JAK2 rearrangement

Our patient carried two acquired molecular abnormalities involving JAK2 gene (PCM1::JAK2 fusion and JAK2 H531Y) along with a germline mutation (BLM Y736fs*5, variant allele frequency VAF 41.7%), whereas his sister had the canonical JAK2 V617F driver mutation. This particular pedigree could arise the hypothesis of a genetic predisposition to acquire different JAK2 molecular abnormalities as a maladaptive somatic genetic rescue of an underlying germline predisposition, namely the germline BLM Y736fs*5 mutation.

The case highlights the importance of distinguishing de novo lymphoid malignancies from MLN-eo-TK, especially when JAK2 rearrangements are detected. Recognition of the clonal myeloid component during or after lymphoid-directed therapy has important diagnostic and therapeutic implications, supporting the use of targeted JAK2 inhibition in addition to standard chemotherapy.

P2, N=10, Recruiting, William Shomali | Trial completion date: Nov 2025 --> Dec 2028 | Trial primary completion date: Nov 2025 --> Dec 2028

Undiagnosed Ph-like ALL correlates with worse survival (5-year OS: 35-45% in LMICs vs. 60-65% in HICs) due to chemotherapy overuse instead of TKIs (e.g., dasatinib improves EFS by 30%). A tiered diagnostic approach, initial CRLF2 flow cytometry ($15, 80% sensitivity), confirmatory PHi-RACE PCR ($42, 95.2% sensitivity), and selective NGS referral could bridge 85% of the detection gap at 90% cost reduction. Cost-effective tools, subsidized NGS networks, workforce training, and WHO-endorsed guidelines could prevent 40-50% of relapses in LMICs.

In patients with suspected BIA-ALCL, it is critical to properly handle the periprosthetic fluid when the disease first presents and the capsule at the time of initial capsulectomy to make a correct diagnosis and pathologic staging because a missed diagnosis may lead to disease progression. Comprehensive immunohistochemical analysis; fluorescence in situ hybridization for DUSP22, TP63, or JAK2 rearrangement; assessment of clonality of the T-cell receptor and immunoglobulin genes; and sequencing for mutations were performed as part of the workup of the submitted cases, particularly on ALK-negative ALCL cases, emphasizing the importance of ancillary testing in establishing the diagnosis.

In the current case, the BCR-ABL fusion was detected and CML was confirmed after the recurrence of splenomegaly. Subsequent treatment with a combination of flumatinib and ruxolitinib was demonstrated to be safe and effective.

Biopsies showed new onset myeloid sarcoma (MS), with continued remission of B-ALL. 18F-FDG PET/CT showed numerous markedly hypermetabolic soft tissue lesions located in the skin and subcutaneous tissues, muscles, osseous structures, mucosa, pleura, mediastinum, peritoneum, retroperitoneum, and testes.

The response of disease to ruxolitinib may be transient and it may only serve as a temporary treatment prior to transplantation. The patient achieved complete hematologic remission and molecular response during the long-term follow-up; however, a complete molecular remission was not attained. The underlying mechanism of lenalidomide in these diseases necessitates further comprehensive investigation through fundamental research and clinical trials.

Blinatumomab was not used during consolidation therapy in the reported patients. Its incorporation in the routine therapy of newly diagnosed patients may increase the proportion of patients receiving AHCT in a MRD negative state and further improve outcomes in this historically poor risk patient population.

Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.

We also reviewed all cases with BCR::JAK2 rearrangement reported in the literature. In conclusion, a suspected t(9;22)/BCR::JAK2 rearrangement warrants further characterization with genomic assays such as OGM, whole chromosome sequencing, and RNA sequencing to explore other gene disruptions and/or rearrangements.