Matching-adjusted indirect comparison of the pelabresib-ruxolitinib combination vs JAKi monotherapy in myelofibrosis.

Janus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease and toxicities frequently lead to JAKi discontinuation. Preclinical data indicate that combining JAK and bromodomain and extraterminal (BET) domain inhibition leads to overlapping effects in MF. Pelabresib (CPI-0610), an oral, small-molecule BET1,2 inhibitor (BETi), in combination with ruxolitinib showed improvements in spleen volume reduction (SVR35) and total symptom score reduction (TSS50) from baseline in the phase 2 MANIFEST study (NCT02158858) in patients with MF. Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for the comparison of SVR35, TSS50, and TSS measured at several timepoints in arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment-naive patients with MF), with data from the following JAKi monotherapy studies in JAKi treatment-naive patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib and momelotinib), and JAKARTA (fedratinib). Response rate ratios >1 were observed for pelabresib with ruxolitinib vs all comparators for SVR35 and TSS50 at week 24. Improvements in TSS were observed as early as week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment-naive MF.

Utilization of real-world data in assessing treatment effectiveness for diffuse large B-cell lymphoma.

Direct comparisons of the effectiveness of the numerous novel therapies in the diffuse large B-cell lymphoma (DLBCL) treatment landscape in a range of head-to-head randomized phase 3 trials would be time-consuming and costly. Comparative effectiveness studies using real-world data (RWD) represent a complementary approach. Recently, several studies of relapsed/refractory (R/R) DLBCL have used RWD to create observational cohorts to compare patient outcomes with cohorts derived from single-arm phase 2 trials. Using propensity score methods to balance clinically and prognostically relevant baseline covariates, closely matched patient-level cohorts can be generated. By incorporating appropriate measures to assess covariate balance and address potential bias in comparative effectiveness study designs, robust comparative analyses can be performed. Results from such studies have been used to supplement regulatory approval of therapies assessed in single-arm trials. While RWD studies have a greater susceptibility to bias compared to randomized controlled trials, well-designed and appropriately analyzed studies can provide complementary real-world evidence on treatment effectiveness.

Effect of mode of administration on Edinburgh Postnatal Depression Scale in the South Indian population: A comparative study on self-administered and interviewer-administered scores.

BACKGROUND: Edinburgh Postnatal Depression Scale (EPDS) is a validated screening tool widely used to assess perinatal depression (PND). However, due to stigma associated with PND, respondents could answer sensitive questions differently depending on the mode of administration, especially in culturally and linguistically diverse country like India. The present study explored longitudinal differences in EPDS scores between self-administered and interviewer-administered modes. METHODS: 177 women from rural South India were administered EPDS, self-administration followed by interviewer-administered for four visits, twice each during prenatal and postnatal visits. EPDS scores were compared between the two modes descriptively, graphically and by repeated mixed measure models. Classification of antenatal depression (AD), postnatal depression (PD) and PND based on the two modes were compared by McNemar Chi-square test. Clinical and psychosocial characteristics were examined to identify factors associated with differences in the scoring modes. Concordance rates and Goodman Kruskal's Gamma coefficients were measured for individual EPDS items. RESULTS: Longitudinal EPDS scores and rates of AD, PD and PND were significantly higher in self-administered mode. Recent adverse life events were the only factor observed to be significantly associated with the differences between the two modes. Rank correlation and concordance rates suggested stronger association for EPDS items relating to anhedonia subscale and moderate/weaker association for EPDS items relating to anxiety/depression subscales. CONCLUSION: Our study findings suggest that the effect of mode of administration should be taken into account while using PND screening tools such as EPDS, especially in countries such as India with higher levels of illiteracy.

RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma.

PURPOSE: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. PATIENTS AND METHODS: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. CONCLUSIONS: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.

Identification of clinical and psychosocial characteristics associated with perinatal depression in the south Indian population.

BACKGROUND: Longitudinal perinatal depression (PND) data is sparsely available in the Indian population. We have employed Edinburgh Postnatal Depression Scale (EPDS) to assess the prevalence and identify characteristics associated with PND in the south Indian population. PND was assessed longitudinally using EPDS scores with traditional cut-off approach as well as a novel method of latent class mixture modeling (LCMM). The LCMM method, to the best of our knowledge, has been used for the first time in the Indian population. METHODS: Three hundred and forty seven women, predominantly from economically-weaker sections of rural and urban South India were longitudinally assessed for antenatal depression (AD) and postnatal depression (PD) using EPDS cutoff-scores ≥13 and ≥10, respectively. Uni/multivariable analyses were used to identify PND associated characteristics. LCMM was then implemented, followed by risk characteristics identification. RESULTS: PND prevalence from traditional approach was 24.50 % (12.68 % AD; 18.16% PD). Characteristics associated with PND were urban-site and recent adverse life events. Irregular menstrual history and chronic health issues were associated with AD and PD, respectively. Three distinct PND trajectories were observed from LCMM-analysis: low-risk (76.08%), medium-risk (19.89%) and high-risk (4.04%). Urban-site, recent adverse life events, irregular menstrual history and pregnancy complications were associated with medium-risk/high-risk trajectories. LIMITATIONS: EPDS is a screening tool and not a diagnostic tool for depression. Since the study population included women from economically-weaker sections, the results need verification in other socio-economic groups. CONCLUSIONS: Both the traditional cut-off-based approach and LCMM provided very similar conclusions regarding the prevalence of PND and characteristics associated with it. Higher PND prevalence was observed in urban women compared to rural women. In low-income countries, identifying risk characteristics associated with PND is a critical component in designing prevention strategies for PND related conditions because of the limited access to mental health resources.

A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours.

BACKGROUND: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436). PATIENTS AND METHODS: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1. RESULTS: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%). CONCLUSION: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.