Relapse after remission remains the primary cause of treatment failure in acute myeloid leukemia (AML), underscoring the need for strategies to eliminate residual leukemic cells. The bone marrow (BM) microenvironment, largely orchestrated by the CXC chemokine receptor 4 (CXCR4)-CXC motif chemokine 12 axis (CXCL12), enables leukemia cell survival and chemoresistance by anchoring blasts in their protective BM niche. Motixafortide, a selective CXCR4 antagonist, mobilizes leukemic cells and disrupts tumor microenvironment interactions in preclinical models. In this randomized, double-blind, placebo-controlled phase 2 trial, 128 patients in first remission received high-dose cytarabine plus motixafortide or placebo. Median relapse-free survival did not substantially differ between groups: 10.3 months (95% confidence interval [CI], 8.0-12.0) for motixafortide and 11.5 months (95% CI, 8.6-24.1) for placebo (log-rank P = .98). But single-cell measurable residual disease (scMRD) analysis, performed before consolidation, demonstrated heterogeneity of CXCR4 inhibition benefit; in the placebo group, higher CXCR4 expression was associated with increased relapse risk (P = .02), whereas in the motixafortide group, higher CXCR4 expression was linked to a reduced relapse rate (P = .047). Exploratory analyses identified scMRD levels at which higher MRD burden was associated with inferior overall survival. Taken together, combining functional MRD profiling with biomarker-driven patient selection, such as CXCR4 expression, may enable more precise and effective postremission interventions in AML. This trial was registered at www.clinicaltrials.gov as NCT02502968 and at EudraCT as 2014-002702-21.

The optimal graft-versus-host disease (GVHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation remains controversial. In this open-label, phase 3 study, patients aged 14 to 70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose antithymocyte globulin (ATG; 5 mg/kg) plus posttransplant cyclophosphamide (PTCy; 50 mg/kg; referred to as ATG/PTCy), standard-dose ATG (total dose, 10 mg/kg), or a PTCy-based (total dose, 100 mg/kg) regimen for GVHD prophylaxis. The coprimary end points were the cumulative incidence (CI) of grade 2 to 4 acute GVHD (aGVHD) by day 100 and GVHD-free, relapse-free survival at 1 year after transplant. A total of 407 patients were randomized to receive an ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GVHD prophylaxis. By day +100, the CI of grade 2 to 4 aGVHD did not differ significantly among the 3 groups (P = .210). Although the overall incidence of chronic GVHD (cGVHD) was comparable across all groups (P = .110), the 2-year CI of moderate-to-severe cGVHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups than the PTCy group (28.3%), without reaching statistical significance (P = .095). No significant differences were observed in survival outcomes among the 3 groups. Notably, the CI of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group than in the other groups (P< .001). This trial suggested that the 3 GVHD prophylaxis strategies presented similar efficacy in preventing grade 2 to 4 aGVHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.

Intensive chemotherapy is standard for acute myeloid leukemia (AML) but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients with AML aged <18 years. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and granulocyte colony-stimulating factor (G-CSF) or standard-dose chemotherapy (SDC; cytarabine, daunomycin, and etoposide). All patients received postremission consolidation with standard chemotherapy and/or hematopoietic stem cell transplantation. The primary end point was to compare response rates between treatments. The secondary end points were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The 2 treatment arms showed no significant differences in outcomes. Complete remission (CR)/CR with incomplete count recovery rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease <0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs 83.6% (P = .611), and a 4-year event-free survival (EFS) of 61.5% vs 63.1% (P = .832). In conclusion, the LDC regimen was well tolerated, and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at www.chictr.org.cn as ChiCTR1800015883.

The phase 3 CRISTALLO trial compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia (CLL), using undetectable minimal residual disease (uMRD) as the sole primary end point. Previously untreated patients with a cumulative illness rating scale score ≤6 and creatinine clearance ≥70 mL/min without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary end point was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary end points included uMRD (<10-4) in PB and bone marrow (BM) at end of treatment (EOT) and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (19 March 2024), 80 patients received VenO, and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary end point was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (<10-4) in PB at month 15 (P = .0004). uMRD (<10-4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (<10-6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high risk for tumor lysis syndrome (TLS) after obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies. This trial was registered at www.clinicaltrials.gov as NCT04285567.

Quadruplet therapy with Isa-VRd (isatuximab, Velcade [bortezomib], Revlimid [lenalidomide], and dexamethasone) followed by Isa-Rd in the randomized phase 3 IMROZ study provided a significant progression-free survival benefit to transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). In the primary analysis, more Isa-VRd/Isa-Rd-treated patients achieved minimal residual disease (MRD) negativity and MRD-negative complete response (CR) at any time point than patients receiving VRd followed by Rd. Here, we report landmark analysis results of MRD negativity over time and its impact on clinical outcomes in IMROZ. Treatment with Isa-VRd/Isa-Rd led to deeper responses, with higher rates of MRD negativity and MRD-negative CR at the end of induction and during maintenance vs VRd/Rd, up to 60 months of follow-up. Benefit with Isa-VRd/Isa-Rd was observed across key patient subgroups, including older (>70 years) and frail patients. Time to progression (TTP) was significantly prolonged with Isa-VRd/Isa-Rd vs VRd/Rd in patients who converted from MRD negative to MRD positive at any time point. In a landmark analysis of the time of conversion to MRD positivity, TTP in patients who converted from MRD negative at the end of induction to MRD positive also favored Isa-VRd/Isa-Rd. Evaluating MRD status of patients at >1 time point may therefore be useful to support decisions on treatment selection and treatment continuation/discontinuation. Our findings on the degree of MRD negativity and MRD-negative CR benefit achieved during induction and maintenance by patients receiving Isa-VRd/Isa-Rd vs VRd/Rd extend the IMROZ primary analyses and further support Isa-VRd as standard of care for frontline treatment of transplant-ineligible patients with NDMM. This trial was registered at www.clinicaltrials.gov as #NCT03319667.

The phase 1/2 Intergroup study E4412 investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) combined with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) in relapsed/refractory classic Hodgkin lymphoma. A total of 147 patients aged ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients were included in the primary efficacy analysis. The complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (1-sided P = .29). The median survival follow-up was 38.0 months (interquartile range, 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the 2 arms (hazard ratio [HR], 0.78, confidence interval [CI], 0.39-1.57; 1-sided P = .24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, were similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was a higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared with BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned before hoc comparison; 58 patients received SCT, and 36-month PFS (from SCT) was >90% for both arms. Sixty-six patients were progression free after the first scan and did not undergo SCT. The 36-month PFS was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared with 45.8% (26.3, 63.4) for BV/Nivo (HR, 0.45; CI, 0.19-1.08; 1-sided P = .03). The study did not meet its primary end point of superior CR rate for the triplet, but it supports the use of checkpoint antibody-drug conjugate induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT with the triplet of BV/Ipi/Nivo. This trial was registered at www.clinicaltrials.gov as NCT01896999.

Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.

Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic-phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from the ASC4FIRST trial, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years' median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4% [95% confidence interval (CI), 13.6-31.3]; 1-sided P< .001) and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7% [95% CI, 17.6-41.8]; 1-sided P< .001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1% [95% CI, 2.3-28.0]; 1-sided P< .05), suggesting possible clinical benefit, although the study was not designed to formally confirm statistical significance for this secondary end point. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5%; 46.5%), imatinib (23.2%; 47.5%), and 2G TKIs (54.9%; 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215-0.997). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP. This trial was registered at www.clinicaltrials.gov as NCT04971226.

To prevent graft-versus-host disease (GVHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT), a calcineurin inhibitor plus methotrexate is routinely used. Early phase studies suggested improved outcomes with Orca-T, an allogeneic T-cell immunotherapy that uses purified donor regulatory T cells to prevent GVHD with significantly less immunosuppression. This phase 3 trial randomized adult patients (N = 187) with acute leukemias or myelodysplastic syndrome undergoing myeloablative conditioning to receive either Orca-T with tacrolimus or a conventional allograft with tacrolimus and methotrexate (Tac/MTX), using granulocyte colony-stimulating factor-mobilized peripheral blood from HLA-matched donors. The primary end point was survival free from moderate-to-severe chronic GVHD (cGVHD; cGFS). Using a stratified log-rank test, cGFS was significantly higher in the Orca-T arm than in Tac/MTX (hazard ratio, 0.26; 95% confidence interval, 0.14-0.47; P< .001). One-year estimates were as follows: cGFS was 78.0% with Orca-T vs 38.4% with Tac/MTX; cumulative incidence of moderate-to-severe cGVHD was 12.6% with Orca-T and 44.0% with Tac/MTX (Gray test P< .001); overall survival was 93.9% with Orca-T vs 83.1% with Tac/MTX (P = .12); GVHD-free and relapse-free survival was 63.1% and 30.9% in the Orca-T and Tac/MTX arms (P< .001), respectively; nonrelapse mortality (NRM) was 3.4% with Orca-T vs 13.2% with Tac/MTX (P = .03). Orca-T met the primary end point of improved survival free from cGVHD compared with Tac/MTX prophylaxis and should be considered a new therapeutic option with low toxicity for GVHD prophylaxis. Moreover, significantly less toxicity was observed with Orca-T patients, including fewer serious infectious complications and less NRM. This trial was registered at www.clinicaltrials.gov as NCT05316701.

We assessed the overall survival (OS) impact of time to relapse (TTR) in multinational cohorts with independent observational and randomized validation. Patients with nMTCL with frontline complete response were assigned to TTR12 (≤12 months) or without TTR12 based on time to progression or next therapy. OS analyses included modified landmark (m-LM), standard landmark (s-LM), and time-dependent Cox (td-Cox), adjusting for age, histology, and prognostic index for T-cell lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed at ≥12 months, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.58-2.90; P< .001), s-LM (HR, 1.92; 95% CI, 1.39-2.66; P< .001); and td-Cox (HR, 5.81; 95% CI, 2.94-11.46; P< .001). Results were consistent in the independent validation cohorts. TTR12 consistently conferred worse OS irrespective of frontline stem cell transplantation or PIT score, in peripheral T-cell lymphoma, not otherwise specified (m-LM: HR, 2.32; 95% CI, 1.51-3.55; P< .001; s-LM: HR, 2.10; 95% CI, 1.33-3.31; P = .001), anaplastic large cell lymphoma (m-LM: HR, 3.34; 95% CI, 1.18-9.50; P = .023; s-LM: HR, 2.96; 95% CI, 1.02-8.81; P = .046), and angioimmunoblastic T-cell/T follicular helper cell lymphoma (m-LM only: HR, 1.92; 95% CI, 1.15-3.21; P = .013). Second-line novel therapies improved OS (second-line start to death) vs chemotherapy in TTR12 only (HR, 0.60; 95% CI, 0.37-0.97; P = .038; without TTR12: HR, 0.82; 95% CI, 0.51-1.32; P = .407). TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment.

The phase 1/2 BelaRd (belantamab mafodotin [belamaf], lenalidomide, and dexamethasone) study evaluated the efficacy and safety of belamaf combined with lenalidomide and dexamethasone in unfit and frail transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Part 1 (n = 36) established a recommended belamaf phase 2 dose (RP2D) of 1.9 mg/kg every 8 weeks (median follow-up, 39.3 months). In part 2, 30 patients were randomized 1:1 in group A (n = 15), where belamaf dosing was guided by ophthalmologist-assessed ocular adverse events (OAEs), whereas in group B (n = 15), belamaf dosing was based on hematologist-led vision-related anamnestic (VRA) tool and ophthalmologist-assessed grade ≥3 OAEs. Among the RP2D patients (n = 42), overall response rate was 97.6%, median progression-free survival (PFS)/overall survival have not been reached yet, and the 18-month PFS and time to progression rates were 83.0% and 97.2%, respectively. Ocular toxicities were similar between assessments by hematologists and ophthalmologists, and no ophthalmologist withholding of a hematologist-led dosing occurred. Less than 1% of patients stopped driving/reading because of OAEs. Median time to belamaf reinfusion was 13 weeks. Overall, BelaRd is an effective regimen for transplant-ineligible patients with NDMM and warrants a phase 3 study in this setting. OAEs' impact on quality of life appears limited, and implementation of the hematologist-led VRA tool may eventually reduce the necessity for ophthalmologist assessments. This trial was registered at www.clinicaltrials.gov as #NCT04808037.

We compared daunorubicin/cytarabine plus fractionated gemtuzumab ozogamicin (DAGO2) with CPX-351 (CPX; 1:2 randomization) in 439 patients with acute myeloid leukemia (AML) aged ≥60 years (median age, 68 years) without known adverse-risk cytogenetics. Median follow-up was 35 months. Patients not in measurable residual disease (MRD)-negative remission after course 1 could enter a second randomization between standard and intensified chemotherapy. Post-course 1, the overall response rate (complete remission [CR] + CR with incomplete hematological recovery) was greater after DAGO2 (60% vs 47.5%; odds ratio [OR], 0.61; P = .016). Following course 2, the overall response was not significantly different (85% for DAGO2 vs 78% for CPX; P = .095). More patients attained CR with MRD negativity after course 1 in the DAGO2 arm (47% vs 29% for CPX; OR, 0.46; P = .004). We observed better 3-year event-free survival (34% vs 27%; hazard ratio [HR], 0.73; P = .012) and overall survival (52% vs 35%; HR, 0.62; P = .001) with DAGO2. CPX did not provide a survival benefit in patients with myelodysplasia (MDS)-related mutations and was associated with poorer survival in patients with NPM1 (HR, 2.83) and FLT3 mutations (HR, 2.14). Overall, 37% of patients underwent transplantation in first remission, with no difference in transplantation frequency or survival after transplant between randomization groups. Among patients entering the course 2 randomization (n = 107), survival was equivalent between standard and intensified CPX doses (P = .565). In conclusion, in this population of older patients with AML without known adverse-risk cytogenetics, DAGO2 resulted in superior survival compared with CPX. CPX did not benefit patients with MDS-related mutations over DAGO2. This trial was registered at www.ClinicalTrials.gov as #NCT02272478.

Circulating tumor cells (CTC) represent a high-risk biomarker in newly diagnosed multiple myeloma (NDMM); however, their prognostic value among transplant-eligible (TE) patients receiving daratumumab/bortezomib/lenalidomide/dexamethasone (D-VRd) remains unknown. In this study, we analyzed CTC in the phase 3 PERSEUS/EMN017 trial. TE-NDMM patients were randomized (1:1) to D-VRd with daratumumab/lenalidomide maintenance (D-VRd group) or bortezomib/lenalidomide/dexamethasone (VRd) with lenalidomide maintenance (VRd group), both with transplant. A subset of 451 of 709 patients from PERSEUS (D-VRd, 231/355; VRd, 220/354) had screening blood samples collected for CTC analysis by flow cytometry. CTC were detected in 370 patients (82%; median limit of detection, 0.0004%). CTC were prognostic of progression-free survival (PFS), independent of other factors, as a continuous (hazard ratio [HR], 1.36 [95% confidence interval (CI), 1.15-1.60]; P< .001) and categorical variable (≥0.175% CTC-high, optimal threshold). D-VRd improved PFS vs VRd in CTC-low patients (4-year rates: 88% vs 74%; HR, 0.42 [95% CI, 0.25-0.70]; P = .0013). Regardless of study treatment, minimal residual disease (MRD)-negativity rates were lower in CTC-high vs CTC-low patients (10-5: 52.2% vs 66.2%; 10-6: 34.8% vs 52.4%). D-VRd significantly increased MRD-negativity rates vs VRd among CTC-high (10-5: 69.4% vs 33.3%; 10-6: 47.2% vs 21.2%; both P< .05) and CTC-low patients (10-5: 74.4% vs 57.8%; 10-6: 65.6% vs 38.5%; both P< .001), with similar observations for sustained MRD-negativity. CTC levels are an independent prognostic factor in TE-NDMM treated with standard-of-care frontline quadruplet. D-VRd improved and sustained MRD-negativity rates in CTC-high and CTC-low, and improved PFS for CTC-low with a positive trend in CTC-high patients. This trial was registered at www.clinicaltrials.gov as #NCT03710603.

Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

The CASSIOPEIA trial demonstrated superior progression-free survival (PFS) with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (D-VTd) induction/consolidation, and with daratumumab maintenance vs observation in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The companion study, CASSIOPET, assessed the prognostic value of premaintenance (PM) positron emission tomography (PET)/computed tomography (CT) response, based on the standardized Deauville score on PFS and overall survival (OS), in addition to bone marrow (BM) minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) at 10-5 level. PM PET/CT was available for 225 patients: 112 patients treated with daratumumab after D-VTd (59) or bortezomib, thalidomide, and dexamethasone (VTd; 53), and 113 patients followed by observation after D-VTd (56) or VTd (57). At PM, 92% of the 175 baseline PET-positive patients achieved PET negativity, with a longer PFS in univariate analysis (P = .019) and a major trend of prolonged OS (P = .056). In univariate analysis, patients who achieved both PET and MFC negativity were found to have a better PFS (P < .0001) than those who had at least 1 positive result. In daratumumab-treated patients, PM PET negativity was associated with prolonged PFS and OS in univariate analysis (P = .0023 and P = .033, respectively), and double MFC and PET negativity was independently associated with PFS by multivariate analysis (P = .0006). This study confirms the prognostic relevance of a PM PET response in patients with NDMM treated with daratumumab in addition to MRD detection by MFC at the BM level. This trial was registered at ww.clinicaltrials.gov as #NCT02541383.

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post-autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG- and GEP-standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.

T-cell engagers (TCEs) are transformative therapeutics in hematologic malignancies, including non-Hodgkin lymphoma. Initially approved for relapsed/refractory disease settings, TCEs are now explored in first-line and second-line settings, often combined with standard-of-care (SOC) treatments, including chemotherapy and antibody-drug conjugates. This study investigates glofitamab (CD20×CD3 TCE) combinations in preclinical humanized lymphoma models, addressing heterogeneity of tumor antigen expression, immune evasion, and T-cell exhaustion. Combining glofitamab with R-CHP-Pola (rituximab, cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin) chemotherapy or Pola demonstrated strong synergistic antitumor efficacy with rapid tumor regression and reduced tumor cell proliferation. Glofitamab combination with gemcitabine/oxaliplatin also demonstrated strong efficacy, enhancing intratumor T-cell number, activation, and reduced exhaustion. These combinations were particularly advantageous in models with low and heterogeneous CD20 expression, facilitating rapid tumor debulking and elimination of CD20-low/CD20- cells. Translational studies with patient-derived peripheral blood mononuclear cells receiving glofitamab combination with chemotherapies demonstrated sustained T-cell functionality throughout extended treatment cycles. Novel chemotherapy-free combinations, including CD19-targeted 4-1BBL and CD19-CD28, amplified glofitamab activity, especially in CD20 high- and homogenous-expressing tumor models, with dual costimulatory approaches revealing synergy. In addition, the combination with checkpoint inhibitors (programmed cell death protein 1/Lag3-bispecific antibody) and regulatory T-cell depletion (α-CD25) emerged as promising approaches for enhanced efficacy and to sustain T-cell functionality. These findings highlight the versatility of glofitamab when integrated with SOC and innovative combinations, addressing resistance and improving patient outcomes. The preclinical investigations provide a strong foundation for ongoing and future clinical trials, emphasizing the need to tailor TCE-based combination therapies to maximize efficacy while minimizing toxicity in lymphoma treatment. These trials were registered at www.clinicaltrials.gov as #NCT04408638 and NCT03467373.

With up to 10 years of follow-up, we report results from the final analysis of RESONATE- 2, a phase 3 study of first-line ibrutinib vs chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/d; n = 136) or chlorambucil (0.5-0.8 mg/kg; ≤12 cycles; n = 133). With a median follow-up of 9.6 years in the ibrutinib arm, the median progression-free survival (PFS) was 8.9 years (95% confidence interval [CI], 7.0 to not estimable [NE]) vs 1.3 years (95% CI, 0.9-1.6) for the chlorambucil arm. Among patients with unmutated immunoglobulin heavy chain variable (uIGHV), del (11q), mutated TP53, or complex karyotype, the median PFS was 8.4 years (95% CI, 6.8 to NE) with ibrutinib and 0.7 years (95% CI, 0.4-1.2) with chlorambucil. Median overall survival (OS) with ibrutinib was not reached. The most common adverse events (AEs) of any grade included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), arthralgia (31%), peripheral edema (31%), and hypertension (30%). During the entire study period, 34 of 136 patients (25%) had an ibrutinib dose reduction due to AEs; these AEs improved in 30 of 34 patients (88%). At study completion, 27% of patients remained on first-line ibrutinib treatment. This landmark RESONATE-2 study defines median PFS and demonstrates continued OS benefit of first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Sustained efficacy and tolerability of ibrutinib reemphasize the favorable benefit-risk profile. This trial was registered at www.ClinicalTrials.gov as NCT01722487/NCT01724346.

Attempting to induce a complete remission before allogeneic hematopoietic cell transplant (alloHCT) is current practice in patients with acute myeloid leukemia (AML). However, benefit of remission induction strategy (RIST) before alloHCT has never been proven in a prospective trial. Potent conditioning regimens exist that allow for successful alloHCT in patients with active AML. Therefore, the ASAP trial was conducted to test RIST by salvage chemotherapy before alloHCT against immediate transplant after intensified conditioning. In total, 281 patients with AML with poor response after first induction or untreated first relapse were randomized 1:1 to RIST with high-dose cytarabine plus mitoxantrone vs immediate alloHCT with sequential conditioning after nonintensive disease control (DisC) measures, preferentially watchful waiting only. Overall survival at 5 years from randomization analyzed according to intention-to-treat was 46.1% for DisC vs 47.5% for RIST (P = .82). In multivariable Cox regression analysis, genetic AML risk according to European LeukemiaNet criteria (P < .0001), age (P = .001), and comorbidities (P = .046) predicted survival, but not treatment arm (hazard ratio, 1.08 for DisC vs RIST; P = .67). In conclusion, long-term follow-up of the ASAP trial showed no survival advantage for standard salvage chemotherapy before alloHCT as opposed to immediate alloHCT. The trial results question the general concept of RIST with intensive standard salvage therapy before alloHCT for all patients, because immediate alloHCT may reduce time in hospital and health care expenses. Novel bridging therapies that are well tolerated, and posttransplant maintenance with targeted drugs are urgently warranted, especially for adverse-risk AML, to improve outcomes after alloHCT. This trial was registered at www.ClinicalTrials.gov as #NCT02461537.

Modakafusp alfa is a first-in-class immunocytokine-directing interferon alfa to CD38+ cells. Our previous phase 1/2 trial identified 2 potential phase 2 doses of modakafusp alfa for patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks. The overall response rate (ORR) among 30 patients treated at 1.5 mg/kg was 43%. This phase 2 dose optimization study randomized 147 patients with triple-class refractory disease and ≥3 previous lines of therapy 1:1 to modakafusp alfa 120 mg (n = 71) or 240 mg (n = 75) every 4 weeks (fixed-dose equivalents of 1.5 and 3 mg/kg every 4 weeks). Patients had received a median of 6 previous lines of therapy; 66% were penta-exposed and 45% had previously been exposed to anti-B-cell maturation antigen (BCMA) therapy. Modakafusp alfa development was discontinued for strategic reasons by the sponsor and the study was terminated early. At median follow-up of 7.3 and 7.6 months in the 120- and 240-mg arms, ORRs were 32% and 41%, and median progression-free survival was 4.1 and 5.3 months, respectively. ORRs were higher in patients who had not received previous BCMA therapy (46% vs 29%). The most common treatment-related adverse events (TEAEs) in the 120- and 240-mg arms were thrombocytopenia (75% and 84%; grade ≥3, 55% and 61%; respectively) and neutropenia (68% and 73%; grade ≥3, 56% and 68%; respectively); 90% and 96% of patients, respectively, experienced grade ≥3 TEAEs; 39% and 44%, respectively, experienced serious TEAEs. Our results confirm the efficacy of single-agent modakafusp alfa for patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT03215030.