Prince, H. Miles

Background: In the absence of high-quality evidence, there is a need for guidelines and multidisciplinary consensus recommendations on breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL). The purpose of this expert consensus conference was to evaluate the existing evidence regarding the diagnosis and management of BIA-ALCL caused by textured implants. This article aims to provide evidence-based recommendations regarding the management and prevention of BIA-ALCL. Methods: A comprehensive search was conducted in the MEDLINE, Cochrane Library, and Embase databases, and supplemented by manual searches of relevant English-language articles and “related articles” sections. Studies focusing on breast surgery and lymphoma associated with breast implants were included for analysis. Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons using a Delphi consensus method. Results: A total of 840 articles published between January of 2011 and January of 2023 were initially identified and screened. The full text of 188 articles was assessed. An additional 43 articles were excluded for focus, and 145 articles were included in the synthesis of results, with 105 of them being case reports or case series. The analysis encompassed a comprehensive examination of the selected articles to determine the incidence, risk factors, clinical presentation, diagnostic approaches, and treatment modalities related to BIA-ALCL. Conclusions: Plastic surgeons should be aware of the elevated risks by implant surface type, implement appropriate patient surveillance, and follow the recommendations outlined in this statement to ensure patient safety and optimize outcomes. Ongoing research on the pathogenesis, genetic drivers, and preventative and prophylactic measures for BIA-ALCL is crucial for improving patient care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.

Abstract The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

7502 Background: The BCL-2i venetoclax is active in certain HMs but can increase the risk of tumor lysis syndrome (TLS), requiring a 5-week dose ramp-up for CLL patients. Cases of severe neutropenia with venetoclax treatment have also been reported. Lisaftoclax is a novel, potent, selective BCL-2i that is active against HMs and is under clinical development. Methods: This first-in-human global phase I dose study assessed the safety, PK, PD, efficacy, and MTD/RP2D of lisaftoclax in patients with R/R CLL and other HMs. Lisaftoclax was orally administered daily in a 28-day cycle. Patients with CLL or intermediate-high TLS risk were initiated on a daily ramp-up schedule until the assigned dose before the study cycles. Results: On January 7, 2021, 35 pts had been enrolled and treated with lisaftoclax at doses ranging from 20 to 1,200 mg, with a median (range) of 2 (1-13) prior lines of treatment, and had diagnoses of R/R CLL or SLL (n = 15), MM (n = 6), FL (n = 5), WM (n = 4), and either AML, MCL, DLBCL, MDS, or HCL (n = 1 each). No DLT has been observed, even though 1,200 mg was considered as the highest dose treated. The MTD has not been reached, and no laboratory or clinical TLS has been reported. Any grade TRAEs in > 10% of pts included neutropenia (22.9%) and anemia (17.1%; hematologic), and fatigue (28.6%), diarrhea (17.1%), and nausea (11.4%; nonhematologic). Grade >3 TRAEs were neutropenia (14.3%) and thrombocytopenia, leukopenia, lymphopenia, fatigue, and nausea (2.9% of pts each). In CLL/SLL pts, grade 3-4 TRAEs included neutropenia (13.3%) and thrombocytopenia (6.7%), which did not cause treatment-related discontinuation. In all, 12 of 35 pts (34.3%) had non-treatment-related SAEs, and only two pts experienced > 1 SAE. With a median (range) treatment of 7 (3-20) cycles, 12 of 14 evaluable R/R CLL/SLL pts achieved PR, for an ORR of 85.7% and a median (range) time to response of 3 (2-7) cycles. Absolute lymphocyte counts (ALCs) were reduced at lisaftoclax doses as low as 20 mg/day. The preliminary PK profile showed that exposures increased with lisaftoclax doses from 20 to 1,200 mg (average half-life: 4-5 hours). On BH3 profiling, lisaftoclax rapidly triggered changes in BCL-2 complex in CLL/SLL pt samples, which were consistent with rapid clinical reductions in ALCs. Conclusions: Lisaftoclax was well tolerated up to 1,200 mg/day. No TLS was observed, even with the daily ramp-up schedule. There were no significant new or unmanageable safety findings, and the ORR in R/R CLL/SLL pts was 85.7%. Grade 3-4 TRAEs were infrequent, even at dose levels of 800 mg and above. BCL-2i lisaftoclax offers a treatment alternative for patients with R/R CLL/SLL and other HMs, with a daily ramp-up schedule that may be more pt “user friendly” and a favorable preliminary safety profile. Internal study identifier APG2575-001. Clinical trial information: NCT03537482.

8004 Background: The primary objective of this phase 3 trial was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti-CD38 monoclonal antibody, combined with pomalidomide (P)/dexamethasone (d) versus (vs) Pd. Methods: Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4mg PO days 1-21; 40mg [20mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity. Results: 307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36-86) yrs; median prior lines of therapy: 3 (2-11); estimated GFR: <60ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high-risk cytogenetics. At median follow-up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44-0.81), P=0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P<0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10-5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461-1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3h at 1st inf. and 2.8h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3-4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd. Conclusions: IsaPd significantly improved PFS and ORR vs Pd, with a manageable safety profile. IsaPd is an important new treatment option for the management of RRMM. Clinical trial information: NCT02990338.

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

Purpose Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. Patients and Methods The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. Conclusion The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.