Treatment Discontinuation Rates Research Articles

Effectiveness and Safety of Biological Therapies in Very Severe Plaque Psoriasis: A Real-Life Retrospective Study.

Psoriasis can have a significant impact on quality of life and productivity, especially with increased severity. However, there is limited evidence on biologics' efficacy in highly severe cases compared to moderate-to-severe ones. This study aimed to evaluate the effectiveness and safety of novel biological therapies in very severe psoriasis. We conducted a retrospective analysis on patients ≥ 18 years old affected by very severe psoriasis who had received a biological agent for at least 16 weeks. We used PASI to assess disease severity and effectiveness at weeks 16, 52, 104, and 156. Safety was evaluated by tracking treatment discontinuation rates and adverse events. This study included 29 males and 11 females, with a mean age of 55.80 years (SD 13.82). Cardiometabolic diseases were the most common comorbidities (25.00%). Twenty-eight (70.00%) patients had psoriasis involvement in at least one difficult-to-treat area. All patients completed 16 weeks of treatment. The mean PASI was 31.60 (SD 2.57) at baseline, 3.48 (SD 4.13) at week 16, 0.58 (SD 1.70) at week 52, 0.77 (SD 1.66) at week 104, and 1.29 (SD 2.12) at week 156. PASI90 and 100 were achieved by 52.50% and 30.00% of patients at week 16, by 96.15% and 80.77% at week 52, by 93.33% and 66.67% at week 104, and by 85.71% and 42.86% at week 156. PASIs ≤ 2 were achieved by 50.00% of patients at week 16, 88.46% at week 52, 86.67% at week 104, and 85.71% at week 156. Only two patients discontinued biologics due to complete remission, and mild AEs were reported by four patients. Our findings show that biologics are effective and well tolerated for treating very severe psoriasis, maintaining long-term effectiveness.

Discontinuation risk from adverse events: immunotherapy alone vs. combined with chemotherapy: a systematic review and network meta-analysis

BackgroundWhile immunotherapy combined with chemotherapy (Chemo-IO) is generally recognized for providing superior outcomes compared to monotherapy (mono-IO), it is associated with a higher incidence of treatment-related adverse events (TRAEs), which may lead to treatment discontinuation. In this study, we compared the rates of treatment discontinuation between mono-IO and Chemo-IO as first-line treatments for various solid tumors.MethodsWe systematically reviewed clinical trials from databases (PubMed, Embase, Cochrane Library, and an additional source) published from January 1, 2018, to July 10, 2023. We included phase III randomized controlled trials (RCTs) that utilized immunotherapy agents in at least one arm as first-line treatments for a variety of solid tumors. Data extraction followed the Preferred Reporting Items for Systematic Reviews (PRISMA) extension statement for network meta-analysis. A random effects model was used for the network meta-analysis, with the risk of bias assessed using the Cochrane risk-of-bias tool II. The primary outcomes encompassed treatment discontinuation rates due to TRAEs among patients who underwent immunotherapy, either alone or combined with chemotherapy, for various solid tumors. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated to compare between treatment groups.ResultsFrom 29 RCTs, a total of 21,677 patients and 5 types of treatment were analyzed. Compared to mono-IO, Chemo-IO showed a significantly higher rate of discontinuation due to TRAEs (RR 2.68, 95% CI 1.98–3.63). Subgroup analysis for non-small cell lung cancer (NSCLC) patients also exhibited a greater risk of discontinuation due to TRAEs with Chemo-IO compared to mono-IO (RR 2.93, 95% CI 1.67–5.14). Additional analyses evaluating discontinuation rates due to either treatment emergent adverse events (TEAEs) or AEs regardless of causality (any AEs) consistently revealed an elevated risk associated with Chemo-IO.ConclusionsChemo-IO was associated with an elevated risk of treatment discontinuation not only due to TRAEs but also any AEs or TEAEs. Given that the treatment duration can impact clinical outcomes, a subset of patients might benefit more from mono-IO than combination therapy. Further research is imperative to identify and characterize this subset.

COMPARABLE CLINICAL OUTCOMES IN PEDIATRIC PATIENTS WITH CROHN’S DISEASE TREATED WITH ACCELERATED VS. STANDARD INFLIXIMAB DOSING DURING INDUCTION

Abstract BACKGROUND Accelerated infliximab administration during induction is used extensively in pediatric patients with Crohn’s disease (CD), though the overall effect of this approach on patients’ outcomes in several studies has been questionable. We aimed to assess in a real-life cohort whether accelerated infliximab administration during induction resulted in improved clinical outcomes in pediatric CD. METHODS This single-center retrospective study included patients aged<18 years diagnosed with CD between 2016-2021 that were treated with infliximab. We compared outcomes of patients treated with standard-dosing (0,2,6,14, up to 8mg/kg) vs. accelerated-dosing. Primary outcome with steroid-free clinical remission by week 52. RESULTS Sixty-eight patients were included, of whom 7 discontinued infliximab prior to week 14, due to infusion reactions or primary non-response resulting in surgery. 25 received standard-dosing, and 36 accelerated-dosing, including 19 patients that received >8mg/kg infliximab at 1st infusion. Comparison of both groups at time of infliximab initiation showed similar demographic features, Paris classification, prior rates of medication failure and rates of current immunomodulator use. Importantly, the baseline median pCDAI (23.0 [12.5-26.5] vs. 18.8 [13.1-26.9]), CRP (1.5 [0.3-5.5] vs. 1.4 [0.4-3.4] and calprotectin (782 [66-3840] vs. 1060 [576-2900]) values were comparable in the standard- and accelerated-dosing groups, respectively. Patients in the accelerated-dosing group achieved a higher trough infliximab level by end of induction (10.3±6.6 vs. 3.3±3.4, P<0.001), and more patients were above the target trough infliximab level (78.1% vs. 21.8%, P<0.001). However, the median PCDAI and inflammatory markers at week 14, 26 and 52 were comparable between groups. Moreover, the rates of patients above the desired trough levels were also comparable at week 52 (71.4% vs. 70.6% in the accelerated vs. standard-dosing group). Finally, rates of treatment discontinuation were also similar among groups. CONCLUSIONS In a retrospective cohort, accelerated infliximab dosing during induction didn’t result in improved clinical outcomes up to 52 weeks.

P616 Prescribing practices of tofacitinib and preferences amongst high-risk patients in the UK

Abstract Background Tofacitinib was licensed for use in patients with ulcerative colitis in August 2018. Because it is administered orally, has a rapid onset of action and is relatively inexpensive, it was quickly adopted in real-world practice. Safety warnings linking high-dose tofacitinib use to venous thromboembolic events (VTE) and death followed. Further warnings were issued linking its use to an increased risk of malignancy and adverse cardiovascular events in patients: over 65 years, with a history of diabetes, current or past smokers, and those with a history of coronary vascular disease. The most recent Medicines and Healthcare products Regulatory Agency (MHRA) statement advised against the use of all commercially available JAKi in this high-risk cohort unless a suitable alternative is unavailable (MHRA 2023). We sought to define the number of patients who had, or were, being treated with tofacitinib who were in this high-risk group and the proportion who opted to switch therapy once we had outlined their risk-status and the MHRA advice to them. Methods We conducted a retrospective observational cohort study of 131 patients with UC and IBD-U (61% male [80/131]; median age 43 years [range 16-85]; 46% [60/131] patients had previously had at least one biologic agent) treated with tofacitinib from October 2018 to December 2022 in our centre with at least 3 months follow-up. Patients were categorised as high-risk according to the MHRA statement if they had at least one of the criteria above. Results Overall, about one-third, 31.3% [41/131] patients that we had treated with tofacitinib were classified in the MHRA high-risk group. Rates of treatment discontinuation were similar in the high-risk versus no risk group. In the high-risk group ten patients (24.4% [10/41]) had discontinued treatment due to lack of response (4) or an adverse event (6). The most common adverse events were herpes zoster infections (14.6%), malignancy (3.3%) and infections requiring hospitalisation (3.3%). Two patients died while on treatment (one due to complications following cervical spinal surgery and the other due to ischaemic heart disease). There were no incidences of VTE. We clinically reviewed 29 high risk patients who were being treated with tofacitinib after a median of 2.4 years (range 0.6-4.56) of treatment. 25/29 high-risk patients decided on continuing their treatment in spite of the health care warnings and alternative therapies being available. Conclusion About one-third of our tofacitinib-treated patients were classified as at high-risk. The majority of high-risk patients opted to continue therapy even though alternative therapies were available.

P254 Outcomes of endoscopic and histologic remission in ulcerative colitis under advanced therapy

Abstract Background Current expert-based recommendations suggest that clinical and endoscopic remission should be pursued as treatment targets in ulcerative colitis (UC). However, combined endoscopic and histologic remission may be associated with improved outcomes. Methods Retrospective single-center cohort study including consecutive patients with UC under advanced therapy (biologics and small molecules) with endoscopic and histologic evaluation. We evaluated the rates of hospitalization, surgery, steroid-free remission, and treatment discontinuation after 1-year of follow-up according to the type of remission. Endoscopic remission was defined as a Mayo endoscopic subscore of 0. Histologic remission was defined as the absence of ulcers, erosions and neutrophils in the lamina propria. Results One hundred and six patients were included. Thirty-five patients (33.0%) achieved combined endoscopic and histologic remission, 21 patients (19.8%) endoscopic but not histologic remission and 50 patients (47.2%) did not achieve endoscopic remission. At the end of 1-year, 85 patients (79.4%) achieved steroid-free remission, 14 (13.0%) required hospitalization, 4 (3.7%) surgery, 15 (14.1%) discontinued treatment. A compound outcome was reached by 31 (29.2%) patients. In multivariate analysis including age at diagnosis, age at biologic, type of advanced treatment, disease duration, immunomodulation, previous biologic exposure and type of remission, only the type of remission was associated with a lower chance of reaching any unfavourable outcome (reference no remission) - combined endoscopic and histologic remission (OR 0.162 95%CI 0.05-0.528, P=0.003) and isolated endoscopic remission (OR 0.286 95%CI 0.084-0.971, P=0.045). Kaplan-Meier analysis showed longer outcome-free survival in patients with combined endoscopic and histologic remission. Conclusion Achieving combined endoscopic and histologic remission is associated with better clinical outcomes after 1 year of advanced treatment compared to no remission. However, we could not confirm a significant advantage of combined endoscopic and histologic remission over endoscopic remission alone.

Immune-related adverse events in patients with gastrointestinal cancer undergoing pembrolizumab monotherapy: A systematic review of clinical trials.

744 Background: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is widely employed in the treatment of various gastrointestinal (GI) cancers. This systematic review aims to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab monotherapy in GI cancer patients. Methods: A comprehensive search of PubMed/MEDLINE was conducted to identify full-text articles of clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Two independent authors reviewed the articles and extracted data, with discrepancies resolved by consensus. Primary endpoints included the incidence of grade 3 or higher irAEs and the treatment discontinuation rate due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs and specific irAEs such as pneumonitis, colitis, hepatitis, myositis, myocarditis, nephritis, pancreatitis, peripheral neuropathy, skin toxicity, endocrine toxicity, infusion reactions, and deaths. Results: After excluding duplicates and articles not meeting inclusion criteria, data extraction and analysis were performed on 25 selected articles. Common reasons for exclusion included concomitant use of chemotherapy or targeted therapy and trials involving non-GI cancer patients. The analysis included 2866 patients with a median age of 62 years, of which 29% were female. Tumor types included colorectal (13%), esophagogastric (46%), hepatocellular carcinoma (25%), and others (16%). The aggregate incidence of grade 3 or higher irAEs was 8.7%, with reported rates ranging from 3% to 41% across different trials. The incidence of any grade irAEs varied from 39% to 98%. The treatment discontinuation rate due to irAEs was 6.8%. The most common grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). irAE-related deaths were infrequent (0.9%). Detailed irAE data are summarized in the Table. Conclusions: In GI cancer patients receiving pembrolizumab monotherapy, severe irAEs are rare. Treatment discontinuation and deaths attributed to pembrolizumab-related irAEs are infrequent, underscoring the safety profile of this therapy in patients with GI cancer. [Table: see text]

Comparing the rate of immunotherapy treatment change due to toxicity by sex.

Immuno-oncology therapy (IO) is associated with a variety of treatment-related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune-related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females. Our aim was to determine if there was a difference in the rate of immunotherapy treatment change due to toxicity between males and females. The Oncology Research Information Exchange Network Avatar Database collected clinical data from 10 United States cancer centers. Of 1035 patients receiving IO, 447 were analyzed, excluding those who did not have documentation noting if a patient changed treatment (n = 573). Fifteen patients with unknown or gender-specific cancer were excluded. All cancer types and stages were included. The primary endpoint was documented treatment change due to toxicity. Four hundred and forty-seven patients (281 males and 166 females) received IO treatment. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course than males (median 3.7 vs. 5.1 months, respectively, p = .02). Fifty-four patients changed treatment due to toxicity. There was no significant difference between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and multivariable logistic regression (OR 0.924, 95% CI 0.453-1.885, p = .827). Significantly more patients with chronic obstructive pulmonary disease (COPD) changed therapy due to toxicity (OR 2.491, 95% CI 1.025-6.054, p = .044). Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity-related treatment change was associated with COPD.

Comparison of Treatment Patterns in Patients with Migraine Initiating Calcitonin Gene-Related Peptide Monoclonal Antibodies: A Retrospective Real-World US Study.

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are indicated for migraine prevention in the United States. Limited data comparing real-world treatment patterns for CGRP mAbs are available. To compare the treatment patterns among patients with migraine initiating galcanezumab, fremanezumab, and erenumab. This retrospective study included adult patients with one or more claims for a self-injectable CGRP mAb (galcanezumab, fremanezumab, or erenumab), with continuous enrollment in medical and pharmacy benefits for 12 months pre-index and 6 and 12 months post-index using MerativeTM MarketScan® Commercial and Medicare databases from May 2017 through March 2021. Propensity-score matching was used to address confounding by observed covariates. Outcomes analyzed included proportion of days covered (PDC), medication-possession ratio (MPR), persistence (≤60-day gap), treatment discontinuation, and switch to a non-index drug. Descriptive X2 and t-test analyses were conducted. At the 12-month follow-up, matched galcanezumab and fremanezumab cohorts each comprised 2674 patients and the galcanezumab and erenumab cohorts 3503 each. The mean (SD) PDC and MPR were both 0.6 (0.3) across all cohorts. Based on PDC ≥0.80 and MPR ≥0.80, a greater proportion of galcanezumab vs fremanezumab (46.2% vs 43.7%, p=0.053; 46.8% vs 44.3%, p=0.053) and galcanezumab vs erenumab (46.2% vs 44%, p=0.156; 46.7% vs 44.5%, p=0.262), respectively, initiators were adherent. Compared to galcanezumab, fremanezumab (248.0 days vs 236.5 days, p=0.001), and erenumab (247.8 days vs 241.7 days, p=0.061) initiators had lower mean persistence. Galcanezumab initiators were less likely to discontinue treatment than fremanezumab (47.8% vs 51.7%, p=0.005) and erenumab (47.7% vs 50.2%, p=0.040) initiators. Across cohorts, most switchers initiated onabotulinum toxin A as subsequent treatment. Similar results were observed for 6-month follow-up cohorts. Patients with migraine who initiated treatment with galcanezumab showed higher persistence and lower treatment discontinuation rates than those initiating either fremanezumab or erenumab.

Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups. No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% vs. 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% vs. 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups. ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.

Maribavir: Mechanism of action, clinical, and translational science.

Maribavir is an oral benzimidazole riboside for treatment of post-transplant cytomegalovirus (CMV) infection/disease that is refractory to prior antiviral treatment (with or without resistance). Through competitive inhibition of adenosine triphosphate, maribavir prevents the phosphorylation actions of UL97 to inhibit CMV DNA replication, encapsidation, and nuclear egress. Maribavir is active against CMV strains with viral DNA polymerase mutations that confer resistance to other CMV antivirals. After oral administration, maribavir is rapidly and highly absorbed (fraction absorbed >90%). The approved dose of 400 mg twice daily (b.i.d.) achieves a steady-state area under the curve per dosing interval of 128 h*μg/mL and trough concentration of 4.90 μg/mL (13.0 μM). Maribavir is highly bound to human plasma proteins (98%) with a small apparent volume of distribution of 27.3 L. Maribavir is primarily cleared by hepatic CYP3A4 metabolism; its major metabolite, VP44669 (pharmacologically inactive), is excreted in the urine and feces. There is no clinically relevant impact on maribavir pharmacokinetics by age, sex, race/ethnicity, body weight, transplant type, or hepatic/renal impairment status. In phase II dose-ranging studies, maribavir showed similar rates of CMV viral clearance across 400, 800, or 1200 mg b.i.d. groups, ranging from 62.5-70% in study 202 (NCT01611974) and 74-83% in study 203 (EudraCT 2010-024247-32). In the phase III SOLSTICE trial (NCT02931539), maribavir 400 mg b.i.d. demonstrated superior CMV viremia clearance at week 8 versus investigator-assigned treatments, with lower treatment discontinuation rates. Dysgeusia, nausea, vomiting, and diarrhea were commonly experienced adverse events among patients treated with maribavir in clinical trials.

Risk of T2 lesions when discontinuing fingolimod: a nationwide predictive and comparative study.

Fingolimod is a frequently used disease-modifying therapy in relapsing-remitting multiple sclerosis. However, case reports and small observational studies indicate a highly increased risk of disease reactivation after discontinuation. We aimed to investigate the risk of radiological disease reactivation in patients discontinuing fingolimod. We performed a nationwide cohort study in Denmark, including patients who discontinued fingolimod between January 2014 and January 2023. Eligibility was a diagnosis with relapsing-remitting multiple sclerosis and two MRIs performed respectively within 1 year before and after discontinuing fingolimod. The included patients were compared with those discontinuing dimethyl fumarate with the same eligibility criteria in an unadjusted and matched propensity score analysis. Matching was done on age, sex, Expanded Disability Status Scale, MRI data, cause for treatment discontinuation, treatment duration and relapse rate. The main outcome was the presence of new T2 lesions on the first MRI after treatment discontinuation. To identify high-risk patients among those discontinuing fingolimod, we made a predictive model assessing risk factors for obtaining new T2 lesions. Of 1324 patients discontinuing fingolimod in the study period, 752 were eligible for inclusion [mean age (standard deviation), years, 41 (10); 552 females (73%); median Expanded Disability Status Scale (Q1-Q3), 2.5 (2.0-3.5); mean disease duration (standard deviation), years, 12 (8)]. Of 2044 patients discontinuing dimethyl fumarate in the study period, 957 were eligible for inclusion, presenting similar baseline characteristics. Among patients discontinuing fingolimod, 127 (17%) had 1-2 new T2 lesions, and 124 (17%) had ≥3 new T2 lesions compared with 114 (12%) and 45 (5%), respectively, for those discontinuing dimethyl fumarate, corresponding to odds ratios (95% confidence interval) of 1.8 (1.3-2.3) and 4.4 (3.1-6.3). The predictive model, including 509 of the 752 patients discontinuing fingolimod, showed a highly increased risk of new T2 lesions among those with disease activity during fingolimod treatment and among females under 40 years. This nationwide study suggests that discontinuing fingolimod in some cases carries a risk of developing new T2 lesions, emphasizing the importance of clinical awareness. If feasible, clinicians should prioritize the prompt initiation of new disease-modifying therapies, particularly among young females.

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the ‘JAK-pot’ study)

BackgroundIn a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor...

Comprehensive systematic review and pooled analysis of real-world studies evaluating immunomodulator and biologic therapies for chronic pouchitis treatment.

Pouchitis is a common complication after restorative ileal pouch-anal anastomosis following proctocolectomy for ulcerative colitis. Antibiotic-dependent or antibiotic-refractory chronic pouchitis (CP), which is a common cause of pouch failure affecting 15-20% of patients, is challenging to treat. The efficacy of second-line immunomodulator and biologic therapy remains poorly defined. We present a pooled analysis of real-world efficacy data from peer-reviewed full-text manuscripts, focusing on immunomodulator and biologic therapies in CP. Embase and PubMed databases were searched for full-text articles describing the treatment of CP. We performed a systematic review and pooled analysis of published studies to assess the efficacy of immunomodulators, including thiopurines and methotrexate, and biologics including antitumor necrosis factor, anti-integrin, and interleukin-12/23 antagonists. Clinical and endoscopic response and remission rates were combined for pooled analyses. Rates of treatment discontinuation and safety were also assessed. Pooled analysis comprised 20 full-text articles (485 patients). Overall clinical response rate was 46% (95% CI: 35-59%) and clinical remission rate was 35% (95% CI: 21-52%). Overall endoscopic response and remission rates were 41% (95% CI: 18-68%) and 15% (95% CI: 5-39%), respectively. Individual agents' safety profile was reassuring, with vedolizumab being the most favorable. The real-world efficacy data of immunomodulators in the treatment of CP is insufficient. Vedolizumab and ustekinumab appeared effective and safe for CP, whereas anti-TNFs showed higher rates of adverse events. The high heterogeneity within the studies is attributed to the real-world study design, obfuscating drug efficacy comparisons across the studies. Further studies are required to define the comparative effectiveness of available treatments of CP.

ARTICLE REVIEW: THE TREATMENT PROBLEM AND ADVERSE DRUG REACTIONS IN THE TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS

Multidrug-resistant tuberculosis (MDR-TB) is the resistance of Mycobacterium tuberculosis to at least two tuberculosis (TB) drugs, rifampicin and isoniazid. The disease requires a long treatment duration with several second-line drugs. This leads to a globally low success rate of approximately 56% for MDR-TB treatment. Studies have reported that adverse drug reactions (ADRs) contribute to high rates of non-compliance, treatment discontinuation, and failure. This narrative review aimed to provide information about MDR-TB treatment modalities, various ADRs, challenges encountered in MDR-TB treatment, and instances of ADRs that can impact treatment success. This narrative review study was conducted by searching for scientific information from the primary electronic databases PubMed and Google Scholar, covering 2012-2022. Based on the literature search results, 14 studies were identified, demonstrating challenges in TB and MDR-TB treatment, along with 6 ADRs that can influence treatment success in MDR-TB patients. ADRs during MDR-TB treatment can affect patients’ physical, mental, and social well-being as well as their beliefs and behaviors related to treatment. Comprehensive support from families, communities, and healthcare providers is essential to assist patients in addressing treatment challenges and adverse ADRs. Rapid identification and strategies for monitoring and managing treatment challenges and ADRs can improve compliance and success of MDR-TB treatment. Keywords: Adverse Drug Reactions, Drug Side Effects, Multi Drug-Resistant Tuberculosis (MDR-TB), Treatment Success

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P <0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P<0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Real-World Evaluation of Treatment Discontinuation and Healthcare Resource Utilization in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Introduction: Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are the most prevalent types of leukemia in the United States. Given the emergence of novel CLL/SLL therapies, it is important to understand real-world treatment characteristics and unmet needs. The objectives of this retrospective cohort study were to examine patient characteristics, treatment patterns, and associated outcomes for patients with CLL/SLL, overall, and by CLL and SLL, respectively. Methods: A retrospective study was conducted using Symphony Integrated Dataverse (IDV ®), a comprehensive, longitudinal, open-claims database, and integrated electronic medical record data. Patients aged ≥18 years with ≥1 diagnosis for CLL or SLL and who initiated a first-line or second-line treatment between January 1, 2020, and December 31, 2022 (index period) were included in the study. Index date was defined as the date of treatment initiation. Patients were required to be continuously enrolled for 365 days prior to the index date and ≥90 days following the index date. Patient data were included until patients were lost to follow-up or to the end of the study period (March 31, 2023). Treatment patterns were examined with the following treatment regimens and stratified by line of therapy: chemotherapy (including bendamustine-based and other chemotherapy), anti-CD20-based, Bruton tyrosine kinase inhibitors (BTKiibrutinib- and acalabrutinib-based), and venetoclax-based therapy. Zanubrutinib use was not captured in the BTKi treatment category as its CLL/SLL indication approval date (January 19, 2023) was outside the index period. Discontinuation rate was defined as the percentage of patients who discontinued their current treatment regimen within 90 days. Healthcare resource utilization was measured by number of outpatient visits, inpatient visits, and other medical/hospital services per patient per month (PPPM) during the treatment regimen. Results:There were 17,748 and 5,667 patients with CLL/SLL who initiated a first-line or second-line treatment regimen during the index period, respectively. The most frequently used treatment regimens in first line were BTKi (49.9%), followed by anti-CD20 (26.1%), venetoclax (15.4%), and chemotherapy (8.6%). BTKi continued to be the predominant treatment (49.6%) in second line, followed by venetoclax (30.9%), chemotherapy (10.4%), and anti-CD20 (9.2%). First-line patients treated with BTKi regimens were older and Medicare-insured when compared with patients receiving venetoclax-based regimens (65+ years: 77.1% vs 66.9%, P-value <0.001; Medicare: 61.7% vs 53.0%, P-value <0.001). Patients receiving BTKi had significantly lower discontinuation rates compared with other treatment regimens during both first and second lines of therapies (Figure 1). Mean PPPM outpatient visits, inpatient visits, and other medical/hospital services were less frequent with BTKi therapies vs other treatment regimens across both lines of therapy (Table 1). Of the 17,748 patients initiating first line of therapy, 13.3% had SLL while the remaining 86.7% had CLL. The proportion of patients with SLL vs CLL decreased in second line and second line or later (8.0% vs 92.0% and 6.8% vs 93.2%, respectively). Treatment discontinuation rate in SLL patients was higher than that in CLL patients in first line (32.41% and 25.08%, respectively); however, discontinuation rates became comparable with later lines of therapy. Across all lines of therapy, healthcare resource utilization was significantly higher in SLL patients than CLL patients. Median PPPM outpatient visits were 1.02 for SLL and 0.67 for CLL. Median PPPM for other medical/hospital services was 0.7 for SLL and 0.23 for CLL. Conclusions: BTKi therapy, the primary treatment regimen across first- and second-line therapies, has significantly lower discontinuation rate and healthcare resource utilization compared with other treatment regimens. Further studies are needed to evaluate real-world clinical outcomes of CLL/SLL regimens to support evidence-based treatment decisions.

Baseline CD57 + and CD16 + NK-Cells Predict Treatment Outcome in Non-Transplant Eligible Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab-Ixazomib-Dexamethasone

Background Non-fit multiple myeloma (MM) patients have inferior survival, increased toxicity, and higher rates of treatment discontinuation compared with their fit peers. Effective and less toxic treatment strategies are therefore urgently needed for this vulnerable population. The HOVON-143 trial (EudraCT: 2016-002600-90) was specifically designed to assess the efficacy and safety of daratumumab-ixazomib-dexamethasone in non-transplant eligible (NTE), intermediate fit and frail newly diagnosed (ND)MM patients. Patients were treated with nine 28-day induction cycles comprising daratumumab 16 mg/kg intravenously (cycles 1-2: days 1, 8, 15, and 22; cycles 3-6: days 1 and 15; cycles 7-9: day 1), ixazomib 4 mg orally (days 1, 8, and 15) and dexamethasone orally (only on days that daratumumab was given; cycle 1-2: 20 mg; cycle 3-9: 10 mg), followed by 8-week maintenance cycles consisting of daratumumab (day 1) and ixazomib (days 1, 8, 15, 29, 36, 43) for two years or until disease progression. Aims Since daratumumab has well-known NK-cell-mediated effector mechanisms and T-cell-stimulating immunomodulatory effects, we monitored these cell subsets in bone marrow (BM) and peripheral blood (PB) samples obtained before and during treatment. We specifically aimed to better understand these cell subsets related to frailty status, their predictive value for treatment outcome, and their dynamics during treatment. Methods 126 NDMM patients, among which 64 intermediate fit and 62 frail, were monitored. BM was collected at study-entry (baseline) and at disease progression; PB was collected at baseline, before cycle 4, before maintenance, and at disease progression. Absolute numbers of total T-cells and NK-cells (in PB) or percentages of T-cell and NK-cell subsets (in PB and BM) were profiled by flow cytometry. Data were analyzed using FlowSOM and UMAP. Total cells and cell subsets at baseline were compared between intermediate fit and frail patients, between responders (≥ partial response) and non-responders (< partial response), and associated with progression-free survival (PFS) and overall survival (OS). Results At baseline, we found no difference in absolute numbers of total T-cells and NK-cells between intermediate fit and frail patients. Besides, NK-cell phenotype was similar between both groups. However, within the T-cell compartment frail patients had a decreased CD4 +:CD8 + T-cell ratio, reduced naïve CD4 + and CD8 + T cells, and increased PD1 + CD4 + T-cells compared with intermediate fit patients in both BM and PB, independent of age. Interestingly, differences in T-cell phenotype were more pronounced in female than in male patients. Response data were available for 124 patients, of which 92 (74%) responded to treatment. In both BM and PB, preliminary results showed no clear association between response and absolute numbers of total T-cells or certain T-cell phenotypes at baseline. However, responders had higher absolute numbers of total NK-cells and higher percentages of NK-cells positive for maturation marker CD57 or fc-gamma receptor CD16 than non-responders, while higher absolute numbers of total NK-cells and higher percentages of CD57 + NK-cells were also associated with superior PFS and OS (Figure 1). Conversely, higher proportions of baseline NK-cells positive for inhibitory markers TIGIT and PD1 were associated with non-response, while higher percentages of CD56 bright and PD1 + NK-cells were negatively associated with PFS and OS. As expected, absolute numbers of total NK-cells markedly declined during the treatment course. Interestingly, percentages of CD57 + and CD16 + NK-cells decreased during treatment and remained low at disease progression, while percentages of CD56 bright and NKG2A + NK-cells substantially increased compared with baseline. Conclusions Frail patients had a distinct T-cell profile compared with intermediate fit patients, while NK-cell profiles were similar. Treatment outcome of NTE-NDMM patients treated with daratumumab-ixazomib-dexamethasone was positively associated with higher absolute numbers of total NK-cells and higher percentages of CD57 + and CD16 + NK-cells at baseline, corresponding to a mature and cytotoxic phenotype capable of mediating potent antibody-dependent cellular cytotoxicity. This study highlights the importance of NK-cell phenotype for the effectivity of daratumumab-based combination therapies in NTE-NDMM.

Lower-Initiating Dose of Bosutinib for Resistant or Intolerant to Prior Therapy Chronic Myeloid Leukemia Patients (BOGI trial): A Single-Arm, Multicenter, Phase II Trial

Introduction: The introduction of ABL1 tyrosine kinase inhibitors (TKIs) has markedly improved the survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Second-generation TKIs are highly active for patients with newly diagnosed and resistant/intolerant CML-CP. Although bosutinib is generally safe, drug-related toxicities (DRTs) such as diarrhea or increased transaminase leading to treatment discontinuation, are often observed. The standard initial daily dosage of bosutinib is 400 mg for newly diagnosed or 500 mg for resistant/intolerant patients with CML-CP, whereas some experts suggest lower dose (200-300 mg) initiation is recommended to reduce adverse events (AEs). However, the safety and efficacy of lower dose initiation of bosutinib are unknown. Hence, we conducted a phase 2 study of BOsutinib Gradual Increase as a second/third-line treatment for CML-CP (BOGI trial, UMIN 000032282) to clarify whether a lower initiating dose of bosutinib (200 mg daily) would reduce discontinuation or interruption of treatment due to DRTs. Patients and methods We included CML patients who developed at least one line of treatment failure (resistant or intolerant), aged >18 years with an ECOG performance status of 0-2 and adequate organ function. After enrollment, the patients initiated 200 mg of bosutinib daily; subsequently, dose escalation was performed by 100 mg daily (up to 500 mg daily) every 2 weeks if no grade 3 or higher AEs occurred. BCR::ABL1 mRNA levels were measured by the standardized international scale at a central laboratory at 3, 6, 9, and 12 month since treatment initiation. The primary endpoint was the treatment discontinuation rate due to DRTs at 12 months. Secondary endpoints included the treatment interruption rate, mean bosutinib dosage, dosing days and relative dose intensity until 12 months, achievement of cytogenetic response (CCyR), cumulative rates of major molecular response (MMR) or deep molecular response (DMR). Sample size calculation was performed by research and biostatistics SWOG statistical tools (at null proportion = 0.32, alternative proportion = 0.14, one-sided α error = 5% and β error = 20%, power 80%) with the discontinuation rate of the previous Japanese phase 1/2 study of bosutinib as a reference (Nakaseko C, et al. Int J Hematol. 2015). Considering protocol deviations, sample size was 35 participants. Results Between Feb 4, 2019, and May 24, 2022, 35 patients enrolled from four Japanese hospitals. The median age was 61 years (range, 26 - 81 years); 19 patients were male and 16 were female and 16, 12, and 7 patients had low,intermediate, and high Sokal scores, respectively. Ten patients had hypertension, five had diabetes millitus, three had chronic heart disease, two had solid tumor, and one had cerebrovascular disease, respectively. Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. In the intention to treat population, the bosutinib discontinuation rate at 12 months was 25.7% (95% CI, 15.6-39.3%) which is significantly lower than that of the previous report (v.s. 43.0%, p=0.019). Similarly, bosutinib discontinuation rate due to DRTs was 11.4% (95% CI, 5.2 - 23.2%), which is also significantly lower (v.s. 32%, p = 0.005). These results suggest lower initiating dose of bosutinib reduced bosutinib discontinuation rate due to DRTs, thus the primary endpoint was met. A total of 22 patients (62.9%) interrupted bosutinib at least once. Median bosutinib dosage, bosutinib dosing days and relative dose intensity until 12 months were 391.7 (204.9-477.3) mg/day, 351.0 (20-365) days and 78% (41-95), respectively. 28 patients (80.0%) achieved cytogenetic response (CCyR) at 6 months; cumulative incidence of MMR and DMR at 12 months were 23 (65.7%; 95%CI, 49.2-79.2%) and 15 (42.9%; 95%CI, 28.0-59.1%), indicating these secondary endpoints were comparable with the previous report. Grade 3 to 4 transaminase elevation was 20% which is comparable with the previous report (v.s. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

Final Analysis of the Daliah Trial: A Randomized Phase III Trial of Interferon-α Versus Hydroxyurea in Patients with MPN

Background: Hydroxyurea (HU) is the most commonly used first-line cytoreductive treatment option for patients with myeloproliferative neoplasms (MPN) worldwide. However, increasing evidence on the efficacy and safety of pegylated interferon-alpha2 (IFNα) is emerging, and optimal first-line treatment is to be established. Aims: To compare the efficacy and safety of HU vs. low-dose IFNα in patients with MPN over five years. Methods: DALIAH (NCT01387763) was a randomized phase III trial of HU vs. IFNα in newly diagnosed or untreated patients with MPN (essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF)). Patients > age 60 were randomized (1:1:1) to HU, IFNα-2a, or IFNα-2b whereas patients ≤ age 60 were randomized to IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F molecular response (MR) rate at 18, 36, and 60 months per 2009 European LeukemiaNetwork (ELN) (ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET) (PMF) criteria. Secondary outcomes included the complete clinicohematologic response (CHR) rate at 12 months. The JAK2V617F allele burden was measured using quantitative polymerase chain reaction (qPCR) on peripheral blood (assay sensitivity: 0.1%). Primary and secondary outcomes were compared between groups (HU vs. IFNα or HU vs. IFNα > 60 years) using Fisher's exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables). Paired comparisons (within groups) were made using Wilcoxon signed-rank test. Serial JAK2V617F measurements were compared by unadjusted mixed-effects linear regression analysis. Results: We included 203 patients (ET: 73 (36%), PV: 89 (44%), PreMF: 16 (8%), and PMF: 25 (12%)) in the modified intention-to-treat (ITT) population. Baseline characteristics were well balanced except for median age (HU: 68 years vs. IFNα: 59 years, p<0.0001) ( Table 1). The MR rate by ITT analysis was similar between HU and IFNα (18 months: 19% vs. 21%, p=1.00; 36 months: 19% vs. 26%, p=0.64; 60 months: 23% vs. 24%, p=1.00) (Figure 1A). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond (Figure 1B) and the absolute median (IQR) change in JAK2V617F allele burden (baseline to 60 months) was greater with IFNα (-20% (-9;-49) vs. -7% (3;-15), p=0.0053) (Figure 1C). Two patients (IFNα: n=2) were in complete molecular remission (undetectable JAK2V617F) at 60 months. The CHR rate by ITT analysis was higher with HU at 18 months (58% vs. 38%, p=0.03) but similar at all other time points (12 months: 50% vs. 36%, p=0.21; 60 months: 24% vs. 22%, p=0.83) ( Figure 1D). A post hoc subgroup analysis comparing HU with IFNα > age 60 showed comparable efficacy results. Among patients remaining on treatment (per-protocol analysis), the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond. The MR and CHR rates (HU vs. IFNα) by per-protocol analysis were: MR at 36 months: 23% vs. 56%, p=0.01; MR at 48 months: 27% vs. 59%, p=0.02; MR at 60 months: 35% vs. 67%, p=0.03; CHR at 36 months: 33% vs. 67%, p=0.002; CHR at 60 months: 38% vs. 62%, p=0.05. Overall treatment discontinuation at 60 months was 60% (HU: 37% vs. IFNα: 65%, p=0.0019). The most common cause of treatment discontinuation was adverse events (HU: 6/38 (16%); IFNα: 71/165 (43%)). Adverse events ≥ grade 3 occurred in 46% (HU: 58% vs. IFNα: 45%, p=0.15). Nineteen major thrombotic events were reported in 16 patients (HU: 4 events in 4 patients; IFNα>60: 12 events in 10 patients; IFNα≤60: 3 events in 2 patients), corresponding to an incidence rate of 2.6 per 100 person-years for HU and 3.4 per 100 person-years for IFNα (IFNα>60: 6.2; IFNα≤60: 1.2). None of the patients transformed into secondary acute myeloid leukemia. Five patients died during follow-up (HU: 2; IFNα: 3). Bone marrow histologic remission rates at 36 and 60 months will be presented at the meeting. Conclusion: ITT analysis detected no significant difference in the MR or CHR rates between HU and IFNα with long-term treatment (5 years) among patients with MPN, reflecting a higher treatment discontinuation rate in the IFNα group (65%). Thus, using the per-protocol principle, the MR and CHR rates were superior in the IFNα group at 36 months and beyond.

Single-Center Experience of Carfilzomib-Based Combinations for Patients with Lymphoplasmacytic Lymphoma

Single-Center Experience of Carfilzomib-based Combinations for patients with Lymphoplasmacytic Lymphomas Background Use of bortezomib in Waldenstrom macroglobulinemia (WM) produces a response rate of 60-70% in treatment naïve or relapsed WM(Dimopoulos et al., 2005)(Chen et al., 2006). However, it is associated with an increased risk of peripheral neuropathy (PN). This is important considering that WM can be associated frequently with PN. Carfilzomib(K) is a second-generation proteasome inhibitor that is associated with a lower PN risk and offers a PN-sparing approach for treatment for patients(pts) with WM. In the CARD trial, K-based combinations produced a high ORR with a tolerable safety profile(Treon et al., 2014). We report our single-center experience with the use of K-based combinations in pts with treatment naïve or relapsed lymphoplasmacytic lymphoma (LPL). Patients and Methods We conducted a single-center retrospective study on an IRB-approved protocol for all pts who were treated with K-based combinations at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Efficacy outcomes included overall response rates (ORR), progression free survival (PFS), overall survival (OS). Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). PFS was defined as time from initiation of treatment to progression of disease or death whichever occurred first. OS was defined as time from initiation of treatment to death. The consensus criteria from the 6 th International Workshop on WM were utilized for response assessment. Results We identified 36 patients with a diagnosis of WM and 1 patient with IgA-kappa LPL who were treated with K-based combinations between June 2015 and July 2022. 4 patients (10.8%) had a concomitant diagnosis of systemic light chain amyloidosis (AL). 67.6% pts were male, the median age at treatment initiation was 67.5 yrs. Majority of the pts were treatment naïve (86.4%, N=32). Data for MYD88 mutation was available in 30 pts, 93.3% (n=28) were found to have MYD88 mutation on next generation sequencing (NGS) performed on bone marrow aspirate samples. As per the RPISSWM risk stratification, 30% (9) pts were found to have poor risk, 33.3% (10) had intermediate risk and 36.7% (11) had good risk. Median bone marrow involvement by WM was 30%. The majority of the pts (91.9%, n=34) received KCD-R (Carfilzomib, cyclophosphamide, dexamethasone and rituximab) as their treatment regimen, while the remaining patients received KD-R(carfilzomib, dexamethasone and rituximab). Pts received a median of 6 cycles of treatment. ORR was found to be 97.3% (n=36) with 48.6%(n=18) pts achieving a very good partial response or better (>=VGPR). Median PFS was found to be 51.08 months and median OS was not reached (NR). Two patients needed treatment discontinuation following 1 cycle or less, due to toxicity (dyspnea, one of which was non-cardiogenic) associated with carfilzomib and were changed to an alternative regimen (Bortezomib, cyclophosphamide, dexamethasone and rituximab). Further data for toxicities are being gathered and will be presented at the meeting. Baseline characteristics and outcomes data are summarized in Table 1. Conclusions K-based combinations produce a high ORR with durable responses in patients with symptomatic LPL. Treatment discontinuation rate due to toxicity was low with only two patients needing change of therapy in our cohort. Our data supports the use of K-based combinations in pts with treatment naïve or relapsed LPL.