Cost Effectiveness of Molecular Diagnostic Testing Algorithms for the Treatment Selection of Frontline Ibrutinib for Patients with Chronic Lymphocytic Leukemia in Australia

BACKGROUND: Clinical indications for ibrutinib reimbursement in Australia should consider the inclusion of patients with chronic lymphocytic leukemia (CLL) harboring prognostically unfavorable TP53/IGHV genomic aberrations. This study assessed the cost effectiveness of five first-line treatment strategies in CLL for young (aged ≤ 65 years), fit patients without significant comorbidities: (1) no testing (fludarabine, cyclophosphamide and rituximab [FCR] for all), (2) test for del(17p) only, (3) test for TP53 gene mutation status, (4) test for TP53 and IGHV gene mutation status and (5) no testing (ibrutinib for all).METHOD: A decision analytic model (decision tree and partitioned survival model) was developed from the Australian healthcare system perspective with a lifetime horizon. Comparative treatment effects were estimated from indirect treatment comparisons and survival analysis using several studies. Costs, utility and adverse events were derived from public literature sources. Deterministic and probabilistic sensitivity analyses explored the impact of modeling uncertainties on outcomes.RESULTS: Strategy 1 was associated with 5.69 quality-adjusted life-years (QALYs) and cost 458,836 Australian dollars (AUD). All other strategies had greater effectiveness but were more expensive than Strategy 1. At the willingness-to-pay (WTP) threshold of 100,000 AUD per QALY gained, Strategy 1 was most cost effective with an estimated probability of 68.8%. Strategy 4 was cost effective between thresholds 155,000-432,300 AUD per QALY gained, and Strategy 5 &gt;432,300 AUD per QALY gained.CONCLUSION: Population targeting using mutation testing for TP53 and IGHV when performed with del(17p) testing specifically in the context of frontline ibrutinib choice does not make a cost-ineffective treatment into a cost-effective treatment.</p

Biallelic deleterious germline SH2B3 variants cause a novel syndrome of myeloproliferation and multi-organ autoimmunity

SH2B3 is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss-of-function SH2B3 variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss-of-function SH2B3 variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi-organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the sh2b3 crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin-derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL-3, GH, GM-CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants in SH2B3 to be considered a valid gene-disease association for a clinical syndrome of bone marrow myeloproliferation and multi-organ autoimmune manifestations

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Health economic evidence for the use of molecular biomarker tests in hematological malignancies: A systematic review

Objectives: Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies. Methods: We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020. Publications were independently screened by two reviewers. Clinical study characteristics, economic methodology, and results were extracted, and reporting quality was assessed. Results: Fourteen studies were identified, of which half (n = 7; 50%) were full economic evaluations examining both health and economic outcomes. Studies were predominantly conducted in a first-line treatment setting (n = 7; 50%) and adopted a non-lifetime time horizon to measure health outcomes and costs (n = 7; 50%). Five studies reported that companion diagnostics for associated therapies were likely cost-effective for acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Four studies suggested molecular biomarker tests for treatment monitoring in chronic myeloid leukemia were likely cost-saving. Conclusions: Although there is initial confirmation of the promising health economic results, the present research for molecular biomarker tests in hematological malignancies is sparse with many applications of technological advances yet to be evaluated