Mark Blaine Geyer

Triplet regimens induce high rates of undetectable measurable residual disease (MRD) at ≤10−4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) chronic lymphocytic leukemia (CLL), but the optimal treatment duration to minimize the risk of infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL. Our MRD-driven study was designed to optimize treatment duration, balancing efficacy against toxicities associated with extended treatment exposure, and to evaluate zanubrutinib with venetoclax (Z+V) retreatment. With a median observation of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary end point). BOVen was well-tolerated, with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; no grade 5). Median MRD4-free survival was 34.1 months (95% confidence interval [CI], 23.1-50.5), and the 48-month PFS was 79.7% (95% CI, 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD [immunosequencing] at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, P< .001) and longer MRD4-free survival (50.5 vs 18.1 months, P< .001), despite shorter treatment duration (8 vs 13 months, P< .001). This manuscript also reports safety/efficacy of Z+V retreatment and pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent uMRD4 and durable remissions in TN CLL with a short treatment duration (median, 10 months). ΔMRD400 is undergoing evaluation as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL. This trial was registered at www.clinicaltrials.gov (#NCT03824483).

Although adults with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) may achieve a measurable residual disease-negative (MRD-) complete response (CR) after frontline treatment and blinatumomab (blina) consolidation, survival outcomes are heterogeneous, and known prognostic factors are limited. We conducted a retrospective, multicenter study of 81 adults with Ph+ B-ALL in MRD- (<10-4) CR1 after blina consolidation and stratified them by pre-blina MRD status as determined by multiparametric flow cytometry (flow). Patients who were pre-blina flow MRD- (n = 56) and flow MRD+ (n = 25) had similar baseline characteristics. With a median follow-up of 31.0 months, pre-blina flow MRD- patients had superior disease-free (DFS) and overall survival (OS) on univariate (p = 0.049 and p = 0.045, respectively) and multivariable analyses (HR 0.27, 95% CI 0.08-0.87 and HR 0.17, 95% CI 0.03-0.90, respectively) relative to pre-blina flow MRD+ patients. Inferior DFS was seen with the IKZF1-plus genotype (HR 3.51, 95% CI 1.08-11.44) and extramedullary disease at diagnosis (HR 3.90, 95% CI 1.19-12.73). In exploratory analyses, pre-blina flow MRD+ status remained associated with inferior DFS (p = 0.0005) and OS (p < 0.0001) for patients who did not receive a subsequent hematopoietic cell transplant (HCT) in CR1, but not in patients who did (p = 0.55 and p = 0.99, respectively). In summary, flow MRD+ status before blina consolidation was associated with inferior survival in patients with Ph+ B-ALL in CR1 despite subsequent clearance, and consolidative HCT may reduce this prognostic effect.

Adolescents and young adults (AYA) with acute myeloid leukemia (AML) represent a biologically and clinically distinct population managed across pediatric and adult oncology services, with no established optimal treatment paradigm. In this single-center retrospective study, we analyzed 81 AYA patients aged 14-29 years with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between 2010 and 2025. Patients were stratified by treating service, European LeukemiaNet (ELN) 2022 risk category, and induction regimen. Pediatric patients received two cycles of cytarabine, daunorubicin, and etoposide (ADE)-based induction, while adult patients received one cycle of cytarabine plus daunorubicin (7+3) induction-three of whom required 7+3 reinduction-followed by risk-adapted consolidation including allogeneic hematopoietic stem cell transplantation. Composite complete response rates were similar between adult and pediatric cohorts (79% vs. 78%), as were rates of MRD negativity by multicolor flow cytometry among responders (63% vs. 55%). Despite comparable depth of response, five-year overall survival favored adult-service patients in both the full cohort (77.9% vs. 56.7%) and the ELN 2022 intermediate-adverse risk subgroup (62.7% vs. 47.9%), while relapse-free survival was nearly identical. On multivariable analysis, ELN 2022 risk retained independent prognostic significance, whereas treatment protocol did not. These findings demonstrate that pediatric-style and adult AML regimens achieve comparable remission depth in AYA patients. The survival advantage observed with adult protocols challenges the assumption that further cytotoxic intensification improves outcomes in this population.

Hemophagocytic lymphohistiocytosis (HLH) is an interferon gamma–driven hyperinflammatory syndrome with high morbidity and mortality. Identifying reliable prognostic biomarkers is challenging due to various predisposing conditions and triggers. C-X-C-motif ligand 9 (CXCL9) is a clinically validated biomarker and surrogate marker of interferon gamma–mediated inflammation. We aimed to identify the role of CXCL9 in predicting severe disease and death in adults with HLH using a multicenter retrospective cohort of consecutively hospitalized patients who underwent a clinical evaluation for HLH that included CXCL9 testing. Patients were classified as HLH if they met HLH-2004 and/or HScore criteria. Conditional inference decision trees and Cox regression models were used to identify which clinical variables associated with acute mortality in patients with HLH. Overall, 171 patients were reviewed, and 126 patients met HLH criteria. The median age was 55 years (interquartile range, 40-66), with 62% male and 51% White. CXCL9 was markedly elevated in patients with HLH. Unbiased decision tree modeling, incorporating all clinical laboratory values, identified only CXCL9 of >16 100 pg/mL as the optimal predictor of inpatient mortality. Cox regression models demonstrated that CXCL9 of >16 100 pg/mL was significantly associated with 90-day mortality when controlling for important covariates. This shorter time to death in the elevated CXCL9 subgroup remained significant even after subdividing patients into those with malignancy (n = 53) and nonmalignancy HLH (n = 73). Continuous increases in CXCL9 within the cohort strongly associated with greater mortality. CXCL9 is a novel clinical marker that identifies high-risk HLH independent of underlying disease and could be used to select patients for early and aggressive targeted immunomodulatory therapy.

Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and nucleophosmin 1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 US centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n = 53; 23% NPM1c, n = 19) who received MENINi were heavily pretreated: 86% (n = 72) had previous intensive chemotherapy (IC) and 77% venetoclax (VEN; n = 67). After MENINi failure, 40% of patients (n = 34) received supportive care. For the treated patients (n = 50), common regimens included hypomethylating agent (HMA)/VEN (26%, n = 13), clinical trial (26%, n = 13), and gilteritinib-based therapy (18%, n = 9). The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate for nontrial therapies was 19% (n = 7); overall response rate was 32% (n = 12). All CR/CRi occurred with HMA/VEN (n = 2, 15%), IC + VEN (n = 4, 67%), or MENINi switching (bleximenib to revumenib, n = 1 [50%]). No patient with FLT3-ITD mutation responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival from start of next therapy was 4.4 months and superior for patients who achieved CR/CRi, (15.4 vs 3.4 months, P = .048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.

Success of chimeric antigen receptor (CAR) T-cell therapy in lymphoid malignancies has not yet been recapitulated in acute myeloid leukemia (AML). We developed CAR T cells targeting CD371 with a mutated CD28 costimulatory domain to limit T-cell exhaustion, and constitutive interleukin-18 (IL-18) secretion to enhance immune function (CD371/SAVVY/IL-18 CAR). We initiated a phase 1 trial (NCT06017258), successfully manufactured and administered CD371/SAVVY/IL-18 CAR T cells in 5 patients with relapsed/refractory AML and observed expansion following a single infusion of 3 × 104 or 3 × 105 CAR T cells per kg; 3 patients refractory to ≥5 lines of therapy and postallogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease. Dose-limiting toxicity in the 2 patients treated with 3 × 105 CAR T cells per kg dose (prolonged cytopenias with marrow hypoplasia; severe cytokine release syndrome) led to dose reduction to 3 × 104 CAR T cells per kg in the following 3 patients. Single-cell analyses revealed that circulating CAR T cells in responders included predominantly cytotoxic CD8+ effector T cells 2 weeks after infusion while coexisting natural killer (NK) cells expressed markers of activation. This pilot study highlights the activity of low-dose IL-18 “armored” CAR T cells against refractory AML and their potential to promote CAR T-cell cytotoxicity and innate endogenous antitumor immunity. This trial was registered at www.ClinicalTrials.gov as #NCT06017258.