Secondary ALL May be Independent of Prior Cytotoxic Therapy
Authors: Ganzel Chezi , Devlin Sean M. , Douer Dan , Stein Eytan M. , Rowe Jacob M. , Tallman Martin S. 
Published: October 2019

Abstract
Background: Little is known about secondary acute lymphoblastic leukemia (ALL). The entity 'secondary ALL', refers to a diagnosis of ALL following a previous malignancy and includes 2 types of patients: those who received chemo-/radio-therapy for their prior malignancy (therapy-associated ALL, t-ALL) and those who did not (antecedent-malignancy ALL, am-ALL). This retrospective single center study describes a cohort of secondary ALL patients and assesses the features of t-ALL and am-ALL.
Methods: Patients included in this study were treated for ALL at Memorial Sloan Kettering Cancer Center (MSKCC), in the years 1993-2013. Inclusion criteria were a diagnosis of ALL and a history of any previous malignancy, irrespective of whether therapy was given for the prior malignancy. Patients with Burkitt leukemia or non-melanoma skin cancer were excluded. Fisher's exact test, Wilcoxon rank-sum test and Kaplan-Meier methodology were used.
Results: Thirty two patients with secondary ALL were identified representing 3.8% of all ALL patients treated at MSKCC during these 20 years. Among 328 adults (age>21 yrs) the incidence was 8.8%. Of the 32 patients 25% had a history of breast cancer (n=8), 19% lymphoma or myeloma (n=6) and 16% colorectal cancer (n=5). Thirty one of B ALLs (91%) were CALLA positive (CD10+). Thirteen patients (56%) received both chemotherapy and radiotherapy, 6 (26%) only chemotherapy, 2 (9%) - radiotherapy only and another 2 (9%) received radioactive iodine for thyroid carcinoma. In the t-ALL group, 89% of chemotherapy recipients received alkylating agents for their first malignancy and 47% received topoisomerase II inhibitors.
The table summarizes the characteristics, complete response (CR) rate and overall survival (OS) of the whole cohort as well as a comparison between t-ALL and am-ALL. No significant difference between groups was found regarding the incidence of B/T ALL, extramedullary disease (EMD), WBC counts, LDH level, incidence of Ph+ ALL, CR rate and OS. The estimated 3- year OS for the entire cohort was 20%.
Conclusion: Although as far as we knowthis is the largest reported study of secondary ALL, the overall number is small and should be interpreted with caution. The overall incidence of secondary ALL is not low among adults (8.8%) while secondary T-cell ALL is very rare. In contrast to previous reports, most of the secondary ALLs are CALLA-positive and do not have MLL abnormalities. Radioactive iodine may be associated with development of secondary ALL. The similar characteristics and behavior of t- and am-ALL patients, together with high incidence of family-malignancy in both groups raise the possibility that secondary ALL patients may have an inherent predisposition to develop more than one malignancy and a history of previous therapy may be of lesser importance in the pathogenesis of secondary ALL. Molecular genetic profiling of secondary ALL patients, in the future, may provide insights into this issue. The long-term survival of secondary ALL patients appears similar to other ALL patients of the same age, thus the diagnosis of secondary ALL should not impact on the therapeutic strategy.
Abstract 3648 Characteristics of secondary ALL, t-ALL and am-ALL Combined t-ALL am-ALL P N=32 N=23 N=9 Age at 1st malignancy Dx, yrs med. (range) 46 (2.4-83) 44 (2.4-75) 73 (18-83) .01 Age at ALL Dx, yrs med. (range) 55.5 (3.3-83) 52 (3.3-76) 75 (23-83) .01 Male, n (%) 17 (53) 10 (43) 7 (78) .12 Malignancy in 1st degree relative 15/26 (58) 11/19 (58) 4/7 (57) .99 1st malignancy, n (%) .39 Carcinoma 20 (63) 13 (57) 7 (78) Hematologic 5 (16) 5 (22) 0 Other 7 (22) 5 (22) 2 (22) Interdiagnoses interval, yrs med. (range) 5.33 (0.1-28) 7 (0.75-28) 4 (0.1-16) .06 B-ALL, n (%) 28/31 (90) 20/23 (87) 8/8 (100) .55 EMD, n (%) 9 (28) 7 (30) 2 (22) .99 Blood tests at diagnosis WBC, med. (range) 5.2 (0.4-90.6) 6.9 (0.7-68.4) 5.1 (0.4-90.6) .60 ANC, med. (range) 1.2 (0.1-13) 0.95 (0.1-13) 2.1 (0.2-12.1) .76 HgB, med. (range) 10.1 (5.9-14.9) 10.4 (8.1-14.9) 8.6 (5.9-12.8) .23 PLT, med. (range) 48 (11-251) 43 (20-212) 106 (11-251) .49 LDH, med. (range) [N 60-200] 360 (61-866) 371 (61-858) 273 (181-866) .87 Cytogenetics t(9,22) 12 (38) 8 (35) 4 (44) .68 Hyperdiploid 5 (16) 4 (17) 1 (11) - del 7/7p 6 (19) 4 (17) 2 (22) - del11q23 (MLL) 2 (06) 2 (09) 0 - t(4,11) 2 (06) 2 (09) 0 - CR, n (%) 25/26 (96) 18/19 (95) 7/7 (100) .99 OS .97 12 months, (95% CI) 0.49 (0.33-0.72) 0.41 (0.24-0.69) 0.71 (0.45-0.99) 24 months, (95% CI) 0.25 (0.12-0.49) 0.29 (0.14-0.59) 0.14 (0.02-0.88)

Disclosures
Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy.