Philadelphia (Ph) Chromosome (BCR-ABL1 fusion) As a Recurrent Genetic Abnormality Among Therapy-Related Acute Leukemia
Authors: Aldoss Ibrahim , Stiller Tracey , Song Joo Y. , al Malki Monzr M , Ali Haris , Salhotra Amandeep , Khaled Samer K , Aribi Ahmed , Gaytan Popsie , Murata-Collins Joyce L. , Snyder David S. , Stein Anthony S. , O'Donnell Margaret , Nakamura Ryotaro , Palmer Joycelynne M. , Forman Stephen J. , Marcucci Guido , Pullarkat Vinod 
Published: October 2019

Abstract
Philadelphia (Ph) chromosome [t(9;22)] was reported as a rare recurrent balanced translocation among therapy-related acute leukemia (N=10, 2%) [Gene Chromosomes Cancer. 2002]. Here, we conducted a retrospective analysis of therapy-related acute leukemia with Ph chromosome (Ph+ t-AL) to better understand this entity. We included cases diagnosed at our institution between 2000 and 2016, excluding patients with CML in blastic phase. We defined Ph+ t-AL as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) harboring Ph chromosome that developed after prior exposure to cytotoxic therapy (chemotherapy, radiation or both).
Of the 330 patients with Ph+ AL, 28 cases (8.4%) met our definition of Ph+ t-AL, including 25 (89%) B-cell ALL, 1 case of T-cell ALL, and 2 cases of AML. The median age at diagnosis was 56 years (range: 29-79), and 64% (N=18) of them were female. Breast cancer was the most common prior malignancy [N=8, 29%], followed by lymphoma [N=6, 21%] and sarcoma [N=4, 14%]. Prior cytotoxic therapy consisted of chemotherapy (32%), radiotherapy (29%) and chemoradiation (39%). Among 20 patients who had prior chemotherapy, 70% had received alkylating agents (i.e., cyclophosphamide, temozolomide), 70% had received topoisomerase II inhibitors (i.e., etoposide, anthracycline), 40% had received antimetabolites, (i.e., methotrexate) and 50% both alkylators and topoisomeraseII inhibitor. The median interval between prior malignancy and Ph+ t-AL diagnosis was 6.8 years (range: 2.5-19.6) and was not different according to prior cytotoxic therapy modality [chemotherapy/radiotherapy vs. either chemotherapy or radiotherapy alone (P = 0.66)]. The median white blood cells count at presentation was 20 x103/µL (range: 1.4-230). Myelodysplastic syndrome preceded one case of AML. Among 22 patients with available standard cytogenetics, 7 (32%) had Ph chromosome as the sole abnormality, while 15 (68%) had an additional cytogenetic abnormality (ACA). Complex (≥ 3 abnormalities) or monosomal karyotypes were observed respectively in 12 and 9 cases. Chromosome 7 abnormality was observed in 6 (27%) cases, including 5 of them with monosomy 7. In 18 patients (ALL = 17; AML = 1) with available molecular study for BCR/ABL1, all were positive for p190 fusion transcript, including 3 patients who carried both p210 and p190 (ALL =2; AML =1). The median time from prior diagnosis to AL onset was not different according to cytogenetics (isolated Ph chromosome vs. complex/monosomy karyotype) (P> 0.99). However, prior exposure to topoisomeraseII inhibitor was more common among patients with isolated Ph chromosome compared to patients with complex/monosomy karyotype (86% vs. 33%, P= 0.02).
Tyrosine-kinase inhibitor (TKI) was administered as part of initial induction regimen to all patients except 4 (N= 24, 86%), who received TKI only upon leukemia relapse/progression. Of the 28 patients, 25 (89%) achieved complete remission (CR) with induction, and 17 (61%) patients subsequently underwent alloHCT; of them, 13 (76%) were in CR1. The 2-year overall survival and event-free survival were respectively 48% and 36% for all patients, and 63% and 41% for those who underwent alloHCT, respectively. The 2-year cumulative incidence rates of relapse and non-relapse mortality for transplanted patients were 19% and 25%, respectively.
In conclusion, Ph+ chromosome is a recurrent therapy-related chromosomal aberration presenting most often as a B-cell ALL phenotype, and only rarely as T-cell ALL or AML. Ph+ t-AL is associated with high incidence of ACA, including complex and monosomal karyotype as well as chromosome 7 abnormalities, similar to therapy-related myeloid neoplasms. Similar to de novo Ph+ ALL, a high response rate to TKI-based regimen was observed among Ph+ t-AL. Given its therapeutic implication, presence of Ph chromosome should be excluded in all cases of t-AL.

Disclosures
Song: Seattle Genetics: Consultancy. Ali:Incyte Corporation: Research Funding. Salhotra:Alexion: Consultancy. Snyder:Ariad: Consultancy; Novartis: Consultancy. Stein:Amgen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.