Relapse-free Survival Benefit Research Articles

Significance of Adjuvant Chemotherapy for Obstructive Colorectal Cancer After Stent Placement: A Multicenter Retrospective Study.

To explore the survival benefit of adjuvant chemotherapy for obstructive colorectal cancer (OCRC) managed by self-expandable metallic stent (SEMS) placement as a bridge to surgery (BTS). One hundred twenty-nine patients with pathological stage II/III OCRC who underwent BTS using a SEMS were included in this multicenter retrospective study. Patients were divided into the no-adjuvant chemotherapy group (No-Adj group) (n=52) and adjuvant chemotherapy group (Adj group) (n=77), and relapse-free survival (RFS) was compared. The No-Adj group had more fragile patient background factors, such as higher age, higher American Society of Anesthesiologists score, and lower preoperative albumin compared with the Adj group. The 3-year RFS rates for the overall cohort were significantly different between the No-Adj and Adj groups (56.4% and 78.5%, respectively; p=0.003). Significant RFS benefits of adjuvant chemotherapy were observed in both pathological stage II and III cancer. Characteristics of more advanced cancer, such as high carcinoembryonic antigen (CEA), pathological T4, and lymphovascular invasion, were associated with survival improvement by adjuvant chemotherapy. T4 and adjuvant chemotherapy were significantly associated with RFS in the multivariate Cox proportional analysis. To our knowledge, this is the first study to show a survival benefit of adjuvant chemotherapy in patients with OCRC undergoing BTS using a SEMS. Adjuvant chemotherapy is basically recommended regardless of the cancer stage and is strongly recommended with more advanced characteristics, such as high CEA, T4, and lymphovascular invasion.

Evaluation of the safety and efficacy of high-dose rate brachytherapy for radiorecurrent prostate cancer: asystematic review and meta-analysis.

High-dose-rate brachytherapy (HDR-BT) plays an important role in the treatment of locally recurrent prostate cancer after definitive treatment. The objective of this study is to summarize the efficacy and toxicity of HDR-BT in these patients. We performed asystematic review of PubMed and EMBASE from inception to July 2023. The primary endpoint was relapse-free survival (RFS) in different subgroups, and the secondary endpoint was gastrointestinal (GI) and genitourinary (GU) toxicity. Asemi-automated tool (WebPlotDigitizer) and anew Shiny application combined with Rsoftware (R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/ ) helped to reconstruct survival curves. Twenty-six studies met the inclusion criteria for quantitative analysis, including 1447 patients. Atotal of 761 patients from 13studies were included in survival reconstruction, and the median RFS time was 61.2 months (57.6-72.0months). The estimated 2‑, 3‑, and 5‑year rates were 75.9% (95% confidence interval [CI] 72.8 ~ 79.2%), 66.7% (95% CI 63.0 ~ 70.5%), and 52.3% (95% CI 47.5 ~ 57.4%), respectively. Whole-gland irradiation with multiple fractions (≥ 2F) resulted in better RFS compared with focal gland irradiation with fewer fractions (1F mostly; hazard ratio [HR]: 0.60, 95% CI 0.47-0.77, p < 0.0001). According to the different median time from primary treatment to salvage therapy (TRS) and median age at recurrence, short median TRS (56-67.2 months vs. 70-120 months; HR 0.52, 95% CI 0.68-0.40; p < 0.0001) and younger median age (60-70years vs. 71-75years; HR 0.58, 95% CI 0.46-0.74; p < 0.0001) were positive factors for RFS. The cumulative incidences estimated for grade ≥ 3 acute and late GU toxicities were 1% (95% CI 0 ~ 1%) and 5% (95% CI 4 ~ 7%), respectively. Three patients (3/992) experienced grade ≥ 3 late GI toxicity, and no cases of grade ≥ 3 acute GI toxicity were reported. HDR-BT has ahigh safety profile and good RFS benefit for salvage treatment of radiorecurrent prostate cancer. In terms of RFS, whole-gland irradiation with multiple fractions seems to be better than focal gland irradiation with fewer fractions, while short TRS and younger age are good prognostic factors. In view of the low level of evidence in the included studies and the large heterogeneity of each study, these conclusions still need to be confirmed by randomized controlled trials.

CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - a Single Center Retrospective Study

Title: CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - A Single Center Retrospective Study Introduction: Patients with Human Immunodeficiency Virus (HIV) are known to develop Lymphoma at a higher rate compared with the general population, with Diffuse Large B-Cell Lymphoma (DLBCL) being the most common subtype. Historically, before the advent of HIV treatment with antiretroviral therapy (ART), HIV-associated DLBCL was considered a more aggressive type of lymphoma and all patients were treated with central nervous system (CNS) prophylaxis. However, since ART has been widely adopted, there is some data to suggest that HIV-associated DLBCL among those taking ART more closely resembles de-novo DLBCL and may not need to be universally treated with CNS prophylaxis. There are no good prospective trials evaluating which patients who develop HIV-associated DLBCL while on ART should receive CNS prophylaxis. Furthermore, studies that tried to predict which DLBCL patients are at greater risk for CNS relapse explicitly excluded patients with HIV. Despite the absence of data, guidelines have shifted and current NCCN guidelines now recommend that HIV patients with DLBCL should be risk stratified as de-novo DLBCL patients with respect to CNS directed therapy. In this study, patients with HIV-associated DLBCL were retrospectively analyzed to understand the patterns of CNS prophylaxis and effects on relapse free survival. Methods: The Electronic Medical Record was queried at a large academic medical center in New York City for patients with HIV-associated DLBCL between the years of 2012 and 2021 using ICD-10 codes. Other subtypes of Lymphoma such as Burkitt's or Plasmablastic Lymphoma were excluded. Patients who did not receive their entire treatment course within the institution were also excluded. Clinical characteristics at diagnosis, treatment type, CNS prophylaxis, and survival data was collected and analyzed. Results: A total of 38 patients were identified according to the inclusion criteria. 26 patients (68%) underwent screening lumbar punctures (LPs) for CNS disease while 12 patients (32%) did not. The two groups were not statistically different within any categories except for LDH, where the LP group had a median LDH of 492 units/L and the non-LP group had a median LDH of 241 units/L (p-value: 0.031). The two groups were not statistically different in cell of origin subtypes, stage, bone marrow involvement, kidney/adrenal involvement, the use of ART prior to diagnosis, IPI or CNS-IPI scores. In addition, among the group that had an LP done with no CNS involvement (n=25), there was no statistical difference in relapse-free survival among those who received adequate CNS prophylaxis and those who did not (p-value 0.886). Conclusions: Among patients with HIV-associated DLBCL in a large academic medical center in New York City, there is no reliable indicator to predict which were offered screening lumbar punctures and which were not. Clinicians may be using additional measures of aggressiveness not accounted for in standard IPI and CNS-IPI scoring algorithms. Furthermore, there was no clear benefit in relapse free survival among high-risk patients who received adequate CNS prophylaxis versus those who did not in this limited sample size. Further research is needed to determine whether patients with HIV-associated DLBCL should be risk stratified similarly to de-novo DLBCL patients with respect to CNS prophylactic therapy.

Intraoperative computed tomography perfusion navigation for maximal resection of high grade gliomas: a prospective non-randomized trial

Background: The main purpose of surgery for glioblastoma is to ensure the maximally possible cytoreduction. Computed tomography perfusion imaging has non-invasive tools for assessment of tumor blood flow and allows for visualization of the tumor borders and its most malignant zones.&#x0D; Aim: To evaluate the efficacy of intraoperative computed tomography perfusion navigation (ICTPN) during surgery for high grade gliomas.&#x0D; Materials and methods: This prospective non-randomized study included 142 patients (76 men and 66 women) with morphologically verified diagnosis of glioblastoma or diffuse astrocytoma grade 4 (World Health Organization 2021 criteria), who had surgery from 2016 to 2022. The ICTPN-based procedures were performed in 94 patients, with 55 with gross total and 39 with subtotal tumor resection. The control group included 48 patients with non-ICTPN-based surgical procedures. All patients were treated with standard adjuvant chemoradiation therapy. The efficacy of surgery was assessed every 3 months. The study endpoint was any tumor progression. The duration of the follow-up was 15 months. Baseline and contrast-enhanced preoperative imaging and postoperative follow-up assessments were performed with a 3T magnetic resonance imaging scanner (General Electric Discovery W750). ICTPN was done with a 32 slice computed tomography scanner (Toshiba Aquilion LB).&#x0D; Results: In the totally resected ICTPN group, the mean duration of the relapse-free period was 13.05 months; the relapse-free survival at 6 and 12 months was 92 and 55%, respectively (p 0.001). These results were significantly better than those in the subtotally resected ICTPN patients (8.98 months, 66 and 9%, respectively; log rank test for Kaplan-Meier curves, p 0.001) and in non-ICTPN patients (5.81 months, 23 and 0%, respectively, log rank test, p 0.001).&#x0D; Conclusion: ICTPN enables a more objective assessment of the tumor borders and the extent of its resection, as well as relapse-free survival benefits for the patients.

Survival impact of immediate complete lymph node dissection for Chinese acral and cutaneous melanoma with micrometastasis in sentinel nodes: a retrospective study

Sentinel node biopsy (SNB) has become a critical part of standard surgical treatment for melanoma with no clinical metastatic evidence. However, for patients with a positive sentinel node, the MSLT-II and DeCOG-SLT trials have shown that immediate complete lymph node dissection (CLND) does not bring further survival benefits. There is still an argument among the Chinese population dominated by acral subtypes on whether CLND can be omitted. Thus, this study aims to investigate the impact of immediate CLND on relapse-free survival (RFS) in Chinese melanoma patients with a positive sentinel node. Patients with acral or cutaneous melanoma of clinical Stages I–II who received SNB procedure and were detected with nodal micrometastasis were retrospectively collected at Fudan University Cancer Center (FUSCC) from January 2017 to December 2021. The clinicopathologic features and prognostic factors for RFS were analyzed. Out of 381 patients who received SNB in the past 5 years, 130 (34%) cases with SN micrometastasis detected were included in this study. Ninety-nine patients underwent immediate CLND while the other 31 patients received observation alone. Among patients who received CLND, the non-SN(NSN)-positive rate was 22.2%. Most of the clinicopathologic factors were balanced well between the CLND and non-CLND groups. However, more patients in the CLND group were detected with BRAF and NRAS mutation (P = 0.006) and received adjuvant PD-1 monotherapy (P = 0.042) as well. There were slightly fewer N1 patients in the CLND group, although the difference did not reach statistical significance (P = 0.075). The study found no significant difference in RFS between the two groups (P = 0.184). Even for patients with the acral subtype (P = 0.925), primary T4 lesion (P = 0.769), or presence of ulceration (P = 0.249), immediate CLND did not bring more survival benefits. Immediate CLND did not bring further RFS benefit for Chinese melanoma patients with SN micrometastasis in real-world clinical practice, even for patients with acral subtype or more tumor burden such as thick Breslow invasion and ulceration.

The impact of response-directed surgery and adjuvant therapy on long-term survival after neoadjuvant ipilimumab plus nivolumab in stage III melanoma: Three-year data of PRADO and OpACIN-neo.

101 Background: Neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) has been shown to induce high pathologic response rates associated with an excellent relapse-free survival (RFS) in high-risk stage III melanoma. While OpACIN-neo tested different neoadjuvant IPI + NIVO regimens followed by therapeutic lymph node dissection (TLND) without adjuvant systemic therapy (ST), PRADO tested a personalized approach. In patients (pts) achieving a major pathologic response (MPR; ≤10% viable tumor), TLND and adjuvant ST were omitted, and pts with pathologic non-response (pNR; &gt;50% viable tumor) were treated with adjuvant ST (BRAFi/MEKi or anti-PD1) ± radiotherapy after TLND. Here, we address 1) whether omitting TLND in MPR pts had an adverse effect on long-term survival and 2) whether adding adjuvant ST in pNR pts had a favorable effect on survival. Methods: The 3-year (3y) RFS and distant metastasis-free survival (DMFS) of pts with MPR and pNR from PRADO and OpACIN-neo were analyzed, comparing MPR pts with TLND versus without TLND and pNR pts with adjuvant ST versus without adjuvant ST. Survival rates were calculated and compared with Kaplan-Meier and log-rank methods. Associations between baseline characteristics and RFS or DMFS were examined by Cox regression analysis. Results: Median follow-up was 37.9 months in PRADO (cutoff Jan 8, 2023) and 46.8 months in OpACIN-neo (cutoff Feb 14, 2022). For MPR pts, TLND omission did not affect survival, with a 3y RFS of 93% versus 96% (p=0.47) and 3y DMFS 98% versus 98% (p=0.92) for pts without TLND (n=59) versus with TLND (n=53), respectively. In pNR pts, an indication for a RFS and DMFS benefit was seen favoring pts with adjuvant ST (n=17: n=10 BRAFi/MEKi and n=7 anti-PD1) over pts without adjuvant ST (n=23), with 3y RFS rates being 64% versus 35% (p=0.10) and 3y DMFS rates 70% versus 52% (p=0.24). Baseline clinical characteristics did not differ between PRADO and OpACIN-neo pts or were not associated with RFS and DMFS. Conclusions: Omitting TLND in MPR pts after neoadjuvant IPI + NIVO seems not to affect RFS/DMFS. Given the high survival rates, adjuvant ST is unlikely to give further benefit in these pts. In pts with pNR, addition of adjuvant ST with ongoing anti-PD1 or switch to BRAFi/MEKi appears to improve RFS and DMFS. Clinical trial information: NCT02977052 . [Table: see text]

Efficacy of Therapy vs Surveillance in Patients with Resected Early-Stage Intermediate to High-Risk Renal Cell Carcinoma

BACKGROUND: The historical standard of care for locally advanced renal cell carcinoma (RCC) is nephrectomy + active surveillance. Despite a high recurrence rate ( 40%), adjuvant therapy was previously not included in the standard of care. This review of adjuvant pharmacotherapy reflects conflicting results from multiple trials. OBJECTIVE: The objective of this review is to summarize the efficacy of therapy vs surveillance in resected early-stage intermediate to high-risk renal cell carcinoma. METHODS: We performed a systematic literature search using PubMed, EMBASE, and SCOPUS. Keywords such as “renal cell carcinoma”, “adjuvant therapy” and “nephrectomy” were used. In the literature search, 2,711 studies were identified and screened. RESULTS: We included a total of 21 publications. The most common histology seen in trials was clear cell carcinoma. A variety of interventions were reviewed including immunotherapy, medroxyprogesterone acetate, interferon alfa, and tyrosine kinase inhibitors. Most trials did not demonstrate a benefit in relapse-free survival (RPS) or overall survival (OS). Pembrolizumab demonstrated a significant difference in disease recurrence in the KEYNOTE-564 trial although median data was not reached. Blinded independent reviewers identified a benefit in disease-free survival (DFS) with Sunitinib in the S-TRAC trial. CONCLUSION: There was not a clear benefit in using adjuvant therapy broadly for resected locoregional RCC; however, further investigation should be done in the highest-risk group to elucidate potential benefit.

Multiparameter Flow Cytometry-Based Residual Disease Analysis Identifies Intermediate-Risk AML Patients Who May Benefit from Allogeneic Hematopoietic Stem Cell Transplantation

Background Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative therapeutic modality in acute myeloid leukemia (AML). While numerous studies have confirmed the benefit of alloSCT - improved overall survival (OS) and reduced cumulative incidence of relapse (CIR) - restricted mainly to the intermediate and high-risk groups, indications for alloSCT are becoming more restricted over time. Residual disease (RD) monitoring has been proven to be highly predictive of long-term AML outcomes and is now used commonly to guide ongoing therapy decisions. RD-based guidelines in AML propose the use of multiparameter flow cytometry-based RD (FRD) analyses in patients whose disease cannot be followed by molecular means (e.g. CBF AML, APL, NPM1-mutated AML). Methods We performed a retrospective review to evaluate the potential therapeutic benefit of alloSCT in AML patients who achieved first complete remission (CR1) and to further define this benefit based on the FRD status at remission. We performed a time-dependent analysis using the covariate of time-to-alloSCT as the primary endpoint of the study. The Mantel-Byar method was applied to compare time to event between the alloSCT and non-transplant groups, addressing time bias concerns that occur with alloSCT studies, according to the FRD status at the time of remission. Results The FRD assay has been part of our standard of care since 2015 with a sensitivity of 0.1%. The cohort analyzed included 435 patients treated between 2015 and 2018, of which 336 patients had FRD assessment at CR1. The patients were risk classified using the European Leukemia Network (ELN) 2017 classification which integrates cytogenetic and mutational analyses. The proportion of patients with positive FRD (RDpos) at the post-induction time-point was 35.1% (n=118). Negative residual disease (RDneg) status after induction occurred more frequently in de novo, favorable risk, and NPM1-mutated AMLs, than in the adverse risk or secondary AML groups. Overall, across all ELN 2017 groups, the impact of alloSCT was neutral for both OS and relapse free survival (RFS). A potential impact of alloSCT could be discerned, however, when patients were grouped by FRD status at CR assessment. Overall, in the RDpos group, alloSCT improved OS and RFS, while not benefitting the RDneg group. The impact of alloSCT was defined further by considering ELN 2017 risk groups, with an OS/RFS benefit observed in adverse risk patients (n=186; HR for OS 0.55 [0.31-0.99]; p=0.05); HR for RFS 0.57 [0.31-1.05], p=0.07), while an increased risk of death or of an RFS event was seen in favorable risk patients (n=151; HR for OS 4.3 [1.65-11.2], p=0.003; HR for RFS 2.29 [1.07-4.93], p=0.03). In the ELN 2017 intermediate risk patients (n=98), a survival benefit of alloSCT was not seen (HR for OS 1.05 [0.45-2.46], p=0.92; HR for RFS 0.86 [0.42-1.78], p=0.69), although alloSCT was associated with a lower CIR (HR 0.43 [0.20-0.90], p=0.03). However, when only RDpos patients were considered (n=27), trends towards benefit from alloSCT in OS (HR 0.52 [0.11-2.52], p=0.42), RFS (HR 0.38 [0.09-1.62], p=0.19), and CIR (HR 0.44 [0.07-2.72], p=0.38) were observed. In RDneg patients (n=53), alloSCT was associated only with a lower CIR (HR 0.18 [0.05-0.66], p=0.01). We then re-analyzed the data using the older UK-MRC risk classification of AML based exclusively on cytogenetics at diagnosis. This approach increased the patients in the intermediate group from 98 (ELN 2017) to 298 (UK-MRC). When using UK-MRC, an RFS benefit from alloSCT was observed for intermediate risk RDpos patients (n=211; HR 0.44 [0.20-0.96], p=0.04). Trends for benefit in OS (HR 0.45 [0.19-1.03], p=0.06) and CIR (HR 0.45 [0.20-1.04], p=0.06) were observed as well. In RDneg patients, however, an RFS/CIR benefit of alloSCT was not observed, while inferior OS was seen in the alloSCT group from increased non-relapse mortality. Conclusion Our data underscore the established benefit of alloSCT in adverse risk AML and suggest a potential benefit of this treatment modality in RDpos intermediate risk patients, thus confirming the utility of ongoing RD assessment in AML. Our results also indicate that ongoing sophistication in AML risk assignment, based on mutational profile at diagnosis, influences the potential benefit of alloSCT. Further studies are needed to better define the subgroup of RDpos intermediate risk patients who may benefit from alloSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Major clinical benefit from adjuvant chemotherapy for stage II–III non-small cell lung cancer patients aged 75 years or older: a propensity score-matched analysis

BackgroundData are currently insufficient to support the use of adjuvant chemotherapy (ACT) after surgical resection for stage II or III non-small cell lung cancer (NSCLC) in patients aged ≥ 75 years. In this study we evaluated efficacy and safety profile of ACT in this population.MethodsWe retrospectively evaluated 140 patients ≥ 75 years who underwent curative surgical resection for stage II–III NSCLC from 2010 to 2018 with an indication to ACT according to current guidelines. A propensity score-matched analysis was performed to avoid cofounding biases.ResultsThirty of 140 patients (21%) received ACT. Most patients (n = 24, 80%) received carboplatin in combination with vinorelbine, while 5 patients (17%) received cisplatin plus vinorelbine and one patient (3%) carboplatin plus gemcitabine. The occurrence of adverse events led to treatment discontinuation in 8 (27%) cases, while 19 (63%) patients completed 4 chemotherapy cycles. Common reported adverse events with ACT were anemia (n = 20, 67%), neutropenia (n = 18, 60%), thrombocytopenia (n = 9, 30%), renal impairment (n = 4, 13%) and transaminase elevation (n = 4, 13%). No toxic deaths occurred. The median follow-up was 67 months (IQR: 53–87). ACT was associated with a significant benefit in both relapse-free survival (median 36 vs. 18.5 months, p = 0.049) and overall survival (median not reached [NR] vs. 33.5 months, p = 0.023) in a propensity score-matched analysis which controlled for cofounders.ConclusionACT confers a survival benefit after curative resection of stage II–III NSCLC in selected patients aged 75 years or older with a manageable toxicity profile.

Platinum-based adjuvant therapy was efficient for triple-negative breast cancer: a meta-analysis from randomized controlled trials

ABSTRACT Triple-negative breast cancer (TNBC) is the most aggressive breast cancer. Neoadjuvant chemotherapy was widely accepted for treating TNBC. This systematic review and meta-analysis aimed to evaluate the efficacy, safety, and survival benefit of platinum-based adjuvant therapy (PBAT) in treating TNBC. The keywords were searched in Medline, Embase, Pubmed, and Cochrane Library database up to July 24, 2022. All the randomized control trials (RCTs) comparing PBAT and non-PBAT in treating TNBC were included in our study. The pathological complete remission (pCR) and complications were compared by odds ratio (OR) and 95% confidence intervals (CIs). The overall survival (OS) and relapse-free survival (RFS) were compared by hazard ratio (HR) and 95% CIs. A total of 19 RCTs were included in our meta-analysis, among which 2,501 patients were treated with PBAT and 2,290 with non-PBAT. The patients treated with PBAT combined a significantly higher pCR rate compared to those patients treated with non-PBAT (49.8% versus 36.4%, OR = 1.27, 95%CI = 1.14–1.43, P < 0.001). Besides, patients treated with PBAT had a significantly better RFS (HR = 0.78, 95%CI = 0.63–0.95, P = 0.016), but not in OS (HR = 0.84, P = 0.304). Although the occurrence of neutropenia and nausea were slightly different between the PBAT group (51.5% and 24.4%) and the non-PBAT group (47.0% and 29.4%), the complications were acceptable in the two treatments groups. Our results demonstrated that TNBC patients treated with PBAT could achieve a higher pCR rate and better RFS benefit without a higher complication rate. Highlights Platinum-based adjuvant therapy provided a higher pCR rate for TNBC. Platinum-based adjuvant therapy prolonged the RFS but without prolongingthe OS. Neutropenia and nausea rate was different between group PBAT and non-PBAT.

Systemic adjuvant therapy for high-risk cutaneous melanoma.

Cutaneous melanoma continues to increase in incidence and poses a significant mortality risk. Surgical excision of melanoma in its early stages is often curative. However, patients with resected stages IIB-IV are considered at high risk for relapse and death from melanoma where systemic adjuvant therapy is indicated. The long-studied high-dose interferon-α was shown to improve relapse-free survival (RFS) and overall survival (OS) but is no longer in use. Adjuvant therapy with ipilimumab at 10 mg/kg (ipi10) demonstrated significant RFS and OS improvements but at a high cost in terms of toxicity, while adjuvant ipilimumab 3 mg/kg was shown to be equally effective and less toxic. More recently, the adjuvant therapy for resected stages III-IV melanoma in clinical practice has changed in favor of nivolumab, pembrolizumab, and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutant melanoma) based on significant improvements in RFS as compared to ipi10 (nivolumab and pembrolizumab) and placebo (dabrafenib plus trametinib). For resected stages IIB-IIC melanoma, pembrolizumab achieved regulatory approval in the United States based on significant RFS benefits. In this article, we review completed and ongoing phase III adjuvant therapy trials. We also briefly discuss neoadjuvant therapy for locoregionally advanced melanoma. Finally, we explore recent studies on predictive and prognostic melanoma biomarkers in the adjuvant setting.

Efficacy and safety of adding gemtuzumab ozogamicin to conventional chemotherapy for adult acute myeloid leukemia: a systematic review and meta-analysis

ABSTRACT Introduction: Compared with the 3 + 7 regimen, the addition of gemtuzumab ozogamicin (GO) has improved survival in patients with acute myeloid leukemia (AML). We conducted a systematic review and meta-analysis to examine the overall efficacy and safety of GO in combination with conventional chemotherapy regimens in patients with AML. Methods: We searched several databases (MEDLINE, Embase, Web of Science and Cochrane Library). Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for overall survival (OS) and relapse-free survival (RFS); odds ratios (ORs) with 95% CIs were calculated for the other outcomes. Results: Ten records involving 11 randomized controlled trials (RCTs) met the inclusion criteria. GO plus induction chemotherapy significantly increased RFS (HR: 0.84, 95% CI: 0.73–0.98), decreased the incidence of relapse (OR: 0.78, 95% CI: 0.68–0.91) and resistant disease (OR: 0.72, 95% CI: 0.61–0.84), and had no significant effect on the rate of complete remission (CR) with or without incomplete platelet recovery (OR: 1.21, 95% CI: 0.94–1.55), 30-day mortality (OR: 1.25, 95% CI: 0.99–1.57). Subgroup analysis showed significant OS benefits for patients with favorable cytogenetic (HR: 0.50, 95% CI: 0.28–0.89) or given GO at induction stage (HR: 0.91, 95% CI: 0.84–1.00). Compared with other dosing schedule groups, 3 mg/m2 fractionated schedule had a greater RFS benefit (HR: 0.52, 95% CI: 0.36–0.76) and lower relapse risk (OR: 0.48, 95% CI: 0.28–0.84). Conclusions: Adding low-dose GO to induction or both induction and post-remission chemotherapy has considerable efficacy and unequivocal safety for newly diagnosed adult AML.

Impact of Post-Remission Maintenance Therapy (MT) on Outcomes in Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) in Real-World Practice

INTRODUCTION: Therapeutic advances have led to improved survival outcomes in patients (pts) with AML. Consolidation therapy helps to eradicate residual leukemia and prevent relapse. However, relapse remains a major concern and contributes to suboptimal outcomes in pts with newly diagnosed AML who attain remission following induction chemotherapy (IC). Strategies for maintenance therapy (MT) attempt to prolong AML remission and extend survival. MT approaches have included chemotherapy, hypomethylating agents (HMAs), and targeted small-molecule drugs. Overall, the evidence in favor of MT is limited. The oral formulation of azacitidine (Oral-AZA), an HMA, is the first and only MT to demonstrate significant overall survival (OS) and relapse-free survival (RFS) benefits in pts with a broad range of AML subtypes (Wei, NEJM 2020), leading to regulatory approvals in the United States (2020), Canada (2021), and European Union (2021). This study aimed to determine in real-world practice whether the use of MT after IC, with or without consolidation, conferred any clinical advantage before Oral-AZA became available.METHODS: This study included pts in the US-based Flatiron TM Health cancer-specific electronic health record-derived database diagnosed with AML between January 2014 and December 2020. Eligible pts in this study obtained remission (< 5% bone marrow blasts) from first-line (1L) induction chemotherapy or venetoclax (VEN)-based therapy, had not previously taken Oral-AZA or any clinical study drug, and did not undergo transplant prior to relapse. Pts were grouped into 2 cohorts: Cohort A comprised pts who did not receive MT, and Cohort B comprised pts who did receive MT. RFS and OS were estimated using Kaplan-Meier (KM) methods. Multivariate Cox regression models that retained baseline (BL) characteristics (age, sex, BMI, ECOG performance status [PS], and cytogenetic risk) were used to examine the relationships between use of MT and relapse (> 5% bone marrow blasts), and MT and survival.RESULTS: A total of 952 pts met the selection criteria: 808 pts (84.9%) in Cohort A and 144 pts (15.1%) in Cohort B. The most commonly received MTs for pts in Cohort B were injectable AZA (34.7%; n = 50), decitabine (24.3%; n = 35), and VEN-based regimens (21.5%; n = 31). Cohorts A and B were comparable for sex, BL BMI, ECOG PS score, and practice type (Table). Pts who did not receive MT (Cohort A) were younger (mean age 62.1 vs 66.0 years; P = 0.006) and more commonly presented with favorable cytogenetic risk (17.2% vs 6.9%; P = 0.011) compared with pts who received MT (Cohort B).The percentage of pts receiving IC in a 7+3 regimen was similar between Cohort A and Cohort B (69.1% vs 67.4%, respectively; P = 0.685), as were the proportions of pts receiving VEN + an HMA (23.3% vs 17.4% P = 0.118).The KM analysis indicated that although median RFS of Cohort A was longer than Cohort B, differences between cohorts were not statistically significant (303 vs 276 days, P = 0.175). In a subanalysis of pts with intermediate/poor cytogenetic risk, median RFS was 201 days for Cohort A and 230 days for Cohort B (P = 0.952). In the multivariate Cox model, treatment with MT was not a significant predictor of improved RFS vs no MT (hazard ratio [95% CI]: 0.97 [0.79, 1.20]). Age and cytogenetic risk were significantly associated with RFS.The median OS was 659 days for Cohort A and 389 days for Cohort B (P = 0.006). In the subanalysis excluding pts with favorable or unknown cytogenetic risk, median OS was 400 days for Cohort A and 366 days for Cohort B (P = 0.561). A multivariate Cox regression model suggested that treatment with MT was not a significant predictor of improved OS (hazard ratio [95% CI]: 0.88 [0.70, 1.10]). Age, sex, ECOG PS, and cytogenetic risk were all significantly associated with OS.CONCLUSIONS: These Flatiron data provide real-world evidence that despite decades of study, optimal MT in AML had remained elusive. Prior to approval of Oral-AZA, the most common MT options for pts with AML in first remission after 1L induction therapy were limited and appeared to lack clinical benefit. Pts with AML need an MT that prolongs remission and improves long-term survival. Further research is needed to elucidate the benefits and disadvantages of different MT options and may lead to establishment of optimal MT as standard of care. [Display omitted] DisclosuresPotluri: Bristol Myers Squibb: Consultancy. Rotter: SmartAnalyst Inc.: Current Employment. Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Measurable Residual Disease Status and FLT3 Inhibitor Therapy in Patients with FLT3-ITD Mutated AML Following Allogeneic Hematopoietic Cell Transplantation

BACKGROUNDMeasurable residual disease (MRD) is associated with increased risk of relapse and death in acute myeloid leukemia (AML), even after allogeneic hematopoietic cell transplantation (HCT). Recently, next-generation sequencing (NGS) has emerged as a sensitive and specific method to detect MRD from both bone marrow and peripheral blood. NGS methods are particularly useful for detecting internal tandem duplication mutations of the FMS-like tyrosine kinase 3 gene (FLT3-ITD), which define a subgroup of AML patients who may be at higher risk for relapse and who often undergo consolidative allogeneic HCT. The SORMAIN trial recently reported a highly significant relapse-free survival benefit for the first generation FLT3 inhibitor sorafenib as post-HCT maintenance, particularly among patients with detectable MRD following HCT.In 2019 our program initiated prospective FLT3-ITD monitoring by NGS using a commercially available assay (Invivoscribe, Inc., San Diego, CA) of the peripheral blood or bone marrow throughout the first three months following HCT for all patients with FLT3-ITD mutated AML undergoing HCT. We encouraged but did not mandate FLT3 inhibitor use, regardless of MRD status. In this study, we describe the clinical impact of sensitive FLT3 MRD testing early after HCT, maintenance FLT3 inhibitor use in a non-clinical trial setting, and the ability of early post-HCT FLT3 inhibitor therapy to modify transplant outcomes. RESULTSThirty-six adults with FLT3-ITD mutated AML underwent HCT at Stanford University between April 2019 and August 2020 and were included in this observational study (Table 1). These patients were not enrolled in clinical trials evaluating FLT3 inhibitor therapy after HCT. Twenty-nine (81%) received pre-HCT FLT3 inhibitors, and 78% were in first complete remission (CR1) at HCT. Median follow up after HCT was 14.0 months (range 4.6-25.7). Two patients were excluded from subsequent analyses due to early graft failure and receipt of azacitadine/enasidenib maintenance, respectively. Of the evaluable cohort, 9 (26%) experienced clinical relapse at a median of 4.2 months after HCT (range 1.8-6.1), and 10 (29%) died, 5 from transplant-related mortality and 5 from AML (Figure 1A and B).Of the 34 patients evaluable for post-HCT MRD analysis, 10 (29%) had detectable MRD within the first three months while 24 (71%) remained MRD-negative (Figure 2A and B). Although there was a trend towards inferior progression-free survival (PFS) for patients with early post-HCT MRD (p = 0.13, Figure 3A), OS was not significantly impacted by MRD (p = 0.35, Figure 3B). Among the four patients with early post-HCT MRD negativity who ultimately relapsed, only one was FLT3-negative at time of relapse.Twenty-four patients (71%) received FLT3 inhibitor maintenance, initiated a median of 2.8 months after transplant (range 0.7-17.1), and the median duration was 10.6 months (range 1.7-23.7). The most common FLT3 inhibitor used was gilteritinib (n = 15), followed by midostaurin (n = 9), and sorafenib (n = 5). Among the 10 patients (29%) who did not receive post-transplant maintenance, reasons included graft-versus-host disease (GVHD) (n = 4), clinician decision (n = 3), cytopenias (n = 2), and thrombotic microangiopathy (n = 1). The use of maintenance FLT3 inhibitors led to a significantly superior PFS and OS (Figure 3C and D). Interestingly, the use of early FLT3 inhibitors post-HCT augmented PFS and OS in both MRD-negative and MRD-positive patients (Figure 3E and F), and effectively prevented clinical relapse in four patients with post-HCT MRD positivity (Figure 2A). CONCLUSIONIn this cohort study, we evaluated the clinical utility of sensitive post-transplant MRD monitoring and maintenance FLT3 inhibitors on transplant outcomes. We demonstrate that clinical relapse can be prevented even in patients with post-HCT MRD through the incorporation of early FLT3 inhibitors. This finding is in keeping with the results from the SORMAIN trial. We also found that real-time sensitive MRD results allowed clinicians to begin early initiation of FLT3 inhibitor therapy, which positively affected outcomes. [Display omitted] DisclosuresMannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Muffly: Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy.

Autologous Stem Cell Transplant Outcome in Classic Hodgkin Lymphoma Patients in the Era of Post-Transplant Brentuximab Vedotin Consolidation

Introduction:Patients newly diagnosed with classic Hodgkin lymphoma (CHL) have over 80% chance of remission with first-line chemotherapy, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regime. However, 10-40% of patients relapse eventually and require salvage therapy. High-dose therapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed or refractory CHL, offering a cure rate of around 50%. This may be further improved to around 60% with post-transplant consolidation with brentuximab vedotin (BV). Post-SCT BV consolidation has been offered to all patients, regardless of the risk group, in British Columbia since late 2015. We set out to review the ASCT outcome in CHL patients in the recent decade at our institution.Methods:All adult patients who received ASCT for relapsed or refractory CHL between July 2011 and June 2020 were included in this retrospective analysis. Information pertaining to their demographics, disease characteristics, treatment history, transplant details, clinical outcomes and post-relapse therapy was obtained by review of electronic data. The data cut-off date was June 28, 2021. Survival outcomes were censored at the last known clinic visit for patients without relapse or death during follow up. Survival analysis was performed using Kaplan-Meier survival function and log-rank test. Pearson's chi-square test and ANOVA were used for comparison between cohorts. The statistical program used was Stata® version 16.1 (Texas, USA).Results:114 patients underwent ASCT for relapsed/refractory CHL. Bulky disease and extranodal involvement were seen in 11% and 40% respectively at relapse. Looking at the ‘high risk criteria’ as defined in the AETHERA trial: 45/114 (40%) patients had primary refractory CHL, 21/114 (18%) had relapsed within 12 months of completing the front-line chemotherapy and 15/114 (13%) had relapsed beyond one year of completing initial treatment but with an extranodal disease.The most commonly used salvage chemotherapy regime was GDP (gemcitabine, dexamethasone, cisplatin; 111/114; 97%). 10/114 (9%) patients received BV after failing salvage chemotherapy pre-SCT. The median number of lines of therapy pre-SCT was two (range 2-5). 94/108 (98%) had a chemosensitive disease with 35/108 (32%) achieving complete remission. 6/108 (6%) patients had a progressive disease at the time of SCT. For the transplant, all patients had a peripheral blood stem cell source and the conditioning regime was either Carmustine/Etoposide/Cytarabine/Melphalan (76%) or Etoposide/Melphalan (24%).After median follow up of 62.2 months, 50/114 (44%) patients relapsed with median relapse-free survival of 20.2 months (range 0.9 - 113.5) and 16/114 (14%) died. The direct cause of death was lymphoma progression in all but three patients (PJP pneumonia, pulmonary fibrosis, traumatic subdural hematoma).Whereas only 4/51 (8%) patients (2 without relapse) received post-SCT BV consolidation via a compassionate access program between July 2011 and October 2015 (cohort 1), 45/63 (71%) patients (33 in remission) received routine BV consolidation between November 2015 and June 2020 (cohort 2). In cohort 2, 44% had primary refractory CHL compared to 33% in cohort 1 but the number of ‘low risk’ patients was similar at 29% (Table 1). The most common reason for no post-SCT BV consolidation in cohort 2 was patient refusal (7/18; 40%). Other causes included BV pre-SCT, early disease progression and patient comorbidities. Only 9/42 (21%) patients with available data in cohort 2 completed the planned 16 cycles of BV consolidation. The median number of cycles was 10.5 (range 1-16). The most common reasons for early termination of BV consolidation were peripheral neuropathy (22/33; 67%) and disease progression (9/33; 27%). There was no statistically significant difference in PFS or OS demonstrated between the two cohorts (Graphs 1, 2).Conclusion:After median follow up of 5 years, 86% of patients remain alive and 56% are alive in remission. In British Columbia, post-SCT BV consolidation has been widely adopted with over 70% of patients receiving at least one cycle since late 2015. Successful completion of post-SCT BV consolidation is, however, limited by a high rate of treatment-limiting peripheral neuropathy. Relapse-free survival benefit of routine post-SCT BV consolidation is not demonstrated in this single-centre cohort. [Display omitted] DisclosuresWhite: Novartis: Honoraria. Sutherland: Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy; Amgen: Consultancy. Sanford: Abbvie: Membership on an entity's Board of Directors or advisory committees; Stellar: Membership on an entity's Board of Directors or advisory committees. Abou Mourad: Amgen: Consultancy; Paladin: Consultancy; Pfizer: Consultancy. Song: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria.

1075P Regression tree analysis to identify factors associated with relapse-free survival (RFS) in patients with resected stage III BRAF V600E/K–mutant melanoma

The 5-y analysis of the Phase III COMBI-AD trial (NCT01682083) showed long-term RFS benefit with 12 months of adjuvant dabrafenib (dab) plus trametinib (tram) vs placebo (pbo) in patients with resected stage III BRAF V600E/K–mutant melanoma (5-y RFS rate, 52% vs 36%; hazard ratio, 0.51 [95% CI, 0.42-0.61]). A prior regression tree analysis (median follow-up in the dab + tram arm, 44 mo) evaluated 13 patient and clinical characteristics to identify treatment type (dab + tram vs pbo), disease stage, and age as predictive of long-term benefit.

Autologous Transplantation Is Associated with Better Outcomes Compared to Chemotherapy Alone in a Minority-Rich Non-High-Risk Acute Myeloid Leukemia Cohort

Background:The role of autologous stem cell transplantation (autoSCT) in non-high-risk acute myeloid leukemia (AML) is controversial. It remains a frequent consolidation alternative for AML in first complete remission (CR1) in Europe and Asia, especially for intermediate risk disease, but has fallen out of favor over allogeneic transplantation (alloSCT) in the United States (U.S.). Donor availability, however, affects feasibility of alloSCT in ethnic and racial minorities that remain disproportionately underrepresented in donor registries. We explored the survival experience in our predominantly minority non-high-risk AML patients treated with autoSCT in comparison to those treated with chemotherapy alone, the current standard of care in the U.S. for favorable-risk AML as well as for intermediate-risk disease when alloSCT is not available.Methods:All adult patients diagnosed with AML between the years 1997 - 2015 were identified within the Montefiore Medical System in the Bronx, NY. For the purpose of our analysis we only included AML cases with favorable or intermediate cytogenetic risk that received induction with aggressive chemotherapy, achieved CR1 and underwent consolidation with high-dose chemotherapy alone or chemotherapy followed by autoSCT. We used descriptive statistics to compare baseline characteristics of patients treated with one of the two consolidation modalities. We used the Kaplan Meier survivor function to compare overall survival (OS) and relapse-free survival (RFS) between the two groups and multivariable Cox Proportional Hazard models to adjust for key covariates.Results:We identified 149 newly diagnosed adult AML cases with favorable (n=14) or intermediate-risk (n=135) cytogenetic risk. Among the 126 patients treated with aggressive chemotherapy, 96 (76%) achieved CR1 after induction chemotherapy, among which 10 experienced early relapse, 3 were lost to follow up and 83 proceeded to consolidation with either high-dose chemotherapy alone (n=58) or chemotherapy followed by autoSCT (n=25).The cohort was predominantly non-white (n=50/83, 60%). The median age was 57 years. Distribution of age, sex, race and cytogenetic-risk was similar between the two treatment groups (table 1). Median follow up was 17.7 months.Median OS was significantly longer for patients consolidated with autoSCT compared to those treated with chemotherapy alone (1.9 vs. 1.2 years; p=0.046). Recipients of autologous transplantation also had longer RFS compared to those consolidated with chemotherapy alone (1.6 vs. 0.6 years; p<0.01) (Figure 1). No treatment-related deaths were observed in the autoSCT group.In multivariable analysis adjusted for age, sex, race and cytogenetic risk, patients who underwent consolidation with autoSCT had a significantly better OS (HR 0.28; 95%CI 0.11 - 0.72; p<0.01) and RFS (HR 0.20; 95%CI 0.09 - 0.45; p<0.001) compared to those treated with chemotherapy alone.Conclusions:In this minority-rich non-high-risk AML cohort, we showed that consolidation with autologous transplantation provided OS and RFS benefit compared to chemotherapy alone. Survival rates in our multiethnic cohort were comparable to those historically reported in predominantly white AML cohorts. Autologous transplantation remains a beneficial treatment option in non-high risk AML in first remission and is a particularly valuable therapeutic strategy for ethnic/racial minorities when an allogeneic donor is not available. Integration of minimal residual disease assessment may help refine the selection of those more likely to benefit from this approach. [Display omitted] DisclosuresSteidl:Novartis: Research Funding; Aileron Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy; Bayer Healthcare: Consultancy.

Prognostic factors of overall (OS) and relapse-free survival (RFS) for patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy (IC): Multivariate analyses from the QUAZAR AML-001 trial of oral azacitidine (Oral-AZA).

7014 Background: Demographic and disease factors influence outcomes for patients (pts) with AML. In the phase 3 QUAZAR AML-001 trial, Oral-AZA significantly prolonged OS and RFS vs. placebo (PBO) for pts with AML in first remission after IC (Wei, NEJM, 2020). Univariate analyses showed OS and RFS benefits with Oral-AZA vs. PBO across pt subgroups defined by baseline (BL) characteristics. MV analyses were performed to identify BL characteristics independently predictive of OS/RFS in QUAZAR AML-001, and to assess Tx effects of Oral-AZA vs. PBO on survival when adjusted for BL factors. Methods: Pts were aged ≥55 yrs with AML in complete remission (CR) or CR with incomplete count recovery (CRi) after induction ± consolidation. Within 4 months of CR/CRi, pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO for 14d/28d cycle. Cox proportional hazards models were used to estimate Tx effects of Oral-AZA vs. PBO on OS and RFS, adjusting for BL age, sex, ECOG PS score, cytogenetic risk at diagnosis (Dx), prior MDS, geographic region, CR/CRi after induction (per investigator) and at BL (per sponsor), MRD status, receipt of consolidation, number of consolidation cycles, platelet count, and ANC. In a stepwise procedure, randomized Tx and BL variables were selected incrementally into a Cox model if P ≤ 0.25. After each addition, the contribution of the covariate adjusted for other covariates in the model was evaluated and retained in the model if P ≤ 0.15. Results : Oral-AZA Tx remained a significant independent predictor of improved OS (HR 0.70) and RFS (HR 0.57) vs. PBO after controlling for BL characteristics (Table). MRD status, cytogenetic risk, and pt age were each also independently predictive of OS and RFS. Response after induction (CR vs. CRi) and BL ANC were predictive of OS but not RFS, whereas prior MDS, CR/CRi at BL, and number of consolidation cycles were only predictive of RFS. Conclusions: Tx with Oral-AZA reduced the risk of death by 30% and risk of relapse by 43% vs. PBO independent of BL characteristics. Cytogenetic risk at Dx, MRD status, and pt age also independently predicted survival outcomes. Clinical trial information: NCT01757535. [Table: see text]

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis

BackgroundThe impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well...

Immune checkpoint inhibitors in adjuvant setting after radical resection of melanoma: a meta-analysis of the pivotal trials

ABSTRACT Beyond the overall relapse-free survival (RFS) advantage demonstrated in randomized trials (RCT) of adjuvant anti-PD-1 immunotherapy in radically resected stage III–IV melanoma, key issues about subgroups of interest have been raised in recent years, with non-conclusive results when considering single studies. In the present meta analysis, we pooled all RCT data in this setting, analyzing, overall, 3043 patients. The RFS benefit of adjuvant immunotherapy over the comparator (placebo or anti-CTLA-4) was strongly confirmed in the pooled analysis, and it was statistically significant in most subgroups, excluding patients with stage IIIA and stage IV M1c melanoma. Nevertheless, the relative benefit was not statistically significantly different when considering their IIIB-IIIC and M1a-M1b counterparts. Future trials in this setting should consider subgroups of interest for tailoring the adjuvant strategy in terms of duration and drug combination in light of literature data.