Efficacy Of Retreatment Research Articles

Nonsurgical Endodontic Retreatment of a Cystic Apical Lesion Associated with Root Resorption: A Promising Approach

This case report highlights the successful management of a cystic apical lesion associated with root resorption through nonsurgical endodontic retreatment, utilizing calcium-enriched mixture (CEM) cement as an obturating biomaterial. A 35-year-old woman presented with mild discomfort in the mandibular right first molar (#46), with radiographic evidence of a well-defined radiolucent lesion at the apex of the mesial root. The tooth had a history of previous failed endodontic treatment with poor root canal obturation, indicating internal root resorption. Nonsurgical endodontic retreatment was performed, and the canals were filled/sealed with CEM cement. Follow-up radiographs showed a gradual reduction in the size of the cystic lesion. At 54 months, complete bone healing of the cystic apical lesion was evident. This case report provides clinical evidence supporting the potential efficacy of nonsurgical endodontic retreatment using CEM cement in managing certain cystic apical lesions, offering a promising alternative to traditional surgical enucleation, even in cases with inflammatory root resorption. Further research is needed to validate the long-term efficacy of this approach in larger patient populations.

Brain Stem Glioma Recurrence: Exploring the Therapeutic Frontiers.

Gliomas of the brainstem represent a small percentage of central nervous system gliomas in adults. Due to the proximity of the tumor to critical structures, radical surgery is highly challenging and limited to selected cases. In addition, postoperative treatments, which become exclusive to non-operable patients, do not guarantee satisfactory disease control, making the progression of the disease inevitable. Currently, there is a lack of therapeutic options to control tumor growth after the diagnosis of recurrence. The rarity of these tumors, their distinct behavioral characteristics, and the limited availability of tumor tissue necessary for the development of prognostic and predictive biomarkers contribute to the absence of a standardized approach for treating recurrent brainstem gliomas. A salvage radiotherapy (RT) retreatment could represent a promising approach for recurrent brainstem gliomas. However, to date, it has been mainly evaluated in pediatric cases, with few experiences available to assess the most appropriate RT dose, safety, and clinical responses in adult patients. This comprehensive review aims to identify instances of adult patients with recurrent brainstem gliomas subjected to a secondary course of RT, with a specific focus on the analysis of treatment-related toxicity and outcomes. Through this investigation, we endeavor to contribute valuable insights into the viability and efficacy of salvage RT retreatment in managing recurrent brainstem gliomas in the adult population.

Retreatability of Bioceramic-Filled Teeth: Comparative Analysis of Single-Cone and Carrier-Based Obturation Using a Reciprocating Technique

Objectives: To evaluate the retreatment efficacy of premixed bioceramic sealer using a reciprocating system, comparing single-cone and carrier-based obturation techniques. Materials and Methods: Twenty-three monoradicular teeth with oval canals were divided into two groups: NeoSealer Flo with single cone (SC) and NeoSealer Flo with Guttafusion (GF). Retreatment was performed using Reciproc Blue (RB) with a crown-down technique. X-ray and CBCT images were taken to measure the remnant areas and volumes. Results: Apical patency was achieved in all the samples. The remnants were mostly distributed in the middle third in the GF group, while an equal distribution in both the middle and apical thirds was observed in the SC group. The GF group had a lower remnant area and volume after RB 50.05, respectively (0.18 ± 0.33 mm2 vs. 0.39 ± 0.80 mm2 and 0.36 ± 0.59 mm3 vs. 0.51 ± 1.16 mm3). The use of RB 50.05 led to an additional reduction in the remnant areas in the SC (14.89%) and GF (69.49%) groups, while in terms of the volume, the reductions were 20.63% and 36.36%. Conclusions: Reciprocating instruments are effective in removing remnants from root canals filled with both single-cone and carrier-based techniques. The blooming effect in CBCT imaging suggests further in vivo studies for validation.

Efficacy of immunotherapy retreatment in patients with non-small cell lung cancer receiving consolidative durvalumab.

8625 Background: The standard of care for patients with stage III, unresectable non-small cell lung cancer (NSCLC) is curative intent chemoradiation followed by durvalumab consolidation. However, most patients progress necessitating further treatment. Although immunotherapy (IO) is the cornerstone of treatment in advanced/metastatic disease, the benefit in patients who received prior durvalumab is unclear. Clinical trials excluded prior IO exposure and current guidelines do not provide specific recommendations. This study aims to characterize the efficacy of post-durvalumab IO treatment. Methods: This was a retrospective cohort study conducted at the University of North Carolina (UNC) Medical Center. Adult patients with unresectable NSCLC who received chemoradiation and consolidative durvalumab followed by subsequent systemic therapy for disease progression between February 2018 to May 2023 were included. Patients were excluded if they received targeted therapy as subsequent systemic treatment. The primary endpoint was real-world progression-free survival (rwPFS) of post-durvalumab treatment. Key secondary outcomes included physician assessed response, overall survival (OS), and subgroup analyses to identify biomarkers which may predict benefit from IO retreatment. Results: A total of 66 patients met inclusion criteria, of which 39 (59%) received subsequent chemotherapy alone and 27 (41%) received IO-containing therapy. Of those who received IO-containing treatments, 18 received chemotherapy plus IO (chemoIO) and 9 received IO alone. Durvalumab was discontinued for therapy completion (chemotherapy: 18%, IO: 26%), disease progression (chemotherapy: 54%, IO: 48%), or side effects (chemotherapy: 26%, IO: 19%). No significant difference was observed between median rwPFS of chemotherapy versus IO-containing therapy (7.0 months vs 5.8 months, respectively; p = 0.9419) or OS (13.0 months vs 12.6 months, respectively; p = 0.5769). Notably, patients in our cohort who received IO alone had a numerically longer rwPFS compared to chemoIO (12.6 months vs 5.8 months, respectively; p = 0.3951), as well as a numerically longer OS (12.6 months vs 6.4 months, respectively; p = 0.8885). Conclusions: This study found that there were no statistically significant differences in median rwPFS or OS between chemotherapy or IO-based regimens following the conclusion of durvalumab consolidation. Interestingly, we observed a numerically improved rwPFS and OS in those who received IO alone compared to chemoIO, which suggests there may be key clinical or molecular features that may help identify patients who benefit from IO therapy. We acknowledge the limitations of this small, retrospective study. The efficacy of IO-based regimens post-durvalumab warrants further investigation in a larger, prospective manner to assess the risks and benefits of IO retreatment.

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n= 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n= 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Effectiveness and safety of SOF/VEL containing rescue therapy in treating chronic HCV-GT4 patients previously failed NS5A inhibitors-based DAAs

Background and aimsNS5A inhibitors are an important option for treating chronic HCV-GT4 patients. Retreatments after NS5A-based DAAs failure are limited. We aimed to determine the effectiveness and safety of SOF/VEL-containing regimens for HCV retreatment after NS5A-regimen failure.MethodsProspective cohort study assessing the efficacy and safety of retreatment with SOF/VEL in addition to either voxilaprevir or ribavirin in patients who had failed previous NS5A-based DAA treatment. The primary outcome was SVR12. Safety and tolerability data were collected.ResultsOne hundred fifty patients were included. The mean age was 53 years, 64% were male, and 50% of included patients had liver cirrhosis, with a mean FIB-4 score of 3.12 (± 2.30) and Child-Turcotte-Pugh (CTP) score of 7.27 (± 0.48), and failed previous SOF/DCV + RBV, they were assigned to 24 weeks of SOF/VEL + RBV. The remaining 50% of participants had no liver cirrhosis and failed previous SOF/DCV, they were assigned to 12 weeks of treatment with SOF/VEL/VOX. Overall, SVR12 was achieved by 96% (n = 144/150) of included patients; 97.33% for SOF/VEL/VOX and 94.67% for SOF/VEL/RBV. Thirty-one patients experienced mild AEs; the most commonly reported mild AE in the SOF/VEL + RBV group was hyperbilirubinemia (n = 9) whereas in the SOF/VEL/VOX group were headache (n = 4) and vertigo (n = 4). Only one patient in SOF/VEL + RBV reported moderate treatment-related AE in the form of anemia and no reported severe AE.ConclusionRetreatment of non-cirrhotic patients with 12 weeks SOF/VEL/VOX and treatment of cirrhotic patients with 24 weeks with SOF/VEL + RBV after the failure of first-line NS5A-based therapy was an effective and well-tolerated treatment option.

P1008 Efficacy and safety of retreatment with upadacitinib after treatment interruption in ulcerative colitis: Data from the phase 3 open-label extension study U-ACTIVATE

Abstract Background Upadacitinib (UPA) is an oral reversible Janus kinase (JAK) inhibitor designed to preferentially inhibit JAK1 approved for the treatment of moderately to severely active ulcerative colitis (UC). UPA may be temporarily discontinued for many reasons including adverse events (AEs) and lack of efficacy.1 As clinical consequences of discontinuing and restarting UPA are yet to be characterised, here, we assess the efficacy and safety of UPA retreatment in patients (pts) who lost response following UPA treatment withdrawal. Methods Pts with a clinical response to 8 weeks’ (wks) UPA 45 mg once daily (QD; UPA45) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH studies were re-randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for the 52-wk maintenance phase of U-ACHIEVE. Pts randomised to PBO who lost response could enter the long-term extension (LTE), U-ACTIVATE, and be retreated with UPA15. Efficacy was analysed (i) at wk 4 of the LTE and (ii) at wk 48 of the LTE among pts with an inadequate response to UPA15 who dose escalated to UPA30 between wks 2 and 36. Exposure-adjusted event rates (EAERs) of treatment-emergent AE (TEAE) were assessed throughout. Results Of 223 pts with a clinical response to UPA45 induction randomised to PBO during maintenance, 112 (50.2%) lost response (mean [standard deviation (SD)] days to loss of response: 135.4 [84.6]) and 110 subsequently entered the LTE. Pts with loss of response vs those without were more likely to have a history of inadequate response, loss of response, or intolerance to ≥1 biologic (57.1% vs 46.8%, respectively) or corticosteroid use at baseline (42.0% vs 33.3%). After 4 wks of retreatment with UPA15, 75/108 (69.4%) and 39/108 (36.1%) pts achieved clinical response and remission, respectively (Figure A). In total, 38 (34.5%) pts dose escalated to UPA30 (mean [SD] days to escalation: 80.3 [57.8]); 30/31 (96.8%) and 22/31 (71.0%) achieved clinical response and remission at wk 48 of retreatment, respectively (Figure B). For safety during maintenance, 225 pts with 128.7 patient-years (PYs) of exposure (loss of response [n=112], 42.6 PYs; no loss of response [n=113], 86.1 PYs) were analysed. Generally, the EAERs of serious TEAEs were numerically lower in patients with vs without loss of response. However, patient years of exposure were low, restricting interpretation. During the LTE, EAERs were generally similar in pts who underwent dose escalation vs all pts. Conclusion In pts who experience loss of response following UPA withdrawal, efficacy can be recaptured following retreatment with UPA15 and UPA30. No new safety signals were identified. Reference 1. Sandborn WJ, et al. Gastroenterology. 2020;158(8):2139−2149.e14.

Outcomes of Venetoclax Retreatment after MRD-Guided Venetoclax +/- Ibrutinib: Results of the Improve Study

Data from small cohorts of patients (pts) with chronic lymphocytic leukemia (CLL) relapsing after venetoclax-based fixed-duration regimens suggest that venetoclax retreatment may be a feasible option. Information on the efficacy and tolerability of venetoclax retreatment in this setting is still scanty, making it worth exploring venetoclax retreatment in prospective cohorts of well-characterized pts with CLL. We analyzed the efficacy and safety of venetoclax retreatment in pts with relapsed/refractory CLL enrolled in our clinical trial IMPROVE (NCT04754035). BTK- and BCL2-inhibitor naïve pts enrolled into the study were treated with venetoclax single-agent for 12 months; those with undetectable measurable residual disease (uMRD) discontinued therapy while those with detectable MRD received the combination of ibrutinib and venetoclax until uMRD, toxicity or for up to 12 months. Pts with detectable MRD at the end the combination therapy stopped venetoclax and continued with ibrutinib only. In pts who experienced progressive disease (PD) requiring treatment, venetoclax single-agent was restarted according to the standard schedule and continued until PD or unacceptable toxicity. MRD was tested every 3 months in peripheral blood using the 6-color flow cytometry panel validated by the ERIC (European Research Initiative on CLL). After a median follow-up of 58 months (5-67) from C1D1, 20/38 (52.6%) pts experienced PD requiring treatment after discontinuing therapy, including 19 upon reaching confirmed uMRD (11 treated with venetoclax single-agent, 8 with the combination of venetoclax+ibrutinib), 1 who discontinued both venetoclax and ibrutinib in partial response (PR) with detectable MRD (dMRD) due to an unrelated adverse event. Two out of 20 had Richter transformation (RT), 2 developed autoimmune hemolytic anemia, 2 received other treatments (BTK inhibitors) per investigator's decision and all 6 went off study. The remaining 14 pts (1 with detectable MRD, 7 who previously achieved uMRD with venetoclax monotherapy, 6 who were treated with the combination of venetoclax+ibrutinib) received venetoclax retreatment at a median of 32.5 months (12-44) after the end of initial therapy (Table 1); to note, the pt who stopped treatment in PR with dMRD restarted venetoclax after only 13 months. All 13 uMRD subjects experienced MRD relapse at a median of 5 months (0-41) after stopping treatment, 26 (0-37) months before disease progression requiring therapy. At the time of venetoclax initiation tumor lysis syndrome (TLS) risk was high in 6, medium in 3, low in 5. Best overall response rate was 79% (11/14), all partial responses (PR), 2 pts experienced stable disease (on treatment for 2 and 24 months). With a median time on treatment of 10 months, 2 pts achieved uMRD after 3 and 6 months, the second one maintaining uMRD for 6 months and then becoming MRD positive again (Figure 1). Five out of 14 pts progressed after 2, 7, 9 and 11 (n=2) months on venetoclax retreatment, 3/5 received next-line treatment with ibrutinib, 2/5 received non-covalent BTK inhibitor and all achieved a PR. At last follow-up, 57% of pts remain on venetoclax; 12/14 patients undergoing venetoclax retreatment were alive (1 death due to RT on ibrutinib, 1 due to CLL progression on non-covalent BTK inhibitor). Progression-free survival from venetoclax restart to PD on venetoclax retreatment, last follow-up or death was not reached (0-28 months). Venetoclax retreatment was very well tolerated with no patients experiencing TLS, 6/14 having grade 3-4 neutropenia (only in 1 case leading to treatment discontinuation), 8/14 infections (2 grade 1, 4 grade 2, 2 grade 3). No other grade 3/4 hematologic or non-hematologic toxicities were observed. Venetoclax retreatment was effective and well-tolerated in a cohort of pts with relapsed/refractory CLL who have previously received time limited, MRD-guided treatment with venetoclax+/-ibrutinib. MRD relapse occurred at a median of about 2 years before clinical progression requiring treatment. Venetoclax retreatment was started at a median of 32.5 months after the end of initial therapy. Nearly 80% of patients achieved at least a partial response with venetoclax retreatment, 14% of pts achieved uMRD and 57% remain on venetoclax, with a median time on treatment of 10 months.

Traverse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment-Naive Mantle Cell Lymphoma

Background and Significance: Despite advances in treatment for mantle cell lymphoma (MCL), no curative option exists. Currently, the majority of patients with treatment-naive (TN) MCL receive chemoimmunotherapy, which can result in prolonged remissions, but is associated with significant toxicity. Almost all patients inevitably relapse, and therefore, frontline chemotherapy-free options are being increasingly explored. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of adult patients with relapsed/refractory (R/R) MCL. In a phase 1b study in patients with TN MCL, acalabrutinib in combination with venetoclax and rituximab (AVR) demonstrated high rates of clinical and molecular response with an acceptable toxicity profile, supporting its continued development as a chemotherapy-free treatment option (Wang et al. Blood. 2021; Wang et al. Blood. 2022). Furthermore, the occurrence of complete responses (CRs) with clearance of minimal residual disease (MRD) in MCL clinical trials suggests that treatment may be stopped in these patients, as observed in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab. Study Design and Methods: TrAVeRse (NCT#05951959) is a phase 2, open-label, randomized, multicenter, international study of AVR in patients with TN MCL. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0-2 (3 if due to lymphoma), and Ann Arbor stage II, III, or IV disease are eligible. Key exclusion criteria are active central nervous system involvement by lymphoma or leptomeningeal disease, severe/life-threatening illness or medical condition, clinically significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of enrollment, and any active uncontrolled infection. Approximately 125 patients will be screened to achieve a study population of 100 patients. During the induction phase, patients will receive oral acalabrutinib 100 mg twice daily (BID) in 28-day cycles for 13 cycles, starting at cycle 1; oral venetoclax once daily, starting at cycle 2 at a dose of 20 mg daily, with ramp-up to a maximum of 400 mg daily over 5 weeks for a total of 12 cycles; and intravenous rituximab 375 mg/m 2 on day 1 of every cycle for 12 cycles, starting at cycle 1. Patients who complete 13 cycles of AVR induction will be centrally tested for MRD status and continue to receive acalabrutinib 100 mg BID for 1 additional cycle (cycle 14) while awaiting disease response assessment and MRD results. Patients who achieve an MRD-negative CR (in peripheral blood at a threshold of 10 -5) at the end of induction will be randomly assigned in a 1:1 ratio to either continue to receive acalabrutinib 100 mg BID or to observation from cycle 15. Randomization will be stratified according to the simplified MCL International Prognostic Index [sMIPI] score (low [score, 0-3] and intermediate risk [4-5] vs high risk [6-11]), histologic features (blastoid or pleomorphic vs classical histology), and TP53 status (mutated vs unmutated). Those with an MRD-positive CR, partial response (PR), or stable disease (SD) at end of induction will continue to receive acalabrutinib 100 mg BID until disease progression, death, or unacceptable toxicity. Patients who progress during observation may be retreated with acalabrutinib 100 mg BID at relapse. The primary endpoint of this study is the MRD-negative CR rate at the end of AVR induction (ie, end of cycle 13). Secondary endpoints include MRD-negative CR rate at any point during the study, objective response rate and CR rate, duration of response, time to next treatment, progression-free survival, event-free survival, overall survival, safety, and tolerability. The study will also assess the feasibility of response-adapted treatment cessation for those who achieve MRD-negative CR after AVR induction and the efficacy of acalabrutinib retreatment in the subgroup of patients randomized to observation who subsequently relapse. Patients will be followed for 36 months post last patient randomized. Enrollment is planned to begin Q3 of 2023 including sites in North America, Australia, and Europe. Summary: This study will evaluate the efficacy of AVR, a chemotherapy-free triplet combination therapy, in patients with TN MCL.

Daratumumab, Pomalidomide and Dexamethasone (DPd) in Relapsed/ Refractory Light Chain Amyloidosis Previously Exposed to Daratumumab

Daratumumab, Pomalidomide and Dexamethasone (DPd) in Relapsed/ Refractory Light Chain Amyloidosis Previously Exposed to Daratumumab

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<0.0001), to 12.1% after 12 cycles (range, 0.04 - 55.60%, n=9, p<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.

Efficacy, Toxicity, and Prognostic Factors of Re-treatment With [177Lu]Lu-DOTA-TATE in Patients With Progressing Neuroendocrine Tumors: The Experience of a Single Center.

Peptide receptor radionuclide therapy (PRRT) is an effective and safe treatment of unresectable or metastatic, progressive neuroendocrine tumours (NETs). However, if progression occurs after the initial PRRT, treatment options remain limited. Our aim was to evaluate the efficacy and safety of a repeat177Lutetium-[DOTA°,Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) PRRT course in patients with progressive NET after the first [177Lu]Lu-DOTA-TATE PRRT (peptide receptor radionuclide therapy first treatment (PRRT1)). This is a nine-year retrospective observational study of 20 patients who were re-treated with PRRT (peptide receptor radionuclide therapy retreatment (PRRTR)) after PRRT1. The median progression-free survival (PFS) following PRRT1 was 32 months (interquartile range (IQR): 16.5-44.5). After PRRT1, all 20 patients progressed. Of the 20 patients included, two were lost during follow-up. The median PFS after PRRTR was 17.5 months (IQR: 7-39). At the time of analysis, 15/18 patients progressed, and 3/18 had stable disease after PRRTR. Among those patients who progressed, the median time to progression was nine months (IQR: 0-17). The median overall survival from the time of the first cycle of PRRT1 was 66 months (IQR: 65-90). No significant renal or liver toxicity was reported, nor was there a drop in haemoglobin. The decrease in platelet count after PRRTR was statistically significant (p=0.03). Two cycles at PRRTR (vs. 1) were associated with a longer PFS (p=0.014) and the presence of metastases pre-PRRTR was associated with a shorter time to progression following PRRTR (p=0.04). Conclusion: Patients who progressed after PRRT1 can achieve good PFS and minor toxicity. Our study reinforces the efficacy and safety of PRRTR and provides an analysis of factors associated with better outcomes, which can aid clinicians in clinical decision-making.

Efficacy of retreatment with polatuzumab vedotin in combination with rituximab in polatuzumab vedotin-resistant DLBCL models

Polatuzumab vedotin (Pola) was approved for first-line and relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in many countries. This means that retreatment with Pola for r/r DLBCL could be considered after first-line Pola treatment; however, there is currently no evidence on the effectiveness of Pola-retreatment. To address this, we established two Pola-resistant cells from DLBCL cells (SU-DHL-4 and STR-428) and evaluated the combination efficacy of Pola plus rituximab (Rit), the key component of DLBCL therapy. MDR1 overexpression and decreased Bim expression were suggested to be the resistant mechanisms to Pola in Pola-resistant SU-DHL-4 and Pola-resistant STR-428, respectively. In these cells, Pola significantly increased Rit-induced CDC sensitivity either with increased MAC formation or reduced Mcl-1 expression. Additionally, treatment with Pola + Rit significantly enhanced antitumor activity in Pola-resistant STR-428 xenograft mouse models. Based on these results, Pola + Rit retreatment could have preserved efficacy because of the effect of Pola on sensitizing cells to Rit.

Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: Results from the observational study GEM1801.

9547 Background: Most patients with BRAF-mutant melanoma eventually develop resistance to therapy with BRAF/MEK inhibitors and immune-checkpoint blockade. Alternative treatment strategies are required in these patients since further therapy options lack survival benefit. Small series have shown promising activity from re-exposure to BRAF/MEK inhibitors after a treatment free interval of targeted therapy (TT), probably due to regression of resistant tumors and proliferation of clones that maintain sensitivity to BRAF/MEKi. However, prospective evidence for this approach is limited. Here we report the results of 30 patients who received a second course of TT at relapse after adjuvant therapy (retreatment) or after first progression on TT in the advanced setting (rechallenge). Methods: GEM1801 is a prospective observational study from the Spanish Melanoma Group (GEM) including 893 patients with melanoma treated in 37 centers. This is a descriptive analysis of basal characteristics, response rates (RR), progression free survival (PFS) and overall survival (OS) from 30 patients that received retreatment or rechallenge with BRAF/MEKi in GEM1801 study. Results: 4 patients received retreatment and 26 rechallenge. For retreatment, BRAF/MEKi median free interval from end of adjuvant TT to subsequent retreatment was 17.8 months (range: 12.4 - 57.7). RR with retreatment were 25%, with a median PFS and OS of 5.7 and 8.5 months. For rechallenge, RR was 38.5% and median PFS and OS 11.1 and 22.2 months respectively. Patients who were selected for rechallenge had higher complete response (CR) rates to first TT (26.9% vs 20.3%; p= 0.026). Patients who experimented deeper responses with 1st TT in the metastatic setting showed a correlation to longer PFS to 2nd TT with 12-m PFS rates of 66.7% versus 35.7% (HR 9.09 [95%CI: 1.42-58]; p= 0.02). OS showed a not statistically significant improvement in patients who reported CR to first TD (24-m OS rate of 75% versus 40.7% respectively). BRAF/MEKi free interval since first progression and retreatment or rechallenge was not associated with prognosis. Prognostic factors as LDH and number of metastatic sites did not correlate with the efficacy of retreatment. Conclusions: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting achieved encouraging efficacy and may be a valid therapeutic strategy in a selected group of patients. Response to first treatment, retreatment and rechallenge with BRAF/MEKi. Clinical trial information: NCT03605771 . [Table: see text]

Clinical Results of Accelerated Iontophoresis-Assisted Epithelium-on Corneal Cross-linking for Progressive Keratoconus in Children.

To evaluate the clinical characteristics of pediatric patients with progression of keratoconus after accelerated iontophoresis-assisted epithelium-on corneal cross-linking (I-ON CXL) and to assess the efficacy and safety of re-treatment using accelerated epithelium-off CXL (epi-OFF CXL). Sixteen eyes of 16 patients (mean age: 14.6 ± 2.5 years) with keratoconus underwent I-ON CXL. The main outcome measures were uncorrected distance visual acuity, corrected distance visual acuity, maximum keratometry index (Kmax), minimum corneal thickness, elevation front and elevation back measured at the thinnest point, total higher order aberrations root main square (HOA RMS), coma RMS, and spherical aberration. An increment of Kmax greater than 1.00 diopter (D) and a decrease of greater than 20 µm in pachymetry were considered to determine the progression of keratoconus. Patients with progression of keratoconus after I-ON CXL were re-treated using an epi-OFF CXL protocol. Two years after I-ON CXL, 12 patients showed progression of keratoconus, whereas 4 patients were stable. There was significant worsening of Kmax (P = .04) and steepest keratometric reading (P = .01). Furthermore, a significant correlation was documented between progression of keratoconus and age (P = .02). These patients were re-treated using an epi-OFF protocol and after 2 years all patients were stable, and a statistically significant reduction of the mean Kmax (P = .007), HOA RMS (P = .05), and coma RMS (P = 05) was observed. I-ON CXL was ineffective in the treatment of pediatric keratoconus in younger children, whereas it had an efficacy of 2 years in older children. Re-treatment using epi-OFF CXL proved effective to halt progression of keratoconus after I-ON CXL failure. [J Pediatr Ophthalmol Strabismus. 2024;61(1):44-50.].

Successful Retreatment of Metastatic Triple-negative Breast Cancer With Immune Checkpoint Inhibitors and Chemotherapy.

The efficacy of retreatment with immune checkpoint inhibitors (ICIs) in programmed death-ligand 1 (PD-L1) positive metastatic or recurrent triple-negative breast cancer (mTNBC) remains unknown. We report a case of a patient with recurrent triple-negative breast cancer who was successfully treated with two different ICIs in combination with chemotherapy. A 60-year-old female patient was treated with neoadjuvant chemotherapy consisting of epirubicin + cyclophosphamide (EC) followed by docetaxel (DTX). The tumor shrank with EC, but progressed with DTX. One year after the surgery, the patient presented with multiple lung metastases. The patient received combination therapy with atezolizumab and nab-paclitaxel and achieved a partial response (PR). However, the disease progressed after 6 months. She received eribulin as second-line chemotherapy for 4.5 months, and her treatment was changed to pembrolizumab, carboplatin, and gemcitabine as third-line chemotherapy. The tumor immediately reduced and disappeared after three cycles of this treatment and achieved PR. This case illustrated that retreatment with ICIs was effective.

Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors.

The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4β7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

24P Efficacy and safety of 1st generation EGFR TKI retreatment in EGFR mutation-positive, T790M-negative patients previously treated with 1st or 2nd generation EGFR TKI and cytotoxic chemotherapy

Clinical Efficacy and Safety of Immunotherapy Retreatment in Metastatic Cervical Cancer: A Retrospective Study.

Metastatic cervical cancer has a poor prognosis, and treatment options are limited. Immunotherapy has been used to achieve disease control in patients with cervical cancer; however, the efficacy of immunotherapy retreatment after disease progression is unclear. This study aimed to explore the efficacy and safety of immunotherapy retreatment in metastatic cervical cancer. We retrospectively reviewed the clinical data of patients with metastatic cervical cancer who underwent immunotherapy retreatment after disease progression following previous immunotherapy from June 2019 to April 2021. Fifteen patients were included in this study. All patients received combination immunotherapy retreatment consisting of camrelizumab, nab-paclitaxel, and apatinib. Four (26.7%) patients achieved partial response while three (20.0%) achieved stable disease. The objective response rate and disease control rate were 26.7% and 46.7%, respectively. The median progression-free survival and overall survival were 3.0 (95% confidence interval: 1.0-5.0) and 8.0 (95% confidence interval: 3.4-12.6) months, respectively. None of the patients discontinued treatment because of intolerable toxicity. Our findings suggest that the triplet combination immunotherapy retreatment could be a therapeutic option for patients with metastatic cervical cancer who failed initial immunotherapy.

Clinical efficacy of retreatment of daratumumab-based therapy (D2) in daratumumab-refractory multiple myeloma.

Daratumumab demonstrates activity as a single agent and in combination with either immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) in relapsed refractory multiple myeloma (RRMM). However, little is known about the benefit of daratumumab retreatment in daratumumab-refractory MM. This study aimed to analyze the clinical efficacy of daratumumab-based retreatment (D2) in patients who are daratumumab refractory MM. Retrospectively, we identified 43 RRMM patients from a single-center database review. The median age was 65 years, 42% patients had high-risk cytogenetics, and 23% had an extramedullary disease, while the median time between D2 and prior daratumumab was 1 (0.25-39) month. All D2 patients received combination therapy with either pomalidomide, carfilzomib, bortezomib, or lenalidomide. The response rate, median progression-free, and overall survival were 49%, 7.97 and 32.6months, respectively. Our study raises the possibility of re-utilizing daratumumab in combination with different classes of anti-myeloma drugs to generate responses in RRMM patients who are daratumumab-refractory.