CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy

Abstract

Lineage switch (LS) refers to the immunophenotypic transformation of one leukemia lineage to another (ie, lymphoid to myeloid) with retention of baseline genetics. This phenomenon was originally observed in infants with B-lymphoblastic leukemia (B-ALL) with KMT2A rearrangements following chemotherapy, but is now increasingly being observed as a form of immune escape following targeted therapies among children and adults with B-ALL with and without KMT2A rearrangements. In this report, we present two cases of adolescents with B-ALL harboring CRLF2 rearrangements (Philadelphia-like phenotype) who developed LS to acute myeloid leukemia following CD19 targeted therapy. To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

Keywords: Chimeric antigen receptor - CAR; Immunotherapy; Leukemia; Next generation sequencing - NGS.

Figure 1. Cases 1 and 2 flow, NGS, pathology, and imaging. Case 1: (A) Disease burden by multiparametric flow cytometry and next-generation sequencing (NGS) by ClonoSEQ during the peri-CAR period. (B. Leukemic blasts on BM aspirate. At day −1 blasts are of variable size, contain scant basophilic cytoplasm, and fine chromatin representative of B-lymphoblasts. At day +48 monoblasts are uniformly large in size and contain abundant, prominently vacuolated cytoplasm and loose chromatin. (C and D) H&E and CD79a stains of BM biopsy specimens from day −1, day +21, and day +48. At day −1 there is an interstitial infiltrate of CD79a positive B-cells consistent with B-lymphoblastic leukemia. At day +21 the marrow is markedly hypocellular with no evidence of increased blasts and CD79a positive cells are essentially absent. At day +48 there are small foci containing an atypical mononuclear infiltrate consistent with blasts which are negative for CD79a, but positive or CD68 (not shown). (E) F-18 FDG-PET/CT imaging on day −2 demonstrating extensive EMD including peri-nephric and retroperitoneal node involvement, day +30 showing full resolution of kidney disease and retroperitoneal disease, but with emergence of new pancreatic mass, and day +62 demonstrating marked interval disease progression with extensive abnormalities involving the liver, pancreas, upper abdominal and retroperitoneal lymph nodes, internal mammary nodes, and axial and appendicular BM. Case 2: (A) Disease burden by multiparametric flow cytometry and NGS by ClonoSEQ. (B) Leukemic blasts identified in BM aspirates. At diagnosis, blasts were intermediate in size with high nuclear-to-cytoplasmic ratios, fine chromatin, inconspicuous nucleoli, and scant deeply basophilic agranular cytoplasm, consistent with ALL. At lineage switch, blasts were large in size with irregular/folded nuclear contours, multiple small nucleoli, and moderate amounts of basophilic cytoplasm. (C and D) H&E and representative immunohistochemical stains. At diagnosis, BM showed a diffuse infiltrate of intermediate-sized blasts with smooth chromatin and small nucleoli; these blasts expressed CD79a, consistent with B-lymphoblastic leukemia. At lineage switch, skin biopsy demonstrated a diffuse dermal proliferation of large cells with irregular nuclear contours, open chromatin, conspicuous nucleoli, and finely granular amphophilic cytoplasm. The cells expressed CD163 consistent with monocytic differentiation. (E) Coronal and axial contrast enhanced CT and fused FDG PET/CT images demonstrate hypoenhancing renal lesions and mesenteric lymphadenopathy at the time of diagnosis; and hypoenhancing hepatic and splenic lesions and a destructive rib lesion at the time of lineage switch, all of which demonstrate significant radiotracer uptake. Coronal fused PET/CT image also demonstrates a hypermetabolic left femur lesion which is not well appreciated on CT. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; LOD, limit of detection; PB, peripheral blood.