The changing face of clinical genetics service delivery in the era of genomics: a framework for monitoring service delivery and data from a comprehensive metropolitan general genetics service.

PURPOSE: Clinical genetics is an evolving specialty impacted by the availability of increasingly sophisticated investigational technologies. Methods for monitoring the changes in workload and workflow are necessary to ensure adequate service resourcing. METHODS: A literature search of known workload and workflow studies was completed, identifying metrics of value. A framework of metrics to allow consistent capture in clinical genetics practice was developed. This framework was then applied to local general genetics service data to evaluate recent changes in service delivery. RESULTS: Literature regarding service delivery metrics in clinical genetics services is limited and inconsistent in application. The metric framework generated is a useful tool for consistent and ongoing evaluation of general genetics services. Through application of the framework, new service delivery trends and significant changes in workload were identified. CONCLUSION: Studies of clinical genetics service delivery suffer from the use of inconsistent metrics. This framework will allow for monitoring of changes to service delivery, caseload volume, caseload complexity, and workforce over time. Local data presented demonstrate the significant effect that implementing clinical genomic sequencing has had on clinical service delivery. Applying this framework produces a comprehensive service characterization, enabling funding bodies to justify resourcing that addresses the growing demand of clinical genetics.

Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations.

T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.