Limited FISH Testing for MDS-Defining Cytogenetic Abnormalities Rapidly Identifies Patients with Newly Diagnosed AML Eligible for CPX-351
Authors: McMahon Christine M. , Nelson Nya , Ganetsky Alex , Mangan James K. , Frey Noelle V. , Perl Alexander E. , Martin Mary Ellen , McCurdy Shannon R. , Loren Alison W. , Hexner Elizabeth O. , Bagg Adam , Morrissette Jennifer J.D. , Luger Selina 
Published: October 2019

Introduction: CPX-351 (liposomal cytarabine and daunorubicin; VYXEOS) improves survival and complete remission rates compared to standard induction chemotherapy (7+3) in patients 60 to 75 years old with newly diagnosed myelodysplastic syndrome (MDS)-associated and therapy-related AML (Lancet et al., JCO 2018) and was approved by the U.S. Food and Drug Administration in August 2017. In addition to patients with a known history of MDS or cytotoxic and/or radiotherapy, patients with de novo AML with WHO-defined MDS-related cytogenetic changes are also eligible for CPX-351. We have implemented a diagnostic clinical pathway for patients with newly diagnosed AML which includes rapid FISH assessment for the most common MDS-defining karyotypes in patients who are potential candidates for CPX-351. We reviewed outcomes after the first year of this diagnostic pathway in our institutional cohort comparing results of chromosome metaphase analysis and rapid FISH.

Methods: We performed both rapid MDS-FISH testing (turnaround time < 6 hours) and metaphase analysis on all patients who presented to the University of Pennsylvania from 9/2017 through 6/2018 with newly diagnosed AML who were potential candidates for CPX-351 induction therapy based on age and other clinical factors. Our MDS-FISH panel includes probes for EGR1(5q31)/5p15.2, D7S486(7q31)/CEP7, and TP53(17p13.1)/NF1(17q11.2) (MetaSystems). Results of the limited FISH testing were compared with metaphase chromosome analysis. Demographic and clinical information was abstracted from the electronic medical record. This study was approved by the University of Pennsylvania Institutional Review Board.

Results: Twenty-nine patients with newly diagnosed AML from 9/2017 through 6/2018 had both rapid MDS-FISH and karyotype testing performed. Nineteen patients (65.5%) had de novo AML, while 7 (24.1%) had a clinical history of MDS and 3 (10.3%) had a history of prior cytotoxic and/or radiation therapy. Metaphase analysis revealed WHO-defined MDS-related cytogenetic abnormalities in 14/29 patients (48.3%). Of these 14 patients, 11 (78.6%) also had positive MDS-FISH testing in >=1 probe. Of the 3 patients with MDS-related cytogenetic abnormalities that were identified by metaphase analysis but not the FISH panel, 2 had a history of either MDS (n=1) or prior cytotoxic chemotherapy (n=1) and therefore were eligible for CPX-351 based on clinical history alone. Of the 7 patients with de novo AML and MDS-defining cytogenetic abnormalities, 6 (85.7%) were identified by the FISH screen.

Conclusions: Rapid FISH testing for MDS-defining cytogenetic changes using probes for abnormalities of chromosomes 5, 7, and 17 efficiently identifies the majority of patients with newly diagnosed de novo AML who do not have a clinical history of MDS or cytotoxic therapy but are eligible for induction therapy with CPX-351 based on the presence of MDS-defining cytogenetic abnormalities. The combination of rapid FISH testing and clinical history has a high sensitivity for identifying patients with MDS-defining karyotypic abnormalities. This diagnostic clinical pathway allows for the expeditious identification of patients eligible for CPX-351.

Disclosures

Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Astellas: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy.