Surrogates of endothelial injury predict survival after post-transplant cyclophosphamide.

BACKGROUND: Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. OBJECTIVE: We evaluate the prognostic ability of the HCT-CI and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy based GVHD prophylaxis. STUDY DESIGN: Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥ 2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. RESULTS: A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 years after alloHCT (34.5% vs. 12.3%, P = 0.003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 - 6.17, P = 0.005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 - 4.36, P = 0.034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 - 4.33, P = 0.005) and high risk (HR 5.77, 95% CI 2.31 - 14.39, P < 0.001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. CONCLUSION: Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.

Palliative Care for Patients With Cancer: ASCO Guideline Update.

PURPOSE: To provide evidence-based guidance to oncology clinicians, patients, nonprofessional caregivers, and palliative care clinicians to update the 2016 ASCO guideline on the integration of palliative care into standard oncology for all patients diagnosed with cancer. METHODS: ASCO convened an Expert Panel of medical, radiation, hematology-oncology, oncology nursing, palliative care, social work, ethics, advocacy, and psycho-oncology experts. The Panel conducted a literature search, including systematic reviews, meta-analyses, and randomized controlled trials published from 2015-2023. Outcomes of interest included quality of life (QOL), patient satisfaction, physical and psychological symptoms, survival, and caregiver burden. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 52 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations address the integration of palliative care in oncology. Oncology clinicians should refer patients with advanced solid tumors and hematologic malignancies to specialized interdisciplinary palliative care teams that provide outpatient and inpatient care beginning early in the course of the disease, alongside active treatment of their cancer. For patients with cancer with unaddressed physical, psychosocial, or spiritual distress, cancer care programs should provide dedicated specialist palliative care services complementing existing or emerging supportive care interventions. Oncology clinicians from across the interdisciplinary cancer care team may refer the caregivers (eg, family, chosen family, and friends) of patients with cancer to palliative care teams for additional support. The Expert Panel suggests early palliative care involvement, especially for patients with uncontrolled symptoms and QOL concerns. Clinicians caring for patients with solid tumors on phase I cancer trials may also refer them to specialist palliative care.Additional information is available at www.asco.org/supportive-care-guidelines.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Measurable Residual FLT3 Internal Tandem Duplication Before Allogeneic Transplant for Acute Myeloid Leukemia.

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.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RSMLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (P<0.01) but not between MDS-RS with and without SF3B1 mutation (P=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (hazard ratio=1.8, 95% confidence interval: 1.1-2.8; P=0.01) and also identified age (P<0.01), transfusion need at diagnosis (P<0.01), and abnormal karyotype (P<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (P<0.01), RUNX1 (P=0.02) and IDH1 (P=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDS-SF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutation-based, disease classification for MDS-RS might be prognostically more relevant.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.

Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).

SINGLE CELL DISSECTION OF DEVELOPMENTAL ORIGINS AND TRANSCRIPTIONAL HETEROGENEITY IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA.

Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However, ZNF384- r and DUX4- r B-ALL showed composition enrichment of hematopoietic stem cells, BCR::ABL1 and KMT2A -r ALL of Early Lymphoid progenitors, MEF2D -r and TCF3::PBX1 of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.