Time-limited Therapy Research Articles

Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia

Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development. To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment. Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023. Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded. Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted. Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model. A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40). The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

Time-Limited Therapy with Zanubrutinib Plus Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia: Early Results of an Ongoing Phase 2 Trial

Introduction: The Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib has recently been approved for treatment of chronic lymphocytic leukemia (CLL). Zanubrutinib induces durable remissions in most patients with CLL, and treatment is typically given as continuous monotherapy, until disease progression or toxicities prohibit further use. We developed time-limited therapy with zanubrutinib in combination with rituximab as an alternative to long-term BTKi monotherapy. Here, we report early results from the first 17 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04458610) between July 2020 and April 2023 at MD Anderson Cancer Center. Patients and Study Design: Patients with treatment-naïve CLL requiring therapy per iwCLL criteria receive zanubrutinib 160 mg orally twice daily and rituximab (375 mg/m 2 intravenously) on days 1, 8, 15, 22 of cycle 1, and then on day 1 of cycles 2 - 6 (one cycle is 28 days). Patients who achieve a complete remission (CR) by iwCLL 2018 criteria after 6 cycles of combination therapy continue with zanubrutinib alone for another 6 cycles. Patients who achieve a partial remission (PR) or stable disease (SD) after 6 cycles continue for another 6 cycles of the combination. Patients who achieve a CR after 12 cycles will receive 6 additional cycles of zanubrutinib alone, and then stop treatment. Patients who achieve a PR or SD after 12 cycles will continue zanubrutinib alone for 12 cycles and the stop therapy after a total of 24 cycles. After this time-limited therapy, patients transition to observation and can resume therapy if they relapse and fulfill iwCLL criteria for salvage therapy. The primary objective of the trial is to determine the proportion of patients who have treatment-free remission 6 months after discontinuation of zanubrutinib. Secondary objectives are to determine the length of treatment-free remission, identify clinical factors associated with long versus short remissions, and to evaluate the efficacy of re-treatment with zanubrutinib plus rituximab in patients who relapse. Results: The median age of the patients was 68 years (range, 54 - 77 years), 47% had unmutated IgHV and 41% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and β2 microglobulin were 51.9x10 9/L (range, 1.7 - 231.0x10 9/L) and 3.9 mg/L (range, 2.5 - 6.8 mg/L), respectively. After a median follow-up of 13 months (range, 0.5 - 29 months), all patients remain on study, and the estimated one-year progression-free (PFS) and overall survival (OS) is 100%. Seven patients completed therapy (1 patient after 12 cycles, 6 patients after 24 cycles) and have moved on to observation (median observation time post-therapy 4.5 months). So far, we have not observed any progression events after treatment discontinuation. Overall response rate is 100%, with 9% CR and 91% PR after 6 months (n=11), 11% CR and 89% PR after 12 months (n=9), and 33% CR and 67% PR after 24 months of therapy (n=6). The median levels of bone marrow involvement by CLL cells, quantified by flow cytometry, declined from 81.6% at baseline (range, 25.8 - 93.2%, n=16) to 20.3% after 6 cycles (range, 0.07 - 82%, n=11, p&amp;lt;0.0001), to 12.1% after 12 cycles (range, 0.04 - 55.60%, n=9, p&amp;lt;0.0001), and to 7.23% after 24 cycles (range, 0.2 - 41.4%, n=6, p=0.001). Grade ≥3 adverse events (AE) were observed in 9 patients (52.9%), which included hypertension (n=4) and decreased neutrophil counts (n=3). The most frequent grade 1-2 AE were decreased neutrophil (59%) and platelet counts (47%), bruising (41%), chills, increased creatinine, arterial hypertension, nausea (35% each), fatigue, and headache (29% each). No atrial fibrillation events were observed. Conclusion: This early analysis indicates that time-limited therapy with zanubrutinib and rituximab is well tolerated and induces remissions with a major reduction in bone marrow disease burden in patients with treatment-naïve CLL. The first 7 patients who stopped therapy so far have not progressed, but longer follow-up in more patients is needed to determine the durability of responses after therapy discontinuation, and how those compare to more intensive CLL combination regimens.

Multilayer Profiling of MRD in Patients with Relapsed/Refractory CLL Treated with Venetoclax-Based Regimens in a Real-World Setting

Background Clinical trials have shown that patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL) treated with venetoclax monotherapy (Ven) or venetoclax-rituximab (VenR) often achieve unmeasurable MRD (uMRD) in peripheral blood (57% of VenR-patients achieved uMRD in peripheral blood at the 12 months landmark by FCM and/or ASO-PCR in the RCT MURANO; Kater AP. et al. JCO 2019 1). uMRD is a strong prognostic factor for progression free survival (PFS) in RR-CLL treated with venetoclax, but the rate of uMRD has not been systematically validated in RR-CLL cohorts treated in the real-world setting. Venetoclax imposes a strong selective pressure on the MRD clone, but the magnitude of the genetic drift of MRD persisting under venetoclax has not been quantified or qualified. Resistance to venetoclax can be mediated by selection of BCL2 mutant clones, but it is unknown if they already emerge in persistent cells of the MRD when the disease is in remission. Methods We analyzed peripheral blood of Swiss patients enrolled in the VeRVe study (NCT03342144), a prospective non-interventional observational study assessing effectiveness, safety, and quality of life in real-world patients with RR-CLL treated with Ven or VenR according to local label. MRD was measured by 8-color multi-parametric flow cytometry (FCM) following the European Research Initiative on CLL (ERIC) guidelines (sensitivity 10 -4), by high throughput sequencing (Ig-HTS, clonoSEQ® Assay) on gDNA from PBMCs (sensitivity 10 -6) and by NGS LyV4.0 CAPP-Seq ctDNA Assay on plasma ctDNA (sensitivity 10 -3) at diagnosis and at 12 months of treatment. To overcome the limitations imposed by the small size of MRD under venetoclax treatment, we leveraged ctDNA for clonal evolution profiling and for the detection of BCL2 mutations. Tumor gDNA was extracted from pre-treatment CLL cells purified by flow cytometry. Germline gDNA was extracted from PB leukocytes collected at the time of best MRD remission. Results In total, 28 patients were recruited. At the time of the analysis, 7 patients went off study before the one-year landmark, 4 patients have not yet reached the one-year landmark, resulting in 17 patients (Ven=5, VenR=12) assessable at the one-year landmark [17 analyzed by FCM, 16 by CAPP-seq (1 ongoing) and 12 by Ig-HTS (5 ongoing; 3 could not be evaluated because they failed Ig-HTS QC)]. At the 12 months landmark, uMRD was achieved in 58% of the assessed cases by FCM, 56% by CAPP-seq and 33% by Ig-HTS. FCM and CAPP-seq concordantly defined the MRD status in 76% of cases with κ=0.49 (12% had measurable ctDNA despite uMRD by FCM and 12% lacked ctDNA despite having measurable MRD by FCM). FCM and Ig-HTS concordantly defined the MRD status in 67% of cases with κ=0.40 (33% had measurable MRD by Ig-HTS despite uMRD by FCM). All patients, who had measurable MRD by FCM and/or CAPP-seq, had measurable MRD by Ig-HTS, which instead detected measurable MRD in 11% of patients who scored negative by both FCM and CAPP-seq (κ=0.77). By CAPP-seq of gDNA from purified CLL cells collected before therapy, the most frequently mutated genes were TP53, IGLL5, BRAF, SF3B1, NXF1, and ZMYM3. At baseline the concordance in mutation recovery by CAPP-seq of gDNA from purified CLL and ctDNA from plasma was high (73%). Before therapy, BCL2 mutations were never detected in either gDNA from purified CLL cells, or in ctDNA. To overcome the limitations imposed to genomic profiling by the small size of MRD under Ven or VenR treatment, we leveraged ctDNA for tracking the acquisition of BCL2 mutations. A total of 5 longitudinal, post-treatment timepoints spanning up to two years of therapy were analyzed. No patients who had measurable ctDNA at the one-year landmark (n=16) acquired BCL2 mutations. Conclusions The rate of uMRD achievable by venetoclax-based therapy in RR-CLL as measured in this real-world prospective study is congruent with the rate observed in the randomized clinical study MURANO. Ig-HTS has the best diagnostic performance for MRD detection. BCL2 mutations are not detectable in ctDNA after one year of venetoclax-based treatment, confirming that time limited therapy has low risk of selecting resistance. 1.) Kater AP. et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. JCO 2019, 7(4):269-277

Multi-Omics Exploration of Adaptive Mechanism to BTK Inhibition By Ibrutinib in CLL Identified TMBIM6/BI-1 As a Poor Prognosis Variable and Potential Therapeutic Target

Introduction: Ibrutinib is currently part of the therapeutic armamentarium employed in patients with CLL. Despite being an active drug, its usage is not devoid of adverse effects and resistances leading to discontinuation. In addition, current evidence suggests that ibrutinib improves the T cell disfunction associated with CLL progression. The objective of our study was to longitudinally assess the T cell immune profile of ibrutinib-treated CLL patients, and to identify potential adaptive mechanisms to BTK inhibition in B cells in the first 12 months of continuous treatment. Methods: Blood samples from 28 patients from GELLC7 trial (NCT03280160, ibrutinib followed by ofatumumab consolidation) were collected before treatment (BT), and 1, 3, 6 and 12 months on treatment (at least two timepoints). Peripheral blood mononuclear cells and plasma were isolated and stored to perform multi-omics analyses including flow cytometry, RNA sequencing, cytokine determination, migration assays and targeted DNA sequencing. Results: T cell immunophenotyping revealed a decrease of CD4+ and CD8+ T cells expressing PD1 and CD244 and a reduction of regulatory T cells (Tregs) and T follicular helper (Tfh) cells after ibrutinib treatment. In addition, bulk-RNAseq of purified T cells revealed 170 differentially expressed genes (DEG) after 6 months of ibrutinib treatment. These genes participate in pathways related to cell stimulation and regulation of cell activation. Gene set enrichment analysis (GSEA) showed a downregulation of oxidative metabolism, proliferation, and activation pathways, indicating a reduction of the CLL inflammatory burden. Furthermore, there was a significant reduction of several inflammatory/migration chemokines in plasma at 6 months (CCL2/3/4, CXCL10, CXCL12, CXCL13, CCL19). In CLL cells, a decreased expression of adhesion (CD44/CD62L), immunosuppression- (CD200/BTLA), and migration-related markers (CXCR5/CCR7) at 6 months of ibrutinib treatment was observed. However, CXCR4 expression increased upon ibrutinib treatment, and the proliferative CXCR4dimCD5br population was reduced. We investigated CXCR4-mediated migration as a potential mechanism of CLL cell adaptation to ibrutinib in 14 patients at BT and 6 months of BTK inhibition. Reduced CXCR4-migratory capacity was observed, but some cells retained migration under BTK inhibition. Targeted-DNAseq and bulk-RNAseq were performed at BT and 6 months of ibrutinib to characterize CLL cells with retained migratory capacity. There was an alteration of the subclonal composition of CLL cells that retained migratory capacity under BTK inhibition in 7/12 patients with a recurrent enrichment of subclones with mutations in ATM and NFKBIE gene. BTK p.Cys481Ser mutation was acquired in one patient after 6 months of treatment with ibrutinib, while no PLCG2 mutations were detected. GSEA showed an upregulation of mTORC1 and Myc pathways in cells with retained migration. Among the DEG, TMBIM6 was the most significantly upregulated gene. TMBIM6 gene is associated with apoptosis, mTOR-Akt axis and poor prognosis in solid tumors. We evaluated the prognostic impact of TMBIM6 expression using public data from the CLL-map portal (Knisbacher et al. 2022 Nat Genet). TMBIM6 high expression was associated with poor overall survival in both univariate and multivariate analyses including age, gender, IGHV mutation status (Figure 1) and recurrent genetic alterations. When TMBIM6 was targeted with BIA, a TMBIM6 antagonist (Kim et al. 2020 Nat Commun), its effect on CXCR4-mediated migration was limited but it induced CLL cell apoptosis in suspension and co-cultured CLL cells (Figure 2). Moreover, BIA addition to ibrutinib treatment induced synergistic apoptosis. Collectively, these results indicate that TMBIM6 may be a potential novel target for CLL and that combination with ibrutinib could be a valid approach for time-limited therapy. Conclusions: Ibrutinib in T cells reduced the expression of exhaustion markers, Tregs and Tfh cells. In CLL cells, we observed a downregulation of markers related to adhesion, immunosuppression and migration, but an overexpression of TMBIM6 in CLL cells that retained migrative capacity towards CXCL12 under ibrutinib. Finally, we identified TMBIM6 expression as an independent poor prognostic factor and a potential novel target for CLL.

Phase I Safety and Preliminary Efficacy of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), even when treated with novel targeted agents, generally have only limited benefit (Rule et al., Leukemia 2018). The triple combination of the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, the BCL-2 inhibitor, venetoclax, and anti-CD20 monoclonal antibody, obinutuzumab has demonstrated preliminary safety and efficacy in R/R and treatment naïve (TN) MCL (Le Gouill et al., Blood 2021). We therefore hypothesized that given the favorable toxicity profile of the second-generation BTKi, acalabrutinib, when given in combination with venetoclax and obinutuzumab (AVO), would be effective and well tolerated in both R/R and TN MCL. Here, we report the results of the phase I dose-finding cohort of AVO in patients with R/R MCL. Methods: This is an investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695). The primary endpoints of the phase I portion are the recommended phase II dose (RP2D) and the safety and tolerability of AVO in R/R MCL. The study was designed to evaluate up to 2 dose levels of acalabrutinib, starting with the FDA-approved dose (100 mg po bid, dose level 0 [DL0]) followed by a lower dose (100 mg po daily, DL-1) if dose limiting toxicities (DLTs) occurred in &amp;gt; 1/6 patients in DL0 during the first 4 cycles. Patients were treated in 28-day cycles with acalabrutinib starting with cycle 1, followed by obinutuzumab in cycle 2 (100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15, and on day 1 of cycles 3-7), and venetoclax (weekly dose ramp-up starting in cycle 3 to a target dose of 400 mg daily). Acalabrutinib and venetoclax were continued indefinitely and obinutuzumab maintenance was given every 2 cycles starting with cycle 9 for 12 doses. Patients with progressive disease (PD) or who were unable to receive &amp;gt; 80% of the doses of acalabrutinib and venetoclax during the first 4 cycles were replaced. Key eligibility criteria included R/R MCL after at least one anti-CD20 mAb-based therapy, ECOG PS ≤ 2, and adequate hematologic and organ function. Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 26, 2023, 9 patients in DL0 were evaluable for response as 3 patients were replaced prior to reaching the DLT window. The median age was 67 (range 63-79). 78% were male. Median number of prior treatments was 1 (range 1-2). 33% relapsed after autologous stem cell transplant and 22% had primary refractory disease. All patients had advanced stage MCL, with stage IV disease in 89%. MIPI score was 22% high, 56% intermediate, and 22% low risk. Ki67 index ≥ 30% in 44% and ≥ 50% in 33%. 33% patients had complex karyotype, 22% TP53 mutation, 33% p53 IHC expression &amp;gt; 50%, and 33% blastoid variant. No DLTs were observed and DL0 was determined to be the RP2D. All 9 patients were evaluable for toxicity (Figure 1A). Hematologic toxicity included neutropenia (67%; 33% Gr 3), thrombocytopenia (56%; 22% Gr 3/4), and anemia (22%; all Gr 3). The most common toxicities were headache (77%; all Gr 1/2), bruising (67%; all Gr 1), diarrhea (44%; all Gr 1/2), and upper respiratory infection (22%; 11% Gr 3). There were no serious adverse events. There was no occurrence of febrile neutropenia, atrial fibrillation, bleeding, or laboratory or clinical tumor lysis syndrome. Median follow-up was 6 months (range 1-21). ORR was 78% (7/9) and CR rate was 67% (6/9) after 3 cycles of AVO. Both patients with TP53 mutation and 2/3 patients with blastoid variant achieved CR. Of the 3 patients replaced prior to the DLT window, 2 patients had PD and 1 patient was unable to receive &amp;gt; 80% of the acalabrutinib and venetoclax doses due to grade 4 thrombocytopenia, although achieved CR. 5 patients (56%) remain on treatment and in CR. 1 patient achieved PR after cycle 3 but progressed after cycle 7. Median overall and progression-free survival were not reached. Conclusions: AVO is safe and feasible in patients with R/R MCL with no DLTs observed. RP2D was determined at the full FDA approved dosage of all three drugs. Preliminary efficacy is encouraging in this high-risk R/R MCL population. The phase II TN transplant ineligible or TP53 mutated MCL cohort is now enrolling with minimal residual disease (MRD)-guided time-limited therapy (Figure 1B). The phase I R/R expansion cohort will also open to enrollment.

Growth hormone treatment in adults: A lifelong or time-limited therapy? A web-based survey of growth hormone prescribing practice in adults with growth hormone deficiency in the United Kingdom

Growth hormone treatment in adults: A lifelong or time-limited therapy? A web-based survey of growth hormone prescribing practice in adults with growth hormone deficiency in the United Kingdom

Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia

AbstractMany patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10−4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051.

Moving toward disease modification in polycythemia vera

AbstractPolycythemia vera (PV) belongs to the BCR-ABL1–negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient’s age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.

SAVE (Safe Accelerated Venetoclax Escalation): Initial results of a prospective, phase Ib study of venetoclax with an accelerated dose ramp-up in patients with CLL.

7512 Background: Venetoclax (VEN)-based regimens are highly effective for patients (pts) with treatment naïve (TN) and relapsed/refractory (R/R) CLL. Despite high rates of undetectable minimal residual disease (uMRD) and durable responses even with time-limited therapy, uptake of VEN in routine clinical practice has been relatively low, in part due to the inconvenient 5-week dose ramp-up used to reduce the risk of tumor lysis syndrome (TLS). Accelerated ramp-up schedules have been evaluated in retrospective studies (Davids et al., AJH, 2022), but prospective studies are lacking. Here we present initial results of SAVE: Safe Accelerated Venetoclax Escalation, a phase Ib study of VEN with an accelerated dose ramp-up in pts with CLL. Methods: This is an ongoing phase Ib investigator-sponsored trial for pts with TN and R/R CLL (NCT04843904). Key eligibility include CLL requiring therapy per 2018 iwCLL criteria and adequate renal function. The primary endpoint is the highest risk TLS group that can safely tolerate an accelerated VEN ramp-up. Secondary endpoints include safety and tolerability and rates of ORR/CR/uMRD after 3 months of VEN-based therapy. Patients are treated inpatient with a 5-day daily VEN ramp-up schedule (20-50-100-200-400 mg). TLS labs are monitored pre-dose and at 4, 8, 12, and 24 hours following each dose. Anti-CD20 antibody is given per SOC. At least 5 pts from cohort A (low TLS risk using standard assessment) were required to enroll prior to opening cohort B (medium and high TLS risk). Efficacy is assessed using 2018 iwCLL criteria, toxicity using iwCLL and CTCAE v5, and MRD using central 8-color flow at 10-4. Results: As of 2/2/2023, 20 pts have been treated (10 each from cohort A and B) (Table). 19 pts received obinutuzumab with VEN, and 1 pt received VEN monotherapy. All pts completed an accelerated VEN ramp-up without any clinical TLS. One pt with medium TLS risk had lab TLS (phos and uric acid peaked at 8.7 mg/dL) after the first VEN 400 mg dose, which resolved with sevelamer and rasburicase, thereby prolonging the ramp-up to 6 days. Median inpatient time was 6 days (range 5-8). All grade heme tox: neutropenia (45%; 20% G3/4), thrombocytopenia (35%; 10% G3/4). One pt died 2 months into treatment due to complications of a bowel obstruction unrelated to study treatment. ORR after 3 mo. was 89% in 19 evaluable pts including 2 CRs. Among 19 evaluable patients after 3 mo., 74% and 42% had uMRD in PB and BM, respectively. Conclusions: Our early data suggest that an inpatient, accelerated 5-day VEN ramp-up is feasible in CLL, with a low rate of TLS, even among patients with medium or high risk of TLS. The study is currently ongoing. Clinical trial information: NCT04843904 . [Table: see text]

Cytotoxicity of the CD3×CD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or BCL-2 targeting

AbstractChronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) or the Bcl-2 inhibitor venetoclax has profoundly improved treatment outcomes in CLL. To overcome or prevent drug resistance and extend the duration of response after a time-limited therapy, combination regimens are tested. Anti-CD20 antibodies that recruit cell- and complement-mediated effector functions are commonly used. Epcoritamab (GEN3013), an anti–CD3×CD20 bispecific antibody that recruits T-cell effector functions, has demonstrated potent clinical activity in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma. Development of CLL therapy is ongoing. To characterize epcoritamab-mediated cytotoxicity against primary CLL cells, peripheral blood mononuclear cells from treatment-naive and BTKi-treated patients, including patients progressing on therapy, were cultured with epcoritamab alone or in combination with venetoclax. Ongoing treatment with BTKi and high effector-to-target ratios were associated with superior in vitro cytotoxicity. Cytotoxic activity was independent of CD20 expression on CLL cells and observed in samples from patients whose condition progressed while receiving BTKi. Epcoritamab induced significant T-cell expansion, activation, and differentiation into Th1 and effector memory cells in all patient samples. In patient-derived xenografts, epcoritamab reduced the blood and spleen disease burden compared with that in mice receiving a nontargeting control. In vitro, the combination of venetoclax with epcoritamab induced superior killing of CLL cells than either agent alone. These data support the investigation of epcoritamab in combination with BTKis or venetoclax to consolidate responses and target emergent drug-resistant subclones.

Developmental Couple Therapy for Complex Trauma Survivors: A detailed case study of a manualized, time-limited, psychoanalytically informed treatment

ABSTRACT Many couples in distress encounter significant barriers to accessing psychoanalytic treatments, which leaves psychoanalysis far out of the reach of many of those who would benefit from its rich and deep clinical processes. This paper will briefly outline Developmental Couple Therapy for Complex Trauma (DCTCT). DCTCT is a manualized, evidence-based, time-limited therapy built upon the psychoanalytic foundations of attachment, emotion regulation, mentalizing, and repetition-enactment. This four-stage model integrates psychoeducation about psychoanalytic concepts such as attachment, emotion regulation, and mentalizing, to help couples learn about these developmental self-capacities prior to a second stage of explicit skills building, a third stage of deeper analytic working through of traumatic memories, challenges with sexuality, and developing attachment security prior to a fourth stage of consolidation. The case of Cheryl and Cat will illustrate the process of DCTCT and show some of the advantages specific to couple therapy.

Five-Year Results and Overall Survival Update from the Phase 3 Randomized Study Augment: Lenalidomide Plus Rituximab (R2) Vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: The combination of lenalidomide + rituximab (R2) showed superior efficacy vs rituximab + placebo (R-placebo) in patients (pts) with relapsed refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved for the treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL) in the US, Japan, and Brazil, and for FL in Europe. Reported here are updated long-term follow-up results from AUGMENT. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase 3 study of R2 vs R-placebo (control) in pts with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 mo after last rituximab dose). Pts were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 y), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 y. R2 pts received oral lenalidomide 20 mg/d, d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control pts received rituximab and placebo on the same schedule. Dose modifications were prespecified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). During the follow-up period, pts were followed every 6 mo to assess endpoints, including overall survival (OS), time-to-next antilymphoma treatment (TTNLT), progression, second primary malignancies (SPMs), and histological transformation. Results: A total of 358 pts were randomized (n = 178 R2; n = 180 control); baseline characteristics were similar in both groups. As of January 26, 2022 at a median follow-up of 65.9 mo, median PFS per 2007 IWG criteria as assessed by Investigator was 27.6 mo for R2 vs 14.3 mo for control, with HR = 0.50 (95% CI, 0.38-0.66; P < 0.0001). Although median OS was not reached for either group, there was an improvement in OS for R2 (HR = 0.59, 95% CI, 0.37-0.95, P = 0.0285; Figure). 5-y OS rates for the R2 vs control groups were 83.2% (95% CI, 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1). Median TTNLT (after 12 cycles of time-limited therapy) was 73.1 mo for R2 vs 31.8 mo for control with HR = 0.53 (95% CI, 0.39-0.71; P < 0.0001). In the R2 group, 73 pts (41%) received ≥ 1 subsequent antilymphoma treatment compared with 109 (61%) in the control group, most commonly rituximab in both groups (25% and 34%). 3 (2%) and 5 (3%) pts received lenalidomide as part of any subsequent anti-lymphoma treatment in the R2 and control groups, respectively. The updated overall safety profile of both groups was consistent with the 1st analysis. SPMs occurred in 13 (7%) R2-treated and 21 (12%) control pts, an increase from 6 (3%) and 10 (6%), respectively, in the previous analysis. 9 pts died of SPM (n = 3 R2, n = 6 R-placebo), an increase from 2 pts (both R-placebo) in the previous analysis. The incidence rate of SPMs per 100 y was 1.62 (95% CI, 0.94-2.78) in the R2 group vs 2.66 (95% CI, 1.73-4.07) in the control group. Fewer histological transformations occurred in the R2 arm than in the control group (n = 10 vs n = 15, respectively). The updated incidence rate of histological transformation in the overall population was 1.24% (95% CI, 0.66-2.3) in the R2 arm and 1.85% (95% CI, 1.12-3.07) in the control arm. Conclusions: R2 continues to demonstrate superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of PFS (as assessed by Investigator in long-term follow up). The updated results for OS are consistent with the improvement observed in PFS. The OS KM curve separation after 5 y continues to favor R2, providing evidence for a survival benefit. The updated TTNLT KM curves continue to demonstrate that fewer R2-treated patients needed subsequent antilymphoma treatment to date, well beyond the 1-y treatment period. The safety profile of R2 and R-placebo remain consistent with the primary analysis, with continued lower rates of SPM and rates of histologic transformation comparable to historical experience. These updated results, including OS data, provide further support for the use of the R2 regimen as a standard of care for pts with R/R iNHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time-Limited Maintenance with Ibrutinib after First-Line Therapy and the Incremental Impact on Minimal Residual Disease (MRD) for Patients with Chronic Lymphocytic Leukemia (CLL)

Background: Inhibitors of Bruton's tyrosine kinase (BTKi) are approved and clinically used as indefinite treatments (until disease progression) irrespective of the depth of response in patients (pts) with CLL. Despite impressive, sustained efficacy, their ability (as single agent) to target residual disease clone post induction treatment in CLL is not well established. As indefinite treatment is associated not only with cumulative toxicity but also high cost and compromised quality of life, we investigated the benefit of time-limited maintenance treatment (3 years) with ibrutinib to assess the ability of a BTKi to further deepen antitumor response achieved post induction treatment. Methods: CLL pts (n=35) who had residual disease (by clinical or molecular assessment) after primary induction treatment were enrolled on a prospective phase 2 trial (NCT02649387). MRD assessed in blood (PB)/bone marrow (BM), was determined by 8-color flowcytometry (1x10-4) and defined as ≥1 CLL cell per 10,000 leukocytes or ≥0.01%. Patient were eligible if they had detectable residual (non-progressive) disease within 1 year of completing induction and no prior ibrutinib (or other BTKi) treatment. Ibrutinib 420mg PO QD was given on days 1-28 of a 28-day cycle for up to 36 cycles. Clinical (iwCLL 2008 response criteria) and molecule response MRD (on PB) was done at baseline and then every 3 cycles while on treatment. BM-MRD evaluation was conducted only if PB-MRD was negative (on two separate timepoints 3 months apart). Monitoring of the PB-MRD was continued for 24 months after completing time-limited maintenance with ibrutinib. Cumulative toxicity was assessed using the CTCAE v4.0 and iwCLL criteria. Results: Patient characteristics are summarized in Table 1. In 34 out of 35 (97%) patients, obinutuzumab alone was used as induction therapy. The median follow up is 38.6 months (range 0.9-73.2) and the median number of maintenance cycles completed is 34 (range 1-36). Of the 33 patients assessed for PB-MRD, 8 (24.2%) pts became MRD- on at one assessment. Five patients had BM-MRD assessment with 1 (2.8%) converting to MRD-. The median time to achievement of MRD- was 4.4 months (range 2.7-34.7). We noted that single agent ibrutinib was unable to deliver stringent MRD-negativity (defined as achievement of MRD- status both in PB and BM sustained over 2 consecutive evaluations at least 3 months apart).To assess if pre-maintenance response could impact MRD post-treatment; we note that out of the 8 pts that achieved MRD-, 2 (25%) started with CR and 6 (75%) with nPR/PR at registration. Deepening of response was noted in 5 pts (14.3%) after a median of 14 cycles [3 (8.6%) pts improved nPR to CR and 1(2.9%) went from nPR to CRi and 1 (2.9%) went from a CRi to a CR]. Nine patients proceeded to subsequent treatment with the median time to next treatment (mTTNT) of 32.5 m (range: 12.1 - 61.0). One patient died due to a failure to thrive and acute kidney injury on dialysis and six pts have progressed. The median PFS for the entire cohort was 41.1 m (95% CI: 39.8 - NE). The most commonly reported adverse events (AEs) (seen in >10% pts) regardless of attributions were thrombocytopenia (24 pts; 68.6%), anemia (12 pts; 34.3%), neutropenia (9 pts; 25.7%), lymphopenia (9 pts; 25.7%), hypertension (9 pts; 25.7%), leucopenia (6 pts; 17.1%), fatigue (5 pts; 14.3%), headache (4 pts; 11.4%), and skin infections (4 pts; 11.4%). Atrial fibrillation (AFib) was noted in 3 pts (8.6%). Conclusion: We conclude that BTK targeting with ibrutinib alone although able to clear PB-MRD (24.2%), had limited efficacy to eradicate BM-MRD (2.8%) demonstrating a differential impact in these two disease compartments. While the rate of complete MRD eradication was not necessarily high (when compared to recent data with BTKi/BCL2i combination regimens) MRD-kinetics over time demonstrated progressive decrease in disease burden and response improvement with maintenance treatment. The sequential single agent treatment approach was well tolerated, and the time-limited therapy aimed at minimizing cumulative toxicity seemed to be effective in lowering rate of Afib (compared to historical control ~16%). This data warrants further investigation of time-limited maintenance therapy with newer, more favorably tolerated BTKi and/or Bcl2i post induction treatment(s) to optimize response vs. cumulative toxicity. Further evaluation of sequential time-limited treatments in CLL is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S145: THE COMBINATION OF IBRUTINIB PLUS VENETOCLAX RESULTS IN A HIGH RATE OF MRD NEGATIVITY IN PREVIOUSLY UNTREATED CLL: THE RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE PHASE III NCRI FLAIR TRIAL

Background: Ibrutinib (I) and venetoclax (V) improve outcome in CLL. I rarely eradicates measurable residual disease (MRD), whereas V (alone or with anti-CD20) can eradicate MRD permitting time limited therapy. Small studies suggest synergy between I and V, as I+V results in MRD negativity in many patients (pts). Aims: The primary aim was to compare the MRD eradication rate between I and I+V. Key secondary aims were IWCLL overall (ORR), complete response (CR) and safety. Methods: FLAIR (ISRCTN01844152), a phase III, randomised, controlled trial for previously untreated CLL requiring therapy by IWCLL criteria. Pts >75 yrs or with >20% 17p del were excluded. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V. I was given at 420mg/day. For I+V, V was added after two months of I with dose escalation to 400mg/day over 5 weeks. The duration of therapy (DOT) was defined by MRD with treatment for up to 6 years. MRD was assessed centrally by flow cytometry, MRD negativity was defined as <1 CLL cell in 10,000 leucocytes (IWCLL criteria), was assessed in peripheral blood (PB) and bone marrow (BM) at 9 months post-randomisation, in PB at 12 months and then 6 monthly. When PB was MRD negative, this was repeated after 3 months and then in both PB & BM 3 months later. If PB & BM were negative the time to MRD negativity was calculated (treatment start to first MRD negative PB) and DOT was twice this. The earliest therapy could stop was 2 years post-randomisation. A formal interim analysis was performed when 50% pts in I and I+V arms had reached 2 yrs post-randomisation and a p-value of <0.005 was statistically significant. Results: 523 pts were randomised to I or I+V. We report the interim analysis in the first 274 pts (I [n=138] and I+V [n=136]) reaching 2 yrs post-randomisation from 83 UK Centres from 13/07/17 to 15/03/19. 72.3% male, median age 63 yrs (34.3% >65yo) and 40.9% Binet C. IGHV were available for 256 (93.4%) pts - 48.2% IGHV unmutated (≥98% homology to germline), 45.3% IGHV mutated and 9.1% Subset 2. Hierarchical FISH testing revealed 16.1% 11q del, 19% trisomy 12, 21.9% normal and 36.9% 13q del with 6.2% failed. The arms were well-balanced for all variables. For I+V arm, MRD negativity was achieved within 24 months in BM in 89/136 (65.4%) and PB in 97/136 (71.3%) compared to no pts for I (p<0.0001). MRD negativity for I+V in BM within 24 months was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months post-randomisation 49/136 (36%) I+V pts were MRD negative in BM and 56/136 (41.2%) negative in PB compared to 0/138 with I (p<0.0001). ORR at 9 months in 120/136 (88.2%) I+V pts and 119/138 (86.2%) I pts (p=0.6157). At 9 months CR in 81/136 (59.6%) for I+V and 11/138 (8%) for I (p<0.0001). For I+V CR at any time was 93.4%. At 24 months, 54/136 (39.7%) stopped I+V due to meeting MRD stopping criteria. SAEs were reported in 41.5% I+V and 38.2% I pts. Infectious SAEs 14.8% vs 19.9% and cardiac SAEs 11.9% vs 8.1% of pts for I+V & I respectively. Laboratory TLS was reported in 6/136 (4.4%) of I+V pts and none with I. There were no cases of clinical TLS. Most frequent any grade AEs within 12 months of randomisation differing between I+V & I were diarrhoea (52.6% I+V pts, 29.4% I), anaemia (28.9% vs 16.9%), leucopenia (36.3% vs 8.8%), thrombocytopenia (23.7% vs 14%). Leucopenia was the only grade ≥3 SAE reported in >10% of pts (27.4% I+V and 5.1% I). Image:Summary/Conclusion: Ibrutinib plus venetoclax is an effective and well tolerated combination resulting in a high rate of MRD negativity in blood (71.9%) and marrow (65.4%) in the first 2 years of treatment.

Time-Limited Therapy with Belatacept in Kidney Transplant Recipients.

Introduction: In kidney transplant recipients, belatacept is usually pursued indefinitely after it has been started. In the setting of the belatacept shortage and after having evaluated the benefit–risk ratio, we established a strategy consisting of time-limited belatacept therapy/transient calcineurin inhibitor withdrawal, whose results are analyzed in that study. Methods: We considered all the kidney transplant recipients that had been switched from conventional immunosuppressive therapy to belatacept and then for whom belatacept has been withdrawn intentionally. Furthermore, in the first 8 patients, we assessed changes in peripheral blood mononuclear cells (PBMC) transcriptome using RNAseq before and 3 months after belatacept withdrawal. Results: Over the study period, 28 out of 94 patients had belatacept intentionally withdrawn including 25 (89%) switched to low-dose CNI. One rejection due to poor compliance occurred. The eGFR after 12 months remained stable from 48 ± 19 mL.1.73 m−2 to 46 ± 17 mL.1.73 m−2 (p = 0.68). However, patients that resumed belatacept/withdrew CNIs (n = 10) had a trend towards a better eGFR comparing with the others (n = 15): 54 ± 20 mL.1.73 m−2 vs. eGFR 43 ± 16 mL.1.73 m−2, respectively (p = 0.15). The only factor associated with belatacept resumption was when the withdrawal took place during the COVID-19 outbreak. Transcriptome analysis of PBMCs, did not support rebound in alloimmune response. Conclusions: These findings underpin the use of belatacept as part of a time-limited therapy, in selected kidney transplant recipients, possibly as an approach to allow efficient vaccination against SARS-CoV-2.

MO679: Peritonitis May Disrupt Cyclic Periodicity of Ultrafiltration in Peritoneal Dialysis

Abstract BACKGROUND AND AIMS Due to chronic damage of the peritoneal membrane on long-term treatment, peritoneal dialysis (PD) is a time-limited therapy. Effective PD is achieved by adequate peritoneal ultrafiltration (UF) and small solute clearance while maintaining an appropriate fluid and salt homeostasis. Availability of remote patient monitoring on automated PD (APD) allows clinicians to remotely retrieve data for treatment analysis, proposed to improve clinical outcomes. However, machine-derived data are vastly different from traditionally observed data (e.g. quantity, noise, missing normative values). Recently correlation of daily UF changes on APD with changing peritoneal membrane function in association with clinical risk factors and outcomes has been observed. High intra- and interpatient variability of UF remains not fully explained. We aim at a better understanding of UF variability by submitting APD machine readouts to spectral analysis in association with clinical risk factors of membrane dysfunction. METHOD This was a secondary analysis of the Medical University of Vienna APD cycler treatment data from patients using Homechoice Pro cyclers (Baxter, IL, USA), extracted from the cycler management software (PD link, Baxter). Analysis was conducted using R software (R Core Team 2020). Daily UF was processed using the Lomb-Scargle periodogram (LSP), a method commonly used in astrophysics and neurophysiology to detect rhythms in (unevenly sampled) time series. Peaks of power spectrum, frequencies, and periodicities were compared between patients with and without peritonitis episodes during their PD treatment utilizing a Mann–Whitney U-test and associated with the total number of peritonitis episodes using Kendall rank correlation. A P-value &amp;lt; 0.05 was considered significant; all tests were two-sided. RESULTS LSP analysis was performed on daily UF data from n = 129 APD patients with a mean observation time of 598 days (SD ± 517), male: female 61:39% (n = 79:50), incident: prevalent patients 77:23% (n = 99:30), and diabetic: non-diabetic patients 25:75% (n = 32:97). Observation time extended from the introduction of APD until kidney transplantation (43%, n = 55), transfer to hemodialysis (23%, n = 29), death (27%, n = 35), kidney function recovery (8%, n = 1), or loss to follow-up (7%, n = 9). After inspection of LSPs n = 9 patients were excluded from further analysis as their periodicity matched the time of their clinical endpoint. A total of 45 of the remaining 120 patients (38%) never experienced a peritonitis episode, and a total of 0.3 (SD ± 0.7) peritonitis episodes/patient-year were observed. LSP computation revealed cyclic periodicity in UF in all patients with an overall median peak period length of 329 days (IQR 62–882 days), median peak power of 21 (IQR 7–91), and median peak frequency of 0.42 (IQR 0.36–0.46). Differences between patients with and without peritonitis episodes during PD treatment are displayed in Table 1. Correlation analysis revealed significant association between the number of peritonitis episodes and peak periodicity of UF (tau=0.14, P = 0.04), and peak power (tau = 0.21, P = 0.003). Peak frequency of UF was not significantly correlated. CONCLUSION Patients on APD cycler treatment seem to display cyclic periodicity of UF, being significantly associated with the number of peritonitis episodes and significantly different between patients with and without peritonitis episodes. Smaller-scale periodicity (median 216 days) in patients without peritonitis seems to be disrupted by peritonitis resulting in significantly higher periodicity (median 670 days). The causes and implications of these results remain unclear and need further investigation. However, as peritonitis is a known risk factor for peritoneal membrane dysfunction, prolongation of UF periodicity might reflect disruption of peritoneal membrane function.

Treatment dropout among veterans and their families: Quantitative and qualitative findings.

Psychotherapy noncompletion rates for veterans and their families are high. This study sought to (a) measure noncompletion rates of such patients at a university-based treatment center, (b) compare veteran and family member attrition rates, (c) identify dropout predictors, and (d) explore clinicians' perspectives on treatment noncompletion. Using quantitative and qualitative approaches, we analyzed demographic and clinical characteristics of 141 patients (90 military veterans; 51 family members) in a university treatment center. We defined dropout as not completing the time-limited therapy contract. Reviewing semistructured interview data assessing clinicians' perspectives on their patients' dropout, three independent raters agreed on key themes, with interrater coefficient kappa range .74 to 1. Patient attrition was 24%, not differing significantly between veterans and family members. Diagnosis of major depression (MDD) and exposure-based therapies predicted noncompletion, as did higher baseline Hamilton Depression Rating Scale (HDRS) total scores, severe depression (HDRS > 20), lack of Beck Depression Inventory weekly improvement, and history of military sexual trauma. Clinicians mostly attributed noncompletion to patient difficulties coping with intense emotions, especially in exposure-based therapies. Noncompletion rate at this study appeared relatively low compared to other veteran-based treatment centers, if still unfortunately substantial. Patients with comorbid MDD/PTSD and exposure-based therapies carried greater noncompletion risk due to the MDD component, and this should be considered in treatment planning. Ongoing discussion of dissatisfaction and patient discontinuation, in the context of a strong therapeutic alliance, might reduce noncompletion in this at-risk population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Abstract TP92: Inappropriately Prolonged Dual Antiplatelet Therapy In The Treatment Of Stroke And Transient Ischemic Attack At An Urban Safety Net Hospital

Introduction: Time-limited dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has emerged as an important treatment modality for secondary stroke prevention in patients with symptomatic intracranial atherosclerotic disease, minor stroke, or high-risk transient ischemic attack. However, continuation beyond the indicated treatment period may expose patients to bleeding risk without additional benefit. Methods: We conducted a retrospective study of a prospectively maintained registry (the Get-With-The-Guidelines database at our hospital) evaluating patients discharged on time-limited DAPT for secondary stroke prevention between January 1st, 2019 and July 31st, 2020. Intended and actual duration of therapy were extracted from clinical notes and prescription records. We assessed the frequency of inappropriate continuation within the entire cohort and performed univariate analyses to assess for differences in outcome with respect to clinical and demographic characteristics, including social determinants of health (such as race and primary spoken language). Results: Of the 127 patients included, 17 (13%) had inappropriately prolonged treatment with DAPT. Black patients had a significantly higher incidence of inappropriate continuation than non-Black patients and individuals speaking languages other than English or Spanish exhibited a trend toward more frequent occurrence. Patients intended to transition to monotherapy with clopidogrel and those initially presenting with stroke (rather than transient ischemic attack) had similar trends toward more frequent occurrence. Conclusions: Our study represents the first attempt to approximate the incidence of inappropriate prolongation of time-limited DAPT for secondary stroke prevention at a hospital caring for a large underserved population. Our results suggest that social determinants of health may contribute to this phenomenon, but further studies are required to replicate our observations in larger multicenter cohorts. Systems-based interventions should be aimed at ensuring proper duration of therapy to minimize bleeding risk and other side effects.

Quality of Life in Patients

Quality of Life in Patients <=70 Years of Age with Chronic Lymphocytic Leukemia Treated Frontline with Ibrutinib-Rituximab Versus Fludarabine Cyclophosphamide Rituximab: Analysis from ECOG-ACRIN E1912

Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia

Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia