• PDF / 171,329 Bytes
• 1 Pages / 595.245 x 841.846 pts (A4) Page_size
• 2 Downloads / 183 Views

DOWNLOAD

REPORT

---

1 S

Development of resistance to imatinib and nilotinib: case report An approximately 55-year-old woman developed resistance to tyrosine kinase inhibitors (TKIs) nilotinib and imatinib, while being treated for Philadelphia (Ph) chromosome positive B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) [not all routes stated]. The woman presented with abdominal pain at the age of 53 years. Following investigations, she was diagnosed with BCP-ALL with a three-way Ph variant: 45,XX,-9,der(11)t(9;22)(q34;q11)t(9;11)(q23;p13),der(22)t(9;22) in two metaphases. She was enrolled in the GRAAPH-2014 study (a Phase III Randomised Trial of the Reduction of Chemotherapy in Ph Chromosome-positive ALL of Young Adults). She received and intrathecal nilotinib 400 mg/12h infusion, along with concomitant vincristine and dexamethasone, a complete remission was eventually achieved. She underwent allogeneic haematopoietic stem cell transplantation (alloHSCT) in first remission from an unrelated-donor. She then received a post-HSCT maintenance therapy with imatinib 300 mg/12h. However, imatinib was switched to nilotinib due to poor tolerance [details of the poor tolerance not stated]. Two years later (at an approximate age of 55 years), undetectable BCRABL1 fusion transcript quantification was observed and nilotinib was discontinued. Four months later, she presented with a cancer relapse. A new cytogenetic analysis demonstrated a clonal evolution including the loss of the Ph chromosome compared to the initial karyotype: 44, XX,del(3)(q11),-9,der(11)t(9;22)(q34;q11)t(9;11)(q23;p13), add(16)(q24),der(22)t(9;22) in all 10 metaphases analysed. An underlying Ph-positive clone was undetectable in this analysis. FISH analysis demonstrated loss of the BCR-ABL1 fusion, with persistence of the reciprocal ABL1-BCR juxtaposition. Ig/TCR clonality testing finally identified clonal gene rearrangements, identical to those from the diagnostic sample confirming the clonal relationship between the two episodes. The IGKB clonal rearrangement was retrospectively monitored by allele specific oligonucleotide (ASO)-QPCR using standard procedures. Of note, the IGKB minimal residual disease (MRD) was significantly positive at 0.6% in the bone marrow (BM) at 5 months before the clinical relapse, whereas the BCR-ABL1 fusion transcript remained undetectable. Additionally, in single nucleotide polymorphism (SNP)-array the two episodes displayed a similar pattern of gene deletions, with cryptic deletions in IKZF1, CDKN2A/B (biallelic loss), BTG1, and SERP2, as well as broad deletions at 9p and 11p with identical breakpoints. The relapse sample showed additional copy-number aberrations in chromosomes 1 and 3, as well as deletions at 9q34 and 22q11, reflecting the loss of the Ph chromosome. Development of resistance to TKIs (nilotinib and imatinib) was thus determined. The woman finally received vindesine and unspecified corticosteroid, along with ponatinib as a rescue therapy with intrathecal chemotherapy infusions and two courses of blinatumomab as a bridge to tra