Page 235 - 2021_10-Haematologica-web

Letters to the Editor
Therapeutic potential of ruxolitinib and ponatinib in patients with EPOR-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like or BCR-ABL1-like ALL) is a common and genetically heterogeneous subtype of B-acute lym- phoblastic leukemia (B-ALL) associated with high relapse rates and poor clinical outcomes with standard chemotherapy treatment.1,2 Rearrangements in erythro- poietin receptor gene (EPOR) comprise 2-5% of Ph-like ALL cases across the pediatric-to-adult age spectrum and are associated with constitutive JAK/STAT signaling acti- vation.3,4 A recent preclinical study showed sensitivity of EPOR-overexpressing Ba/F3 cell lines and human EPOR-rearranged ALL cells to JAK inhibitors (JAKi),5 a strategy now under clinical investigation in patients with Ph-like ALL.3 Herein, we report three adolescent/young adult (AYA) patients with de novo IGH-EPOR Ph-like ALL with high end-induction measurable residual disease (MRD) treated with post-induction chemotherapy in combination with the JAKi ruxolitinib or multi-tyrosine kinase inhibitor (TKI) ponatinib. We further demonstrate in vitro and in vivo activity of these inhibitors in primary patient leukemia cells or patient-derived xenograft (PDX) models of IGH-EPOR Ph-like ALL (Table 1).
Patient #1 (PAYDRD): An 18 year-old Hispanic/Latina female was diagnosed with National Cancer Institute high-risk B-ALL (NCI HR B-ALL) in December 2016 with an initial white blood cell (WBC) count of 79,000 with 62% peripheral blasts. Cerebrospinal fluid (CSF) showed microscopic evidence of leukemia involvement (CNS2b). Cytogenetics were notable for 46,XX and t(14;19), but fluorescent in situ hybridization (FISH) probes did not identify specific translocation breakpoints. Low density microarray (LDA) analysis of RNA expression demon- strated the kinase-activated Ph-like ALL signature with positive 8-gene and 15-gene scores of 0.739 and 0.956, respectively,3,6 and moderately elevated EPOR expression
(Table 1). ArcherDX FusionPlex (anchored multiplex poly- merase chain reaction [PCR]) analysis and next-genera- tion sequencing (NGS) detected IGH-EPOR fusion and partial deletions of IKZF1 (7p12.2) and PAX5 (9p13.2), respectively. The patient was treated with a four-drug induction chemotherapy regimen on the Children’s Oncology Group (COG) AALL1131 phase III clinical trial (clinicaltrials gov. Identifier: NCT02883049) with end- induction flow cytometry (FC) MRD 48%, consistent with induction failure. She received post-induction chemotherapy with ruxolitinib 20 mg/m2 twice-daily 14- days-on/14-days-off/month (DL-2) on the COG AALL1521 phase II clinical trial (clinicaltrials gov. Identifier: NCT02723994)7 with end-consolidation MRD 9.5% and end-interim maintenance I MRD 7.3%. Chemotherapy-associated complications included steroid-induced hyperglycemia and central venous catheter-associated thrombosis and infection. Given her persistently chemorefractory disease, the patient was subsequently treated with autologous CD19 chimeric antigen receptor T-cell immunotherapy tisagenlecleucel in August 2017 on an institutional phase I clinical trial (clinicaltrials gov. Identifier: NCT02906371) and achieved MRD-negative remission that was electively consolidated with a matched-sibling donor (MSD) allo- geneic hematopoietic stem cell transplant (HSCT) in April 2018. HSCT complications included chronic pul- monary and skin graft-versus-host disease (GvHD). She remains in continued MRD-negative leukemia remission with 100% donor chimerism at >3 years post-HSCT. PDX modeling from the patient’s diagnostic ALL speci- men was attempted and unsuccessful.
Patient #2 (PAZLFZ): A 13 year-old female was diag- nosed with NCI HR B-ALL in February 2019 with WBC 201,400 with 69% peripheral blasts. CSF was negative for leukemia (CNS1). Cytogenetics showed high hyper- diploidy (56,XX with +X,+2,+5,+6,+8,+9,+10,+19,+21, +22) in 20% of cells and 46,XX in 80% of cells. LDA analysis was positive for the Ph-like ALL signature3,6 with 8-gene and 15-gene scores of 0.776 and 0.956, respec-
Table 1. Genetic and demographic characteristics of IGH-EPOR Philadelphia chromosome-like acute lymphoblastic leukemia patients and patient-derived xenograft models.
Age/Sex Diagnostic WBC count
Clinical EOI trial MRD
COG AALL1131 48% and AALL1521
COG AALL1131 5.7% and AALL1521
CAALL-F01 15% COG AALL1131 16.3% COG AALL1131 0.18% NCT02420717 72%
LDA 8-gene score
0.739 0.776
0.747 0.763 0.701 0.756
0.342
EPOR
expression (dCt) by LDA
6.5 3.3
2.4 1.2 3.8 2.8
6.2
Other molecular alterations
IKZF1 and PAX5 dels KRAS G12D
none detected
on 63-gene panel
JAK2 R683G, IKZF1
and CDKN2A/B del
IKZF1, PAX5, and
CDKN2A/B dels
KRAS G12V, STAG1
R61C, IKZF1 and
CDKN2A/B dels
PAYDRD patient
PAZLFZ patient
H25648 patient
PAVRCK patient PDX model PAVDRS patient
PDX model MDACC3 patient
PDX model
18y/F 13y/F 17y/F 20y/M 9y/M 44y/M
79,000 201,400 78,000 136,500 182,000 194,000
Ph-like ALL: Philadelphia chromosome-like acute lymphoblastic leukemia; COG: Children’s Oncology Group: del: deletion; EPOR: erythropoietin receptor; F: female; M: male; LDA: Ph-like ALL low density microarray (>=0.5 is positive for Ph-like ALL expression signature),3 n/a: not available; PDX: patient-derived xenograft; WBC: white blood cell count; y: years; MRD: measurable residual disease. Shaded grey boxes indicate data not applicable or specimen not tested. Lower EPOR dCt values indicate higher EPOR gene expression.
haematologica | 2021; 106(10)
2763