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).