Prognostic Implications of Pre-Treatment Hypodiploidy and Complex Cytogenetics in Adult Patients with Acute Lymphocytic Leukemia (ALL) Treated with Hyper-CVAD
Authors: Issa Ghayas C. , Kantarjian Hagop M. , Yin C. Cameron , Sasaki Koji , Garcia-Manero Guillermo , DiNardo Courtney , Takahashi Koichi , Ravandi Farhad , Cortes Jorge E. , Daver Naval , Kadia Tapan , Verstovsek Srdan , Pierce Sherry , Jabbour Elias 
Published: October 2019

Abstract
Background
Pretreatment cytogenetic analysis is frequently used to predict response and outcome in hematologic malignancies. Hypodiploidy is associated with a poor prognosis in childhood ALL. Similarly, complex cytogenetics is a known adverse prognostic factor in myeloid malignancies. The impact of hypodiploidy and complex cytogenetics has not been extensively assessed in adult patients with ALL. To address this issue, we have conducted a retrospective analysis of all adult patients with ALL treated with frontline Hyper-CVAD based regimens at our institution.
Methods
We reviewed 332 adult patients treated between May 2000 and March 2015. Patients with Philadelphia-positive ALL and those with t(4;11) were excluded. Hyodiploidy was defined as 45 or less chromosomes. Hyperdiploidy was defined as 47 and more chromosomes. Complex karyotype was defined as having 5 or more chromosomal abnormalities (Moorman et al., Blood 2007). We analyzed the clinical outcomes based on the cytogenetic risk groups. Chi-square test was performed to evaluate differences in response rates. Survival was calculated using Kaplan-Meier estimates and compared using the log-rank test.
Results
Patient characteristics, responses to therapy, and outcomes are summarized in Table 1. Thirty-five patients (10%) were hypodiploid, 67 (20%) were hyperdiploid, and 71 (21%) had a complex karyotype. With a median follow-up of 28 months (range 0.5 - 176 months), the median survival was 61, 69, and 45 months for patients with diploid, hypodiploid, and hyperdiploid cytogenetics respectively. The 3-year survival rates were 63%, 59% and 53%, respectively (p=0.18). Similarly, having a complex karyotype did not affect survival when compared to diploid cytogenetics with a median survival of 58 and 61 months respectively. The 3-year survival rates were 63% and 59%, respectively (p=0.27).
Conclusion
Unlike what has been described in childhood ALL, the prognosis of adult ALL patients with a hypodiploid or complex karyotype treated with Hyper-CVAD based regimens is similar to patients with a diploid karyotype. This could be attributed to a different biology of the disease or could be related to the treatment given in this population. The use of genomics combined with cytogenetic analysis could perhaps constitute a better predictive biomarker.
Table 1. Characteristics (n total=332) Diploid (n=147) Hypodiploid(n=35) Hyperdiploid(n=67) Complex (n=71) Median age, y (range) 44 (16-83) 58 (20-80) 54 (18-85) 58 (18-85) Sex no. (M/F) (182/150) 95/52 14/21 34/33 39/32 WBC, median x 109/L(range) 3.85 (0.4-216) 3.6 (0.7-420) 3.9 (0.6 -134) 3 (0.5-87) Hg, median g/L (range) 9.3 (3.5-16) 8.9 (4-11.9) 9.2 (4.5-14) 9.2 (5-14) Platelets, median x 109/L (range) 64 (1-626) 32 (7-233) 36 (7-271) 32 (7-233) Creatinine, median mg/dL (range) 0.9 (0.3-4) 0.8 (0.45-1.5) 0.8 (0.5-2.3) 0.8 (0.4-2.3) Bilirubin, median mg/dL (range) 0.5 (0-8) 0.6 (0.2-5.6) 0.5 (0.2-11) 0.5 (0.2-5.4) LDH, median IU/L (range) 839 (268-32029) 1460 (172-6408) 1177 (345-8953) 1241 (172-8953) Blasts in BM, median % (range) 78 (0-99) 88 (60-98) 83 (26-100) 84(26-97) Blasts in PB, median % (range) 12 (0-99) 36 (0-92) 26 (0-96) 26(0-100) B-ALL (n=282) n 120 33 63 65 T-ALL (n=50) n 27 2 4 6 Complete response (%) 92 88 88 88 3-year survival rate (%) 63 59 53 56

Disclosures
DiNardo: Novartis: Research Funding. Cortes:Teva: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.