Tag: General Medical Oncology & Hematology

SUMMARY: Thrombocytopenia is a frequent finding in hospitalized patients and is one of the most common reasons for inpatient hematology consultations. Thrombocytopenia is usually defined as a platelet count of less than 150,000 per cubic millimeter, whereas severe thrombocytopenia is considered as platelet counts less than 50,000 per cubic millimeter. It is estimated that the prevalence of thrombocytopenia at admission to ICU is around 20-30% of patients, and a similar number of patients develop thrombocytopenia (from a normal platelet count) while being treated in the ICU.

Approximately 18% of hospitalized patients undergo Central Venous Catheter (CVC) placement, an invasive procedure, during admission. Central Venous Catheter facilitates simultaneous infusion of multiple medications, administration of vasoactive drugs, irritating or hypertonic solutions such as TPN, as well as hemodialysis and hemodynamic monitoring. The routine use of ultrasound guided CVC placement has greatly reduced the risk of bleeding complication. In clinical practice, platelet-transfusion thresholds range from 20,000 to 50,000 per cubic millimeter, as there is lack of good-quality evidence. It is however unclear whether the use of prophylactically transfused platelet concentrates is necessary to prevent CVC-related bleeding complications, in patients with severe thrombocytopenia.

The PACER trial is a multicenter, randomized, controlled, noninferiority study of Prophylactic Platelet Transfusion Prior to Central Venous Catheter Placement in Patients with Thrombocytopenia. This trial was conducted on hematology wards and in ICUs at 10 hospitals in the Netherlands, to evaluate whether the omission of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter increased the risk of catheter-related bleeding. This study included 373 patients (N=373) randomized in a 1:1 ratio to receive either one unit of platelet concentrate (N=188) or no platelet transfusion (N=185) before CVC placement. CVC placement was ultrasound guided, performed by an experienced operator, could be of any diameter, could be either tunneled or nontunneled, and could be placed in the internal jugular vein, subclavian vein, or femoral vein. Randomization was stratified according to the trial center and catheter type (large-bore dialysis catheter or regular catheter). Patient characteristics at the time of CVC placement were well balanced between the two trial groups. Exclusion criteria included therapeutically administered anticoagulant, a history of congenital or acquired coagulation factor deficiency or bleeding risk, or a spontaneously prolonged INR of 1.5 or more.

The Primary outcome was the occurrence of catheter-related bleeding of Grade 2-4 within 24 hours after CVC placement. Bleeding was assessed according to the Common Terminology Criteria for Adverse Events. The occurrence of bleeding and any related treatments were recorded by trained staff members at each site immediately after CVC placement, and at 1 hour and 24 hours thereafter. A key Secondary outcome was major bleeding (Grade 3-4).

Grade 2-4 catheter-related bleeding occurred in 4.8% of patients in the platelet transfusion group and in 11.9% of patients in the no-transfusion group. The absolute risk difference was 7.1%, Relative Risk was 2.45, and noninferiority of withholding platelet transfusion was not shown. The risk of Grade 3 or 4 catheter-related bleeding was lower in the platelet transfusion group compared to the no-transfusion group (2.1% versus 4.9%), with Relative Risks consistent with the Primary outcome.

The bleeding risk in the prespecified exploratory subgroup analysis, were similar to the findings of the Primary analysis. The bleeding risk among the patients being treated on the hematology ward was higher than that among patients in the ICU, and the same was true with the use of tunneled catheters as compared with nontunneled catheters. The differences in CVC-related bleeding risk was attributed to patients in the ICU more often having consumptive thrombocytopenia, whereas patients with hematologic problems in the hematology ward more often have hypoproliferative thrombocytopenia.

It was concluded from this study that in patients with severe thrombocytopenia, withholding prophylactic platelet transfusion before Central Venous Catheter placement in those with a platelet count of 10,000 to 50,000 per cubic millimeter resulted in more catheter-related bleeding events, and prophylactic platelet transfusion was associated with a lower risk of bleeding.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. van Baarle FLF, van de Weerdt EK, van der Velden WJFM, et al. N Engl J Med 2023; 388:1956-1965.

SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing. Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. These models provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc.

The Genomics and Population Health Action Collaborative was formed in 2015 with the goal of identifying challenges and potential best practices for the widespread integration of evidence-based genomics applications in population health programs. They endorsed 11 genes associated with the three CDC Tier 1 inherited Autosomal Dominant cancer predisposition conditions – Hereditary Breast and Ovarian Cancer syndrome, Lynch syndrome, and Familial Hypercholesterolemia, as being a reasonable starting point for primary genomic screening in the general population.

Tapestry study is collaboration between Mayo Clinic and Helix, a population genomics company. The Tapestry trial included 44,306 patients who received treatment across Mayo Clinic sites in Minnesota, Arizona and Florida. Researchers gathered and evaluated saliva samples for pathogenic mutations in BRCA1 and BRCA2 (denoting Hereditary Breast and Ovarian Cancer), as well as MLH1, MSH2, MSH6, PMS2 and EPCAM (denoting Lynch syndrome). The mean age was 55 years, 63% were women and 90% were Caucasian. The aim of this study was to evaluate whether screening in a multisite tertiary medical center using Whole Exome Sequencing (WES) could efficiently identify carriers of two conditions, Hereditary Breast and Ovarian Cancers and Lynch syndrome, and determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines.

The researchers identified 550 carriers of pathogenic mutations, including 387 individuals with Hereditary Breast and Ovarian Cancer syndrome (HBOC) and 163 with Lynch syndrome. Of these individuals with pathogenic mutations, 52.1% had no knowledge prior to this study that they carried cancer predisposition genes, and 39.2% of CARRIERS did not meet NCCN criteria for genetic testing, including 56.2% of those with Lynch syndrome and 32% of those with HBOC. Among the patients who were NEWLY DIAGNOSED with Lynch syndrome and HBOC syndrome during this study, 60% were ineligible for genetic testing per the current guidelines. They included 78% of those with Lynch syndrome and 51% of those with HBOC syndrome. Some of the reasons for not meeting NCCN criteria included having no personal history of cancer (63.3%), an insufficient number of relatives who had cancer (60.5%) and a cancer type or types not related to a genetic syndrome (58.6%). Among those who met NCCN guidelines for testing, 34.2% reported not knowing their diagnosis prior to the study. The researchers also noted that patients with HBOC or Lynch syndrome from racial and ethnic minority groups were significantly more likely than white patients to not meet NCCN screening criteria (49% versus 32%, respectively).

It was concluded that genomic screening in the broad general population for CDC Tier 1 genetic conditions has the potential to identify 50% of at-risk carriers who are otherwise not detected in current medical practice. Early diagnosis and intervention could have a positive impact on public health, and a systemic bias in the current guidelines could potentially be overcome by universal genetic testing. The authors added that the limitation of this study is that the patient population in this study may not reflect the demographics of the general population.

Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines (AACR press release). Available at: www.aacr.org/about-the-aacr/newsroom/news-releases/exome-sequencing-identifies-individuals-with-cancer-predisposition-syndromes-missed-by-current-screening-guidelines/. Published April 18, 2023.