Effect Of Discontinuities Research Articles

PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG BIO-EXPERIENCED PATIENTS WITH CROHN'S DISEASE INITIATED ON USTEKINUMAB COMPARED TO ADALIMUMAB

Abstract BACKGROUND In Crohn’s disease (CD), dose escalation on biologic therapy may be required to maintain effectiveness, while adverse events or non-response, among other factors, may lead to lack of persistence. Understanding persistence while on labeled maintenance dose is particularly important in bio-experienced patients with CD, as they may have reduced response to subsequent lines of therapy. This analysis compared persistence while on labeled maintenance dose among bio-experienced patients on ustekinumab versus adalimumab in the United States (US). METHODS Adults with CD initiated on ustekinumab or adalimumab (index date) between 09/23/2016 (ustekinumab approval for CD in the US) and 08/01/2019 were selected from IBM® MarketScan® Commercial Database. Patients were bio-experienced (≥1 claim for another CD-indicated biologic in the 12 months baseline period pre-index date). Patients with other auto-immune diseases at baseline were excluded. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence to the index agent while on labeled maintenance dose was defined as (1) no gaps between days of therapy supply >120 days for ustekinumab (2 x 8-week on-label maintenance dose interval) or >60 days for adalimumab (2 x days of supply mode) and (2) no dose change relative to the US label maintenance dose. It was assessed from index date until the earliest of discontinuation (event), dose change during maintenance phase (censoring), or last day of supply (censoring). Weighted Kaplan-Meier and Cox proportional hazards models adjusted for baseline classes of biologics were used to assess the outcome at 12 months post-index. RESULTS 903 bio-experienced patients with CD were included in the ustekinumab cohort (mean age 40.9 years old; 57.1% female) and 525 in the adalimumab cohort (mean age 41.3; 56.3% female). During the baseline period, 71.1% and 72.6% used corticosteroids, 41.2% and 40.8% used immunomodulators, and 11.1% and 12.6% had a prior CD-related surgery, in the ustekinumab and adalimumab cohorts, respectively. At 12 months post-index, the probability of persisting on the index biologic while on labeled maintenance dose was higher in the ustekinumab cohort versus adalimumab cohort (78.8% vs. 67.8%; Fig. 1). Patients in the ustekinumab versus adalimumab cohort had a 71% higher rate of persistence while on labeled maintenance dose (hazard ratio [HR] 1.71; 95% confidence interval: 1.31-2.23; P-value: <0.001*). CONCLUSIONS Bio-experienced patients with CD initiated on ustekinumab were significantly more persistent while on labeled maintenance dose compared to patients initiated on adalimumab. These results confirm results on persistence to biologics in bio-experienced patients with CD from a prior study.

SUPERIOR PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG BIO-NAÏVE PATIENTS WITH CROHN'S DISEASE INITIATED ON USTEKINUMAB COMPARED TO ADALIMUMAB

Abstract BACKGROUND Treatment of Crohn’s disease (CD) may require biologics. Dose escalation may be necessary to maintain efficacy, while adverse events or non-response may lead to treatment discontinuation. This analysis aimed to generate real-world evidence of persistence to ustekinumab versus adalimumab while on labeled maintenance dose (United States [US] prescribing information) among bio-naïve patients with CD in the US. METHODS Adults with CD initiated on ustekinumab or adalimumab from 09/23/2016 (approval of ustekinumab for CD in the US) to 08/01/2019 were selected from a de-identified health insurance claims database (IQVIA PharMetrics® Plus). Patients who used other biologics indicated for CD or had diagnoses for other autoimmune disorders in the 12 months before the initiation of the index agent (baseline) were excluded. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence to the index agent while on labeled maintenance dose was defined as (1) absence of gaps between days of therapy supply >120 days for ustekinumab (twice the 8-week on-label maintenance dosing interval) or >60 days for adalimumab (twice the mode of days of supply in claims) and (2) absence of any dose change during the maintenance phase relative to the dose per US label. It was assessed from the index date until the earliest of discontinuation (event), dose change during the maintenance phase (censoring), or the last day of index agent supply before the end of follow-up (censoring). Weighted Kaplan-Meier and Cox proportional hazards models were used to assess the outcome at 12 months post-index. RESULTS 948 bio-naïve patients with CD were included in the ustekinumab cohort (mean age 42.5 years old; 58.1% female) and 4,143 in the adalimumab cohort (mean age 42.3 years old; 56.7% female). During the baseline period, 8.4% and 9.2% previously had CD-related surgery, 66.6% and 67.7% used corticosteroids, and 25.9% and 26.3% used immunomodulators in the ustekinumab and adalimumab cohorts, respectively. At 12 months post-index, a higher proportion of patients in the ustekinumab cohort versus adalimumab cohort were persistent to the index biologic while on labeled maintenance dose (74.1% vs 65.4%; Fig. 1). Patients in the ustekinumab versus adalimumab cohort had a 47% higher rate of persistence while on labeled maintenance dose (hazard ratio [HR] 1.47; 95% confidence interval [CI]: 1.25-1.73; P-value: <0.001*). CONCLUSIONS Bio-naïve patients with CD initiated on ustekinumab were significantly more persistent while on labeled maintenance dose compared to patients initiated on adalimumab. These results are consistent with previous work, which demonstrated significantly higher persistence to the index agent and a trend of lower dose escalation rates among bio-naïve patients with CD initiating ustekinumab versus adalimumab.

A retrospective clinical study of dolutegravir- versus efavirenz-based regimen in treatment-naïve patients with advanced HIV infection in Nanjing, China.

Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/μL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%, P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ T-cell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/μL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/μL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery.

Impact of antioxidants in improving semen parameters like count, motility and DNA fragmentation in sub-fertile males: a randomized, double-blind, placebo-controlled clinical trial.

Clinical Trials Registry-India Identifier: CTRI/2020/12/029590.

The use of lichen and fungal collections in Australian herbaria to identify temporal changes in air pollution and assist environmental management: challenges to conserving herbarium specimens for the future

Context Global environmental modification is placing increased demand on taxonomic resources, especially herbarium collections, which are being utilised for information and as biological resource material in ways never previously envisaged. This increased use of herbarium collections presents current and on-going management challenges. Aims To demonstrate, with two Australian studies, the essential role of herbarium collections in investigating long-term pollution; to emphasise the importance of on-going collecting for herbaria and make recommendations for future collection management. Methods Australian case studies of a long-term pollution problem are used to show how verified lichen and fungal taxa in Australian herbaria were crucial in identifying sources of air pollution over time. Key results Chemical and isotopic analyses of lead in samples from curated herbarium collections were used to reconstruct patterns of atmospheric lead deposition over 150 years in eastern Australia. This extended time series of samples facilitated documentation of the full cycle from natural background concentrations to the introduction and increasing usage of lead both in industry and motor vehicles, to the eventual discontinuation of its use in automotive fuel. In addition to demonstrating the value of regular, long-term sampling of selected taxa and potential applications to emerging environmental problems, the importance of strict protocols for destructive sampling and analysis of herbarium specimens, especially for older collections containing small quantities of material, has been highlighted. Conclusions Both the Australian and previous studies have identified a number of problems and potential challenges to maintaining and maximising the utilisation of finite herbarium resources for the future. While acknowledging that Australasian herbaria have well documented policies and protocols for studies that sample their collections, six recommendations are made, for future implementation as appropriate. Implications Current management strategies for finite reference collections are summarised and recommendations for the future include the following: repeated, ongoing collecting over broader areas; periodic re-collection of larger samples from select reference sites with detailed field data; preparation and storage of specimens under controlled environmental conditions, with minimal chemical pest control; utilisation of common widespread taxa for research; careful supervision of destructive sampling techniques to assess compounds present; and adequate funding to facilitate the digitisation of herbarium specimens to increase access and optimise use of curated collections.

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

BackgroundIn a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.MethodsWe randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.ResultsAt a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P=0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.ConclusionsIn patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.)

Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study

Introduction: CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter. Results: Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1. With a median follow-up of 29.6 mo (data cutoff, 8 Aug 2022), zanubrutinib PFS, assessed by independent review committee (PFSIRC), was superior to ibrutinib in the ITT population (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=.0024 [Fig 1]); identical statistical values were reported when assessed by investigator (INV). Median PFSIRC was 35.0 mo (95% CI, 33.2-44.3) for ibrutinib-treated pts but not reached for zanubrutinib-treated pts. In a predefined subgroup of pts with del(17p)/TP53 mutation, longer PFSIRC was demonstrated with zanubrutinib than ibrutinib (Fig 2). PFS, regardless of IRC or INV assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib had a higher ORRIRC (86.2 vs 75.7%, nominal 2-sided P=.0007), with a rate of PR-L or better of 91.7% vs 83.1% (nominal 2-sided P=.001). Treatment discontinuation rate was lower with zanubrutinib (26.3%) vs ibrutinib (41.2%) with most due to AEs (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%); discontinuation rates due to cardiac disorders were 0.3% vs 4.3%. Rates of grade ≥3 AEs (67.3 vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3 vs 17.0%) were also lower with zanubrutinib vs ibrutinib. Rate of atrial fibrillation/flutter was lower with zanubrutinib compared with ibrutinib (5.2% vs 13.3%); rates of other AEs of special interest were similar between treatments. There were no grade 5 AEs due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib. Overall, 48 (14.7%) pts treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]). Conclusions: As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S14 Duration of Response After Ozanimod Withdrawal: Phase 3 True North Study Results

Background: The phase 3 True North (TN) randomized trial demonstrated efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis (UC). Temporary discontinuation of UC treatment can occur in clinical practice. Understanding the duration of response after treatment discontinuation can assist in clinical decision making. This analysis examined time to disease relapse in patients who discontinued ozanimod and switched to placebo in the TN maintenance period (MP). Methods: In TN, patients were randomized to once-daily oral ozanimod 0.92 mg or placebo or to open-label ozanimod during a 10-week induction period (IP). Patients with clinical response to ozanimod at Week 10 were rerandomized to ozanimod (continuous ozanimod) or placebo (ozanimod/placebo) in the MP through Week 52. Disease relapse was defined as an increase in partial Mayo score (PMS) of ≥2 points versus Week 10 with absolute PMS ≥4, endoscopic subscore ≥2, and exclusion of other causes of increased disease activity unrelated to UC. A subanalysis compared outcomes in continuous ozanimod and ozanimod/placebo patients who entered the MP after achieving clinical remission or clinical response only (excluding patients in clinical remission) at Week 10. Results: In the TN MP, 230 patients continued ozanimod (clinical remission, n = 82; clinical response only, n = 148) and 227 patients switched to placebo (clinical remission, n = 79; clinical response only, n = 148). Baseline characteristics were generally similar between groups, except the group achieving clinical remission had less severe disease at baseline and fewer patients had a history of other prior immunosuppressive medication use than the group achieving clinical response only. Endoscopic disease severity improved from baseline, with all patients in clinical remission and 15.5% in clinical response achieving an endoscopic score of 0 or 1 at Week 10 (ie, MP entry). In the overall MP population, differences in disease relapse between groups became apparent after MP Week 8, after which a significantly higher proportion of patients on continuous ozanimod were without relapse versus those who switched to placebo. Kaplan-Meier (KM) estimates of no relapse at MP Week 42 were 86.1% for continuous ozanimod and 62.6% for ozanimod/placebo groups. Additionally, patients in clinical remission at Week 10 had higher rates of nonrelapse during the MP versus those in clinical response only at MP entry. KM estimates of nonrelapse at MP Week 42 were 90.9% for patients on continuous ozanimod and 67.9% for patients in the ozanimod/placebo group who achieved clinical remission, and 83.4% and 59.7% in the continuous ozanimod and ozanimod/placebo groups with clinical response only, respectively. Conclusion(s): This analysis shows that ozanimod is effective at preventing disease relapse over 42 weeks of maintenance treatment in patients who achieved clinical response at Week 10. These data show that ozanimod maintains disease control even in the event of temporary discontinuation. However, extended discontinuation should be minimized in clinical practice.

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Biomarker-Selected Patients with Relapsed or Refractory Multiple Myeloma: Implication for Dose Selection

Introduction: Venetoclax, a potent BCL-2 inhibitor, is approved for CLL and AML and is currently under development for treatment of multiple myeloma and other hematological malignancies. The objective of this analysis was to assess the exposure-response relationships of venetoclax from a phase 1/2 study (NCT01794520) evaluating venetoclax monotherapy and in combination with dexamethasone in relapsed or refractory (R/R) multiple myeloma (MM) subjects to inform dose selection for the CANOVA Phase 3 study (NCT03539744). Methods: A total of 117 subjects receiving venetoclax at 300, 600, 800, 900, or 1200 mg either as monotherapy or in combination with dexamethasone were included in the analysis. VenDex was only administered in t(11;14)-positive subjects. Individual subject venetoclax exposures (average area under the concentration time curve [AUCavg] up to the event of interest or discontinuation of venetoclax were determined based on the population pharmacokinetic analysis using the post-hoc empirical Bayes parameter estimates. The impact of venetoclax exposures on efficacy (objective response [OR] progression-free survival [PFS], time to progression [TTP], and overall survival [OS]) as well as safety (treatment-emergent adverse effects [grade ≥ 3] of neutropenia, serious infection, and any grade of serious treatment-emergent adverse effects) was explored. Safety analysis was conducted for total population and for the t(11;14)-negative and t(11;14)-positive subpopulations. Results: Venetoclax exposure relationships to PFS and TTP indicated a trend of longer progression free survival with higher exposures. Moreover, cumulative logistic regression analyses for clinical response rates (stable disease or better [≥SD], partial response or better [≥PR], and very good partial response or better [≥VGPR]) demonstrated a statistically significant (p<0.05) relationship with venetoclax exposure in the t(11;14)-positive subpopulation. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures and serious infection (grade ≥ 3) or serious treatment-emergent adverse events (any grade) in the total population as well as the t(11;14)-positive and t(11;14)-negative subpopulations at the exposure range evaluated. Venetoclax exposures were comparable between the two subpopulations. With respect to grade ≥3 neutropenia, lack of a significant exposure-response relationship was only observed in the t(11;14)-positive subpopulation. Higher rates of grade ≥3 neutropenia trended with higher venetoclax exposures in the t(11;14)-negative subpopulation. Conclusion: In t(11;14)-positive R/R MM subjects, higher venetoclax exposures resulted in improved efficacy without an increase in safety events compared to lower exposures. These findings support dosing venetoclax at 800 mg QD dose in combination with dexamethasone in this patient population in the CANOVA Phase 3 Study.

High Cell Death Rates at Start of Ibrutinib Therapy Predict for Deeper Remissions in Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: The BTK inhibitor ibrutinib blocks B-cell receptor and other signaling pathways in CLL cells and has become a standard CLL therapy. Isotopic labeling with deuterated water (2H2O) to measure the effects of ibrutinib on CLL cell proliferation and death directly in patients revealed that ibrutinib profoundly inhibits proliferation and induces high rates of leukemia cell death (registered at clinicaltrials.gov as NCT01752426; Burger et al., JCI Insight, 2017). Here, we report a long-term follow-up of this trial in which we analyzed long-term outcomes and correlated CLL cell birth and death rates with depth of response over time. Methods: Thirty patients with previously untreated CLL/SLL enrolled in the study to receive continuous long-term ibrutinib monotherapy, after one month of labeling with deuterated water. For our analyses, we stratified patients in groups based on high or low CLL cell death rates in the peripheral blood (PB) or lymphatic tissues (lymph nodes, spleen), i.e. death rates above or below the median, assessed over the first months on therapy, as detailed in the original publication. Responses were assessed according to 2008 IWCLL guidelines, with the exception that lymphocytosis was not used as a sole criterion for progression. PB MRD was quantified by flow cytometry with a sensitivity 10-4. Results: The median age of the participants was 64 years (range, 48 - 78); 63.3% were male. Thirteen patients (43%) had advanced stage disease, 57% had unmutated IGHV genes, and 10% carried 17p deletion (del17p). Twenty-two patients (73%) completed 5 years of protocol treatment and subsequently continued treatment with commercial supply ibrutinib. The patients were followed for a median time of 107 months (range, 6 - 111). The reasons for eventual treatment discontinuation (n=21) were adverse events (n=8, 38%), progressive disease (n=4, 19%), change to another treatment (n=5, 24%), death (n=2, 7%) and other reasons (n=2, 7%). To date, nine patients are still receiving ibrutinib. Five patients (17%) achieved a complete remission, 24 (80%) achieved partial remission, and one patient (3%) had stable disease, resulting in an overall response rate of 97%. Median progression-free (PFS) and overall survival (OS) were not reached at a median follow-up of 107 months. Five-year PFS was 80.6%, and OS was 90%. PB MRD was measured in 18 patients after 5 years of ibrutinib (54 to 60 cycles); all patients had detectable MRD (median 11.8%, range, 0.06 - 47.30%). We found that CLL cell death rates in PB and tissues after treatment initiation inversely correlated with the level of PB MRD after 5 years (r=-0.5872, P=0.0104 and r=-0.4407, P=0.0672). MRD levels were significantly lower in patients with high CLL cell death rates in PB (7.03% ± 3.68% vs. 29.46% ± 5.53%, mean ± SEM, P=0.0056) and in tissues (9.73% ± 5.49% vs. 28.89% ± 4.42%, P=0.0155) as compared with patients with lower CLL cell death rates (Figure 1). Tissue CLL cell death rates were significantly higher in patients with IGHV-unmutated CLL compared to mutated (28.88% ± 2.75% vs. 13.16% ± 2.82%, P=0.0005), and MRD levels trended lower (IGHV-unmutated: 10.71% ± 5.39% vs. IGHV-mutated: 28.36% ± 6.02%, P=0.0878). No statistically significant correlation was found between CLL cell birth rate at baseline or after start of ibrutinib and MRD levels after 5 years of treatment. Conclusion: CLL cell death rates during early treatment correlated with achieving lower MRD levels. We found that CLL cell death rates are higher in IGHV-unmutated patients suggesting a higher dependency of IGHV-unmutated clones on BCR signaling and, therefore, resulting in deeper responses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utilization of Pharmacogenomics in Assessment of Tolerability and Efficacy of BTK Inhibitors

Background: Oral inhibitors of Bruton's tyrosine kinase (BTKi) are used for a number of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL). Despite excellent hematologic responses often seen with this class of medications, discontinuation may occur due to progression or intolerable side effects. It is not fully understood why some patients develop adverse events and discontinue BTKi therapy. A previous study suggested and association between intolerance to BTKi or phosphoinositide 3-kinase (PI3K) inhibitors in CLL patients with genetic polymorphisms in cytochrome P450 enzymes. Polymorphisms in CYP3A and CYP2D6 affect the metabolism of these agents and may lead to higher-than-expected plasma levels, leading to more adverse events. We therefore evaluated the results of pharmacogenomic testing in Veterans treated with BTKi to determine the extent to which pharmacogenomics polymorphisms are associated with response and intolerance to BTKi therapy. Methods: We identified Veterans receiving care through the Veterans Administration (VA) who were prescribed a BTKi and had undergone pharmacogenetic testing through the Pharmacogenomic Testing for Veterans (PHASER) program, currently offered to veterans at 22 sites across the United States. We retrospectively analyzed clinical factors including time on BTKi, reasons for temporary or permanent discontinuation or dose changes, medical comorbidities, and grade of pertinent side effects associated with BTKi (arrhythmia, hypertension, bleeding, fatigue, arthralgias, rash, diarrhea) as well as use of concomitant medications known to interact with CYP3A or CYP2D6. Results: A total of 61 Veterans were identified, of which 97% (59) were male and 72% (44) were diagnosed with CLL. Of the remaining patients, three were diagnosed with MCL, three with WM/LPL, two with refractory diffuse large B cell lymphoma (DLBCL), one with MZL, and one with monoclonal gammopathy and cold agglutinin disease. Forty-three patients (70.5%) were prescribed ibrutinib, while eight were prescribed acalabrutinib and two zanubrutinib. Twelve patients (20%) permanently discontinued therapy due to intolerance and eight patients (13%) progressed. Another 10 patients temporarily discontinued therapy due to side effects or infection. Median time treated with BTKi was 6.7 months for patients discontinuing for intolerance, 30.1 months for those discontinuing for progression, and 32.9 months for those not requiring discontinuation. The majority of patients who either temporarily or permanently discontinued therapy did so due to new arrhythmia (10 patients), while other complications included infection, pancytopenia, arthralgias, and fatigue. Nearly half of patients were concurrently taking another medication also metabolized through the CYP3A or CYP2D6. Of the 20 patients who progressed or were intolerant of BTKi, 14 (70%) were identified as CYP3A5 poor metabolizers, while 6 (30%) exhibited CYP2D6 intermediate metabolizing function. In comparison, of patients who did not discontinue BTKi, 31 patients (76%) were CYP3A5 poor metabolizers and 11 patients (27%) were CYP2D6 intermediate metabolizers. Conclusions: In our cohort of patients with B cell malignancies who were prescribed BTKi, we identified those who discontinued either due to intolerable side effects or progression at a rate lower than previously reported in the Veteran population. We identified patient with pharmacogenomics polymorphisms that can affect plasma drug levels and are evaluating concurrent use of medication with can affect BTKi metabolism, as well as their effect on time to therapy discontinuation and adverse events. These results will inform the personalized selection of BTKi therapy for patients with B cell malignancies.

Next Generation BTK Inhibitor Acalabrutinib with Bendamustine-Rituximab in First Line Waldenstrom's Macroglobulinemia: The Brawm Study

Background: Waldenström's macroglobulinaemia is an uncommon lymphoproliferative disorder. Although the life expectancy is relatively long there are no curative therapies for this disease. Several different first line treatment options are available and include chemotherapy immunotherapies such as bendamustine and rituximab (BR) or BTK inhibitor therapy. Neither of these therapies generate a high frequency of complete responses (CR) or very good partial responses (VGPR). We postulated that combining bendamustine and rituximab with a next generation BTK inhibitor would result in deeper responses as measured by the CR and VGPR rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the Complete and Very good partial response rate. Methods: The BRAWM clinical trial combines standard of care first line treatment of bendamustine and rituximab with Acalabrutinib in a fixed duration treatment course including six cycles of bendamustine and rituximab and 12 months of Acalabrutinib. This trial is taking place at nine clinical sites across Canada and 19 patients have been enrolled, with a recruitment goal of 59. Results: An interim analysis of the first 10 patients showed that the median age of patients at screening was 66, and 6 of the subjects were males. Based on the IPSS-WM scoring system, one patient was low risk, one was intermediate risk and 8 were high risk. Eight patients required treatment due to already symptomatic disease with cytopenia or neuropathy. The remaining two started treatment due to hematological and biochemical compromise related to their lymphoma. The median screening IgM was 28.5 and all but two normalized their IgM by cycle 6 cycle of treatment (one patient had not finished cycle 6 assessment). Although adverse events occurred in all patients, grade 3 or 4 AEs only occurred in 9.2% and 1.7% of all AEs, respectively. The most common grade 3 and grade 4 toxicities were cytopenias, which represented 61.5% of grade 3 or 4 events, all of which were neutropenias. Other important grade 3/4 toxicities included 1 event each of transaminitis, atrial fibrillation, and infection. No events of anemias, secondary malignancies, hepatotoxicity events, or deaths were reported. There were 7 study drug interruptions related to AEs, of those, six patients restarted Acalabrutinib, five at full dose, and one required a dose reduction. The single drug discontinuation event was due to a combination of grade 3 atrial fibrillation, and grade 2 pericardial effusion and pericarditis that were all possibly related to Acalabrutinib. With a median follow up of 5 months for the 8 patients who have completed BR cycles, all achieved a very good partial response at cycle 7. There have been no patients yet with recurrent or progressive disease. All 10 patients have MyD88 mutations, and one has a CXCR4 mutation. Minimal residual disease analysis will be performed at cycle 7, 12, and month 18 in all patients. Conclusions: Bendamustine, Rituximab and Acalabrutinib front-line therapy for Waldenström's macroglobulinaemia is safe and well tolerated and initial clinical results show all 8 patients who completed 6 cycles of BR and Acalabrutinib to date have achieved a VGPR.

Methadone Maintenance Treatment Discontinuation Among Young People who use Opioids in Vancouver, Canada.

Retaining adolescents and young adults (AYA) in medications for opioid use disorder (MOUD), like methadone maintenance treatment (MMT), is critical to reducing toxic drug fatalities. This analysis sought to identify factors associated with MMT discontinuation among AYA. Data were derived from the At-Risk Youth Study, a prospective cohort study of street-involved AYA in Vancouver, Canada, between December 2005 and June 2018. Multivariable extended Cox regression identified factors associated with time to MMT discontinuation among AYA who recently initiated MMT. In subanalysis, multivariable extended Cox regression analysis identified factors associated with time to "actionable" MMT discontinuation, which could be addressed through policy changes. A total of 308 participants reported recent MMT during the study period. Participants were excluded if they reported MMT in the past 6 months at baseline and were retained in MMT (n = 94, 30.5%); were missing MMT status data (n = 43, 14.0%); or completed an MMT taper (n = 11, 3.6%). Of the remaining 160 participants who initiated MMT over the study period, 102 (63.8%) discontinued MMT accounting for 119 unique discontinuation events. In multivariable extended Cox regression, MMT discontinuation was positively associated with recent weekly crystal methamphetamine use (adjusted hazard ratio [AHR] = 1.67, 95% confidence interval [CI]: 1.19 to 2.35), but negatively associated with age of first "hard" drug use (per year older) (AHR = 0.95, 95% CI: 0.90 to 1.00) and female sex (AHR = 0.66, 95% CI: 0.44 to 0.99). In subanalysis, recent weekly crystal methamphetamine use (AHR = 4.61, 95% CI: 1.78 to 11.9) and weekly heroin or fentanyl use (AHR = 3.37, 95% CI: 1.21 to 9.38) were positively associated with "actionable" MMT discontinuation, while older age (AHR = 0.87, 95% CI: 0.76 to 0.99) was negatively associated. Efforts to revise MMT programming; provide access to a range of MOUD, harm reduction, and treatments; and explore coprescribing stimulants to AYA with concurrent stimulant use may improve treatment retention and reduce toxic drug fatalities.

Persistence with daily growth hormone among children and adolescents with growth hormone deficiency in the UK.

Children with growth hormone deficiency (GHD) are treated with daily somatropin injections; however, poor treatment persistence and adherence have been recognized previously and have been shown to negatively impact growth outcomes. A recent real-world study of a US pediatric GHD population found that a substantial proportion of children discontinued somatropin therapy, but similar data for a real-world UK population are lacking. To describe the discontinuation of, and persistence with, daily somatropin treatment among children with GHD in the UK. This was a retrospective cohort study of children (≥3 and <16years old) with ≥1 medication prescription for daily injectable somatropin from 1 July 2000 to 31 December 2020 in the IQVIA Medical Research DATA (IMRD) database. Early persistence was defined as the proportion of children prescribed ≥1 somatropin refill (≥2 prescriptions). Discontinuation was defined as the first date at which a medication gap for somatropin (of >60 or >90days between prescriptions) occurred. Kaplan-Meier methods were used to evaluate persistence (non-discontinuation) over time to assess time to first discontinuation event. Cox proportional hazards models were used to evaluate the relationship between patient characteristics and time to medication discontinuation. Among the cohort identified in this study (n=117), the majority (n=84, 71.8%) had 48months of available follow-up; 56.4% were boys and the mean (median) age was 8.6 (8.0) years. About 98% exhibited early persistence, but persistence over the follow-up period decreased with follow-up duration. Using the conservative 90-day gap definition of persistence, an estimated 72.4%, 52.8%, and 43.3% were persistent at 12, 36, and 48months. Lower persistence rates were observed using the 60-day definition. No significant patient predictors of time to discontinuation were identified. Despite high early persistence with somatropin, a high percentage of children with GHD were increasingly non-persistent over time. More than 1 in 4 were non-persistent at 12months and more than 1 in 2 were non-persistent at 48months of follow-up. These results suggest that strategies to support improved medication-taking behavior among children with GHD in the UK are warranted.

ODP392 Persistence with daily growth hormone treatment among pediatric patients with growth hormone deficiency in the UK

Abstract Background Suboptimal adherence to, and persistence with, daily somatropin therapy to treat children with growth hormone deficiency (GHD) has been documented previously, and has also been shown to have negative effects on the growth response. Objectives To describe discontinuation of, and persistence to, daily somatropin treatment among pediatric patients with GHD in the UK. Methods This was a retrospective cohort study of pediatric patients (≥3 and &amp;lt;16 years) with &amp;gt;1 medication prescription for daily injectable somatropin from 1 st July 2000 to 31 st December 2020 in the IQVIA Medical Research DATA (IMRD) database. Patients were required to have &amp;gt;1 diagnostic code for GHD during the 6 months preceding and including the first somatropin prescription date ("index date"), and to be continuously enrolled in the database &amp;gt;6 months preceding and &amp;gt;3 months following index date. Patients with &amp;gt;1 somatropin prescription during the 6 months prior to index date, or with diagnoses for other causes of short stature were excluded. Patients were followed for up to 48 months post-index. Early persistence was defined as the proportion of patients prescribed ≥1 somatropin refill subsequent to the initial prescription. Discontinuation was defined as the first date at which a medication gap (defined as either &amp;gt;60 days or &amp;gt;90 days between prescriptions) for somatropin occurred. Persistence (non-discontinuation) over time was evaluated using Kaplan-Meier methods to assess time to first discontinuation event. The relationship of patient characteristics with time to medication discontinuation was evaluated using Cox proportional hazards models. Results Among pediatric patients included in this study (n=117), the majority (n=84, 71.8%) had 48 months of available follow-up; 56.4% were male and mean (median) age was 8.6 (8. 0) years. About 98% of patients exhibited early persistence. Persistence over the follow-up period decreased with follow-up duration. Using a 60-day gap definition, persistence at 12, 24, 36, and 48 months was estimated among 48.3%, 35.4%, 26.7%, 16.5% of patients; using a more conservative 90-day definition, an estimated 72.4%, 58.6%, 52.8%, and 43.3% were persistent at the same time periods. No significant patient predictors of time to discontinuation were identified. Conclusions Despite high early persistence with somatropin, a sizable proportion of patients were increasingly non-persistent over time. In this UK-based study more than 1 in 4 patients were non-persistent at 12 months and more than 1 in 2 were non-persistent at 48 months. These results suggest that strategies to support improved medication-taking behavior among pediatric patients with GHD in the UK are warranted. Presentation: No date and time listed

PSAT192 Hypercalcemia of Immobility in a Patient with Post-Surgical Hypoparathyroidism

Abstract Background Hypercalcemia of immobility is a rare diagnosis in the general population, and thus requires careful evaluation to rule out other causes of non-PTH mediated calcium excess. The pathogenesis is not clearly established, however, likely involves a reduction in mechanical loading stimulus from osteocytes with resultant decreased bone formation and increased bone resorption. Management requires careful assessment to maintain normal calcium. We present a case of hypercalcemia of immobility in a patient with a known history of surgical hypoparathyroidism. Clinical Case A 64-year-old man with a history of transglottic cancer s/p total laryngectomy and tracheostomy with resulting post-surgical hypoparathyroidism and hypothyroidism presented for a tracheostomy change and was found to be hypercalcemic. Since his laryngectomy four years ago, the patient had a low PTH of 2.9 pg/mL (10.0 - 65.0 pg/mL) with resulting prolonged hypocalcemia from 5.9 to 7.9 mg/dL (8.5-10.5 mg/mL) requiring calcium and daily calcitriol treatment. Four months prior to current hospitalization, he developed avascular necrosis of the hip and became essentially bedbound from severe hip pain. Since immobilization, his calcium was noted to increase, with the highest corrected calcium of 10.9 mg/dL (8.5-10.5 mg/mL), necessitating tapering and eventual discontinuation of calcium supplements and calcitriol. During this admission, corrected calcium was 12 mg/dL (8.5-10.5 mg/mL). PTH-rP was 16 pg/mL (14 - 27 pg/mL), PTH was 11.2 pg/mL (15-65 pg/mL), vitamin D 25-hydroxy total was 14.7 ng/mL (30-60 ng/mL), 1,25 dihydroxy vitamin D was 18.2 pg/mL (19.9 to 79.3 pg/mL), SPEP did not detect monoclonal protein, thyroid function was normal and bone scan showed no evidence of metastasis, thus excluding other causes of hypercalcemia. Bone specific alkaline phosphatase was 11.7 (7.6-14.9 mcg/L). C-telopeptide, a marker of bone resorption, was markedly elevated at 2079 (87-345 pg/mL), suggesting hypercalcemia of immobility. The patient was started on vitamin D supplementation, intravenous fluid hydration and physical therapy was initiated to encourage mobilization. The patient was carefully monitored with regular labs to avoid the risk of hypocalcemia once mobilization improved. His calcium began to decline to 10.5 (8.5-10.5 mg/mL) at time of discharge, eventually requiring calcium and calcitriol supplementation to maintain normocalcemia. Conclusion Hypercalcemia of immobility should be suspected in patients witha history of post-surgical hypoparathyroidism who present with new onset hypercalcemia that persists despite titrating or discontinuing calcium and calcitriol therapy. It is a diagnosis of exclusion and thorough laboratory assessment is needed to rule out other causes of hypercalcemia. These patients are at risk of hypocalcemia once the underlying etiology is corrected i.e restoration of mobility. Therefore, bisphosphonates should be avoided for acute treatment of hypercalcemia unless refractory to intravenous hydration. Once mobilization improves, calcium levels should be carefully monitored, and calcitriol and calcium supplementation should be resumed to maintain normocalcemia. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP242 Safety of SGLT2-Inhibitors in Patients with Multiple Myeloma and Diabetes

Abstract Background An estimated 10-20% of patients with multiple myeloma (MM) have type 2 diabetes (T2DM). About half of patients with MM will experience renal insufficiency,the risk of which increases in the setting of T2DM. While sodium-glucose cotransporter 2 inhibitors (SGLT2i) are beneficial in patients with chronic kidney disease (CKD) due to diabetic or hypertensive nephropathy, the role of SGLT2i in MM-related CKD is unknown. Moreover, as MM therapies target the immune system, concurrent use with SGLT2i may increase the risk of adverse events such as infections. The current work is the first to examine the potential benefit and safety of SGLT2i in patients with MM and T2DM. Methods This study was approved by the Institutional Review Board. A retrospective cohort study was performed on patients aged 18 years or older with MM who received SGLT2i therapy between March 2013 and December 2020 at a quaternary academic medical center. Electronic medical records were reviewed for the following data: demographics, comorbidities, MM parameters, medication and medical history, SGLT2i usage and duration, and hemoglobin A1c(HbA1c) and serum creatinine pre- and post-SGLT2i initiation. Data are presented as mean ± standard deviation or counts and percentages, and was analyzed using SPSS software (version 25. 0, IBM Corp). Results In total, 50 patients were identified. Patients who were diagnosed with MM after initiation of SGLT2i (n= 12), did not have any MM data available (n=1), or for whom SGLT2i usage could not be verified (n= 4) were excluded. Thirty-three patients were included in the final analysis. The mean age was 63 (±7.8) years, 63.6% were male, and 87.9% had active MM or MM in remission. Most had received stem-cell transplantation (55. 0%) and multiple lines of chemotherapy (63.6%) prior to SGLT2i initiation. The average HbA1c was 7.4% (±1.2%) and 20% of patients had CKD prior to SGLT2i initiation. The overall SGLT2i discontinuation rate was 42.4%, and the mean duration of therapy was 2.2(±1.5) years. Notably, 21.4% of discontinuation events were due to an increase in creatinine; however, for the entire cohort, there were no statistically significant changes in serum creatinine, total body weight, HbA1c, or 24-hour urine protein at 15 months’ follow-up. Other reasons for SLGT2i discontinuation included loss to follow-up, change of health insurance coverage for SGLT2i, and unrelated hospital admission. Genitourinary infection was not cited as a reason for any SGLT2i discontinuation. Conclusion SGLT2i therapy may be safe in patients with MM and T2DM, but no benefit was found with respect to serum creatinine, HbA1c, or 24-hour urine protein. Prospective research is required to further evaluate the potential benefit and safety of SGLT2i therapy in this population. Presentation: No date and time listed

Monkeypox: is topical cidofovir a good idea?

We report the use of topical cidofovir to treat patients with human monkeypox. We found that lesions on the trunk and limbs responded better than facial lesions, while anogenital lesions were affected by local irritation, leading to eventual discontinuation of treatment.

Real-World Time on Treatment Analysis of Pembrolizumab Treated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) Patients Stratified by ECOG PS in the United States

<h3>Purpose/Objective(s)</h3> There is limited evidence on the real-world use of pembrolizumab therapy post-approval in 1L R/M HNSCC. The study estimated real-world time on treatment (rwToT) of pembrolizumab monotherapy and pembrolizumab + platinum + 5-fluorouracil for 1L R/M HNSCC patients, stratified by ECOG PS. <h3>Materials/Methods</h3> This retrospective study of the nationwide de-identified electronic health record (EHR)-derived Flatiron Health Advanced H&N database selected patients initiating pembrolizumab monotherapy or pembrolizumab + platinum + 5-fluorouracil between 07/01/19 - 12/31/20 with follow-up until 07/31/21. Patients with prior platinum-based therapy ≤6 months, prior primary cancers, or treatment with a clinical study drug were excluded. rwToT was defined as length of time between first and last documented administration date pembrolizumab. Patients with a record of next line of therapy, death, or treatment gap ≥120 days from the last administration date were considered discontinued. Patients without a discontinuation event were censored at the end of follow up. Kaplan-Meier analysis was conducted to assess median rwToT and landmark on-treatment rates. All results were stratified by ECOG PS 0-1 (similar to KEYNOTE-048, the registrational clinical trial) and ECOG PS 2-3. <h3>Results</h3> A total of 402 patients initiated 1L treatment with pembrolizumab therapy. Of those patients, 297 (73.9%) had a recorded ECOG PS score, majority with an ECOG PS score of 0/1 (Overall: 77.8%, pembrolizumab monotherapy: 70.5%, pembrolizumab + platinum + 5-fluorouracil: 84.1%). The median rwToT was higher among the ECOG 0/1 patients compared to ECOG 2/3 patients for both regimens (pembrolizumab monotherapy: 4.4 vs 2.2 months, pembrolizumab + platinum + 5-fluorouracil: 5.0 vs 3.5 months). <h3>Conclusion</h3> In the real-world, treatment duration with pembrolizumab monotherapy or pembrolizumab+platinum+5-fluorouracil in 1L R/M HNSCC was similar to KEYNOTE-048, when restricted to a trial-matched population of ECOG PS 0-1 patients. Treatment duration tended to be shorter in the real-world ECOG PS 2/3 population, who are commonly excluded from clinical trials.

Outcomes in Infants with Supraventricular Tachycardia: Risk Factors for Readmission, Recurrence and Ablation.

Supraventricular tachycardia (SVT) is the most common arrhythmia in infants. Once diagnosed, infants are admitted for antiarrhythmic therapy and discharged after observation. There are limited data on risk factors for readmission and readmission rates, while on medication. The objective of this study was to investigate risk factors for readmission and outcomes in infants diagnosed with SVT. This is a single-center retrospective study over a 10-year period of infants under 6months of age with documented SVT. Infants with congenital heart disease requiring surgical or catheter intervention, gestational age less than 32weeks or diagnosis of atrial flutter or fibrillation were excluded.The primary outcome was readmission within 31days of hospital discharge. Long term need for ablation and eventual discontinuation of medications were assessed. Ninety patients were included. Beta blockers were the initial therapy in 66 and 28 required a medication change. Nineteen were readmitted within 31days of discharge.The only clinical factor associated with early readmission was presence of ventricular pre-excitation (6/19 vs. 8/71, p = 0.03). Patientswhowere readmitted within 31days had a longer length of treatment (12 [11.5, 22.0] vs. 10 [7.5, 12.0] months, p = 0.007) and were more likely to undergo ablation (4/19 vs. 2/71, p = 0.017). In this cohort of infants with SVT, readmission was common and ventricular pre-excitation was identified as a risk factor for readmission. Infants who were readmitted within 31days of discharge had longer length of antiarrhythmic therapy and were more likely to undergo catheter ablation.