Food insecurity (FI), defined as the lack of continuous access to adequate food, affects 17–55

IntroductionAllogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with hematologic malignancies and other diseases, but there is significant risk of treatment-related morbidity and mortality. Targeted interventions to reduce vulnerabilities before, during, and after HCT could therefore improve treatment tolerance and outcomes. Acceptance and Commitment Therapy (ACT) is an evidence-based cognitive behavioral therapy that improves human functioning and adaptability by increasing psychological flexibility. Among HCT patients, increased psychologic flexibility may help patients adapt behaviors to improve or maintain physical activity.ObjectivesIn the phase I clinical trial, ACTIVATE, we aimed to assess the preliminary efficacy of ACT at improving physical functioning and other outcomes 30 and 90 days after HCT.MethodsAt a single center, we recruited patients ≥18 years old receiving HCT to participate in up to six sessions of ACT between transplant days -30 and +90. We selected three matched controls for each study patient who received an allogeneic transplant at the same center within five years. Matching was based on disease, conditioning regimen intensity, age, and gender. All patients were evaluated in various domains of physical function, cognitive function, mental health, diet, and nutrition, which is standard of care for the transplant center. Clinical outcomes were obtained from the electronic medical record.ResultsA total of 12 patients receiving ACT underwent HCT, and 36 patients were selected as matched controls. There were no significant differences in baseline patient demographics or clinical baseline measures between the two groups, as seen in table 1. The primary outcome measured was the mean change from baseline in the 6 minute walk test (6MWT) distance at 30 and 90 days after HCT. The mean change in 6MWT at 30 days was +33 m and -45 m for the ACT and control patients, respectively (p value = 0.039). The mean change at 90 days was +18 m and -19 m for the ACT and control patients, respectively (p value = 0.352). As seen in table 2, there were no statistically significant differences between the groups in change from baseline at 30 or 90 days in clinical outcomes, patient reported quality of life, nutritional outcomes, or depression screening scores.ConclusionACT may be an effective intervention for improving physical functioning for patients undergoing HCT. This phase 1 clinical trial demonstrated a statistically significant mean change in 6MWT distance from baseline at 30 days and a non-statistically significant change at 90 days compared to matched controls. These findings support pursuing future randomized studies to better assess associations of ACT on adaptability and resilience, measured in the domains of physical functioning, quality of life, mental health, and nutrition in this patient population.

Introduction: Chimeric Antigen Receptor (CAR)- T cell therapy has revolutionized the treatment of hematologic malignancies. However, access to CAR-T therapy remains limited, especially for underserved populations. We hypothesize that disparities in age, gender, race, and insurance type affect access and progression through key stages of CAR-T therapy-referral, evaluation, and infusion of CAR- T cells. These disparities contribute to inequities in the utilization of CAR-T therapy. Method: This retrospective study analyzed data from July 2019 to June 2022, incorporating records from the North Carolina Central Cancer Registry (NCCCR) and Duke Cancer Institute. The study focused on adults aged 19-79 with lymphoma or multiple myeloma residing in 67 North Carolina counties, which are designated as Duke's primary catchment area. Cohort 1 comprised NCCCR-Eligible patients-those identified in the NCCCR dataset as eligible for CAR-T infusion. Cohort 2 included Duke Referred patients, further divided into: 2A) Referral Only-patients who were referred but did not receive an appointment; 2B)Appointment without infusion-patients who had an appointment but did not receive CAR-T therapy; and 2C) CAR-T -patients who underwent CAR-T infusion. Statistical analyses included chi-square tests, ANOVA or Wilcoxon Signed Rank tests, and logistic regression. Referrals to other centers within the DCI catchment and out-of-state counties were excluded from the study. Results: NCCCR eligible vs. Duke Referred (Cohort 1 vs 2): Comparing the NCCCR cohort with CAR-T candidates referred to Duke, Duke referrals are younger median 64 [22-79] versus 66 years [19-79] in NCCCR, p = 0.004) and with fewer Caucasian/White patients (60% DCI vs. 71% NCCCR) and more Black or African American (30% DCI vs. 24% NCCCR). Private insurance is higher at DCI (50% vs. 31% NCCCR). Both cohorts are predominantly in metropolitan areas (81% DCI vs. 78% NCCCR, p < 0.001) and Medicare was less common than in NCCCR (40%, vs. 53%, p<0.001). DCI has a higher median income ($67,000 vs. $58,646, p < 0.001) and a lower social vulnerability index (0.61 vs. 0.66, p < 0.001). Referral Only vs Appointment without Infusion (Cohort 2A vs. 2B): Analysis of the referral-only cohort versus those who attended an initial evaluation appointment for CAR-T revealed significant sociodemographic differences. African Americans were more prevalent among the referral-only group (37% vs. 30%, p = 0.004) and had lower odds of attending initial evaluation appointments (OR = 0.55, 95% CI [0.35-0.87], p = 0.010). Univariate analysis indicated that a lower proportion of the referral-only group had private insurance (44% vs. 49%, p = 0.007) and Medicare coverage (40% vs. 44%, p = 0.007). However, these differences did not persist in multivariate analysis (OR = 0.78, 95% CI [0.49-1.23], p = 0.3 for Medicare). Non-private, non-Medicare insurance showed a trend towards lower attendance at initial appointments (OR = 0.35, 95% CI [0.14-1.03], p = 0.040), but this trend was not significant, likely due to the small sample size. The median time to appointment was 20 days (range 1-253). Age, sex, RUCA classification, income, and social vulnerability index did not show significant effects (p > 0.1). Appointment without Infusion vs CAR-T (Cohort 2B vs. 2C): Comparison of patients evaluated without infusion versus CAR-T recipients revealed higher odds of proceeding to CAR-T for males (OR = 2.68, 95% CI [1.63-4.56], p < 0.001) and Black or African American patients (OR = 1.87, 95% CI [1.06-3.23], p = 0.027). The median time to CAR-T was 141 days (range 41-1,248). No significant differences were observed in age, insurance type, RUCA classification, income, or social vulnerability index. Conclusion: Barriers to CAR-T therapy access at Duke appear to vary by stage. Initially, African American race and non-private insurance are linked to lower attendance at evaluation appointments post-referral. After evaluation, female gender and African American race are associated with a lower likelihood of proceeding to CAR-T infusion, highlighting significant gender and racial disparities. Further research is needed to determine if these disparities are due to demographic, socioeconomic, or healthcare system factors. Tailored interventions and collaborations with community partners and patient navigators are crucial for addressing these disparities and ensuring equitable access to CAR-T therapy.

Background: Hematopoietic Stem Cell Transplantation (HCT) is a life-saving treatment for many patients with hematologic malignancies. Disparities persist across the transplant continuum. We hypothesize that sociodemographic factors disproportionately impact referral rates and completion of HCT. Understanding these disparities is essential for developing effective strategies to improve HCT access and mitigating healthcare inequities among patients with hematologic malignancies. This study assesses how social factors are associated with referral by primary hematologists, patient attendance at HCT evaluation, and receipt of HCT among North Carolina residents within our catchment area. Method: This retrospective study utilized data covering July 2019 to June 2022 from the North Carolina Central Cancer Registry (NCCCR) and Duke Cancer Institute (DCI) for adults aged 19-79 with HCT-eligible hematologic malignancies in 67 North Carolina counties designated as DCI's primary catchment area. Cohort 1includes NCCCR-Eligible patients (N = 8,557)-eligible for HCT in the NCCCR dataset. Cohort 2 includes Duke Referred patients (N = 761)-referred to Duke for HCT, further divided into: 2A) Referral Only (N = 124)-referred but did not receive an appointment; 2B)Appointment Only (N = 471)-had an appointment but did not undergo HCT; 2C) Transplanted (N = 166)-received HCT. Statistical analyses included chi-square, ANOVA, Wilcoxon Signed Rank tests, and logistic regression. Referrals to other centers within the DCI catchment and out-of-state counties were excluded. Result: NCCCR eligible vs. Duke Referred (Cohort 1 vs 2): Duke-referred patients were younger (median age 64 vs. 66 years, p = 0.004), had a higher percentage of African Americans (30% vs. 24%, p < 0.001), and had higher median income ($67,000 vs. $58,546, p < 0.001). They also had better access to resources (lower social vulnerability: 0.66 vs. 0.68, p < 0.001) and higher private insurance coverage (50% vs. 31%, p < 0.001). Additionally, a higher proportion of Duke-referred patients had Multiple Myeloma (48% vs. 28%, p < 0.001) and a lower proportion had Lymphoma (28% vs. 43%, p < 0.001) compared to the NCCCR cohort. Referral Only vs. Appointment Only (Cohort 2A vs 2B): Non-Caucasian/Non-African-American patients were less likely to attend their initial evaluation appointments (OR 0.35, 95% CI[0.19-0.66], p < 0.001), as were those with non-private or non-Medicare insurance (OR 0.45, 95% CI [0.22-0.96], p = 0.032). Although the Referral Only cohort had a higher proportion of African Americans (37% vs. 30%, p = 0.004) and showed a trend toward greater overall vulnerability (0.73 vs. 0.66, p = 0.045), these differences were not significant in multivariate analysis (African Americans: OR 0.66, 95% CI [0.42-1.06], p = 0.082; overall vulnerability: OR 0.02, 95%CI [0.00-1,484], p = 0.50). Other factors, including age, gender, income, and RUCA status, did not affect appointment attendance. Appointment-Only vs. Transplant Receipt (Cohort 2B vs 2C): Patients who only attended the initial appointment were older (median age 65 vs. 62 years, p = 0.002) and had a lower proportion under 65 (48% vs. 61%, p < 0.001). Multivariable analysis showed less likely receipt of transplant after appointment for patients >=70 years of age (vs. <=60, OR 0.34, 95% CI [0.18-0.62], p < 0.001). A higher proportion of those without a transplant had Medicare insurance (44% vs. 33%, p = 0.002), but this difference did not show clinical significance in multivariate analysis (OR 0.84, 95% CI [0.53-1.31], p = 0.40). However, those with non-private or Medicare insurance who attended the initial evaluation appointment had a higher likelihood of proceeding to HCT (OR 2.54, 95% CI [1.20-5.35], p = 0.014). Conclusion: Our analysis reveals barriers for non-Caucasian and non-African American patients and those with non-private or Medicare insurance, impacting access to initial HCT evaluations. While these factors hinder progression to evaluation, overcoming early barriers may improve access to HCT. To ensure equity, we must address insurance disparities, implement financial assistance programs, and tailor outreach for minoritized racial groups. These steps are crucial for achieving equitable access to HCT therapy for all patients.

e18517 Background: Myeloproliferative neoplasms (MPN) and myelodysplastic syndrome (MDS)/MPN overlap syndromes are rare hematopoietic malignancies in which allogeneic hematopoietic cell transplantation (HCT) is the only treatment with curative potential. Even for higher risk patients, the optimal timing for HCT is largely unknown. We interrogated HCT outcomes of myelofibrosis (MF) and the rest of MPN, MDS/MPN overlap based on the timing of HCT from diagnosis (Dx) to help oncologists determine the optimal timing to refer patients for HCT. Methods: This retrospective, single-center study obtained data from our HCT database. We included adult (>18 years; y) patients who received their first allogeneic HCT between 2015 and 2022 for initial Dx of MPN or MDS/MPN overlap. We included all donor types and graft sources. Analysis was separated by MF vs. others (other MPN and MDS/MPN) to account for fibrotic vs proliferative nature of disease progression and sample size. The primary variable was the time from Dx to HCT. The primary endpoint was overall survival (OS) from HCT. Secondary endpoints were progression free survival (PFS) and non-relapse mortality (NRM) from HCT. Results: 46 patients (n=27 for MF, n=19 for others) were included. 59% were male (56% for MF, 63% for others). The median age at HCT for MF was 57y (range 45-72) and for others was 63y (32-75). For patients with MF and others, 85% and 84% received myeloablative conditioning, respectively. In the MF group, all patients had PBSC grafts and 37% of grafts were from match-related donors; in the others group, 89% had PBSC grafts (11% had BM grafts) and 53% of grafts were from match-related donors. The median time from Dx to HCT for patients with MF was 28 months (m; range 4-166) and for others was 11m (2-423). In the MF group, those whose HCT <1y from Dx had improved OS (Table) and PFS (1y, 83.3% vs. 53.3%, p=0.031) compared to HCT ≥1y after Dx. However, no differences were found in OS or PFS for <6m vs. >6m from Dx to HCT. No differences in OS/PFS were seen based on the timing of HCT in the others group. Conclusions: Patients with MF, but not with other MPN or MDS/MPN, who received allogenic HCT <1y from Dx had significantly improved OS and PFS. Our results suggest that early referral to HCT after confirmation of marrow fibrosis for higher risk MF may influence HCT outcomes positively. However, lack of improvement in OS/PFS at 6m suggests that addressing individual risks and initiating appropriate therapies for MF first may more effectively balance risks of post-HCT complication with disease progression. Additional studies investigating timing of HCT will help oncologists to direct management of MPN and MDS/MPN overlap. [Table: see text]

Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of ‘terminal’ (TEX) and ‘precursor’ (TPEX) exhausted subsets, respectively, defined DLI response. A contrasting, heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, TPEXcells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Our unbiased dissection of the TME using a Bayesian method, Symphony, defined the T cell circuitry underlying effective human anti-leukemic immune responses that may be broadly relevant to other exhaustion antagonists across cancers. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of therapeutic scenarios beyond oncology.

Supplementary Figure 1 from Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells

Supplementary Tables 1-3, Figure Legend from Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells

Supplemental Table 1. Targets identified in protein microarray screening with post-vaccination sera from AML patient 12.

Key Points GVAX vaccination early after allogeneic HSCT was well tolerated but did not improve long-term disease-free survival after transplantation. This study highlights the challenges of conducting planned early posttransplant intervention trials after allogeneic HSCT.

Chronic graft-versus-host disease (cGVHD) remains a frequent cause of nonrelapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Despite recent advances, options for steroid-refractory (SR) cGVHD are limited. In previous trials of low-dose interleukin-2 (LD IL-2), the immunomodulatory properties of regulatory T cells (Tregs) have been harnessed to treat SR-cGVHD safely and effectively. In the present study, we combined a single infusion of Treg-enriched lymphocytes (Treg DLI) from the original stem cell donor with in vivo Treg expansion using LD IL-2 (1 x 10(6) IU/m2 per day for 8 weeks) in 25 adult patients with SR-cGVHD. Treg were not expanded ex vivo. Treg DLI was initiated at 0.1 x 10(6) cells per kg patient and escalated to a maximum dose of 1 x 10(6) cells per kg. Treg DLI plus LD IL-2 was well tolerated and led to partial responses (PR) in 5 of 25 patients (20%) after 8 weeks of therapy. Ten additional patients (40%) had stable disease with minor responses not meeting PR criteria. Patients at all dose levels had similar Treg expansion without significant changes in CD4(+) conventional T cells or CD8(+) T cells. High -throughput sequencing of the T-cell receptor beta locus showed selective improvement of Treg diversity. A subset of DLI-derived Treg clones showed preferential expansion at week 8 and long-term persistence 1-year postinfusion. We demonstrate for the first time that infusion of polyclonal healthy donor Tregs followed by expansion with LD IL-2 is safe in patients with SR-cGVHD, thus establishing a foundation for future adoptive Treg therapies in the posttransplant setting. This trial was registered at www.clinicaltrials.gov as #NCT01937468.

Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.

Background: Methodological advances and improvements in supportive care have increased the number of patients eligible for allogenic hematopoietic cell transplantation (HCT), yet the procedure is a highly technical process that remains available only at select centers in the United States. For this reason, many patients live at great distances from their HCT center, and the need for close and specialized follow-up in the months after the procedure can cause a substantial burden on familial finances, caregivers, and quality of life (QOL). One way of potentially ameliorating these effects is to allow some post-HCT care to be provided by non-HCT local hematologic oncologists closer to where patients live. Such a "shared care" model could reduce patient-centered burdens post-HCT; however, it is not known if, given its complexity, post-HCT care can be safely shared with local providers without compromising HCT outcomes. Methods: From December of 2017 to December of 2021, we conducted a randomized controlled trial to assess the effectiveness of a post-HCT shared care program. We enrolled patients referred to Dana-Farber Cancer Institute (DFCI) for HCT from eight local sites: Lifespan (RI); Dartmouth-Hitchcock (NH); New York Oncology Hematology (NY); Northern Light Medical Center (ME), New England Cancer Specialists (ME), and three DFCI Community Satellites (in MA and NH). Patients were approached about randomization to Shared Care vs. Usual Care when they first presented to DFCI for HCT consultation, and randomized 1:1 after HCT consent, stratified by referring site. The Shared Care model involved four care delivery strategies to allow patients to be safely seen locally after HCT: a formal online care coordination plan, patient engagement and education, local physician engagement and education (including yearly face-to-face training with DFCI transplant physicians), and a shared patient-physician-transplanter web portal and communication platform. The study design included alternating visits between the local site and DFCI through day 100 in the Shared Care arm, and visits exclusively at DFCI in the Usual Care arm. The two co-primary outcomes were non-relapse mortality at day 100 and QOL at day 180 (scores on the FACT-BMT and EORTC QLQ-C30). We also assessed overall survival (OS) and QOL at day 100. Results: At the end of the study period, 326 patients who consented for allogeneic HCT had enrolled and 2 withdrew. Of the remaining 324, 302 underwent HCT, with 152 randomized to Shared Care and 150 to Usual Care. The median age at HCT was 63, with 65.1% males and 91.7% White. Baseline characteristics were similar except cell source, with more bone marrow in Usual Care (p=0.03; Table). The day 100 non-relapse mortality rate was 2.6% for Shared Care and 2.7% for Usual Care (p=0.98). There were 7 deaths for any cause in the Shared Care group and 9 in the Usual Care group, and the OS rate at day 100 was 94% vs 95%, respectively (p=0.62; Figure). Grade II-IV acute GVHD (p=0.60) and grade ≥3 infection (p=0.63) were both similar at day 100. The day 100 QOL survey response rate among those still alive was 60.5%; the day 180 response rate was 67.3%. There were no significant differences in QOL at day 180 on the FACT-BMT total score (p= 0.36) or QLQ-C30 global score (p=0.54), nor the various subscales of each (all p > 0.05). In contrast, at day 100, the FACT-BMT total score was significantly better in the Shared Care group (p= 0.02) compared to the Usual Care group, with the physical well-being (p=0.004), emotional well-being (p=0.04) and bone marrow transplantation subscales (p=0.007) all better as well. This pattern was also seen on the QLQ-C30 at day 100, where the global (p=0.02), emotional (0.03), cognitive (0.04), fatigue (0.01), nausea (0.01) and dyspnea (0.02) scores were all better for Shared Care. Conclusion: As compared to Usual Care, Shared Care with local providers after HCT did not compromise day 100 non-relapse mortality, and led to improved QOL as measured by the FACT-BMT and QLQ-C30 at day 100. These data suggest that Shared Care has the potential to become a standard model for follow-up care after allogeneic HCT. Implementation will require rigor adherence to the four care delivery strategies detailed above. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PURPOSE:Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown.METHODS:Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died.RESULTS:Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication.CONCLUSION:This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.

Abstract Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME; bone marrow) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of ‘terminal’ (TEX) and ‘precursor’ (TPEX) exhausted subsets, respectively, defined DLI response. In contrast to the common, shared pathways marking DLI response, a heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, TPEX cells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Further, we introduce a Bayesian method, Symphony, to define the T cell regulatory circuitry and master regulators underlying TEX and TPEX subsets that may be broadly relevant to other exhaustion antagonists across cancers. In conclusion, our data implicate the hierarchy of both TEX and TPEX subsets for immunotherapeutic responses in leukemia, extending the scope of their relevance beyond checkpoint blockade to adoptive cellular therapy. Moreover, our results provocatively suggest that immunologic ‘help’ from DLI, rather than direct transfer of anti-leukemic T cells, drove leukemic remission. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of how immune therapies differentially shape the evolutionary trajectories of the TME in accordance with clinical outcome. Citation Format: Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang Nguyen, Christina Ennis, Zi- Ning Choo, Shuqiang Li, Kenneth Livak, Donna Neuberg, Robert Soiffer, Jerome Ritz, Edwin Alyea, Dana Pe'er, Catherine Wu. Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT008.

There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of >= 2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Ibrutinib is a highly effective therapeutic agent with multiple hematologic indications, most notably chronic lymphocytic leukemia (CLL). It achieves therapeutic effects through irreversible inhibition of Bruton's tyrosine kinase (BTK). Many patients have achieved durable progression-free and overall survival since its regulatory approval. While ibrutinib carries a favorable toxicity profile compared with prior generations of therapy, cardiac toxicities have emerged as a major clinical consideration.

Approximately 2-10% of chronic lymphocytic leukemia (CLL) cases develop into Richter’s transformation (RT), a more aggressive disease typically manifesting as diffuse large B-cell lymphoma (DLBCL). Targeted therapies such as ibrutinib are now commonly used to treat CLL but the transformation rate remains comparable to the chemoimmunotherapy era. Moreover, these targeted therapies are often used to treat RT despite limited efficacy, and prognosis for these patients is poor. The treatment of RT therefore remains challenging in the current era of targeted therapy. Graft-versus-leukemia activity after allogeneic hematopoietic cell transplantation (alloHCT) is evident in patients with CLL where durable remissions can be achieved in all genetically defined high-risk subsets. Indeed, several small studies have reported benefit from alloHCT in RT. In order to better understand the therapeutic value of alloHCT in the modern era, we report alloHCT outcomes for 28 consecutive patients with RT who received chemoimmunotherapy and/or targeted therapy prior to alloHCT. The Blood and Marrow Transplant data repository of the Dana-Farber Cancer Institute was queried to identify all patients aged ≥18 years who underwent alloHCT for RT between January 1, 2010 and May 31, 2019. After obtaining Institutional Review Board approval in accordance with the Declaration of Helsinki, a retrospective chart review was performed to confirm the diagnosis of CLL and transformation to RT and 28 patients were identified. Clinical characteristics of these patients are summarized in the Online Supplementary Table S1. Median age was 61 years (range: 41-73 years) and 24 (85.7%) were male. Twenty-six patients received reduced intensity conditioning (RIC) HCT. The histologic diagnosis at alloHCT was DLBCL (n=27) and Hodgkin lymphoma (n=1). Median time from CLL diagnosis to RT was 4.5 years (range: 024.4 years). Median time from RT to alloHCT was 0.6 years (range: 0.2-3.8 years). Twenty-six patients (92.8%) were in complete remission (CR) or partial remission (PR) at the time of alloHCT. Positron emission tomography (PET) scan was available for 23 patients and seven (30%) of these 23 patients were PET positive. Of note, since RT is a high risk disease, our current practice is to offer alloHCT only to those patients in at least PR. Median number of total therapies for CLL and RT combined prior to alloHCT was three (range: 1-7): one (range: 0-4) for CLL and two (range: 1-7) for RT. Nine patients received targeted therapies (4 for CLL and 5 for RT) in addition to chemoimmunotherapies before alloHCT. No patient received CAR-T cell therapy. All prior and post-transplant therapies are listed in Online Supplementary Table S2. Time from CLL diagnosis to RT and alloHCT, relapse, post HCT therapy, and duration of overall survival (OS) for the entire cohort are depicted in Figure 1 along with selected clinical features such as age, prior targeted therapy, total number of prior therapies, complex karyotype (defined as ≥5 abnormalities), HCT comorbidity index, disease status, donor type, bulky disease, high lactate dehydrogenase (LDH) and/or low platelet counts (<100x10/L), and a PET scan result at transplant and occurrence of grade 2-4 acute graft-versus-host disease (GvHD). Strikingly, the cohort is dichotomized into a group of long survivors and a group that experienced early deaths. In the first group (subjects 15-28), all patients remain alive (4-year overall survival [OS] 100%) with median follow-up 4.9 years (range: 2.2-7.7 years). In the second group (subjects 1-14), 11 of 14 died within 1 year (1-year OS 21%). Remarkably, two of three patients aged >70 years survived over 5 years. Subject 27 was 73 years old at the time of alloHCT, relapsed 11 months after alloHCT, and subsequently received post-transplant therapy (CHOP) and donor lymphocyte infusion from his brother. This patient remains alive 7.3 years after alloHCT. Subject 22 was also 73 years old at the time of alloHCT, had del(17p) and developed RT while on ibrutinib. This subject subsequently responded to R-EPOCH prior to alloHCT and remains alive in remission 5.2 years after alloHCT. For the entire cohort, eight relapses (7 RT and 1 CLL) and 13 deaths have occurred: five from disease progression, six from infection and two from GvHD. Of the eight non-relapse deaths, six died within 1 year and two within 2 years of alloHCT. Median follow-up among sur-