Isatuximab is an immunoglobulin G1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multicenter, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered IV weekly during the first 28-day cycle, and then every other week during cycles 2 to 24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a very good partial response (VGPR) or better. The median time to partial response (PR) or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement, and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing N-terminal pro b-type natriuretic peptide (NT-proBNP) with cardiac involvement. The most common treatment-related grade ≥3 adverse events included lymphopenia (n = 3, 8.5%) and infection (n = 2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis, and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as #NCT03499808.

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.

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.

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.

The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.

We found that 8 of 10 patients with aplastic anemia experienced resolution of platelet transfusion refractoriness following daratumumab administration. Notably, 4 responders achieved hematopoietic recovery, including 3 participants who showed improvements in multilineage blood cell counts, even with daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT05832216.

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). Palifermin, a recombinant N-truncated keratinocyte growth factor (KGF), protects epithelial tissues, including the thymus and gut. Although high-dose KGF prevents GVHD in preclinical models, lower doses of palifermin were ineffective in humans. We conducted a phase 1/2 trial evaluating high-dose palifermin for preventing severe chronic GVHD (CGVHD) in matched unrelated donor T-cell replete peripheral blood HCT after reduced-intensity conditioning (RIC). Using a 3+3 design, we determined the recommended phase 2 dose (RP2D), followed by an expansion phase. Palifermin (180-720 μg/kg) was given on day -7 before HCT. All 31 patients received fludarabine/cyclophosphamide RIC with tacrolimus, methotrexate, and sirolimus for GVHD prophylaxis. Palifermin was well tolerated, with self-limiting rash and pancreatic enzyme elevations as notable grade 3/4 adverse events. The RP2D was 720 μg/kg. Remarkably, no patients at this dose developed grade 2 to 4 acute GVHD (AGVHD [0/19]), although severe CGVHD rates (primary end point) remained unchanged compared to historical controls. Posttransplant lymphocyte phenotyping suggests palifermin modulates regulatory and naïve CD4+ T-cell numbers. These findings indicate that high-dose palifermin with RIC is safe and may prevent AGVHD, although it did not affect CGVHD rates in this study. This trial was registered at www.ClinicalTrials.gov as #NCT02356159.

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.

This study reports outcomes of Pediatric Leukemia Adoptive Therapy 02 (PLAT-02), a phase 2 trial of SCRI-CAR19, a second-generation chimeric antigen receptor (CAR) T-cell product with FMC63 single-chain variable fragment and 4-1BB costimulation, in pediatric and young adult patients with B-cell acute lymphoblastic leukemia; and PLAT-03, a companion study evaluating exogenous CD19 antigen stimulation with serial infusions of T cells expressing truncated CD19, T-cell antigen-presenting cells (T-APCs). The efficacy cohort of PLAT-02 (n = 72 patients; median age 12.5 years) received fludarabine/cyclophosphamide lymphodepletion followed by a dose of 1 × 106 CAR+ T cells per kg. The minimal residual disease-negative complete remission rate was 89%. Leukemia-free survival (LFS) at 1 and 2 years was 0.71 (95% confidence interval [CI], 0.58-0.81) and 0.64 (95% CI, 0.51-0.75), respectively. Patients with low disease burden had significantly higher 1-year LFS (0.91 vs 0.42). Rapid in vivo contraction of CAR T cells after infusion was associated with CAR loss within 6 months compared to those without rapid contraction (57% vs 19%). Most common grade 3/4 adverse events included cytokine release syndrome in 13% and neurotoxicity in 16%. The companion pilot, PLAT-03, enrolled 26 patients, and 19 received T-APCs. Neither cytokine-release syndrome nor neurotoxicity was observed after T-APC infusion. T-APC infusions in patients improved persistence (P = .03), with rapid CAR T-cell contraction being associated with decreased early CAR loss (20% with T-APC vs 57% without). Further exploration of serial artificial CD19 antigen exposure is warranted based on these pilot results. PLAT-02 and PLAT-03 trials were registered at www.clinicaltrials.gov as #NCT02028455 and #NCT03186118, respectively.

Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, and then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary end point was overall survival (OS); key secondary end points included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis owing to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (hazard ratio, 1.178; 95% confidence interval, 0.848-1.637). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML who were ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.