Outcome of Patients with Relapsed/Refractory (R/R) Acute Lymphoid Leukemia (ALL) after Failure of Inotuzumab Ozogamicin
Authors: Chahoud Jad , Kantarjian Hagop M. , Garcia-Manero Guillermo , Sasaki Koji , Kadia Tapan , Cortes Jorge E. , Khouri Maria R. , Ravandi Farhad , Dahl Jenny , Ferrajoli Alessandra , Jacob Jovitta , Pemmaraju Naveen , Daver Naval , Garris Rebecca , Jabbour Elias 
Published: October 2019

Abstract
Background: Patients with relapsed/refractory (R/R) ALL have limited therapeutical options. Monoclonal antibodies have shown to be effective. Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 antibody conjugated to calicheamicin that has shown activity as a single agent in R/R ALL with 58% ORR in a phase II trial. More recently, a randomized phase III trial showed improvement of response rates of up to 80% compared to 30% for standard of care. Despite the high overall response rate to inotuzumab, responses are short-lived and most patients relapse.
Aim: The purpose of this study is to assess the outcome of patients with R/R ALL post inotuzumab ozogamicin failure.
Methods: We reviewed 151 patients with R/R ALL treated with inotuzumab ozogamicin as single agent (n=103) or part of a salvage regimen therapy (n=48) between 2009 and 2015. From this cohort of 151, we identified 67 (44%) patients with a median age of 47 years (4-84) who had either not responded to inotuzumab (n=42) or failed after a prior response of 2 months, range (<1 - 29) (n=25) and in whom a follow-up was available. These patients were evaluated for outcome analysis.
Results: Patient characteristics are listed in Table 1. The best prior response to inotuzumab included CR in 7 (10%) patients, CRp in 14 (21%), and CRi in 4 (6%). After a median follow-up of 19 months, (range, 1- 54) from inotuzumab failure, 6 patients (9%) remain alive. The median survival was 4 months, and the estimated 12-month survival rate was 13%. The median survival were 9 months, 3.5 months, and 3.4 months, respectively, for patients who received and failed inotuzumab as first salvage therapy, second salvage therapy, and third or more salvage therapy (P= 0.006). The estimated 12-month survival rates were 29%, 4%, and 10%, respectively. Patients with inotuzumab refractory disease had worse outcome post intozumab failure compared to those who responded and lost their response subsequently; the median overall survival post inotuzumab failure was 3 and 6 months (p=0.01), respectively . Among patients who relapsed, two received subsequent salvage therapy with blinatumomab. One of them responded and achieved a CR for 4 months. Four patients received an allogeneic stem cell transplantation; one of them remain alive at 55+ months.
Conclusion: Outcome after inotuzumab failure is poor with a median survival of 4.4 months; these patients should be referred to clinical trials. Further use of inotuzumab ozogamicin earlier in the course of treatment may further improve the outcome.
Table 1. Patient Characteristics Characteristics n = 67 N (%) Median age, [range] 47 [4-84] Age < 40 29 (43) 40-60 16 (24) >60 22 (33) Sex M 30 (45) F 37 (55) Performance Status 0-1 59 (88) 2 7 (10) 3 1 (1) ALL sub-type Pre-b ALL 65 (97) biphenotypic 2 (3) Cytogenetics Ph+ 11 (16) t(4;11) 9 (13) Complex 13 (19) Diploid 8 (12) Other 26 (39) Hematological Parameters Median WBC at start 4.1 [0.3-48.5] Median WBC at Fail 2.3 [0-121.4] Median PB, blasts at start 24.5 [0-93] Median, PB, Blasts at fail 5.1 [0-96] Median BM Blasts at start 75 [13-98] Median BM Blasts at fail* 65 [0-99] Timing of Inotuzumab after Relapse as first salvage therapy 21 (31) as second salvage therapy 27 (40) as ≥ third salvage therapy 19 (28) Number of Inotuzumab cycles 1 to 2 cycles 42 (63) 3 to 4 cycles 18 (27) 5 to 6 cycles 7 (10) *Patients with 0 BM Blast had extramedullary disease

Disclosures
Chahoud: American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Off Label Use: Inotuzumab.. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: 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. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria.