Abstract
Donor-derived CD19-directed chimeric antigen receptor-modified T (CAR-T)
cell therapy seems be effective and safe for relapsed B-ALL after
allogeneic haematopoietic stem cell transplantation (allo-HSCT). We
report two cases of children who received Donor-derived CAR-T cell
therapy. After transfusion, the children experienced different degrees
of chronic graft-versus-host disease (cGVHD). Early intervention
included strengthening immunosuppressant, FAM regimen, tyrosine kinase
inhibitor, and auxiliary cell therapy. Their dyspnoea and lung function
were significantly improved and recovered. They did not receive the
second transplant. Timely and effective intervention is crucial to
improve both prognosis and quality of life.
Key words: Donor-derived, CD19-directed chimeric antigen
receptor modified T (CAR-T), chronic graft-versus-host disease
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an
effective method for the treatment of refractory and relapsed acute
lymphoblastic leukaemia (R / R-ALL) in children, but relapse after
transplantation is still the main reason for treatment failure. Chimeric
antigen modified T (CAR-T) cell therapy has a strong ability to clear
leukemic cells and is associated with a high remission rate in R/R B-ALL[1-2]. CAR‑T cell sources can be autogenous or
donor. It can be difficult to collect enough T lymphocytes for children
with a high leukaemia burden or relapse after transplantation. CAR-T
cells from a donor can overcome this problem but carry the risk of
graft-versus-host disease (GVHD) after infusion. We describe two cases
of chronic GVHD (cGVHD) secondary to donor-derived CAR-T therapy.
Cases description
Patient 1: A 17-year-old boy was diagnosed with acute
lymphocytic leukaemia (B cell). Chemotherapy was stopped per protocol in
December 2016, and continuous complete remission (CR) of bone marrow was
observed during the treatment. Unfortunately, minimal residual disease
(MRD) increased to 0.18% at 3 months after discontinuation. Morphology
suggested relapse with testicular leukaemia, and two courses each of
consolidation and shelter treatment were completed. The infiltration of
testis improved, and MRD continued to turn negative after treatment. On
October 4, 2017, we completed a matched-sibling donor HSCT (sister
donor, human leucocyte antigen (HLA) 10/10). There was no GVHD
expression after transplantation, and cyclosporine was gradually reduced
from 2 months after transplantation. MRD was 1.67% at 5 months after
transplantation. Two weeks later, bone marrow morphology and MRD were
6% and 4.65%, respectively. A comprehensive evaluation and diagnostic
workup showed R/R-ALL with an indication for CAR-T cell treatment. On
May 1, 2018, donor-derived CAR-T cells were infused(Table.1).
A total of 12.6 × 106/kg CAR-T cells were infused and
evaluated as cytokine release syndrome (CRS)grade II. At + 14 days,
bone marrow was in CR, with MRD <0.01%; + 21 days, rashes of
upper limbs, face, and back appeared, and acute GVHD (aGVHD) was
considered. After methylprednisolone (0.5 mg/kg.d) for 2 weeks, and the
rash gradually subsided. At +52 days, the rash appeared again, body-wide
(Fig. 1A), and methylprednisolone (1 mg/kg.d) was added again. At the
same time, basiliximab was given for symptomatic treatment, and the rash
gradually subsided, but with pigmentation. At +76 days, liver damage was
indicated (ALT 603 IU/L; R-GGT 305 IU/L), and in addition to continued
methylprednisolone, sirolimus and ursodeoxycholic acid were added so
that the liver damage would gradually recover. At +93 days, there was
repeated persistent oral ulcer (Fig. 1B), a clinical diagnosis of cGVHD,
so oral immunosuppressant treatment was continued, and oral care was
strengthened. At +110 days, the patient developed signs of bronchiolitis
obliterans syndrome[3-4] (BOS; Fig. 1C–E). We
tried to use the FAM (fluticasone, azithromycin, and montelukast)
regimen [5], mesenchymal stem cells (MSCs) (once
every 2 weeks, four units each time, four times total), low-dose
ruxolitinib (10 mg, once a day), and prednisone (0.25 mg/kg.d), which
was gradually reduced to 5 mg prednisone for maintenance. At this
writing, there was no significant wheezing attack or chest tightness
during 20 months after CAR-T. Chest CT and lung function were improved,
and the primary disease evaluation always showed CR.
Patient 2: A 5-year-old boy was diagnosed with B-ALL (pre-B)
after intermittent lower extremity pain and left eyelid oedema for half
a year. Genetics analysis was positive for E2A-PBX1 and chromosome 46,
XY, t (1,19) (q21; p13). After induction of chemotherapy with the VPDL
regimen (vincristine + prednisolone + daunorubicin + L-asparaginase),
the bone marrow showed remission, immune residue turned negative, and
E2A-PBX1 dropped to 0.02%. Regular chemotherapy was administered, and
maintenance treatment began on February 6, 2017. In October 2017, the
bone puncture was re-evaluated because of systemic bone pain. Results
indicated that the tumour cells could not be controlled, and MRD
continued to be positive. On December 7 and 8, 2017, auto CAR-T cells
were retransmitted. The bone marrow showed CR, and MRD turned negative.
On February 28, 2018, haploid HSCT (father donor, HLA 6/10) was
performed. At 3 months after transplantation, bone puncture showed 8%
immature lymphocytes and 1.02% MRD, indicating another relapse. The
father gave peripheral blood for the preparation of CD19 CAR-T, and then
Flu/CTX pretreatment was administered. On June 8 and June 13, 2018,
donor-derived CAR-T cells were retransmitted (Table 1).
A total of 13.3 × 106/kg CAR-T cells were infused and
evaluated as CRS grade I. There was no obvious GVHD manifestation. At
+28 days, we evaluated the continuous remission state of the bone
marrow. At +3 months, this patient also received a clinical diagnosis of
BOS. Prednisone (2 mg/kg) was given combined with the FAM regimen. At +4
months, chest CT showed resolution of mediastinal emphysema, wheezing
was improved, lung function still showed moderate obstruction of
ventilation function, and prednisone was gradually reduced to small dose
maintenance. At +6 months, wheezing was reported, while lung function
was not improved, and imatinib treatment was increased. Finally, lung
symptoms were controlled, and lung function was improved. At this
writing, 18 months after CAR-T, the patient’s condition was stable and
in complete remission from leukaemia (Table I).