Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

PURPOSE To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

Intensification of radiation therapy for localized breast cancer in the settings of the COVID-19 pandemic: A literature review

Relevance: Since 2004, breast cancer steadily ranks first in the structure of the incidence of malignant neoplasms in the Republic of Kazakhstan in both sexes. In 2020, its share was 14.5% (vs. 15.2% in 2019). Breast cancer also constantly ranks first in the structure of female cancer incidence, with 44.3‰ in 2020 (vs. 51.6‰in 2019). In the early 1980s, radiation therapy was a standard specialized treatment for breast cancer. The current realities of the COVID-19 pandemic require a reorganization of healthcare facilities to determine the priorities. It is also important to balance the economic and clinical efficacy of radiotherapy methods applied. The study aimed to analyze the results of large randomized trials and compare breast cancer outcomes after hypofractionated and standard fractionation radiation treatment. Methods: We reviewed the results of large randomized trials of hypofractionated radiation therapy, emphasizing adequate patient selection according to the American Society of Therapeutic Radiology and Oncology (ASTRO) guidelines. Radiobiological aspects of hypofractionation were considered due to its implementation in clinical practice. The research materials were obtained from the “PubMed” database of evidence-based medicine by the keywords “radiotherapy,” “breast cancer,” “hypofractionation dose” for the period 2000-2021. Large randomized trials involving patients of any age diagnosed with stages T1-3, N0-1 breast cancer, who underwent beam therapy in standard or hypofractionated mode, met the criteria for inclusion in this study. Results: According to the results of large randomized trials, the hypofractionated regimen is similar to the standard regimen in terms of late effects on normal tissues and ensures good control over the oncological process. Conclusions: Hypofractionation has proven effectiveness and safety and has lower late and/or acute radiation toxicity when treating early breast cancer. Hypofractionation can become a new standard of radiation therapy at early stages after breast-conserving surgery.

Real world practice of medical treatment for moderate and severe inflammatory bowel diseases in Russian Federation, Republic of Belarus and Republic of Kazakhstan: intermediate results of the INTENT study

Background: The analysis of data obtained from real world clinical practice of management of patients with inflammatory bowel diseases (IBD) is an effective tool to improve medical care for this patient category. Studies of the kind are rare in Russia, which hinders a critical assessment of the current situation and optimization of the established approaches.Aim: To study real world practice of medical treatment of patients with moderate and severe IBD in the Russian Federation, Republic of Belarus and Republic of Kazakhstan.Materials and methods: We analyzed intermediate results from the INTENT study (NCT03532932), which is a multinational, multicenter, retrospective and prospective, non-interventional observation trial being performed in the Russian Federation, Republic of Belarus and Republic of Kazakhstan. The retrospective analysis included data from 706 patients above 18 years of age with confirmed diagnosis of moderate/severe ulcerative colitis (UC) and Crohn's disease (CD) made at least 2 years before the study entry, with acute exacerbations of the disease at the study entry or within the last 2 years. Data were collected during routine management; at the study entry the patients were treated with a standard regimen including 5-aminosalicylic acid (5-ASA) agents, glucocorticosteroids (GCS) and immunosuppressants (IS), as well as genetically engineered biological agents (GEBA).Results: Among 706 IBD patients, 465 had UC and 241 had CD. The male to female ratios in both groups were similar. Mean age of the UC patients was higher than that of the CD patients (41.8 [95% confidence interval (CI) 40.6–43.0] years vs 35.6 [95% CI 33.9–37.3] years, p = 0.0001). The same difference was noted for the mean age of disease manifestation (34.5 [95% CI 33.29–35.61] vs 29.7 [95% CI 28.03–31.3] years, p = 0.0001) and for mean duration of disease from the time of diagnosis to the study entry (7.3 [95% CI 6.77–7.9] for UC and 5.9 [95% CI 5.3–6.59] years for CD, p = 0.0027). The proportion of patients with familial history of IBD was low (3.2 and 0.8%, respectively, p = 0.0672). The number of smokers with CD was more than 2-fold higher than those with UC (11.2% vs 5%, p < 0.001). 58.1% of the patients in the UC group and 47.0% of those from the CD group were employed (р < 0.05). 36.6% of the UC patients and 56.0% of the CD patients had the legal disability status due to underlying disease (p < 0.005).The relapsing course of the disease was noted in 72.9% with UC and 60.6% with CD, while in the rest of the patients the disease had the continuous course. The degree of UC involvement corresponded to pancolitis in 58.9% of the cases, to left-sided colitis in 33.1%, and to proctitis in 8%. The distribution of CD location was as follows: ileocolitis 54.8%, terminal ileitis 23.7%, colitis 20.3%, isolated upper gastrointestinal tract involvement 1.2%. The prevalence of complicated UC was 12.9%, and that of the complicated CD 57.4% (р = 0.0001). There were no difference in the rate of extraintestinal manifestations between UC and CD (23.4 and 28.2%, respectively, p = 0.1705).UC and CD groups differed by their treatment patterns. In the UC group, 5-ASA + GCS regimens were given to 25.4% of the patients, whereas in the CD group, to 3.7% (р ≤ 0.0001). The second frequent regimens were: 5-ASA with subsequent IS ± GCS (17.9% in UC, 22.8% in CD, p = 0.1331); standard regimen (any 5-ASA agent, IS or GCS, but not GEBA) with subsequent treatment withdrawal or its reduction to GCS monotherapy (14.8% in UC, 5% in CD, р = 0.0001); 5-ASA with a subsequent combination with IS, then any tumor necrosis factor-α inhibitor (iTNF-α) as the basic treatment with continuation of 5-ASA and/or IS (22% in CD vs 13.5% in UC, р = 0.0052); treatment initiation from iTNF-α combined with any standard agent without any subsequent modification (24.1% in CD and 13.6% in UC, р = 0.0007). Less frequent the following treatment regimens were used: initial treatment with 5-ASA and subsequent iTNF-α with continuation of 5-ASA (4.5% in UC and 2.5% in CD, р = 0.2181); initial treatment with iTNF-α in combination with any standard agent with subsequent GEBA withdrawal and continuation of a standard regimen or its withdrawal (4.3% in UC and 7.5% in CD, р = 0.0812).The cumulative frequency of GEBA administration at various stages of treatment for CD (66.4%) was significantly higher than for UC (39.4%). Vedolizumab for CD was administered more frequently than for UC (10.4 and 3.4%, respectively, p = 0.0003). The analysis of habitual GCS use revealed a number of negative trends, namely, half of the IBD patients received more than 2 GCS courses within 2 years, and in some cases the number of GCS courses amounted to 5–8. Mean duration of a GCS course in most regimens for UC and CD was in the range of 91 to 209 days, which is significantly higher than the recommended treatment duration of 12 weeks (83 days).Conclusion: With a number of its demographic characteristics and clinical particulars, the study cohort of patients with IBD is compatible to global trends: the male to female ratio, mean patients’ age, young age at disease manifestation, smoking status, prevalence of extraintestinal manifestations and the location of CD. It is of note that 5-ASA is included into almost all treatment regimens for CD, which does not meet the treatment strategy recommended in the guidelines. Frequent administration and long duration of GCS therapy also is in contradiction with the guidelines. Of significant concern is rather rare and late administration of GEBA, especially for UC. We believe that the identified pitfalls are associated both with low awareness of doctors on the current strategies of IBD management and with low patients' compliance to treatment.

Systemic Therapy Decision Making in Advanced Cancer: A Qualitative Analysis of Patient-Oncologist Encounters

PURPOSE: We sought to characterize patient-oncologist communication and decision making about continuing or limiting systemic therapy in encounters after an initial consultation, with a particular focus on whether and how oncologists foster shared decision making (SDM). METHODS: We performed content analysis of outpatient oncology encounters at two US National Cancer Institute–designated cancer centers audio recorded between November 2010 and September 2014. A multidisciplinary team used a hybrid approach of inductive and deductive coding and theme development. We used a combination of random and purposive sampling. We restricted quantitative frequency counts to the coded random sample but included all sampled encounters in qualitative thematic analysis. RESULTS: Among 31 randomly sampled dyads with three encounters each, systemic therapy decision making was discussed in 90% (84 of 93) encounters. Thirty-four (37%) broached limiting therapy, which 27 (79%) framed as temporary, nine (26%) as completion of a standard regimen, and five (15%) as permanent discontinuation. Thematic analysis of these 93 encounters, plus five encounters purposively sampled for permanent discontinuation, found that (1) patients and oncologists framed continuing therapy as the default, (2) deficiencies in the SDM process (facilitating choice awareness, discussing options, and incorporating patient preferences) contributed to this default, and (3) oncologists use persuasion rather than deliberation when broaching discontinuation. CONCLUSION: In this study of outpatient encounters between patients with advanced cancer and their oncologists, when discussing systemic therapy, there exists a default to continue systemic therapy, and deficiencies in SDM contribute to this default.

O-OGC09 PD-1 inhibitors in Oesophageal Cancer: A systematic review of the oncological outcomes associated with PD-1 blockade and the evolving therapeutic landscape

Background Patients with oesophageal or gastro-oesophageal junction (GOJ) cancer that fail to respond to chemoradiotherapy have a poor clinical prognosis. Recent clinical trials have investigated the use of immune checkpoint inhibitors in these patients. The use of programmed cell death protein 1 (PD-1) inhibitors have emerged as exciting therapeutic options in other solid tumors, such as non-small cell lung cancer, renal cell carcinoma and melanoma. We assessed the efficacy and safety of PD-1 inhibitors in oesophageal and GOJ cancers. Methods This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive electronic literature search from the EMBASE, Pubmed, Scopus, MEDLINE and Google Scholar databases was conducted up to April 1st 2021. Results This review identified nine eligible studies reporting outcomes of 2149 patients treated with PD-1 blockade compared with 1244 patients treated with either a placebo or the standard regimen of chemotherapy for oesophageal and GOJ cancer. Clinically significant improvements in median overall survival have been demonstrated in advanced and metastatic oesophageal and GOJ cancer while maintaining acceptable safety profiles. Promising survival data has also recently emerged from PD-1 blockade in the adjuvant setting. Conclusions PD-1 blockade in oesophageal and GOJ cancer has delivered impressive survival benefit whilst remaining well tolerated. Its use in the adjuvant setting may further advance our treatment options for this difficult-to-treat tumour, and more advancements in the immunotherapy landscape are highly anticipated. However, further characterization of the PD-1/PD-L1 pathway is required to optimise patient selection.

Clinical Outcomes of Secondary Prophylactic Granulocyte Colony-Stimulating Factors in Breast Cancer Patients at a Risk of Neutropenia with Doxorubicin and Cyclophosphamide-Based Chemotherapy

Doxorubicin and cyclophosphamide (AC)-based chemotherapy has been a standard regimen for early-stage breast cancer (ESBC) with an intermediate risk (10–20%) of febrile neutropenia (FN). Secondary prophylaxis of granulocyte colony-stimulating factor (G-CSF) is considered in patients receiving AC-based chemotherapy; however, relevant studies are limited. Here, we retrospectively reviewed the electronic medical records of 320 patients who completed adjuvant AC-based chemotherapy from September 2016 to September 2020. Approximately 46.6% of the patients developed severe neutropenic events (SNE) during AC-based chemotherapy. Secondary prophylaxis of G-CSF reduced the risk of recurrent SNE (p < 0.01) and the relative dose intensity (RDI) < 85% (p = 0.03) in patients who had experienced SNE during AC-based chemotherapy. Age ≥ 65 years (p = 0.02) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 60 IU/L (p = 0.04) were significant risk factors for RDI < 85%. The incidences of FN, grade 4 neutropenia, unscheduled hospitalization, and interruption to the dosing regimen were reduced in patients administered secondary prophylaxis with G-CSF (before vs. after administration: FN, 19.4% vs. 4.6%; grade 4 neutropenia, 86.1% vs. 14.8%; unscheduled hospitalization, 75.9% vs. 11.1%; interruption to the dosing regimen, 18.5% vs. 8.3%). This study indicated the importance of active intervention of G-CSF use to prevent recurrent SNE and improve clinical outcomes in patients with breast cancer who receive AC-based chemotherapy.

The Preferred Premedication Order to Prevent Infusion Reactions in Patients with Breast Cancer Receiving Pertuzumab Plus Trastuzumab and Docetaxel

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.

Meta-Analysis of Chemotherapy-Induced (Febrile) Neutropenia and Chemotherapy Disruptions Associated with Same-Day Versus Standard (24-72h) Pegfilgrastim Administration in Non-Hodgkin Lymphoma Patients

Background: While the product label and international guidelines recommend pegfilgrastim administration 24-72 hours following completion of chemotherapy, increasingly clinicians administer pegfilgrastim using a same-day protocol. We performed a meta-analysis to compare the incidence of febrile neutropenia (FN), chemotherapy-induced neutropenia (CIN) grade 4, and CIN/FN-related chemotherapy delays and dose reductions in non-Hodgkin lymphoma (NHL) patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab (R±CHOP) who were provided with pegfilgrastim on the same-day of chemotherapy versus the standard 24-72h post-chemotherapy time window. Methods: Six databases were searched for studies that compared same-day pegfilgrastim with the standard regimen in NHL patients. Given the low heterogeneity (I 2&lt;50%, Cochrane Q test P&gt;0.10, fixed-effect model was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs) for all outcomes of interest. Results: We identified 7 studies, including one clinical trial (Burris et al. 2010) and six retrospective cohort studies (Woods et al. 2010, Ibrahim et al. 2011, Karol et al. 2013, Cheng et al. 2014, Bartels et al. 2021, McBride et al. 2021), that evaluated same-day versus standard 24-72h administration of pegfilgrastim in NHL patients. Results were statistically non-significant for all outcomes (Figure 1): FN across all chemotherapy cycles (OR=1.48, 95%CI= 0.98-2.23, P=0.06, N of studies=7); FN after the first cycle (OR=1.98, 95% CI=0.80-4.90, P=0.14, N=4); CIN grade 4 across all cycles (OR=0.73, 95% CI=0.37-1.47, P= 0.38, N=3); CIN grade 4 after the first cycle (OR=2.58, 95%CI= 0.86-7.73, P=0.09, N=3); and chemotherapy dose delays or reductions (OR=2.25, 95%CI=0.42-11.97, P= 0.34, N=2). Conclusion: In this independent study, the likelihood of developing FN and CIN grade 4 in the first cycle or across all chemotherapy cycles, and the likelihood of chemotherapy dose delays or reductions were statistically not different in NHL patients treated with R±CHOP and administered pegfilgrastim same-day or 24-72h post-chemotherapy. In the setting of NHL treated with R±CHOP, administering pegfilgrastim on the day of completion of chemotherapy may be a safe and effective method of prophylaxis. Figure 1 Figure 1. Disclosures Alrawashdh: Genentech: Current Employment. McBride: BMS: Current Employment. Abraham: Matrix45, LLC: Current holder of individual stocks in a privately-held company.

Efficacy of interleukin 17 inhibitor therapy in overweight and obese psoriasis patients (preliminary data)

In recent years, comorbidity in psoriasis has been actively studied, one of the most significant of which is obesity. Obesity is a risk factor for dermatosis in susceptible individuals, which can affect the effectiveness of therapy for the disease, including genetically engineered biological drugs.The aim of the study. To study the effectiveness of therapy with an interleukin‑17 inhibitor (iskekizumab) and the dynamics of lipid parameters in patients with psoriasis and overweight and obesity.Material and methods. A retrospective study of 25 patients diagnosed with psoriasis vulgaris was carried out. Inclusion criteria were PASI more than 12 points, BSA more than 10% and sPGA more than 3 points, age over 18 years. Anthropomeric parameters and lipid profile data were studied. All patients received iksekizumab treatment according to the standard regimen. Evaluation of the effectiveness of therapy was carried out according to the dynamics of PASI indicators, as well as the frequency of patients achieving the response PASI 75, PASI 90 and PASI 100.Results. Obesity and overweight were diagnosed in 13 patients who made up the main observation group. The comparison group included 12 nonobese patients. Patients in the observation groups did not differ in sex and severity of psoriasis. In patients of the main group, hypertriglyceridemia was significantly more often diagnosed (55.6%; 95% CI: 33.7–75.4; in its absence in the comparison group; p = 0.0200), as well as other comorbidity – hypertension and metabolic syndrome (p = 0.0016 and p = 0.0052, respectively). On the background of therapy, skin rashes were resolved in patients of both observation groups. By the seventh week of therapy, there was a significant decrease in PASI, sPGA and BSA, by the 36th week, the rash was completely resolved in all patients (p < 0.001). There were no significant differences between the groups in the dynamics of clinical indicators of the severity of the disease. Body mass index did not change statistically significantly over the observation period in patients of both groups (p = 0.6690). Changes in lipid profile for all parameters were statistically insignificant. There were no significant differences in the frequency of achieving PASI of 75, 90 and 100% between the groups.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens.Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT&gt;MIC), 100% fT&gt;MIC, and 100% fT&gt;4xMIC.Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT&gt;MIC. However, the standard regimen did not attain more aggressive target of 100% fT&gt;MIC or 100% fT&gt;4xMIC.Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT&gt;MIC are adopted, dose increase may be needed.