Immunotherapy- (Blinatumomab-) Related Lineage Switch of KMT2A/AFF1 Rearranged B-Lymphoblastic Leukemia into Acute Myeloid Leukemia/Myeloid Sarcoma and Subsequently into B/Myeloid Mixed Phenotype Acute Leukemia

Abstract

The presence of KMT2A/AFF1 rearrangement in B-lymphoblastic leukemia (B-ALL) is an independent poor prognostic factor and has been associated with higher rate of treatment failure and higher risk of linage switch under therapy. Blinatumomab has shown promising therapeutic results in refractory or relapsed B-ALL; however, it has potential risk of inducing lineage switch, especially in KMT2A/AFF1 rearranged B-ALL into acute myeloid leukemia and/or myeloid sarcoma. We report a 40-year-old female with KMT2A/AFF1-rearranged B-ALL that was refractory to conventional chemotherapy. Following administration of blinatumomab, she developed a breast mass proven to be myeloid sarcoma, in addition to bone marrow involvement by AML. Approximately six weeks after cessation of blinatumomab, a repeat bone marrow examination revealed B/myeloid MPAL.

Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia

“…The current designation of mixed phenotype acute leukemia (MPAL) includes a specific category for MLL -r, as well as BCR-ABL+ leukemia, because of their prevalence in this mixed lineage group [ 46 , 47 ]. Consistent with this concept of high lineage plasticity in MLL-r leukemia, evasion of CD19-targeted immunotherapy through relapse with myeloid markers has been reported under treatment with blinatumimab [ 20 − 27 , 32 ] or treatment with CD19 CAR T cells ( Table 1 ) [ 10 , 18 , 30 , 31 , 33 ]. Loss of not only the CD19 cell surface protein but complete loss of all B-lineage markers and acquisition of a myeloid phenotype characterizes these cases ( Table 1 ).…”

“…In contrast to TCF3-PBX1 translocations, MLL translocations are enriched in myeloid relapses in B-ALL [ 18 , 45 ]. The propensity for lineage switching, particularly toward a myeloid identity, is likely an underlying property of MLL -r B-ALL, based on historical clinical observations [ 18 , 20 − 27 , 31 − 33 ]. It would clearly be beneficial to study processes leading to CD19 neg relapse under immunotherapeutic pressure using a model system in which B-ALL is driven by MLL -r. B-ALL initiated by MLL fusion oncoproteins has been surprisingly difficult to produce in mouse models despite nearly 30 years of investigator efforts [ 60 ].…”

Lineage Switch in an Infant B-Lymphoblastic Leukemia With t(1;11)(p32;q23); KMT2A/EPS15, Following Blinatumomab Therapy

“…6 Previous reports have described lineage switch in KMT2A -rearranged acute leukemias after treatment with standard chemotherapy, 6 CD19-specific chimeric antigen receptor (CAR) T cells, 7,8 and blinatumomab. 9–17 A literature review focused on lineage switch after blinatumomab identified 9 reported cases: five harboring KMT2A-AFF1 , 9–12,14,15 one with KMT2A-AFF4 , 16 two with BCR-ABL1 , 17 and one with hyperdiploidy. 13 Our patient had a KMT2A/EPS15 fusion, which has not been previously reported in association with lineage switch.…”

The landscape of bispecific T cell engager in cancer treatment

“…Interestingly, the lineage switch of B lymphocytes from the lymphoid lineage to the myeloid lineage can be seen in patients with B-ALL who experienced CD19-directed immunotherapy in which CD19 expression was lost while myeloid marker levels such as CD33 were upregulated [124,125]. The reasons for lineage switch may be associated with a strong selective advantage for subclones who did not express CD19 and gene rearrangements such as KMT2A/AFF1 and ZNF384 [126][127][128]. Therefore, multitargeted strategies may be effective to overcome antigen loss including developing a single drug that can simultaneously target dual or multiple TAAs or combining various immunotherapies that each of these targets a different TAA [129,130].…”