Faculty Bibliography

Mosunetuzumab plus polatuzumab vedotin has shown promising activity versus rituximab plus polatuzumab vedotin (R-Pola) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL; NCT03671018). We present results from the Phase II randomized cohort, evaluating subcutaneous mosunetuzumab plus polatuzumab vedotin (Mosun-Pola), with > 2 years of follow-up. Patients with R/R LBCL and ≥ 1 prior line of therapy were randomized to receive Mosun-Pola or R-Pola. Mosunetuzumab was administered subcutaneously with Cycle (C) 1 step-up dosing (5/45/45 mg) then 45 mg on C2 Day (D) 1-C8D1 (21-day cycles). Polatuzumab vedotin (1.8 mg/kg) was given intravenously (IV) on D1 of C1-6. Rituximab IV (375 mg/m²) was given on D1 of C1-8. Primary endpoint was best objective response rate (ORR). As of November 15, 2024, 80 patients had been enrolled (Mosun-Pola, n = 40; R-Pola, n = 40). Best ORR was 77.5% (95% confidence interval [CI] 61.6-89.2) for Mosun-Pola and 50.0% (95% CI: 33.8-66.2) for R-Pola; complete response (CR) rates were 55.0% (95% CI: 38.5-70.7) and 35.0% (95% CI: 20.6-51.7), respectively. Median progression-free survival was 25.4 months for Mosun-Pola and 6.4 months for R-Pola (hazard ratio [HR] 0.47); median overall survival was not reached and 25.5 months (HR: 0.78), respectively. Cytokine release syndrome occurred in 12.5% of Mosun-Pola-treated patients (all Grade 1/2). Fixed-duration Mosun-Pola demonstrated benefit across all efficacy endpoints compared with R-Pola in patients with R/R LBCL. These findings are consistent with the observed benefit of Mosun-Pola for patients with R/R LBCL in the global Phase III SUNMO study (NCT05171647). Trial Registration: Clinicaltrials.gov number: NCT03671018.

INTRODUCTION/BACKGROUND:Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL. PATIENTS AND METHODS/METHODS:Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity. RESULTS:We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients. CONCLUSION/CONCLUSIONS:Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.

The Phase 1/2 Intergroup study E4412 (NCT01896999; ClinicalTrials.gov) investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) in relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) while concurrently targeting CD30+ Hodgkin Reed Sternberg cells with the antibody-drug conjugate brentuximab vedotin (BV). 147 patients ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients are included in primary efficacy analysis. The primary endpoint, 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 (one-sided p=0.29). The median survival follow-up is 38.0 months (interquartile range 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the two arms (HR=0.78, CI 0.39-1.57, one-sided p=0.24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, was similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared to BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned post-hoc comparison; 58 patients received SCT; 36-month PFS (from SCT) was greater than 90% for both arms. Sixty-six patients were alive and progression free after the first scan (disease evaluation) and did not undergo SCT. The 36-month PFS (from first scan) was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared to 45.8% (26.3, 63.4) for BV/Nivo (HR=0.45, CI 0.19-1.08, one-sided p=0.03). The study did not meet its primary endpoint of superior CR rate for the triplet, but it supports the use of checkpoint-ADC induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT for the triplet of BV/Ipi/Nivo.

INTRODUCTION/UNASSIGNED:Obinutuzumab is a standard treatment for chronic lymphocytic leukemia (CLL) in combination with venetoclax, following the CLL-14 trial. The purpose of the gradual ramp-up dosing is to mitigate toxicity and prevent tumor lysis; while these ramp-up doses are considered active, they are not considered to be definitive therapy. We describe the case of a CLL patient who had an exceptional response to obinutuzumab in the ramp-up phase followed by limited venetoclax. CASE REPORT/UNASSIGNED:A 73-year-old female with CLL, with trisomy 12 (70.5%), deletion of 13q (14%), and 3 copies of 11, who had been monitored for 10 years, developed bulky disease, and treatment was initiated following CLL-14. On cycle 1 day 1 (C1D1), she was treated with 100 mg of obinutuzumab; she received 900 mg on C1D2. When she returned for treatment on C1D8, she was found to have profound pancytopenia, and obinutuzumab was held. She received no further obinutuzumab but was started on venetoclax and received 12 weeks of treatment, with maximum dose reached in ramp-up being 400 mg daily. Further treatment was limited by cytopenias. Bone marrow biopsy within 4 months of treatment with a total of 1,000 mg of obinutuzumab and ∼13,000 mg venetoclax revealed trilineage hematopoiesis with only trace evidence of CLL at 0.14%. She was then treated with 4 weeks of rituximab for presumed immune thrombocytopenic purpura, and subsequent peripheral blood flow cytometry analysis revealed no evidence of CLL. The patient remains in complete remission 34 months following obinutuzumab therapy. CONCLUSION/UNASSIGNED:The degree of pancytopenia and the exceptional clinical response to minimal dose of obinutuzumab by this patient suggests an unusual sensitivity to obinutuzumab.

Antibiotic-induced microbiome injury, defined as a reduction of ecological diversity and obligate anaerobe taxa, is associated with negative health outcomes in hospitalized patients, and healthy individuals who received antibiotics in the past are at higher risk for autoimmune diseases. Postbiotics contain mixtures of bacterial fermentation metabolites and bacterial cell wall components that have the potential to modulate microbial communities. Yet, it is unknown if a fermentation-derived postbiotic can reduce antibiotic-induced microbiome injury. Here, we present the results from a single-center, randomized placebo-controlled trial involving 32 patients who received an oral, fermentation-derived postbiotic alongside oral antibiotic and probiotic therapy for non-gastrointestinal (GI) infections. At the end of the antibiotic course, patients receiving the postbiotic (n = 16) had significantly higher fecal bacterial alpha diversity (+40%, inverse Simpson index) compared to the placebo group (n = 16), and the treatment was well-tolerated. Analysis of 157 longitudinal fecal samples revealed that this increased diversity was driven by enrichment of health-associated taxa, notably obligate anaerobic Firmicutes, particularly Lachnospiraceae. In contrast, Escherichia/Shigella species, often linked to pathogenicity and antibiotic resistance, were reduced in postbiotic-treated patients at the end of antibiotic treatment and remained lower up to 10 days later. Our findings suggest that postbiotic co-administration during antibiotic therapy may augment health-associated gut microbiome composition and mitigate antibiotic-induced microbiome injury.Trial registration ISRCTN30327931 retrospectively registered.

Autologous T-cells engineered to express CD19-directed chimeric antigen receptor (CAR) have shown high overall response rates in treatment-refractory large B-cell lymphoma (LBCL). However, more than half of patients do not attain a durable response and will eventually relapse. Thus, strategies to improve long-term efficacy of CAR T-cell products are needed. In this phase 2, randomized, double-blind, placebo-controlled, multicenter study of NKTR-255 versus placebo following CD19 CAR T-cell therapy, eligible patients with R/R LBCL were treated with one of two FDA-approved CAR T-cell products, axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel). In total, 15 patients received CD19 CAR T-cell therapy and received study treatment, 11 patients were randomized to the NKTR-255 group (5 at 1.5 µg/kg; 3 at 3.0 µg/kg; 3 at 3 µg/kg then 6 µg/kg cycle 2+) and 4 to placebo. NKTR-255 post CD19 CAR T-cell administration led to augmented CR rates with 8 of 11 (73%) in the NKTR-255 group versus 2 of 4 (50%) in the placebo group reaching complete response rate at month 6 (CR6). Clinical response was accompanied by re-expansion of CD8+ CAR T-cells. The most common (≥20%) grade ≥3 NKTR-255-related adverse events were decreased neutrophil, platelet, and lymphocyte counts; all resolved without clinical sequelae. No cytokine-release-syndrome (CRS) or immune-effector-cell-associated-neurotoxicity-syndrome (ICANS) were reported in the NKTR-255 group. NKTR-255 was well-tolerated, safe, and augmented CR6 for LBCL patients. Based on the findings, additional confirmatory studies with NKTR-255 as adjuvant treatment to CAR T-cell, including other cellular therapies, are warranted (ClinicalTrials.gov number NCT05664217).

BACKGROUND:FT596 is an induced pluripotent stem-cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy with three antitumour modalities: a CD19 CAR; a high-affinity, non-cleavable CD16 Fc receptor; and interleukin-15-interleukin-15 receptor fusion. In this study, we aimed to determine the recommended phase 2 dose (RP2D) and evaluate the safety and tolerability of FT596 as monotherapy and in combination with rituximab. We also aimed to evaluate the antitumour activity and characterise the pharmacokinetics of FT596 as monotherapy and in combination with rituximab. METHODS:) intravenously on day -4. Supportive care was determined by the treating investigator. Patients were observed for dose-limiting adverse events for 28 days. Patients who tolerated therapy and derived clinical benefit could receive subsequent cycles of study treatment, with modification of conditioning chemotherapy dose if clinically indicated. The dose-expansion phase evaluated additional patients at selected doses and dosing schedules that had been found to be tolerable. The primary endpoints of the study were the incidence and nature of dose-limiting toxicities within each dose-escalation cohort to determine the maximum tolerated dose or maximum assessed dose to establish the RP2D and the incidence, nature, and severity of adverse events, with severity determined according to National Cancer Institute Common Toxicity Criteria and Adverse Events version 5·0. The trial was registered with ClinicalTrials.gov, NCT04245722. FINDINGS/RESULTS:Between March 19, 2020, and Jan 12, 2023, 86 patients with B-cell lymphoma received FT596 on regimen A (n=18) or regimen B (n=68). 22 (26%) of 86 patients were female and 72 (84%) of 86 patients were White. Patients had received a median of four previous lines of therapy (range 1-11) and 33 (38%) of 86 patients had received previous CAR T-cell therapy. The maximum tolerated dose was not reached. Cytokine release syndrome was reported in one (6%) of 18 patients (maximum grade 1) on regimen A and nine (13%) of 68 patients on regimen B (six with maximum grade 1 and three with grade 2). Neurotoxicity was not observed. INTERPRETATION/CONCLUSIONS:cells for three doses per cycle. This study supports that cell therapy using iPSC-derived, gene-modified NK cells is a potent platform for cancer treatment and suggests that such a platform might address limitations of currently available immune cell therapies, including manufacturing time, heterogeneity, access, and cost. FUNDING/BACKGROUND:Fate Therapeutics.

The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies (NCT03547115). Initially, voruciclib was administered daily continuously on a 28-day cycle (Group I). After two patients with prior allogeneic stem cell transplantation had a dose limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1-14 of a 28-day cycle (Group II). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in Group II was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%) and dyspnea (15%). In AML, one patient achieved a morphologic leukemia-free state and two had stable disease. Voruciclib treatment led to a decrease in MCL1 mRNA expression, downregulation of MYC and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase II. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax in patients with previously treated AML.

BACKGROUND:Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies. MATERIALS AND METHODS:We present interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL. RESULTS:Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved). CONCLUSION:Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included.