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.