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Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with two-year overall survival (OS) rates of 66-70% reported in prospective clinical trials. Induction therapy with high-dose methotrexate (HD-MTX) followed by consolidation has become the mainstay of treatment, however, there are few contemporary and robust prognostication indices widely available for clinical use. Some of the most used indices were developed prior to the routine use of rituximab and include the International Extranodal Lymphoma Study Group (IELSG; 1980-1999), Memorial Sloan-Kettering Cancer Center (MSKCC; 1983-2003), Nottingham/Barcelona (NB; 1986-2001), and Taipei Score (TS; 2003-2015). Herein, we describe a contemporary comparison of clinical prognostication indices using a single-center cohort of PCNSL patients treated at the Mayo Clinic. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified and retrospectively reviewed. Patients with prior or concurrent systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from diagnosis to relapse, progression, or death due to any cause; and OS defined as time from diagnosis to death due to any cause. PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. The association between baseline characteristics and survival outcome were assessed in univariate Cox regression models. Any characteristics showing significant (p-value <0.05) association with outcome were combined using a multivariate Cox regression model. All characteristics that maintained significant association with outcome were combined into a new prognostic model. We compared the performance of each prognostic index model using Harrell's C (HC). Results: A total of 148 patients were identified (50.7% female) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32.4%) age >70 (Table 1). Most had multifocal disease (60.1%) and deep brain involvement (67.6%) at diagnosis with elevated CSF protein (58.1%) but no documented CSF involvement (93.9%). In total, 117 patients (79.1%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (20.9%) received methotrexate and rituximab (MR) induction therapy with various consolidation strategies. The median follow-up for all patients was 4.5 years and the two-year OS was 79% (95% CI: 73-86%). This cohort was stratified using previously published prognostication indices (Table 1). Upon analysis, PFS was not accurately predicted using the IELSG (score 4-5: HR 0.7 (CI 0.3-2.0); HC 0.6), MSKCC (3: 1.3 (0.4-4.0); 0.5), NB (3: 0.9 (0.4-2.5); 0.6), or TS (3: 0.9 (0.1-7.2); 0.5) prognostication indices. Furthermore, OS was not accurately predicted using the IELSG (4-5: 1.5 (0.6-4.0); 0.6), MSKCC (3: 1.2 (0.5-3.2); 0.6), NB (3: 1.2 (0.5-3.2); 0.6), or TS (3: 1.3 (0.2-9.8); 0.6) prognostication indices. Upon multivariate analysis, no variables listed in Table 1 were associated with PFS within this cohort. The two variables predicting a worsened OS were an ECOG performance status of 2 or more (1.9 (1.01-3.6)) and an MR induction regimen instead of MRT (2.1 (1.05-4.3)) (Figure 1). The two-year OS with no risk factors was 86.1% (95% CI: 78.8-94.1%), one risk factor was 75.7% (95% CI: 63.6-90.1%), and two risk factors was 61% (95% CI: 43-86%) (Figure 1). Conclusions: This study reports overall improved outcomes in patients with PCNSL compared to prior prospective and retrospective cohorts, likely in part due to treatment advances and supportive care strategies. This single-center, retrospective cohort of rituximab-exposed patients with PCNSL were not well prognosticated using previously published indices, indicating that further study and more sophisticated approaches to prognostication are warranted. Although multivariate analysis did not demonstrate any variables associated with PFS, it did demonstrate an inferior OS with a performance score of 2 or more and in patients treated with MR rather than MRT.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with historically poor outcomes. Induction therapy with high-dose methotrexate (HD-MTX)-based regimens followed by consolidation with autologous stem cell transplant (auto-SCT) has become the mainstay of treatment with overall response rates (ORR) of 69-87% and two-year overall survival (OS) of 66-70% reported in prospective clinical trials. Limited data are available regarding a maintenance approach with single-agent HD-MTX, particularly in patients who are not auto-SCT candidates. Herein, we describe a comparison of outcomes in patients with PCNSL who underwent HD-MTX-based induction followed by either HD-MTX maintenance or auto-SCT consolidation at Mayo Clinic, Rochester. Methods: Patients with a diagnosis of PCNSL who received HD-MTX as part of induction therapy at Mayo Clinic between October 2010 and June 2022 were identified. Patients with prior or concurrent diagnosis of systemic lymphoma were excluded. Primary endpoints were progression-free survival (PFS) defined as time from post-induction treatment initiation to relapse, progression, or death due to any cause; and OS defined as time from post-induction treatment initiation to death due to any cause. We compared baseline characteristics by post-induction therapy using descriptive statistics. The primary endpoints PFS and OS were evaluated using Kaplan-Meier curves and compared by risk scores using a log-rank test. Results: A total of 148 patients were identified (51% female, 95% white) with median age at diagnosis of 66 years (range 29-85), with 48 patients (32%) age > 70. Most patients had multifocal disease (n=89, 60%) and deep brain involvement (n=100, 70%) at diagnosis. Few had vitreoretinal (n=15, 10%) or CSF involvement (n=9, 6%) at diagnosis. Using the Memorial Sloan Kettering (MSKCC) prognostic score for PCNSL, 35 patients (26%) scored class 3 (poor prognosis), 85 (62%) scored class 2, and 17 (12%) scored class 1. In total, 117 patients (79%) received methotrexate, rituximab, and temozolomide (MRT) induction therapy, and the remaining 31 patients (21%) received methotrexate and rituximab (MR) induction therapy (Table 1). A total of 70 patients (47%) underwent consolidation with auto-SCT and 37 patients (25%) received maintenance methotrexate. The patients who received maintenance methotrexate had higher median age of 72 versus 62 years, higher proportion of patients older than 70 (54% versus 16%, p<0.001), higher proportion of MSKCC prognostic score class 3 patients (33% versus 17%, p=0.026), and trend towards higher proportion of patients ECOG 2 or higher (41% versus 29%, p=0.109). A higher proportion of patients who underwent auto-SCT received MRT (vs MR) induction (n=64, 91%) compared to those who received maintenance methotrexate (n=24, 65%, p=0.004) (Table 1). The median follow-up for all patients was 4.5 years. At 1-, 3-, and 5-years post-induction treatment initiation, the PFS in the auto-SCT cohort was 85.8% (95% CI 77.7-94.9), 81.0% (95% CI 72.0-91.0), and 74.6% (95% CI 63.3-87.9), respectively; and the PFS in the HD-MTX maintenance cohort was 88.6% (95% CI 78.7-99.8), 72.6% (95% CI 58.8-89.8), and 72.6% (95% CI 58.8-89.8), respectively. At the same time points, the OS in the auto-SCT cohort was 94.0% (95% CI 88.4-99.9), 81.3% (95% CI 71.8-92.0), and 76.0% (95% CI 65.0-89.0), respectively; and the OS in the HD-MTX maintenance cohort was 94.3% (95% CI 86.9-100.0), 87.5% (76.8-99.8%), and 82.4% (69.0-98.4), respectively. Overall, there was no significant difference in PFS (p=0.64) or OS (p=0.95) based on post-induction treatment (Figure 1). Conclusions: Our study demonstrates comparable outcomes in PCNSL between a post-induction treatment approach with maintenance HD-MTX and consolidation auto-SCT, even though baseline characteristics indicate that patients who went on to receive auto-SCT were younger and had overall better performance status. This suggests that maintenance HD-MTX is a reasonable, time-limited strategy for patients with PCNSL responding to initial induction therapy, particularly in patients who are not candidates for auto-SCT.

Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 63.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 5-year OS and PFS (progression-free survival) estimates of 42.6% (95% CI, 32.8-51.9) and 31.8% (95% CI, 22.9-41.1), respectively (Neelapu, Blood 2023). We previously reported outcomes of axi-cel patients treated with standard of care therapy, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 58 months, as well as late outcomes of interest. Results The US Lymphoma CAR-T Consortium is comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel (n=298) as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After a median follow-up of 58 months, median OS was 34.9 months (95% CI 23.4 - 44.8) with the OS at 3, 4, and 5 years of 49.1% (95% CI 42.9 - 54.9%), 43% (95% CI 36.8 - 48.9%), and 40.3% (95% CI 34.2 - 46.4%), respectively. The median PFS was 8.7 months (95% CI 5.87 - 16.6) and the 3-,4-, and 5- year PFS were 36.1% (95% CI 30.4 - 41.8%), 30.7 (95% CI 25.2 - 36.4%), and 28.5% (95% CI 23 - 34.2%), respectively. Results of multi-variable modeling were similar to our prior analysis: male sex (HR 1.56, 95% CI 1.08 - 2.27, p =0.02); LDH above the upper limit of normal (HR 1.6, 95% CI 1.12 - 2.30, p = 0.01); ECOG status of 2-4 (HR 2.02, 95% CI 1.33 - 3.07, p = <0.001); and elevated bilirubin > 1.5 (HR 5.68, 95% CI 2.21 - 14.6, p = <0.001) were associated with decreased OS. Factors associated with decreased PFS included male sex (HR 1.68, 95% CI 1.20 - 2.37, p = 0.003), LDH above the upper limit of normal (HR 1.82, 95% CI 1.31 - 2.53, p = <0.001), ECOG status of 2-4 (HR 1.93, 95% CI 1.30 - 2.86, p = 0.001), elevated bilirubin (HR 3.68, 95% CI 1.45 - 9.37, p = 0.006) and receipt of 3 or more prior lines of therapy (HR 1.49, 95% CI 1.03 - 2.13, p = 0.032). We also assessed events of interest including late PFS events and causes of non-relapse mortality (NRM). One hundred and ninety-one PFS events occurred after axi-cel infusion during the follow-up period, 151 due to lymphoma progression and 40 NRM. In the first 12 months post infusion, 131 progression events occurred,13 between 1 and 2 years post infusion, and 7 relapses after 2 years with the latest occurring 46.4 months after infusion. Thirteen NRM events occurred in the 1st year post infusion, 6 between 1- and 2-years post infusion and 21 occurring later than 2 years after infusion. Of the 40 NRM events, 21 were secondary to infection including fungal infections (n = 3, 2 candidemia, 1 candidemia and pneumocystis jiroveci pneumonia), JC encephalitis (n=1) and COVID-19 (n = 2). Nine deaths were attributed to secondary malignancy. Other causes of NRM included cerebral edema (n=1), HLH (n=1), intracranial hemorrhage (n=1), suicide (n=1), and unknown (n=6). The 5-year cumulative risk of relapse was 55.2% and the 5-year risk of non-relapse mortality was 16.2%. Excluding non-melanoma skin cancers, twenty-three of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=11), AML (n=2), CMML (n=1)); other malignancies included anal squamous cell carcinoma (ca) (n=1); histiocytic sarcoma (n=1); prostate ca (n=1); endometrial ca (n=1); lung ca (n=1); merkel cell ca (n = 1), mesothelioma (n=1), B-ALL (n = 1), and AITL (n=1). Conclusion This multi-center retrospective study showed similar 5-year results to the ZUMA-1 trial with a 5-year PFS and OS of 28.5% and 40.3%, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Non-relapse mortality was primarily due to infection and secondary malignancy. This report supports the curative potential of axi-cel but highlights the competing risk of NRM in this high-risk patient population.

Background Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Background In unfit patients (pts) with newly diagnosed (ND) AML, long-term survival remains short (mOS 14.7 months) despite improved responses (CR 37% and CR/CRi 66%) with azacitidine (AZA) and venetoclax (VEN) (VIALE-A, DiNardo NEJM 2020). In a pooled analysis of AZA-VEN in ND AML pts with poor risk cytogenetics the response rates were higher in TP53wt pts (CR/CRi 70%) compared with TP53mut pts (CR/CRi 41%) (Pollyea Clin Cancer Res 2022). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). Pivekimab sunirine (PVEK, IMGN632) is a first-in-class antibody-drug conjugate (ADC) comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The novel IGN payload alkylates DNA and causes single strand breaks without crosslinking (Kovtun Blood Adv 2018). Methods This is an ongoing, open-label, multicenter, Phase 1b/2 study of PVEK in combination with AZA +VEN in adults with ND CD123-positive AML (any CD123+ expression by local flow cytometry or IHC). Pts received the recommended phase 2 dose of PVEK 0.045 mg/kg IV on D7 + AZA 75 mg/m 2 SC or IV daily on D1-7 + VEN up to 400 mg PO daily for 14 to 28 days (based on cohort assignment) in a 28-day cycle. Bone marrow assessment was performed at D14 (cohort 1) or D21 (cohort 2) of cycle 1 to determine VEN duration. The primary endpoints are composite CR rate (CCR [CR+CRh+CRp+CRi]), MRD rate (assessed centrally [Hematologics, Inc.] by flow cytometry; <0.1% defined as negative) and duration of remission. Key secondary endpoints are safety, pharmacokinetics and immunogenicity. Responses were determined using ELN 2017 criteria (with the addition of CRh) and a 14-day post-marrow count recovery window. Results As of July 17, 2023, data is available for 50 ND pts (n=25 per cohort) treated with PVEK+AZA+VEN and are aggregately reported here. The median age was 74 years (range, 46-83), 42% were ≥ 75 years old, 26% had secondary AML, 64% were ELN 2017 adverse risk, and 38% had a TP53mut. The most common non-hematologic treatment-emergent adverse events (TEAE) (all grades [grade 3+]) seen in > 20% of all pts were febrile neutropenia (44% [38%]), constipation (42% [2%]), peripheral edema (36% [4%]), diarrhea (36% [2%]), hypophosphatemia (32% [0%], nausea (28% [4%]), and hypokalemia (24% [2%]). No veno-occlusive disease (VOD) events were reported. In responders, the median time to achieve absolute neutrophil count ≥500/µL and platelet count ≥50,000/µL was 35.5 days (range, 20-55) and 22 days (range, 20-55), respectively. The median post-remission cycle delay (beyond cycle day 28) was 14 days. Two pts discontinued PVEK due to a TEAE (edema; marrow aplasia). The 60-day mortality was 4%. In the ITT population (N=50) the CR rate was 52% (26/50), and the CCR rate was 66% (33/50). In pts ≥ 75 years old, the CCR rate was 76% (16/21). In pts known to be TP53wt, both the CR and CCR rate was 88% (22/25). Additional response subsets in Table 1. Twenty-one pts received 9-14 days of VEN, 9 pts received 15-21 days of VEN and 20 pts received ≥ 22 days of VEN in cycle 1; of those who received ≤ 14 days of VEN the CR rate was 71% (15/21) and the CCR rate was 76% (16/21). Of the 26 pts who achieved CCR and had an MRD-evaluable sample, 73% (19/26) achieved MRD negativity (CCR MRD-, <0.1% residual blasts); notably all had undetectable MRD levels (lower level of detection is 0.02%). MRD-negativity was achieved rapidly with a median of 1.7 months (range, 0.8-4.5). CCR MRD- rates were high across major molecular subsets, including FLT3 (ITD/TKD) at 100% (7/7), IDH1/2 at 89% (8/9), and NPM1 at 89% (8/9), as well as ELN risk groups (intermediate 80% [8/10]; adverse 64% [9/14]). Conclusion With a manageable safety profile in pts with ND AML, the PVEK+AZA+VEN triplet demonstrated anti-leukemia activity with robust CR rates and early MRD negative responses in a cohort enriched for adverse disease characteristics (64% ELN adverse risk; 38% TP53mut). Encouraging CCR MRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

Introduction: Our group previously published that the infusion autograft inhibitor KIR2DL2 (CD158b+CD337-) and activating NKp30 (CD158b- CD337+) Natural killer (NK) cells receptors were predictors of clinical outcomes in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) (Porrata et al. Leukemia Research 2019; 81: 1-9). To assess if these subsets of NK cells still hold clinical relevance, we set up to investigate their prognostic ability to predict clinical outcomes at Day 100 post-APBHSCT. Methods: 107 lymphoma patients who participated in our double-blind phase III trail (Porrata et al, Biology of Blood and Marrow Transplantation 2016; 22(6); 1017-1023) and had clinical assessment at Day 100 post-APBHSCT were included in this study. Nkp30 and KIR2DL2 at Day 100 were assessed by flow cytometry analysis. Results: With a median follow-up for the entire cohort from Day 100 was 94.7 months (range: 4.83-158.1 months). Figure 1 shows the overall survival (OS) and progression-free survival (PFS) based on the absolute numbers of KIR2DL2 and Nkp30 NK cells. At Day 100, patients with a KIR2DL2 < 0.08 and Nkp30 ≥0.19 experienced superior OS and PFS compared with patients with a Day 100 KIR2DLD2 ≥0.08 and NKp30 < 0.19. In the multivariate analysis both the KIR2DL2 [OS: HR = 1.767, 95%CI, 1.302-30.31, p < 0.04; and PFS: HR = 2.663, 95%CI, 1.108-6.403, p < 0.03] and Nkp30 [OS: HR = 2.594, 95% CI, 1.239-5.432, p < 0.01; and PFS: HR = 3.676, 95% CI, 1.875-7.206, p < 0.01] were independent predictors for OS and PFS. Conclusion: Day 100 inhibitory KIR2DL2 and activating NKp30 NK cells are prognostic immune-biomarkers in lymphoma patients undergoing APBHSCT.

Background Pancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival (OS). We hypothesized that adding programmed cell death protein 1 (PD-1) blockade to chemoradiotherapy would be well tolerated and increase TILs among patients with localized PDAC. Methods Patients were randomized 2:1 to Arm A (receiving pembrolizumab plus chemoradiotherapy (capecitabine and external beam radiation)) or Arm B (receiving chemoradiotherapy alone) before anticipated pancreatectomy. Primary endpoints were (1) incidence and severity of adverse events during neoadjuvant therapy and (2) density of TILs in resected tumor specimens. TIL density was assessed using multiplexed immunofluorescence histologic examination. Results Thirty-seven patients were randomized to Arms A (n=24) and B (n=13). Grade ≥3 adverse events related to neoadjuvant treatment were experienced by 9 (38%) and 4 (31%) patients in Arms A and B, respectively, with one patient experiencing dose-limiting toxicity in Arm A. Seventeen (71%) and 7 (54%) patients in Arms A and B, respectively, underwent pancreatectomy. Median CD8+ T-cell densities in Arms A and B were 67.4 (IQR: 39.2–141.8) and 37.9 (IQR: 22.9–173.4) cells/mm2, respectively. Arms showed no noticeable differences in density of CD8+Ki67+, CD4+, or CD4+FOXP3+ regulatory T cells; M1-like and M2-like macrophages; or granulocytes. Median OS durations were 27.8 (95% CI: 17.1 to NR) and 24.3 (95% CI: 12.6 to NR) months for Arms A and B, respectively. Conclusions Adding pembrolizumab to neoadjuvant chemoradiotherapy was safe. However, no convincing effect on CD8+ TILs was observed.

AbstractBackgroundPatients in the intensive care unit (ICU) often experience extended periods of immobility. Following hospital discharge, many face impaired mobility and never return to their baseline function. Although the benefits of physical and occupational rehabilitation are well established in non‐ICU patients, a paucity of work describes effective practices to alleviate ICU‐related declines in mobility.ObjectiveTo assess how rehabilitation with physical and occupational therapy (PT‐OT) during ICU stays affects patients' mobility, self‐care, and length of hospital stay.DesignRetrospective cohort study.SettingInpatient ICU.ParticipantsA total of 6628 adult patients who received physical rehabilitation across multiple sites (Arizona, Florida, Minnesota, and Wisconsin) of a single institution between January 2018 and December 2021.InterventionsNot applicable.Main Outcome MeasuresDescriptive statistics, linear regression models, and gradient boosting machine methods were used to determine the relationship between the amount of PT‐OT received and outcomes of hospital length of stay (LOS), Activity Measure for Post‐Acute Care Daily Activity and Basic Mobility scores.ResultsThe 6628 patients who met inclusion criteria received an average (median) of 23 (range: 1‐89) minutes of PT‐OT per day. Regression analyses showed each additional 10 minutes of PT‐OT per day was associated with a 1.0% (95% confidence interval [CI]: 0.41–1.66, p < .001) higher final Basic Mobility score, a 1.8% (95% CI: 1.30%–2.34%, p < .001) higher final Daily Activity score, and a 1.2‐day (95% CI: −1.28 to −1.09, p < .001) lower hospital LOS. One‐dimensional partial dependence plots revealed an exponential decrease in predicted LOS as minutes of PT‐OT received increased.ConclusionHigher rehabilitation minutes provided to patients in the ICU may reduce the LOS and improve patients' functional outcomes at discharge. The benefits of rehabilitation increased with increasing amounts of time of therapy received.

Abstract Background: Precursor plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) always precede the development of active malignancies such as multiple myeloma (MM). There is a need for novel biomarkers to identify those patients with such precursor plasma cell disorders who rapidly progress to MM. Plasma-derived extracellular vesicles (EVs) may serve as a reservoir of potential biomarkers that can shed light on the pathogenesis and disease biology in MM. Methods: This study isolated small EVs (SEVs) and large EVs (LEVs) from the platelet-poor peripheral blood plasma of MGUS (n=9) and MM (n=12) patients using the size exclusion chromatography (SEC)-based method and evaluated their proteome using a label-free proteomics workflow. Results: In total, 2,055 proteins were identified in SEVs, while 2,794 proteins were identified in LEVs. The transferrin receptor (TFRC or CD71) protein was upregulated in both populations of EVs derived from MM patients compared to MGUS patients and was of prognostic significance. Similarly, three isoforms of serum amyloid A (SAA) protein, SAA1, SAA2, and SAA4, were also highly upregulated in SEVs within MM patients relative to MGUS patients. Finally, CD40 expression was also higher within the LEVs derived from MM patients than MGUS patients. Conclusions: This study demonstrates the feasibility of successfully isolating both SEVs and LEVs from the peripheral blood of patients with plasma cell disorders and quantifying protein biomarkers within these EVs that could be of prognostic and diagnostic interest.