Outcome of Adult Patients with Philadelphia Negative B Cell Acute Lymphoblastic Leukemia after Frontline Therapy Failure
Authors: Jain Punit L , Sasaki Koji , Kantarjian Hagop , Ravandi Farhad , Cortes Jorge E. , Garcia-Manero Guillermo , Bose Prithviraj , Daver Naval , Kadia Tapan , Verstovsek Srdan , Konopleva Marina , Jain Nitin , Bravo Montalban Guillermo , Pierce Sherry , Jabbour Elias 
Published: October 2019

Abstract
Introduction: Intensive induction-consolidation chemotherapy achieves high rates of complete response (CR) in 90% of patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, almost a half of the patients relapse and their outcome after frontline chemotherapy failure is essentially poor.
Methods: We retrospectively reviewed 463 patients with newly diagnosed Philadelphia-negative ALL from June 2002 to February 2015 at our institution. Overall survival was defined as the time interval from the date of relapse to the date of death. Kaplan-Meier method was used for survival analysis.
Results: Of the 463 patients, 155 (33%) relapsed. Data on salvage therapy and long term follow-up was available in 76 patients (17%). The median time to relapse was 15 months (range, 1-111 months). The median number of salvage regimens administered was 1 (range, 1-7). Overall, 76 patients received at least 1 salvage therapy. Thirty (39%) patients received at least 2 salvage regimens and 18 (24%) received 3 or more salvage regimens. Baseline patient characteristics are summarized in the table 1. Median follow-up after frontline therapy failure was 16 months. The median survival after relapse was 8.3 months with the 1- year and 2-year survival rates being 46 % and 28% respectively.
Salvage 1 included augmented HCVAD [n=13; 7/13 responses (6 CR, 1 CRp) for a median of 6 months], asparaginase based therapies [n=6; 2/6 response (2 CR) for a median of 2 months], monoclonal antibodies (MAB), blinatumomab, inotuzumab ozogamicin [n=19; 11/19 responses (6 CR, 5 CRp) for a median of 7 months], HCVAD + anti-CD20 antibody [n=11; 8/11 responses (5 CR, 3 CRp) for a median of 6 months], Miscellaneous [n=22; 2/22 responses (2 CR)] and HCVAD [n=5; 1/5 response (1 CR) for 1 month]. The overall response rate to Salvage 1 was 41% (22 CR, 9 CRp) for a median of 6 months. Nineteen (25%) patients received subsequent allogeneic stem cell transplantation (ASCT); 11 of them are alive with a median of 2 years with 7 of them in CR.
Thirty patients received a second salvage regimen; the most commonly used one consisted of MAB (blinatumomab; inotuzumomab ozogamicin) [n=8; 4/8 responses (2 CR, 2 CRp) for a median of 2.5 months]. The overall response rate to salvage 2 was 30% (6 CR, 3 CRp) for a median of 3 months.
At the last follow-up, overall 23 patients remained alive, 9 of them in CR.
Conclusions: Outcome of patients with Philadelphia-negative ALL post frontline therapies failure is poor with a median survival of only 8.3 months. Though some salvage therapies can induce remissions, response durations are limited. Stem cell transplant after remission offers a potential of long term cure. These patients should be referred to clinical trials.
Table 1. Baseline characteristics and outcome of adults with relapsed B cell ALL (Ph -) who received salvage chemotherapy: N (%)/ Median [range] N= 76 Age (years) 36 (18-86) Age ³ 60 15 (20) Male 46 (61) PS 2-3 9 (12) WBC at diagnosis (x 109/L) 7.2 [1-602] CD20 positivity at diagnosis 24 (32) Cytogenetic Abnormality Diploid 22 (29) Hypodiploid 8 (11) Hyperdiploid 12 (16) t(4;11) 5 (7) Miscellaneous 28 (37) Type of Induction chemotherapy, No. (%) Augmented BFM 28 (37) HCVAD 21 (28) HCVAD + anti-CD20 antibody 27 (35) Overall response to frontline therapy CR 73 (96) CR without platelet count recovery 2 (3) Partial response 1 (1) Median response duration, (month) 15[1-63] Response duration <12 months 35 (46) Complete response to salvage chemotherapy S1 31/76 (41) S2 9/30 (30) S3 or more 3/18 (17) Allogeneic stem cell transplant 19 (25)
Figure 1. Overall survival Figure 1. Overall survival

Disclosures
Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Daver:ImmunoGen: Other: clinical trial, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.