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Case Reports
. 2022 Mar 4;27(2):82-86.
doi: 10.1093/oncolo/oyab052.

Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy

Valentina Nardi  1   2 , Steven L McAfee  1   3 , Paola Dal Cin  1   4 , Harrison K Tsai  1   5 , Philip C Amrein  1   3 , Gabriela S Hobbs  1   3 , Andrew M Brunner  1   3 , Rupa Narayan  1   3 , Julia Foster  1   3 , Amir T Fathi  1   3 , Hanno Hock  1   3   6   7
Affiliations
Case Reports

Chemotherapy Resistance in B-ALL with Cryptic NUP214-ABL1 Is Amenable to Kinase Inhibition and Immunotherapy

Valentina Nardi et al. Oncologist. .

Abstract

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantation. This case illustrates that next-generation sequencing approaches designed to discover cryptic gene fusions can benefit patients with Ph-like ALL.

Keywords: BCR-ABL1 l-like; NUP214-ABL1; Ph-like; acute lymphoblastic leukemia; cryptic translocation.

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Figures

Figure 1.
Figure 1.
Histology and genetic testing results. (A) Bone marrow core biopsy showing sheets of blasts and minimal residual hematopoiesis (20×, hematoxylin and eosin). (B) Partial G-banding karyotype showing the aberrations: add(7)q31, del(7)(q32q34),i(8)(q10), der(16)t(1;16)9q12;p13.3) as well as a pair of normal chromosomes 9, one of them with a cryptic inv9(q34q34) (see G, below). (C) Comparison between the structures of wild type IKZF1 and dominant negative isoform IK6. The numbers 2-8 indicate exons. The black vertical boxes indicate Zinc Finger domains. The dashed line indicates deletion of exons 4-7 corresponding to the IK6 splice variant, a dominant-negative isoform. (D) Visualization of the log2 ratio of sequencing reads for genes in chromosome 7. IKZF1 exons/amplicons are indicated with triangles and the amplicons showing copy number loss are included in a shaded box. E. NUP214-ABL1 fusion transcripts. Five representative of ~72 cDNA reads containing the fusion transcripts and corresponding amino acid sequence. (F) Interphase FISH and (G) Metaphase FISH on a pair of chromosomes 9 with an ABL1 break-apart probe. The orange probe labels the 3ʹ and green probe the 5ʹ of ABL1. Note that the disruption of the ABL1 locus is not apparent due to the resolution of the assay.
Figure 2.
Figure 2.
Treatments and response. (A) Clinical time course after diagnosis of relapsed ALL (months/days shown below axis). Bmbx: bone marrow biopsy. Mini-hyper-CVD: hyperfractionated cyclophosphamide, vincristine, dexamethasone. See results for details. (B) Next generation sequencing Tracing measurable residual disease (MRD) by next generation sequencing (ClonoSEQ, Adaptive Biotechnologies). At diagnosis (bmbx 1), 3 unique immunoglobulin heavy chain sequences were identified at high frequencies (>50% of nucleated cells). After treatment, MRD levels became undetectable (bmbx 2, detection limit: 1 cell/ million), eventually recurred (bmbx 3), but were abolished again after change in treatment (bmbx 4). See A, above and results for details.
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