Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Salvage Therapy for Adult Patients with Refractory/Relapse (R/R) Acute Lymphoblastic Leukemia (ALL)
Authors: Jabbour Elias , O'Brien Susan , Thomas Deborah A. , Sasaki Koji , Garcia-Manero Guillermo , Kadia Tapan , Jain Nitin , York Sergernne , Garris Rebecca , Cortes Jorge E. , Kantarjian Hagop M. 
Published: October 2019

Abstract
Background: Outcome of pts with R/R ALL is poor. Addition of IO to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might further improve outcome.
Methods: Pts ≥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. Pts received IO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles.
Results: Thirty-five pts (14 men, 21 women) have been treated so far. Pts characteristics and outcome are summarized in Table 1. Median age is 35 yrs (range 9-87). Median follow-up is 10 months (mos). The overall response rate was 71%: 18 (51%) CR, 6 (17%) CRp, and 1 (3%) marrow CR. Four (11%) pts were refractory and early death was reported in 6 (17%) pts. Grade 3-4 non-hematological toxicities included infections, mucositis, increased LFTs, and VOD (1 on study who had prior allogeneic stem cell transplantation, 3 were post transplantation following IO therapy). Four (11%) pts were switched early to maintenance therapy due to poor functional status (n=1), infectious complications (n=2), and prolonged myelosuppression (n=1). Twelve (34%) pts proceeded to receive allogeneic stem cell transplantation; of the rest, 6 (17%) relapsed within 3 mos (range, 1 to 7). At the last follow-up, 17 pts (49%) are alive, 18 (51%) died: 6 early death (3 hemorrhage, 2 sepsis, and 1 unknown cause); 8 were responders (5 died post relapse after subsequent salvage, 2 died post transplantation VOD in 1, and 1 died due to sepsis and multiple organ failure), 4 were refractory and died of disease progression. The 6-month PFS and OS rates were 79% and 58%, respectively. Median survival for pts with CR/CRp/marrow CR was 14 mos versus less than 1 mo in pts with refractory disease. Furthermore, median survival was not reached in pts with S1, 4 mos in pts with S2 and 5 mos in pts with S3+.
Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results (71% ORR) in pts with R/R ALL. Pts with previous liver damage and transplant candidate should be considered carefully for this treatment to minimize the risk of VOD.Table 1Patient characteristics and outcomeParameterCategoryN (%)/Median [Range]Follow-up (mos)10 [1-14]Age (yrs)35 [9-87]Performance Status (ECOG)0-130 (86)Salvage StatusS119 (54)S1, primary refractory4 (12)S1, CRD1 <12 mos8 (23)S1, CRD1 ≥12 mos7 (20)S28 (23)≥ S38 (23)KaryotypeDiploid8 (23)T(4;11)5 (14)Miscellaneous16 (46)Insufficient metaphases6 (17)CD2296 [29-100]CD20≥ 20%5 (14)CR18 (35)CRp6 (17)Marrow CR1 (3)No response4 (11)ORR25 (71)Early death6 (17)6-months PFS %79Median (months)Not reached6-month OS %58Median (months)7

Disclosures
Kadia: GSK: Research Funding; ARIA: Honoraria. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.