Patients R2 Research Articles

Subcutaneous Epcoritamab with Rituximab + Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma:Phase 1/2 Trial Update

Background: For patients with relapsed or refractory (R/R) follicular lymphoma (FL), therapies such as rituximab + lenalidomide (R2) have demonstrated efficacy and acceptable safety. However, better treatments are needed to help more patients achieve deeper and more durable responses. Epcoritamab is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells to kill malignant B cells. R2 and epcoritamab have nonoverlapping toxicity profiles and, therefore, may be safely combined. In addition, the immunomodulatory properties of lenalidomide may enhance the therapeutic potential of epcoritamab. Preliminary results from arm 2b of the phase 1/2 EPCORE NHL-2 trial (NCT04663347), which tested R2 and epcoritamab in patients with R/R FL, showed an overall response rate of 93% and a complete metabolic response rate of 61% at the first assessment (6 wk; Falchi et al, ASCO 2022). Here we present updated data on a larger cohort and longer follow-up from arm 2b of EPCORE NHL-2. Methods: Adults with R/R CD20+ FL were treated with subcutaneous epcoritamab 48 mg + standard R2 for 12 cycles of 28 d each. Epcoritamab was dosed as follows: QW, cycles 1 and 2; Q4W, cycles ≥3 up to 2 y. Step-up epcoritamab dosing and corticosteroid prophylaxis were required during cycle 1 to mitigate CRS. PET-CT was used to assess responses per Lugano 2014 criteria. Results: As of the data cutoff date of June 10, 2022, 62 patients had received epcoritamab (48 mg) + R2. The median age was 65 y (range, 30-79), 58% of patients had stage IV disease, 52% had FLIPI 3-5, 31% had primary refractory disease, and 47% had experienced disease progression within 24 mo after starting first-line treatment. Half of patients (50%) had received 1 prior line of therapy (range, 1-9). Treatment was ongoing in 56 patients (90%), with a median follow-up of 4.0 mo. Six patients discontinued therapy due to disease progression (n=4) or other reasons (death due to COVID-19, n=1; reason unknown, n=1). The most common treatment-emergent AEs of any grade were CRS (37%; 27% grade 1, 10% grade 2, no grade 3-4), neutropenia (29%; 5% grade 1-2, 24% grade 3-4), fatigue (26%; 24% grade 1-2, 2% grade 3-4), and injection-site reactions (26%; all grade 1-2). Most CRS events (in 35% of all evaluable patients) occurred after the first full dose of epcoritamab. All CRS events resolved (median time to resolution, 2 d; range, 1-4), no patients discontinued treatment due to CRS, and 5 patients received tocilizumab. ICANS (grade 1) occurred in 1 patient 22 d from the start of treatment, and it resolved in 7 d. There were no clinical tumor lysis syndrome events. Among 41 efficacy-evaluable patients, the overall response rate was 95% (39/41), with 73% of patients (30/41) achieving a complete metabolic response (CMR) as their best overall response. Most CMRs (27/30) were achieved by the first assessment (6 wk), and nearly all (29/30) were ongoing at the time of data cutoff. Of the 9 patients with a partial metabolic response, 6 had an ongoing response at the time of data cutoff. The longest duration of response was 4.5+ mo. Median progression-free survival was not reached (Figure). Conclusions: In patients with R/R FL, subcutaneous epcoritamab + R2 demonstrated a manageable safety profile with only low-grade CRS events, mostly observed following the first full dose and all of which resolved. No new safety signals were detected. Data from this cohort are very encouraging with a high CMR rate observed in patients with R/R FL. These data are consistent with prior results from the EPCORE NHL-2 trial and supportive of ongoing investigation of epcoritamab + R2 in patients with R/R FL. A phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1) will open in 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IBCL-460 Subcutaneous Epcoritamab With Rituximab + Lenalidomide (R2) in Patients With Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Update from Phase 1/2 Trial

R/R FL is associated with a poor prognosis and remains incurable; thus, better treatment options are needed. Epcoritamab is a subcutaneously administered CD3xCD20 bispecific antibody that has shown substantial antitumor activity in R/R FL. Evaluate safety and efficacy of epcoritamab with R2 in patients with R/R FL in arm 2 of a phase 1/2 open-label trial (EPCORE NHL-2; NCT04663347). Adults with R/R CD20+ FL were included. As of December 1, 2021, 30 patients (median age, 68 y) had enrolled. Patients received subcutaneous epcoritamab (QW, cycle [C] 1-3; Q2W, C4-9; Q4W, C≥10 up to 2 y) + R2 for 12 cycles of 28 d. Step-up dosing and corticosteroid prophylaxis were required. Of the 30 patients (epcoritamab 24 mg, n=3; 48 mg, n=27), 21 (70%) had stage IV disease and 20 (67%) had FLIPI scores 3-5. Median (range) number of prior lines of therapy was 1 (1-5), 30% had primary refractory disease, and 40% had disease progression within 24 mo after starting first-line treatment. At a median (range) follow-up of 5.1 mo (0.8-12.3), 25 patients (83%) remained on treatment; 5 patients discontinued treatment due to progression (n=2), AEs (n=2), or consent withdrawal (n=1). Common treatment-emergent AEs (TEAEs) of any grade (G) included infections (57%), injection-site reactions (50%), constipation (37%), fatigue (37%), and neutropenia (37%). CRS events occurred in 15 patients (50%; G1-2 43%, G3 7%), primarily in C1. All CRS events resolved; 3 patients were treated with tocilizumab, and 1 patient discontinued treatment due to CRS. One patient experienced G2 ICANS. No fatal TEAEs occurred. Overall response rate for the 27 evaluable patients was 100%; 93% had a complete metabolic response (CMR) and 7% had a partial metabolic response by PET-CT. As of the data cut, the longest duration of response was 7.0+ mo and ongoing. Subcutaneous epcoritamab + R2 exhibits promising efficacy, including a high CMR rate, in patients with R/R FL. The safety profile was consistent with prior data. Updated data will be presented. This study was funded by Genmab A/S and AbbVie.

Updated interim analysis of the randomized phase 1b/3 study of tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma.

7572 Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, showed antitumor activity as monotherapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R2) demonstrated an objective response rate (ORR) of 73%–78% and median progression-free survival (PFS) of 36–39 months. This global, multicenter phase 1b/3 study is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R2 in patients with R/R FL after ≥1 prior therapy. We report an updated interim analysis of the phase 1b safety run-in where we assess the clinical activity and pharmacokinetics (PK) of TAZ when administered with R2 in patients with R/R FL. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily) in 28-day cycles with standard-dose R2 (NCT04224493). In addition to PK and safety, preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, PFS, and duration of response (DOR) per investigator assessment according to Lugano 2014 response criteria. Results: As of January 22, 2022, 43 patients were enrolled and receiving TAZ + R2 (400 [n = 4], 600 [n = 18], and 800 mg [n = 21]). These patients had a median age of 67 years (range, 39–83) and received a median of 1 prior therapy (range, 1–4). Overall, 15/43 (34.9%) patients were refractory to rituximab, 10/39 (25.6%) had POD24, and 6/41 (14.6%) had mutant-type EZH2. Median duration of treatment exposure was 32.0 weeks (range, 4.1–68.1). Mean Cmax and AUC0–t of TAZ 800 mg + R2 at steady state were similar to those found for TAZ as monotherapy. PK of TAZ was not altered by concomitant administration of daily oral lenalidomide 20 mg, and PK of lenalidomide was not altered by concomitant administration of TAZ. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the January 2022 data cutoff. Serious treatment-emergent adverse events (TEAEs) were observed in 14 (32.6%) patients. Grade 3–4 TEAEs were observed in 24 (55.8%) patients; the most common grade 3–4 TEAE was neutrophil count decrease (n = 13; 30.2%). Of 38 patients evaluable for tumor assessment, 19 (50.0%) had a complete response, 17 (44.7%) had a partial response, and 2 (5.3%) had stable disease. ORR was 94.7% (n = 36). With a median follow-up of 5.8 months, median PFS and DOR were not reached and appeared to be similar, regardless of mutation status. Conclusions: TAZ + R2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide as well as a favorable safety profile and efficacy trend. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL. Clinical trial information: NCT04224493.

Pituitary Volume and Iron Overload Evaluation by 3T MRI in Thalassemia.

To evaluate pituitary volume and iron overload in beta thalassemia major, with the objective of assessing the reliability of this method in predicting hypogonadism. 3T MRI was used to measure pituitary R2 and T2* in 57 beta thalassemia major patients and 30 controls. Anterior pituitary volume was evaluated by MRI planimetry. Cardiac, hepatic, and pancreatic iron overload were also assessed using MRI T2*. Mean serum ferritin was estimated by sandwich immuno-assay. Short stature was defined as height < 3 rd percentile for age, and clinical hypogonadism defined as absence of secondary sexual characteristics at ages ≥13 y for females and ≥ 14 y for males. Short stature was present in 32 patients (56.1%). Of the 47 patients in the pubertal age group, 11(23.4%) had hypogonadism. Serum ferritin correlated positively with pituitary R2 (p = 0.004) and negatively with anterior pituitary volume (p = 0.006), whereas pituitary R2 correlated negatively with cardiac T2* (p = 0.001). Patients with hypogonadism had lower pituitary R2 (p = 0.186), T2* (p = 0.048), and anterior pituitary volumes (p = 0.012) compared to those with normal sexual maturity. Regardless of stature, no significant difference was observed between pituitary R2 (p = 0.267) and T2* (p = 0.451). Mean pituitary R2 in patients (78.99Hz) was higher than in controls (20.8Hz) (p = 0.0001). Anterior pituitary volume was lower in patients (264.83mm3) than in controls (380.87mm3) (p = 0.0001). A threshold value of 22.85Hz for pituitary R2 gave a sensitivity of 84.2% and a specificity of 73.3% in distinguishing pituitary iron content of patients from controls, with an area of 0.864 under the ROC curve. 3T MRI is a reliable method to detect pituitary iron overload and predict risk of hypogonadism in beta Thalassemia.

Symptoms of voiding dysfunction and other coexisting pelvic floor dysfunctions: the impact of transvaginal, mesh-augmented sacrospinous ligament fixation.

The objective was to investigate the prevalence for voiding dysfunction and if symptom improvement can be achieved by adequate pelvic floor surgery. We evaluated the Propel Study data from 281 women with pelvic organ prolapse (POP) stage 2-4. Bother caused by obstructive micturition, voiding dysfunction, and coexisting pelvic floor symptoms were assessed using the Pelvic Floor Distress Inventory (PFDI) preoperatively and 6, 12, and 24months after vaginal prolapse repair. Successful reconstruction (Pelvic Organ Prolapse Quantification [POP-Q] stage 0-I throughout the 2-year follow-up at all compartments, "responders"), was compared with all others ("non-responders"). Prevalence of voiding dysfunction was significantly reduced after surgery for all patients with "moderate" to "quite a bit" of bother ("R2") regarding all examined PFDI questions. Defects of the posterior/apical compartment and lower stage defects were found to cause obstructive micturition, which improved significantly after POP surgery. Sixmonths after surgery, the prevalence of R2 for voiding dysfunction symptoms was reduced significantly for responders compared with non-responders. Significant reduction of R2 in patients with rectoceles could be shown for some PFDI questions, whereas the rate was lower in patients with cystoceles. Other pelvic floor symptoms often coexisted in patients with voiding dysfunction symptoms and improved significantly after surgery as well. Symptoms of voiding dysfunction are frequent in female patients with POP and can significantly improve after vaginal mesh-augmented prolapse repair even for posterior and minor defects. Before counseling patients to undergo POP surgery because of their obstructive symptoms, other causes of voiding dysfunction must first have been ruled out.

Validation of a Dutch Version of the Reproductive Concerns Scale (RCS) in Three Populations of Women

We investigated the psychometric properties of a Dutch version of the Reproductive Concerns Scale (RCS). Questionnaires (N = 515) were administered to 90 women with breast cancer, 227 women with fertility problems, and 198 healthy controls. Principal axis factor analysis suggested a one-factor structure with 11 items (breast cancer patients R2 =.48, α =.87, ICC =.95; women with fertility problems R2 =.45, α =.89, ICC =.86). Women with fertility problems reported the most concerns (M = 21.8, SD = 9.6), followed by breast cancer patients (M = 14.8, SD = 10.0) and healthy controls (M = 6.4, SD = 7.0). Theoretically related constructs were correlated to the RCS (.33 < r >.73). The RCS seems to be a valid tool for assessing women's reproductive concerns.

Clinical and Correlative Analysis of a Phase 2 Study of Lenalidomide and Rituximab in Previously Untreated Indolent Non-Hodgkin Lymphoma

Background: Despite an increase in our understanding of the pathophysiology of indolent non-Hodgkin lymphoma(iNHL) and the recent advances in targeted therapies, the optimal treatment for patients has not been determined. Rituximab has demonstrated clinical benefit in combination with chemotherapy for indolent NHL, and rituximab-based chemotherapy combinations are used both in first-line and salvage therapy. The immunomodulatory agent, lenalidomide, has demonstrated clinical activity as a single agent and in combination with rituximab in most NHL subtypes.Aims: The goals of this study were to determine the clinical benefit, safety profile, and immunological effects associated with response to R2 in patients with previously untreated iNHL.Methods: Patients with previously untreated iNHL with measurable disease and an ECOG Performance Status Score ≤ 2 were enrolled. Oral lenalidomide (20 mg/day) was given on days 1–21 of a 28-day cycle, with 4 weekly doses of rituximab (375mg/m2) as an induction phase. This was followed by lenalidomide maintenance that was continued until disease progression or unacceptable toxicity. Overall response rate (ORR) was the primary endpoint, and secondary endpoints included response duration, overall survival, progression-free survival (PFS), immune correlates and safety. For immunology studies, plasma and viable PBMC were obtained at baseline, day 15, day 30, day 60 and day 120. Levels of plasma IL-1β, 2, 6, 8, 10, 12, GM-CSF, IFN-γ, TNF-α and CXCL-10 (IP-10) were measured by a multiplex assay (Meso Scale Discovery). T cell activation (CD38+/HLA-DR+) and expression of PD-1 markers on CD4+ and CD8+ lymphocytes were examined by flow cytometry assays using viable cryopreserved PBMCs. Th1, Th2 and Th17 cells were examined after in vitro stimulation. NK cell activity was examined after in vitro culture with PMA. Subsets of dendritic cell (DC) subsets (CD11c+ and CD123+) were also examined.Results: Twenty-two patients are enrolled and 18 are currently evaluable for response assessment. The median age is 60 years (50–78). The histological subtypes included: 19 patients with follicular lymphoma (FL) and 3 with marginal zone lymphoma. Responses were achieved in 17 patients (94%), and 10 (62%) had a CR. At a median follow-up time of 27 months, the median PFS for all patients has not yet been reached (Figure 1). Ten patients (62%) needed at least one dose reduction and 2 patients came off-study due to toxicity (rash). Fatigue (13%), neutropenia (19%), lymphopenia (25%), and hyponatremia (19%) were the most common grade 3 or 4 adverse events. Immunologic examinations indicated a marked increase in D15 IFN-γ and IP-10 levels in patients achieving CR. High baseline levels of TNF-α, IL-10, and IL-1β predicted a poor outcome. Further analyses of immune correlates are currently ongoing, including T cell activation, NK cell functions, DC subsets, and Th1/Th2/Th17/Treg subsets. The results of immune correlates in this trial were compared with those obtained in a trial of equivalently treated patients with relapsed/refractory (R/R) iNHL.Conclusion: These results demonstrate that the R2 combination has significant clinical activity in patients with previously untreated NHL, with an ORR of 94%, a CR rate of 62% and a median PFS that has not been reached after 27 months. Toxicities were mild and manageable. Immunological studies in this trial, as well as in the trial with R/R patients indicated that lenalidomide-mediated induction of IP-10 and IFN-γ predicted CR and high baseline levels of TNF-α, IL-10, and IL-1β were associated with a poor outcome. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A study of the M235T variant of the angiotensinogen gene and hypertension in a sample population of Calabar and Uyo, Nigeria

A common molecular variant of the angiotensinogen gene had been reported to predispose some ethnic groups to hypertension. This case–control study was designed to determine the frequency and association of the angiotensinogen M235T allele with hypertension in residents of Calabar and Uyo cities, south–south Nigeria.The study involved 1308 subjects, 612 patients and 696 controls. The M235T variant was investigated using an allele specific polymerase chain reaction and enzymatic digestion to determine allele frequencies. Hypertensinogenic factors such as dietary habits, physical activity, smoking and drinking habits were assessed using questionnaires. Descriptive statistics, chi-square and multiple regression analysis were used to analyze the data obtained.The M235T allele frequency was high (0.94 for hypertensives and 0.96 for controls) though it was not associated with hypertension status. The odds ratio for hypertension was 0.64 (95% confidence interval: 0.39–1.06) there were no significant differences between the genotype frequency of hypertensives and controls. By multiple regression, Hypertension was observed to be associated with age and was a predictor for systolic blood pressure in both patient r2=0.359; p<0.05 and control groups r2=0.26.Age and body mass index were predictors for diastolic blood pressure in the control group, r2=0.28.Although the frequency of the M235T variant was high, it was not a significant risk factor for hypertension in the study population.

Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects.

Growth hormone (GH) secretion declines with age and is affected by body composition. The signal that mediates the latter relationship remains III-defined. Leptin, the protein product of the adipocyte specific ob gene, is thought to accurately reflect fat mass and could therefore be a candidate to influence GH secretion. We have therefore investigated the relationship between GH status, leptin and body composition in normal and GH-deficient elderly subjects. GH Secretion was assessed by 20-minute sampling over 24 hours and serum leptin concentrations were measured in a single morning, fasted sample. Twenty-one GH deficient elderly patients (61-83 years) and 22 gender- and BMI-matched controls (61-88 years). Body composition was assessed by dual-energy X-ray absorptiometry (DEXA). GH was measured in an ultrasensitive chemiluminescent assay and serum leptin was determined by radio-immunoassay. Leptin was correlated with percentage body fat in both sexes (male r = 0.75, female r = 0.89, both P < 0.001). Male patients had increased fat mass (FM) (P < 0.01) and leptin concentrations (P < 0.05) but similar lean mass (LM) compared with controls. However, leptin concentration per unit FM was identical in both groups (P = 0.3). In contrast, female patients had lower LM (P < 0.05) but similar FM to controls, yet their leptin concentration per unit FM was twice that of the controls (P < 0.05). In multiple linear regression (MLR) leptin was determined positively by FM and negatively by LM (controls r2 = 76%; patients r2 = 73%, both P < 0.0001). When controlled for gender, GH secretion in the controls was correlated negatively with leptin (r = -0.68, P < 0.01) and negatively with percentage body fat (r = -0.73, P < 0.01). In MLR, using leptin as a marker of body composition, 66% of the variability in GH secretion in the controls could be explained by gender (38%) and by leptin (28%). Both decreased lean mass and increased fat mass raise serum leptin concentrations in normal and growth hormone-deficient elderly subjects. Leptin is therefore a marker of body composition rather than fat mass alone. The influence of body composition on growth hormone secretion in the elderly may be mediated through leptin, acting as a peripheral signal from adipose tissue to decrease GH secretion.

Distribution of phosphatidylcholine molecular species between mixed micelles and phospholipid-cholesterol vesicles in human gallbladder bile: dependence on acyl chain length and unsaturation.

The partitioning of phosphatidylcholine (PC) molecular species between mixed micelles and vesicles was studied in each of seven human gallbladder biles. Biles were fractionated by Sephacryl S-300 SF gel filtration chromatography, and PC species in the micellar and vesicular fractions were quantitated by high performance liquid chromatography. Micelles were enriched in species containing unsaturated acyl groups (e.g., 16:1-18:2, 18:1-18:2, and 18:1-18:3); vesicles were enriched in more highly saturated species (e.g., 16:0-16:1, 16:0-18:1, and 18:0-18:1). Separate multivariate analyses for each bile demonstrated that the distribution of PC species between vesicles and micelles was related to the degree of sn-1 and sn-2 unsaturation, and sn-1, but not sn-2, chain length. In addition, the tendency to partition into the micellar phase was particularly marked when unsaturation was present at both the sn-1 and sn-2 positions. When this interaction was included in the multivariate analyses, the regression models accounted for virtually all of the variation in PC partitioning (for each of the seven patients r2 = 0.92-0.98, P less than 0.03). These results suggest that the partitioning of PC species between micelles and vesicles is strictly determined by sn-1 chain length and the degree of unsaturation at both the sn-1 and sn-2 positions. In light of recent reports that fatty acyl composition influences the cholesterol content of vesicles and micelles in model biles, these results raise the possibility that diet-induced alterations in the phospholipid species and the relative proportions of biliary lipid particles may influence the cholesterol-carrying capacity of bile.