Complete Remission Duration Research Articles

Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) harboring select FGFR mutations or fusions: Phase 1 first-in-human study.

TPS583 Background: Treatment options are limited for pts with NMIBC and MIBC who experience disease recurrence or who are ineligible for or refuse standard of care. Erda, an oral selective pan-FGFR tyrosine kinase inhibitor, is approved in adults with locally advanced or metastatic urothelial cancer with select FGFR3/2 alterations ( alt) who have progressed during or after ≥1 line of platinum-containing chemotherapy. FGFRalt are among the most common oncogenic drivers detected in NMIBC and MIBC, and are more prevalent in NMIBC. TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erda within the bladder, thus limiting systemic toxicity. This study evaluates the safety, pharmacokinetics (PK), and efficacy of TAR-210 in pts with NMIBC or MIBC with select FGFRalt. Methods: Open-label, multicenter phase 1 study of TAR-210 in pts with recurrent NMIBC or MIBC (NCT05316155). Eligible pts are aged ≥18 yrs with adequate organ function and tumors with select FGFRalt. A flexible molecular eligibility strategy is used to allow for local or central fresh/archival tissue-based FGFR testing by next-generation sequencing (NGS) or PCR, or urine cell-free DNA NGS testing. Four cohorts will be enrolled: pts with recurrent, bacillus Calmette-Guerin (BCG)-experienced papillary-only high-risk (HR) NMIBC (high-grade Ta/T1) refusing or ineligible for radical cystectomy (RC) (Cohort 1) or scheduled for RC (Cohort 2); pts with recurrent, intermediate-risk NMIBC (Ta/T1) with a history of low-grade disease (Cohort 3); pts with cT2-T3a MIBC scheduled for RC refusing or ineligible for neoadjuvant cisplatin (Cohort 4). Pts in Cohorts 1 and 2 will have TURBT with resection of all visible disease prior to dosing, whereas pts in Cohort 3 must have visible disease prior to dosing. The primary end point is safety (adverse events, including dose-limiting toxicity). Secondary end points include PK, recurrence-free survival (Cohorts 1 and 2), complete response (CR) rate and duration of CR (Cohort 3), and pathologic CR rate, pT0 rate, and rate of downstaging to <pT2 (Cohort 4). Dose escalation (Part 1; n≈12, Cohorts 1 and 3 only) will be followed by dose expansion (Part 2; n≈50-80). Cohorts 1 and 3: response assessment will be after a 3-mo dosing cycle; pts with CR may receive ≤3 additional 3-mo dosing cycles if no recurrence, progression, or unacceptable toxicity. Cohorts 2 and 4: response assessment will be at RC after 8 wks of dosing. Follow-up disease surveillance (cystoscopy, urine cytology, imaging) will be every 3 mos to end of Yr 2 and every 6 mos in Yr 3 in Cohorts 1 and 3 and at 3 mos post-RC in Cohorts 2 and 4. Four pts were enrolled since April 2022 (1 in Cohort 1, 3 in Cohort 3); enrollment for Cohorts 2 and 4 is planned soon. Clinical trial information: NCT05316155 .

A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis).

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]

Quality of life in QUILT 3.032 study: Patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) receiving IL-15RαFc superagonist N-803 plus BCG.

495 Background: Patients (pts) with BCG-unresponsive NMIBC have limited treatment options and are at an increased risk for cystectomy. Nogapendekin alfa inbakicept (NAI, also known as N-803), is an interleukin-15 superagonist (IL-15RαFc), which synergizes with BCG to elicit innate immune memory resulting in durable complete responses (CRs) in this patient population. In an open-label, 3-cohort, multicenter Phase 2/3 study of intravesical BCG plus NAI in BCG-unresponsive high-grade NMIBC (QUILT 3.032; NCT03022825), pts with carcinoma in situ (CIS; Cohort A) have a CR rate of 71% (median duration 26.6 months), 89.2% cystectomy avoidance and 100% bladder cancer specific survival at 24 months. We submit here the first quality of life (QOL) data report in the same pts cohort. Methods: Cohort A: 86 pts (median age 73 years; 87% male) with histologically confirmed BCG-unresponsive CIS with or without Ta/T1 disease, treated with intravesical BCG 50 mg plus NAI 400 μg. Mean baseline ECOG score was 0.183, with 82% of pts having score = 0. QOL was measured by the EORTC QOL Questionnaire Core 30 (QLQ-C30) and QOL NIMBC-Specific 24 Questionnaire (QLQ-NMIBC24). Results: Multivariate analyses have shown no significant changes over time for any of the measured QOL domains. Mild worsening vs. baseline in feeling ill was reported by 6% and 3% of pts by week 27 and 52, while 4% and 6% reported improvement. By week 78 and 104, 7% and 9% of pts reported improvement vs. baseline in their wellbeing with the majority being stable (non-significant). No statistically significant variations were detected in the physical function (PF) score (baseline vs. week 27, 52, 78 and 104). Higher PF scores were observed in pts responding to the therapy vs. non-responders; however, baseline value of PF was also higher in responders vs. non-responders. In contrast to historical results of BCG alone, week 27 physical function scores were numerically higher than baseline, with a subsequent nadir at week 78 and recovery to baseline by week 104 (non-significant). Hospitalizations for any reason remained low (0% - 6% per assessments) during the study. Conclusions: QOL measurement supports good tolerability of the intravesical NAI plus BCG in BCG-unresponsive, high-grade NMIBC pts with CIS. These results further strengthen the evidence of a favorable benefit: risk ratio of this novel combination immunotherapy, in a challenging disease. Clinical trial information: NCT03022825 .

Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC.

512 Background: enGene is developing non-viral gene therapy platforms to deliver nucleic acids (plasmids) to epithelial mucosal tissues such as urothelium of urinary bladder. EG-70 is a nanoparticle formulation of plasmids that activates both innate and adaptive immune responses to activate the immune system within the bladder. The plasmid encodes both IL-12 and activators of the innate immune receptor RIG-I. EG-70 is administered intravesically to elicit local stimulation of anti-tumor immune responses providing durable efficacy in high grade non-muscle invasive bladder cancer (NMIBC) while avoidingsystemic toxicities. Methods: In the Phase 1 study(LEGEND; NCT04752722), escalating doses of EG-70 were administered intravesically to patients with BCG-unresponsive Carcinoma in situ (CIS) NMIBC on weeks 1 and 2 or weeks 1, 2, 5, 6 of 12-week treatment cycle. At the week 12 assessment, patients with stable disease (SD) or complete response (CR), as assessed by urine cytology, cystoscopy, and bladder biopsy, were allowed electively to remain on EG-70 for up to 3 additional 12-week cycles. Results: To date, 19 patients have been treated. There have been no DLTs. AEs (48 GR1, 17 GR 2 and 1 GR3) have been largely consistent with urinary tract instrumentation, and were not dose related. Eighteen patients have completed one cycle of EG-70, and 67% have achieved CR. Fifteen patients with CR or SD at the end of cycle 1 elected to receive additional treatment cycles (continuation rate of 15/18 ( 83%)). Durable CRs were seen at all dose levels. Patients who receive additional cycles are followed for durability of response (Table). Complete Response. Conclusions: These results demonstrate the safety, tolerability and durable therapeutic potential of intravesical EG-70 in patients with BCG-unresponsive CIS. A Phase 2 study will proceed in 2023. Clinical trial information: NCT04752722 . [Table: see text]

Clinical outcomes of patients with metastatic renal cell carcinoma who discontinued nivolumab +/- ipilimumab therapy electively or due to toxicity.

625 Background: Immune checkpoint inhibitor (ICI) based regimens are the standard of care for patients with metastatic renal cell carcinoma (mRCC). In other tumor types such as melanoma, there is evidence that cancer control can persist long after discontinuation of ICI therapy. Outcomes after ICI discontinuation for mRCC are less characterized. Our aim is to characterize the durability of treatment response in mRCC patients who discontinued ICI therapy electively or due to toxicity. Methods: We identified patients with mRCC who responded to nivolumab +/- ipilimumab and then discontinued ICI therapy either for elective reasons or due to toxicity. Patients who discontinued therapy due to progressive disease or who died within 3 months of their last ICI dose were excluded. Complete response (CR) duration was calculated from last ICI dose to the most recent documentation of CR status. Time to progression was defined as the time from last ICI dose to documentation of disease progression or initiation of next-line therapy. Durability of treatment response was calculated from the date of last ICI dose to the most recent follow up date at which sustained response was noted. Results: We identified a total of 56 patients treated with nivolumab +/- ipilimumab therapy who discontinued treatment for toxicity (n=30) or for elective reasons (n=26) and achieved CR or partial response/stable disease (PR/SD). Of the entire cohort, 19 patients (34%) achieved CR, and the majority (95%) were still alive and disease-free with a median follow up of 906 days (range 86-2143 days). Among all patients who discontinued treatment with best response of PR/SD, 49% experienced disease progression, with a median progression-free survival of 382 days (range 77-1267). 42% of patients who stopped ICI electively achieved CR and all (100%) were still alive with sustained CR (median follow-up = 735 days) at data collection. Among those with best response of PR/SD after elective discontinuation, about half (53%) maintained disease control while the rest had disease progression or death (47%). Conclusions: Patients with mRCC who achieve CR with nivolumab +/- ipilimumab and then subsequently discontinue therapy for reasons other than disease progression have excellent long-term cancer outcomes. Recurrence and subsequent progression are rare in this group. These results are similar to the durability of ICI treatment response observed in complete responders in melanoma. Outcomes were less favorable for patients who obtained PR/SD as best response prior to ICI discontinuation, although some patients had ongoing and durable cancer control for up to several years. More research is indicated to ascertain which disease/patient features predict long-term disease control after ICI discontinuation in patients who respond favorably to ICI therapy.

A Phase 1b/2 Study of Atezolizumab with or Without Bacille Calmette-Guérin in Patients with High-risk Non–muscle-invasive Bladder Cancer

BackgroundBacille Calmette-Guérin (BCG) is the standard therapy after transurethral resection of bladder tumour for high-risk non–muscle-invasive bladder cancer (NMIBC). However, post-BCG recurrence/progression occurs frequently, and noncystectomy options are limited. ObjectiveTo evaluate the safety and clinical activity of atezolizumab ± BCG in high-risk BCG-unresponsive NMIBC. Design, setting, and participantsThis phase 1b/2 GU-123 study (NCT02792192) treated patients with BCG-unresponsive NMIBC who had carcinoma in situ with atezolizumab ± BCG. InterventionPatients in cohorts 1A and 1B received atezolizumab 1200 mg IV q3w for ≤96 wk. Those in cohort 1B also received standard BCG induction (six weekly doses) and maintenance courses (three doses weekly starting at month 3) with optional maintenance at 6, 12, 18, 24, and 30 mo. Outcome measurements and statistical analysisCoprimary endpoints were safety and 6-mo complete response (CR) rate. Secondary endpoints included 3-mo CR rate and duration of CR; 95% confidence intervals were calculated using the Clopper-Pearson method. Results and limitationsAt data cut-off (September 29, 2020), 24 patients were enrolled (cohort 1A, n = 12; cohort 1B, n = 12), and the recommended BCG dose was 50 mg in cohort 1B. Four patients (33%) had adverse events (AEs) leading to BCG dose modification/interruption. Three patients (25%) in cohort 1A reported atezolizumab-related grade 3 AEs; cohort 1B had no atezolizumab- or BCG-related grade ≥3 AEs. No grade 4/5 AEs were reported. The 6-mo CR rate was 33% in cohort 1A (median duration of CR, 6.8 mo) and 42% in cohort 1B (median duration of CR, not reached [≥12 mo]). These results are limited by the small sample size of GU-123. ConclusionsIn this first report of the atezolizumab-BCG combination in NMIBC, atezolizumab ± BCG was well tolerated, with no new safety signals or treatment-related deaths. Preliminary results suggested clinically meaningful activity; the combination favoured a longer duration of response. Patient summaryWe studied atezolizumab with and without bacille Calmette-Guérin (BCG) to determine whether this combination was safe and had clinical activity in patients with high-risk noninvasive bladder cancer (high-grade bladder tumours that affect the outermost lining of the bladder wall) that has previously been treated with BCG and is still present or occurred again. Our results suggest that atezolizumab with or without BCG was generally safe and could be used to treat patients unresponsive to BCG.

Survival outcomes of children with relapsed or refractory myeloid leukemia associated with Down syndrome

AbstractChildren with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between year 2000 to 2021. Median time from diagnosis to relapse was 6.8 (range, 1.1-45.5) months. Three-year event-free survival (EFS) and overall survival (OS) were 20.9 ± 5.3% and 22.1 ± 5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (hazard ratio [HR], 0.28), duration of first complete remission (CR1) (HR, 0.31 for > 12 months) and attainment of remission after relapse (HR, 4.03). Patients who achieved complete remission (CR) before HSCT, had an improved OS and EFS of 56.0 ± 11.8% and 50.5 ± 11.9%, respectively compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0 ± 9.5%). Treatment failure after HSCT was predominantly because of disease recurrence (52%) followed by treatment-related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.

Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates.

Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy.

The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid leukemias and lymphomas. Nevertheless, about 50% of patients treated with these approved CAR products experience relapse or refractory disease necessitating salvage strategies. Moreover, in the vast majority of patients suffering from solid tumors, CAR-T-cell infusions could not induce durable complete remissions so far. Crucial obstacles to CAR-T-cell therapy resulting in a priori CAR-T-cell refractory disease or relapse after initially successful CAR-T-cell therapy encompass antigen shutdown and CAR-T-cell dysfunctionality. Antigen shutdown predominately rationalizes disease relapse in hematological malignancies, and CAR-T-cell dysfunctionality is characterized by insufficient CAR-T-cell proliferation and cytotoxicity frequently observed in patients with solid tumors. Thus, strategies to surmount those obstacles are being developed with high urgency. In this review, we want to highlight different approaches to combine CAR-T cells with drugs, such as small molecules and antibodies, to pharmacologically boost CAR-T-cell therapy. In particular, we discuss how certain drugs may help to counteract antigen shutdown and CAR-T-cell dysfunctionality in both hematological malignancies and solid tumors.

Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma

BackgroundT cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer.MethodsWe previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial.ResultsET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6–38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion.ConclusionsCD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients.Trial registration: NCT04014894.

Evaluation of Serum Paraoxonase and Lipid Profile in Patients with Chronic Renal Failure Pre and post Hemodialysis

Chronic Renal Failure (CRF) is the progressive and irreversible loss of normal functioning of kidneys. this is associated with increased levels of some biochemical parameters and decreased others. This study aims to evaluate the value of serum paraoxonase-1 (PON1) activity as biochemical marker for patients with chronic renal failure (CRF) before and after hemodialysis (HD).
 The samples of this study consists of 100 patients (55 males, 45 females) and 100 apparently healthy individuals (57 males, 43 females) from 20 - 70 years old of age. All patients included in this study were those who were receiving hemodialysis therapy in the dialysis unit in Kirkuk general Hospital from the period between February 2013 and May 2014. Serum PON1, BU, Cr, TC, TG, HDL, LDL levels were measured by spectrophotometric methods.Paraoxonase1 activity level was significantly lower in cases of CRF patients than in normal healthy control in pre hemodialysis (HD). It's level was significantly increased in post HD (P> 0.05). The blood urea (BU), serum creatinine (Cr), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) were significantly higher than normal healthy control in pre HD (P˂ 0.05), In post HD their levels were significantly decreased as compared to the pre HD (P˂ 0.05) but still lower than normal control, the serum high density lipoprotein (HDL) of CRF patients was significantly lower than normal controls (P˂ 0.05) in pre HD and was significantly increased in post HD as compared to pre HD but remained lower than normal healthy control. Conclusion: PON1 activity was significantly decreased in CRF patients before HD and significantly increased after HD but remained lower than controls. PON1 was significantly and negatively correlated with the age, BMI, duration of disease, BU, Cr, TC, TG, LDL, and VLDL. This study demonstrates that there is an increased risk of cardiovascular complications in CRF patients undergoing hemodialysis by increasing TC, TG, LDL, VLDL and decreasing HDL.

Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition.

B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma.

Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score-matched cohort analysis.

Blinatumomab showed a higher complete remission (CR) rate and a safe bridging to allogeneic hematopoietic cell transplantation (allo-HCT) in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). We tried to analyze the outcome of blinatumomab compared with the real-world historical data. We expected superior outcome of blinatumomab compared with historical conventional chemotherapy. We conducted a retrospective study using real-world data in the Catholic Hematology Hospital. Total 197 consecutive cases of R/R BCP-ALL were treated with conventional chemotherapy (n = 113) or blinatumomab, which was available since late 2016 (n = 84). Patients who achieved CR underwent allo-HCT if donor was available. We conducted a propensity score-matched cohort analysis using 5 criteria of age, CR duration, cytogenetics, previous allo-HCT, and salvage lines between historical group and blinatumomab. Each cohort consisted of 52 patients. In blinatumomab group, CR rate was higher (80.8% versus 53.8%, p = 0.006) and more patients proceeded to allo-HCT (80.8% versus 46.2%, p < 0.001). Among the CR patients with available minimal residual disease (MRD) results, 68.6% in blinatumomab group and 40.0% in conventional chemotherapy group were MRD-negative. Regimen-related mortality during the chemotherapy cycles was significantly higher in the conventional chemotherapy group (40.4% versus 1.9%, p < 0.001). Estimated 3-year overall survival (OS) was 33.2% (median, 26.3 months) after blinatumomab, and 15.4% (median, 8.2 months) after conventional chemotherapy (p < 0.001). Estimated 3-year non-relapse mortality were 30.3% and 51.9% (p = 0.004), respectively. In multivariate analysis, CR duration < 12 months showed more relapses and poor OS, and conventional chemotherapy showed higher non-relapse mortality and poor OS. Matched cohort analysis showed superior outcomes of blinatumomab compared with conventional chemotherapy. However, large numbers of relapses and non-relapse mortalities continue to occur even after blinatumomab followed by allo-HCT. Novel therapeutic strategies are still needed for R/R BCP-ALL.

Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.

Duration of Chemotherapy-Induced Nausea and Vomiting (CINV) as a Predictor of Recurrent CINV in Later Cycles.

The relationship between CINV duration and recurrence in subsequent cycles is largely unstudied. Our objective was to determine if patients experiencing CINV in their first cycle of chemotherapy (C1) would face increased risk of CINV in later cycles and whether the duration of the CINV would predict increased risk of recurrence. Using data from a previously reported phase III trial, we assessed patients' recurrence of breakthrough CINV after antiemetic prophylaxis for anthracycline+cyclophosphamide (AC) for breast cancer, comparing C1 short CINV vs. extended CINV as a secondary analysis. Complete response (CR) and CINV duration were primary and secondary endpoints, respectively. CR was considered prophylaxis success; lack of CR was considered treatment failure (TF). Among 402 female patients, 99 (24.6%) had TF in C1 (TF1). The remaining 303 patients (CR1) had ≥93% CR rates in each subsequent cycle, while the 99 patients with TF1 had TF rates of 49.8% for cycles 2-4 (P < .001). The 51 patients with extended TF (≥3 days) in C1 had recurrent TF in 73/105 later cycles (69.5%, P < .001), while the 48 patients with short TF (1-2 days) in C1 had recurrent TF in 33/108 later cycles (30.6%). The relative risk of recurrence after C1 extended TF was 2.28 (CI 1.67-3.11; P < .001) compared to short TF. Prophylaxis success in C1 led to >90% repeat success across cycles of AC-based chemotherapy. For patients with breakthrough CINV, extended duration strongly predicted recurrent CINV. The duration of CINV should be closely monitored, and augmenting antiemetic prophylaxis considered for future cycles when extended CINV occurs.

Efficacy and tolerability of a 12-week combination chemotherapy followed by lomustine consolidation treatment in canine B- and T-cell lymphoma

BackgroundHigh-grade lymphoma in dogs is a chemotherapy-responsive neoplasia with remission rates exceeding 80% under combination chemotherapy protocols. Usually these protocols are intensive and 24 + weeks. The objective of the present study was to investigate if a shorter protocol combined with an oral lomustine maintenance treatment (3 × in 8 weeks) would present an acceptable result, both for B- and T-cell lymphomas, and for the different types of lymphomas normally encountered in private veterinary practice.Results144 dogs entered the study. Lymphoma types included multicentric (n = 123), alimentary (n = 13), miscellaneous (n = 7), and mediastinal lymphoma (n = 1). Overall response rate was 83.3% (B-cell: 86.6%, T-cell: 79.4%). Complete remission (CR) was achieved in 72.2% (B-cell: 77.3%, T-cell: 67.6%) and partial remission (PR) in 11.1% (B-cell: 9.3%, T-cell: 11.8%) of the dogs. Median duration of first CR amounted to 242 days (B-cell: 263 d, T-cell: 161 d). Median survival in dogs with CR was 374 days (B-cell: 436 d, T-cell: 252 d), and median overall survival time was 291 days (B-cell: 357d, T-cell: 210d). Immunophenotype demonstrated an independent significant influence on duration of remission and survival in the whole group. Findings of splenic and hepatic cytology were not significant associated with patient outcome. Treatment was well tolerated; the majority of adverse events were classified as grade 1 or 2.ConclusionsShort-term chemotherapy followed by lomustine consolidation leads to compara-ble remission and survival times compared to conventional protocols with cyclophosphamide, doxorubicin, vincristine and prednisolone with acceptable toxicosis in dogs with both B-cell and T-cell lymphoma.

Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model

Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC0) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC24-NC and MC37-NC) replicated invitro and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration ofMC0-NC led to faster tumor responses than MC24-NC or MC37-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC0-NC versus MC24-NC or MC37-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC24- and MC37- viral genomes, but not in MC0-NC. Overall, MC0-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.

Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT): A Novel Variant of Primary Cutaneous Follicle Center Lymphoma (PCFCL).

Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma (FL) based on genomic and clinical features. The nature of other extranodal FLs is not well defined. We report 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization for BCL2 gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5y) with a 5-year overall survival of 100%. We conclude that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas.

Adoptive cell transfer therapy for melanoma.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) for melanoma is an example of the most successful cancer immune therapy. It achieves a durable complete response about ~20% of patients, and they might be cured. However, the ratio of patients with durable benefits is not high, and its complicated procedure prevents its diffusion. Therefore, many efforts to enhance the effect and simplify the protocol of TIL therapy have been made so far, resulting in the establishment of a simple and effective current TIL therapy that has been propagated to other institutes and countries. Moreover, TIL therapy and translational research using clinical samples derived from durable responders elucidate the important element for developing more effective cancer immune therapies in the future. This review introduced the brief history, attempts for the improvement and important findings elucidated by translational research of ACT for melanoma.

Venetoclax in Combination with Hypomethylating Agents or Low-Dose Cytarabine for Relapsed/Refractory Acute Myeloid Leukemia: A Retrospective Single-Centre Experience

Background. Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical condition with an overall dismal outcome owing to the lack of standardized, effective treatment approaches. The only curative option for R/R AML patients (pts) is allogeneic hematopoietic stem cell transplantation (HSCT), that can be exploited in a minority of otherwise eligible pts due to poor efficacy and high toxicity of salvage regimens used to induce leukemia remission as bridge-to-transplant. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML pts. Since its first accelerated approval by the Food and Drugs Administration in 2018, the Bcl-2 inhibitor venetoclax (VEN), in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), has steadily become the standard therapeutic approach for newly diagnosed AML in elderly or unfit pts, while its role in R/R disease is not well defined yet. Aim. To gain insights into the potential effectiveness of VEN-based regimens in patients with R/R AML. Patients. We retrospectively analyzed the clinical outcomes of 67 R/R AML pts treated at our Institution with venetoclax-based regimens on an off-label basis, between March 2018 and April 2022. Fifty-eight pts (87%) carried a de-novo AML diagnosis, 6 pts (9%) had AML secondary to myelodysplastic syndrome and 3 pts (4%) had therapy-related AML. Median age was 58y (33-74y); 30 pts (45%) were aged >60, while 7 pts (10%) were aged >70y at VEN initiation. Thirty-eight pts (56%) were treated for first (n=32) or second relapse (n=6); last complete remission (CR) duration was <6 mo in 18 pts, 6-12 mo in 16 pts and >12 m (12-56) o in 4 patients; 11 pts (16%) had relapsed after HSCT; remaining 18 pts (27%) were treated for primary refractory disease. All pts received conventional immunophenotypic and cytogenetic characterization and at least NPM1, FLT3, CBFB/MYH11 and RUNX1/RUNX1T1 mutation/rearrangement detection. Next-generation sequencing (NGS) data were available for 56 pts (83%); specifically, 40 pts (primary refractory, n=18; relapsed, n=22) had NGS analysis carried out on bone marrow samples shortly before VEN initiation, while in 16 pts NGS was carried out on baseline diagnostic specimens. VEN partner drug was azacitidine in 45 pts (68%), LDAC in 15 (22%) and decitabine in 7 (10%). Thirty-nine pts (58%) were treated with an intention-to-transplant (ITT). Median follow-up duration was 11.8 mts (1.1 - 44). Results. Overall, we report a composite complete response (CCR) rate of 55% (n=37); 10 of complete responders (27%) had incomplete peripheral counts recovery. Minimal residual disease (MRD) negativity was achieved in 21/37 pts (56%). All CR invariably occurred during the first 8 weeks of treatment. Although it did not reach significance level (p=0.065), there was considerable variation in CCR rate among treatment settings: relapsed pts, 66%; primary refractory, 50%; post-HSCT relapse, 27%. Conventional risk stratification parameters (age, leukocyte counts, ELN 2017 risk category, NPM1/FLT3 mutational status, secondary disease, last CR duration) were poorly predictive of CR probability. A positive trend towards higher CCR rate, although not statistically significant, was found for NPM1 (CCR rate: 57%) and IDH1/2 mutation (66%) while FLT3/Ras pathway mutations were detrimental (23%). Median overall survival (OS) but not event-free survival (EFS), differed significantly among settings: relapsed pts, 11.9 mo; refractory, 8.6 mo; post-HSCT, 6.7 mo. (p=0.030). Stratifying pts based on NPM1 and FLT3-ITD status resulted in markedly different EFS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 6.2 mo; NPM1mut, FLT3-ITDpos, 3.4 mo (p=0.031); as well as different OS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 10.5 mo; NPM1mut, FLT3-ITDpos, 5.6 mo (p=0.003). Among the ITT population, HSCT actualization rate was 66%. Four pts are currently long-term survivors with follow-up exceeding 24 mo without receiving HSCT; notably, they all carried a NPM1mut/FLT3-ITDneg/Ras pathwayneg genotype. Conclusions: Overall, these findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal