Salvage Chemotherapy with Inotuzumab Ozogamicin (INO) Combined with Mini-Hyper-CVD for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)
Authors: Sasaki Koji , Kantarjian Hagop M. , O'Brien Susan , Thomas Deborah A , Ravandi Farhad , Garcia-Manero Guillermo , Kadia Tapan , Jain Nitin , Konopleva Marina , Estrov Zeev , Takahashi Koichi , Khouri Maria R. , Jacob Jovitta , Garris Rebecca , Cortes Jorge E. , Jabbour Elias 
Published: October 2019

Abstract
Background: Outcome of patients with R/R ALL is very poor. INO is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve clinical outcome.
Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles.
Results: Forty-eight patients (23 men, 25 women) have been enrolled so far. Patient characteristics and outcome are summarized in Table 1. Median age is 35 years (range 9-87). Median follow-up is 9.4 months (range, 1-27), and patients received a median of 2 cycles (1-8). Of 46 evaluable patients (2 patients, too early to assess response), 5 patients (11%) were refractory to mini-hyper-CVD + INO and died of progressive disease. Early death was encountered in 7 (15%) patients. The overall response rate was 74%: 24 (52%) CR, 8 (17%) CRp, and 2 (4%) marrow CR. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (n=6; 1 in a patient who had prior allo-SCT; 1 at D35 of CAR T-cell; and 3 post allo-SCT following INO therapy). Four (9%) patients were switched early to maintenance therapy due to poor performance status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Nineteen (41%) patients proceeded to receive allo-SCT. At the last follow-up, 20 (43%) patients are alive in response; 2 (4%) too early to assess response; 4 (8%) relapsed post transplantation. 22 (43%) patients died: 7 early death; 5 refractory disease; 5 post relapse after subsequent salvage, 1 post-transplantation VOD, 3 due to post-transplant complications, and 1 in response to IO due to sepsis and multiple organ failure. The 1-year PFS and OS rates were 60% and 46%, respectively. Median survival for patients with CR/CRp/marrow CR was 18 months versus 1 month in patients with refractory disease (p<0.001). Median survival was 17 months in patients with S1, 6 months in patients with S2 and 7 months in patients with S3+ (Figure).
Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored.
Table 1. Patient characteristics and outcome Median (range) / No. (%) N=48 Age (yrs) 35 [9-87] Male 23 (48) Performance Status (ECOG) ≥2 7 (15) Salvage Status S1 S1, Primary Ref S1, CRD1<12m S1, CRD1>12m S2 >S3 24 (50) 4 11 9 11 (23) 13 (27) Karyotype Diploid T(4;11) Misc IM/ND 11 (23) 5 (10) 24 (50) 8 (17) CD22, (%) 96 [26-100] CD20 ≥ 20% 10 (21) Response CR 24 (52) CRp 8 (17) CRi 2 (4) ORR 34 (74) No response 5 (11) Early death 7 (15) Too early 2
Figure 1. Survival by salvage number Figure 1. Survival by salvage number

Disclosures
O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.