of second primary cancers, a chemotherapy-free approach is increasingly favoured. Aims: The objectives of this prospective multicentre study in newly diagnosed APL patients were: 1. to evaluate the efficacy and safety of an entirely oral AAA-induction in a risk-adapted strategy; 2. to evaluate the molecular responses during oral-AAA-based induction/consolidation/maintenance. Methods: Newly-diagnosed APL patients were stratified by presentation leucocyte count into standard-risk (≤ 10 x 10 9/L) and high-risk (> 10 x 10 9/L) groups. Standard-risk patients and high-risk patients ≥ 65 years old received AAA induction comprising oral-ATO (Arsenol ®, Jacobson Pharma Corporation, Hong Kong) (10 mg/day, or 0.16 mg/kg in patients < 18 years old, days 1-42), ATRA (45 mg/m 2/day, or 25 mg/m 2/day in patients <18 years old, in 2 divided doses, days 1-42), and oral ascorbic acid (1 g/day, or 15mg/kg/day in patients <18 years old, days 1-42). High-risk patients < 65 years old received in addition daunorubicin (50 mg/m 2/day i.v. for 3 days). On reaching first complete remission (CR1), consolidation with AAA (days 1-14) every 28 days for 2 cycles was given, followed by maintenance with AAA (days 1-14) every 8 weeks for 12 cycles. Real-time quantitative polymerase chain reaction for PML:: RARA with a sensitivity of 10 -5 was performed (weekly during induction, every 4 weeks during consolidation, every 8 weeks during maintenance and thereafter every 12 weeks for 2 years). For molecular response, the normalized copy number ratio was defined as PML::RARA copy number/ ABL copy number. Primary outcomes were overall survival (OS, time from presentation to death or last follow-up), and relapse-free survival (RFS, time from CR1 to molecular or haematological relapse, death or last follow-up), and safety (according to the Common Toxicity Criteria for Adverse Events (AE) version 5.0). The secondary outcome was molecular response. Data were censored on July 22, 2023. Results: Between January 1, 2018 to July 22, 2023, 5 paediatric/adolescent patients (male, N=2; female, N=3) at a median age of 12 (3-15) years and 116 adult (> 18 years old) patients (male, N=47 ; female, N=69) at a median age of 49 (19-91) years were accrued (standard risk: paediatric/adolescent, N=3; adults, N=87; high-risk: paediatric/adolescent, N=2; adults, N=29). Seven patients (all high-risk adults) died at presentation before induction (intracranial haemorrhage, N=6; severe APL differentiation syndrome, DS, with leucocyte >100 x10 9/L, N=1). One-hundred and fourteen patients received oral-AAA-based induction (AAA alone, N=90; AAA+daunorubicin, N=24), all achieving CR1. For PML:: RARA normalized copy number, all treated patients at week 8 achieved a ratio of <0.01; and on completion of AAA maintenance, all evaluable patients (N=56) achieved a ratio of <0.0001. The median follow-up was 29 (IQR: 8-47) months, with 56 patients (49%) having completed 2 years of AAA maintenance. There was only one relapse, occurring in an adult patient 12 months after completion of AAA maintenance. Molecular analysis showed a PML B2 domain A216V mutation that conferred resistance to ATO. One adult patient died of an unrelated gastrointestinal bleeding while in CR1. The 3-year OS was 99.1% (paediatric/adolescent: 100%; adult: 99%). The 3-year RFS was 97.9% (paediatric/adolescent: 100%; adult: 97.9%). The most common non-haematological AEs (all grade 1-2) were transaminitis (N=54, 47.3%) and headache (N=32, 28%) Notably, no cardiotoxicity (arrhythmias/cardiac failure) was observed. APL-DS occurred in 67 patients (58.7%) after initiation of AAA, all responding fully to intravenous dexamethasone. There were no treatment discontinuations. Conclusion: The use of an entirely oral AAA-based induction in a risk-adapted strategy that minimized chemotherapy was highly effective and safe in newly-diagnosed APL of all risk categories and age groups. Early deaths remained an obstacle to realizing a cure-for-all in APL.

High Success Rates Utilizing Local Standard of Care Cytogenetic Testing for Risk Stratified Frontline Therapy for Newly Diagnosed Multiple Myeloma: Experience from the Ukmra RADAR Study

Background. Recent studies in genetically high risk (HR) multiple myeloma (MM) such as the UKMRA OPTIMUM study have reported high response rates with intensive induction and post-ASCT consolidation and maintenance strategies, providing the rationale for stratified therapy based on genetic risk. Whilst centralised testing in clinical trials offers ready uniformity and quality control, the use of local laboratories for testing within a clinical trial paves the way for genetic testing to be available for all patients, facilitating risk stratified therapy in routine care. We designed the UKMRA RADAR study to use local laboratories for cytogenetic (CGN) testing to assign treatment according to genetic risk. Methods. RADAR is an ongoing national, multi-center, risk-adapted, response-guided multi-arm, multi-stage (MAMS) phase II/III trial for patients with newly diagnosed MM eligible for ASCT. Patients receive induction with RCyBorD (lenalidomide, cyclophosphamide, bortezomib, dexamethasone), followed by high-dose melphalan and stem cell rescue. Post ASCT, HR patients are randomised to receive isatuximab or not, alongside RBorD consolidation and R maintenance whilst standard risk (SR) patients receive MRD response guided regimens. A protocol amendment (2022) included isatuximab throughout the HR pathway, removing the post-ASCT randomisation. Risk assessment, failure rates and turnaround time are overseen by a genomics working group (GWG) including clinical and specialist cytogenetic representation. Genetic risk testing is undertaken in local genetic labs on CD138 selected bone marrow (BM) plasma cells. HR is assigned based on the presence of at least two of: t(4;14), t(14;16), t(14:20), del(17p), del(1p) and gain(1q). Clone size cut-offs are 10% for IgH translocations and 20% for copy number changes. CGN results from local laboratories are centrally reviewed to assign risk in real-time. Indeterminate cases are discussed by the GWG. Repeat testing is mandated if the initial sample fails to yield a definitive risk result for risk. Subjects with no definitive result despite 2 samples are treated as SR. Results. As of 19 th June 2023, the trial has recruited 472 patients from 72 sites across the UK. Median age is 61 years, 59.3% male, 79.9% white, 11.7% other ethnicity and 8.5% missing ethnicity data. 25 local laboratories were used for CGN testing. Of those with CGN results 354/453 patients (78.1%) were assigned standard risk, 84 (18.5%) high risk and 15 (3.3%) risk category undefined. Risk stratification is ongoing for 19 patients. Of the high risk lesions gain(1q) was most prevalent (35%), followed by t(4;14)(10.6%), del(17p)(8.7%), del(1p32)(8.7%), t(14;16)(3.8%) and t(14;20)(0.8%). In 376/453 patients (83.0%), risk was assigned from a first BM sample. 77 (17.0%) patients required a second sample; the success rate of repeat samples is 71.4%, 22 (4.9%) patients were unable to be risk-stratified despite 2 samples. Figure 1 shows the success rate of first and repeat tests. The overall median turnaround time (from D1 cycle 1 until site notified of result) was 11 days (IQR 0 to 21). Sites were sent risk status prior to cycle 1 in 99 (21.9%) patients , 285 (62.9%) prior to cycle 2 and 341 (75.3%) cycle 3. Note this is calculated where treatment data is available. Conclusion. The RADAR study demonstrates that risk-stratified treatment approaches are feasible in the context of a national phase II/III clinical trial with the use of local laboratories for risk assignment. The vast majority of patients have been successfully allocated to a risk-adapted treatment pathway following a first FISH test (83.0%). Protocol v4 requires time-critical risk-stratification for addition of isatuximab to induction treatment from cycle 2 in high-risk patients, and this has proven to be achievable in almost 2/3 of patients with over ¾ by the end of cycle 2. The RADAR study also enables hospitals across the UK to access CGN testing via a network model of laboratories with standardization of testing and clinically relevant turnaround times. This model is applicable internationally in both public and privately funded healthcare systems and supports the infrastructure for accessible genetic risk stratification for all newly diagnosed MM patients. Ongoing studies within the RADAR trial are evaluating novel and clinically deliverable risk stratification protocols to inform risk stratified approaches in newly diagnosed MM.

Real-World Performance of 2022 Revised World Health Organization (WHO) Criteria for Mixed Phenotype Acute Leukemia (MPAL) B/Myeloid Defined Only By Isolated MPO Expression (isoMPO)

Mixed phenotype acute leukemia (MPAL) is biologically and immunophenotypically heterogeneous, and optimal diagnostic criteria remain unclear. The two current pathologic classifications [2022 World Health Organization (WHO) 5 th Ed. and International Consensus Classification (ICC)] group MPAL by cell lineages and, when present, cytogenetic drivers. In both, myeloperoxidase (MPO) is a key determinant of myeloid lineage. However, the diagnosis of MPAL has been inconsistently applied to cases of acute leukemia expressing MPO alone to define myeloid lineage. To address this, the 2022 WHO revised prior cell lineage definitions to emphasize antigen intensity (≥50%) relative to a positive control population, attempting to standardize lineage assignment across flow cytometer settings and pathologist interpreters. Distinction between pediatric B-lymphoblastic leukemia (B-ALL) and MPAL B/Myeloid with isolated MPO is crucial for therapeutic decision-making. For example, on Children's Oncology Group (COG) regimens, patients with MPAL B/Myeloid receive an anthracycline during induction and intensified chemotherapy post-induction, whereas standard-risk B-ALL patients do not. We hypothesized that the 2022 WHO criteria applied to MPO expression in children with acute leukemia would identify leukemic subtypes (B-ALL vs. MPAL B/Myeloid with isolated MPO) with differences in clinical characteristics and/or outcome. We applied 2022 WHO criteria to flow cytometry data from a multicenter pediatric cohort of leukemias originally classified as MPAL B/Myeloid or B-ALL (Oberley AJCP 2017; Raikar Blood 2018; Oberley Leukemia 2020). Maximal antigen intensity on the leukemic population was measured in 0.5 log increments and normalized to maximal intensity of a control (neutrophil) population. MPO expression was scored as none, low (<50% intensity of mature neutrophils, the typical level in B-ALL with isolated MPO expression) or high (≥50% intensity of neutrophils, meeting 2022 WHO criteria for myeloid lineage assignment). Since the current study focused on MPAL B/Myeloid cases with isolated MPO expression, cases of MPAL T/Myeloid and of MPAL B/Myeloid with myeloid lineage assignment based on monocytic markers were excluded. Clinicopathologic data were compared with MPO expression scores by univariate and multivariate analyses. Primary endpoint was categorical difference in presenting features. Secondary endpoints were end of induction minimal residual disease (EOI MRD) ≥0.01%, event-free survival (EFS) and overall survival (OS). All analyses were two-sided; p<0.05 was the threshold for statistical significance. Among all patients at diagnosis (n=176), median age was 6.14 years (range 0.3-21), 68% were <10 years old, 59% were male, 63% were Hispanic, 76% had initial white blood cell (WBC) count <50K/µL, and 81% were CNS1. MPO was absent, low (<50%) or high (≥50%) in 48%, 29% and 23% of the cohort, respectively. Prevalence of favorable cytogenetics ( ETV6:: RUNX1 or double trisomy) was inversely proportional to MPO intensity [no MPO (50%), low MPO (27%), high MPO (17%); p<0.001). MPO expression (low or high) was more prevalent in patients >10 years of age (p<0.001). There was no difference in MPO by presenting WBC count (p=0.40). Among patients treated with ALL induction with known EOI MRD results (n=166), MPO intensity was not significantly associated with EOI MRD positivity, EFS or OS (multivariate p>0.40 for all three endpoints after accounting for presenting features and initial therapy). Our study demonstrates that 2022 WHO criteria for interpreting MPO intensity can be consistently applied to flow cytometry data from a variety of laboratories. Based on our analysis, only 44% of previous MPAL B/Myeloid cases with isolated MPO were now classified as MPAL. However, the clinical significance of this distinction remains unclear. After accounting for differences in presenting features, MPO expression was not additionally predictive of MRD positivity, EFS or OS. Further investigation is required to support the proposed threshold of 50% MPO intensity of a neutrophil control population as clinically relevant to assign myeloid lineage. Prospective standardized application of 2022 WHO cell lineage assignment criteria across centers will facilitate detailed understanding of the biological underpinnings and optimal therapeutic strategies for this heterogeneous disease.

Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone (DIPD) As Salvage Therapy in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with RRMM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with RRMM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report results from a phase 2 multicenter trial of the addition of Ixazomib to DPd (DIPd) in patients with early RRMM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR) and safety of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or Ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB for subsequent patients. An amendment allowed for subcutaneous (SC) Daratumumab administration and all active patients transitioned to or started with SC dosing for ongoing therapy. MRD assessments were performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: The study has completed the planned enrollment of 46 patients. The median age is 61.6 years (range 41-87), with 47% female, 72% White, 17% Asian, and 5% Black patients. Patients had a median of 1 prior line of therapy (range 1-3), and 56% (23/41) of patients had at least one high-risk cytogenetic abnormality including del 17p, +1q, t(14;16), t(14;20), or t(4;14). Grade 3-4 treatment emergent adverse events (AE) include neutropenia (72%), infection (19%), febrile neutropenia (8%), lymphopenia (8%), electrolyte disturbance (6%), leukopenia (3%), thrombocytopenia (3%), respiratory condition (3%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). ORR to date is 83% (38/46) in evaluable patients, and best responses include 12 (26%) sCR, 12 (26%) VGPR, and 14 (30%) PR. The median duration of response (DOR) is 21.1 months for all patients, with 11 patients currently remaining on DIPd therapy, and 9 deaths all unrelated to study treatment (5 progressive disease [PD], 2 sepsis, 1 COVID, 1 unrelated surgical complication). Of the 35 patients off therapy, 20 patients had PD, 6 patients had AEs, 5 patients stopped per physician discretion or withdrew consent, and 4 patients received an autologous stem cell transplant. After a median follow up of 15 months, the median PFS is 16.6mo (95% CI: 8.19-NR ) for all patients, 16.6mo (6.9-NR) for standard risk patients, and 22.3mo (7.6-NR) for high risk patients (p=0.9). The median OS for all patients is 30.3mo (95 CI: 30.3-NR). Data will be updated for the conference to include MRD negativity rates and completed data analysis of the primary endpoint. Conclusion: The quadruplet regimen DIPd shows that the addition of a 4 th agent results in high overall response rates and early PFS rates, with manageable toxicity, and the convenience of a nearly all-oral drug regimen in patients with early RRMM. These data are particularly compelling for high-risk disease as more than half of the patients treated had at least one high-risk cytogenetic abnormality, offering a promising option for the management of early relapse in high-risk patients.

Outcomes for Children with High Risk Acute Myeloid Leukemia on the Myechild 01 International Phase III Clinical Trial

Background: Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups. Methods: The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m 2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Patients classified as HR after course 1 received FLA-Ida for course 2 followed by allogeneic HSCT. If required, a third course of bridging therapy (FLA) was given prior to HSCT. HR patients in MyeChild 01 included those with NUP98 fusions, selected KMT2A fusions ( KMT2A::MLLT10, KMT2A::MLLT4, KMT2A::AFF1, KMT2A::ABI1), CBFA2T3::GLIS2, DEK::NUP214, MECOM ( EVI1) rearrangements and all 12p abnormalities including MNX1::ETV6, in addition to the traditional HR abnormalities -7, -5/del(5q) and FLT3-ITD (without concurrent good risk abnormalities, including NPM1 mutations). Patients with induction failure after course 1 (≥ 5% blasts confirmed by flow) and those with non-HR cytogenetics/molecular genetics who remained MRD positive after course 2 (intermediate risk cytogenetics) or 3 (good risk cytogenetics) were also classified as HR. Here, we report the estimated 2-year outcomes for patients assigned HR post course 1 who received mitoxantrone and cytarabine and at least 1 dose of GO during course 1 (MA-GO). Outcomes of trial randomisations (1 vs 2 or 3 GO doses; consolidation for standard risk patients; HSCT conditioning) will be reported separately. Results: Of 749 patients enrolled at initial diagnosis, 183 received MA-GO during course 1 and were assigned HR post course 1. Of these, 172 (94%) patients had poor risk cytogenetic/molecular genetics, of which 32 also failed to achieve CR. Additionally, 11 (6%) patients did not have poor risk cytogenetic/molecular genetics but failed to achieve CR with MA-GO and thus were assigned to the HR group. Post course 1, 140 (77%) of these HR patients achieved CR/CRi, with 102/155 (66%) patients with evaluable samples achieving MRD negativity post course 1. Following course 1, 174 (95%) remained on trial and received FLA-Ida as course 2 and 163 patients (89%) proceeded to HSCT, 55 on trial and 108 following discontinuation from the trial. Estimated event-free survival (EFS) and overall survival (OS) at 2 years was 62% (95% CI: 56-70%) and 71% (64-78%) respectively (Figure 1 & 2). Estimated cumulative incidence of relapse (CIR) and death in remission at 2 years was 26% (19-33%) and 7% (3-11%) respectively. For HR patients who received MA-GO in course 1, on trial FLA-Ida as course 2 and on or off trial HSCT (n = 156), 2 year estimated outcomes were EFS 69% (62-77%), OS 77% (70-85%) and CIR 24% (17-32%). The most common cytogenetic/molecular genetic abnormalities were rearrangements of KMT2A (50/183, 27%), with KMT2A::MLLT10 predominating (70%). FLT3-ITD (19%), NUP98 fusions (14%), -7 (13%), abn(12p) (11%), del(5q) (8%) and CBFA2T3::GLIS2 (6%) accounted for the majority of other abnormalities with outcomes varying by subtype. Collectively, KMT2A-rearranged patients had EFS and OS of 68% (55-83%) and 71% (59-86%) respectively and CIR of 26% (12-40%). For FLT3-ITD, the EFS and OS was 75% (62-92%) and 83% (69-99%) respectively with a CIR of 14% (1-26%). Of the 25 patients with a NUP98 fusion, 17 (68%) were NUP98::NSD1. The EFS and OS for patients with NUP98 fusions was 71% (55-92%) and 96% (88-100%) respectively with CIR 25% (1-48%). Conclusions: Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Prognostic significance of molecular subgroups in survival outcome for children with medulloblastoma in Malaysia.

Advancements in genomic profiling led to the discovery of four major molecular subgroups in medulloblastoma (MB), which have now been incorporated into the World Health Organization classification of central nervous system tumors. The current study aimed to determine the prognostic significance of the MB molecular subgroups among children in Malaysia. We assembled MB samples from children <18 years between January 2003 and June 2017 from four pediatric oncology centers in Malaysia. MB was sub-grouped using 850k DNA methylation testing at German Cancer Research Centre, Heidelberg, Germany. Fifty samples from patients diagnosed and treated as MB were identified. Two (4%) of the 50 patients' tumor DNA samples were insufficient for analysis. Of the remaining 48 patients, 41 (85%) samples were confirmed as MB, while for 7 (15%) patients, DNA methylation classification results were discrepant with the histopathological diagnosis of MB, with various other diagnoses. Of the 41 MB patients, 15 patients were stratified as standard-risk (SR), 16 patients as high-risk (HR), and ten as infants (age <3 years old). Molecular subgrouping of the whole cohort revealed four (14%) WNT, 11 (27%) SHH, 10 (24%) Group 3, and 16 (39%) Group 4. Treatment abandonment rates for older children and infants were 22.5% and 10%, respectively. After censoring treatment abandonment, for SR patients, the 5-year event-free survival (EFS) and overall survival (OS) were 43.1% ± 14.7% and 46.9 ± 15.6%, respectively, while in HR, 5-year EFS and OS were both 63.6% ± 14.5%. Infants had a 5-year EFS and OS of 55.6% ± 16.6% and 66.7% ± 15.7%, respectively. WNT tumors had the best 5y-OS, followed by Group 3, Group 4, and SHH in children ≥3 years old. In younger children, SHH MB patients showed favorable outcomes. The study highlights the importance of DNA methylation profiling for diagnostic accuracy. Most infants had SHH MB, and their EFS and OS were comparable to those reported in high-income countries. Due to the relatively small cohort and the high treatment abandonment rate, definite conclusions cannot be made regarding the prognostic significance of molecular subgroups of MB. Implementing this high-technology investigation would assist pathologists in improving the diagnosis and provide molecular subgrouping of MB, permitting subgroup-specific therapies.

Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment.

Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.

Adoption and Diffusion of Transcarotid Artery Revascularization in Contemporary Practice.

In 2015, the FDA approved transcarotid artery revascularization (TCAR) as an alternative to carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF-CAS) for high-risk patients with carotid stenosis. This was granted in the absence of level 1 evidence to support TCAR. We aimed to document trends in TCAR utilization, its diffusion over time, and the clinical phenotypes of patients undergoing TCAR, CEA, and TF-CAS. We used the Vascular Quality Initiative to study patients who underwent TCAR. We calculated the number of TCARs performed and the percent of TCAR utilization versus CEA/TF-CAS. Using data from before TCAR was widespread, we calculated propensity scores for patients to receive CEA. We applied this model to patients undergoing carotid revascularization from 2016 to 2022 and grouped patients by the procedure they ultimately underwent, examining overlap in score distribution to measure patient similarity. We measured the trend of in-hospital stroke/death after TCAR. We studied 31 447 patients who underwent TCAR from January 1, 2016 to March 31, 2022. The number of centers performing TCAR increased from 29 to 606. In 2021, TCAR represented 22.5% of carotid revascularizations at centers offering all 3 procedures. The percentage of patients that underwent TCAR who met approved high-risk criteria decreased from 88.5% to 80.9% (P<0.001). Those with a prior ipsilateral carotid procedure decreased from 20.6% in 2016 to 12.0% in 2021 (P<0.001). Patients undergoing TCAR after stroke increased from 19.7% to 30.7% (P<0.001). Propensity-score overlap was 55.4% for TCAR/CEA, and 58.6% for TCAR/TF-CAS, demonstrating that TCAR patients have a clinical phenotype mixed between those who undergo CEA and TF-CAS. The average in-hospital stroke/death risk after TCAR was 2.3% in 2016 and 1.7% in 2022 (P trend: 0.954). TCAR now represents nearly 1-in-4 procedures at centers offering it. TCAR was increasingly performed among standard-risk patients and as a first-line procedural option after stroke. The absence of level 1 evidence underscores the importance of high-quality registry-based analyses to document TCAR's real-world outcomes and durability.

Risk-Adapted Treatment Strategies with Pre-Irradiation Chemotherapy in Pediatric Medulloblastoma: Outcomes from the Polish Pediatric Neuro-Oncology Group.

Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone for childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyzed treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-Oncology Group were included in the analysis. The median age at diagnosis was 8.0 years, and median follow-up time was 6.4 years. Sixty-seven patients were classified as standard-risk and eighty-six as high-risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (±standard error) were 87 ± 4.3% and 84 ± 4.6%, respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5%, respectively. Only one patient had disease progression prior to radiotherapy. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where the initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.

Management Practices for Standard-Risk and High-Risk Patients With Bronchiolitis.

Management guidelines for bronchiolitis advocate for supportive care and exclude those with high-risk conditions. We aim to describe and compare the management of standard-risk and high-risk patients with bronchiolitis. This retrospective study examined patients <2 years of age admitted to the general pediatric ward with an International Classification of Diseases, 10th Revision discharge diagnosis code of bronchiolitis or viral syndrome with evidence of lower respiratory tract involvement. Patients were defined as either standard- or high-risk on the basis of previously published criteria. The frequencies of diagnostic and therapeutic interventions were compared. We included 265 patients in this study (122 standard-risk [46.0%], 143 high-risk [54.0%]). Increased bronchodilator use was observed in the standard-risk group (any albuterol dosing, standard-risk 65.6%, high-risk 44.1%, P = .003). Increased steroid use was observed in the standard-risk group (any steroid dosing, standard-risk 19.7%, high-risk 14.7%, P = .018). Multiple logistic regression revealed >3 doses of albuterol, hypertonic saline, and chest physiotherapy use to be associated with rapid response team activation (odds ratio [OR] >3 doses albuterol: 8.36 [95% confidence interval (CI): 1.99-35.10], P = .048; OR >3 doses hypertonic saline: 13.94 [95% CI: 4.32-44.92], P = .001); OR percussion and postural drainage: 5.06 [95% CI: 1.88-13.63], P = .017). A varied approach to the management of bronchiolitis in both standard-risk and high-risk children occurred institutionally. Bronchodilators and steroids continue to be used frequently despite practice recommendations and regardless of risk status. More research is needed on management strategies in patients at high-risk for severe disease.

Bortezomib, lenalidomide and dexamethasone (VRd) vs carfilzomib, lenalidomide and dexamethasone (KRd) as induction therapy in newly diagnosed multiple myeloma

Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48–64%) for VRd and 67% (60–75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27–42%) for VRd and 52% (45–60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75–87%) and 90% (85–95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60–78%) for VRd and 75% (65–85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81–94%) and 93% (87–99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8–61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24–51%) and 69% (58–82%) for VRd and 58% (47–71%) and 88% (80–97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.

Propensity-Score Matched Analysis of Three Years Survival of Trans Carotid Artery Revascularization Versus Carotid Endarterectomy in the Vascular Quality Initiative Medicare-Linked Database.

Carotid endarterectomy (CEA) remains the gold standard procedure for carotid revascularization. Transfemoral carotid artery stenting (TFCAS) was introduced as a minimally invasive alternative procedure in patients who are at high risk for surgery. However, TFCAS was associated with an increased risk of stroke and death compared to CEA. Transcarotid artery revascularization (TCAR) has outperformed TFCAS in several prior studies and has shown similar perioperative and 1-year outcomes compared with CEA. We aimed to compare the 1-year and 3-year outcomes of TCAR versus CEA in the Vascular Quality Initiative (VQI)-Medicare-Linked [Vascular Implant Surveillance and Interventional Outcomes Network (VISION)] database. The VISION database was queried for all patients undergoing CEA and TCAR between September 2016 to December 2019. The primary outcome was 1-year and 3-year survival. One-to-one propensity-score matching (PSM) without replacement was used to produce 2 well-matched cohorts. Kaplan-Meier estimates, and Cox regression was used for analyses. Exploratory analyses compared stroke rates using claims-based algorithms for comparison. A total of 43,714 patients underwent CEA and 8089 patients underwent TCAR during the study period. Patients in the TCAR cohort were older and were more likely to have severe comorbidities. PSM produced two well-matched cohorts of 7351 pairs of TCAR and CEA. In the matched cohorts, there were no differences in 1-year death [hazard ratio (HR)=1.13; 95% CI, 0.99-1.30; P =0.065]. At 3-years, TCAR was associated with slight increased risk of death (HR=1.16; 95% CI, 1.04-1.30; P =0.008). When stratifying by initial symptomatic presentation, the increased 3-year death associated with TCAR persisted only in symptomatic patients (HR=1.33; 95% CI, 1.08-1.63; P =0.008). Exploratory analyses of postoperative stroke rates using administrative sources suggested that validated measures of claims-based stroke ascertainment are necessary. In this large multi-institutional PSM analysis with robust Medicare-linked follow-up for survival analysis, the rate of death at 1 year was similar in TCAR and CEA regardless of symptomatic status. The slight increase in the risk of 3-year death in symptomatic patients undergoing TCAR is likely confounded by more severe comorbidities despite matching. A randomized controlled trial comparing TCAR to CEA is necessary to further determine the role of TCAR in standard-risk patients requiring carotid revascularization.