Inotuzumab ozogamicin
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Development of resistance and off-label use: case report A 7-year-old boy in USA showed development of resistance following off-label administration of inotuzumab ozogamicin for precursor B-cell acute lymphoblastic leukaemia (pre-BALL). The boy was diagnosed with pre-BALL and presented due to its second relapse. Previously, he was treated with various chemotherapy medications without durable remission. Upon admission, B-ALL blasts showed a positive result for CD22. Thereafter, he received off-label therapy with inotuzumab ozogamicin because the medication was given under Food and Drug Administration’s (FDA’s) expanded access compassionate use program. He received the first IV inotuzumab ozogamicin infusion at a dose of 0.8 mg/m2 over one hour on day 1 and again at a dose of 0.5 mg/m2 on days 8 and 15. He also received pre-medication with paracetamol [acetaminophen], methylprednisolone and diphenhydramine. Prior to the initiation of inotuzumab ozogamicin and then throughout the treatment course, he remained on ursodeoxycholic acid [Ursodiol] given prophylactically against sinusoidal obstruction syndrome of the liver. On day 22, bone marrow aspiration after the first cycle showed a partial response with 7.5% blasts in the bone marrow by flow cytometric minimal residual disease testing. He further received another two doses of inotuzumab ozogamicin at a dose of 0.5 mg/m2 on days 1 and 8 of cycle 2. Bone marrow evaluation on day 15 of cycle 2 revealed morphologic remission with 1.1% blasts by flow cytometric minimal residual disease testing. The boy’s therapy with inotuzumab ozogamicin was paused. After three weeks, the bone marrow showed 1.7% blasts by flow cytometric minimal residual disease testing. He was then started the third cycle of inotuzumab ozogamicin, but he showed peripheral blasts after 20 days. Bone marrow aspiration demonstrated relapsed for the third time with 99% lymphoblasts. Flow cytometry of the blasts revealed loss of CD22 expression, which indicated target antigen loss as a pathway for development of inotuzumab ozogamicin resistance. At that time, the blast population also showed chromosomal aberrations, which included reciprocal translocation between 5p10 and 10q10, reciprocal translocation between 11p21 and 12q24.1 and deletion from 15q15 to 15q26.1. Prior to the third relapse, inotuzumab ozogamicin well tolerated and he showed improvement in the underlying condition. However, after the relapse with CD22 loss, he had rapidly progressing multi-organ failure due to leukemic progression and eventually died. Author comment: "To our knowledge, this is the . . . case of CD22 expression loss as a mechanism of therapy resistance for inotuzumab ozogamicin". "At the time our patient received inotuzumab ozogamicin, the medication was not approved by the Food and Drug Administration, and therefore the patient received the medication from . . . FDA’s Expanded Access (Compassionate Use) program." Paul MR, et al. Treatment of Recurrent Refractory Pediatric Pre-B Acute Lymphoblastic Leukemia Using Inotuz
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