DISCUSSION
Here, we report the application of InO for the treatment of MRD in a patient with r/r ALL who relapsed post allo-HSCT and anti CD19 CART therapy. The adverse effect related to InO therapy is mild and reversible. Our data provides rationale for the utilization of InO at the scenario of MRD positivity in B-ALL.
Antibody drug conjugate offers high possibility of achieving remission in r/r B-ALL. InO is a humanized monoclonal antibody which binds CD22 and deliver the conjugated calicheamicin inside the cell after the link is hydrolysed [8]. The efficacy and safety of InO in patients with r/r Ph-negative B-ALL has been demonstrated. Hagop reported the results of the phase 3 inotuzumab ozogamicin trial ( the InO-VATE study ), which investigate the tolerability and efficacy of InO in r/r B-ALL [9]. A significantly higher rate of complete remission was observed in InO cohort compared with the standard-therapy group (80.7% vs. 29.4%). A significantly longer progression-free survival (PFS) (5 months vs. 1.8 months, hazard ratio, 0.45) and median overall survival (OS) (7.7 monthes vs. 6.7 monthes, hazard ratio, 0.77) were both observed in the InO cohort. Grade 3 or higher thrombocytopenia and febrile neutropenia were significantly lower in the InO cohort than in the standard-therapy cohort (37% vs. 59%; 24% vs. 49%). These results confirmed both efficacy and safety of InO for the treatment of B-ALL. VOD is a unique nonhematologic adverse event associated with InO. The patient in this study didn’t complicate VOD, hence our experience supported the use of ursodeoxycholic acid to prevent VOD.
Achievement of MRD negativity associate with improved survival in B-ALL[2]. InO was also efficacious to induce MRD negativity in B-ALL. In the INO-VATE study, 76 of 164 patients receiving InO achieved and remained MRD negativity until the end of follow-up. The survival benefit was more obvious in MRD negative patients. The superior PFS and OS were also demonstrated in the MRD negative patients compared with those in the MRD positive patients [10]. In a phase 2 trial of InO in children and adolescents with r/r B-ALL, 18 of 27 patients (66.7%) achieved MRD negativity after 1 cycle of InO treatment. Wiley retrospectively analyzed 8 patients who relapsed post-HSCT and received InO followed by donor lymphocyte infusion. 6/8 (75%) patients obtained MRD negative CR after the second cycle of InO[11]. Hence, InO is a preferential option for the treatment of r/r B-ALL.
This patient had persistent MRD prior to HSCT and suffered twice relapses (one hematologic and one molecular relapse) after HSCT, and her prognosis was deemed to be poor. Blasts in the second relapse were positive for CD19, indicating the relapse was caused by loss of CD19 CAR T-cells persistence. A second infusion of CD19 CAR T-cells was reported to induce CR in only 21% of patients with ALL[12], so this patient declined another round of CD19 CART. DLI is the conventional preempative therapy for MRD clearance but carries a high risk of acute GVHD [13]. Blinatumomab is a CD19/CD3 bispecific T-cell engager antibody, which has notable single agent activity in r/r B-ALL. Blinatumomab combined with DLI was reported to salvage a patient with r/r B-ALL from relapse after haplo-HSCT [14]. Blinatumomab and DLI was not chosen for our patient due to concerns about DLI-related GVHD and the inconvenience of blinatumomab requiring continuous infusions. Due to the high CD22 expression (63.74%), low tumor burden and the extended infusion interval of InO, this patient chose InO monotherapy. Overall, our preliminary result showed that InO is effective and safe in eradicating MRD in the setting of multiple relapses after anti-CD19 CART therapy and allo-HSCT. A prospective clinical study with expanded sample size will provide a basis for the use of InO for MRD eradication and guide the choice of preemptive immunotherapy for r/r B-ALL.
ACKNOWLEDGEMENT
None.
CONFLICT OF INTEREST
The authors declare no competing interests.
AUTHOR CONTRIBUTIONS
SMH, CLW and HYC performed literature review, drafted manuscript. LYY, CSQ, HXZ, MZX and XHH treated the patient. LD performed the flowcytometry analysis. HPD and SLX edited the manuscript and involved in supervision.
ETHICAL APPROVAL
The patient has provided written informed consent for the publication of this case report.
CONSENT
Written informed consent of the patient was obtained for publication.
DATA AVAILABILITY STATEMENT
The data presented in this study are available in this article
FUNDING
This work was supported by the grants from the National Natural Science Foundation of China (Grant No. 81970138, 82270165), National Key R&D Program of China (2022YFC2502703), Jiangsu Province Natural Science Foundation of China (Grant No. BK20221235), Translational Research Grant of NCRCH (Grant No. 2020ZKMB05), Jiangsu Province “333” Project, Social Development Project of the Science and Technology Department of Jiangsu (Grant No. BE2021649) and Gusu Key Medical Talent Program (Grant No. GSWS2019007).