Repeated Lineage Switches in an Elderly Case of Refractory B-Cell Acute Lymphoblastic Leukemia With MLL Gene Amplification: A Case Report and Literature Review

Abstract

Lineage switches in acute leukemia occur rarely, and the underlying mechanisms are poorly understood. Herein, we report the case of an elderly patient with leukemia in which the leukemia started as B-cell acute lymphoblastic leukemia (B-ALL) and later changed to B- and T-cell mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) during consecutive induction chemotherapy treatments. A 65-year-old woman was initially diagnosed with Philadelphia chromosome-negative B-ALL primarily expressing TdT/CD34/HLA-DR; more than 20% of the blasts were positive for CD19/CD20/cytoplasmic CD79a/cytoplasmic CD22/CD13/CD71.The blasts were negative for T-lineage markers and myeloperoxidase (MPO). Induction chemotherapy with the standard regimen for B-ALL resulted in primary induction failure. After the second induction chemotherapy regimen, the blasts were found to be B/T bi-phenotypic with additional expression of cytoplasmic CD3. A single course of clofarabine (the fourth induction chemotherapy regimen) dramatically reduced lymphoid marker levels. However, the myeloid markers (e.g., MPO) eventually showed positivity and the leukemia completely changed its lineage to AML. Despite subsequent intensive chemotherapy regimens designed for AML, the patient’s leukemia was uncontrollable and a new monoblastic population emerged. The patient died approximately 8 months after the initial diagnosis without experiencing stable remission. Several cytogenetic and genetic features were commonly identified in the initial diagnostic B-ALL and in the following AML, suggesting that this case should be classified as lineage switching leukemia rather than multiple simultaneous cancers (i.e., de novo B-ALL and de novo AML, or primary B-ALL and therapy-related myeloid neoplasm). A complex karyotype was persistently observed with a hemi-allelic loss of chromosome 17 (the location of the TP53 tumor suppressor gene). As the leukemia progressed, the karyotype became more complex, with the additional abnormalities. Sequential target sequencing revealed an increased variant allele frequency of TP53 mutation. Fluorescent in situ hybridization (FISH) revealed an increased number of mixed-lineage leukemia (MLL) genes, both before and after lineage conversion. In contrast, FISH revealed negativity for MLL rearrangements, which are well-known abnormalities associated with lineage switching leukemia and MPAL. To our best knowledge, this is the first reported case of acute leukemia presenting with lineage ambiguity and MLL gene amplification.

Myeloid lineage switch in <i>KMT2A-</i>rearranged acute lymphoblastic leukemia treated with lymphoid lineage-directed therapies

“…2 In our cohort, this phenomenon occurred in 7% of patients with KMT2Ar B-ALL treated in our institution. LS occurs primarily in KMT2Ar leukemias, usually in pediatric patients with ALL with t(4;11)/KMT2A::AFF1 rearrangement, [4][5][6] this last characteristic present in five of the six patients presented here. Patients with LS have poor prognosis, and current treatments do not have a high rate of success.…”

“…1,2 LS is rare, but its incidence may increase with the use of lymphoid lineage-targeting treatments, such as CD19-directed therapies. [3][4][5][6][7] Herein, we report one of the largest case series of patients with B-cell acute lympho-blastic leukemia (B-ALL) with KMT2Ar that had LS to a myeloid phenotype, all after receiving CD19-or CD22-directed therapy. The patients' baseline characteristics and the evolution of their diseases are detailed in Table 1 and Figure 1.…”

“…Patients with LS have poor prognosis, and current treatments do not have a high rate of success. 4 Therefore, a better understanding of the mechanisms of LS is needed to develop strategies to prevent and treat it.…”

Myosin 1g as a high-risk biomarker in a pediatric patient with lineage switch from acute lymphoblastic leukemia to myeloid phenotype

“…However, this is more frequent when the initial neoplasm is of myeloid phenotype. Another hypothesis to explain the changes in the immunophenotype during relapse is clonal selection 15 . A previous study showed that MLL rearrangements were prevalent in almost 80% of pediatric patients with B-ALL who underwent lineage conversion to AML after chemotherapy with or without hematopoietic stem cell transplantation 11 .…”

“…However, the underlying mechanisms are poorly understood. Moreover, the prognosis for these patients is variable, and there is no standard treatment 15 .…”