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.