Diagnostic approach to the evaluation of myeloid malignancies following CAR T-cell therapy in B-cell acute lymphoblastic leukemia

Abstract

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.

Keywords: adoptive; chimeric antigen; immunotherapy; receptors.

Figure 1

Immunophenotypic evolution of disease in cases 1 and 2. Case 1. (A) Represents sequential flow cytometric evolution of CD19 and CD22 expression following CD22 CAR T-cell immunotherapy. (B) Concurrent changes in MFI of several B cell antigens, including CD10, CD19, CD22, CD24 and CD34. (C) Demonstrates immunophenotypic evaluation of concurrent myeloid sarcoma alongside morphological appearance of myeloid blasts from the aspirate. (D) H&E, MPO and CD33 immunohistochemistry from the myeloid lesion. Case 2. (E) Select flow plots from B-ALL sample prior to treatment with CD22 CAR T cells, demonstrating both CD19 and CD22 positivity. (F) Select flow plots from T/myeloid ALL at relapse demonstrating loss/diminution of CD19 and CD22 with new expression of CD3 and CD33. B-ALL, B-cell acute lymphoblastic leukemia; CAR, chimeric antigen receptor; MFI, mean fluorescence intensity; MPO, myeloperoxidase.