Outcome of Patients with T-Cell ALL Post Frontline Therapy Failure
Authors: Parseghian Christine , Kantarjian Hagop M , Cortes Jorge E. , Garcia-Manero Guillermo , Konopleva Marina , Wierda William , Kadia Tapan , Verstovsek Srdan , Sasaki Koji , Ravandi Farhad , Takahashi Koichi , Jain Nitin , Pierce Sherry , Jabbour Elias 
Published: November 2019

Abstract
Background: Significant progress has been made in the management of patients with ALL. However, unlike in pediatric acute lymphoblastic leukemia (ALL), where close to 90% of patients are cured with the use of multi-agent chemotherapy regimens, in adult ALL, and particularly T-cell acute lymphoblastic leukemia (T-ALL), therapeutic options are limited. It has been previously demonstrated that the hyper-CVAD (HCVAD) regimen as frontline therapy achieves high rates of complete remission (CR) and improves clinical outcomes in patients with T-ALL. However approximately 50% of these patients relapse.
Aims: To assess the outcome of patients with T-ALL who have failed frontline therapy. To assess their median survival and the impact of salvage therapy. This will be important when determining further therapeutic strategies in this clinical setting, such as allogeneic stem cell transplantation or therapy with investigational agents.
Methods: We reviewed 80 patients with a diagnosis of T-ALL who received HCVAD between 1/2001 and 11/2014. Of those, 31 patients (39%) who had either induction failure (n=4) or relapsed after a first remission (n=27), and in whom long-term follow up was available, were currently analyzed. Impact of salvage therapy from time of failure was assessed.
Results: Patient characteristics are summarized in Table 1. Frontline treatment administered included the hyperCVAD in 24 patients and the Augmented BFM in 7. Median duration of response was 6 months (range, 0 to 48). Post frontline failure, 20 patients (64%) received Salvage 1 regimen, 15 (48%) received Salvage 2, and 10 (32%) received Salvage 3 or more. Salvage 1 included nelarabine [n=8; 2/8 responses (1 CR, 1 CRp) for a median of 5 months], HCVAD [n=7; 1/7 response (1CR) for 2 months], asparaginase based regimen [n=3; 2/3 responses (1 CR, 1 CRp) for 2 months], liposomal vincristine [n=1; 1/1 response (1CR) for 3 months], and clofarabine [n=1; 0/1 response]. The overall response rate to Salvage 1 was 30% (4 CR, 2 CRp) for a median of 3 months. Three patients received subsequent allogeneic stem cell transplantation (ASCT); 1 of them is alive in CR after 7.5+ years. Salvage 2 included asparaginase based regimen [n=7; 5/7 responses (4 CR, 1 CRp) for a median of 4 months], nelarabine [n=4; 0/4 response], HCVAD [n=3; 1/3 response (1PR) for 3 months], and clofarabine [n=1; 0/1 response]. The overall response rate to Salvage 2 was 40% (4 CR, 1 CRp, 1 PR) for a median of 4 months. One patient received subsequent ASCT and is alive in CR after 4.5+ years. Median follow-up from the time of failure was 8 months (range, 1 to 95). Median survival from time of failure was 5 months (range, 1 to 95). The 1-year survival rate from time of failure was 23%. At the last follow up 4 patients (13%) are alive; 2 of them in CR post ASCT.
Conclusion: The outcome of patients with T-ALL post frontline therapy failure is poor, with a median survival of 5 months with minimal impact of available salvage therapy. Therapy is needed; these patients should be referred to clinical trials.
Table 1. Patient characteristics at time of diagnosis Characteristics at time of diagnosis, N=31 N (%)/Median [Range] Age (years) 29 [19-76] Age < 30 years 16 (52) Sex (Male) 24 (77) Subtype Early 14 (52) Thymic 10 (37) Mature 3 (11) Unknown 4 (13) Karyotype Diploid 14 (45) Complex 9 (29) Miscellaneous 7 (23) Not done 1 (3) WBC x 109/L 27 [0.8-292] WBC ≥ 30 x 109/L 14 (45) Hgb (g/dL) 10.5 [7.2-15] PLT < 100 x 109/L 22 [7.2-15] BM blasts % at diagnosis 82 [6-98] LDH (IU/L) 278 [236-3600] Total bilirubin (mg/dL) 0.5 [0.1-1.7] Creatinine (mg/dL) 31 Albumin 31

Disclosures
Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Wierda:Celgene Corp.: Consultancy; Glaxo-Smith-Kline Inc.: Research Funding.