Case Descriptions
An 8-year-old boy with trisomy 21 and high-risk B-ALL presented with
early marrow relapse fourteen months after initial diagnosis. He was
diagnosed at age 7 years with an initial WBC of 4,100 cells/µl and was
CNS 1. He did not have cytogenetic or molecular genetic alterations
besides his known constitutional trisomy 21. He underwent chemotherapy
per Children’s Oncology Group (COG) AALL0932 with detectable minimal
residual disease (MRD) [0.022% by flow cytometry] at the end of
induction. He received consolidation chemotherapy per COG AALL1131 but
was switched to treatment per COG AALL0232 due to significant
methotrexate toxicity during interim maintenance. He received CTL019
(tisagenlecleucel) on clinical trial (NCT02228096) due to the increased
risk of treatment-associated toxicity with trisomy 21 and poor prognosis
associated with HSCT in the setting of early relapse. He received CTL019
infusion following standard cyclophosphamide and fludarabine
lymphodepleting chemotherapy and developed grade 1 CRS without evidence
of ICANS. Bone marrow evaluation 28 days following CAR-T infusion was
MRD negative by flow cytometry.
Loss of BCA, indicating functional loss of CAR-T cells, occurred three
months post-CAR-T. CTL019 was undetectable on study-performed polymerase
chain reaction (PCR). Despite this, the patient remained in an
MRD-negative complete remission (CR) by flow cytometry. Since loss of
BCA prior to six months is highly predictive for subsequent
relapse15, the following options were considered:
proceeding immediately with an unrelated donor HSCT while in remission,
proceeding with chemotherapy and HSCT if relapse occurred, or
administering a second CTL019 infusion through a single-patient
Investigational New Drug application to the Food and Drug
Administration. The patient received a second CTL019 infusion six months
after his original infusion. Parents declined preceding lymphodepleting
chemotherapy. Infusion was well tolerated without CRS. Before the second
CTL019 infusion bone marrow evaluation showed a tiny population of CD19+
blasts (0.0092%), though the patient remained in a morphologic
remission. However, bone marrow evaluation 28 days following the second
CAR-T infusion was MRD-positive with 3% blasts. CTL019 was absent by
PCR at that time. A third CTL019 infusion was given one month following
the second infusion, preceded by lymphodepleting chemotherapy. The
patient developed grade 1 CRS but otherwise tolerated treatment well.
His bone marrow evaluation 28 days after the third CAR-T infusion
demonstrated an MRD-negative remission by flow cytometry. Notably, he
failed to achieve BCA; however, he remains in an MRD-negative remission
seven years following his third CAR-T infusion.
Data for the other seven patients are summarized in Table 1. Patients
received initial tisagenlecleucel infusion for either refractory or
multiply relapsed B-ALL. Two patients had extramedullary isolated CNS
relapses. Two patients experienced grade 1 CRS, and no patients
experienced ICANS with initial infusion. No patients required
corticosteroid or anti-IL-6 treatment. All seven patients achieved an
MRD-negative CR and negative CNS status at evaluation 28 days
post-CAR-T.
Four of seven patients received reinfusion in disease remission for
early B cell recovery, as B cell recovery less than six months from
infusion is known to portend a higher risk of
relapse.15 Three patients received reinfusion for
frank disease relapse. Only one relapsed patient experienced CRS with
reinfusion, for which he required tocilizumab, and this same patient was
the only one to experience ICANS. Five of seven patients achieved an
MRD-negative CR following reinfusion, and one patient had 1.2% residual
disease. The remaining patient achieved a marrow MRD-negative CR and had
biopsy-proven cutaneous B-ALL at assessment 28 days following CAR-T
reinfusion. Two patients who were MRD-negative failed to re-establish
BCA and required subsequent therapies. For one patient CAR-T reinfusion
was used as a direct bridge to HSCT, so the presence of BCA was not
monitored. CAR-T reinfusion remained the definitive therapy for one
patient, who experienced BCA for only two additional months and is alive
with no evidence of disease.