Abstract:
Infant acute lymphoblastic leukemia (infant ALL) is known for its poor
prognosis. Current treatment protocols include aggressive chemotherapy
and stem cell transplantation but prognosis remains poor. Immunotherapy
is a new approach with promising results. CAR-T cell therapy has
recently been approved for relapsed or refractory childhood ALL but
lacks documentation regarding infant ALL. We describe here two cases of
patients suffering from infant ALL who were treated with CAR-T cell
therapy, the feasibility and efficiency of treatment and their outcome.
Introduction
Infant acute lymphoblastic leukemia (ALL), defined as occurring before
12 months of age, is a rare disease, occurring in 40 cases per million
births1. In up to 80% of cases, a KMT2A gene
rearrangement, or KMT2A-r, occurs in utero and leads to a rapid
progression to leukemia2. Very early relapse is
common, leading to a 5-year overall survival of about 50%, and below
15% for high risk groups3,4.
There is hope that cancer immunotherapy may provide the long awaited
breakthrough in treating these children. As such, CD19 directed chimeric
antigen receptor (CAR)-T cells have recently been approved for relapsed
or refractory childhood ALL, but their usage in infant ALL is not yet
well documented.
We present two cases of infant ALL treated with this new therapy.
Case 1 (figure 1A)
This patient was diagnosed with high risk infant B-ALL at 5 months of
age.
Minimal residual disease (MRD) was negative after induction therapy
according to the Interfant 06 protocol5, but
cerebrospinal fluid (CSF) became positive at the start of consolidation,
and bone marrow MRD became detectable three weeks later.
He proceeded to a 10/10 HLA matched umbilical cord blood transplant
after a busulfan-fludarabine and thiotepa conditioning regimen,
according to the FORUM study6.
Unfortunately, he developed a bone
marrow relapse two months after the transplant. It was decided to
proceed to CAR-T cell therapy with the close collaboration of the
hospital of Frankfurt, Germany, as Tisagenlecleucel was not available
yet in Switzerland. At 13 months of age and 8.1 kg, he was the smallest
patient referred there for CAR-T cell therapy. Two apheresis were needed
to collect enough cells, and in waiting for the re-infusion, he received
a low intensity bridging chemotherapy according to the Frankfurt
protocol7.
He then went back to Frankfurt and received the CAR-T cells at a dose of
2x10e6/kg. He did not show side effects of the T cells, but developed
bacteremia due to an infection of the apheresis catheter. MRD was
negative after CAR-T cell therapy.
Unfortunately, the CAR-T cells started decreasing and the patient
presented a second bone marrow relapse as well as a subcutaneous
chloroma four months after the infusion.
The Novartis facility had enough CAR-T cells to allow a new
administration with a similar dose (1.8x10e6/kg). This took place in the
Children’s Hospital of Zurich, Switzerland, without any complications,
and his MRD became negative again. The circulating CAR-T cell numbers
however showed a progressive decline over the next months, and it was
decided to proceed to a second HSCT in Geneva, after a Fludarabine,
Thiotepa and Treosulfan conditioning regimen.
He is currently in remission with negative MRD, 9 months after his
second transplant.
Case 2 (figure 1B)
The second patient was diagnosed with high risk infant B-ALL at less
than two months of age. During consolidation according to the Interfant
06 protocol, her MRD became positive (10e-4) and she presented a very
early CNS relapse.
Blinatumomab was started as a bridge to stem cell transplant, but her
disease progressed with a bone marrow and CNS relapse, and she proceeded
to a 10/10 matched cord blood stem cell transplant from an unrelated
donor, after conditioning according to the FORUM
protocol6.
Unfortunately, only a month after transplant, she presented a new
medullary and CNS relapse. She was elected to receive CAR-T cell
therapy, and was started on the Frankfurt ALL relapse
protocol7. As soon as the absolute lymphocyte number
reached 500/ul, she was transferred to the Children’s Hospital of Zurich
for the apheresis, at 12 months of age and with a weight of 9.5 kg. The
procedure had to be repeated twice to collect enough T cells.
In the meantime, the CNS infiltration progressed with meningeal
chloromas, facial palsy and then impaired neurological status.
Tisagenlecleucel was infused at 2x10e6 cells/kg after a conditioning
with Fludarabine and Cyclophosphamide. She developed a grade IV cytokine
release syndrome which was treated with three doses of tocilizumab. She
also presented a grade I CAR-T encephalopathy, which she seemed to
recover from after a week. However her CNS disease progressed further,
and she passed away less than a month after receiving the CAR-T cells.
Discussion
We report the first two cases of high risk infant B-ALL treated with
Tisagenlecleucel (Table 1).
CAR-T cell therapy has shown promising results in pediatric ALL. It
involves autologous T cells which are genetically modified to express a
chimeric antigen receptor (CAR), usually targeting CD19.
Tisagenlecleucel is a commercially available CAR-T cell developed by the
University of Pennsylvania and by Novartis which has been approved by
the FDA in 2017 and by the European and Swiss agencies in 2018 for
refractory/relapsed B-ALL in young people aged 3 to 25 years. It is a
second-generation CAR, meaning it includes an intracellular
co-stimulatory domain (4-1BB) next to the primary TCR CD3ζ domain,
allowing for better cellular expansion and survival.
The production starts with a leukapheresis to collect T cells. The prior
treatments may lower white blood cell and lymphocyte counts, making it
harder for the apheresis centrifuge to separate the cell
populations8, 9 and get a sufficient
yield10. To alleviate this problem, some groups
perform apheresis early in the treatment, with freezing of the cells.
In a Novartis facility, the cells are transduced with a lentiviral
vector to express the CAR and are expanded, a process which takes just
over three weeks. After a lymphodepleting chemotherapy, the cells are
reinfused to the patient at a recommended dose of 0.2 to 5 x10e6 T cells
per kg in children11.
Early studies showed CR rates in relapsed pediatric and young adult
B-ALL of 79 to 93%12–15, and recent data on
follow-up show remissions of over 60 months in non-CNS3
patients16. CAR-T cells also cross the blood-brain
barrier and are able to target CSF disease17. The two
main causes of treatment failure are early loss of CAR-T cells and
CD19-negative relapses.
The differences in CAR-T construct, conditioning therapy and previous
treatments make it difficult for clinicians to decide exactly when and
how it should be used. For instance, the role of HSCT after CAR-T
therapy is still an open question10, 18-19.
As for infant ALL, it is worth noting that the trials which led to the
approval of Tisagenlecleucel in children only included patients over 1
year of age. Seattle Children’s Hospital recently reported the largest
cohort of relapsed or refractory infant ALL treated with CAR-T cells
with 18 patients, aged 14 to 40 months at enrollment, 16 of which
received the treatment, with an MRD negative CR rate of 93% and one
year OS of 71%20. Of the 14 patients who achieved
MRD-negative CR, 6 went on to subsequent HSCT.
In our situation, the CAR-T treatment had to be repeated for the first
patient, but it induced an MRD negative response both times. Careful
surveillance of the CAR-T cell numbers then enabled us to proceed to a
timely second stem cell transplant, with the patient remaining in
complete remission with negative MRD until now and in excellent
condition.
As for the second child, the disease was never in molecular remission
but instead progressed in spite of the treatment, especially the CNS
involvement which ultimately caused her death. Although less than two
months went by from the day of the apheresis to the infusion of the
cells, this time constraint remains an issue. Also, this child initially
received Blinatumomab in an effort to reach negative MRD for transplant,
and recent data suggest that prior use of Blinatumomab might decrease
the efficacy of CD19 targeted CAR-T cells21.
The low patient weight and previous chemotherapies rendered the
apheresis challenging, but these cases show that the procedure can be
safely performed.
However, practical challenges remain, with relatively few manufacturing
facilities worldwide, requiring tight coordination with the
pharmaceutical company. In situ CAR-T production, available in some
University Hospitals, alleviates these hurdles.
The cost of this therapy is also an issue. Compared to standard
treatment, CAR-T cell therapy in pediatric ALL leads to an estimated
increased cost of $528’200, or $64’600 per quality-adjusted
life-year22. This is usually considered
cost-effective, but is not easily affordable.
Finally, relapses may still occur in up to 50% of patients, emphasizing
the importance of the ongoing research into new generations of CAR-T
constructs, with better persistence and/or dual targets to avoid CD19
negative relapse.
Conclusion
We report the first two cases of
infant ALL treated with Tisagenlecleucel.
These cases underline the practical challenges involved, with the
apheresis notably still quite challenging in infants. However, we
demonstrate its feasibility in two cases of a disease once thought to be
incurable: infant ALL relapsed after HSCT. It is our hope that with the
more widespread use of CAR-T cells, progresses in their production and
more efficacious constructs, the process will become more streamlined
and hence easier for patients and their families. This may even allow
treatment earlier in the disease course, sparing toxicities and allowing
for more efficient treatment.
Conflict of Interest Statement
SL Maude: clinical trial support:
Novartis; consulting, advisory boards, or study steering committee:
Novartis, Kite, Wugen
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