Treatment-naïve Research Articles

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.

6541 Background: Investigational agent lisaftoclax (Lisa) was shown in preclinical findings to synergistically induce apoptosis in acute myeloid leukemia (AML). Here, we present follow up safety and efficacy data from a phase 1b/2 study evaluating Lisa + azacitidine (AZA) in adults with AML. Methods: Elderly (≥ 75 years)/unfit treatment-naïve (TN) and relapsed or refractory (R/R) AML (≥ 18 years) patients (pts) were enrolled. Lisa (400/600/800 mg) was administered orally once daily in 28-day cycles (a daily ramp up schedule was used for Lisa to prevent tumor lysis syndrome, TLS) combined with AZA (75 mg/m2/day on D1-7). Results: As of January 25, 2024, 76 AML pts were enrolled (R/R [n = 37]; elderly/unfit TN [n = 39]). The median (range) age was 66 (20-81) years and 61.8% of pts were male. All pts treated with Lisa + AZA reported TEAEs, with 89.5% Grade 3/4 AEs; and 43.4% SAEs. Common TEAEs (≥ 30%) included neutropenia (60.5%), thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%), pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of pts were neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported, and the 30-/60-day mortality rates were 1.3% and 3.9%, respectively. In pts with R/R AML treated with Lisa + AZA, the overall response ([ORR] = CR + CRi + morphologic leukemia-free state [MLFS] + PR) and composite complete remission (CRc = CR + CRi) rates were 72.7% and 45.5%, respectively. In the 600 mg cohort (n = 30), ORR and CRc were 76.7% and 50.0%; the median (range) duration of treatment (mDoT), 3.8 (0.8‒15.4) month (mo); median time to CRc (mTTCRc), 2.5 (95% CI, 1.5-6.1) mo; median PFS was 10.2 (95% CI, 6.5-NR) mo; and median OS was 14.7 (95% CI, 7.8-NR) mo. Among 39 pts with TN AML treated with Lisa + AZA, ORR and CRc were 64.1% and 51.3%, respectively (Table). In the 600 mg cohort (n = 29), mDoT was 3.3 (1.0- 9.9) mo; mTTCRc was 1.9 (95% CI, 1.2-3.3) mo; median PFS was not reached (3.5, NR). 600 mg of Lisa + AZA was established as the recommended phase 2 dose. Conclusions: Our data support an emerging role for this new BCL-2 inhibitor Lisa combined with AZA for the treatment of elderly/unfit TN and R/R AML pts, especially with low early mortality and promising mPFS. A phase 3, randomized, double-blind clinical study is in progress to determine whether Lisa + AZA improves OS in elderly/unfit pts with AML. *HW, XW, and YL are co-first authors. Clinical trial information: NCT04501120 . [Table: see text]

Rituximab, chidamide, and zanubrutinib (ZCR) ± CHOP as a regimen for treatment naive (TN) double-expressor DLBCL (DE-DLBCL).

e19053 Background: DLBCL patients with co-expression of MYC (≥40%) and BCL2 (≥50%) by immunohistochemistry are considered as DE-DLBCL. The prognosis of DE-DLBCL is usually worse than DLBCL-NOS. The Smart Start trial had established the feasibility of chemotherapy-free targeted therapy before 1L chemotherapy. The BTK inhibitor Zanubrutinib (Z) or epigenetic drug Chidamide (C) with R-CHOP regimen has a potential synergistic effect in the treatment of DE-DLBCL. Under the inspiration of Smart Start, this trial aim to explore the feasibility of ZCR±CHOP regimen in TN DE-DLBCL. Methods: This is a multicenter, open-label, single-arm phase 2 study (NCT05527912) conducted in China. If patients achieve complete response (CR) after cycle-2 (C2), ZCR will be continued for up to 8 cycles. Otherwise, ZCR-CHOP will be given for another 6 cycles. The primary endpoint is CR rate at the end of treatment (CRR-EOT); secondary endpoints included ORR (overall response rate) ,2y-PFS, and 2y-OS. Plasma samples were collected at baseline, C2 and the EOT. In evaluable samples, circulating tumor DNA (ctDNA) assays were performed. Results: From February 2023 till now, 34 TN DE-DLBCL patients were enrolled, with 32 patients evaluable. The median age was 52y (range: 22-68), 55.9% were male, 79.4% were Non-GCB (Table 1). 12 patients who achieved CR by C2 were continued with RCZ chemo-free therapy, and CHOP were added to the 14 PR and 3 SD patients. In the 32 evaluable patients, ORR after C2 of RCZ was 81.25% (26/32, CR 37.5%, PR 43.75%, SD 9.4%, PD 9.4%). Up to now, 12 patients have completed 8 courses (C8) and all of them have achieved CR, both ORR and CR are 100% (12/12). 3 patients withdrew due to PD. For safety information in the trial, 64.3% patients reported grade (G)-3/4 AEs. In the Chemo-Free subgroup, only 4 patients (36.4%, 4/11) reported G-3/4 AEs. the majority of G-3/4 AEs is hematological events, including leukopenia, neutropenia and thrombocytopenia. The CR rate at C2 was 66.7% (6/9) in patients with negative baseline ctDNA results. The patients with BCL6 fusion of ctDNA at baseline were more prone to PD (3/4, 75.0%). Compared to baseline, plasma ctDNA levels decreased significantly after C2. 29 patients were evaluable for ctDNA after C2, 100% (12/12) of C2-CR patients and 58.8% (10/17) of non-C2-CR patients were negative, P=0.023. Compared with Non-C2-CR patients, the number of detected mutations and average VAF level were decreased in C2-CR patients. Conclusions: This trial demonstrates ZCR±CHOP could be a promising regimen with active antitumor effect and acceptable toxicity in TN DE-DLBCL patients. Clinical trial information: NCT05527912 .

Effectiveness, safety and discontinuation rates of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in people with HIV using real-world data: a systematic review and meta-analysis.

The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is based on the results of robust clinical trials. To assess the effectiveness and safety of BIC/FTC/TAF in treatment-naïve (TN) and treatment-experienced (TE) people with HIV using available real-world cohort studies. Systematic review and meta-analysis of publications and communications identified via Boolean search in Medline, PubMed and Embase, and conference abstracts reporting retrospective real-world use of BIC/FTC/TAF, published until 31 January 2024. The primary endpoint was the proportion of TN and TE people with HIV with viral load (VL) < 50 copies/mL at 48 weeks while on treatment. Of the 38 identified publications and conference abstracts, for the present analysis we included 12 publications (comprising 792 TN and 6732 TE individuals). For the three publications including 507 TN participants reporting the primary outcome, VL suppression was 97% [95% confidence intervals (CI): 89-100]. For the nine publications including 4946 TE participants reporting the primary outcome, VL suppression was 95% (95% CI: 94-96), with suppression >93% in all studies. Total discontinuations at 48 weeks in TE individuals were 3% (95% CI: 2-5), 1% (95% CI: 0-2) due to side effects. A total of four publications with 151 TE individuals with previous presence of M184V substitution were identified, reporting a suppression rate at 48 weeks of 95% (95% CI: 88-100). Real-world studies demonstrate low discontinuation rates and high rates of virologic suppression in individuals treated with BIC/FTC/TAF, both TN and TE with and without previous detection of M184V substitution.

A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitisC (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitisC virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials

AbstractBefore targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy. Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. A total of 808 patients were included (TN cohort, n = 320; R/R cohort, n = 488). Median follow-up was 59.1 months (TN cohort) and 44.3 months (R/R cohort); 51.3% and 26.8% of patients in the TN and R/R cohorts, respectively, remained on treatment at last follow-up. In the del(17p)/TP53m, uIGHV, and CK subgroups in the TN cohort, median progression-free survival (PFS) and median overall survival (OS) were not reached (NR). In the del(17p)/TP53m, uIGHV, and CK subgroups in the R/R cohort, median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and median OS was 60.6 months, NR, and NR, respectively. The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. Our analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.

Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia.

The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

High prevalence of pre-treatment and acquired HIV-1 drug resistance mutations among non-citizens living with HIV in Botswana.

Approximately 30,000 non-citizens are living with HIV in Botswana, all of whom as of 2020 are eligible to receive free antiretroviral treatment (ART) within the country. We assessed the prevalence of HIV-1 mutational profiles [pre-treatment drug resistance (PDR) and acquired drug resistance (ADR)] among treatment-experienced (TE) and treatment-naïve (TN) non-citizens living with HIV in Botswana. A total of 152 non-citizens living with HIV were enrolled from a migrant HIV clinic at Independence Surgery, a private practice in Botswana from 2019-2021. Viral RNA isolated from plasma samples were genotyped for HIV drug resistance (HIVDR) using Sanger sequencing. Major known HIV drug resistance mutations (DRMs) in the pol region were determined using the Stanford HIV Drug Resistance Database. The proportions of HIV DRMs amongst TE and TN non-citizens were estimated with 95% confidence intervals (95% CI) and compared between the two groups. A total of 60/152 (39.5%) participants had a detectable viral load (VL) >40 copies/mL and these were included in the subsequent analyses. The median age at enrollment was 43 years (Q1, Q3: 38-48). Among individuals with VL > 40 copies/mL, 60% (36/60) were treatment-experienced with 53% (19/36) of them on Atripla. Genotyping had a 62% (37/60) success rate - 24 were TE, and 13 were TN. A total of 29 participants (78.4, 95% CI: 0.12-0.35) had major HIV DRMs, including at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) associated DRM. In TE individuals, ADR to any antiretroviral drug was 83.3% (20/24), while for PDR was 69.2% (9/13). The most frequent DRMs were nucleoside reverse transcriptase inhibitors (NRTIs) M184V (62.1%, 18/29), NNRTIs V106M (41.4%, 12/29), and K103N (34.4%, 10/29). No integrase strand transfer inhibitor-associated DRMs were reported. We report high rates of PDR and ADR in ART-experienced and ART-naïve non-citizens, respectively, in Botswana. Given the uncertainty of time of HIV acquisition and treatment adherence levels in this population, routine HIV-1C VL monitoring coupled with HIVDR genotyping is crucial for long-term ART success.

Long-term follow up of the combination of ofatumumab, high-dose methylprednisolone, and lenalidomide for untreated chronic lymphocytic leukemia with biomarker analysis

BackgroundAdvancements in frontline therapy and chemotherapy-sparing treatments in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have altered the treatment algorithms of this disease. We present a frontline alternative for treatment- naïve (TN) CLL/SLL patients. MethodsThis was a single-center, phase 2 study of high-dose methylprednisolone (HDMP) and ofatumumab with lenalidomide and ofatumumab consolidative therapy for all comers with TN CLL/SLL. Treatment was continued until disease progression or intolerable side effects. Patients were assessed for response per iwCLL 2008 criteria after completing cycles 3 and 12. ResultsForty-five patients were enrolled (median age, 62.6 years). High-risk features included del17p (18%), Del11q (22%), and unmutated IGHV gene (76%). Median treatment duration was 32·2 (2·7-75·9) months. Thirty-six patients discontinued treatment due to disease progression (22%), adverse events (40%), allogeneic hematopoietic cell transplantation (allo-HCT) (7%), consent withdrawal (4%), and secondary malignancies (7%). The best overall and complete response rates were 96& and 29% respectively. At median follow-up of 61·7 (5·6-84·9) months, 9 patients remained on treatment. Median progression-free survival was 54·4 (2·9-77·6) months. Three patients underwent allo-HCT after a median of 3 (3-4) treatment cycles. Treatment was well tolerated, with a grade 3/4 infusion reaction in one patient. The most common grade 3/4 hematological adverse event was neutropenia (69%). Four patients had grade 3/4 infections. No grade 3/4 tumor flares, tumor lysis syndrome, or thrombosis were observed. ConclusionThe combination of ofatumumab, HDMP, and lenalidomide was effective and relatively well tolerated in treatment-naive CLL/SLL. Its role in the frontline setting remains unclear given the current available and effective treatment options. FundingThe funders had no role in the study.

Assessment of interleukin 6 (IL-6) as a marker of inflammation among adult patients with pulmonary tuberculosis in Zaria, Nigeria

Tuberculosis (TB) remains a significant cause of morbidity and mortality worldwide. Complications of the disease are associated with the host’s inflammatory response. The study aimed to determine the plasma level of interleukin-6 as a biomarker of inflammation among adult patients with pulmonary tuberculosis in Zaria.Method This was a cross-sectional study. Blood samples were taken from 30 treatment-naïve (TN), 30 treatment-experienced (TE), and 30 healthy controls (HC).Results The means and standard deviations of interleukin-6 plasma levels for tuberculosis treatment naive, treatment experience and apparently healthy control are 64.4 ± 19.4, 57.9 ± 21.4, and 49.9 ± 7.7 pg/L, respectively. This study found upregulated plasma levels of interleukin-6 among treatment naive compared to treatment experience but the statistically not significant and significantly upregulated level of interleukin 6 among treatment naïve compared to apparently healthy control (p = 0.006). There was a downregulated level of interleukin-6 among HC compared to TN and TE but statistically not significant.Conclusion The role of interleukin-6 as a surrogate biomarker for the management of patients with pulmonary tuberculosis is promising but requires further study.

Impact of Crisaborole in Treatment-Experienced Patients With Mild-to-Moderate Atopic Dermatitis.

Background: Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of patients with mild-to-moderate atopic dermatitis (AD). Objective: To assess the efficacy and safety of crisaborole in patients with AD who had received prior treatment with (a) corticosteroids (systemic or topical) or topical calcineurin inhibitors (TCIs) or (b) topical corticosteroids (TCSs) or TCIs or (c) who were treatment-naive (TN). Methods: This post hoc analysis comprised patients aged ≥2 years with mild-to-moderate AD. Patients were assigned (2:1) to receive crisaborole or vehicle twice daily for 28 days. Patient response was assessed with the Investigator's Static Global Assessment (ISGA), Dermatology Life Quality Index (DLQI), Children's Dermatology Life Quality Index (CDLQI), and Dermatitis Family Impact (DFI) tools. Safety was also assessed. Results: A significantly higher percentage of patients treated with crisaborole versus vehicle achieved ISGA success regardless of treatment history. Patients treated with crisaborole had significant reductions in DLQI, CDLQI, and DFI scores versus those who received vehicle regardless of treatment history, with the exception of DLQI and DFI scores in the TN group. Crisaborole was well tolerated in all subgroups. Conclusion: Crisaborole demonstrated a favorable efficacy and safety profile in both treatment-experienced and TN patients. ClinicalTrials.gov, NCT02118766 and NCT02118792.

Characteristics of blood immune cell profile and their correlation with disease progression in patients infected with HIV-1

BackgroundAntiretroviral therapy (ART) can reduce viral load in individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals still cannot achieve optimal immune recovery even after ART. Hence, we described the profile of peripheral immune cells and explored the association with disease progression in patients infected with HIV-1.MethodsMass cytometry analysis was used to characterize the circulating immune cells of 20 treatment-naïve (TNs), 20 immunological non-responders (INRs), 20 immunological responders (IRs), and 10 healthy controls (HCs). Correlation analysis was conducted between cell subpopulation percentages and indicators including HIV-1 cell-associated (CA)-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio.ResultsGlobal activation, immunosenescence, and exhaustion phenotypes were observed in myeloid cells and T cells from individuals with HIV-1 infection. We also found that specific subsets or clusters of myeloid, CD4+ T, and CD8+ T cells were significantly lost or increased in TN individuals, which could be partially restored after receiving ART. The percentages of several subpopulations correlated with HIV-1 CA-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio, suggesting that changes in immune cell composition were associated with therapeutic efficacy.ConclusionThese data provide a complete profile of immune cell subpopulations or clusters that are associated with disease progression during chronic HIV-1 infection, which will improve understanding regarding the mechanism of incomplete immune recovery in INRs.

Eligibility Criteria for Active Ulcerative Pyoderma Gangrenosum in Clinical Trials: A Delphi Consensus on Behalf of the UPGRADE (Understanding Pyoderma Gangrenosum: Review and Assessment of Disease Effects) Group

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG.

Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy.

Introduction: High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadliest subtype of epithelial ovarian cancer (EOC), killing over 140,000 people annually. Morbidity and mortality are compounded by a lack of screening methods, and recurrence is common. Plasminogen-activator-inhibitor 1 (PAI-1, the protein product of SERPIN E1) is involved in hemostasis, extracellular matrix (ECM) remodeling, and tumor cell migration and invasion. Overexpression is associated with poor prognosis in EOC. Platelets significantly increase PAI-1 in cancer cells in vitro, and may contribute to the hematogenous metastasis of circulating tumor cells (CTCs). CTCs are viable tumor cells that intravasate and travel through the circulation-often aided by platelets - with the potential to form secondary metastases. Here, we provide evidence that PAI-1 is central to the platelet-cancer cell interactome, and plays a role in the metastatic cascade. Methods: SK-OV-3 cells where PAI-1 had been silenced, treated with healthy donor platelets, and treated with platelet-conditioned medium were used as an in vitro model of metastatic EOC. Gene expression analysis was performed using RNA-Seq data from untreated cells and cells treated with PAI-1 siRNA or negative control, each with and without platelets. Four cohorts of banked patient plasma samples (n = 239) were assayed for PAI-1 by ELISA. Treatment-naïve (TN) whole blood (WB) samples were evaluated for CTCs in conjunction with PAI-1 evaluation in matched plasma. Results and discussion: Significant phenotypic changes occurring when PAI-1 was silenced and when platelets were added to cells were reflected by RNA-seq data, with PAI-1 observed to be central to molecular mechanisms of EOC metastasis. Increased proliferation was observed in cells treated with platelets. Plasma PAI-1 significantly correlated with advanced disease in a TN cohort, and was significantly reduced in a neoadjuvant chemotherapy (NACT) cohort. PAI-1 demonstrated a trend towards significance in overall survival (OS) in the late-stage TN cohort, and correlation between PAI-1 and neutrophils in this cohort was significant. 72.7% (16/22) of TN patients with plasma PAI-1 levels higher than OS cutoff were CTC-positive. These data support a central role for PAI-1 in EOC metastasis, and highlight PAI-1's potential as a biomarker, prognostic indicator, or gauge of treatment response in HGSOC.

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Background: Covalent Bruton tyrosine kinase inhibitor (cBTKi) is a standard treatment for chronic lymphocytic leukemia (CLL). Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib. Mutations in BTK C481 and to a lesser extent PLCG2 are frequently detected in ibrutinib-treated pts at the time of progressive disease (PD). In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib. A recent study identified 3 pts with BTK C481 mutations and no pts with PLCG2 mutations among 8 acalabrutinib-treated pts with progressive disease (PD) (Black, et al. Blood 2022). A second study found a kinase-dead BTK L528W mutation in 7/13 zanubrutinib-treated pts (Blombery, et al. Blood Adv 2022). Although cBTKi share the same mechanism of action by binding to BTK C481, the latter report discloses differences in clonal selection and underscores the need for further investigation in pts treated with next generation cBTKi. In a phase 2 study of acalabrutinib in pts with treatment naïve (TN) CLL or small lymphocytic lymphoma (SLL) with 17p deletion, or TP53 or NOTCH1 mutation, or relapsed/refractory (R/R) CLL/SLL regardless of cytogenetics or somatic mutations (Sun, et al. Blood 2020), we sought to understand clonal evolution during treatment. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 48 pts at baseline, after 6 months, then annually on treatment until PD. Current analysis includes 14 PD pts [excluding 3 Richter transformation (RT) pts] comprising 10 R/R and 4 TN CLL pts. Additionally, paired baseline and PD bone marrow (BM) from 6 pts and lymph node (LN) samples from 2 pts were included. Targeted next-generation sequencing of ~700 recurrently mutated genes in hematological malignancies (Collins, et al. Leuk Lymphoma. 2021) was performed using DNA isolated from CD19 + enriched cryopreserved PBMCs and BM aspirates, as well as fresh-frozen core LN biopsies. Filtered variants in putative CLL driver genes (Knisbacher, et al. Nat Genet. 2022) with variant allele frequencies (VAF) ≥1% for BTK and PLCG2, ≥5% for variants with known oncological significance, and ≥7.5% for all other variants were included in downstream analysis. Results: After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years. Best response was complete remission in 2/20 (10%) pts and partial remission in 18/20 (90%) pts with CLL PD. IGHV was unmutated in all but one PD patient. At baseline, 34 CLL driver genes were mutated in 41/45 pts (91%; excluding 3 RT pts) with most mutations in NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE. During acalabrutinib treatment but before PD, 14/45 pts (31%; 8 R/R and 6 TN) acquired mutations in 11 driver genes, most commonly in BRAF (n=4), CREBBP (n=4), and KMT2D (n=2). At the time of PD, 11/14 pts (79%) had newly acquired mutations in 4 genes, predominantly BTK (n=6) and PLCG2 (n=4). BTK C481 mutations (VAF 2-42%) were detected in 6/14 (43%; 4 R/R and 2 TN) pts and T474I mutation (VAF 4-46%) in 3/14 (21%; 1 R/R and 2 TN) pts. Paired BM samples in 2 pts and LN samples in 2 pts showed the same BTK mutations as PBMCs with similar VAFs. PLCG2 mutations (VAF 1-8%) were found in 4/14 (29%; 2 R/R and 2 TN) pts. BTK C481 co-occurred with BTK T474I in 3 pts, but on different sequencing reads suggesting independent subclones, and with a PLCG2 mutation in 1 pt. There have been no pts with BTK L528 mutations. In conclusion, mutations in BTK and PLCG2 are the predominant resistance mechanism to acalabrutinib. Among BTK mutations, C481 was the most common. All T474I mutations co-occurred with C481.

A Phase (Ph) 2 Study of TL-895, a Highly Selective, Novel Covalent BTK Inhibitor (BTKi), in Patients (pts) with Treatment-Naïve (TN) and Relapsed/Refractory (R/R) BTKi-Naïve Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Background: Covalent BTKi have become the backbone of CLL/SLL therapy. Through improved target kinase selectivity, second generation BTKi offer improved safety with potentially better efficacy, yet compartmental clearance leading to complete remission (CR) remains elusive. TL-895 is a potent, second generation, irreversible, oral BTKi with best-in-class selectivity (Gulrajani 2023) over other second generation BTKi; which may lead to improved safety and clearance of leukemic disease to induce deeper and more durable responses. Methods: This multicenter Ph 2 study (NCT02825836) enrolled symptomatic, BTKi-naïve CLL/SLL pts ≥18 years with ECOG PS 0-2. The R/R and TN arms enrolled sequentially and pts were randomly assigned to receive TL-895 at 100 mg (Arm 1 [R/R] and Arm 4 [TN]) or 150 mg (Arm 2 [R/R] and Arm 3 [TN]) twice a day continuously until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR: partial remission [PR], nodular PR [nPR], or CR) per iwCLL 2018 criteria and key secondary were CR rate, safety and BTK occupancy. Results: As of 11 July 2023, 84 pts were enrolled at 12 sites throughout the US and Europe. In TN Arms 3 and 4 (n=21 each), 57% of pts were IGHVUNMUT, 14% had del17p/ TP53MUT and 29% bulky (≥5 cm) adenopathy. Median baseline ALC was 77x10 9/L (range 2-444) in Arm 3 and 46x10 9/L (range 3-215) in Arm 4. In R/R Arms 1 and 2 (n=21 each), pts received a median of 2 prior therapies (range 1-5), 69% of pts were IGHVUNMUT, 48% had del17p/ TP53MUT and 52% bulky adenopathy. Median baseline ALC was 21x10 9/L (range 1-235) in Arm 1 and 34x10 9/L (range 2-178) in Arm 2. In TN Arms 3 and 4, at a median follow-up of 8 months ([mo] range 1-10), the ORR was 86%. In the R/R Arms 1 and 2, at a median follow-up of 23 mo (range 1-26), the ORR was 86% and 81%, respectively. At the 100 mg dose, two unconfirmed CRs (uCR) pending bone marrow (BM) biopsy were reported in R/R Arm 1. At the 150 mg dose, one CR, one uCR pending BM biopsy and two nPRs were reported, two each in R/R Arm 2 and TN Arm 3. All CRs/uCRs and nPRs occurred by week 48. In TN Arm 3 150 mg dose, a faster time to response was observed compared to TN Arm 4 100 mg dose ( Figure 1), with a median ALC reduction of 50% by 3 mo compared to 6 mo, respectively (Figure 2). Additionally, at a median of only 5 mo (range 0.3-8.3), 62% (13/21) of pts in Arm 3 compared with 20% (4/21) of pts in Arm 4 had complete resolution of lymphocytosis in their blood (&amp;lt;4 x10 9/L). Full trough target occupancy (median ≥95%) was achieved in both TN and R/R pts, with low intrapatient variability and near complete inhibition of signaling proteins downstream of BTK by FACS analysis. In the TN arms, treatment-emergent adverse events (TEAEs) regardless of causality were reported in 88% of pts (36% grade [Gr] 3, 0% Gr 4). Most common TEAEs (&amp;gt;10%), were anemia (21%), neutropenia (14%), COVID-19 and upper respiratory tract infection (URTI; 12% each). Most common Gr 3/4 TEAEs (&amp;gt;10%) were anemia and neutropenia (12% each). In the R/R arms, TEAEs were reported in 98% of pts (31% Gr 3, 14% Gr 4). Most common TEAEs were neutropenia (31%) and COVID-19 (21%), thrombocytopenia (19%), diarrhea (17%), anemia, hypertension (HTN) and URTI (14% each), sinusitis and pneumonia (12% each). Most common Gr 3/4 TEAE was neutropenia (26%). In the TN arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (2%; 0%), HTN (5%; 2%), and headache (2%; 0%) with no events of atrial fibrillation (AFib) or major hemorrhage. In the R/R arms, incidence of TEAEs of interest (any Gr; Gr 3/4) were rash (5%; 0%), HTN (14%; 5%), headache (5%; 0%), AFib (5%; 5%) and major hemorrhage (2%, 2%). Gr 5 TEAEs occurred in six R/R pts (three in each arm) and one TN Arm 4 pt, including three COVID-related deaths; none were considered related to TL-895. Excluding COVID-related deaths, median progression free survival (PFS) was not reached with an estimated 8 mos PFS rate of 93% (95% CI, 79-95) in TN pts and 84% (95% CI, 69-93) at 22 mos in R/R pts. Treatment discontinuations included 2 Richter's transformations, one each in TN Arms 3 and 4. Conclusion: Treatment with TL-895 resulted in rapid clearance of leukemic compartments, particularly in TN pts, leading to earlier and deeper responses than expected with monotherapy BTKi. In R/R pts with a very high frequency of del17p/ TP53MUT, remissions have been durable. With a very low incidence of AEs typical of less selective BTKi (e.g., AFib, major hemorrhage, rash and headache), TL-895 has the potential to be a best-in-class backbone BTKi.

A Real-World Study of Zanubrutinib Treatment in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Background: Zanubrutinib, a second-generation non-covalent Bruton's Tyrosine Kinase inhibitor (BTKi), with better BTK specificity, and fewer off-target effects. Zanubrutinib has demonstrated the confirmed effectiveness and safety in clinical trials such as SEQUOIA and ALPINE in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), and earlier studies showed its efficacy and safety profile of zanubrutinib monotherapy in the real world. Meanwhile, more valuable insights hope to be gained on zanubrutinib treatment in Chinese CLL/SLL patients (pts) outside of the clinical trial setting. This report provides some outcomes evaluated in a real-world study. Aims: This study further evaluated the effectiveness and safety of zanubrutinib monotherapy/combination treatment in Chinese CLL/SLL pts in a real-world setting. Methods: CLL/SLL pts who received zanubrutinib monotherapy/combination treatment for at least 3 months from Aug. 2017 to Jul. 2023 were enrolled from Jiangsu Province Hospital. The primary outcome was progression free survival (PFS). Baseline characteristics were also collated. Results: 77 pts were analyzed in all. Zanubrutinib was administered orally at 160 mg, twice daily (BID), mono or combined. Among the monotherapy pts, 20 (35.1%) pts were treatment naïve (TN) and 37 (64.9%) pts were refractory/relapsed (R/R). Among the combination treatment pts, 14 (70.0%) pts were TN and 6 (30.0%) pts were R/R. Baseline characteristics were shown in Table 1. The median follow-up time was 31.8 months, and the median PFS was not reached in the entire cohort. The 12-month PFS rate was 95.8% (95%CI 91.3-100.0%) while the 24-month PFS rate was 90.9% (95%CI 84.2-98.2%) (Figure A). After stratified by line of therapy in monotherapy, the estimated 12-month PFS rates of TN and R/R zanubrutinib monotherapy pts were 100.0% (95%CI 100.0-100.0%) and 91.3% (95%CI 82.3-100.0%) (Figure B). The estimated 24-month PFS rates of TN and R/R zanubrutinib monotherapy pts were 93.8% (95%CI 82.6-100.0%) and 84.9% (95%CI 73.5-98.1%). 4 (5.2%) pts interrupted treatment due to AE. 2 pts were TN and 2 pts were R/R. 2 pts received zanubrutinib monotherapy and 2 pts received combination treatment. The AEs included hemoptysis (1, 1.3%), platelet hemoglobin reduction and atrial fibrillation (1, 1.3%), bleeding points in both lower limbs (1, 1.3%), rash and edema (1, 1.3%). All treatment-interrupted pts still received zanubrutinib after interruption by the latest follow-up. 17 (22.1%) pts experienced treatment discontinuation due to progressive disease (PD) or transformation. No pts discontinued zanubrutinib treatment due to AE. PD was the most common reason for treatment discontinuation. 13 (16.9%) pts experienced PD and 4 (5.2%) pts experienced transformations. S ummary/Conclusion: Zanubrutinib shows good efficacy in Chinese CLL/SLL pts in the real-world study. Incidence of AE was low, and no treatment discontinued due to AE, revealing a good safety of zanubrutinib. PD was the main reason for treatment discontinuation. Therefore, the effectiveness and safety of zanubrutinib have been validated in the real world, consistent with clinical trials.

Real-World Analysis of Obinutuzumab-Based Immunochemotherapy in Follicular Lymphoma in Chinese Population

Background Obinutuzumab is a first-in-class glycoengineered humanized type II anti-CD20 antibody. Immunochemotherapy based on obinutuzumab has demonstrated an advantage in prolonging progression-free survival (PFS) in pts with follicular lymphoma(FL) in a number of clinical trials(Marcus R, et al. N Engl J Med. 2017; Cheson BD, et al. J Clin Oncol. 2018). In Jun, 2021, obinutuzumab came into the market of China. However, few studies have investigated the efficacy and safety of obinutuzumab-based immunochemotherapy aiming at Chinese population. Therefore, we retrospectively analyzed the data of Chinese pts with treatment-naïve(TN) or relapsed/refractory(R/R) follicular lymphoma who received obinutuzumab-based immunochemotherapy in our center, hoping to provide treatment reference for Chinese pts. Methods Eligible pts were age ≥18 years with histologically documented, CD20-positive follicular lymphoma (grade 1 to 3a, stage III/IV or stage II with tumor ≥7 cm in the greatest dimension), and at least 2 cycles of obinutuzumab-based treatment. Efficacy was assessed by objective response rate (ORR) and best of response (BOR), with toxicity evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) (The 5th Edition). In addition, we recorded the incidence and severity of corona virus disease 2019 (COVID-19) infection according to Scheme for Diagnosis and Treatment of COVID-19 (The 10th Trial Edition). Results Between Nov 1, 2021 and Apr 1, 2023, the data of 27 pts with TN FL who received G-CHOP (obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen and 7 R/R pts treated with GB (Obinutuzumab, bendamustine) regimen was collected. The demographic and clinical characteristics at baseline were shown in Table 1. The median age of TN pts was 52 years, and 63.0% were female. The efficacy evaluation of TN pts was displayed in Figure 1. All of 27 pts achieved partial response (PR) after 2 cycles of GCHOP regimen. Eventually, 21 patiens completed 6 cycles of treatment, with 95.5% (21/22) assessed as complete response (CR) and 4.5% (1/21) maintaining PR. Three pts discontinued treatment due to COVID-19 infection and 2 for severe infections of other reasons. The end of treatment (EOT) ORR was 100% and the BOR of 96.3% (26/27) pts was assessed as CR. In 7 R/R pts, 5, 1 and 1 pts received 1, 2 and 3 lines of previous treatment regimens, respectively. The median age of this subgroup was 56 years. Totally, 6 pts achieved CR with an ORR of 85.7%, except for one pt who was evaluated as SD after 2 cycles of GB regimen and switched to another regimen. Two pts continued with maintenance therapy of obinutuzumab, and the rest 5 pts went on with autologous hematopoietic stem cell transplantation. By the end of follow-up, no pts showed progressive disease (PD) except for one who died of COVID-19 infection. All these pts in this study were infected with COVID-19 during the pandemic in China. For TN pts, mild, ordinary, severe and critical cases accounted for 14.8%, 44.4%, 29.6% and 11.1% respectively, and no pt died of COVID-19 infection. The median duration of COVID-19 infection was 23 (14-68) days, and over half of them were tested positive for more than 3 weeks. Of the R/R pts, 57.1% (4/7) presented severe, 14.3% (1/7) was critical and finally died of respiratory failure. The median duration of positive was 26 (21-95) days. Among pts treated wih GCHOP regimen, common grade 3-5 adverse events included infection (excluding COVID-19 infection) (25.9%) and hematological adverse events consisting of neutropenia (51.8%), thrombocytopenia (22.2%). Grade 3 infection, neutropenia and thrombocytopenia were observed in 14.3% (1/7) R/R pt each. The median follow-up time of TN pts and R/R pts was 8.9 (12.1-13.7) months and 11.7 (11.2-14.0) months, respectively. The median PFS of both was not achieved, 1-year PFS rate was 100% and 85.7% in TN and RR pts, respectively. Conclusions This real-world analysis with small sample size indicates that similar efficacy and toxicity was observed in Chinese patients with FL who were treated with obinutuzumab-based immunochemotherapy to that reported in literature. However, it is noteworthy that long-lasting immunosuppression may result in higher incidence and severity of COVID-19 infection in these patients compared to the general population.

Real-World Outcomes of Zanubrutinib Monotherapy in Chronic Lymphocytic Leukemia: A Multicenter Retrospective Study

Background The second-generation Bruton's Tyrosine Kinase inhibitor (BTKi) zanubrutinib had better BTK specificity and less off-target inhibition than first-generation BTKi ibrutinib. SEQUOIA study demonstrated superior efficacy of frontline zanubrutinib than bendamustine-rituximab combination, and ALPINE study showed improved overall response rate (ORR) and progression free survival (PFS) of zanubrutinib than ibrutinib in relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Meanwhile, adverse event (AE) remained one of the main reasons of zanubrutinib dose reduction and discontinuation. We previously reported the first real-world data of zanubrutinib monotherapy in Chinese CLL patients in our single center, demonstrating zanubrutinib discontinuation significantly deteriorated PFS and overall survival (OS). Herein, we reported the updated results to a multicenter scale, with a special focus on the impact of zanubrutinib dose reduction. Methods From Aug. 2020 to Mar. 2023, CLL pts received zanubrutinib monotherapy for at least 3 months in 7 medical centers in Shanghai were enrolled. Data cut-off time was Jul. 2023. AEs were evaluated and graded according to CTCAE 5.0 and IWCLL criteria. ORR included partial response with lymphocytosis or above. Results In total, 124 pts were enrolled and analyzed. 83 (66.9%) were treatment-naïve (TN) pts and 41 (33.1%) were R/R pts. Zanubrutinib was given 160mg, twice a day. The median age of zanubrutinib initiation was 68 years old (range, 37-87) with a M/F ratio of 2.1:1. Among evaluable pts, 25.0% had TP53 aberration (deletion and/or mutation) and 45.2% had unmutated IGHV. With a median follow-up time of 21.8 months, ORR of the entire cohort, TN and R/R pts were 93.5%, 96.4% and 87.8%, respectively. The estimated PFS and OS rates at 24 months in the entire cohort were 79.6% (95%CI 75.0-84.2%) and 94.2% (95%CI 91.9-96.5%). When stratified by line of therapy, the estimated 24-month PFS rates of TN and R/R pts were 82.7% (95%CI 77.5-87.9%) and 71.8% (95%CI 62.1-81.5%), and 24-month OS rates were 96.1% (95%CI 93.9-98.3%) and 89.1% (95%CI 83.1-95.1%), respectively. Pts with TP53 aberration had a trend of inferior PFS ( P=0.102), and pts received 1 st or 2 nd line zanubrutinib monotherapy had significantly longer PFS compared with 3 rd line or above ( P&amp;lt;0.001) (Fig.1A). No significant impact of gender, age, Binet or Rai stages, 11q deletion or IGHV mutation status on PFS or OS was observed. One hundred and two (82.3%) pts experienced AEs of any grade, and 30 (24.2%) pts experienced AEs of grade 3 or above. The most common grade 3 or above AEs were neutropenia (10.5%) and pneumonia (8.1%). Two pts (1.6%) experienced grade 2 atrial fibrillation. AEs of interest (AEI) are shown in Table 1. Overall, 21 (16.9%) pts had zanubrutinib dose reduction, and the most common reason was AE (61.9%). Zanubrutinib reduction was associated with both inferior PFS (Fig.1B) and OS. Nineteen (15.3%) pts had zanubrutinib discontinuation, and the most common reason was progressive disease (57.9%). Conclusion In our real-world study, the efficacy of zanubrutinib monotherapy in both TN and R/R Chinese CLL pts were slightly inferior to that of clinical trials. Pts receiving ≤ 2 nd line zanubrutinib monotherapy had significantly improved PFS. The toxicity spectrum was similar to data previously reported. Despite an improved safety profile, AE remained the main reason of zanubrutinib dose reduction, and dose reduction significantly associated with shorter PFS and OS. Therefore, better treatment strategies such as combined targeted therapy are required to improve the outcomes of these pts.