Cancer-related microangiopathic hemolytic anemia in patients with advanced gastric cancer: A retrospective single-center analysis

BACKGROUND Microangiopathic hemolytic anemia(MAHA) with thrombocytopenia and organ failure caused by tumor-associated thrombotic microangiopathy(TMA) is a lifethreatening oncological emergency. Rapid diagnosis and precise distinction from other forms of TMA is crucial for appropriate therapy, which aims at treating the underlying malignancy. However, the prognosis of patients with cancer-related(CR)-MAHA is limited. To date, less than 50 patients with gastric cancer and CRMAHA have been reported, mainly as single case reports, and detailed information on treatment strategies and outcome are scarce. We analyzed the characteristics and outcomes data of CR-MAHA patients with gastric cancer treated at our center between 2012 and 2019.AIM To gain knowledge about CR-MAHA and the course of disease.METHODS We retrospectively analyzed patients using an institutional prospectively maintained database. Patients who had CR-MAHA but other cancer types or cancer of unknown primary were excluded. The basic requirements for inclusion were: Histologically proven gastric adenocarcinoma;and clinical diagnosis of hemolytic anemia with schistocytes with or without thrombocytopenia. The observation period for each patient started with the first day of documented symptoms. The follow-up period for this analysis ended on February 1, 2020.RESULTS We identified eight patients with a median age of 54 years. Histologically, all patients had(partial) diffuse subtypes of gastric adenocarcinoma with partial or complete signet cell morphology. All patients had metastatic disease and one patient had a microsatellite instability-high(MSI-H) tumor. In three patients, clinical signs of MAHA preceded the diagnosis of cancer, and in two patients, CRMAHA indicated recurrent disease. All patients had severe hemolytic anemia and thrombocytopenia. Six patients experienced severe bone pain, and five patients had dyspnea. Systemic, 5-fluorouracil-based combination chemotherapy was initiated in six patients, which resulted in rapid initial response with significant improvement of clinical symptoms and blood values. Progression-free survival(PFS) of the whole cohort was 1.9 wk and median overall survival(OS) was 1.9 wk. For patients with chemotherapy, PFS was 9.0 wk and OS was 10.3 wk. The patient with the MSI-H tumor has been undergoing immunotherapy for more than 3 years.CONCLUSION The benefit of chemotherapy in CR-MAHA patients is limited. Immunotherapy for patients with MSI-H tumors may lead to long-term tumor control even in CRMAHA patients.

Precision medicine becomes reality- tumor type--agnostic therapy

Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.