Baseline Liver Elastography Does Not Predict Risks of Hepato-Toxicity to Reduced Dose Inotuzumab Therapy Combined with Minihcvd in B-Cell Acute Lymphoblastic Leukemia

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody drug conjugate that is FDA approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-cell ALL). Liver toxicity, particularly veno-occlusive disease (VOD) was the most important grade 3 toxicity in the Phase III INO-VATE study of InO, driven by the active cytotoxic agent calicheamicin conjugated to InO, especially in pts who underwent subsequent stem cell transplantation (SCT) (Kantarjian et. al, NEJM 2016). However proper assessment of liver function and fibrosis through elastographic measurements might predict the risks of subsequent liver toxicity with InO.

Aim: We aimed to study the extent of liver toxicity, including VOD, in pts treated with InO and its correlation to baseline liver elastography.

Methods: Pts with B-cell ALL treated with InO containing low intensity combination regimen [miniCVD-InO- blinatumomab-rituximab (previously published; Jabbour et. al. Cancer 2018)] as part of a clinical trial (NCT01371630) underwent baseline liver elastography and were prospectively monitored for any evidence of liver toxicity, including VOD. Elastography was done within 4 weeks prior to the first infusion of InO and liver stiffness was stratified based on the median shear wave velocity (SWV) using the acoustic radiation force impulse (ARFI) technique. Elastographic median SWV >1.7 m/s was considered as evidence of definite liver fibrosis. We captured the patient characteristics, history of known liver disorders, baseline liver function tests, total dose of InO administered and any subsequent liver toxicities including VOD. Any antecedent or subsequent history of SCT was noted; liver toxicity was graded according to the NCI CTCAE, v5.

The dose of InO was capped at a cumulative maximum of 2.7mg/m² of body surface area (administered in fractionated doses) and all pts received concurrent ursodiol prophylaxis with InO.

Results: From Jan 2018- April 2022, 50 consecutive pts treated with the above regimen and with baseline elastography reports available as part of the research protocol were analyzed. The median age of the pts was 54.9 years (yrs) (range, 21.7-87.7 yrs) and only 1 pt had a known prior liver ailment of non-alcoholic fatty liver disease (NAFLD). Baseline characteristics are mentioned in Table 1. The median InO dose received by the pts were 1.5 mg/m² (range, 0.9-2.7 mg/m²) and only 11 pts (22%) received the maximum cumulative InO dose of 2.7 mg/m².

A total of 11 pts (22%) had a baseline maximum SWV >1.7 m/s which radiologically corresponds to possible compensated advanced chronic liver disease (cACLD) and no pts had a SWV >2.1 m/s (corresponds to clinically significant portal hypertension; CSPH). All pts achieved CR/CRi as best response and 14 pts (28%) underwent consolidative SCT. Only one pt developed a VOD of the liver, diagnosed based on clinical and radiological findings, at D+60 post haploidentical-SCT with Flu/Mel140 conditioning and post-transplant cyclophosphamide. This pt had normal baseline liver elastography and had received a cumulative InO dose of 1.5 mg/m². Another 5-pts (10%) had ≥ grade 3 liver toxicity (1 pt with hyperbilirubinemia and 4 pts with ALT elevation), all of whom had baseline SWV <1.7 m/s on elastography. On regression analysis using age, cumulative InO dose, baseline values of total bilirubin, ALT and INR, and SWV cutoffs as covariates, no factor significantly affected the risks of ≥ grade 3 liver toxicity.

After adopting the use of reduced dose fractionated InO administration regimen, routine ursodiol prophylaxis and avoiding peri-transplant azole antifungal prophylaxis in InO exposed B-cell ALL pts at our center, the frequency of liver toxicites including VOD has significantly reduced compared to the 11% rate of VOD described in the INO-VATE study. With these improvisations reducing the overall frequency of InO induced liver toxicity, the positive predictive value of a pre-InO elastography to envisage the risks of subsequent VOD and other liver toxicity in these pts is highly limited.

Conclusion: In a prospectively monitored group of pts of B-cell ALL treated with fractionated InO containing combination regimen, baseline liver elastography did not predict the risk of subsequent liver toxicity. Sequential liver elastographies to monitor dynamic changes in SWV needs to be analyzed in future studies to further assess its predictive role for InO induced liver toxicity.

Short:Amgen: Consultancy, Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Stemline Therapeutics: Research Funding; Novartis: Consultancy; Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy. Jain:Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; ADC Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Honoraria, Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Mingsight: Research Funding; Takeda: Research Funding; Medisix: Research Funding; Loxo Oncology: Research Funding; Novalgen: Research Funding; Dialectic Therapeutics: Research Funding; Newave: Research Funding; TransThera Sciences: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Ipsen: Honoraria; CareDx: Honoraria. Ravandi:Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Consultancy; Biomea Fusion, Inc.: Research Funding; Novartis: Consultancy; Xencor: Research Funding; Syos: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding. Daver:Celgene: Consultancy; Syndax: Consultancy; FATE Therapeutics: Research Funding; Trovagene: Research Funding; Jazz: Consultancy; Novartis: Consultancy; Astellas: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Consultancy, Research Funding; Novimmune: Research Funding; Arog: Consultancy; Glycometrics: Research Funding; Shattuck: Consultancy; Agios: Consultancy. Kadia:cyclacel: Research Funding; Delta-Fly: Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; PinotBio: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Research Funding; Astex: Honoraria; AstraZeneca: Research Funding; JAZZ: Consultancy, Research Funding; Regeneron: Research Funding; Glycomimetics: Research Funding; Iterion: Research Funding; Astellas: Research Funding; Genfleet: Research Funding; Ascentage: Research Funding; cellenkos: Research Funding; Servier: Consultancy; Pfizer: Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Jabbour:Genentech: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Amgen: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding.