Graded Organ Response and Progression Criteria for Kidney Immunoglobulin Light Chain Amyloidosis.

Importance: Kidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes. Objective: To validate graded kidney response criteria and their association with kidney and overall survival (OS). Design, Setting, and Participants: This retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023. Exposure: Four kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response. Main Outcomes and Measures: Cumulative incidence of progression to KRT and OS. Results: Seven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS. Conclusions and Relevance: The results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

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

The mechanism of action, pharmacological characteristics, and clinical utility of the amyloid depleter birtamimab for the potential treatment of AL amyloidosis.

Amyloid light chain (AL) amyloidosis is a progressive plasma cell disorder caused by amyloid deposition resulting in organ damage and failure. Current standard-of-care treatments target clonal plasma cells, the source of misfolded light chains (amyloid precursors), yet only half of patients with advanced disease survive ≥6 months. The amyloid depleter birtamimab is an investigational humanized monoclonal antibody that binds misfolded κ and λ light chains with high specificity and was designed to neutralize soluble toxic light chain aggregates and promote phagocytic clearance of deposited amyloid. Post hoc analyses from the Phase 3 VITAL trial suggested birtamimab plus standard of care confers a survival benefit in patients with advanced (Mayo Stage IV) AL amyloidosis. AFFIRM-AL (NCT04973137), a Phase 3 confirmatory trial of birtamimab plus standard of care in patients with Mayo Stage IV AL amyloidosis, is ongoing. This review summarizes birtamimab's mechanism of action, attributes, and potential clinical utility.

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

ABSTRACT: The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results.

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.