Induction Chemotherapy In Patients Research Articles

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real-World Data: A Retrospective Observational Study.

Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL). Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥7 days before RIC in 2012-2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed. Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03-0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25-1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses. Prephase steroid treatment for ≥7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.

Relationship between Mitochondrial Oxphos Kinetics and Response to Induction Chemotherapy in Patients with Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy carrying a poor prognosis. Relative to non-leukemic myeloid progenitors, AML cells present with elevations in mitochondrial metabolism driven by higher mitochondrial content. Despite having more mitochondria per cell, AML cells are inefficient at coupling respiration to ATP synthesis, indicative of intrinsic deficiencies in oxidative phosphorylation (OXPHOS) flux. The present study aimed to determine the relationship between mitochondrial OXPHOS kinetics and chemotherapy response in a clinical cohort of AML patients by comparing mitochondrial bioenergetic profiles between responders to induction chemotherapy with those who have persistent disease, and between adverse risk and intermediate risk AML. Methods: In this prospective study from January 2020 to February 2023, we collected bone marrow aspirate samples from patients with new diagnosis of AML on day 1 to evaluate the bioenergetic phenotype of the AML cells. We collected data on primary induction therapy, response to induction therapy, relapse, and other clinical features. We compared the bioenergetic phenotypes between the responders to primary induction chemotherapy and non-responders who had persistent disease post induction chemotherapy. We did the same comparison between patients with adverse risk and intermediate risk AML per European LeukemiaNet (ELN) 2022 risk stratification. Mitochondrial bioenergetic profiles were generated via high resolution respirometry using freshly isolated mononuclear cells from each patient's bone marrow aspirate. The Fisher exact test was used for categorical variables and the Wilcoxon Rank Sum for continuous variables. Results: In 18 AML patients included in the study, median age was 64 years (range 30-85 years), 67% (N=12) were male, 33% female, 61%(n=11) were Caucasian and 39%(n=7) were African Americans. Day 1 median blast count was 57% (range 20-92%). Initial induction therapy with cytarabine/daunorubicin (standard 7+3) with or without midostaurin (in patients with FLT3 mutations) was done in 12 (67%) patients and hypomethylating agent/venetoclax was used in 5 (28%) patients. One patient was managed with azacitidine only. Seven (39%) patients had persistent disease after induction and others responded to the initial induction. Relapsed disease after achieving remission with initial induction was seen in 8 (44%) patients. No patients had favorable risk cytogenetics/molecular findings, 10 had adverse risk AML and 9 had intermediate risk AML. TP53 mutation was observed in 4 patients, FLT3 mutation in 5 patients, IDH1 mutation in 4, and IDH2 mutation in 3 patients. The fraction of the respiratory network capable of performing OXPHOS (i.e., Fractional OXPHOS) was 0.426 in responders and 0.629 in non-responders (p=0.93). In responders, basal respiration in intact cells was non-significantly (p=0.54) lower ( JO2 9.838 pmol/s/million cells) compared to non-responders ( JO2 11.52 pmol/s/million cells). Adverse risk patients had lower fractional OXPHOS, and higher basal and maximal respiration rates as compared to intermediate risk AML patients (Table 1). Conclusion: While Fractional OXPHOS and basal respiration were lower in the patients who had remission after induction therapy, this difference was not statistically significant. We did not find a clinically significant correlation in the bioenergetic profile of AML cells; however, our study is limited by small sample size. Further research is warranted to investigate the role of OXPHOS kinetics in patients of AML that can translate into clinically meaningful outcomes.

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real World Data

Introduction: Remission induction chemotherapy (RIC) is a primary treatment strategy for pediatric acute lymphoblastic leukemia (ALL), aiming to rapidly reduce leukemic cells in the bone marrow. However, this swift reduction can lead to significant complications such as tumor lysis syndrome (TLS). Pretreatment with steroids such as prednisolone or dexamethasone a week before initiating multi-agent RIC can potentially prevent TLS, but the effectiveness and utility of this approach remains unclear. We investigated whether steroid pretreatment before RIC can decrease TLS incidence and improve overall survival. Methods: We utilized clinical databases from two university-affiliated tertiary-care hospitals in Seoul, South Korea, constructed according to the OMOP Common Data Model (CDM) specifications. Eligible patients were children with ALL aged <18 who received RIC consisting of vincristine, prednisolone, L-asparaginase with or without daunorubicin between 2012 and 2021. Patients who received steroid pretreatment ≥7 days before RIC constituted the treated group, whereas those who didn't receive any steroid pretreatment or received it <7 days before were the untreated group. We used propensity score (PS) matching to make baseline characteristics comparable between the groups, based on logistic regression model that incorporated the following covariates: age at ALL diagnosis, sex, presence of Down syndrome, risk group, and baseline laboratory measurements including white blood cell count, hemoglobin, platelet count, absolute neutrophil count, uric acid, phosphorus, potassium, calcium, blood urea nitrogen, creatinine, and lactate dehydrogenase. The primary and secondary outcomes were the incidence of TLS within 14 days of starting RIC and overall survival (OS), respectively. Sensitivity analyses were performed to evaluate if unmeasured confounders resulted in any difference in the main results. Likewise, a rule-out approach and a negative control method was applied to adjust for confounders like immunophenotype and genetic alterations and for other residual confounding, respectively. Results: The study included 574 pediatric patients with ALL, with 275 in the treated group and 299 in the untreated group. After PS matching, each group included 142 patients with all baseline characteristics being comparable. Among the untreated patients, TLS was observed 32 out of 299 (10.7%), whereas in the treated group, 6 out of 275 (2.2%) developed TLS. The significant association between the treatment and reduced TLS risk persisted after adjusting for potential confounders (adjusted OR = 0.08, 95% CI: 0.01-0.31, p = 0.01). OS was numerically greater in the treated group that in the untreated group although it failed to reach statistical significance (HR 0.78, 95% CI 0.35-1.71, p=0.53). Sensitivity analyses including a rule-out approach and a negative control method indicated no substantial impact from unmeasured confounders such as immunophenotype, genetic alterations, or other residual factors. Conclusions: Steroid pretreatment ≥7 days before RIC significantly reduced the risk of TLS in pediatric patients with ALL although no significant reduction in OS was seen in the treated group than in the untreated group, partly because median OS was not reached. Because prospective randomized studies are ethically challenging to assess the efficacy and safety of steroid pretreatment before RIC, our results can provide its critical real-world evidence.

P186 - Overall Response rate with baby-BOP induction chemotherapy in patients with poor-risk, metastatic germ-cell tumors patients: A Retrospective Study in a Mexican hospital.

P186 - Overall Response rate with baby-BOP induction chemotherapy in patients with poor-risk, metastatic germ-cell tumors patients: A Retrospective Study in a Mexican hospital.

A Phase I Trial of Sirolimus with "7&3" Induction Chemotherapy in Patients with Newly Diagnosed Acute Myeloid Leukemia.

Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.

Xerostomia: An easily ignored symptom induced by induction chemotherapy in patients with nasopharyngeal carcinoma.

To investigate the prevalence and predictive factors of xerostomia during induction chemotherapy (IC) in patients with nasopharyngeal carcinoma (NPC). We prospectively enrolled NPC patients who received IC between October 2020 and October 2021. The Visual Analogue Scale (VAS) and Xerostomia Inventory (XI) were used to evaluate the condition of xerostomia. The volume of the submandibular gland (SMG) was also calculated before and after IC. Fifty-two patients were enrolled in this study. Of these patients, 32.7% (n = 17) experienced xerostomia before IC. There were 32 (61.5%) patients suffered from xerostomia after IC, including 21 (40.4%) patients with newly diagnosed xerostomia after IC and 11 (21.1%) patients complained their xerostomia aggravated in those with xerostomia before IC. The median XI scores increased from 11 (standard deviation [SD], 2.930) to 18 (SD 3.995), 16 (SD 3.605), and 17 (SD 4.331) after the first, second, and third cycles of IC, respectively. The median score of VAS also increased from 0 to 4 during the following three cycles of IC. In those with IC-related xerostomia, the SMG volume after IC was significantly decreased compared with those without IC-related xerostomia (P = 0.001). The reduction of the SMG volume after IC was the independent risk factor for xerostomia (P = 0.002). Approximately two-thirds of NPC patients suffered from IC-related xerostomia and patients with a reduction of SMG volume after IC had a higher risk of xerostomia.

Role of induction chemotherapy for locally advanced oral squamous cell carcinoma. A systematic review and meta-analysis based on the GRADE approach

ObjectiveA few reports have demonstrated the additional survival benefit obtained from induction chemotherapy. However, some facilities have differing opinions regarding the suitability of induction chemotherapy. The aim of this systematic review was to investigate the effectiveness of induction chemotherapy in patients with unresectable oral cancers without distant metastases. MethodsA comprehensive search of randomized controlled trials was conducted specifically targeting patients with primary unresectable oral cancer, defined as an intervention group (induction chemotherapy followed by chemoradiotherapy) and a control group (chemoradiotherapy alone). The electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Ichushi-Web database were searched for relevant papers. The primary outcome was overall survival, and the secondary outcomes were progression-free survival and treatment-related deaths, all of which were judged to be of critical importance. Data available for integration were subjected to a meta-analysis, and the certainty of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation approach. ResultsA search was conducted until February 2022, and four articles were included. The meta-analysis showed that the point estimates (95 % confidence interval) of the hazard ratios were 0.87 (0.74–1.01) for overall survival, 0.85 (0.75–0.97) for progression-free survival, and 0.98 (0.97–1.00) for treatment-related death. The certainty of the evidence for each item was very low. ConclusionLittle data are available to support the use of induction chemotherapy before chemoradiotherapy in patients with unresectable primary locally advanced oral cancer.

The effect of smoking on the immediate effectiveness of induction chemotherapy in the combined treatment of HPV-associated oropharyngeal cancer

Purpose. Evaluation of the effect of smoking on the immediate effectiveness (achievement of objective response – OR) of induction chemotherapy in patients receiving combined treatment for locally advanced HPV-positive squamous cell carcinoma of the oropharynx.Patients and methods. Sixty-eight patients (51 men and 17 women) with locally advanced squamous cell cancer of the oropharynx associated with papillomavirus were included in the study, which was carried out from 2021 to 2023 at the P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre, Ministry of Health of the Russian Federation, Moscow, Russian Federation and the Municipal Clinical Oncological Hospital № 1 of the Department of Health of Moscow. The patients were divided into 2 equal groups, fully comparable in terms of the main characteristics (smoking history, stage, histological type, and degree of tumour differentiation). At the first stage, patients of the 1st (main) group received de-escalated induction chemotherapy: three 21-day courses according to the TR scheme (docetaxel in the dose of 75 mg/m2 + cisplatin 75 mg/m2); patients of the 2nd (control) group were treated with standard scheme (docetaxel 75 mg/m2 + cisplatin 75 mg/m2 + 5-fluorouracil 1000 mg/m2). Patients in both groups received prophylactic granulocyte colony-stimulating factor. At the second stage, standard chemoradiotherapy was carried out against the background of drug radiomodification with carboplatin. Correlation analysis was performed by calculating the Spearman coefficient with Bonferroni correction. Differences were considered reliable at p < 0.05.Results. When evaluating the objective response to treatment, it was revealed that disease control was achieved in 33 (97 %) patients from group 1 and in all 34 (100 %) patients from group 2. Complete response was observed in 3 (8.8 %) patients from group 1 and 4 (11.8 %) from group 2; partial regression in 22 (64.7 %) and 24 (70.6 %); stabilisation of the tumour process in 8 (23.5 %) and 6 (17.6 %) respectively. Further analysis showed that there was no direct or inverse correlation between smoking and differentiated level of response (primary lesion, altered lymph nodes); all patients (smokers and those who had never smoked) responded equally effectively to the first stage of combined treatment, regardless of the ICT regimen.Conclusion. In our study, no statistically significant effect of smoking on the immediate effectiveness of induction chemotherapy in the combined treatment of locally advanced HPV-associated squamous cell carcinoma of the oropharynx regardless of the induction regimen was found. However, a longer follow-up period is needed to evaluate the effect of smoking on long-term oncological outcomes.

Comparison of efficacy between homoharringtonine, aclarubicin, cytarabine (HAA) and idarubicin, cytarabine (IA) regimens as induction therapy in patients with de novo core binding factor acute myeloid leukemia.

To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

Induction chemotherapy with nanosomal docetaxel lipid suspension (NDLS), cisplatin, and fluorouracil in patients with locally advanced head and neck squamous cell carcinoma.

6074 Background: Nanosomal docetaxel lipid suspension (NDLS), a polysorbate-80 and ethanol free formulation, was developed to overcome the toxicity issues and to improve disease outcomes associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS based TPF (NDLS, cisplatin and 5-fluorouracil [FU]) induction chemotherapy in patients with inoperable/unresectable Locally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC). Methods: In this multicentric, single arm, open label, Phase IV clinical study, patients with inoperable/ unresectable LA HNSCC received induction chemotherapy with NDLS (75 mg/m2; Day 1), cisplatin (75 mg/m2; Day 1) and 5-FU (750 mg/m2/day for 5 days) based TPF regimen every 3 weeks (q3w) for 4 cycles followed by radiotherapy. The study outcomes were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Fifty patients were enrolled in this study. Most of the patients belonged to the age group of 35-64 years (86%) and had a WHO performance status of 1 (66%). In the modified intent-to-treat (mITT) population ( n = 40), the ORR after NDLS based TPF induction chemotherapy was 42.5%, which increased to 60.0% after loco-regional therapy. In the per-protocol (PP) population ( n = 14), the ORR was 64.3%, which increased to 80.0% after loco-regional therapy (Table). At 2 years, the PFS and OS rates were 82.5% and 97.5%, respectively, in the mITT population and 85.7% and 100% respectively, in the PP population. The most common grade 3/4 adverse effects reported were neutropenia (10%), leukopenia (6%), febrile neutropenia (4%), asthenia (2%), diarrhea (2%), and thrombocytopenia (2%) respectively. Grade 3/4 infusion-related reactions, hyperglycemia or neuropathy were not reported. Conclusions: NDLS based induction chemotherapy was effective and well-tolerated in the treatment of inoperable LA HNSCC and showed high response rates. Clinical trial information: CTRI/2017/12/010938 .[Table: see text]

Results of complex treatment of patients with locally advanced squamous cell carcinoma of the paranasal sinuses and nasal cavity using induction chemotherapy

Introduction. About 600 new cases of malignant neoplasms of the paranasal sinuses and nasal cavity are detected annually in Russia. To date, there are no randomized trials to determine the optimal treatment algorithm for this group of patients. Data on the use of induction chemotherapy in squamous cell carcinoma of sino-nasal tract are limited to a small series of clinical observations and, often, are retrospective in nature.Aim. Evaluation of the effectiveness of induction chemotherapy in patients with locally advanced squamous cell carcinoma of the paranasal sinuses and nasal cavity.Materials and methods. Since 2012, 22 patients with locally advanced cancer of the paranasal sinuses and nasal cavity have been treated in our center, who underwent 3-component induction chemotherapy according to the TPF protocol. Evaluation of the effectiveness of treatment was carried out according to the criteria of Response evaluation criteria in solid tumors 1.1 (RECIST 1.1). Patients with a decrease in the tumor size by 30 % or more, were followed by radiation therapy in doses of 66–70 Gy. Patients with a residual tumor underwent surgery after the end of chemoradiotherapy.Results. In 21 patients available for analysis, overall response rate after induction chemotherapy was 71 %: complete response was registered in 3 (14 %) patients, partial response in 12 (57 %), stable disease in 4 (19 %). Progression disease after 3 courses of induction chemotherapy was detected in 2 (10 %) patients.Conclusions. Thus, induction chemotherapy in patients with squamous cell carcinoma of sino-nasal tractseems to be a promising direction for investigation, that can significantly improve the long-term results of treatment of this category of patients and help to avoid of disabling surgery in some of them.

Cost-effectiveness analysis of capecitabine maintenance therapy plus best supportive care vs. best supportive care alone as first-line treatment of newly diagnosed metastatic nasopharyngeal carcinoma.

Maintenance therapy with capecitabine after induction chemotherapy for patients with newly diagnosed metastatic nasopharyngeal carcinoma (mNPC) has been confirmed to be effective. This study aimed to evaluate the cost-effectiveness of capecitabine as maintenance therapy for patients with mNPC from the Chinese payers' perspective. Markov model was conducted to simulate the disease progress and evaluated the economic and health outcomes of capecitabine maintenance plus best-supported care (CBSC) or best-supported care (BSC) alone for patients with mNPC. Survival data were derived from the NCT02460419 clinical trial. Costs and utilities were obtained from the standard fee database and published literature. Measured outcomes were total costs, quality-adjusted life-years (QALYs), life-years (LYs), incremental cost-utility ratios (ICURs), incremental cost-effectiveness ratios (ICERs), incremental net monetary benefit (INMB), and incremental net-health benefit (INHB). Sensitivity analyses were performed to assess model robustness. Additional subgroup cost-effectiveness analyses were accomplished. Throughout the course of the disease, the CBSC group provide an incremental cost of $9 734 and additional 1.16 QALYs (1.56 LYs) compared with the BSC group, resulting in an ICUR of $8 391/QALY and ICER of $6 240/LY. Moreover, the INHB was 0.89 QALYs, and the INMB was $32 034 at the willingness-to-pay threshold of $36 007/QALY. Subgroup analyses revealed that CBSC presented a positive trend of gaining an INHB in all subgroups compared with the BSC group. The results of sensitivity analyses supported the robustness of our model. Compared with BSC, after induction chemotherapy, CBSC as a first-line treatment was cost-effective for newly diagnosed mNPC. These results suggest capecitabine maintenance therapy after induction chemotherapy as a new option for patients with newly diagnosed mNPC.

Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma.

There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.

Efficacy and safety of anlotinib as maintenance therapy after induction chemotherapy in extensive-stage small-cell lung cancer.

Anlotinib has been approved as the third-line or beyond treatment regimen for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, it is indistinct whether there are survival benefits of anlotinib in the maintenance therapy of ES-SCLC. Therefore, this study aims to evaluate the efficacy and safety of anlotinib monotherapy as maintenance therapy after induction chemotherapy for patients with ES-SCLC. The median progression-free survival (mPFS) was considered to be the pivotal symbol as the primary endpoint. The median overall survival (mOS) and safety were recognized as the second endpoints. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mg/d, d1-d14, every 21 days as a course). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The mPFS was 7.7 months (95% CI, 7.20-8.20 months) and the mOS was 11.0 months (95% CI, 9.19-12.82 months), respectively. The most common treatment-related adverse events were hypertension ( n = 9; 64.3%), fatigue ( n = 6; 42.9%), followed by decreased appetite ( n = 5; 35.7%), nausea ( n = 5; 35.7%), weight decrease ( n = 4; 28.6%), and rash ( n = 4; 28.6%). There were no patients who required dose reduction because of severe adverse events. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC. These above outcomes demonstrated that anlotinib was a tolerable and potent maintenance treatment option after induction chemotherapy in ES-SCLC.

Impact of Fluoroquinolone Prophylaxis on Neutropenic Fever, Infections, and Antimicrobial Resistance in Newly Diagnosed AML Patients.

Fluoroquinolone prophylaxis is recommended during induction chemotherapy for patients with acute myeloid leukemia (AML) to reduce risk of neutropenic fever and systemic bacterial infections. We evaluated the effectiveness of primary fluoroquinolone prophylaxis in an area with high fluoroquinolone resistance. We performed a retrospective chart review of newly diagnosed adult AML patients who received frontline therapy at Mount Sinai Hospital in New York, NY, between 2012 and 2019. Primary outcome was development of neutropenic fever. Secondary outcomes were development of systemic bacterial infections and infections with multidrug-resistant organisms and Clostridioides difficile. Infectious outcomes were collected through 6 months after therapy initiation. We estimated the effect of fluoroquinolone prophylaxis with a time-dependent Cox proportional hazards model. Of 121 included patients, 87 received antibiotic prophylaxis and 34 did not. There was no difference in baseline characteristics, although the prophylaxis group had longer neutropenia duration (median 30 vs. 23 days, P=.013). The prophylaxis group had a reduced risk of neutropenic fever (hazard ratio 0.59, P=.039). The prophylaxis group had fewer gram-positive (P=.043) and gram-negative (P=.049) bloodstream infections and fewer clinically documented infections during frontline therapy (P=.005) and follow-up (P=.026). There was no difference in incidence of C. difficile or infection with fluoroquinolone-resistant or multidrug-resistant organisms. There was no mortality difference between groups. In an area with high fluoroquinolone resistance, primary fluoroquinolone prophylaxis in newly diagnosed AML patients reduced the risk of neutropenic fever and systemic bacterial infections without increased antimicrobial resistance. Prospective, randomized studies are needed to confirm these observations.

Different Subsets of Exhausted and Senescent-like T Cells Correlate with Response and Survival in Patients with Acute Myeloid Leukemia (AML) Undergoing Chemotherapy

Introduction Novel immunotherapies have changed the treatment paradigm for several oncohematologic diseases. In AML, these strategies have found limited application so far, in part due to incomplete understanding of bone marrow (BM) immune microenvironment. Several studies have identified T-cell exhaustion and senescence as two dominant states of dysfunction. We hypothesized that T cell dysfunctional states will predict response to induction chemotherapy in patients with AML. Methods We analyzed serial BM samples from healthy donors (HD); and AML patients responding (Res) and not responding (NonRes) to chemotherapy. We performed flow-cytometry in 10 Res, 6 NonRes (at diagnosis and at time of response assessment) and 12 HD. We subsequently performed single-cell RNA sequencing (scRNAseq) to analyze BM of 2 HD, 3 Res, and 2 NonRes at diagnosis and response assessment. This was followed by a scRNAseq-guided 26-color spectral flow-cytometry panel (12 Res and 10 NonRes). In-vitro assays were conducted to study the impact of blasts and metabolites on CD8+ T cells differentiation. Results Flow-cytometry identified a PD1+CD28+ CD8+ T-cell subset significantly (p<0.01) increased in Res versus NonRes at baseline and post-chemotherapy. Unsupervised clustering of scRNAseq data identified 6 main CD8+ subsets: naive, GZMK+IL7R+, intermediate GZMK+ (int-GZMK), intermediate(Int), senescent-like (SL), and terminally exhausted (Ttex). The GZMK+IL7R+, int-GZMK and Ttex expressed ITGAE and ENTPD1, supporting the idea that these subsets are tumor reactive and exhaustion is antigen-driven. Additionally, GZMK+IL7R+ cells had a progenitor-exhausted signature expressing stemness (TCF7, IL7R), anti-apoptotic (BCL2) and exhaustion (PDCD1, TIGIT) markers. This stem-like signature may allow long-term in-vivo persistence and anti-tumor immune surveillance consistent with the significant increase of GZMK+IL7R+ and Int-GZMK in Res vs NonRes. Conversely, Ttex and SL were significantly increased in NonRes. Trajectory inference algorithms identified two pathways with different end stages (SL; Ttex) demonstrating that senescence and exhaustion coexist but are different states in AML patients (Figure 1A). At trajectory's divergence, GNLY, NKG7, PRF1 and GZMB were the most upregulated genes in the "senescent” lineage while GZMK was upregulated in the "exhaustion” lineage. At the clonal level, the most expanded subsets were GZMK+IL7R+ and int-GZMK in Res and SL in NonRes, revealing a strong relationship between CD8+ T-cell subsets abundance and clonal expansion. The same subsets were confirmed by spectral flow-cytometry. GZMK+IL7R+cells were significantly increased in Res vs NonRes and SL where significantly increased in NonRes vs Res. In this larger cohort we corroborated at the protein level the differentiation path found in scRNAseq, confirming senescent and terminally exhausted CD8+ T cells as end differentiation T-cell states in AML (Figure 1A). Patients with a higher-than-median CD8+ GZMK+IL7R+/SL had a significantly (p<0.05) prolonged overall survival, affirming the clinical relevance of the differential abundance of the identified subsets in AML (Figure 1B). Gene-set enrichment analysis on scRNAseq showed increased hypoxia in NonRes VS Res, suggesting that anaerobic (non-oxidative) metabolism could promote senescence or terminal exhaustion. In vitro experiments with flow cytometry-sorted BM T cells and AML blasts demonstrated that adding lactic acid promotes CD8+ T cells senescence (p<0.05) whereas sodium bicarbonate prevents the development of senescence (p<0.05). These effects appear to be AML blast-specific since co-culture of HD T cells with AML blasts resulted in similar phenotypic changes. Conclusion Our study provides novel insights in understanding T-cell differentiation in the BM microenvironment of AML patients. We found that terminal exhaustion and senescence are derived from two different differentiation paths and that the ratio between stem-like and senescent CD8+ T cells is predictive of survival. Based on our scRNAseq and in-vitro results, we hypothesize that blasts and diverse metabolic microenvironments in Res and NonRes may have a different impact on T-cell differentiation and be responsible for different patients outcomes. Further studies could explore strategies that promote stem-like functional T cells to gain long-term AML control. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Carotid space involvement is a prognostic factor and marker for induction chemotherapy in patients with nasopharyngeal carcinoma

ObjectivesThe carotid space is an integral part of the parapharyngeal space, with ambiguous prognostic value for patients with nasopharyngeal carcinoma (NPC). This study aimed to investigate the prognostic significance of carotid space involvement (CSI) and propose a treatment strategy. Materials and methodsThis retrospective study enrolled 792 patients with biopsy-confirmed, non-distant metastatic NPC staged by magnetic resonance imaging before treatment. We used multivariable Cox regression models and Kaplan–Meier methods to assess the association between the variables and survival outcomes. A matched-pair method (1:1) was used to compare the survival differences between the patients with CSI treated with induction chemotherapy (ICT)and that of those who were not. ResultsThe incidence rate of CSI was 21.7 % (172/792). Multivariate analysis revealed that CSI was not an independent prognostic factor for survival outcomes in the 792 patients with NPC; however, the Chi-square test showed a different distribution of treatment strategies with ICT for patients with and without CSI. After stratification by ICT, CSI was an independent prognostic factor for overall survival (OS) (p = 0.049) in patients without ICT, but not for distant metastasis-free, local recurrence-free, or progression-free survival (p˃0.05). Additionally, ICT improved OS in patients with CSI (hazard ratio, 0.42; p = 0.019). Matched pair analysis showed that patients with CSI gained prolonged OS from ICT compared with the non-ICT group (88.4 % vs 69.4 %, p = 0.028). ConclusionCSI was an independent negative prognostic factor for OS in patients with NPC without ICT and might be an imaging marker for identifying eligible candidates for ICT.

Complications during Induction Chemotherapy in Acute Promyelocytic Leukemia: An Institutional Experience.

Stalin Chowdary BalaIntroduction Acute promyelocytic leukemia (APL) has transformed from a highly fatal disease to a highly curable one. Induction deaths continue to represent one of the major impediments in modern therapy of APL. Sepsis, hemorrhage, and differentiation syndrome are the major complications during induction therapy in APL. The present study reports the incidence and prognostic factors of major complications during induction chemotherapy in patients with newly diagnosed APL. Materials and Methods The present study was a single institutional, observational, retrospective study. All cases of APL diagnosed by morphology and confirmed by RT PCR (PML RARα) were included in this study. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25. Results A total of 73 patients were analyzed. The median age at presentation was 30 years (range, 3-60 years) with a female to male ratio of 1.02:1. The most common symptom at presentation was fever (80%), followed by fatigue (56%) and gum bleeding (37%). The majority of the patients at presentation were high risk (42.4%), followed by intermediate risk (38.4%) and low risk (19.2%). Fifty-seven (78%) patients achieved complete hematological remission and 16 (22%) succumbed during induction chemotherapy. Infection was the most common cause of induction death (50%), followed by hemorrhage (37.5%) and differentiation syndrome (12.5%). On univariate analysis of prognostic factors, bcr3 variant, grade 3/4 bleeding during induction, and low levels of albumin at presentation were significant for induction mortality ( p = 0.034, 0.041, and 0.008 respectively). On multivariate analysis, only serum albumin < 3.5 g/dL was an independent predictor for induction mortality ( p = 0.043). Conclusion The majority of patients were high risk at presentation. Sepsis was the most common complication during induction and also the leading cause of induction death. Identifying induction complications at the earliest and providing aggressive supportive measures can further improve outcomes in APL.

Added value of 3T MRI and the MRI-halo sign in assessing resectability of locally advanced pancreatic cancer following induction chemotherapy (IMAGE-MRI): prospective pilot study

BackgroundRestaging of locally advanced pancreatic cancer (LAPC) after induction chemotherapy using contrast-enhanced computed tomography (CE-CT) imaging is imprecise in evaluating local tumor response. This study explored the value of 3 Tesla (3 T) contrast-enhanced (CE) and diffusion-weighted (DWI) magnetic resonance imaging (MRI) for local tumor restaging.MethodsThis is a prospective pilot study including 20 consecutive patients with LAPC with RECIST non-progressive disease on CE-CT after induction chemotherapy. Restaging CE-CT, CE-MRI, and DWI-MRI were retrospectively evaluated by two abdominal radiologists in consensus, scoring tumor size and vascular involvement. A halo sign was defined as replacement of solid perivascular (arterial and venous) tumor tissue by a zone of fatty-like signal intensity.ResultsAdequate MRI was obtained in 19 patients with LAPC after induction chemotherapy. Tumor diameter was non-significantly smaller on CE-MRI compared to CE-CT (26 mm vs. 30 mm; p = 0.073). An MRI-halo sign was seen on CE-MRI in 52.6% (n = 10/19), whereas a CT-halo sign was seen in 10.5% (n = 2/19) of patients (p = 0.016). An MRI-halo sign was not associated with resection rate (60.0% vs. 62.5%; p = 1.000). In the resection cohort, patients with an MRI-halo sign had a non-significant increased R0 resection rate as compared to patients without an MRI-halo sign (66.7% vs. 20.0%; p = 0.242). Positive and negative predictive values of the CE-MRI-halo sign for R0 resection were 66.7% and 66.7%, respectively.Conclusions3 T CE-MRI and the MRI-halo sign might be helpful to assess the effect of induction chemotherapy in patients with LAPC, but its diagnostic accuracy has to be evaluated in larger series.

Efficacy and safety of decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) for newly diagnosed acute myeloid leukemia

The 7 + 3 regimen is the front-line induction chemotherapy in patients with newly diagnosed acute myeloid leukemia, with a response rate of 60-80%. But it’s not suitable for all patients especially old/unfit patients because of a higher treatment related toxicity. Therefore, safer and more effective induction therapies are required. In this retrospective study, 50 patients with newly diagnosed acute myeloid leukemia received decitabine combined with HAAG (homoharringtonine, aclarubicin, low-dose cytarabine and G-CSF) as induction chemotherapy. Complete remission (CR) rate was 96% (48/50) and overall response rate was 100%. Of note, All 7 patients harboring FLT3-ITD mutation achieved CR. The median overall survival (OS) was 40.0 months (range 2.0, 58.0). The OS at 1, 3, and 5 years were 75.3%, 54.2%, and 49.3%. The median relapse free survival (RFS) was 38.0 months (range 2.0, 58.0). The RFS at 1, 3, and 5 years were 67.3%, 48.9%, and 45.1%. The OS and RFS of patients who received hematopoietic stem cell transplantation (HSCT) were significantly higher than those who did not undergo HSCT (p=0.017; 0.016). The incidence of grade 3-4 neutropenia and thrombocytopenia was 84% and 88%. Meanwhile, the incidence of grade 3-4 infection and bleeding was only 16% and 6%. There was no early death. In conclusion, DAC+HAAG regimen is effective and well-tolerated as induction therapy in patients with newly diagnosed AML.