Blinatumomab/inotuzumab ozogamicin
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Acquired drug resistance in B-acute lymphoblastic leukaemia: case report A 17-year-old boy developed acquired resistance to blinatumomab and inotuzumab-ozogamicin while being treated for B-acute lymphoblastic leukaemia [dosages and routes not stated]. The boy presented with leucocytosis and anaemia following several weeks of lethargy, lightheadedness, night sweats, bruising, weight loss and abdominal fullness. His bone marrow (BM) biopsy revealed 97% blasts with an immunophenotype consistent with pre-B-acute lymphoblastic leukaemia (pre-B-ALL). Chromosome analysis showed a normal male karyotype. He was started on the French Acute Lymphoblastic Leukaemia Group (FRALLE)-93 protocol and had the undetectable measurable residual disease (MRD) by flow cytometry at day 94. He received consolidation and maintenance therapy as per protocol with no major complication. He relapsed with a BM aspirate revealing 92% blasts, with an immunophenotype and karyotype unchanged from diagnosis at 1 month following completion of maintenance. He then received treatment with blinatumomab and achieved a morphological remission with persistent MRD. He was scheduled for allogeneic transplantation; however, following a single cycle of blinatumomab, he had overt disease progression with a BM aspirate demonstrating 51% blasts. The boy then received treatment with inotuzumab-ozogamicin [InO] and achieved undetectable MRD after the first cycle. However, after two cycles, his disease progressed with 75% blasts in the BM and an immunophenotype still consistent with pre-BALL but was now notably negative for CD22 was observed. Thereafter, whole-genome sequencing (WGS) and whole transcriptome RNA-sequencing (WTS) was performed on relapse samples, which were collected 59 days after 1st administration of inotuzumabozogamicin to understand potential mechanisms contributing to leukaemia progression following inotuzumab-ozogamicin treatment. WGS detected a truncating mutation in exon 4 of CD22 (NM_0017713:c.712_713insCT; p.(Val238Alafs*2)). This mutation was identified to be homozygous, occurring within a region of copy neutral loss of heterozygosity on chromosome 19q and was present in a high proportion of the cancer cell fraction given a variant allele frequency (VAF) of 51.1% in a sample with an estimated tumour purity of 56%. It was also observed that 99.6% of leukaemic blasts were CD22 negative by flow cytometry and this finding was consistent with this truncating mutation leading to loss of surface CD22 expression on leukaemic blasts. WTS performed on the R-InO sample revealed expression of the mutant allele, indicating at least partial avoidance of nonsense-mediated decay. For the determination of time of emergence of CD22 mutation, sensitive allele-specific droplet digital polymerase chain reaction (ddPCR) for the CD22 Val238Alafs*2 mutation was done. The CD22 Val238Alafs*2 mutation was detected at 49% VAF in RInO, consistent with the allele fraction estimated by WGS, but was undetectable to an assay limit of detection of 0.01% in five prior BM
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