Histopathology of graft-vs-host disease of gastrointestinal tract and liver: An update

© American Society for Clinical Pathology, 2016. All rights reserved. Objectives: Graft-vs-host disease (GVHD) is a donor T-cellmediated disorder affecting the recipient\u27s skin, gastrointestinal tract, lungs, and liver. It complicates up to 70% of hematopoietic cell transplantation and is associated with high morbidity and mortality rates. Methods: An extensive review of the literature has been performed to include the most current consensus on the histopathologic diagnosis of gastrointestinal and liver GVHD. Results: In this review, we present an overview of GVHD, with emphasis on the histopathologic evaluation of gastrointestinal and liver specimens, including the most important differential diagnoses and possible pitfalls. Conclusions: Histopathologic examination remains the mainstay of diagnosis of gastrointestinal and liver GVHD and is interpreted in conjunction with clinical and laboratory data

ABCL-351: Promising Tolerability and Efficacy Results from Dose-Escalation in an Ongoing Phase Ib/II Study of Mosunetuzumab with Polatuzumab Vedotin (Pola) in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Mosunetuzumab (Mosun), a full-length, humanized, IgG1 CD20xCD3 bispecific antibody, showed promising efficacy/safety for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). Mosun combined with the anti-CD79b antibody-drug conjugate Pola showed synergistic anti-lymphoma activity in a mouse xenograft model, supporting the Phase Ib/II, open-label, multicenter trial of Mosun-Pola for R/R B-NHL (GO40516, NCT03671018). To present early clinical data from the Phase Ib cohort of GO40516. Patients with R/R follicular lymphoma (FL, grade 1–3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), and grade 3b FL (FL3b), received Cycle (C)1 step-up doses of Mosun on Day (D)1 (1 mg) and D8 (2 mg), and target dose on C1D15, continuing from C2D1. Mosun was given every 21 days for eight cycles, continuing for ≤17 cycles. Pola (1.8 mg/kg) was administered with Mosun on D1 of six cycles. As of November 17, 2020, 22 patients received Mosun-Pola (Mosun target doses: 9 mg, n=7; 20 mg, n=3; 40 mg, n=6; 60 mg [D1 dose 30 mg from C3 onward], n=6). Patients had DLBCL (n=12), FL (n=3), FL3b (n=3), and trFL (n=4). Median age: 70 (38–81) years; median 3 (1–10) prior lines of therapy; prior chimeric antigen receptor T-cell (CAR-T) therapy (n=7; 32%). Median follow-up duration: 9.6 (0.7–23.7) months. Most frequent treatment-related adverse events (AEs): neutropenia (45.4%), fatigue, nausea, and diarrhea (all 36.4%). Cytokine release syndrome was observed in two patients (9.1%; both grade 1 [Lee, et al. Biol Blood Marrow Transplant 2019]). One dose-limiting toxicity (grade 3 new-onset atrial fibrillation) was observed in the 40 mg cohort; maximum tolerated dose not exceeded. Most common grade ≥3 AE: neutropenia (n=8; 36.4%). Two (9.3%) grade 5 AEs occurred (sudden cardiac death [n=1]); respiratory failure [n=1]); neither was deemed treatment-related. Complete responses were achieved with Mosun-Pola in patients with R/R aNHL (n=9; 47.4%), prior CAR-T therapy (n=2; 28.6%) and FL (n=3; 100%). These data indicate that Mosun-Pola has an acceptable safety profile and shows promising efficacy in patients with predominantly aggressive R/R NHL. The Phase II expansion cohort in patients with R/R DLBCL is ongoing, with no requirement for mandatory hospitalization

Promising tolerability and efficacy results from dose-escalation in an ongoing phase Ib/II study of mosunetuzumab (M) with polatuzumab vedotin (Pola) in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin’s lymphoma (B-NHL)

7520 Background: Mosunetuzumab (M), a full-length, humanized, IgG1 bispecific antibody targeting CD20 and CD3, has shown promising efficacy and safety as monotherapy for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). The combination of M with the anti-CD79b antibody-drug conjugate, Pola, showed synergistic anti-lymphoma activity in a mouse xenograft model. These data supported a Phase Ib/II, open-label, multicenter trial of M-Pola for R/R B-NHL (GO40516, NCT03671018). Here we present early clinical data from the Phase Ib cohort. Methods: Pts with R/R follicular lymphoma (FL, grade [Gr] 1–3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL) and FL Gr 3b (FL3b), received Cycle (C) 1 step-up doses of M on Day (D) 1 (1mg) and D8 (2mg), the target dose on C1D15, then continued at the target dose on C2D1 onwards. M was given every 21 days for eight cycles (or 17 cycles if stable disease or a partial response after C8). Pola (1.8mg/kg) was given with M on D1 of each cycle for six cycles. Results: As of November 17, 2020, 22 pts had received M-Pola (M target doses: 9mg, n=7; 20mg, n=3; 40mg, n=6; 60mg [with D1 dose of 30mg from C3 onwards], n=6). Pts had DLBCL (n=12), FL (n=3), FL3b (n=3) and trFL (n=4). Pt characteristics include: median age of 70 (38–81) years; median of 3 (1–10) prior lines of therapy; 7 (32%) pts had prior CAR-T therapy; 17 (77%) and 19 (86%) pts had disease refractory to last prior therapy and prior anti-CD20 therapy, respectively. Median follow-up duration was 9.6 (0.7–23.7) months. The most frequent treatment-related adverse events (AEs) were neutropenia (45.4%), fatigue, nausea and diarrhea (all 36.4%). Cytokine release syndrome (CRS) was observed in 2 pts (9.1%; both Gr 1 by ASTCT 2019 criteria). One dose-limiting toxicity (Gr 3 new onset atrial fibrillation) was observed in the 40mg cohort. The maximum tolerated dose was not exceeded. The most common Gr ≥3 and serious AEs were both neutropenia, observed in 8 (36.4%) and 3 (13.6%) pts, respectively. Two (9.3%) Gr 5 AEs occurred: sudden cardiac death (n=1) and respiratory failure (n=1); neither was deemed treatment related. No immune effector cell-associated neurotoxicity was observed. The Table shows preliminary efficacy data. Preliminary efficacy in the dose-escalation cohort. Conclusions: These data indicate that M-Pola has an acceptable safety profile, with no Gr ≥2 CRS observed, and promising efficacy in pts with R/R NHL with predominantly aggressive disease. The Phase II expansion cohort in R/R DLBCL is ongoing, with no mandatory hospitalization required. Clinical trial information: NCT03671018. [Table: see text

Mosunetuzumab Plus Polatuzumab Vedotin Demonstrates a Favorable Safety Profile and Efficacy in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Primary Analysis of a Phase Ib/II Study

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. The ongoing Phase Ib/II GO40516 study (NCT03671018) investigates Mosun in combination with polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). The Phase II expansion phase of the M-Pola regimen (with conventional Mosun and Pola dose and dose schedule), showed an acceptable safety profile and promising anti-tumor activity in pts with R/R B-NHL at interim analysis (Budde et al. ASH 2021). With enrollment complete, we present full dose-expansion cohort results. Methods: Eligible pts had confirmed R/R LBCL (including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma [tFL], and follicular lymphoma [FL] grade [Gr] 3b) and had received ≥1 prior line of therapy (including an anti-CD20 antibody). Treatment cycles were 21 days. Pola (1.8mg/kg; intravenous [IV]) was administered on Day (D) 1 of Cycles (C) 1-6. Mosun IV was administered with C1 step-up dosing to mitigate cytokine release syndrome (CRS), with the following dose and dose schedule: 1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3+. Pts with a complete response (CR) completed Mosun after C8, and pts with stable disease or partial response at the end of C8 continued Mosun for a total of 17 cycles. Primary endpoint was best overall response rate (ORR) by independent review committee (IRC) using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of April 7, 2023, 98 pts received M-Pola in the dose-expansion cohort. Median age was 68.0 years (range: 20-88), 71.4% were male, 87.8% had de novo DLBCL, 8.2% had tFL, 4.1% had Gr 3b FL, 18.4% had HGBCL (including double/triple-hit lymphoma), 7.1% had bulky disease (≥10 cm), 51.0% had an International Prognostic Index score 3-5, and 85.7% had Ann Arbor stage III/IV disease. The median number of prior lines of therapy was 2 (range: 1-8), 35.7% had prior CAR-T therapy, and 11.2% had prior ASCT. Most pts (80.6%) were refractory to prior anti-CD20 therapy, 58.2% were primary refractory, 77.6% were refractory to their previous therapy, and 26.5% were refractory to CAR-T therapy. The median number of cycles received was 8 for Mosun (range: 1-17) and 6 for Pola (range: 1-6). Adverse events (AEs) occurring in ≥15% of pts were fatigue (42.9%), neutropenia (28.6%), nausea (26.5%), diarrhea (23.5%), pyrexia (23.5%), headache (21.4%), CRS (18.4%), chills (17.3%), and peripheral sensory neuropathy (16.3%). Gr 3/4 AEs that occurred in ≥5% pts were neutropenia (20.4%) and fatigue (7.1%). Gr 5 AEs occurred in 3 (3.1%) pts, of which 2 were due to COVID-19 pneumonia and 1 was due to pneumonia. None were considered related to treatment. CRS events were observed in 18.4% of pts: Gr 1 n=11, Gr 2 n=4, Gr 3 n=3. All CRS events were resolved by data cut-off. Three pts received tocilizumab, 2 pts had a vasopressor, 2 pts received high flow oxygen, and 2 pts required ICU admission for CRS. Mosun-related neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 5 pts (5.1%); all were Gr 1/2 except 1 Gr 4 encephalopathy event. Treatment-related neuropathy occurred in 25.5% of pts (all Gr 1/2). Eleven pts (11.2%) discontinued treatment due to AEs, of which 5 (5.1%) were treatment-related: 1 (1.0%) due to encephalopathy (Mosun-related) and 4 (4.1%) due to peripheral neuropathy (Pola-related). Investigator-assessed ORR and CR rate were 62.2% and 50.0%, respectively ( Table). Median duration of response was not reached (NR; 95% confidence interval [CI]: 11.6-NR); median duration of CR was NR (95% CI: 20.5-NR). Median progression-free survival was 9.6 months (95% CI: 5.6-18.6) and overall survival was 23.3 months (95% CI: 15.2-NR), with a median follow-up of 18.6 months (95% CI: 17.7-23.7). In pts with prior CAR-T therapy (n=35), the ORR and CR rates were 60.0% and 45.7%, respectively. In primary refractory pts (n=57), the ORR and CR rates were 56.1% and 40.4%, respectively. Conclusions: M-Pola continues to show a favorable safety profile and compelling efficacy in highly refractory pts, including those with prior CAR-T therapy and/or primary refractory disease. Primary analysis data, including IRC responses and biomarker analyses, will be presented