The genomic and clinical consequences of replacing procarbazine with dacarbazine in escalated BEACOPP for Hodgkin lymphoma [Retrospective study].

Highlight(s): Procarbazine induces a higher mutation burden and novel mutational signatures in patients with Hodgkin lymphoma (HL) treated with escalated-dose bleomycin–etoposide–doxorubicin–cyclophosphamide–vincristine–procarbazine–prednisolone (eBEACOPP) and their germline DNA, raising concerns for the genomic health of survivors of HL and hereditary consequences for their offspring. Replacing procarbazine with dacarbazine (“Dac”) appears to mitigate gonadal and stem-cell toxicity while maintaining similar clinical efficacy.

In this two-part retrospective, observational study, the authors first compared mutational landscapes in hematopoietic stem and progenitor cells (HSPCs) from patients with advanced-stage HL in remission for at least 6 months who had been treated with eBEACOPDac (eBEACOPDac cohort), eBEACOPP (real-world eBEACOPP cohort), or doxorubicin–bleomycin–vinblastine–Dac (ABVD); in buccal DNA from five children of a female patient with classical HL treated with eBEACOPP before conceiving the third child; in sperm DNA from a patient with mild oligospermia treated with eBEACOPP; and in cecal adenocarcinoma and healthy colon tissue from a survivor of HL treated with chlorambucil–vinblastine–procarbazine–prednisolone. For the second part, the authors analyzed efficacy and toxicity data from adult patients (aged >16 years) treated with first-line eBEACOPDac (eBEACOPDac cohort) at 25 centers across the UK, Ireland, and France; efficacy was compared with the German HD18 eBEACOPP trial data and toxicity with a UK real-world dataset. Participants in the German HD18 and UK real-world datasets were adults (aged >16 years) with previously untreated HL, treated with first-line eBEACOPP.

In the first part of the study (mutational analysis), patients treated with eBEACOPP (n=5) exhibited a

higher burden of point mutations in HSPCs compared with those treated with eBEACOPDac (n=4) or ABVD (n=3; excess mutations 1150 [95% confidence interval (CI) 934–1366] vs. 290 [241–339] vs. 186 [116–254]). Two novel mutational signatures, SBSA (SBS25-like) and SBSB were identified in HSPCs and in a single neoplastic and healthy colon sample from patients who received procarbazine-containing chemotherapy. SBSB was also identified in the germline DNA of three children conceived after eBEACOPP and in the sperm of a male patient treated with eBEACOPP. SBSC was detected in patients treated with either ABVD or eBEACOPDac.

In the second part of the study (efficacy and toxicity analysis), dacarbazine substitution did not appear to compromise efficacy or safety. 312 patients treated with eBEACOPDac (eBEACOPDac cohort; treated 2017–22, 186 [60%] male, median follow-up 36 months [IQR (interquartile range) 25–50]) had a 3-year progression-free survival (PFS) of 93% (95% CI 90–96), which was similar to the 93% [95% CI 92–94]) PFS seen in 1945 patients in the German HD18 eBEACOPP trial (treated 2008–14, 1183 [61%] male, median follow-up 57 months [35-65]). Patients treated with eBEACOPDac required fewer blood transfusions (mean 1.7 units, standard deviation (SD) 2.8] vs. 3.7 units [SD 3.9]; p<0.0001), demonstrated higher post-chemotherapy sperm concentrations (median 23 million per mL [IQR 11–632] vs. 0.0 million per mL [0–0.001]; p=0.0040) and had earlier resumption of menstrual periods (mean 5 months [SD 3] vs. 8.8 months [SD 5.6]; p=0.0036) compared with 73 patients treated with eBEACOPP in the UK real-world dataset.

Real-World Safety and Health Care Resource Utilization of Teclistamab Under an Outpatient Model for Step-Up Dosing Administration [Retrospective study].  

Highlight(s): As teclistamab is increasingly used in the real world, the step-up dosing (SUD) model for teclistamab continues to evolve, shifting from inpatient to outpatient settings to reduce health care resource utilization and improve treatment experience while ensuring patient safety. Findings of this study add evidence to support institutions and providers that seek to initiate teclistamab SUD in an outpatient setting.

This study evaluated safety and health care resource utilization (HRU) in real-world patients with multiple myeloma who initiated teclistamab SUD in an outpatient setting. This retrospective study used Mayo Clinic’s electronic medical records from October 26, 2022, to October 31, 2023. Patient characteristics were summarized for all patients treated with teclistamab and separately for patients who started SUD as outpatients. SUD pattern, safety, HRU, and post-SUD dosing schedule were described in patients with complete SUD. At the data cutoff, 65 patients received ≥1 teclistamab dose, including 58 patients who initiated SUD in outpatients (median age, 69.2 years). Among 57 patients who completed SUD in an outpatient setting, all received pre-medications on the days of teclistamab administrations per label recommendation; 18 (31.6%) developed cytokine release syndrome (CRS; 13 grade 1, four grade 2, and one grade 4) and two developed immune effector cell–associated neurotoxicity syndrome (ICANS; one each with grade 2 and 4). All CRS and ICANS were resolved with supportive care, and all patients continued treatment. Eighteen patients were admitted to the hospital for CRS treatment, with a median CRS-related hospital stay of 2 days per admission. Most (60%) doses during SUD required <1 hour of clinic time between administration and checkout. Post-SUD, clinic time for treatment doses decreased to <30 minutes for most (82%).

Efficacy and Safety of Venetoclax Plus Azacitidine for Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes [Phase 1 clinical trial].  

Highlight(s):  Venetoclax (14 days) + azacitidine regimen was well tolerated in patients with treatment-naive high-risk myelodysplastic syndromes (HR MDS), with no unexpected safety findings. The regimen produced complete remission (CR) in 29.9% of patients and a 26-month median overall survival (OS).

This phase 1b study investigated the safety and efficacy of venetoclax, a selective BCL-2 inhibitor, at the recommended phase 2 dose (RP2D: 400 mg for 14 days/28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days/28-day cycle) for treatment-naive HR MDS (NCT02942290). As of May 2023, 107 patients had received a venetoclax and azacitidine combination at the RP2D. Best response of CR or marrow CR was observed in 29.9% (primary efficacy outcome) and 50.5% of patients, respectively. Modified overall response was 80.4%. Median OS was 26.0 months, with 1 year and 2-year survival estimates of 71.2% and 51.3%, respectively. Of 59 patients who were red blood cell and/or platelet transfusion-dependent at baseline, 24 (40.7%) became transfusion-independent on study, including 11 (18.6%) who also achieved CR. The median time to next treatment excluding transplantation was 13.4 months. Adverse events reflected known safety profiles for venetoclax and azacitidine (primary safety outcome), including constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%). A phase 3 study (NCT04401748) is ongoing to confirm the survival benefit of this combination.

Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms [Retrospective study].

Highlight(s): This study shows that TP53 aberrations (mutations and/or allelic loss) are an independent factor that affects survival outcomes, and this impact depends on the burden of this aberration. Secondly, the diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)  and the burden of TP53 aberrations independently affect survival, and allogeneic hematopoietic stem cell transplantation (HSCT) leads to equivalent improved outcomes in both diagnosis groups.

This retrospective analysis included patients with newly diagnosed MDS (>5% blasts) and AML with TP53 mutation(s) treated at MD Anderson Cancer Center. The authors factored patient age, TP53 aberration burden, therapy intensity, use of venetoclax in the AML subgroup, and HSCT to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation + allelic deletion, or a single mutation with variant allele frequency (VAF) ≥40%; TP53 low risk (TP53LR) included a single TP53 mutation VAF ≥40%. 413 patients (291 AML, 122 MDS) at a median age of 69.4 years were included, 350 (85%) with TP53HR (253 AML [87%], 97 [79%] MDS). The overall response (OR) rate was 53% in AML and 62% in MDS. OR and composite complete response (CRc) rates were similar in patients with AML, irrespective of treatment

intensity, but higher when treated with venetoclax. At a median follow-up of 77 months, median OS was superior in patients with MDS than with AML (10.8 versus 5.9 months). On multivariate analysis, MDS had lower hazards of death compared to AML, as did TP53LR and HSCT. In the AML cohort, TP53LR and HSCT were favorable on multivariate analysis, though venetoclax did not improve survival.

The significance of free light-chain ratio in light-chain monoclonal gammopathy of undetermined significance: a flow cytometry sub-study of the iStopMM screening study [Retrospective study].

Highlight(s): These findings support using a kappa involved free light-chain (FLC) ratio cutoff of >3.15 to more accurately identify individuals at increased risk of developing symptomatic plasma cell (PC) disorders.

Light-chain (LC) monoclonal gammopathy of undetermined significance (LC-MGUS) is characterized by FLC levels outside defined reference intervals, indirectly indicating underlying PC monoclonality. In this study, next-generation flow cytometry (NGF) was used to evaluate clonal PC presence in bone marrow (BM) samples from individuals with LC-MGUS in the iStopMM study (based on screening 75,422 individuals for monoclonal gammopathy), aiming to assess the predictive value of the FLC ratio for clonal PC presence and its prognostic implications. BM samples from 61 individuals with LC monoclonal gammopathy were analyzed. Clonal PCs were detected in 53.6% of LC-MGUS samples (n = 28) and in all samples from individuals with more advanced conditions (n=33). The FLC ratio was predictive of clonal PC presence for kappa-involved FLC ratios (p<0.05; n=42), with an optimal cutoff of 3.15 (96.7% sensitivity, 91.7% specificity). Of 195 individuals with kappa-involved LC-MGUS in follow-up within the iStopMM study, none with FLC ratios >1.65 to 3.15 progressed to MM (n=124), whereas 4/71 (5.6%) with FLC ratios >3.15 progressed over a median follow-up of 55 months.