Philadelphia chromosome as a recurrent event among therapy‐related acute leukemia
Authors: Ibrahim Aldoss, Tracey Stiller, Joo Song, Monzr Al Malki, Haris Ali, Amandeep Salhotra, Ahmed Aribi, Samer Khaled, Popsie Gaytan, Joyce Murata‐Collins, Joycelynne Palmer, David Snyder, Margaret O'Donnell, Ryotaro Nakamura, Anthony S. Stein, Stephen J. Forman, Guido Marcucci, Vinod Pullarkat
Journal: American Journal of Hematology (2016)

The majority of therapy-related acute leukemias (t-AL) have a myeloid phenotype. However, therapy-related acute lymphoblastic leukemia (t-ALL) is increasingly being recognized as a subset of t-AL 1-5. Intriguingly, in addition to the expected high incidence of MLL gene rearrangement, Philadelphia chromosome (Ph) [t(9;22)(q34.1;q11.2) resulting inBCR-ABL1 fusion] was frequently observed among these t-ALL cases. In fact, Ph chromosome was the most common cytogenetic finding in our previous t-ALL case series (11 out of 28 cases) as well as in other reports of t-ALL 1-5. The vast majority of reported cases of therapy-related Ph+ AL have precursor B-cell phenotype although rare cases with T-cell ALL and acute myeloid leukemia (AML) phenotype have been reported 6, 7. In examined study of 511 cases of t-AL and myelodysplastic syndrome (MDS), 10 (2%) patients carried t(9;22), including 5 cases presenting as ALL and the remaining 5 as AML 6. This association is further supported by one study showing a high incidence of Ph chromosome (24%) among children who met criteria for secondary/t-ALL 8, and this rate is considerably higher than what would be expected in children with de novo ALL (∼3%) 9. Herein we report the clinical features, relationship to prior therapy, immunophenotyping, cytogenetics, and clinical outcome of a cohort of t-AL that carried the Ph chromosome. We retrospective reviewed all patients diagnosed with Ph+ t-AL at City of Hope Medical Center between 2000 and February 2016. We defined t-AL as acute leukemia that developed after prior documented exposure to chemotherapy and/or radiation therapy. We included in this analysis cases of ALL and AML who had t (9;22)(q34.1;q11.2) documented by conventional cytogenetics and/or fluorescence in situ hybridization (FISH). We excluded cases of AL arising from chronic myeloid leukemia (CML) as blast crisis, and cases of AL who had a prior malignancy but had no exposure to cytotoxic therapy. Demographics as well as disease and treatment characteristics for all patients were summarized using descriptive statistics. The differences in time between diagnoses were determined using either Wilcoxon or Kruskal-Wallis tests. The relationship between topoisomerase II inhibitor (topoIIi) treatment and cytogenetics was assessed using a chi-square test. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier product limit method, and confidence intervals were calculated using the logit transformation and the Greenwood variance estimate. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated using competing risks analysis. We reviewed 350 cases of Ph+ AL (excluding blastic phase CML). This included cases of precursor B-cell ALL (N = 342), T-cell ALL (N = 2), and AML (N = 6)]. We identified 30 (8.6%) cases that met our definition of Ph+ t-AL of which, 27 (90%) were diagnosed as precursor B-cell ALL, 1 (3.3%) as T-cell ALL, and 2 (6.6%) as AML. The median interval from prior malignancy/disease diagnosis to AL diagnosis was 6.4 years (range: 2.1–19.6). Breast cancer was the most commonly observed prior malignancy (N = 8, 27%). Patient demographics, details of prior malignancies/disease, prior cytotoxic therapy modality, and drug class of chemotherapies are shown in Table 1. The median time from prior diagnosis to AL onset was not different according to the type of prior therapy (chemotherapy vs. radiation vs. chemoradiation) exposure (P =0.48). Among 21 patients who had prior treatment with chemotherapy, the median onset for developing AL after prior malignancy was 6.3 years (range: 3.3–19.6) for patients with prior exposure to topoIIi and 6.8 years (range: 2.1–15.7) for patients without prior exposure to topoIIi; however, this difference was not statistically significant (P = 0.53) (Supporting Information Table 1). One case of AML had antecedent MDS. Among the 24 patients with available conventional karyotype, 7 had Ph chromosome as the sole abnormality, while 17 (71%) had an additional cytogenetic abnormality (ACA). Complex cytogenetics (CK) (defined as ≥3 abnormalities) was observed in 12 cases, and 9 cases met the definition of monosomal karyotype (MK), including 3 cases that were non-complex MK. Chromosome 7 abnormality was observed in 6 (25%) cases, including 5 cases with monosomy 7. The median latency from prior diagnosis to AL onset was similar for patients with CK/MK and those with sole Ph chromosome (7.4 years vs. 6.8 years, P = 0.48). However, prior exposure to topoIIi was more common among patients with Ph chromosome as the sole abnormality compared to patients with CK/MK (86% vs. 33%, P = 0.02) (Supporting Information Table 2). There was no difference in OS and EFS between patients with sole Ph chromosome and those with ACA. Tyrosine-kinase inhibitor (TKI) was administered as part of the initial induction regimen to all patients (N = 26, 87%) except for four who did receive TKI afterward upon leukemia relapse or progression. Twenty-seven (90%) patients achieved complete remission (CR) with induction regimen. Seventeen (57%) patients underwent allogeneic HCT as part of AL treatment, including 13 (76%) in first CR. Myeloablative conditioning was used in 9 (53%) patients, and the source of stem cells was peripheral blood in 15 (88%). The stem cell donor was HLA-identical related matched in 6 (35%), unrelated matched in 10 (59%), and haplo-identical in 1 (6%) patient. The median follow-up for all patients from the time of diagnosis was 1.4 years (0.15-8.9), and for surviving patients was 2.3 years (0.15–8.2). Two-year OS and EFS were 44% and 35% for all patients, and 63% and 57% for patients who underwent allogeneic HCT at any time after diagnosis of AL, respectively. Two-year CIR and NRM were 19% and 25%, respectively. We report an association between cytotoxic therapy and development of Ph+ t-AL, mostly with the phenotype of precursor B-cell ALL. Ours is the largest cohort to date of therapy-related Ph+ AL and our data are consistent with observations made in various reports linking Ph chromosome to prior cytotoxic therapy 1-4, 6. Similar to de novo Ph+ ALL, a high CR rate was observed with use of a TKI-based chemotherapy regimen for Ph+ t-AL. Given the therapeutic implication, the presence of Ph chromosome should be excluded by FISH in all cases of t-AL, even in cases with T-cell or myeloid phenotype where conventional cytogenetics is unavailable or suboptimal. In the future, genomic profiling may help further characterize this entity of Ph+ t-AL and may differentiate it from de novo AL occurring in patients with prior malignancies. Ibrahim Aldoss1, Tracey Stiller2, Joo Song3, Monzr Al Malki1, Haris Ali1, Amandeep Salhotra1, Ahmed Aribi1, Samer Khaled1, Popsie Gaytan3, Joyce Murata-Collins3, Joycelynne Palmer2, David Snyder1, Margaret O'Donnell1, Ryotaro Nakamura1, Anthony S. Stein1, Stephen J. Forman1, Guido Marcucci1, Vinod Pullarkat1 1Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope, Duarte, California 2Division of Biostatistics, Department of Information Sciences, City of Hope, Duarte, California 3Department of Pathology, City of Hope, Duarte, California Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.