Results of Intensive Chemotherapy in 434 Adult Patients (pts) with Philadelphia-Negative Acute Lymphoblastic Leukemia (ALL): Predictive Prognostic Model for Survival
Authors: Yilmaz Musa , Kantarjian Hagop M. , Cortes Jorge , Garcia-Manero Guillermo , Chahoud Jad , Ravandi Farhad , Sasaki Koji , Konopleva Marina , Takahashi Koichi , Wierda William G. , Jain Nitin , Verstovsek Srdan , Estrov Zeev , Bose Prithviraj , Pierce Sherry , Jabbour Elias 
Published: October 2019

Abstract
Introduction: Older age, poor performance status, diminished organ function and adverse genetic features are poor prognostic factors in treatment of ALL. Our goal is to develop prognostic models predicting complete response (CR), death in CR, 2-month mortality and survival in adult pts with ALL, which would be used to assist pts and oncologists to establish expectations with intensive chemotherapy.
Methods: A total of 434 pts with ALL treated with intensive chemotherapy between 2000 and 2015 were analyzed. Frontline treatments included hyperCVAD alone (n=152) or in combination with rituximab (n=156) [Thomas D, et.al, JCO 2010], or ofatumumab (n=34), and Augmented-BFM (n=92) [Rytting ME, et al Cancer 2014]. Following clinical features were analyzed; age, gender, diagnosis (B or T-ALL), performance status (Zubrod), prior malignancy, prior chemotherapy, white blood cell count, platelet count, hemoglobin level, peripheral blood (PB) blast, bone marrow (BM) blast, mixed lineage leukemia (MLL) gene rearrangements, albumin level, total bilirubin level, estimated glomerular filtration rate (GFR by the Modification of Diet in Renal Disease Study equation) and chemotherapy type. Univariate and multivariate analyses of clinical features associated with CR, death in CR, 2-month mortality and survival were performed.
Results: Pts characteristics are summarized in Table 1. The overall CR rate, death in CR rate, 2-month mortality rate, 1-year and 5-year survival rates were 94%, 15%, 8%, 80%, and 47%, respectively. In multivariate analysis, we identified prognostic factors associated with CR, death in CR, 2-month mortality, and survival (Table 2). Age > 40 years, performance status ≥ 2, total bilirubin >1 mg/dL, GFR < 60 mL/min/1.73m2, albumin < 3.5 g/dL, WBC > 50 x109/L and presence of MLL gene rearrangements were identified as independent adverse prognostic features for overall survival (OS). Because all predictive features identified had similar statistical impact, patients were divided into four different risk categories: 1) low (no adverse feature) 92 pts (21%), 2) intermediate-1 (1 adverse feature) 138 pts (32%), 3) intermediate-2 (2 adverse features) 111 pts (26%), and 4) high (≥ 3 adverse features) 93 pts (21%). Median OS survival was not reached in low and intermediate-1 categories, and it was 40 and 15 months for intermediate-2 and high risk categories respectively (p<0.001). The 5-year survival rates were 65%, 57%, 42%, and 22%, respectively (Figure 1).
Conclusion: Prognostic model predicting survival in adult ALL pts were developed based on standard readily available baseline clinical features, which may assist in therapeutic and investigational decisions. This prognostic model is based on retrospective analysis, and further validation is needed in independent study groups.
Table 1. Characteristics of the Study Group (n=434) Parameter Category No. (%) Age > 40 years old yes 207 (48) no 227 (52) Sex female 198 (46) male 236 (54) Diagnosis Pre-B 419 (97) Pre-T 15 (3) Prior Malignancy yes 46 (11) no 388 (89) Prior Chemotherapy yes 31 (7) no 403 (93) Prior Radiotherapy yes 21 (5) no 413 (95) Performance Status ≥ 2 yes 69 (16) no 365 (84) MLL Gene Rearrangement yes 34 (8) no 400 (92) WBC, x109/L ≤ 50 389 (90) > 50 45 (10) Platelet, x109/L < 100 93 (21) ≥ 100 341 (79) Hg, gr/dl < 8 144 (33) ≥ 8 290 (67) PB Blast yes 337 (78) no 97 (22) BM Blast, % ≥ 50 388 (89) <50 46 (11) Albumin, gr/dl < 3.5 213 (49) ≥ 3.5 221 (51) Total Bilirubin, mg/dl > 1 53 (12) ≤ 1 381 (88) GFR, ml/min/1.73m2 < 60 45 (10) ≥ 60 389 (90) Chemotherapy HCVAD 152 (35) HCVAD + Rituximab 156 (36) HCVAD + Ofatumumab 34 (8) AUG-BFM 92 (21)
Table 2. Multivariate Analysis of Adverse Factors Associated with the Clinical Outcomes Outcome Factor p O.R. C.I. Death in CR Age > 40 years old 0.004 3.0 1.4-6.3 2-Month Mortality Total Bilirubin > 1 mg/dl 0.018 3.0 1.2-6.0 Albumin < 3.5 gr/dl 0.023 2.6 1.1-6.0 GFR < 60 ml/min/1.73m2 0.009 3.2 1.3-7.6 Complete Response GFR < 60 ml/min/1.73m2 0.001 0.2 0.1-0.5 Overall Survival Age > 40 years old 0.002 0.6 0.5-0.8 Performance Status ≥ 2 <0.001 0.5 0.4-0.7 Total Bilirubin > 1 mg/dl 0.029 0.7 0.4-0.9 GFR < 60 ml/min/1.73m2 0.003 0.6 0.4-0.8 Albumin < 3.5 gr/dl 0.045 0.8 0.6-0.9 WBC > 50 x109/L 0.030 0.6 0.4-0.9 MLL Gene Rearrangement 0.032 0.6 0.4-0.9
Figure 1. Overall Survival by Risk Categories Figure 1. Overall Survival by Risk Categories

Disclosures
Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.