Low Discontinuation Rate Research Articles

Vedolizumab more likely to be discontinued than ustekinumab in anti-TNF-experienced patients with fistulizing Crohn's disease.

Data on the performance of newer biologics in patients with fistulizing Crohn's disease (CD) are limited. Our study's objective was to evaluate the response to ustekinumab (UST) and vedolizumab (VDZ) in patients with fistulizing CD. Retrospective cohort. We used natural language processing of electronic medical record data to identify a retrospective cohort of individuals with fistulizing CD at a single academic tertiary-care referral center and then performed a chart review. Individuals were eligible for inclusion if a fistula was present at the time of UST or VDZ initiation. Outcomes included medication discontinuation, surgical intervention, development of a new fistula, and fistula closure. Groups were compared with unadjusted analyses and competing risk analyses using multi-state survival models. In all, 68 patients were included (48 UST and 20 VDZ). Most patients had one fistula (79%) and had prior anti-tumor necrosis factor-α treatment (98% in UST group, 80% in VDZ group, p = 0.01). VDZ was significantly more likely to be discontinued than UST (p < 0.0001), most frequently due to inadequate clinical response. Those on UST had a longer median time to surgery for CD than those on VDZ (p = 0.008). In those without surgical fistula repair, 79% on UST and 100% on VDZ still had an active fistula at 1 year (p = 0.30). In individuals with fistulizing CD, our data suggest that UST has better clinical utility than VDZ based on lower rates of discontinuation, though the sample size is small. These findings highlight the importance of further research on the treatment of perianal fistulizing Crohn's disease.

Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.

To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS). Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking. We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93). Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).

A Retrospective Study on the Efficacy of Subcutaneous Immunoglobulin as Compared to Intravenous Formulation in Patients with Chronic Lymphocytic Leukemia and Secondary Antibody Deficiency.

Secondary antibody deficiency (SAD) is a common complication in chronic lymphocytic leukemia (CLL) which favors the development of life-threatening infections. Subcutaneous immunoglobulins (IG) (SCIG) have been proven to be as effective as intravenous immunoglobulin (IVIG) in primary immunodeficiencies. Since only a few studies investigated SCIG in secondary antibody deficiency, the aim of this study was to assess the efficacy and safety of SCIG or IVIG in CLL patients with secondary antibody deficiency. One hundred and sixteen CLL patients were recruited, 63% were males, and the median age was 68 years; 44% had bronchiectasis and 76% never smoked. Forty-nine patients received IVIG and 88 SCIG, including 28 patients who shifted from IVIG to SCIG. Despite similar baseline IgG levels, patients receiving SCIG achieved higher IgG after at least +6 months (p = 0.0009). We observed that SCIG can decrease the cumulative incidence of first (HR 0.39 p < 0.0001) and second (HR 0.56 p = 0.0411) infection more than IVIG. The effect was remarkable in that patients were able to reach at least 6 g/L of IgG after 6 months of treatments (p < 0.0001). Replacement therapies were well tolerated with less adverse events and a lower discontinuation rate in patients was managed with SCIG than IVIG. In this study we describe the clinical features of a large cohort of CLL with secondary antibody deficiency receiving IG. We demonstrated that SCIG are active and well tolerated drugs that allows to reach higher IgG levels and decrease the rate of infections better than IVIG, in particular when IgG levels reach 6 g/L.

Lecanemab (BAN2401) Infusion Reactions and Immunogenicity: Results from Randomized Phase 2 Study and an Open‐Label Extension (OLE).

AbstractBackgroundTreatment with 10 mg/kg lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species, has been shown to reduce amyloid PET standard uptake value ratio (SUVr) and slow clinical decline in an 18‐month, phase 2 proof‐of‐concept study (Study 201 Core) in early Alzheimer’s disease with an OLE. The present analysis aimed to review infusion related reactions from Study 201 and the results of immunogenicity assessments from the completed lecanemab clinical trial.MethodsInfusion related reactions were summarized by treatment group using descriptive statistics. All adverse events were coded using MedDRA version 24.0 and graded based on CTCAE guidelines.Analysis of anti‐drug antibodies (ADA) and its impact on pharmacokinetics, pharmacodynamics, efficacy, and safety during Study 201 were undertaken. All ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach.ResultsIn Study 201 Core, 854 treated subjects (lecanemab:609; placebo:245) were randomized across 6 treatment groups. In the OLE phase a total of 180 subjects were treated with lecanemab 10 mg/kg biweekly (LEC10BW). Infusion‐related reactions were the most common adverse event associated with LEC10BW treatment, with 19.9% (32/161) of subjects compared to 3.3% (8/245) of placebo subjects. All events were mild/moderate in severity, most occurred with the first infusion, resulted in a low rate of discontinuations (LEC10BW:2.5%; placebo:0.8%). Over 70% of patients who initially experienced infusion‐related reactions had no further reactions with preventative medications. Infusion reaction data from the OLE were consistent with the Core study. The incidences of ADA for LEC10BW in the Core and OLE were 40.9% and 11.1% (Core placebo‐treated subjects), respectively; titers were very low (most ≤125). Detailed analysis of lecanemab ADA demonstrated no meaningful impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.ConclusionsIn the lecanemab Study 201 Core and OLE, infusion‐related reactions were the most common adverse event, however were readily manageable with preventative medication, were of low severity, and resulted in minimal discontinuations. Lecanemab is a low‐risk molecule for immunogenicity based on ADA profile and minimal impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.

Fibromyalgia Concomitant with Seropositive Rheumatoid Arthritis in a Tertiary Hospital in South-Western Saudi Arabia: Prevalence and Treatment Patterns

Introduction: Rheumatoid arthritis (RA) patients with fibromyalgia syndrome (FMS) report worse functional status and quality of life hence the association has important clinical implications. FMS can be challenging to treat, and the current evidence recommends a multidisciplinary treatment approach focused on symptom management. Aim: Information regarding the current prevalence of FMS in RA patients is lacking. Thus, this study aims to address the prevalence and predictors of FMS in seropositive RA patients and demonstrate our clinical practice in the management of FMS. Methods: Participants’ data was gathered from Aseer central hospital (ACH) rheumatology clinics and daycare units over a period of 2 years. Subjects were assessed using the 2010 American College of Rheumatology (ACR) criteria for FMS. Data were collected from medical records, including patient demographics, comorbidities and concomitant FMS-related data. Results: Out of 310 seropositive RA patients, 15% (n = 47) fulfilled the diagnostic criteria for FMS. Of them, 29, 11 and 7 were on pregabalin, amitriptyline and duloxetine, respectively. Half of FMS patients showed one or more therapy changes. A significant difference between RA patients with and without concomitant FMS was observed, including age, gender and comorbidities. Conclusion: In this retrospective study, a high prevalence of FMS in individuals with seropositive RA was identified. This study explores real-world practice in the treatment of FMS with remarkable findings regarding underdosing and lower discontinuation rate of pregabalin.

Real World Data on Unique Challenges and Outcomes of Older Patients with AML from Resource Limited Settings: Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC)

Despite significant advances in the treatment of acute myeloid leukemia (AML), outcomes in older patients continue to be suboptimal, due to a combination of adverse disease characteristics and increasing prevalence of co-morbidities. This challenge is further magnified in resource-limited settings where logistical and financial barriers often preclude effective therapy. In addition, a significant number of patients do not undergo any evaluation after diagnosis, resulting in very little real-world data on treatment outcomes in this cohort. We present data on epidemiology and treatment patterns in older patients with AML from the Indian Acute Leukemia Research Database [INwARD] established by Hematology Cancer Consortium (HCC). Retrospective data from 17 centres was collected to include patients older than 55 years diagnosed between January 2018 and April 2021. A lower age cut off of 55 years was used based on previous data indicating adverse physiologic characteristics comparable to a 65 year old individual in the West. No exclusion criteria were specified. The primary objectives were to ascertain the proportion of patients receiving therapy and one-year overall survival among treated patients. Patient status was assessed as on March 31, 2022. A total of 733 patients (M:F=1.48) were included in this study, of which only 339 (46%) patients underwent further evaluation and treatment. The most common reasons for not initiating treatment were to begin evaluation at another centre (37%) and financial constraints(13%). Among treated patients, the median age at diagnosis was 63 years (IQR, 59-69), with 130 (40.2%) having an ECOG performance score ≥ 2 and 203 (60.4%) having at least one comorbidity. No differences in baseline attributes were noted among treated or untreated patients.(Table 1) Of the 339 patients who received treatment, initial therapy comprised hypomethylating agents (HMA) in 247 (72.8%) patients, standard or modified 7+3 regimen in 64 (18.8%) and other intensive regimens in 2 (0.59%) patients. Infections requiring treatment were diagnosed in 117 (40.3%) patients, with 36 (13.79%) requiring intensive care. A second induction was required in 26 patients, of which 5(19%) received intensive chemotherapy and 8 (30%) received HMA. Early mortality (within 60 days of diagnosis) was noted in 58(20.1%) out of 288 evaluable patients at this time point. Poor performance status baseline was significantly associated with early mortality(p=0.015) with no effect of age or associated co-morbidities. Among patients who died within 60 days, a significantly higher white cell count was observed at baseline (median, 20310 vs 7200/mm3,p=0.005). Complete remission (CR) was achieved in 24(36%) patients after intensive chemotherapy. Among 146(59%) evaluable patients receiving HMA, 62(42%) achieved CR at any time point after therapy. The probability of achieving CR significantly decreased with increasing age (p=0.037). Allogeneic stem cell transplant was utilized for only 11 (3.2%) patients in the treated cohort. After a median follow up of 5 months (IQR 1.4 to 14.6 months), 102 (32.2%) patients were lost to follow up and only 72 (26%) had completed treatment. For survival analysis, patients lost to follow up were considered dead at the date of last follow up. At the end of one year, probability of survival was 32.9%, (Figure 1) with the median overall survival being 190 days (95% CI, 143 to 236) in the treated cohort. Among 145 patients with available data, the most common cause of death was progressive disease (52%), followed by infectious complications (29%). Conclusions Our data highlights dual challenges of low rates of treatment initiation and significant treatment discontinuation within one year in patients older than 55 years of age with AML in India. Poor disease biology is also highlighted by low rates of CR irrespective of initial therapy and low probability of survival at one year. Financial challenges emerge as major modifiable factors leading to incomplete treatment. This large registry dataset indicates the need for more effective, affordable and safer treatment options for this group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Carfilzomib Use Among Patients with Relapsed/Refractory Multiple Myeloma in the Asia Pacific Region: Characteristics and Outcomes By Regimen from a Prospective, Real-World Study

Background: Carfilzomib (CFZ) is a next-generation proteasome inhibitor currently approved in combination with lenalidomide and dexamethasone (KRd) or with dexamethasone alone (Kd) for treatment of multiple myeloma (MM) patients with ≥1 prior line of therapy in the Asia-Pacific (APAC) region. Here, we describe utilization of KRd and Kd in routine clinical practice in APAC, including treatment patterns, patient profile, reasons for discontinuation, clinical outcomes, and frequency of adverse events (AEs). Methods: This prospective, single-arm cohort study recruited adults with relapsed/refractory MM who received ≥1 dose of CFZ in routine clinical practice as either a combination or monotherapy regimen and had received ≥1 prior line of MM treatment before CFZ initiation. Between July 2019 and June 2021, approximately 300 patients were planned to be enrolled in this study. Medical history, patient characteristics, and clinical data are collected at baseline and throughout the 2-year observation period or until death, withdrawal of consent, or loss of follow-up. Follow-up data are collected through chart reviews every 3 months. AEs leading to treatment discontinuation are collected; common AEs associated with drugs/disease were excluded from collection by the protocol (all serious AEs were collected). The study is ongoing, and last patient record for the analysis will be collected no later than Q1 2023. Results: As of data cutoff April 1, 2022, 311 patients were enrolled, of whom 38 are excluded from the present analysis (11 died before waiver of informed consent approval and 27 patients had missing data for the first medical chart review or first CFZ administration). The 273 patients included in this ad hoc interim analysis were enrolled from 5 countries/regions: Australia (n=46), Hong Kong (n=17), Korea (n=172), Singapore (n=13), and Taiwan (n=25). To date, the regimens prescribed were KRd (n=160, 59%), Kd (n=103, 38%), and other CFZ-based regimens (n=10, 4%; monotherapy [n=1]; not classified [1]; or with dexamethasone and cyclophosphamide [5], pomalidomide [2], or daratumumab [1]). Table 1 displays detailed patient and disease characteristics, and Table 2 displays CFZ utilization and response. Overall, 33% of patients reported a history of hypertension, 11% of cardiac disorders, 7% of diabetes mellitus, and 3% of pulmonary embolism, prior to CFZ initiation. On average, patients prescribed KRd were slightly younger than those prescribed Kd. The majority of KRd patients (68%) had received 1 prior line of treatment, whereas one-third of Kd patients (36%) had received ≥4 prior lines of treatment. Similar proportions of KRd (33%) and Kd (34%) populations were bortezomib refractory, and 73% of Kd patients were lenalidomide refractory. The planned CFZ dose at first cycle was in accordance with the local product information and was used in 89% of KRd and 69% of Kd patients (27 and 56 mg/m2 twice weekly, respectively). At data cutoff, 43.1% and 30.1% of KRd and Kd patients, respectively, remained on CFZ treatment. The most common reason for CFZ discontinuation was disease progression/refractory disease. With KRd and Kd, respectively, the best overall response rate was 79.0% (n=94/119) and 54.7% (n=29/53) and median overall survival was 60.9 (95% confidence interval [CI], 55.9-not estimable [NE]) and 54.5 (95% CI, 33.3-NE) months. CFZ-treatment-related AEs of interest occurred in 10 (3.7%) total patients (cardiac arrhythmia, n=1 Kd; cardiac failure, 1 KRd; dyspnea, 2 KRd, 2 Kd, 1 other CFZ; hematopoietic thrombocytopenia, 1 KRd and 1 Kd; ischemic heart disease, 1 KRd; no incidence of treatment-related acute renal failure, hypertension, and peripheral neuropathy). Overall, 10 (3.7%) patients discontinued CFZ owing to an AE. Conclusions: This study investigates the real-world use of CFZ for relapsed/refractory MM in a predominantly Asian patient population across the APAC region. Interim results confirm that the standard dosing schedules for KRd and Kd are well tolerated in real-world practice and suggest a very low rate of discontinuation due to CFZ-related AEs, even in heavily pretreated MM. Further prospective data collection of patients in routine practice is ongoing to assess patterns of longer-term patient management, patterns after CFZ treatment failure, CFZ toxicity according to number of previous lines of therapy, response, survival outcome, and AEs, which will inform optimal use of CFZ. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

In Vitro Evidence of Double Blockade of Asciminib with Reduced Dose of ATP-Binding Pocket Inhibitors in the Treatment of Chronic Myeloid Leukemia Harboring ABL1 Kinase Domain Mutation

Background Asciminib (ASC), a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, inhibiting BCR-ABL1 via allosteric binding. ASCEMBL trial showed superior efficacy of ASC to Bosutinib (BOS) with a higher molecular response rate, and a lower rate of discontinuation due to lack of efficacy (24.2% vs 35.5% at week 96). However, 24.2% of the patients still experienced lack of efficacy with ASC monotherapy. Also, out of the 39 patients who discontinued ASC due to lack of efficacy, 22 patients (56%) showed a new or persistent ABL1 kinase domain (KD) mutation either on ATP binding sites or Myristoyl pocket site. This finding suggests that ASC monotherapy is not always sufficient to overcome TKI-resistance particularly in those who already experienced multiple TKI failure. Accordingly, dual inhibition of ABL1 kinase protein with ASC combined with ATP binding pocket inhibiter (ABPI) is very attractive option to overcome TKI resistance. The remaining question is dose. A phase 1 study attempted to determine appropriate dose of ASC in combination with fixed dose of ABPIs including Imatinib (IMA), Dasatinib (DAS) and Nilotinib (NIL). But, this approach with fixed dose of ABPIs could add up toxicities not just from ABPIs but also from the combination of two drugs. Accordingly, a different strategy is to be developed to reduce the exposure to ABPI, while combining with ASC. In the present study, we simulated the combination treatment of ASC with ABPIs based on a clinically accessible fixed-dose for various ABL1 mutations to obtain answers to the following questions:Can combination of ASC with 4 different type of ABPIs be universally effective to suppress CML cell growth via dual blockade?Is there a specific ABPI for dual blockade in a specific ABL1 kinase domain mutation?What is the drug concentration of ABPIs for dual blockade when combined with fixed dose of ASC? Methods and Materials In order to simulate the combination treatment of ASC with ABPIs, the IC50 for ASC and ABPI measured from wild type K562 and BaF3BCR-ABL+cell lines were applied: ASC (3nM), IMA (150nM), BOS (10nM), DAS (0.8nM) and NIL (10nM) was applied in the wild type (WT) BaF3 cell lines and cell inhibition was assessed with WST-8 assay. 8 different BaF3 cell lines including wild type, G250E, Y253H, E255K, M244V, M351T, F317V and H369P mutant lines were treated with ABPI alone, ASC alone, and in combination by serial dilution based starting from the measured IC50 concentration, and the Dose-Response matrix was calculated and analyzed through SynergyFinder. Results A part of the results are summarized in the figure. As shown, with each ABPI at the baseline IC50 concentration in K562 cells, cell growth was inhibited to 59.8%, 56.9%, 61.5%, 59.9% and 71.6-79.4% with IMA, BOS, DAS, NIL and ASC (Fig A). When cell growth inhibition was assessed with combination treatment of reduced dose of ABPI and fixed dose of ASC (3nM), we observed that the combination treatment of ASC with ABPI can inhibit BaF3 cell growth even at a reduced concentration of ABPI from IC50 (Fig B). When combined of ABPI at baseline doses with 3nM ASC, 100% of cell inhibition was noted as expected. When treated with 3nM ASC with with 50% reduced dose of ABPI, 84.6-100% of cell inhibition was noted in WT, 99.2-99.6% in G250E, 96.8-99.4% in E255K mutant BaF3 cell lines, concluding that these cell lines were highly sensitive to double blockade; M351T and F317V BaF3 cell lines showed in the range between 30-77% of cell inhibition with a half dose of ABPI/baseline dose ASC, referring it intermediate sensitive cell lines; H369P, Y253F and M244V cell lines showed less effective cell inhibition compared to other cell lines, indicating the low sensitive cell lines. It implies that each cell line does have its own inherent profile of resistance to double blockade (Fig C). In addition, DAS and BOS seems to be better ABPIs for double blockade for intermediate to low sensitive mutations except the F317V mutation, which can be overcome with IMA or NIL combination. Conclusion The current study strongly suggests that 1) double blockade with reduced dose of ABPI in combination with fixed dose of ASC is effective to control CML cells with different ABL1 KD mutations. Each cell lines does have its inherent resistance level to double blockades, which needs to be further explored. A phase 1 study with reduced dose of ABPI in combination with fixed dose ASC is strongly warranted to define an optimal dose for combination. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Transplant-Ineligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Clinical Assessment of Key Subgroups of the Phase 3 Maia Study

Introduction: The MAIA study (NCT02252172) evaluated D-Rd versus Rd alone in transplant-ineligible pts with NDMM. At a median follow-up of 56.2 months, D-Rd significantly improved progression-free survival (PFS) and overall survival versus Rd (Facon T, Lancet Oncol 2021). Here, we present an analysis of clinically important subgroups in MAIA, including pts aged ≥75 years, pts with International Staging System (ISS) stage III disease, pts with renal insufficiency (defined as baseline creatinine clearance [CrCl] ≤60 mL/min), pts with extramedullary plasmacytomas at baseline, and pts with high cytogenetic risk (defined as having ≥1 of the following high-risk cytogenetic abnormalities: t[4;14], t[14;16], del17p [per IMWG recommendations]). Methods: In MAIA, pts with NDMM who were ineligible for high-dose chemotherapy and autologous stem-cell transplant were randomized 1:1 to receive D-Rd or Rd. All pts received 28-day cycles of oral Rd (R: 25 mg [10 mg recommended if CrCl was 30-50 mL/min] on Days 1-21; d: 40 mg [20 mg if aged >75 years or body-mass index <18.5 kg/m2] on Days 1, 8, 15, 22). Pts in the D-Rd arm received intravenous daratumumab (16 mg/kg QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter). Pts in both arms were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS, and key secondary endpoints included overall response rate (ORR) and minimal residual disease (MRD)-negativity rate (10-5 sensitivity). Results: 737 pts were randomized (D-Rd, n=368; Rd, n=369); most subgroups had a similar number of pts per treatment arm: age ≥75 years (n=160; n=161); ISS stage III (n=107; n=110); renal insufficiency (n=162; n=142); extramedullary plasmacytomas (n=15; n=9); and high cytogenetic risk (n=48; n=44). After a 64.5-month median follow-up, PFS (Figure A) and ORR (Figure B) generally favored D-Rd versus Rd across subgroups. MRD-negativity rates were higher with D-Rd versus Rd for pts aged ≥75 years (26.9% vs 9.9%; P<0.0001), pts with ISS stage III disease (27.1% vs 10.9%; P=0.0030), pts with renal insufficiency (29.6% vs 7.7%; P<0.0001), pts with extramedullary plasmacytomas (33.3% vs 0%; P=0.1181), and pts with high cytogenetic risk (25.0% vs 2.3%; P=0.0019). Sustained (≥6 months and ≥12 months) MRD-negativity rates were higher with D-Rd versus Rd across subgroups: age ≥75 years (≥6 months, 15.6% vs 5.0%; ≥12 months, 13.8% vs 3.1%), ISS stage III disease (≥6 months, 17.8% vs 3.6%; ≥12 months, 15.9% vs 2.7%), renal insufficiency (≥6 months, 21.0% vs 1.4%; ≥12 months, 18.5% vs 1.4%), extramedullary plasmacytomas (≥6 months, 26.7% vs 0%; ≥12 months, 13.3% vs 0%), and high cytogenetic risk (≥6 months, 12.5% vs 0%; ≥12 months, 12.5% vs 0%). In an analysis of safety among pts aged ≥75 years, grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 95.5% of D-Rd pts and 95.0% of Rd pts; the most common (≥20%; D-Rd/Rd) were neutropenia (62.4%/41.5%), lymphopenia (21.0%/12.6%), anemia (20.4%/25.2%), and pneumonia (20.4%/14.5%). Serious TEAEs occurred in 80.9% and 79.2% of D-Rd and Rd pts, respectively. TEAEs led to study treatment discontinuation in 15.3% of D-Rd pts and 27.7% of Rd pts. TEAEs with an outcome of death occurred in 11.5% of D-Rd pts and 13.2% Rd pts. Conclusions: In this subgroup analysis of MAIA, D-Rd improved PFS, ORR, and MRD-negativity rates versus Rd across clinically important subgroups, including pts aged ≥75 years, pts with ISS stage III disease, pts with renal insufficiency, pts with extramedullary plasmacytomas, and pts with high cytogenetic risk. In pts aged ≥75 years, the rates of grade 3/4 and serious TEAEs were similar with D-Rd and Rd, with a lower rate of discontinuation due to TEAEs for D-Rd versus Rd. Results for these clinically important subgroups provide confidence in using D-Rd across all pt types, supporting D-Rd as a standard of care for transplant-ineligible pts with NDMM. Results for additional cytogenetic risk subgroups that include pts with gain and/or amp 1q21 will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns and Outcomes after Ibrutinib Discontinuation Among Elderly Medicare Beneficiaries with Chronic Lymphocytic Leukemia: An Observational Study

Background: Most prior studies of ibrutinib discontinuation in chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) rely on data from clinical trials and/or selected medical centers, which are often limited to younger and/or commercially insured patients and may not be generalizable to routine clinical practice. Also, limited data are available on the next line of treatment initiated after ibrutinib discontinuation in the real-world setting. The objective of this study was to examine ibrutinib discontinuation patterns, overall survival (OS) and factors associated with these patterns among elderly Medicare beneficiaries in the U.S. Methods: This retrospective cohort study used 2013-2019 100% Medicare claims data to identify beneficiaries who newly initiated ibrutinib from 1/1/2014 to 12/31/2018. Study eligibility criteria included: continuous Medicare Part A, B, and D coverage in 12-months before and at least 4-months after the index date (first ibrutinib prescription claim date), CLL/SLL diagnosis in the 12-month pre-index period and at any time over follow-up, ≥66 years on index date, absence of ≥2 diagnoses for another FDA-approved indication for ibrutinib, and absence of ibrutinib prescription in the 12-month pre-index period. Outcomes included ibrutinib discontinuation (defined as the presence of a consecutive 60-day gap in ibrutinib treatment), time to ibrutinib discontinuation, type of CLL/SLL treatment initiated after ibrutinib discontinuation, and OS. Cox regression models were used to examine factors associated with ibrutinib discontinuation. Results: Our final sample included a total of 11,870 Medicare patients newly initiating ibrutinib treatment. Nearly two-thirds (65.2%) of our cohort discontinued ibrutinib use over a median follow up of 25.2 months (IQR: 14.4-39.6) from initiation. Among those who discontinued ibrutinib, 51.1% discontinued within 6 months and 69.2% within 12 months. Among discontinuers, approximately 39% initiated another CLL/SLL treatment after ibrutinib discontinuation over a median follow up of 14.4 months (IQR: 4.8-27.6) post-ibrutinib discontinuation. Of the patients who initiated another CLL/SLL treatment after ibrutinib discontinuation, 21.3%, 18.9%, 10.8%, and 10.0% received venetoclax, rituximab, bendamustine and idelalisib, respectively, either as monotherapy or combination therapy. About 25% of patients who discontinued ibrutinib restarted treatment with ibrutinib at some point during follow-up. In multivariable analysis, patients aged ≥80 years (Hazard ratio [HR]: 1.51; 95% CI: 1.41-1.63); lack of low-income subsidy (LIS) to cover all or part of prescription out-of-pocket costs (HR: 1.08; 95% CI: 1.01-1.16); initiation of ibrutinib as part of combination therapy (HR: 1.16, 95% CI: 1.08-1.25); evidence of prior history of CLL treatment (HR: 1.14, 95% CI 1.08-1.20); atrial fibrillation (HR: 1.27, 95% CI 1.19-1.35); conduction disorders (HR: 1.11, 95% CI 1.03-1.20); heart failure (HR:1.09, 95% CI: 1.01-1.17) and; any hospitalization in the 12-month pre-index period were associated with discontinuation (HR:1.10, 95% CI:1.04-1.16). Lastly, median OS in the entire sample was 4.4 years after ibrutinib initiation. The 3-year survival rate was 72.2% for non-discontinuers but only 56.8% for discontinuers. Among patients who discontinued ≤12 months after initiation, less than half (47.4%) were still alive after 3 years. Conclusions: In this large real-world analysis utilizing 100% Medicare files, the majority (65.2%) of elderly individuals initiating ibrutinib for CLL/SLL discontinued therapy over a median follow up of 25.2 months. Discontinuation was most likely in those with advanced age and baseline comorbidities. Overall, our findings demonstrate a high unmet need with ibrutinib, the widely used first generation Bruton-tyrosine kinase inhibitor (BTKI), in the elderly U.S. population with CLL/SLL. With the development of second and later generations of BTKIs, it will be important to confirm they offer lower discontinuation rates and improved real-world outcomes.

Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis

BackgroundTo compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing–remitting multiple sclerosis switching from fingolimod.MethodsUsing data from MSBase registry, this multicentre cohort study included...

CLL-410 Adherence and Discontinuation Among Medicare Beneficiaries Initiating Venetoclax versus BTKis for Relapsed/Refractory Chronic Lymphocytic Leukemia

Compelling clinical trial data for BCL2 (i.e., venetoclax) and BTK inhibitors (BTKis) have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. However, contemporary real-world studies evaluating venetoclax and BTKis remain limited, with real-world adherence and discontinuation in patients treated with venetoclax versus BTKis uncertain. To compare real-world venetoclax versus BTKis treatment patterns in older adults with relapsed/refractory (R/R) CLL. We performed a retrospective claims-based study using 2015-2019 100% Medicare Parts A/B/D, identifying fee-for-service Medicare beneficiaries aged ≥66 years newly initiating venetoclax between 1/1/2016 and 12/31/2018. From the remaining individuals during the same period, we also identified patients newly initiating a BTKi. Treatment outcomes in the 12-month post-index period included adherence (proportion of days covered [PDC] ≥0.80) and discontinuation (evidence of a 90-day consecutive gap in treatment [sensitivity analyses: 60- and 120-day gaps]). Logistic regressions controlling for differences in sociodemographic and clinical characteristics between the two study groups were used to estimate adjusted outcomes. We identified 711 and 1,566 mutually exclusive groups of beneficiaries initiating venetoclax and BTKi, respectively. Compared to BTKi initiators, those initiating venetoclax tended to be slightly younger (mean age 75.6 [SD 6.0] vs. 77.6 [SD 6.9] years, P<0.001) but had poorer clinical characteristics (for example, 39.4% vs. 30.4% with ≥8 comorbidities [P<0.001] and 51.5% vs. 42.5% with any hospitalization in the 12-months pre-index [P<0.001]). Beneficiaries initiating venetoclax had a higher unadjusted rate of adherence (57.9% vs. 47.3%, P<0.001) and a lower unadjusted rate of discontinuation at 12 months compared to BTKi (32.8% vs. 45.1%, P<0.001). Sensitivity analyses using a 60- and 120-day gap showed similar results. After risk adjustment, the venetoclax group had even higher adherence (61.9% vs. 45.4%, P<.0001) and lower discontinuation when compared to the BTKi group (28.5% vs. 47.4%, P<0.001). In this large, real-world study utilizing national Medicare data, older heavily pre-treated adults with R/R CLL initiating venetoclax had higher rates of adherence and lower rates of discontinuation relative to those initiating BTKis, despite poorer clinical characteristics. These favorable real-world venetoclax results are encouraging and support the goal of developing well-tolerated novel combinations for older adults.

LONG-TERM SAFETY OF ONCE-NIGHTLY SODIUM OXYBATE: INTERIM ANALYSIS OF DATA FROM RESTORE

LONG-TERM SAFETY OF ONCE-NIGHTLY SODIUM OXYBATE: INTERIM ANALYSIS OF DATA FROM RESTORE

Dalbavancin in the treatment of acute bacterial skin and skin structure and other infections: a safety evaluation

ABSTRACT Introduction Dalbavancin is a second-generation lipoglycopeptide approved since 2014 to treat acute bacterial skin and skin-structure infections (ABSSSI). Dalbavancin is characterized by Gram-positive activity and novel pharmacokinetic properties allowing prolonged terminal half-life andonce weekly dosing . A good safety profile was reported in clinical trials . Areas covered Dalbavancin safety and tolerability from trials and post-marketing studies were reviewed. While most reports included predominantly ABSSSI, two clinical trials and recent observational studies have explored the use of dalbavancin for off-label indications, mainly including bloodstream and osteoarticular infections. Expert opinion The occurrence of drug-related adverse effects (AE) was similar between dalbavancin and comparators in clinical trials enrolling patients with ABSSSI. Most common AE included gastrointestinal symptoms, infusion reaction, and hypersensitivity. Low rates of drug discontinuation and serious AE were reported across studies. In the past 5 years, several observational studies have reported safety data on the use of dalbavancin, confirming its favorable safety profile. Nevertheless, data from dalbavancin off-label use, often derived from prolonged (>2 weeks) treatments with variable dosing regimens, were mainly retrospective and lacked comparators. Further research is required to allow a reliable analysis of short- and long-term dalbavancin-related AE in non-ABSSSI.

Dermal Safety of Tapinarof Cream 1%: Results From 4 Phase 1 Trials

Tapinarof (VTAMA&reg;; Dermavant Sciences, Inc.) is a novel, non-steroidal, topical, aryl hydrocarbon receptor agonist, FDA approved for psoriasis treatment and under investigation for atopic dermatitis treatment as a 1% cream formulation for once-daily (QD) application. Evaluate cumulative skin irritation, sensitization, and photoallergic and phototoxic potential of tapinarof cream 1% across a range of dosing frequencies and conditions. We conducted 4 randomized, controlled, phase 1 trials of topical tapinarof cream 1% vs vehicle or other appropriate controls in healthy adults. Cumulative skin irritation was assessed following QD application for 21 days under fully occlusive patch conditions. Contact sensitization, photoallergenicity, and phototoxicity were assessed under semi-occlusive patch conditions. The contact sensitization and photoallergenicity trials used an induction phase of repeated applications followed by a 2-week rest period and a 1-time challenge, with rechallenge if responses indicated sensitization/photosensitization; the phototoxicity trial comprised a single application. Ultraviolet A and B irradiation was used to assess photoallergenicity/toxicity. 376 participants were randomized across the 4 trials. In the cumulative irritation trial, tapinarof cream 1% QD was classified as having a slight potential for very mild cumulative irritation under the exaggerated test conditions of repeated dosing for 21 days. There was no evidence of sensitization, photosensitization, or phototoxicity. Tapinarof was well tolerated and there was a low discontinuation rate across all trials. Tapinarof cream 1% was well tolerated, non-sensitizing, non-phototoxic, and non-photoallergic, with no evidence of clinically meaningful cumulative skin irritation in 4 dermal safety trials in healthy adults. IND 104601 J Drugs Dermatol. 2022;21(10):1084-1090. doi:10.36849/JDD.6627R1.

Long-term safety, discontinuation and mortality in an Italian cohort with advanced Parkinson’s disease on levodopa/carbidopa intestinal gel infusion

IntroductionLevodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson’s disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors.MethodsWe conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan–Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson’s correlation was used to analyze predictors of WL.ResultsThe average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain–Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008).ConclusionsLCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.

Multidisciplinary approach to treatment with immune checkpoint inhibitors in patients with HIV, tuberculosis, or underlying autoimmune diseases.

We reviewed the available information on the use of immune checkpoint inhibitors (ICIs) in populations with special conditions, namely, patients with HIV, tuberculosis, or underlying autoimmune disease. Available data show that treatment with ICIs is safe in patients with HIV; it is advisable, however, that these patients receive adequate antiretroviral therapy and have an undetectable viral load before ICIs are initiated. Tuberculosis reactivation has been reported with the use of ICIs, possibly due to immune dysregulation. Tuberculosis has also been associated with the use of immunosuppressors to treat immune-related adverse events (irAEs). Active tuberculosis must be ruled out in patients with symptoms or signs, and selected patients may benefit from screening for latent tuberculosis infection, although more data are required. Limited data exist regarding the safety of ICIs in patients with cancer and autoimmune disease. Data from observational studies suggest that up to 29% of patients with a preexisting autoimmune disease treated with an ICI present with an autoimmune disease flare, and 30% present with a de novo irAE of any type. The frequency of flares appears to differ according to the type of ICI received, with higher rates associated with PD-1/PD-L1 inhibitors. The most common autoimmune diseases for which patients reported flares with ICI therapy are rheumatoid arthritis, other inflammatory arthritis, and psoriasis. Most studies have reported flares or de novo irAEs associated with ICIs that were mild to moderate, with low rates of discontinuation and no deaths due to flares. Therefore, the use of ICIs in these patients is possible, but careful monitoring is required.

P717: BOSUTINIB IN NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA: GASTROINTESTINAL, LIVER, EFFUSION AND RENAL SAFETY CHARACTERIZATION IN THE BFORE TRIAL

Background: Bosutinib is approved for the treatment of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Efficacy and safety of bosutinib vs imatinib in patients with newly diagnosed CP CML was assessed in the phase 3 BFORE trial (NCT02130557). Aims: The safety profile of bosutinib after 5 years follow-up, with a focus on gastrointestinal, liver, effusion and renal treatment-emergent adverse events (TEAEs), was characterized. Methods: Patients who received ≥1 dose of bosutinib (n=268) or imatinib (n=265) 400 mg/day in BFORE were included. Adverse events (AEs) of special interest were analyzed by selecting prespecified MedDRA terms to generate TEAE clusters. This analysis is based on the final database lock: June 12, 2020. Results: Median duration of treatment was 55 months for patients receiving bosutinib or imatinib; respective median (range) dose intensity was 393.6 (39–583) vs 400.0 (189–765) mg/d. Any grade TEAEs occurred in 98.9% and 98.9% of bosutinib- vs imatinib-treated patients. The most common newly occurring TEAEs (any grade) after 12 months were increased lipase (9.0%) with bosutinib, and diarrhea (8.3%) with imatinib. In bosutinib- vs imatinib-treated patients, 25.4% vs 14.3% had AEs leading to permanent treatment discontinuation; the majority discontinued in year 1 (14.2% vs 10.6%). The most frequent AEs leading to discontinuation were increased ALT (overall, 4.9%; year 1, 4.5%) with bosutinib vs thrombocytopenia (overall, 1.5%; year 1, 1.5%) with imatinib. Gastrointestinal, liver, effusion and renal TEAEs, respectively, occurred in 79.9%, 44.0%, 6.0% and 10.4% (maximum grade 3/4 [G3/4]: 9.0%, 26.9%, 1.1% and 2.2%) of bosutinib- vs 61.5%, 15.5%, 2.3% and 9.8% (G3/4: 1.1%, 4.2%, 0.4% and 0.8%) imatinib-treated patients. One grade 5 renal TEAE occurred in the bosutinib arm and was not considered related to treatment. Cumulative rates per treatment year are shown in the Table. The most common gastrointestinal TEAEs were diarrhea (bosutinib vs imatinib: 75.0% vs 40.4% [G3/4: 9.0% vs 1.1%]) with bosutinib, and nausea (37.3% vs 42.3% [G3/4: 0% vs 0%]) with imatinib. In both arms, the most common liver, effusion and renal TEAEs, respectively, were increased ALT and/or AST (34.0% vs 8.3% [G3/4: 22.0% vs 2.3%]), pleural effusion (5.2% vs 1.9% [G3/4: 0.7% vs 0.4%]) and increased blood creatinine (6.7% vs 8.3% [G3/4: 0.4% vs 0.4%]). Gastrointestinal, liver, effusion and renal TEAEs infrequently led to treatment discontinuation (1.9%, 7.8%, 0.7% and 0.7% vs 1.1%, 0.8%, 0% and 0.4%). Image:Summary/Conclusion: The safety profiles of bosutinib and imatinib in BFORE were distinct, with no new safety signals identified after 5 years of follow-up. The onset of TEAEs occurred primarily during year 1 (e.g., gastrointestinal and liver), with an increased incidence of some TEAEs (e.g., effusion and renal) in later years. Discontinuations due to AEs generally occurred early into treatment, with low rates of discontinuation due to gastrointestinal, liver, effusion and renal AEs. These long-term safety results further support the use of first-line bosutinib as a standard of care in patients with CP CML.

CPAP setup by mail: we're not there yet.

CPAP setup by mail: we're not there yet.

Comparative efficacy and safety of systemic antifungal agents for candidemia: a systematic review with network meta-analysis and multicriteria acceptability analyses

Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia. A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included. Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%). Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.