Hematopoietic stem cell involvement in BCR-ABL1–positive ALL as a potential mechanism of resistance to blinatumomab therapy

Abstract

Key Points BCR-ABL1–positive cells outside the B-lineage compartment are found in 40% of adult patients with BCR-ABL1–positive BCP-ALL. Selection of preexisting CD19– subclones is a potential source of tumor escape after CD19-targeted therapies in adult Philadelphia chromosome–positive ALL.

Mechanisms of resistance to CAR T cell therapy

“…This phenomenon was appreciated before the era of targeted therapies in the context of infant, KMT2A-rearranged leukaemia subtypes, which often present as mixed-lineage leukaemias, with patients having transformation to AML following ALL-specific therapy or vice versa 129 . In both the preclinical and the clinical setting, an analogous phenomenon with emergence of myeloid subtypes following CD19-directed immunotherapy has now been described in ALL with or without KMT2A rearrangement 16,17,110,125 . Similarly, targeting of FLT3 with CAR T cells in preclinical ALL models was found to induce a reversible B cell to T cell lineage switch (while effectively avoiding transformation to FLT3 + myeloid lineage leukaemias) 130 .…”

“…CD19 has been considered to be ubiquitously expressed on all pre-B cell ALL clones, with development of antigen-negative subclones upon CD19-targeted treatment; however, more-detailed analysis of pre-therapy CD19 expression is necessary, as rare patients have malignant cells with CD19 negativity or partial expression at diagnosis 124 . Indeed, we now have a greater appreciation that pre-existing CD19subclones can be present at diagnosis 115 , with data from some studies indicating the possibility that the malignant B cell progenitors are CD19 -, particularly in patients with BCR-ABL1 ALL 125 . CD22, although also expressed in a high percentage of pre-B cell ALL cells, has a well described heterogeneity in surface expression, particularly in infants with KMT2A (MLL)-rearranged ALL, in whom CD22 -ALL cell subpopulations are more frequently detected 124,[126][127][128] , leading to the emergence of CD22or CD22 dim populations following CD22-targeted therapy 15,127 .…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…Treatment resistance and relapse after blinatumomab correlates with leukemia burden, extramedullary ALL, PD-L1 blast expression [82] and circulating regulatory T cells [83]. The immunological pressure drives CD19À relapses in 10-20% of patients, due to CD19 expression loss or disrupted membrane trafficking [84], selection of preexisting CD19À clones [85] or lineage switch [86], indicating the need to carefully monitor escape variants.…”

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib

“…CD19 – relapse results from loss of cell surface expression of the CD19 antigen, which has been described in several scenarios. These include lymphoid-to-myeloid lineage switch at the time of relapse leading to CD19 – leukemia due to reprogramming, e.g., de-differentiation of a previously committed B-lymphoid blast [9-11] or a BCR-ABL1 + CD19 + hematopoietic stem cell [13]; genetic alterations resulting in lack of CD19 expression due to disrupted CD19 membrane trafficking [12]; and alternative splicing leading to absence or truncation of CD19 [8]. …”

“…CAR-T cell therapy also has robust activity against R/R B-ALL, with CD19 CAR-T cell therapy producing an unprecedented CR rate of 83% and a median survival of 13 months in heavily pretreated patients [7]. While response rates to anti-CD19 immunotherapies are high, resistance can occur [8-13]. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported [14], but it is unclear whether blinatumomab can be efficacious following failure of anti-CD19 CAR-T cell therapy.…”