bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of intramuscular (IM) recombinant Erwinia asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study.
Authors: Maese Luke Devon , Loh Mignon L. , Choi L. Mi Rim , Lin Tong , Aoki Etsuko , Zanette Michelle , Agarwal Shirali , Silverman Jeffrey Alan , Silverman Lewis B. , Raetz Elizabeth A. , Rau Rachel E. 
Published: June 2022

7001 Background: The inability to receive L-asparaginase (ASNase) therapy due to hypersensitivity is associated with inferior outcomes in patients with ALL or LBL. JZP458, a recombinant Erwinia-derived ASNase from a Pseudomonas fluorescens expression platform, is approved by the FDA for patients with ALL/LBL who have developed hypersensitivity to E. coli–derived ASNase. Here, we report the efficacy and safety of IM JZP458 from COG AALL1931, a phase 2/3, open-label, multicenter, pharmacokinetic (PK) study. Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli–derived ASNase. Each remaining dose of pegylated E. coli–derived ASNase was replaced with 6 doses of IM JZP458 on Monday/Wednesday/Friday (M/W/F) over 2-weeks. Three dosing cohorts were enrolled: Cohort 1a, 25 mg/m2 M/W/F; Cohort 1b, 37.5 mg/m2 M/W/F; Cohort 1c, 25 mg/m2 M/W and 50 mg/m2 F. Efficacy was assessed by the proportion of patients who achieved the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) nadir serum asparaginase activity (NSAA) levels ≥0.1 IU/mL in the first treatment course. A population PK (PPK) model was developed based on SAA data from AALL1931 to characterize the PK of JZP458 and to inform dosing decisions. Results: 167 patients were enrolled for IM dosing (Cohort 1a, n = 33; Cohort 1b, n = 83; Cohort 1c, n = 51). The median (range) age was 10 (1, 25) years. The median (range) of JZP458 courses received was 5 (1, 14) for Cohort 1a, 5 (1, 15) for Cohort 1b, and 4 (1, 11) for Cohort 1c. Mean (95% CI) SAA levels (IU/mL) at 72-hour were 0.16 (0.12, 0.19) for Cohort 1a, 0.33 (0.27, 0.39) for Cohort 1b, and 0.47 (0.35, 0.59) for Cohort 1c; and 0.45 (0.37, 0.53), 0.88 (0.76, 1.01), and 0.66 (0.54, 0.77), respectively, at 48-hour. Simulated data from the PPK model matched the observed data well. For Cohort 1c, the proportions of patients (95% CI) achieving NSAA levels ≥0.1 IU/mL at the last 72- and 48-hour in Course 1 were 90% (81%, 98%) and 96% (90%, 100%), respectively, based on observed data; and were 92% (91%, 93%) and 94% (93%, 95%) based on modeled data. The Table shows the rates of treatment-related adverse events (TRAEs; all grades) of interest per cohort. Overall, TRAEs leading to discontinuation included pancreatitis (6%), drug hypersensitivity (4%), anaphylactic reaction (2%), increased alanine aminotransferase (1%), and hyperammonemia (1%). There were no TRAEs leading to death. Conclusions: The totality of the results from AALL1931 demonstrate the positive benefit-risk profile of the IM JZP458 dosing regimen of 25 mg/m2 M/W and 50 mg/m2 F with a safety profile consistent with other asparaginases. Clinical trial information: NCT04145531. [Table: see text]
Risk-adjusted safety analysis of pacritinib (PAC) in patients (pts) with myelofibrosis (MF).
Authors: Pemmaraju Naveen , Scott Bart L. , Savona Michael R. , Oh Stephen T. , Harrison Claire , Vannucchi Alessandro M. , Palandri Francesca , Al-Ali Haifa Kathrin , Sobas Marta , McMullin Mary Frances , Gupta Vikas , Mesa Ruben A. , Buckley Sarah , Roman-Torres Karisse , Verstovsek Srdan , Yacoub Abdulraheem 
Published: June 2022

7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts <50×109/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (by SMQ), major cardiac events (per major adverse cardiovascular events [MACE] classification), infections, thromboses, and secondary malignancies. Results: A total of 160 pts were analyzed as the pooled PAC group (n=106 in PERSIST-2; n=54 in PAC203) and 98 pts in the BAT group (44 on RUX). At baseline, median plt count was 57×109/L; 61% had prior JAK2 inhibitor therapy. The rate of AEs was higher on PAC versus BAT, while the rate of fatal AEs was lower (Table). Both bleeding and cardiac events occurred at slightly lower rates on PAC compared to BAT. There were no MACE events on PAC, whereas there were on BAT. Malignant neoplasms occurred at similar rates on PAC and BAT, though rate of non-melanoma skin cancers was lower in pooled PAC (3/100 pt-yrs) versus BAT (7/100 pt-yrs), including RUX (11/100 pt-yrs). Infection occurred more frequently on PAC, though fungal and viral infections occurred less frequently, as did herpes zoster reactivation (pooled PAC: 0/100 pt-yrs vs BAT: 2.4/100 pt-yrs, including RUX: 5.5/100 pt-yrs). Thrombosis occurred at similar rates on PAC and BAT. Conclusions: Risk-adjusted analysis demonstrates that the safety profile of PAC 200 mg BID is comparable or superior to BAT, including RUX. PAC 200 mg BID may represent a full-dose therapeutic option for pts with MF, including those with thrombocytopenia. Clinical trial information: NCT02055781; NCT04884191. [Table: see text]
Subcutaneous epcoritamab with rituximab + lenalidomide (R2) in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Update from phase 1/2 trial.
Authors: Falchi Lorenzo , Leppä Sirpa , Wahlin Bjorn E. , Nijland Marcel , Christensen Jacob Haaber , De Vos Sven , Holte Harald , Linton Kim M. , Abbas Aqeel , Wang Liwei , Dinh Minh , Elliott Brian , Belada David 
Published: June 2022

7524 Background: R/R FL is associated with poor prognosis and less frequent, shorter responses with each line of treatment (Tx). Although R2 is an effective regimen in R/R FL with an acceptable safety profile, FL remains incurable; thus, better Tx options are needed. Subcutaneous epcoritamab is a bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial, single-agent epcoritamab (0.76–48 mg) resulted in an overall response rate of 90% and a complete response rate of 50% in R/R FL. The distinct mechanisms of action of epcoritamab and R2 may combine to increase antitumor response, with generally non-overlapping toxicity profiles. We present updated data for epcoritamab with R2 in R/R FL (EPCORE NHL-2 arm 2; NCT04663347). Methods: Adults with R/R CD20+ FL received epcoritamab + R2 for 12 cycles (C) of 28 d; epcoritamab was administered at 24 or 48 mg in dose escalation and 48 mg in expansion. During C1, step-up epcoritamab dosing and corticosteroids were required to mitigate CRS. Response was assessed by PET-CT. The epcoritamab regimen for these pts was: Q1W, C1–3; Q2W, C4–9; Q4W, C≥10 up to 2 y. Results: As of December 1, 2021, 30 pts (median age, 68 y) had received epcoritamab + R2 (24 mg, n=3; 48 mg, n=27), 21 pts (70%) had stage IV disease, and 20 pts (67%) had FLIPI scores 3–5. Median (range) number of prior lines of therapy was 1 (1–5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line Tx (20% within 24 mo after starting immunochemotherapy). At a median (range) follow-up of 5.1 mo (0.8–12.3), 25 pts (83%) remained on Tx; 5 pts discontinued Tx due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common Tx-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS was seen in 15 pts (50%; G1/2 43%, G3 7%), with most events in C1. All CRS events resolved with standard management, including tocilizumab in 3 pts, and 1 pt discontinued Tx due to CRS. One pt experienced G2 ICANS. No fatal TEAEs occurred. Antitumor activity is shown in the Table. As of the data cut, all responders remained in response, with the longest duration of response being 7.0+ mo and ongoing. Conclusions: Subcutaneous epcoritamab+ R2 exhibits promising efficacy, including a high CMR rate, in pts with R/R FL. The safety profile was consistent with prior data, and CRS events were generally low grade and in C1. Updated data with an additional 30 pts will be presented. Clinical trial information: NCT04663347. [Table: see text]
Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04.
Authors: Touzeau Cyrille , Perrot Aurore , Hulin Cyrille , Manier Salomon , Macro Margaret , Caillot Denis , Karlin Lionel , Decaux Olivier , Jacquet Caroline , Tiab Mourad , Leleu Xavier , Planche Lucie , Avet-Loiseau Herve , Moreau Philippe 
Published: June 2022

8002 Background: High-risk (HR) cytogenetic is associated with poor outcome in transplant eligible (TE) newly diagnosed myeloma multiple myeloma (NDMM). The triplet combination carfilzomib lenalidomide and dexamethasone (KRD) plus transplantation demonstrated high efficacy with favorable safety profile in TE-NDMM patients (FORTE). The addition of daratumumab (Dara) to frontline therapy also improved response rate and progression free-survival in TE-NDMM patients (CASSIOPEIA, GRIFFIN). Double transplant also improved outcome of HR TE NDMM patients (EMN02, STAMINA). The phase 2 trial 2018-04 from the Intergroupe Francophone du Myelome (IFM) is evaluating an intensive strategy with Dara-KRD induction and consolidation plus double transplant in HR TE NDMM (NCT03606577). Methods: HR MM was defined by the presence of del17p, t(4;14) and/or t(14;16). Stategy includes Dara-KRD induction (6 cycles), autologous stem cell transplantation (ASCT), Dara-KRD consolidation (4 cycles), second ASCT, Dara-lenalidomide maintenance. The primary endpoint was the feasibility of this intensive strategy. Here, we report efficacy and safety analysis of Dara-KRD induction. Results: Fifty patients with previously untreated NDMM were included from july 2019 to march 2021 in 11 IFM centers Median age was 57 (range 38 -65). ISS stage 3 was present in 12 (24%) patients. Based on inclusion criteria, all patients had HR cytogenetic, including 17p deletion (n = 20, 40%), t(4;14) (n = 26, 52%) or t(14;16) (n = 10,20%). Forty-six patients completed Dara-KRD induction. Two patients discontinued treatment due to severe adverse event (COVID-19 infection, n = 1 ; drug-induced hepatitis, n = 1) and 2 patients discontinued treatment due to disease progression. Grade 3-4 treatment related adverse event ( > 5% of patients) were neutropenia (38%), anemia (14%), thrombocytopenia (8%), infection (6%), renal insufficiency (6%) and deep-vein thrombosis (6%). Two patients (6%) experienced stem-cell collection failure. Overall response rate was 96%, including 92 % > very good partial response. Among 37 (/46) evaluable patients post induction, Minimal Residual Disease negativity rate (NGS, 10-5) was 62%. Conclusions: Dara-KRD as induction prior ASCT is safe and allows deep responses in TE NDMM patients with high-risk cytogenetic profile. IFM 2018-04 study is ongoing and longer follow-up is needed to evaluate safety and efficacy of the overall strategy with Dara-KRD induction and consolidation plus double transplant in this subset of HR patients. Clinical trial information: NCT03606577.
Phase I open-label single arm study of GPRC5D CAR T-cells (OriCAR-017) in patients with relapsed/refractory multiple myeloma (POLARIS).
Authors: Huang He , Hu Yongxian , Zhang Mingming , Ding Xiaomin , Tang Yu , He Xiaowen , Chen Siye , Yang Yue 
Published: June 2022

8004 Background: GPRC5D, a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cells from MM patients. The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the 2nd generation CAR-T cell with improvement in expansion and durability. Methods: The primary objective of this study was to evaluate safety and tolerability of OriCAR-017. Key enrolment criteria included measurable MM adults, R/R or intolerant to established therapies. Patient received lymphodepleting chemotherapy with fludarabine 30mg/m2/d and cyclophosphamide 300mg/m2/d for 3 days followed by a single infusion of OriCAR-017. The trial followed 3+3 design with 1×106/kg, 3×106/kg and 6×106/kg CAR+ T cells cohorts. Results: Eleven patients were enrolled and underwent apheresis during June 9, 2021 and January 31, 2022. 9pts have completed infusion and 8pts available for efficacy and safety evaluation, the 9th pt completed infusion at January 23, 2022. 2 pts were suspended infusion due to rapid disease progression. Of the 9 infused pts, median age 65 years (range41-71) and a median of 6 (range3-17) prior therapy lines; 3 (33.0%)/1 (11.0%) triple-class/penta-drug exposed; 2 (22.0%)/1 (11.0%) triple-class/penta-drug refractory; 4 (44.0%) prior BCMA CART therapy. Five out of 6pts had high-risk cytogenetic profiles including 2pts with del(17p). No dose-limiting toxicities occurred. The most common TEAEs were neutropenia (G3/4 100%), thrombocytopenia (G3/4 100%), leukopenia (G3/4 100%), lymphopenia (G3/4 100%) and anemia (G3/4 87.5%). All pts experienced CRS with 7pts in G1, 1pt in G2. All CRSs were rapidly relieved after conventional intervention(tocilizumab and steroids). The median onset time was 3 days (range0-8), median duration 6 days (range5-8). No neurologic toxicities were reported. No nail disorders were reported. 8pts avaliable for efficacy evaluation, median follow up time was 109.5 days (range32-195 days). A 100.0% ORR were observed with 3pts CR/sCR, 2pts VGPR, 3pts PR. Three out of 4pts with prior BCMA CAR-T therapy were available for efficacy evaluation-1sCR, 1VGPR, 1PR. After infusion, 8pts were MRD negative in the bone marrow by flow cytometry (10-5) at day 28, 5pts continued at month 3 and 1pt at month 6. Robust OriCAR-017 expansion in peripheral blood by using qPCR for 8pts, median peak was 507,463.6copies/ml (range152093.7 – 1121996.9), median time to peak expansion was 10 days (range7-14). Conclusions: In this phase I study, OriCAR-017 was showed safe and impressive efficacy in RRMM patients. Majority of AEs were transient and manageable. 100% ORR and 100% MRD negative rate, along with favorable safety support OriCAR-017 to be a competitive therapy for RRMM. Furthermore, patients who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017. Clinical trial information: NCT05016778.
Retrospective review of outcomes of patients with multiple myeloma with COVID-19 infection (two-center study).
Authors: Ehsan Hamid , Britt Alec , Voorhees Peter M. , Paul Barry , Bhutani Manisha , Varga Cindy , Chiad Zane , Ragon Brittany K. , Shahid Zainab , Shahoud Moussa , Abdallah Al-Ola A. , Ahmed Nausheen , Atrash Shebli 
Published: June 2022

8048 Background: Coronavirus-2 has profound effects on patients (pts) with Multiple myeloma (MM). At the beginning of the pandemic, COVID-19 infection resulted an overall mortality around 54% (cook et al. BMJ 2020). Here, we report an updated morbidity and fatality for MM. Methods: After obtaining IRB approvals from each participating institute, retrospectively, between January 1, 2021 and August 30, 2021, we identified pts with MM and COVID-19 in two myeloma centers (Levine Cancer Institute (LCI) & the University of Kansas medical center (KUMC). Results: We identified 162 MM pts who had COVID-19 (LCI n=132, UKMC n=30), including 57% males, with median age of 64 years. Current or former smoking reported in 40% of pts. Most pts have associated comorbid conditions: hypertension (45%), hypogammaglobulinemia (32%), CKD (30%), DM (22%), obesity (16.6%), CHF (14%), and CAD (13.5%). Within 3 months prior to infection, treatment included immunomodulatory combinations in 35%, proteasome inhibitors in 28 %, and Daratumumab in 26.5%. Symptoms are summarized in table. 69% had Mild symptoms (no need for hospitalization), 20 % had moderate symptoms (requiring hospitalization), and 9.8% had severe symptoms (ICU level of care). The 18% of pts required oxygen: 6 pts required invasive oxygenation and 3 pts needed vasopressors. The 32% of pts had RRMM, 29.5% on maintenance, and 12% was getting induction. Regarding MM response: >VGPR in 45% and PD in 18%. The 78 pts had ASCT prior to COVID-19 infection: only 3 pts < 1 year and 3 pts < 6 months. MM response or ASCT did not affect hospitalization or mortality.The case fatality rate (CFR) was 6%. In the univariate analysis, CKD, DM, HTN and hepatic dysfunction were associated with an increased risk of hospitalization. However, in multivariate analysis, only CKD, hepatic dysfunction, and Hypogammaglobulinemia significantly increased the risk of admission with only age and lymphopenia were associated with increased COVID-19 related fatatlity. Conclusions: With implementation of center-specific disease control measures and universal screening, pts might have lower case severity and fatality rate than was initially reported. [Table: see text]
Impact of second primary malignancy post-autologous hematopoietic stem cell transplantation on outcomes of multiple myeloma: A CIBMTR analysis.
Authors: Ragon Brittany K. , D'Souza Anita , Estrada-Merly Noel , Fraser Raphael , George Gemlyn , Gowda Lohith , Shah Nina , Qazilbash Muzaffar H. , Kumar Shaji , Horowitz Mary M. , Usmani Saad Zafar , Shah Mithun Vinod 
Published: June 2022

8057 Background: Following autologous hematopoietic stem cell transplant (auto HCT), maintenance therapies improve survival, reduce relapse risk in multiple myeloma (MM), and are the de facto standard-of-care. However, clinical trials have shown an increased risk of second primary malignancies (SPM) with maintenance therapy, including second hematological malignancies (SHM). We examined data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to evaluate the impact of SPM on progression-free (PFS) and overall survival (OS) and the utilization of allogeneic HCT in patients with therapy-related myeloid neoplasms (t-MN). Methods: Adult patients (pts) with MM who underwent first auto HCT in the United States with a melphalan conditioning regimen from 2011-2018 and subsequently received maintenance therapy were included (N=3948). The primary endpoint of interest was the impact of SPM and SHM on OS. Multivariate analytic (MVA) modelling was applied, accounting for competing risks while integrating significant covariates to determine the impact of SPM on PFS and OS. Finally, we studied the utilization and survival following allogeneic HCT for SHM. Results: Baseline characteristics were similar between the two groups. Maintenance regimens used were lenalidomide (2836, 72%), bortezomib (370,9 %) or lenalidomide + bortezomib (372, 9%) based combinations. At a median follow up of 37 months, 175 (5%) pts developed SPM, including 112 (64%) solid 36 (21%) myeloid, and 27 (15%) lymphoid cancers. In MVA, the development of SPM and SHM was associated with an inferior PFS (HR 2.62, P<0.001 and HR 5.01, P<0.001, respectively) and OS (HR 3.85, P<0.001 and 8.13, P<0.001, respectively). The two commonest causes of death were MM (42%) and SPM (30%) for those developing SPM. Similarly, MM (53%) and SHM (18%) were the two commonest causes of death for those developing SHM. Nine (14%,5 t-MDS and 4 t-AML) of 63 patients with SHM underwent an allogeneic HCT. Patients undergoing allogeneic HCT were more likely to have Karnofsky score ≥90 (100% vs. 50%, P=0.02) compared to those who did not. One year survival from allo SCT was 66.7% (CI 34.6-92%). Conclusions: The three-year cumulative incidence of SPM was 3.3 (2.6-4)% in this large contemporaneous CIBMTR cohort. Disease relapse remains the primary cause of death in MM patients who develop SPM or SHM. Given the median OS for MM is now > 10 years, longer follow-up is needed to assess the SPM and SHM risks with maintenance therapy post-auto HCT.
Clinical features of patients with multiple myeloma harboring t(4;14) and impact on long-term survival.
Authors: Joseph Nisha , Hofmeister Craig C. , Heffner Leonard T. , Gupta Vikas Anand , Kaufman Jonathan L. , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. , Boise Lawrence 
Published: June 2022

8062 Background: Translocation (4;14) is a known adverse prognostic factor in myeloma. However, utilization of proteasome inhibitors (PIs) in myeloma has abrogated the negative impact of t(4;14) in myeloma, and some investigators question whether t(4;14) still needs to be considered a high-risk marker. Here, we present a retrospective analysis of 142 patients with t(4;14) and describe disease characteristics, treatment patterns, and long-term outcomes. Methods: From January 2007 to August 2016, 42 patients with newly diagnosed myeloma and t(4;14) were identified. Demographics, clinical characteristics, and outcomes data for the patients were obtained from our institutional review board-approved myeloma database. Responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 59.6 years (range 33-78). Notable patient characteristics include: W/AA/Asian 25.9%/23.6%/50%; ISS I/II/III 36.4%/22.9%/24.1%; R-ISS I/II/III 0%/27.8%/25.8%. Median lab values at diagnosis include: Hgb 10.4 g/dL, Hct 30.8%, Cr 1.01, and Ca 9.4, Frequency of concurrent cytogenetic abnormalities include del(17p): 19.7%; del(13): 44.4%, and +1q21: 46.5%. A majority of patients (86.7%) were induced with either triplet or quadruplet regimens, with 88% of these regimens including a proteasome inhibitor. 78.9% of patients underwent ASCT. Of those responses captured, 75.3% achieved ≥VGPR (sCR 4.8%, CR 30.5%, VGPR 40%, PR 20%). Post-transplant, 88% achieved ≥VGPR (sCR 35.1%, CR 30.9%, VGPR 22.3%), and 82% received maintenance therapy. The most common maintenance regimens included revlimid (34.8%), bortezomib (16.5%), and RVD (11.3%); one-third of patients received triplet maintenance regimens. With a median follow up of 99.5 months, the overall mPFS and mOS for this cohort of t(4;14) patients was 47.6 m (95% CI 32.3-62.8) and 108.5 months (95% CI 87.9-129.2). In patients with both t(4;14) and del(17p), the mPFS was 20.8 months and mOS was 89.6 months; for concurrent t(4;14) and +1q21, the mPFS was 32.0 months and 89.6 months. In patients that received maintenance therapy versus no maintenance, the mPFS and mOS was 54.9 months (95% CI 47.4-62.4) and 115.3 months (95% CI 96.3-134.3) versus 14.7 months (95% CI 13.1-16.3) and 34.3 months (95% CI 10.1-58.5), respectively. Conclusions: Overall, the prognosis of t(4;14) myeloma patients significantly improved compared to the pre-proteasome inhibitor era. In particular, maintenance therapies (predominantly PI- based) have made a clear survival impact (doubling of mPFS to 4.5 years and mOS to 9.5 years) compared to patients that did not receive maintenance therapy. However, presence of other concomitant cytogenetic abnormalities such as +1q21 and del(17p) continues to confer poorer outcomes, and innovative approaches are needed to obtain better outcomes for this subgroup of patients.