Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved as monotherapy for relapsed/refractory (R/R) follicular lymphoma (FL). We evaluated fixed-duration epcoritamab with rituximab plus lenalidomide (R2) in R/R FL in arm 2 of EPCORE NHL-2 (phase 1b/2). Patients received epcoritamab (2 step-up doses, then 48-mg full doses) for up to 2 years, and R2 for up to 12 cycles (28 days per cycle). The primary end point was overall response rate (ORR) per investigator assessment (Lugano criteria). As of 21 September 2024, 108 patients received ≥1 epcoritamab dose in expansion (median follow-up, 28.2 months). Median age was 65 years; 57% had 1 previous line of therapy. ORR and complete response (CR) rate were 96% and 88%, respectively; CR rates in patients with high-risk features were 90% (primary refractory), 82% (refractory to anti-CD20 and an alkylating agent), and 83% (disease progression within 24 months of first-line therapy). Two-year estimates for remaining in CR, progression-free survival, overall survival, and not starting next antilymphoma therapy were 82%, 76%, 90%, and 84%, respectively. Minimal residual disease negativity was observed in 86% of evaluable patients (clonoSEQ assay). Common treatment-emergent adverse events (TEAEs) included neutropenia (65%), COVID-19 (59%), and cytokine release syndrome (CRS; 51%). Grade ≥3 TEAEs occurred in 87% of patients; 5 had grade 5 TEAEs (all COVID-19). CRS events were mostly low grade (grade 1, 38%; grade 2, 11%; grade 3, 2%), all resolved, and none led to epcoritamab discontinuation. Fixed-duration epcoritamab plus R2 demonstrated deep, durable responses with manageable safety and favorable outcomes in R/R FL, irrespective of risk features. This trial was registered at www.ClinicalTrials.gov as #NCT04663347.

Because frail patients and patients aged ≥80 years with chronic lymphocytic leukemia (CLL) are still underrepresented in clinical trials, the CLL-Frail trial aimed to evaluate the efficacy and safety of acalabrutinib in these patients. The primary end point was the overall response rate (ORR) after 6 cycles of treatment to test the null hypothesis of ORR ≤65%. Fifty-three patients were included in the trial, and 34 patients are still on therapy. Adverse events (AEs) were the most frequent reason for early discontinuation (10 patients), whereas 5 patients stopped treatment because of death. Median age was 81 years, and 47.2% of patients were frail. The ORR for the 46 patients receiving ≥3 cycles of treatment was 93.5% (95% confidence interval, 82.1-98.6) meeting the primary end point of this trial (P < .001). The estimated 12-month progression-free and overall survival rates were 93.3% and 95.7%, respectively, after a median follow-up of 19 months. 53.5% of patients reported an improvement in their self-perceived frailty. Although all patients experienced AEs, and severe (Common Terminology Criteria of ≥3) events were reported in 63.5% of patients, there were no events of severe bleeding and atrial fibrillation was rare (2 cases of Common Terminology Criteria Grades 2 and 3). Five patients died, of which 4 deaths happened during or <28 days after treatment. Infections/COVID-19 were the cause of death in 3 cases. To our knowledge, this is the first prospective trial in older and/or frail patients with CLL demonstrating a high efficacy and safe treatment with acalabrutinib monotherapy. This trial was registered at www.ClinicalTrials.gov as #NCT04883749.

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.

T-cell acute lymphoblastic leukemia (T-ALL) represents a group of aggressive hematological malignancies characterized by unfavorable prognosis, urging the need for innovative therapeutic strategies. LEF1 is a member of the lymphoid enhancer factor (LEF)/T-cell factor family of DNA-binding transcription factors, known for their interaction with nuclear β-catenin in the context of the Wnt signaling pathway. Although the implication of LEF1 in colon cancer is well documented, its clinical relevance and functional consequences remain elusive in T-ALL. In this study, we provide valuable insights into the prevalence and significance of LEF1 alterations in a comprehensive cohort of 474 pediatric and adult patients with T-ALL enrolled in the FRALLE-2000 (French group for childhood ALL) and GRAALL 2003-2005 (Group for Research on Adult Acute Lymphoblastic Leukemia) trials, respectively. LEF1 alterations were detected in 63 cases (13%), including 9 point mutations (14.3%), 18 large deletions (28.6%), and, strikingly, 36 focal deletions (57.1%), which emerge as the most recurrent subtype. LEF1-altered cases were associated with increased central nervous system involvement and improved initial treatment response. Importantly, we unveil the existence of a previously undescribed dominant-negative LEF1 isoform resulting from focal deletions of the exons 2-3. This novel truncated protein, previously unreported in the literature, is associated with the disruption of the Wnt pathway and T-cell receptor signaling, which can be exploited as a therapeutic strategy to enhance chemosensitivity in LEF1-deleted T-ALL cases. The trials were registered at www.clinicaltrials.gov as #NCT00222027 (GRAALL 2003) and #NCT00327678 (GRAALL 2005); FRALLE2000T protocol (FRALLE-2000).

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.

Older patients with diffuse large B-cell lymphoma (DLBCL) present unfavorable genetic and microenvironmental alterations. In this phase 2 trial, we assessed the efficacy and safety of zanubrutinib in combination with rituximab and lenalidomide (ZR2) in patients with de novo DLBCL aged ≥75 years. Forty patients were enrolled, and the primary end point was the complete response rate, which was 65.0% (95% confidence interval [CI], 48.3-78.9) at the end of induction treatment. The 2-year progression-free and overall survival rates were 67.1% (95% CI, 50.1-79.4) and 82.4% (95% CI, 66.5-91.2). The most common grades 3 and 4 hematologic adverse event (AE) was neutropenia (n = 14 [35.0%]). The most common grades 3 and 4 nonhematologic AEs were increased alanine transaminase (n = 5 [12.5%]) and aspartate transaminase levels (n = 5; 12.5%), and pulmonary infection (n = 5 [12.5%]). No events of atrial fibrillation were observed. Importantly, the efficacy of ZR2 was more dependent on tumor microenvironmental than genetic alterations, and was associated with upregulation of class I and II human leukocyte antigen and increased number and function of conventional type 1 dendritic cells. Preexisting expansion of intratumoral CD8+ T cells and treatment-induced clonal T-cell receptor (TCR) repertoire contributed to better clinical outcome. TCR sequencing of the peripheral blood mononuclear cell samples from patients with durable remission detected the expanded T-cell clones 3 years after treatment. These findings thus improve the understanding of the effect of T-cell immunological memory on ZR2-based immunotherapy, and support a paradigm shift toward mechanism-based targeted therapy of aggressive lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT04460248.

We analyzed 217 patients with KMT2A-rearranged acute myeloid leukemia (AML) in 2 large sequential randomized trials. Those randomized to FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubucin) had markedly lower rates of relapse than other chemotherapy regimens. Molecular measurable residual disease assessment after cycle 2 was strongly prognostic for relapse and death. The trials were registered at the ISRCTN Registry as AML17 ISRCTN55675535 and AML19 ISRCTN78449203.

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.

This phase 2 trial assessed CD7 chimeric antigen receptor (CAR) T cells derived from previous transplant or newly HLA-matched donors for relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). Early termination from departmental closure yielded 55 treated patients out of 70 planned. Within 3 months, 89% of treated patients achieved best overall response of partial remission or better. A total of 19 received stem cell transplantation at a median of 1.3 (range, 1.0-10.6) months. After a 26.3-month median follow-up, median event-free survival was 5.0 months (95% confidence interval [4.1-8.4]), with median 8.5-month overall survival (95% confidence interval [6.1-15.6]). No deaths occurred within 30 days; adverse events included cytokine release syndrome in 87% at grades 1 to 2 and 11% at grade 3 and neurotoxicity in 9% at grade 1. In addition, graft-versus-host disease was in 38% at grades 1 to 2 and 2% at grade 3. Grades 1 and 2 infections occurred in 29%. Cytopenias occurred in 4% at grade 2 and 96% at grades 3 and 4. After 30 days, grades 3 to 5 adverse events included cytopenias (grade 3 in 24%; grade 4 in 67%), infections (grade 3 in 9%; grade 4 in 5%; grade 5 in 9%), graft-versus-host disease (grade 3 in 4%; grade 5 in 4%), thrombotic microangiopathy (grade 5 in 4%), and hepatic failure (grade 5 in 2%). Furthermore, 11 encountered nonrelapse mortality after 30 days, representing 20% of treated patients and 35% of responders without consolidatory transplantation. Although effective at inducing remission, death in remission beyond 30 days is a concern. This trial was registered at www.clinicaltrials.gov as #NCT04689659.

RGI-2001, a glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T (NKT) cells and stimulate cytokine-dependent proliferation of regulatory T cells (Tregs). This open-label, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT). RGI-2001 was infused at a dose of 100 μg/kg for 6 weekly doses. The primary end point was grade 2 to 4 acute GVHD by day 100. A total of 49 participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, including decreased appetite, leukopenia, thrombocytopenia, and stomatitis. The cumulative incidence of grade 2 to 4 and 3 to 4 acute GVHD were 24.9% and 4.1%, respectively. Compared with the controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including day-180 grade 2 to 4 acute GVHD-free survival (70.8% vs 50.7%; adjusted hazard ratio, 0.45; 95% confidence interval, 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunologic changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as #NCT04014790.

Advanced mycosis fungoides (MF) and Sézary syndrome (SS) have a poor overall survival (OS) of <5 years. Studies have found the current staging (IA-IVB) is inadequate for risk stratification. The PROCLIPI (Prospective Cutaneous Lymphoma International Prognostic Index) study was launched in 2015 at 46 international expert MF/SS centers, prospectively collecting predefined data sets in patients with newly diagnosed MF/SS, to determine a cutaneous lymphoma IPI (CLIPI). Five hundred fifty-two patients with advanced stage MF/SS were recruited. The 5-year OS was 50.0% for stage IIB, 64.8% for stage IIIA, 43.9% for stage IIIB, 50.8% for stage IVA1, 25.9% for stage IVA2, and 36.9% for stage IVB. Factors at diagnosis associated with a significantly worse survival were N3 status (P < .001), age >60 years (P < .001), raised serum lactate dehydrogenase (P = .005), and large-cell transformation in skin (P = .006). Modeling these 4 independent risk factors into a CLIPI found that there was a worse OS in high- vs low-risk (P < .001), high- vs intermediate-risk (P = .002) and intermediate- vs low-risk (P = .010) groups. Five-year OS was 63.3%, 44.7%, and 18.3% in the low-, intermediate-, and high-risk groups, respectively. In this advanced stage cohort there was a low 5-year survival and increasing stage was not associated with worsening survival. The use of CLIPI to stratify patients into risk groups has the potential to improve outcomes and aid optimal treatment selection. This trial was registered at www.ClinicalTrials.gov as #NCT02848274.

The megakaryocytic (MK)-specific immunoreceptor G6b-B plays an essential role in MK development. Because germ line loss-of-function mutations of G6b-B in humans and its deletion in mouse models lead to thrombocytopenia and a myelofibrosis-like clinical phenotype (MF-MPIG6B), we explored the role of G6b-B in patients with myelofibrosis (MF) due to a myeloproliferative neoplasm (MPN) with thrombocytopenia (MPN-MF-T). We demonstrated that MKs generated from mononuclear cells (MNCs) from a patient with MF-MPIG6B as well as patients with MPN-MF-T failed to express GATA binding protein 1 and G6B and possessed a protein pattern expression characteristic of MKs primed for inflammation rather than platelet production. MNCs from patients with MPN-MF-T also generated fewer MK-biased hematopoietic stem cells and greater numbers of small cytoplasmic immature MKs (CD41+CD42-G6B-) as compared with MNCs from patients with nonthrombocytopenic MPN-MF (MPN-MF-NT). Plasma levels of transforming growth factor β1 (TGFβ1) and chitinase-3-like protein (CHI3L1) also known as YKL-40, which were shown to arrest normal MK maturation, were elevated in the patients with MF-MPIG6B. Although TGFβ1 plasma levels were similarly elevated in patients with MPN-MF-T and MPN-MF-NT, tumor necrosis factor α (TNFα) and YKL-40 levels were upregulated to a greater extent in patients with MPN-MF-T than those with MPN-MF-NT. Moreover, we identified a reciprocal positive regulatory loop involving TGFβ1 and YKL-40 in MF MKs. These findings indicate that impaired MK maturation, and reduced G6B expression lead to the predominance of proinflammatory MKs, which produce factors that further arrest MK development in patients with MF-MPIG6B and MPN-MF-T patients. This trial was registered at www.clinicaltrials.gov as #NCT03895112.

We developed an allogeneic matched donor CD19 chimeric antigen receptor (CAR) product (CAR-donor lymphocyte infusion [DLI]) for adult patients with B-cell acute lymphoblastic leukemia (B-ALL) after failure of allogeneic stem-cell transplantation (allo-SCT). We evaluate the risks and benefits of pre-CAR-DLI lymphodepleting chemotherapy (LD) and the efficacy of repeat CAR-DLI dosing per conventional DLI protocols. Primary outcomes were toxicity and feasibility of CAR-DLI manufacture; secondary outcomes included CAR-DLI engraftment, expansion, and persistence. A total of 17 allo-SCT donors received leukapheresis and 14 patients with B-ALL (median age, 43 years) received infusion. Median disease burden at registration was 50.5% bone marrow blasts (range, measurable residual disease [MRD] to 100%). Patients 1 to 7 received CAR-DLI alone (CAR-DLI-alone); patients 8 through 14 received CAR-DLI and LD with fludarabine/cyclophosphamide (CAR-DLI+LD). CAR-DLI+LD vs CAR-DLI-alone was associated with superior peak CAR-DLI engraftment (93 134 vs 8010 copies per μg genomic DNA [gDNA]), expansion (858 101 vs 39 038 copies per μg gDNA per 28 days) and persistence (median, 197 vs 32 days). CAR-DLI+LD was not associated with more immunotoxicity than CAR-DLI-alone, and graft-versus-host disease (GVHD; grade 1, skin) affected only 2 of 14 patients (14%). CAR-DLI+LD vs CAR-DLI-alone conferred superior event-free-survival and overall survival at 12 months (57% vs 29%; 83% vs 29%). Repeat CAR-DLI dosing was administered to 8 of 14 (57%) patients with morphological/MRD+ relapse, but with minimal engraftment/expansion or toxicity/efficacy. CAR-DLI+LD has a tolerable safety profile without significant GVHD and is associated with significantly better outcomes than CAR-DLI-alone. Repeat CAR-DLI dosing beyond dose 1 was not found to be effective in this analysis. This trial was registered at www.clinicaltrials.gov as #NCT02893189.

Marstacimab targets the tissue factor pathway inhibitor to rebalance hemostasis. Previous phase 1 and 2 trials established marstacimab safety and efficacy in adults with severe hemophilia A (HA) or B (HB). BASIS is an open-label, marstacimab phase 3 trial in males aged 12 to 74 years with severe HA (factor VIII <1%) or moderately severe to severe HB (factor IX ≤2%). Participants without inhibitors received on-demand (OD) or routine prophylaxis (RP) therapy during a 6-month observational phase (OP) before receiving once-weekly subcutaneous 150 mg marstacimab during a 12-month active treatment phase (ATP). Primary end points were annualized bleeding rate (ABR) for treated bleeds vs previous OD or RP during the OP, and safety. Of 128 participants enrolled in the OP, 116 received marstacimab in the ATP. In the OD group (n = 33), mean ABR decreased from 39.86 (95% confidence interval [CI], 33.05-48.07) in the OP to 3.20 (95% CI, 2.10-4.88) in the ATP, demonstrating superiority of marstacimab (estimated ABR ratio, 0.080 [95% CI, 0.057-0.113]; P < .0001). In the RP group (n = 83), mean ABR decreased from 7.90 (95% CI, 5.14-10.66) in the OP to 5.09 (95% CI, 3.40-6.78) in the ATP, demonstrating noninferiority and superiority of marstacimab (estimated ABR difference, -2.81 [95% CI, -5.42 to -0.20]; P = .0349). There were no deaths or thromboembolic events. Weekly subcutaneous marstacimab reduced ABR vs OD or RP therapy in the OP in individuals with severe HA or moderately severe to severe HB without inhibitors. Marstacimab was safe and well tolerated with no unanticipated side effects. This trial was registered at www.clinicaltrials.gov as #NCT03938792.

Patients with follicular lymphoma who experience disease progression within 24 months of diagnosis (POD24) have a lower survival. Positron emission tomography (PET) response and circulating tumor DNA (ctDNA) minimal residual disease (MRD) assessment at end of induction (EOI) may allow their early identification. A representative cohort of 141 patients from the RELEVANCE phase 3 trial with both available serum samples for ctDNA testing and PET images at randomization and at EOI (week 24) was investigated. Twelve percent were POD24. ctDNA was analyzed using a customized 130-kilobase capture panel, with phased variant (PV) enriched regions representing 39% of the panel. ctDNA was detected in 140 patients (99.3%) at baseline. To optimize specificity, only PVs, found in 124 patients (88%), were considered for ctDNA MRD assessment at EOI. Median progression-free survival (PFS) from EOI was not reached (NR) for the 112 patients with undetected ctDNA at EOI vs 17.7 months (95% confidence interval [CI], 1.4 to NR) for patients with positive ctDNA (MRD+) (P = .0038). Similarly, median PFS was NR for the 104 patients with undetected disease on PET at EOI vs 28.3 months (95% CI, 2.9 to NR; P = .0002) for patients with PET positivity. Both tests had a negative predictive value (NPV) of >90% for POD24. The positive predictive value was 58.3% for ctDNA MRD and 45% for PET but increased to 85.7% when both parameters were combined, without alteration of NPV. These data show that the combination of PET response and ctDNA MRD at EOI allows an early prediction of POD24, which may lead to a preemptive treatment decision. This trial was registered at www.clinicaltrials.gov as #NCT01650701.

In retrospective studies, autologous stem cell transplantation (ASCT) conditioning with intravenous busulfan and melphalan (BUMEL) led to longer progression-free survival (PFS) than melphalan alone (MEL200). We compared long-term outcomes of BUMEL vs MEL200 in the context of intensified bortezomib, lenalidomide, and dexamethasone (VRD) induction and consolidation therapies. GEM12 was a phase 3 trial for patients with newly diagnosed multiple myeloma (NDMM) eligible for ASCT including 6 reinforced VRD cycles followed by ASCT conditioned with BUMEL or MEL200 and 2 VRD consolidation cycles. The primary end point was PFS. Subgroup analyses were based on International Staging System (ISS) stages and high-risk genetic abnormalities. Patients were randomized with an open-label 2 × 2 factorial design and 1:1:1:1 allocation ratio to ensure the balance between the GEM12 and the subsequent phase 3 GEM14 trial. Between 2013 and 2015, 458 patients were randomized (BUMEL, n = 230; MEL200, n = 228). The 10⁻⁶ MRD-negative rate was 63%, 68% for BUMEL vs 58% for MEL200 (odds ratio, 1.51; P = .035). The median PFS was 89 months for BUMEL and 73.1 for MEL200 (hazard ratio, 0.89 [95% confidence interval, 0.70-1.14]; P = .3). BUMEL showed benefit for patients with ISS stages II or III, t(14;16), and del(1p). For subcohorts ISS stages II or III treated with BUMEL and ISS I treated with MEL200 the median PFS was 96.5 months (95% confidence interval, 76 to not estimable). No safety concerns were observed. After a median follow-up of 8.4 years, GEM2012 demonstrated one of the longest PFS values reported in patients with NDMM, with significant differences favoring BUMEL in advanced ISS stages. The trial was registered at www.ClinicalTrials.gov as #NCT01916252 and at European Union Drug Regulating Authorities Clinical Trials as EudraCT 2012-005683-10.

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL; T-ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T-cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3+3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received 1 infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 28 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 × 106 cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Two grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and 1 grade 2 acute graft-versus-host disease event occurred (3.8%). One grade 2 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome was observed. Among the 11 patients evaluable for response at the RP2D who received enhanced lymphodepleting chemotherapy, the overall response rate was 90.9%, and the composite complete remission rate was 72.7%. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. This trial was registered at www.ClinicalTrials.gov as #NCT04984356.

No standard of care for older patients with aggressive adult T-cell leukemia/lymphoma (ATL) has been established. We evaluated the efficacy of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 2 weeks with mogamulizumab (Moga; Moga-CHOP-14) for older patients with untreated ATL. In this multicenter phase 2 trial, patients aged ≥66 years and those aged 56 to 65 years ineligible for transplantation received 6 cycles of Moga-CHOP-14, followed by 2 cycles of Moga monotherapy. The primary end point was 1-year progression-free survival (PFS). Secondary end points were the complete response (CR) rate, overall response rate (ORR), overall survival (OS), 1-year event-free survival (EFS), and safety. We also investigated the impact of CC chemokine receptor 4 (CCR4) mutation and Moga-associated cutaneous adverse events (cAEs) on PFS and OS. The study protocol was amended to allow the dosing interval to be extended to 21 days at the physician's discretion. Among 48 evaluable patients, the 1-year PFS was 36.2% (90% confidence interval, 24.9-47.6), with a median follow-up of 1.6 years. The 1-year OS and EFS were 66.0% and 29.9%, respectively. CR and ORR were 64.6% and 91.7%. No unexpected toxicities were observed. Of 47 patients who received ≥2 cycles of CHOP, 20 (42.6%) received CHOP-14, among whom 12 (25.5%) completed 6 cycles. CCR4 mutation and Moga-associated cAEs were associated with better OS. This study showed that Moga-CHOP significantly improved PFS, although the optimal interval for CHOP remains undetermined. Moga-CHOP is now considered a preferable first-line treatment for this patient population. This trial was registered at https://jrct.mhlw.go.jp/en-top as #jRCTs041180130.