To the Editor,
Chimeric antigen receptor redirected T cells (CAR-T cells) have enabled us to offer a promising treatment for relapsed or refractory acute lymphoblastic leukemia (ALL).1 However, there is little information about adverse events associated with the administration of CAR T-cells.2,3 The changes in extramedullary lesion (EL) of relapsed or refractory ALL after CAR T-cell therapy have been recognized only in a few cases.4,5 We report herewith pseudo-progression as an augmented immune response to the EL in a boy with relapsed infant ALL after CAR T-cell therapy.
A 10-year-old boy received Tisagenlecleucel because of intractable treatment course of ALL. This patient had received a diagnosis of infant ALL with MLL-ENL fusion gene at age 4 months. Complete remission (CR) was obtained after the first induction therapy, but a bone marrow (BM) relapse occurred during the course of the salvage chemotherapy. At 14 months of age, he received umbilical cord blood transplantation from an unrelated human leukocyte antigen (HLA)-one locus mismatched donor that led to the second CR. He then underwent a haploidentical BM transplantation from his mother at age 2 because of the second BM relapse. The third CR was achieved after the last BM transplantation, but BM and testicular relapses of ALL occurred at age 7 years. Repeated infusions of mother’s lymphocytes controlled the disease on the developing chronic graft-versus-host disease (cGVHD) until age 9 years, when EL including the left leg bone led to limping. Five courses of blinatumomab failed to control the progressive disease.
Tisagenlecleucel was administered in the non-remitting state following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. Grade 2 cytokine release syndrome (CRS) developed with fever and dyspnea on day 3, and then required tocilizumab for the appreciable control. Prior to CAR-T therapy, his left leg with the bone lesion started to be swollen. The painful leg size increased with heat after CRS occurred. The second dose tocilizumab on day 6 and methylprednisolone on day 7 led to a defervescence and resolution of the affected leg pain. The local inflammation improved by day 14 to the size of contralateral leg (Supplementary figure ). One month later, he obtained cellular and molecular CR without EL.
Pseudo-progression after immunotherapies have been described in malignant tumors including high-grade glioblastomas, non-small-cell lung carcinoma, and melanoma, but less commonly in hematological malignancies. Table 1 summarizes all reported cases of leukemia and lymphoma that presented pseudo-progression during CAR-T therapy.2-5 This patient showed a rapid enlargement of EL with heat and pain after administration of CAR-T cells. Clinical course and serum interleukin-6 dominant cytokine profile (data not shown ) along with the time course of CRS indicated a pseudo-progression but not true-progression of EL. The present patient received CAR-T cells after hematopoietic stem cell transplantation (HSCT). He had controlable cGVHD without immunosuppressants on mixed donor chimerism (mother 99.3%) after repetitive HSCT at the time of CAR-T cell infusion. This condition might augment the immune response to leukemic cells. According to the CRS magnitude and EL sites, careful management are needed for pseudo-progression after CAR-T cell therapy.