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Minnesota acute graft versus host disease (AGVHD) risk score is a validated tool to stratify newly-diagnosed patients into standard-risk (SR) and high-risk (HR) groups with ~85% having SR AGVHD. We aimed to identify factors for further risk-stratification within Minnesota SR patients. A single-center, retrospective analysis of consecutive patients between 1/2010 and 12/2014 was performed. Patients who developed AGVHD within 100 days and treated with systemic corticosteroids were included (N= 416), 356 (86%) of which were Minnesota SR and 60 (14%) had HR AGVHD. Isolated upper gastrointestinal (GI) AGVHD patients had significantly better day 28 and 56 CR/PR rates (90% vs. 72%, p= 0.004) and (83% vs 66%, p= 0.01), respectively, and lower 1-year non-relapse mortality (NRM; 10% vs. 22%; HR 0.4, p= 0.03). Lower GI AGVHD had less favorable outcomes with 1-year NRM of 40% (HR 2.1, p= 0.001), although CR/PR rates were not statistically different. In multivariate analysis, lower GI involvement (HR 2.6, p< 0.001), age ≥ 50 (HR 2.9, p< 0.001) and HCT-CI > 3 (HR 2.1, p= 0.002) predicted for 1-year NRM. Heterogeneity within Minnesota SR patients requires consideration in clinical trials, as distinct outcomes are observed in those with isolated upper GI and lower GI AGVHD, highlighting the importance of stratification in clinical trial design.

•Haploidentical-HCT, especially with younger donors, may offer comparable outcomes to MSD-PTCy HCT.•In older patients, younger haploidentical B-leader–matched donors HCT had superior OS than older MSDs.

Task allocation is a crucial process in modern systems, but it is often challenged by incomplete information about the utilities of participating agents. In this article, we propose a new profit maximization mechanism for the task allocation problem, where the task publisher seeks an optimal incentive function to maximize its own profit and simultaneously ensure the truthful announcing of the agent's private information (type) and its participation in the task, while an autonomous agent aims at maximizing its own utility function by deciding on its participation level and announced type. Our mechanism stands out from the classical contract theory-based truthful mechanisms as it empowers agents to make their own decisions about their level of involvement, making it more practical for many real-world task allocation scenarios. It has been proven that by considering a linear form of incentive function consisting of two decision functions for the task publisher the mechanism's goals are met. The proposed mechanism is initially modeled as a nonconvex functional optimization with the double continuum of constraints, nevertheless, we demonstrate that by deriving an equivalent form of the incentive constraints, it can be reformulated as a tractable convex optimal control problem. Further, we propose a numerical algorithm to obtain the solution.

IMPORTANCE: Persistence of FLT3 internal tandem duplication (ITD) in adults with acute myeloid leukemia (AML) in first complete remission (CR) prior to allogeneic hematopoietic cell transplant (HCT) is associated with increased relapse and death after transplant, but the association between the level of measurable residual disease (MRD) detected and clinical outcome is unknown. OBJECTIVE: To examine the association between pre–allogeneic HCT MRD level with relapse and death posttransplant in adults with AML in first CR. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, DNA sequencing was performed on first CR blood from patients with FLT3-ITD AML transplanted from March 2013 to February 2019. Clinical follow-up was through May 2022. Data were analyzed from October 2022 to December 2023. EXPOSURE: Centralized DNA sequencing for FLT3-ITD in pre–allogeneic HCT first CR blood using a commercially available kit. MAIN OUTCOMES AND MEASURES: The primary outcomes were overall survival and cumulative incidence of relapse, with non–relapse-associated mortality as a competing risk post–allogeneic HCT. Kaplan-Meier estimations (log-rank tests), Cox proportional hazards models, and Fine-Gray models were used to estimate the end points. RESULTS: Of 537 included patients with FLT3-ITD AML from the Pre-MEASURE study, 296 (55.1%) were female, and the median (IQR) age was 55.6 (42.9-64.1) years. Using the variant allele fraction (VAF) threshold of 0.01% or greater for MRD positivity, the results closely aligned with those previously reported. With no VAF threshold applied (VAF greater than 0%), 263 FLT3-ITD variants (median [range] VAF, 0.005% [0.0002%-44%]), and 177 patients (33.0%) with positive findings were identified. Multivariable analyses showed that residual FLT3-ITD was the variable most associated with relapse and overall survival, with a dose-dependent correlation. Patients receiving reduced-intensity conditioning without melphalan or nonmyeloablative conditioning had increased risk of relapse and death at any given level of MRD compared with those receiving reduced-intensity conditioning with melphalan or myeloablative conditioning. CONCLUSIONS AND RELEVANCE: This study provides generalizable and clinically applicable evidence that the detection of residual FLT3-ITD in the blood of adults in first CR from AML prior to allogeneic HCT is associated with an increased risk of relapse and death, particularly for those with a VAF of 0.01% or greater. While transplant conditioning intensification, an intervention not available to all, may help mitigate some of this risk, alternative approaches will be necessary for this high-risk population of patients who are underserved by the current standard of care.

•Retrospective study of NDMM patient outcomes following auto-SCT from 1988-2021.•Average age and comorbidity burden of transplanted patients increased over time.•Outcomes improved following auto-SCT in NDMM patients over the last three decades, including those with high-risk disease.•Median PFS improved from 22.3 months between 1988-2000 to 58.6 months in 2016-2021.•Median OS improved from 55.1 months between 1988-2000 to not reached in 2016-2021.

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n= 53, 36%) and negative pre-transplant (overall survival (OS): p= 0.4; relapse: p= 0.5). For patients with IDH1mutated AML co-mutated with NPM1and/or FLT3-ITD, only detection of persistent mutated NPM1and/or FLT3-ITD was associated with significantly higher rates of relapse (p= 0.01). These data, from the largest study to date, do not support the detection of IDH1mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.

Routine genetic profiling of acute myeloid leukemia (AML) at initial diagnosis has allowed subgroup specific prognostication, drug development, and clinical management strategies. The optimal approach for treatment response assessment for AML subgroups has not yet however been determined. A nationwide cohort of 257 adult patients in first remission (CR1) from AML associated with an IDH2mutation (IDH2m) undergoing allogeneic transplant during the period 2013–2019 in the United States had rates of relapse and survival three years after transplantation of 24% and 71%, respectively. Pre-transplant clinical flow cytometry assessment was not useful in stratifying patients based on risk of post-transplant relapse or death. DNA-sequencing was performed on CR1 blood collected within 100 days before transplant. Persistent detection of IDH2mwas common (51%) and associated with increased relapse and death compared to testing negative. Co-mutation at initial diagnosis with mutated NPM1and/or FLT3-ITD was common in this cohort (41%) and use of these validated MRD markers provided superior stratification compared to IDH2mtesting. Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2min pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.

Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, p= 0.03) and 2-year DOR (93.6% versus 69.2%, p= 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, p= 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS.

Due to the increasing popularity of Electric Vehicles (EVs) and infrastructural limitations, it is vital to manage traffic and Charging Stations (CSs) crowdedness. In Bakhshayesh and Kebriaei (2022), the problem of choosing the route and CSs of EVs is modeled as a non-cooperative game of selfish EVs with probabilistic decision strategies. In this paper, we have proposed a linear pricing policy that ensures global efficiency of the obtained Nash strategies of EVs in Bakhshayesh and Kebriaei (2022) for the Smart City Coordinator (SCC). We model the problem as a hierarchical game with a SCC as the leader and EVs as the followers. The leader aims to design optimal price functions of CSs and Traffic Coordinator (TC) and impose them on the EVs to maximize the social profits of CSs and TC. In response, the followers play a non-cooperative game with coupling constraints to optimally decide on their route and charging destination. Thus, we have a Stackelberg Game (SG) between SCC and EVs and also a Nash game among the EVs in the lower level. Compared to the conventional Nash-based pricing policies, our proposed functional SG formulation enables the possibility of simultaneous and global-optimum management of traffic and CSs’ crowdedness. Moreover, we have proposed a two-level decentralized algorithm that preserves the privacy of EVs and have considered a decentralized computation for equilibrium seeking of followers based on the Alternating Direction Method of Multipliers (ADMM) method. Finally, we carry out simulation studies on the transportation network of Sioux Falls City to compare and evaluate the proposed method.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339.

•Age of >60 years and remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS.•Use of myeloablative conditioning with total body irradiation was predictive for improved DFS and reduced risk of relapse.

•We analyzed all patients with relapsed/refractory (R/R) primary mediastinal large B cell lymphoma (PMBCL) treated with high-dose chemotherapy (HDC)/autologous stem cell transplantation (ASCT) at our center.•The study cohort comprised 60 patients, of whom 37 received R-BEAM and 23 received R-vorinostat/GemBuMel.•The 5-year progression-free survival and overall survival were 51% and 65%, respectively, with R-BEAM and 69% and 82%, respectively, with R-vorinostat/GemBuMel.•A negative positron emission tomography scan at ASCT and receipt of R-vorinostat/GemBuMel were independent favorable predictors.•HDC (particularly with R-vorinostat/GemBuMel) is effective in R/R PMBCL; outcomes are favorable even with late relapse after multiple lines of salvage therapy.

•Myeloablative fractionated busulfan regimen results in low nonrelapse mortality without a higher relapse rate.•This regimen is a viable myeloablative alternative for patients who receive a reduced intensity regimen because of age or comorbidity.

•Younger matched unrelated donors (MUDs; age ≤35 years) are associated with a significantly lower risk of relapse (hazard ratio, .68; P = .002) compared to older matched sibling donors (MSDs; age ≥50 years).•Younger MUDs are associated with a greater risk of chronic graft-versus-host disease (GVHD) and increased nonrelapse mortality (NRM) compared to older MSDs.•Greater NRM likely abrogates the survival advantage driven by the reduced relapse risk with younger MUDs, and combining the use of younger MUDs with improved strategies to reduce GVHD merits further exploration to improve outcomes.

This article presents the equilibrium analysis of a game composed of heterogeneous electric vehicles (EVs) and a power distribution system operator (DSO) as the players, and charging station operators (CSOs) and a transportation network operator (TNO) as coordinators. Each EV tries to pick a charging station as its destination and a route to get there at the same time. However, the traffic and electrical load congestion on the roads and charging stations lead to the interdependencies between the optimal decisions of EVs. CSOs and the TNO need to apply some tolling to control such congestion. On the other hand, the pricing at charging stations depends on real-time distributional locational marginal pricing, which is determined by the DSO after solving the optimal power flow over the power distribution network. This article also takes into account the local and the coupling/infrastructure constraints of EVs, along with transportation and distribution networks. This problem is modeled as a generalized aggregative game, and then a decentralized learning method is proposed to obtain an equilibrium point of the game, which is known as variational generalized Wardrop equilibrium. The existence of such an equilibrium point and the convergence of the proposed algorithm to it are proven. We undertake numerical studies on the Savannah city model and the IEEE 33-bus distribution network and investigate the impact of various characteristics on demand and prices.

•Allogeneic hematopoietic cell transplantation (alloHCT) with younger matched unrelated donors (MUDs) (age ≤35 years) is associated with a significantly decreased relapse risk (hazard ratio, .86; P = .005) and a significantly lower adjusted 5-year cumulative incidence of relapse (35% versus 41%; P = .003) compared to allo-HCT with older matched sibling donors (MSDs) (age ≥50 years).•Compared to older MSDs, younger MUDs are associated with greater nonrelapse mortality (NRM) in earlier years (2011 to 2015) but significantly lower NRM in more recent years (2016 to 2018).•The adjusted 5-year probability of disease-free survival is higher with younger MUDs compared to older MSDs.•Combining the use of younger MUDs with improved strategies to reduce graft-versus-host disease is merits further exploration to improve outcomes.

There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior to the infusion of afami-cel, she received concurrent lymphodepleting chemotherapy and LDRT at 5.6 Gy/4 fractions to the liver. Time to partial response was 10 weeks, and duration of overall response was 18.4 weeks. Although the patient progressed at 28 weeks, the disease was well controlled after high-dose radiotherapy to liver metastases and checkpoint inhibitors. As of the last follow-up, she remains alive over two years after LDRT and afami-cel therapy. This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently been added to the armamentarium in the battle against B-cell acute lymphoblastic leukemia (B-ALL). In this review, we discuss the trials that led to US Food and Drug Administration approval of CAR T-cell therapies in patients with B-ALL. We evaluate the evolving role of allogeneic hematopoietic stem cell transplant in the CAR T-cell era and discuss lessons learned from the first steps with CAR T-cell therapy in ALL. Upcoming innovations in CAR technology, including combined and alternative targets and off-the-shelf allogeneic CAR T-cell strategies are presented. Finally, we envision the role that CAR T cells could take in the management of adult patients with B-ALL in the near future.

•Younger haploidentical donor (PTCy prophylaxis) HCT was associated with improved OS compared with older MUD (conventional prophylaxis) HCT in ALL.•Younger haploidentical donors had a lower risk of chronic GVHD and NRM, but a higher relapse than older MUD.

•Outcomes of patients with t(4;14) multiple myeloma remain poor despite novel agent induction, autologous hematopoietic stem cell transplantation (auto-HCT) and post-transplantation maintenance.•Achieving minimal residual disease-negative very good partial response or better prior to auto-HCT was associated with improved progression-free survival and overall survival (OS).•Post-transplantation lenalidomide-based combination maintenance was associated with improved OS.

•B-leader mismatch was associated with significantly higher nonrelapse mortality (NRM) and a trend towards poor overall survival (OS) in parent and sibling haploidentical donor groups.•HLA-A mismatch was associated with a lower risk of acute graft-versus-host disease (haploidentical sibling) and lower NRM and better progression-free survival and OS (parent donors).•Among non-HLA donor factors, female donors did not have an adverse effect on any outcome.

We investigate the problem of distributed resource allocation in unicast communication networks with strategic/selfish users. First, through mechanism design, the centralized problem is converted to a decentralized problem that induces a network aggregative game among users. At every Nash equilibrium, this mechanism strongly implements the solution of the resource allocation problem, and it is budget balance as well. Then, we establish a relationship between Nash equilibria of the induced game and the solutions of the corresponding variational inequality problem. Next, a distributed algorithm is proposed, and finally, its converges to the Nash equilibrium of the induced game is proved under certain assumptions. Since each link can be shared among a different set of users, there is a specific connectivity graph among the users of each link. Hence, a user simultaneously utilizes multiple connectivity graphs to interact with different sets of neighbors on different links.

Introduction: Daptomycin (DAP) has proven to be a viable alternative amid vancomycin resistance; however, the use of DAP post vancomycin treatment has led to the development of DAP non-susceptible (DNS) strains. Dalbavancin (DAL), a novel single-dosed lipoglycopeptide, has shown enhanced activity against highly resistant Staphylococcus aureusstrains. However, on the basis of previous reports and our observations, DAL does not demonstrate similar activity at high versus low inoculum levels. Therefore, we hypothesized that addition of DAP even at minimal concentrations (single dose on day 1) will lower the inoculum to the level that can be cleared by dalbavancin. Methods: Isolates from methicillin-resistantS. aureus(MRSA)-infected patients with varying susceptibility profiles were evaluated using broth microdilution methods. Two DNS–VISA strains (vancomycin intermediate resistant S. aureus) and one MRSA strain were further evaluated in a one-compartment PK/PD model using a high starting initial inoculum of 109CFU/mL as well as low initial inoculum of 107CFU/mL over 168 h to assess the activity of DAL and DAP monotherapy and in combination. Results: Single therapies were not bactericidal when evaluated in the 168 h in vitro one-compartment model with an initial inoculum of 109; however, the combination of DAL plus single dose of DAP resulted in enhanced killing at the end of the 168-h exposure. DAL single therapy caused reduction in colony counts down to detection limit (2 log10CFU/ml) at a lower inoculum but did not show enhancement (&lt; 2 log10CFU/ml) at higher initial inoculums (P&lt; 0.01) for all three strains. Similarly, DAP caused initial bacterial reduction up to 4 log10CFU/ml with regrowth at about 32 h of exposure, which stayed at initial inoculum levels for the duration of the model for all three strains. Conclusions: Dalbavancin inoculum effect is a major issue in bacterial infections with high bacterial loads and the combination of DAL plus single dose of DAP showed promise in eradicating resistant S. aureusstrains at high inoculums.

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N= 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

With the rapid development of the 5G network and the promising of 6G network, vehicles can report a large amount of real-time traffic information to Road-Side Units (RSUs). However, due to the large communication cost, limited computing resources, and privacy leakage risks, centralized data processing by RSUs is not efficient and not secure. Thereby, federated learning is introduced to enable vehicles to train local models and send the model parameters to the RSUs, without the need for revealing their personal data. Nevertheless, without an efficient incentive mechanism, the vehicles, as data owners, may be unwilling to join the federated learning task. In this paper, we adopt contract theory to design an incentive mechanism with asymmetric information and continuum of types for interaction between the RSU and vehicles. The designed mechanism satisfies the incentive compatibility, individual rationality and also maximizes the RSU's profit. The technical challenge is to solve a non-quadratic functional optimization in continuous space with coupling constraints among the vehicles. To address this challenge, we propose two iterative algorithms to find the RSU's optimal strategies as the functions of vehicles' types. In the first algorithm, a combination of the calculus of variation and dual decomposition methods is utilized to achieve an analytical solution for the optimal strategy of RSU, while in the second one, a combination of approximate dynamic programming and neural networks is used to estimate the optimal strategy of RSU.

Historically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes, and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy, including TKIs, and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (allo-HCT: 98; non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (adjusted hazard ratio [aHR]: 1.05; 95% CI, 0.63-1.73) or relapse-free survival (aHR: 0.86; 95% CI, 0.54-1.37) compared with non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR: 0.32; 95% CI, 0.17-0.62) but higher non-relapse mortality (aHR: 2.59; 95% CI, 1.37-4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.

The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01–2.75 × 109/L) and was significantly higher in patients who achieved complete response (p= 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p= 0.007). Low DLIx was independently associated with shorter progression-free (p= 0.02) and overall survival (p= 0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISPand CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

•This was a retrospective analysis of 231 patients with a high-risk chromosomal abnormality (HRMM) receiving lenalidomide (Len)-based post-transplantation maintenance.•Maintenance with Len-based combinations did not improve outcomes in the entire cohort.•In patients with HRMM other than 1q+, there was a trend toward improved PFS with Len-based combinations for maintenance.

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•Outcomes of allogeneic hematopoietic stem cell transplantation with vorinostat/busulfan (Bu)/fludarabine (Flu)/clofarabine (Clo) conditioning were assessed.•Vorinostat does not increase toxicity of a Bu/Flu/Clo conditioning regimen.•Vorinostat does not increase the benefit of a Bu/Flu/Clo conditioning regimen.

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent “MRD negativity” by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10−4 and NGS at a sensitivity of 1 × 10−6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P = .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival.

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent “MRD negativity” by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10−4and NGS at a sensitivity of 1 × 10−6was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P= .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival.

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60–64; 65–69; 70+). With median follow-up of nearly 3 years, patients aged 60–64 had modestly, though significantly better OS, DFS and lower TRM than those either 65–69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p= 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p= 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.

About 70% of patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel) and who achieve a partial response (PR) or stable disease (SD) on the day 30 (D30) positron emission tomography (PET)–computed tomography (CT) scan progress; however, the factors that are predictive of progression are unknown. This a retrospective study of patients with LBCL who were treated with axi-cel at MD Anderson Cancer Center between January of 2018 and February of 2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to a complete response (CR). Among 95 patients with a D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day −5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (P = .05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was a lower maximum standardized uptake volume (SUVmax; P < .001); all patients with D30 SUVmax ≥ 10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed between patients who converted from D30 PR/SD to subsequent CR and those who had been in CR since D30 (P = .19). Novel predictive and prognostic markers based on tissue biopsy and noninvasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.

About 70% of patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel) and who achieve a partial response (PR) or stable disease (SD) on the day 30 (D30) positron emission tomography (PET)–computed tomography (CT) scan progress; however, the factors that are predictive of progression are unknown. This a retrospective study of patients with LBCL who were treated with axi-cel at MD Anderson Cancer Center between January of 2018 and February of 2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to a complete response (CR). Among 95 patients with a D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day −5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (P= .05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was a lower maximum standardized uptake volume (SUVmax; P< .001); all patients with D30 SUVmax≥ 10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed between patients who converted from D30 PR/SD to subsequent CR and those who had been in CR since D30 (P= .19). Novel predictive and prognostic markers based on tissue biopsy and noninvasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab’s efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P= .01; HR, 1.71; P< .001, respectively). Leukemia-free survival was similar for patients with KMT2Arearrangement or adverse risk (HR, 1.26; P= .002, and HR, 1.47; P< .001), as was overall survival (HR, 1.32; P< .001, and HR, 1.45; P< .001). No differences in outcome were detected when patients were stratified by KMT2Afusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P= .02), grade 3 to 4 aGVHD (HR, 1.59; P= .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P= .01) and increased NRM (HR, 2.13; P≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P= .003), and cGVHD (HR, 1.72; P≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P< .001), worse early LFS (HR, 1.40; P= .007) and increased incidences of NRM (HR, 2.08; P< .001) and grade 3 to 4 aGVHD (HR, 1.97; P< .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.