CD19 antigen negative relapse
Patients treated CD19 CAR T cells may experience CD19-negative relapse.
Three mechanistic hypotheses have been suggested in: antigen loss or
modulation, inherent tumor heterogeneity with pre-existing CD19 negative
subclones, and lineage switching. In antigen loss and modulation,
pathways leading to the loss of CD19 includes alternate splicing (exon 2
skipping) 57, interruption in the transport of CD19 to
the cell surface due to mutations 58, or mutations in
the CD19 chaperone protein CD81 59. Secondly, it is
also possible that pre-existing CD19 negative subclones are present at
diagnosis, which allows for emergence of CD19 negative leukemic blasts60. Specifically, patients with BCR-ABL1 positive
B-ALL have been shown to harbor CD19 negative malignant precursor cells61; although, further studies are needed to determine
whether certain cytogenetics are associated with higher occurrences of
inherent tumor heterogeneity with more CD19 negative subclones. Thirdly,
lineage switch is another mechanism for CD19 loss. Although it is
traditionally associated with infant KMT2A-rearranged leukemic subtypes62, CAR T cell clinical trials have also reported
lineage switch from lymphoid to myeloid leukemic subtypes regardless of
KMT2A rearrangement 56,63. This phenomenon has also
been seen with other CD19 directed therapy, such as blinatumomab64, which highlights the concept that leukemic blasts
with certain cytogenetics may show exceptional plasticity in response to
their microenvironment; therefore, careful monitoring for escape
variants cannot be overemphasized. Though the use of blinatumomab is
effective in disease control in with relapsed/refractory B-ALL65, especially at MRD levels of disease. its prior use
may contribute to the increased risk of immune evasion after CAR therapy
due to selection pressure for CD19-negative malignant cells. Due to
these concerns, treatment with prior anti-CD19 therapy such as
blinatumomab was an exclusion criterion in the ELIANA trial21. Subsequent analysis of 166 patients who received
tisagenlecleucel confirmed this suspicion by demonstrating that prior
therapy with blinatumomab was associated with a significantly higher
rate of failure to achieve MRD negative remission or subsequent loss of
remission with antigen escape that was not associated with the presence
of dim CD19 or rare CD19 negative events by flow cytometry prior to
tisagenlecleucel infusion 66. However, we do not
regard prior CD19-directed therapy as. A contraindication for
tisagenlecleucel infusion. Lastly, a unique case was recently reported
showed introduction of the CAR gene into a single leukemic B cell during
T cell manufacturing. An ALL patient treated on our studies relapsed
with CD19 negative leukemia 9 months after he received tisagenlecleucel.
It was unclear whether the CAR gene resulted in the relapse, but one
hypothesis was that the CD19 molecule was masked but the CRA protein. In
this single case, the relapse resulted from a single ALL cell as shown
by site integration analysis 67.
For patients with antigen negative relapse, targeting of other antigens
such as CD22 using inotuzumab ozogamicin or a CD22-directed CAR T
product are viable options, but no data on the curative potential of
either exist and further prospective studies are needed68,69. Therefore, at this time, allogeneic HSCT
remains as the only option for definitive therapy after achievement of
second remission in this population.