Predictive Markers of First Line Failure of Anti-Retroviral Therapy in HIV Positive Patients in Pakistan

Background: HIV treatment centres register HIV positive patients, specially trained doctors prescribe Antiretroviral Therapy to the selected cases that fulfill the criteria for initiation of HAART. Aim: To establish predictive markers of failure of 1st line ART in HIV positive patients on first line ART under treatment in HIV Treatment Centre of PIMS Islamabad. Study design: Retrospective case control study. Methodology: Retrospective case control study done at HIV Treatment Centre at PIMS Islamabad. Cases were patients who failed 1st line ART and started on second line ART from November 2005 to June 2020. Patients responding well to first line ART since more than five years or more were taken as controls. Various factors were analyzed in both groups and compared to find their level of significance. Data was analyzed by SPSS software, version 25 as qualitative variables were expressed as frequencies and percentages. Results: CD4 count of all 38 patients was below 300 on diagnosis. In 21 patients (55.3%) CD4 count initially increased but there was no rise in CD4 count in 17 patients (44.7%) after start of 1st line ART. Conclusion: We concluded that CD4 count is one of the most important predictive markers in success or failure of ART. Rising number of CD4 count on follow up visits gives a strong indication that patient is responding well to the prescribed treatment and is likely to benefit from the current regimen of ARVs for a longer period in future. Keywords: Predictive Markers, CD4 count, Viral Load, HIV, ART, Compliance and Co-morbidities

Classification and regression tree for estimating predictive markers to detect T790M mutations after acquired resistance to first line EGFR-TKI: HOPE-002

Background and objective: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations.Methods: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment.Results: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P<0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P=0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P=0.004) and OS (1053 vs. 956 days; HR: 0.68; P=0.051) than first-generation EGFR-TKIs.Conclusion: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Body Mass Index, Sarcopenia and Their Variations in Predicting Outcomes for Patients Treated with Nivolumab for Metastatic Renal Cell Carcinoma

Introduction : The advent of immune checkpoint inhibitors (ICI) such as nivolumab has enabled outcomes for metastatic renal cell carcinoma (mRCC) to be improved. Although, only around 25% of patients respond to these therapies without being able to formally identify them. Datas on relevant predictive markers are still laking. The obesity paradox has been shown as a relevant prognostic marker in mRCC with better outcomes for obese patients. Nevertheless, the impact of weight variation and the presence of sarcopenia during ICI is not known for now. Methods : In a retrospective study, weight and its variations were collected at first day of ICI and at 6 weeks of treatment. Scanographic imagery was used to define the skeletal muscle index (SMI) as a reflect of sarcopenia. The impact of these parameters as predictive and prognostic factors for mRCC with nivolumab was evaluated. Results : A higher BMI at baseline was significantly associated with response at the first scan (p=0.036). Longer OS was observed for patients with a weight gain compared to the group with weight loss (p=0.00028). Median OS for sarcopenic patients was 17.2 months, and 31.6 months for the non-sarcopenic group of patients, but there was no statistical difference. Conclusion : This trial showed that a higher BMI and weight gain during nivolumab treatment were good predictive markers for outcomes in mRCC with nivolumab. Sarcopenia and variations in SMI could thus be of interest, but further studies are required.

Circulating predictive markers of immune checkpoint inhibitors in non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have become one of the key approaches in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Evaluation of level of PD-L1 (ligand of the programmed cell death receptor 1) expression on tumor cells using immunohistochemistry is the only approved option for determining the indications of ICIs in this group of patients. However, despite high level of PD-L1 expression, up to 80 % of patients do not respond to therapy due to the presence of primary or acquired resistance, which determines the limited effectiveness of ICI. In addition, 8–17 % of PD-L1-negative patients with NSCLC are also able to respond to ICIs. The limitation of this marker is that it does not allow assessing both intratumoral and systemic immune status. It is necessary to search for additional predictive markers to improve the accuracy of the selection of candidates for immunotherapy, which will avoid costs, wasted time, and a high risk of immune-related adverse events in potentially unresponsive patients. The attention of researchers is devoted to circulating markers in peripheral blood, as a non-invasive alternative to biopsy for predicting and monitoring the response. This review focuses on the most promising immunological markers in peripheral blood as potential predictors of response to ICIs in patients with advanced NSCLC.

Easix-1yearas a Prognostic Index for Late Non-Relapse Mortality after Allogenichematopoietic Cell Transplantation

Introduction Late non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation(allo-HCT) is a problem that is yet to be solved. Moreover, no efficient markers exist to predict late NRM. Vascular endothelial damage is known to be a cause of late NRM after allo-HCT. The transplant endothelial activation and stress index (EASIX) was initially established for the diagnosis of thrombotic microangiopathy. Pre-transplant EASIX (EASIX-pre) quartiles were reported to be predictive markers for early NRM after allo-HCT, but EASIX could also potentially help in the evaluation of late NRM. Since late NRM may be affected by time dependent factors that cannot be evaluated before allo-HCT, the timing of EASIX evaluation may be important. Therefore, we focused on EASIX 1 year after allo-HCT (EASIX-1year). Aims This study aimed to clarify the usefulness of EASIX-pre and EASIX-1year as predictive markers of late NRM and overall survival (OS) after allo-HCT. Methods Among 210 patients with hematological disease who underwent a first allo-HCT between 2006 and 2019at our facility, we evaluated EASIX-1year in 102(53 males and 49 females) patients who were alive after 1 year without relapse and/or withdrawal. EASIX was calculated as LDH level (U/I) × Cre level (mg/dL) / Plt level (nL). EASIX-pre was evaluated 7-10 days before conditioning. EASIX-1year was evaluated within 1 month of 1 year after allo-HCT. Landmark analysis was used to perform statistical analysis of late NRM and OS starting 1 year after allo-HCT. Late NRM and OS assessments using EASIX-pre and EASIX-1year were performed with two risk groups based on the cutoff values from the receiver operating characteristic curve. Forty-four patients had acute myeloid leukemia, 24 had acute lymphoblastic leukemia, 14 had myelodysplastic syndrome, 8 had malignant lymphoma, and 12 had other diseases. The median age of the patients was 40 years (range: 16-66 years). Fifty-seven patients received myeloablative conditioning and the others received reduced intensity conditioning regimens. The number of patients in each HCT-comorbidity index (HCT-CI) risk group was as follows: low risk: 51, intermediate risk: 28, and high risk: 23. This study was performed in accordance with the Japanese Ethical Guidelines for Medical and Health Research Involving Humans and approved by the Ethical Committee of our facility. Results Median EASIX-pre was0.98 (0.12-24.1). The C-statistic of EASIX-pre for late NRM and OS were 0.561 (cutoff value: 0.595) and 0.591 (cutoff value: 0.766), respectively. Univariate analysis revealed that a high EASIX-pre value was not significantly associated with late NRM (5-year NRM 3.4% vs. 0%, p=0.24) and OS (5-year OS 91.3% vs. 93.5%, p=0.22). Moreover, the HCT-CI at pre-transplantation was not an indicator of late NRM (5-year NRM 10.2 % vs. 0%, p=0.29, 5-year OS 79.8% vs. 96.2%, P=0.19). Median EASIX-1year was 0.98 (0.15-21.8). The C-statistic of EASIX-1year for late NRM and OS were 0.63 (cutoff value 2.396) and 0.663 (cutoff value 1.159), respectively. Univariate analysis revealed that a high EASIX-1year value was significantly associated with late NRM (5-year NRM 10.1% vs. 1.3%, p&lt;0.05), but was not significantly associated with OS (5-year OS 88.3% vs. 95.2%, p=0.16). By adjusting age, donor source, HCT-CI, chronic graft versus host disease, and conditioning in multivariate analysis, a high of EASIX-1year was extracted as the risk factor for late NRM (Hazard ratio 4.26, p&lt;0.05). Conversely, neither EASIX-pre nor pre-transplant HCT-CI were extracted as risk factors for late NRM. Conclusion The present study indicated that EASIX-1year may be useful as a prognostic index for late NRM. Otherwise, pre-transplant conditions, such as EASIX-pre and pre-transplant HCT-CI, may have limited effects on late NRM. Disclosures No relevant conflicts of interest to declare.