Discussion
We present an exceptional case of durable remission despite lacking
on-target loss of B cells following reinfusion, as well as a case series
of seven other pediatric patients who received tisagenlecleucel
reinfusion for treatment of post-CAR-T relapse or early loss of BCA.
Approximately 40-50% of pediatric patients with B-ALL relapse
post-CAR-T, and consolidative HSCT is currently the standard of care.
The feasibility of reinfusion with the same product depends on the
availability of additional CAR-T cells, as well the presence of CD19+
blasts if in relapse.17,18 Our institutional
experience has suggested that tisagenlecleucel reinfusion has a limited,
albeit non-zero, likelihood of being a definitive therapy. There is a
subset of patients for whom it is successful, though the identification
of these patients remains unclear. For some, reinfusion can provide
temporary benefit with remission and/or BCA reintroduction.
Our institutional experience has shown mixed success. CAR-T reinfusion
remained the definitive therapy for 25% of patients, who are alive
without evidence of disease. Prior studies have reported similar
experiences with CAR-T reinfusion for either loss of BCA or disease
relapse, where reinfusion was the definitive therapy for 20-25% of
patients.6,19-22 Five of the remaining six patients
reinfused are alive, following additional therapy after tisagenlecleucel
reinfusion including HSCT, humanized CAR-T, and/or immunotherapy. In our
cohort CAR-T reinfusion was safe and generally well tolerated, with only
one patient requiring tocilizumab for CRS.
For our patient who remains in remission seven years following third
CAR-T infusion, his second CAR-T infusion, which was not preceded by
lymphodepleting chemotherapy, failed with disease progression 28 days
post-infusion. Gardner et al. reported a similar experience: of eight
patients reinfused for loss of CAR-T cells, only the two that received
lymphodepleting chemotherapy had CAR-T re-expansion.2For our patient we hypothesized that the third infusion irradicated the
remaining leukemic clone, as the lack of BCA argues against the presence
of persistent, active CAR-T cells for surveillance against recurrence.
While monitoring BCA allowed for the early detection of MRD by flow
cytometry prior to a morphologic relapse following his initial CAR-T
infusion, our current institutional practice includes measuring MRD by
next generation sequencing. This allows for significantly higher
sensitivity and earlier relapse detection but was not commercially
available when our patient was treated.15
Our experience suggests that tisagenlecleucel reinfusion is safe and can
induce remissions in patients with CD19+ relapse, possibly as an
alternative to HSCT or other therapies for post-CAR-T relapse. However,
the subset of patients for whom this is definitive therapy is small. Our
study is limited by sample size, and pooling experiences among pediatric
institutions is needed to make conclusions about tisagenlecleucel
reinfusion. Clinical trials of humanized CAR-T products may also offer a
pathway to durable remission.9 Other potential
strategies to deepen remission include increasing lymphodepleting
chemotherapy dosing, using PD-1 inhibitors to augment T cell response,
and empirically reinfusing as a “boost” while in remission with
ongoing BCA.23,24 CAR-T cell dose has been associated
with improved event-free and overall survival, and multiple CAR-T
infusions improved survival in preclinical mouse
studies.25,26 Such studies suggest that reinfusion may
reduce the rate of B cell recovery, allowing for prolonged CAR-T cell
persistence, and a pediatric phase II study of scheduled reinfusion is
ongoing (NCT05460533).27