Early Discontinuation Of Therapy Research Articles

Extent and causes of unused medications among patients in rural Ethiopia: a prospective multicenter cohort study

BackgroundMedication waste poses health, economic, and environmental challenges. However, the extent among patients living in rural areas is underexplored. This study assessed the proportion of prescribed medications remaining unused by patients living in rural areas of Ethiopia, and identify the causes thereof and disposal practices.MethodsA prospective multicenter cohort study was conducted in 5 rural health centers in Ethiopia. Patients (≥ 18 years), who received a prescription for acute or chronic medication for pick up from the outpatient pharmacy were included. After 3 months, participants received a house visit by a health employee during which a questionnaire was verbally administered to assess the quantity of unused medication, reason thereof, and disposal practices used. Data were analyzed using descriptive statistics and multivariate logistic regression to identify factors associated with presence of unused medications.ResultsIn total, 178 patients participated. Up to 136 out of 601 (22.6%) dispensed medications ended up unused, mainly antibiotics and analgesics, with an average economic value of $0.37. Of 178 patients, 72 (40.4%) ended up with unused medication, and 15 (8.4%) did not use 80% or more of the prescribed quantity. Early discontinuation of therapy was the main reason (61.8%) for patients’ ending with unused medication. Patients reported to primarily dispose of unused medication either through the toilet (43.6%), household garbage (22.7%), burning (13.6%), or returning it to the pharmacy (2.7%). Medications dispensed to be administered with two or more-unit doses at a time were more likely to remain unused (adjusted OR 1.6 [1.0–3.4]) compared to medications dispensed to be administered one-unit dose.ConclusionA substantial amount of prescribed medications remains unused by patients in rural areas, frequently not properly disposed. Interventions are needed to ensure medications are not wasted and reduce the unwanted consequences.

Experience in the management of pregnant patients with highly active multiple sclerosis in the Moscow region

To evaluate the effect of discontinuation or prolongation of DMT on the activity of the disease during pregnancy and in the postpartum period in patients with aggressive MS from the Moscow region. The study included female patients with an aggressive course of MS receiving DMT at the time of pregnancy. The patients were followed-up for the period 2016 to February 2024. There were 17 cases of pregnancy during natalizumab (NZ) therapy; discontinuation of therapy in the first trimester of pregnancy provoked a resumption of disease activity in half of the patients. There were no exacerbations in patients whose therapy was prolonged until the 34th week of pregnancy. In 5 patients receiving fingolimod (FGL), therapy was discontinued upon the establishment of pregnancy, which caused the resumption of disease activity in three out of 5 cases. In 3 patients receiving anti-B-cell therapy, pregnancy occurred within a few months after the next infusion, there were no exacerbations during pregnancy. The cancellation of NS therapy in the early stages of pregnancy in most cases leads to the resumption of disease activity during pregnancy. Exacerbations in the postpartum period also correlated with early discontinuation of therapy and with a long period before the restart of infusions. Prolongation of infusions to 30-34 weeks of pregnancy contributed to stabilization of the condition throughout the perinatal period. Discontinuation of FGL therapy at the onset of pregnancy increased the risk of repeated relapses of the disease, up to the development of inflammatory immune restoration syndrome during pregnancy and contributed to the increase in disability in the postpartum period.

Association of immune-related adverse events and efficacy outcomes in phase II trial of consolidation nivolumab plus ipilimumab or nivolumab alone after chemoradiation in patients with unresectable stage III non–small-cell lung cancer (NSCLC).

8565 Background: Immunotherapy has been widely incorporated into the treatment of patients with non-small-cell lung cancer. Many of these patients will experience immune-related adverse events (irAEs) that may lead to early discontinuation of therapy. Previous studies have reported that patients with Stage III and metastatic NSCLC who experienced irAEs receive fewer cycles of immunotherapy without decreased efficacy. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the BTCRC LUN 16-081 randomized phase 2 trial of consolidation immunotherapy with nivolumab (N) plus ipilimumab (IPI) vs N alone following concurrent chemoradiotherapy in patients with unresectable Stage IIIA/IIIB NSCLC. Methods: A total of 105 eligible patients were enrolled from 9/2017 to 4/2021. Demographics, disease characteristics, and number of immunotherapy cycles received were reported in patients with and without irAEs in the two arms. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). A log-rank test was used to compare groups. Results: In treatment arm A (N alone), any grade irAEs occurred in 64.8% of patients. At a follow up of 48 months, there was no significant difference in number of N cycles started (6 vs 6, p = 0.238), progression free survival (29.4 vs 31.9 mo, p = 0.897), or overall survival (NE vs. 31.9 mo, p = 0.798) in patients with and without irAEs. Patients who discontinued N because of irAEs (n = 8 or 14.8% of patients) received significantly fewer cycles of N (2 vs 6, p = < .0001) and had a shorter PFS (8.2 vs. 31.9 months, p = < .0001) and OS (12.3 months vs. NE, p < .0001). In treatment arm B (IPI+N), any grade irAEs occurred in 84.3% of patients. At follow up of 48 months, there was no significant difference in number of IPI+N started (4 vs. 4, p = 0.260) or overall survival (NE vs. NE, p = 0.576), but there was a significantly longer PFS in those who experienced irAEs (30.9 months vs. 6.8 months, p = 0.0083). Patients who discontinued IPI+N because of irAEs (n = 18 or 35.3% of patients) received significantly fewer cycles of IPI+N (2 vs 4, p = < .0001) without a significant difference in PFS (28.1 vs. 25.3 mo, p = 0.830) or OS (NE vs NE, p = 0.755). Conclusions: The occurrence of irAEs alone in both arms, regardless of number, was not associated with decreased efficacy outcomes in this exploratory analysis. However, if irAEs resulted in the discontinuation of therapy, these patients did have a shorter PFS and OS in the N alone arm. This difference was not observed in the IPI+N arm and those who experienced any irAEs in the IPI+N arm had an improved PFS.

Checkpoint inhibitor-induced immune-related sarcoidosis-like reaction

Immune checkpoint inhibitors are associated with a wide spectrum of immune-related adverse events (AE) of different severity. Immune-related sarcoidosis-like reactions are relatively rare but clinically important AEs. These abnormalities, due to the appearance of active pathological lymph nodes or nodules in other organs on radiographs, can be falsely interpreted as tumor progression or stabilization and thus affect treatment strategy, leading to unreasonably early therapy discontinuation or its unnecessary continuation. So far there were no convincing criteria for differentiation between sarcoidosis-like reaction and sarcoidosis, oncologist should be aware of this reaction and include it in the differential diagnosis in patient with suspected disease progression who are treated with immune checkpoint inhibitors.

A Nursing Educational Intervention to Improve Antiestrogen Adherence and Self-Management of Side Effects.

Antiestrogens prescribed to reduce breast cancer risk or recurrence can have undesirable musculoskeletal side effects that may lead to early discontinuation of therapy. Previous studies have not focused on nurse-led assessmen.

Rituximab, Cyclophosphamide, Etoposide and Prednisone for the Treatment of Post-Transplantation Lymphoproliferative Disorder

Introduction: Post-transplantation lymphoproliferative disorder (PTLD) is a rare disorder with few established therapies. Solid organ transplant (SOT) patients who develop PTLD are often frail. While some patients respond to reduction of immunosuppression (RI) or rituximab monotherapy, aggressive or relapsed disease frequently requires chemoimmunotherapy. Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is a standard of care first-line chemoimmunotherapy for large B-cell lymphomas, but this regimen is often poorly tolerated by frail SOT patients with significant mortality, early discontinuation of therapy, neuropathy and cardiac toxicity. We report our institutional experience with rituximab, cyclophosphamide, etoposide, prednisone (R-CEP), as an alternative, anthracycline-sparing regimen for patients with PTLD. Methods: We retrospectively reviewed records within the Lymphoma Program of the University of Pennsylvania to identify patients who received R-CEP for PTLD. R-CEP was administered on day 1 of each cycle, every 3 weeks for six total cycles in outpatient clinic: rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, and etoposide 100 mg/m2 IV. Three patients received alternative etoposide dosing administered as 50mg/m2 IV on days 1-3. Prednisone was optional and administered at physician discretion; doses ranged from continuous SOT immunosuppression dose to 100 mg daily on days 1 to 5 of each cycle. Overall response rates (ORR), progression free survival (PFS), response duration (RD), and overall survival (OS) were assessed. Adverse effects were described by CTCAE v5. Results: Thirty-four patients were identified (see Table 1 for Patient Characteristics). Eleven patients (32%) initially were managed with RI alone; 2 of 11 (18%) responded for ≥ 6 months before progressive disease (PD). Twenty-four patients (71%) received rituximab monotherapy (either initially or for PD after RI) with 14 of 24 (58%) responding for ≥ 6 months before PD. All who received RI and/or rituximab monotherapy had PD before starting R-CEP. Seven patients (21%) were first treated with R-CEP due to aggressive initial presentation of PTLD. ORR at six months after completion of R-CEP was 47% with 15 complete responses (CR) and 1 partial response (PR). Median follow-up was 9.8 years (range 0.25-12 years). 46% and 41% of patients remained progression-free at 24 and 60 months, respectively (Figure 1). Median response duration (RD) was 47 months (95%CI: 5-NE). Of those who achieved CR at 6 months, median RD was not reached; 93% and 83% of patients in CR maintained responses at 24 and 60 months, respectively. Median OS was 45 months (95%CI: 13-NE), with 58% and 47% of patients alive at 24 and 60 months, respectively. Of the 21 patients who died, 12 (57%) died from PD, 2 (9%) from infections after receiving further salvage therapy, and the remainder from causes unrelated to PTLD. Fifty percent of patients received their first cycle while hospitalized. Seventy-four percent of patients had neutropenia (41% grade 3-4 neutropenia) and 23% had febrile neutropenia. Eight patients had grade 3-4 anemia and 6 developed grade 3-4 thrombocytopenia. Ten patients (29%) required hospitalization during treatment, most commonly for febrile neutropenia, anemia, or dehydration. There were no instances of neuropathy, cardiac toxicity, or treatment-related mortality. Of the 18 patients who did not complete all 6 cycles of chemoimmunotherapy, 11 (61%) stopped due to PD, 4 (22%) due to toxicity (most commonly cytopenias), 2 (11%) elected early stop after achievement of CR, and 1 (6%) due to a need for treatment of a secondary primary malignancy. Patients with PD commonly received R-CHOP for systemic progression (including heart transplant recipients) or radiation therapy for localized disease. Conclusions: R-CEP is a promising alternative to R-CHOP for frail PTLD patients based on our observed efficacy and toxicity and warrants further investigation. Cytopenias were less common than historically reported for PTLD patients treated with R-CHOP (Trappe et al 2012). There was no treatment-related mortality, whereas reported treatment-related mortality with R-CHOP for PTLD is 11% (Trappe et al 2012). Study limitations include its retrospective nature, small sample size, and heterogeneous PTLD population with respect to SOT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Daratumumab Carfilzomib Lenalidomide Dexamethasone Provides Effective Salvage for Functionally and Cytogenetically High-Risk Myeloma Patients, Except Those Expressing Module-1 Transcriptional Signature: Extended Follow-up from Kydar Multicenter Clinical/Translational Trial.

Background Myeloma patients (Pts) with resistance to a bortezomib-based induction therapy, either primary refractory or those relapsing early after completing induction, define a population of functional high-risk myeloma, shown to be associated with dismal prognosis. We designed a phase 2 clinical-translational trial to evaluate the safety and efficacy of a quadruple salvage regimen of carfilzomib (CFZ)/ lenalidomide (LEN)/dexamethasone (DEX) / daratumumab (DARA) (KRD-D) in myeloma Pts with functional high-risk (KyDaR, NCT04065789), and to identify molecular pathways of refractoriness based on transcriptional signatures associated with clinical resistance. Here we report final clinical data following 18-months (mo) study treatment and extended survival follow-up. Methods Forty-one newly diagnosed myeloma Pts treated with a bortezomib-containing induction regimen, who either: i) failed to achieve a minimal response after 2 cycles or a partial response (PR) after 4 cycles (cohort A), ii) had early relapse within 18 months from starting of therapy (cohort B) were enrolled to receive second line KRD-D treatment in eighteen 28-day (d) cycles (C) or until disease progression/unacceptable toxicity. CFZ: 56 mg/m2 IV days 1,8,15 (C 1-9), d 1,15 (C 10-18). LEN: 25 mg (Frail: 15mg) d1-21; Dex 40mg (Frail: 20mg) weekly; DARA: IV 16mg/Kg weekly (C 1-2), q14d (C 3-6), q28d. After 18 cycles, Pts continued to receive DARA/LEN. We applied longitudinally our calibrated protocol for single cell RNA sequencing (scRNA-seq) of myeloma plasma cells (Ledergor et al, Nat Med 2018) to identify transcriptional signatures associate with response or resistance, defined as PR or better (IMWG criteria) after 3 cycles. Primary endpoints were safety and tolerability. Secondary endpoints included overall response rate (ORR); progression free survival (PFS), and overall survival (OS). Results Forty-one Pts enrolled across 14 medical centers in Israel between June 2018-August 2019, patients had highly aggressive MM characteristics: 67% had intermediate/high risk and 30.5% had double hit FISH abnormalities, 39% had extramedullary disease, and 38% were frail. High expression of module-1 scRNAseq transcriptional signature associated with therapy resistance as previously described (Cohen YC et al, Nat Med 2021) was detected in 36%. At end-of study data cut-off (12NOV2021) the median follow-up was 30.7 mo (95% CI 26-35.3), and the median number of CFZ cycles administered was 10 (range 1-18). Nineteen Pts completed 18-months of KRD-D therapy. Reasons for early therapy discontinuation (n=22) included: disease progression (12), adverse event (AE, 6), consent withdrawal (3) and physician decision (1). All Pts had at least 1 treatment emergent AE (TEAEs), most were grade 1-2; There were 35 patients with TEAE grade ≥3, 4 (9.8%) patients discontinued study therapy due to AEs. Grade ≥3 TEAEs occurring in ≥10% of Pts included neutropenia (34%), thrombocytopenia (24%), sepsis (22%), pneumonia (19%) and musculoskeletal pain (12%); 4 patients died due to TEAEs (1 myocardial infarction, 3 sepsis). Durable and deep responses were achieved. ORR was 90% (37/41): near CR-stringent CR 22% / very good partial response 42% / PR 27%. Median duration of response was 25.6 mo (95% CI 11.5-39.7). Median PFS and OS were 15.4 and 28.2 months, respectively; 18-month PFS and OS were 49% and 57%, respectively. In univariable analysis, cohort (A vs B), age (≤70 vs >70) and high-risk cytogenetics (yes vs no) yielded similar OS. Over-expression of module-1 was highly predictive of poor PFS (3.8 mo vs not reached [NR], p=0.000006 and OS (13.8 mo vs NR, p=0.0003) [Fig1A]. A factorial analysis of module-1 X double-hit FISH showed the dominance of the former in prediction of OS [Fig 1B]. Frail Pts (IMWG criteria) had a median OS of 25 mo [95% CI 8.0-41.4] vs NR in intermediate/Fit Pts (p=0.07). Conclusions A cohort of functionally high-risk MM Pts, based on their resistance to an upfront bortezomib-based induction, were effectively salvaged by second line KRD-D quadruple regimen, achieving an ORR of 90% and durable responses. High expression of module-1 transcriptional signature, as discovered by scRNA-seq analysis was present in 36% of these Pts, and identified an ultra-high-risk population in which KRD-D provided inferior survival. Such patients may be considered for early experimental interventions such as novel immune-therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficiency Effectiveness Gap of Durvalumab in Locally Advanced Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Following results of the PACIFIC trial, definitive chemoradiation with one year of adjuvant durvalumab became the standard of care for patients with stage III NSCLC. Using a multi-institutional cohort of patients across the Veterans Health Administration, we recently showed that this treatment was effective in a real-world setting. While veterans receiving chemoradiation and adjuvant durvalumab had significant improvement in both PFS and OS compared to veterans who received chemoradiation alone, their OS was significantly worse than the patients in the PACIFIC trial. Veterans had a shorter median treatment duration and higher discontinuation of treatment secondary to toxicity, suggesting inferior overall treatment tolerance. Adherence and toxicity rates are often worse in real-world patients compared to clinical trial cohorts and no studies have evaluated the optimal duration of adjuvant durvalumab to maximize treatment adherence and effectiveness while minimizing treatment-related toxicities. We sought to determine predictors for early treatment discontinuation and examine the influence of durvalumab treatment duration on oncologic outcomes. <h3>Materials/Methods</h3> We identified patients with stage III NSCLC treated with definitive chemoradiation and at least one dose of adjuvant durvalumab from November 2017 to April 2021 in the United States Veterans Affairs system. Duvalumab infusion dates and reasons for early discontinuation of therapy were determined manually by chart review. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model simulating a three-arm randomized controlled trial. In sensitivity analyses, we used time-dependent Cox modeling to assess the effect of cumulative durvalumab duration on PFS/OS and adjusted for reasons for early discontinuation. <h3>Results</h3> A cohort of 1,006 patients with stage III NSCLC were included in our analysis. The median duration of durvalumab treatment was 7 months (interquartile range 2.8 – 11.5) and only 31% of patients completed the intended course. The most common reasons for early discontinuation were tumor progression (22%), immune-related adverse events (15%), and nonimmune-related toxicity (6.0%). Furthermore, older age was associated with an increased risk of early treatment discontinuation. Marginal structural models showed an equivalent PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months. Finally, sensitivity analyses with time-dependent Cox modeling suggested equivalence of shorter durations of therapy for PFS. <h3>Conclusion</h3> These data suggest that de-escalation of durvalumab treatment duration may be possible while not compromising cancer control. Prospective randomized studies are needed to further evaluate this important clinical question.

Rottlerin promotes anti-metastatic events by ameliorating pharmacological parameters of paclitaxel: An in-vivo investigation in the orthotopic mouse model of breast cancer

Despite substantial breakthroughs in cancer research, there is hardly any specific therapy available to date that can alleviate triple-negative breast cancer (TNBC). Paclitaxel is the first-line chemotherapy option, but its treatment is often associated with early discontinuation of therapy due to the development of resistance and/or precipitation of severe side effects. In the quest to establish a suitable combination therapy with a low dose of paclitaxel, we explored rottlerin (a pure and characterized phytoconstituent from Mallotus philippensis) because of its multifaceted pharmacological actions against cancer. The study was performed to assess the therapeutic effects of rottlerin (5–20 mg/kg) with a low dose of paclitaxel (5 mg/kg) using a highly aggressive mouse mammary carcinoma model. Rottlerin augmented the paclitaxel effect by reducing tumor burden as well as metastatic lung nodules formation. Rottlerin in combination with paclitaxel remarkably altered the expression of vital epithelial-mesenchymal transition (EMT) markers such as E-cadherin, Snail 1, & Vimentin and thus improved the anti-metastatic efficacy of paclitaxel. Significant attenuation of anti-apoptotic protein (Bcl-2) along with amplification of pro-apoptotic (cleaved PARP) marker confers that rottlerin could ameliorate the pro-apoptotic potential of paclitaxel. In this study, a rational combination of rottlerin and paclitaxel treatment curtailed CYP2J2 expression and epoxyeicosatrienoic acids (EETs) levels, responsible for restrain tumor growth and metastasis. Additionally, rottlerin lessened paclitaxel treatment-mediated hematological alterations and prevented paclitaxel treatment-linked key serum biochemical changes related to organ toxicities. These rottlerin treatment-mediated protective changes are closely associated with the lower paclitaxel accumulation in the corresponding tissues. Rottlerin caused significant pharmacokinetic interaction with paclitaxel to boost the plasma level of paclitaxel in a typical mouse model and possibly helpful towards the use of a low dose of paclitaxel in combination. Overall, it can be stated that rottlerin has significant potential to augment the anti-metastatic efficacy of paclitaxel via impeding EMT activation along with attenuating its treatment-associated toxicological alterations. Hence, rottlerin has significant potential to explore further as a suitable neoadjuvant therapy with paclitaxel against TNBC.

Poliosis Is Associated with Response to Checkpoint-Inhibitor Therapy: A Case Report of Two Patients with Multifocal Metastatic Melanoma

The advent of immune-checkpoint inhibitors (ICIs) led to significant improvements in the treatment of patients with advanced melanoma and resulted in durable tumor responses in a considerable number of advanced melanoma patients. Next to the immune-mediated anti-neoplastic effects, ICIs may cause various immune-related adverse events (irAEs), often requiring early discontinuation of therapy. By contrast, cutaneous irAE rarely enforce treatment discontinuation but may represent simple and robust predictive markers for treatment response. The relevance of irAEs as clinical markers for an improved response to immunotherapy is still debated. We report here on two patients with multifocal metastatic melanoma who developed the rare event of generalized poliosis during combined immunotherapy with ipilimumab plus nivolumab, followed by a near-complete and durable response. Our observations suggest that poliosis may be a useful and simple clinical indicator of anti-tumor immunity, clinical response and favorable survival outcome in advanced melanoma patients treated with ICI.

Delphi panel for consensus on the optimal management of dabrafenib plus trametinib-related pyrexia in patients with melanoma.

Dabrafenib and trametinib combination therapy (dab + tram) is indicated to treat BRAF V600 mutation-positive unresectable/metastatic melanoma and as adjuvant treatment for resected stage III disease. Dab + tram-related pyrexia may require early therapy discontinuation. A modified Delphi panel was conducted to develop consensus on the optimal management of dab + tram-related pyrexia in patients with melanoma. In all, 10 UK oncologists experienced in melanoma management participated in a three-round modified Delphi study (Round 1: one-to-one interview; Rounds 2 and 3: email survey). In each round, participants rated the extent of their agreement with statements about defining and managing dab + tram-related pyrexia. Consensus was defined as >80% agreement for critical management (CM) and >60% for non-critical management (NCM) statements. All 10 participants completed Round 1; 9 completed Rounds 2 and 3. Consensus was reached on 42/66 statements (20 CM and 22 NCM). Drug-related pyrexia was agreed as being strictly an elevation of body temperature, although other symptoms may be present (89% agreement). Panelists agreed on the need for simple and generic guidance on dab + tram-related pyrexia management that does not differentiate between patient groups (100%), and that management of first and second dab + tram-related pyrexia episodes should be the same regardless of treatment intent (100%). Regarding CM, participants agreed that both dab and tram should be interrupted for pyrexia (100%) without considering the use of steroids (89%); patients on dab + tram presenting to non-oncology services with pyrexia should be directed to an oncology-specific service as soon as possible and assessed for infection (100%). NCM statements on steroid use following dab + tram interruption and when to restart dab + tram did not reach consensus. These consensus statements provide a framework on optimal management of dab + tram-related pyrexia in patients with melanoma which should inform future guidelines.

Frontline Venetoclax (ven) Based Combination Therapy in Older Adults with Acute Myeloid Leukemia Treated in the Real-World Setting; A Multi-Institutional Retrospective Study

Introduction: Acute myeloid leukemia (AML) is a disease of the older population, with a median age at diagnosis of 68 years. Outcomes remain poor for patients (pts) older than 60 years of age who are unfit to receive intensive chemotherapy. Ven based combination therapy has become the standard of care based on the results of the Viale-A and Viale-C in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), respectively. This combination therapy is myelosuppressive leading to multiple dose adjustments in the real-world setting, which may impact the validity of the trial responses and overall survival (OS) in a community-based practice. We therefore sought to investigate the outcomes of pts treated with ven based combination therapy in the real-world setting to better understand efficacy and patterns of adverse events.Methods: Pts 65 years of age or older, diagnosed with AML on or after January 1, 2019, and who received frontline ven based combination therapy with azacitidine (aza), decitabine (dac) or LDAC were identified in the COTA real-world database. The COTA database is a USA-based dataset comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant data on the diagnosis, clinical management, and outcomes of pts with cancer. Clinical outcomes, including real-world overall response rate (rwORR), OS and adverse events were calculated by treatment group. Responses were defined per treating physician as complete response (CR) or partial (PR) or progressive disease (PD). Categorical variables and rwORR were compared using Fisher's exact test. Survival outcomes were calculated using the Kaplan-Meier method and compared amongst groups using log-rank test.Results: A cohort of 112 pts were treated with ven based combination: ven/aza (n=54), ven/dac (n=52) and ven/LDAC (n=6). Across all treatment groups, the majority (91.1%) of pts were treated in the community setting. The median age at diagnosis was 77 yrs (IQR: 71-81 yrs). Per ELN risk, 6.2% had favorable, 19.6% had intermediate and 62.5% had high-risk AML. Five of the 6 pts receiving ven/LDAC had secondary AML (Table 1). The most common molecular abnormalities across the cohort were TP53 (38.4%), TET2 (26.8%), ASXL1 (27.7%), and DNMT3A (20.5%). The rwORR by treatment was 57.7% for ven/dac, 55.6% for ven/aza and 33.3% for ven/LDAC (ven/dac vs. ven/aza, p=0.85). Median OS (mOS) was similar for ven/dac with a longest mOS of 13.9 mo, followed by ven/aza with a mOS of 11.3 mo, and ven/LDAC mOS of 6.5 mo (ven/dac vs. ven/aza, p=0.77). The most common reasons for treatment discontinuation were toxicity (32.1%) followed by progression/inadequate response (10.7%). The most common toxicities were related to myelosuppression/cytopenias (Table 3). In this cohort, only 6 pts underwent an allogeneic stem cell transplant in first remission and no pts underwent an allogeneic transplant in second remission.Conclusions: To our knowledge, this dataset represents the largest cohort of pts treated with ven based combination therapy in the real world setting across multiple community practices. As less intense regimens are used to treat AML, more pts are receiving induction in the community setting, making these findings relevant in clinical practice. Although ven/dac combination had the longest OS, this was not significantly different from ven/aza. The ven/HMA response rates were lower and survival outcomes were shorter than those reported in the Viale-A trial, which raises concerns about early discontinuation of therapy in the real world setting due to myelosuppression. Ven/LDAC combination had the shortest OS, though most of these patients had sAML. Despite this enriched population for targeted therapies, the outcomes remained poor overall.There are drawbacks to interpreting retrospective outcomes data. First, there were no treatment related AML cases in this dataset, which would be highly unusual in an elderly population of 112 cases of AML. It is more plausible that the diagnosis of treatment related AML was not utilized in the patient's chart. Other data points that were not adequately captured were cause of death and International Working Group response criteria. Mutational panel testing remains underutilized for AML patients in a community-based practice setting. However, this dataset highlights the need for larger datasets to compare the outcomes of AML therapy by practice setting. [Display omitted] DisclosuresMadanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Hansen: COTA, Inc.: Current Employment. Foss: COTA, Inc.: Current Employment. Schulte: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

September 2021 at a glance: focus on biomarkers, sex differences and adherence to medical treatment.

Biomarkers represent useful tools in the management of patients with heart failure (HF). 1-3 Antigen carbohydrate 125 (CA125) is a novel marker of congestion, inflammation and right-sided HF. It emerged as an affordable and widely available tool for tailoring HF therapies and prognostic stratification, since high serum levels are associated with an increased risk of death and HF hospitalization.4 The role of cardiac troponin in HF is well-established.5 In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced), increasing levels of high-sensitivity cardiac troponin T (hs-cTnT) were associated with higher rates of comorbidities (i.e. diabetes and atrial fibrillation), more advanced New York Heart Association functional class, decreased renal function, higher concentrations of natriuretic peptides and worse clinical course. However, empagliflozin reduced the primary endpoint of cardiovascular death or HF hospitalization, regardless of baseline hs-cTnT levels,6 confirming the role of sodium–glucose co-transporter 2 (SGLT2) inhibitors as an essential treatment for patients with HF with reduced ejection fraction (HFrEF).7-9 Sex-based differences exist among patients with HF.10, 11 In the Effects of High-Dose versus Low-Dose Losartan on Clinical Outcomes in Patients with Heart Failure (HEAAL) trial, women appeared to respond similarly to low and high doses of losartan, whereas men had more benefits with high doses. However, women were older compared with men and more frequently presented severe symptoms and renal dysfunction.12 Sex differences were also investigated in the Patient-centered Care Transitions in Heart Failure: A Pragmatic Cluster Randomized (PACT-HF) study, enrolling 986 patients with the aim to test the effect of a patient-centred transitional care model. Such model improved discharge preparedness, transition quality, and the health-related quality of life both at 6 weeks and 6 months, with no differences between men and women. Women had a lower quality of life score at discharge, but experienced more benefits from treatment compared with men.13 Dietary interventions are related to HF incidence and outcome.14, 15 A meta-analysis, including 122 randomized controlled trials and 176 097 participants, summarized and confirmed the impact of nutritional and dietary interventions on HF-related outcomes. In particular, coenzyme Q10 was associated with lower all-cause mortality, whereas Mediterranean diet was related with a lower risk of developing HF.16 Ergoreflex is a cardiorespiratory reflex activated during physical effort. HF patients often develop skeletal myopathy,17 which is associated with increasing ergoreflex sensitivity and dyspnoea on effort. Exercise training represents a valuable strategy to reduce such sensitivity and increase exercise tolerance.18 Among the quality of life measures tested in the PARALLAX trial (a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure with mildly reduced and preserved ejection fraction), the Short Form Health Survey-36 physical functioning score was the most closely correlated with 6-min walk test (6MWT). A modest correlation was found between 6MWT and Kansas City Cardiomyopathy Questionnaire clinical summary score. Many factors were associated with worse values in both quality of life and exercise capacity (i.e. female sex, higher body mass index, higher levels of N-terminal pro-B-type natriuretic peptide and coronary artery disease).19 Adherence to guideline-directed medical therapy (GDMT) improves outcome in patients with HFrEF.20, 21 However, GDMT remains suboptimal in a large proportion of patients.22 A recent multinational observational study confirmed strong patterns of GDMT low-titration in HF patients. Target dose of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers, beta-blockers, and angiotensin receptor–neprilysin inhibitors, was achieved in 15%, 10%, 12%, and 30% of patients, respectively. An early discontinuation of therapy was frequently observed, with ACEi being the most withdrawn agent (55% at 12 months), followed by mineralocorticoid receptor antagonists (MRA) (40% at 12 months).23 Bhatt et al.24 evaluated the effects of both sacubitril/valsartan and enalapril on co-prescribed beta-blockers and MRA in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HH) trial. Sacubitril/valsartan did not influence beta-blocker treatment nor MRA initiation, but led to fewer MRA discontinuation compared to enalapril. The coronavirus disease 2019 (COVID-19) pandemic represented a great burden for the HF community.25-30 Management of heart transplant recipients require even tighter precautionary measures in this historical era.31 In a prospective single centre cohort study, including heart transplant recipients, short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has been evaluated. Only 15% of patients displayed the presence of anti-spike IgG antibodies after the first dose, and a total of 49% responded to the full two-dose vaccine schedule. Older age and anti-metabolite-based immunosuppression were associated with lower immunogenicity.32

Morphologic Assessment of Bone Marrow Samples in AML Patients Treated with Inhibitors to IDH1 and IDH2—a Single Center Experience

INTRODUCTION:Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are reported in about 8% and 13% of patients with acute myeloid leukemia (AML), respectively, and are less common in patients with myelodysplastic syndromes. These recurrent mutations in AML lead to neomorphic enzymatic activity resulting in accumulation of 2-hydroxyglutarate, DNA and histone hypermethylation, blockage of cellular differentiation and, ultimately, leukemogenesis. Inhibitors to both IDH1 and IDH2 are being developed and have shown clinically significant responses. Perhaps unsurprisingly, these IDH inhibitors appear to promote the differentiation of myeloblasts.Serial bone marrow biopsies are considered the standard of care for the evaluation of the effectiveness of AML-directed therapies. However, due to the unique mechanism of action of IDH1 and IDH2 inhibitors, the morphologic assessment of response to these drugs may be challenging to pathologists and hematologists who may not be familiar with their use. Here we describe our single-center experience with IDH1 and IDH2 inhibitors with the goal of improving our understanding of the bone marrow topography in treated patients.METHODS:This retrospective study reports on all patients at our institution with refractory or relapsed AML who have been treated with either an IDH1 inhibitor (FT-2102) on a clinical protocol (NCT02719574) or an IDH2 inhibitor (AG-221, Enasidenib) on a compassionate use basis. A bone marrow biopsy and aspiration was performed on all patients after each 4-week cycle of therapy. All baseline and on-treatment bone marrow specimens were reviewed by a dedicated hematopathologist. Due to the small sample size, which is reflective of the low prevalence of this particular patient population, reported results are primarily descriptive in nature.RESULTS:A total of three patients were treated with an IDH1 inhibitor (cases 1,2,3), one of whom was treated in combination with azacitidine (case 3). Two patients were treated with an IDH2 inhibitor (cases 4,5). One patient (case 5) is still undergoing early treatment and therefore a full assessment of response and bone marrow morphology is not included at the time of this writing. Ages ranged from 53 to 71 years. All patients had relapsed and/or refractory AML with a median of three prior lines of therapy. Complete response (CR) to IDH1 or IDH2 inhibitor therapy was seen in 3 out of the 4 evaluable patients (cases 2,3,4). Two of the CRs were associated with incomplete platelet count recovery (CRp).In 3 of 4 patients, the end of cycle 1 bone marrow was markedly hypercellular (>90%) with sheets or large aggregates of myeloblasts suggestive of refractory disease. In case 1, the IDH inhibitor therapy was discontinued. In the other two cases, therapy was continued and CRp was eventually achieved after 2 cycles in case 2 and after 3 cycles in case 4. In cases 2 and 3 the morphology in the bone marrow at the time of remission was considered markedly abnormal by the pathologist. In case 2, the marrow was markedly hypercellular (>95%) with a profound myeloid expansion and increased reticulin fibrosis reminiscent of a myeloproliferative disorder. In case 3, the marrow was again markedly hypercellular (>95%) with marked myeloid and megakaryocytic hyperplasia and significant dysplastic features in all three lineages.CONCLUSION:Bone marrow assessments in patients on IDH inhibitor therapy can be challenging. Clinicians should be aware that responses may be delayed and early discontinuation of therapy may be premature particularly in patients who otherwise appear to be deriving clinical benefit. Pathologists should be made aware of this new class of drugs with a novel mechanism of action which can produce unusual bone marrow morphologies, presumably due to a differentiating effect on leukemic myeloblasts. This may mimic other myeloid malignancies such as myelodysplasia and myeloproliferative neoplasms. Thus, communication between the treating hematologist and interpreting pathologist is important for accurate response evaluations and optimal patient outcomes. Results will be updated at the ASH Annual Meeting including results from case 5 and photomicrographs of representative marrow specimens. DisclosuresNo relevant conflicts of interest to declare.

Efficacy of Lenalidomide As Salvage Therapy for Patients with AL Amyloidosis

Current treatment approach to AL amyloidosis aims at the elimination of the plasma cell clone that produces the amyloidogenic light chains. Bortezomib-based regimens are used in most centers as primary treatment; however, there are limited data on the outcomes of patients with AL who fail bortezomib. Lenalidomide is a standard treatment for patients with myeloma who fail bortezomib. In patients with AL amyloidosis there data from mixed cohorts of previously untreated and pretreated patients, indicating that lenalidomide with dexamethasone with or without a third agent (cyclophosphamide or melphalan) is active but is not well tolerated at standard doses; however, data regarding the efficacy of lenalidomide specifically in patients with relapsing or refractory AL, especially after bortezomib, are limited. The aim of the current study was to evaluate lenalidomide as salvage therapy in consecutive patients with pretreated AL amyloidosis, in order to assess its efficacy and toxicity in this setting.This analysis included 50 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis; all were diagnosed, treated and followed in the Department of Clinical Therapeutics, Athens, Greece. Definition of hematologic and organ response and progression was based on consensus criteria.The median age was 63 years (range 42-82) and 67% were males. Heart was involved in 72%, kidneys in 75%, peripheral nerve in 33% and liver in 24%. At the time of initiation of lenalidomide, median eGFR was 53 ml/min/1.73 m2 and 12% were on dialysis; median NTproBNP was 2369 pg/ml and 21% were Mayo stage -1, 41% stage -2 and 38% stage -3. Median time from the start of primary therapy to lenalidomide was 14 months (range 1 to 108) and the median number of prior therapies was 1 (range 1-4), while, 72% of the patients had prior bortezomib: 42% were bortezomib refractory and 30% were potentially bortezomib sensitive (i.e. had responded to bortezomib and relapsed > 6 months after last bortezomib dose).On intention to treat, hematologic response rate was 57% (5% CRs, 24% VGPRs and 28% PRs); was similar for patients with and without prior bortezomib (56% vs 58%) and was 38% vs 62% for bortezomib refractory vs non-refractory patients (p=0.084).Organ responses were recorded in 10% of evaluable patients and included 11% renal responses and 8% liver responses; however, no cardiac responses were recorded based on NTproBNP criteria, probably due to increase of NTproBNP in most patients after start of lenalidomide therapy. Among patients not in dialysis, 10 (20%) eventually progressed to end stage renal disease requiring dialysis.Median overall survival post lenalidomide initiation was 29 months. There was no difference in the survival of patients who were potentially bortezomib sensitive vs refractory (p=0.395); however, bortezomib naive patients had better survival, even after adjustment for Mayo stage (p=0.028).Median dose of lenalidomide was 10 mg (range 5 to 15); no patient received the 25 mg dose. Median duration of lenalidomide therapy was 7.2 months (7 cycles) and 46% of the patients discontinued lenalidomide before completion of planned therapy. Main reasons to discontinue lenalidomide were disease progression/no response in 10%, toxicity in 26%, patient's or physician's decision in 10%, while 17% died while on therapy with lenalidomide due to AL-related complications. Common hematologic toxicities (≥Gr3) included thrombocytopenia in 6%, anemia in 15%, neutropenia in 6%. Most common non hematologic toxicities (≥Gr3) that led to dose reduction or early discontinuation of therapy were diarrhea in 9%, fatigue in 15%, skin rash in 15%, pneumonitis in 4%. Transient increases in serum creatinine (up to Gr1) were common; however, in 8% this was associated with acute renal failure.We conclude that lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, with hematologic responses in 57% of patients, including patients who are refractory to bortezomib. However, organ responses were poor, probably because of the prolonged disease course which may have affected the ability of organ function recovery, at the time of initiation of lenalidomide, while NTproBNP based cardiac response criteria are challenging to use with IMiDs-based therapies. The toxicity of lenalidomide in patients with AL amyloidosis is significant and dose adjustments are commonly required. DisclosuresKastritis:Amgen: Honoraria; Genesis Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Prothena: Honoraria. Terpos:BMS: Honoraria; Janssen: Honoraria, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Amgen: Honoraria, Other: SC member, Research Funding; Abbvie: Honoraria; GSK: Honoraria. Dimopoulos:Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Novartis: Consultancy, Honoraria.

Suboptimal Completion Rates, Adverse Events, Costs, Resource Utilization, and Cost Impact of Noncompletion in Oral Adjuvant Capecitabine–Based Chemotherapy in Patients With Early-Stage Colon Cancer

BackgroundSuboptimal completion of chemotherapy, which may involve reduced patient adherence, remains a serious issue and leads to reduced treatment efficacy. This study assessed the completion rates, risk factors for noncompletion, and cost impact for noncompletion in patients on capecitabine monotherapy (Cape) or capecitabine with oxaliplatin (CAPOX) for the adjuvant treatment of early-stage colon cancer. MethodsPatients with a diagnosis of early-stage colon cancer between April 2013 and March 2017 were retrospectively identified. Treatment completion was evaluated. Multivariate logistic regressions analyses were used to assess the baseline factors associated with noncompletion. Adverse events, costs, healthcare resource utilization, and cost impact for noncompletion were investigated. ResultsA total of 673 patients met the eligibility criteria, of which 382 (57%) were treated with Cape and 291 (43%) with CAPOX. The overall completion rate for adjuvant therapy was 40% (Cape 46%; CAPOX 33%). Noncompletion was associated with CAPOX treatment and higher healthcare costs within 6 months prior to chemotherapy. The 6-month unadjusted total healthcare costs were $44,444 for Cape and $71,247 for CAPOX. The nonchemotherapy costs were 41% higher for noncompleters than completers in both treatment groups (P = .002). ConclusionsThe real-world completion rates for adjuvant capecitabine–based chemotherapy in early-stage colon cancer patients are low. Noncompletion of therapy is associated with higher baseline healthcare costs. The nonchemotherapy costs are significantly higher in noncompleters than completers, highlighting the financial burden of managing adverse events and preexisting comorbidities, which may lead to early discontinuation of therapy. Effective strategies to optimize completion of oral chemotherapy may consider adherence monitoring.

Abstract 15440: Bleeding Complications May Outweigh the Risk of Thrombosis in Patients With End-stage Liver Disease Taking Dual Antiplatelet Therapy After Percutaneous Coronary Intervention

Introduction: Randomized trials have demonstrated the safety and efficacy of one month of dual antiplatelet therapy (DAPT) after placement of drug-eluting stents in patients with high bleeding risk. Patients with end-stage liver disease (ESLD) are underrepresented in these trials. Patients who undergo percutaneous coronary intervention (PCI) in preparation for orthotopic liver transplantation (OLT) exhibit a high incidence of bleeding complications on DAPT. The rates of bleeding versus thrombotic complications in ESLD patients placed on DAPT following PCI are poorly described. Methods: We retrospectively collected data from 61 patients who were evaluated for OLT between 2016 and 2019 and underwent PCI prior to listing. Bleeding events were classified using the Bleeding Academic Research Consortium (BARC) definitions and included if the following criteria were met: events occurred in the setting of DAPT, were non-procedural in etiology, and occurred during the time following PCI and prior to OLT. Ischemic complications were evaluated by the incidence of myocardial infarction (MI), stent thrombosis, in-stent restenosis (&gt;50%) and all-cause mortality at 1 year follow-up. Results: A total of 55/61 patients (90%) were placed on DAPT following PCI. Among them, 21/55 patients (38%) bled while taking DAPT, including 15 patients (27%) with BARC types 3-5 first-time bleeding events and 10 patients (18%) requiring early discontinuation of therapy. The median time to first bleeding event was 8 days (range 1 to 477 days, 85 th percentile 17 days). Among ischemic complications, MI occurred in 11/55 patients (20%) however only one patient had a type 1 MI with the remaining being type 2 in etiology. There were no episodes of stent thrombosis and 2 episodes of in-stent restenosis during the 1 year follow-up. A total of 12/55 patients (22%) went on to receive OLT and 18/55 (33%) passed away by 1 year post-PCI. Conclusions: Patients with ESLD exhibit a high rate of clinically significant bleeding on DAPT when compared to overall thrombotic events. The majority of bleeds occurred within the first month after PCI. These findings illustrate the need for larger studies to assess the safety of single instead of dual antiplatelet therapy in patients with ESLD who receive PCI.

Aromatase Inhibitor Symptom Management Practices: A Retrospective Study

PurposeAromatase inhibitor (AI)-associated symptoms contribute to early therapy discontinuation. Although guidelines exist for management of these symptoms, little is known about the degree to which physicians address symptoms and adhere to the guidelines for treatment. Patients and MethodsIn this retrospective chart review, women with hormone receptor–positive breast cancer who were prescribed an AI between October 15, 2012, and September 14, 2017, were randomly selected from the institution’s cancer registry. Patient medical records were reviewed to identify the prevalence of symptom documentation and management. Documented symptoms were categorized into musculoskeletal, vasomotor, and urogenital. Symptom treatment guidelines were compiled from the National Comprehensive Cancer Network (NCCN) and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO). Treatments were categorized as either meeting or not meeting the guidelines. Among patients with symptoms recorded, chi-square tests and time-to-event models were used to examine factors associated with treatment and factors associated with guideline-based treatment. ResultsAmong 179 women prescribed an AI, 82% had at least one symptom and 46% had multiple symptoms. Of the 147 women with any documented symptom, 97 (66%) received some form of symptom-palliating treatment. Seventy-seven patients (52%) received guideline-based treatments or guideline-based treatments in combination with non–guideline-based treatments. There were no differences in receipt of treatment overall (ie, guideline based or non–guideline based) for either vasomotor or musculoskeletal symptoms by age, race, or stage. ConclusionAlthough 82% of patients had symptoms documented in their medical records, just over half of those patients received guideline-based treatment.

Abstract IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities

Abstract IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities

777. Experience with Liposomal Amphotericin B in Outpatient Parenteral Antimicrobial Therapy (OPAT)

BackgroundWhile OPAT is known to be a safe, effective, and convenient treatment strategy for patients receiving intravenous antimicrobials in the outpatient setting, the risk of adverse events (AEs) increases when high-risk medications, such as liposomal amphotericin B (L-AMB), are utilized. There is limited data available describing the use and safety of L-AMB in the OPAT setting.MethodsElectronic medical records of patients discharged from Barnes Jewish Hospital on L-AMB between January 2015 and July 2018 were retrospectively reviewed. The primary objective of this study was to describe the population of OPAT patients discharged on L-AMB and to evaluate factors associated with readmission and AEs. Univariate analysis was performed to evaluate for predictors of worse outcomes.ResultsForty-two patients (67% male, median age 50 years) were identified. The most common indications were histoplasmosis (n = 13, 31%) and aspergillosis (n = 7, 17%). The majority of patients were discharged to home (n = 35, 83%) on a median dose of 4 mg/kg L-AMB. More than half of the patients completed their anticipated course of L-AMB (n = 26, 62%), 17 without any interruption or change in therapy, while 16/42 patients required early discontinuation of therapy, 11 of which required a change in therapy. Twenty-one patients (50%) were readmitted during their L-AMB course with a median time to readmission of 10 days (IQR 4–18). While hypokalemia and AKI (increase in serum creatinine by 0.5 mg/dL or 50% from baseline) were common AEs, occurring in 62% (n = 26) and 49% (n = 20), only 5 (12%) were readmitted to the hospital due L-AMB-associated AE (hypokalemia (K < 3 mEq/L), n = 2; AKI, n = 3. Factors associated with all-cause readmission included malignancy (not readmitted 6/21 vs. readmitted 13/21, P = 0.02) and duration of therapy (median of 15 vs. 32 days in not readmitted vs. readmitted, P = 0.02). OPAT lab monitoring was performed at a median of 2 times per week. No patients required hemodialysis due to AKI.ConclusionL-AMB is associated with significant AEs; however, these results suggest treatment is feasible in the outpatient setting with close monitoring. The majority of AEs were managed effectively as an outpatient without long-term sequelae.Disclosures All authors: No reported disclosures.