DISCUSSION
Following the success of haplo-HCT, in both malignant and non-malignant
disorders in recent years, multiple variations to conditioning intensity
and GVHD prophylaxis have been employed to improve the outcome even
further.
The use of PTCy in haplo-HCT, either with BM or PBSC grafts, has been
proven to be safe and associated with low incidence of GVHD in adults
(1, 20-22). Although promising results have been reported with the use
of PTCy in haplo-HCT in a few pediatric studies published to date
(23-25), an alternative regimen may be necessary in children with recent
prior exposure to high dose cyclophosphamide, those with a
contraindication to the use of alkylating agents, organ dysfunction and
possibly in younger children (< 10 years) due to the reported
unacceptable higher rate of acute GVHD (aGVHD) and early NRM (26).
Abatacept has emerged as an attractive alternative since a reduction of
aGVHD was demonstrated in its first in-human trial with the addition of
four peri-transplant doses to standard GVHD prophylaxis in patients with
malignant diseases receiving matched unrelated donor (MUD) graft (17).
Aba2, a phase II trial, enrolled patients older than 18 years of age
with hematological malignancies, to study the addition of abatacept to
calcineurin inhibitor (CNI)/MTX-based GVHD prophylaxis to reduce aGVHD.
In 8/8 HLA-MUD, grade III-IV GVHD was 6.8% in the abatacept group vs
14.8% in the group. Severe aGVHD free survival (SGFS) was 93.2%
(CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P=0.05). The
addition of abatacept did not increase relapse in the 7/8 or 8/8 MUD
recipients (7/8s HR, 0.45; P=0.21 and 8/8s HR, 0.86; P=0.66), a key
safety outcome when adding an adjunctive immunomodulating agent to
transplants for hematologic malignancies. There was a significant
improvement demonstrated in survival indicators in the 7/8 HLA-MUD
cohort as well (27). A phase II trial comparing cyclophosphamide and
abatacept with standard of care treatment in haematological malignancies
is currently recruiting (NCT03680092)
This approach has since been extended to patients with non-malignant
diseases. There has been encouraging results with the use of abatacept
in haemoglobinopathies, where unlike malignant disorders, the aim is not
to produce a graft versus leukemia effect. Ngwube et al recently
published results of a phase 1 trial (NCT03128996) of MUD HCT in
patients with severe sickle cell disease (SCD) using reduced intensity
conditioning followed by tacrolimus, methotrexate or MMF and abatacept
as GVHD prophylaxis (28). The continued risk of cGVHD in the first 2
participants in this trial prompted an amendment to extend
co-stimulation blockade with abatacept to 1 year posttransplant in SCD
patients receiving bone marrow product. The incidence of grades III-IV
aGVHD at day +100 was 7% with a 2-year overall and disease-free
survival was 100% and 92.9%, respectively. One-year incidence of
chronic GVHD was 57% and mild/limited in all but 1 patient who received
abatacept for a longer duration. Phase 2 trial of unrelated donor HCT,
adding abatacept to standard GVHD prophylaxis are underway.
Khandelwal et al built on their previous experience of using a
myeloablative regimen on 24 children with transfusion dependent
thalassemia with the addition of four doses of abatacept to CNI and
corticosteroids. They also found that abatacept reduced the incidence of
aGVHD (No grade II-IV aGVHD in the abatacept cohort vs 50% in standard
cohort) without impacting engraftment or survival (29). All of the above
studies were in the unrelated donor setting.
A pilot study by Jaiswal et al, trialed the concept of extended T cell
co-stimulation blockade (COSBL) with Abatacept until day +180 to achieve
long term tolerance and decrease incidence of cGVHD. This was
administered along with sirolimus and PTCy in 10 patients with severe
aplastic anemia. The GVHD and disease-free survival at one year in the
COSBL group was 80% vs. 30% in the control group (p=0.05). This
protocol did result in reduced cGVHD, low incidence of CMV and better
immunosuppression free survival at one year (30). Another trial is
exploring the benefits of intermediate duration abatacept on the risk of
GVHD in sickle cell disease HCT (31). The ideal dosing schedule for
abatacept to yield the optimal GVHD free relapse free survival (GRFS) in
different disorders is still being investigated.
Another reported application of abatacept pertained to its effects on
Natural killer (NK) cells. NK resistance to CTLA4Ig mediated anergy has
been shown in both murine and canine models (32, 33). NK cells were also
found to have augmented anti-tumor effect in the presence of CTLA4Ig
(34). Jaiswal et al reported the use of early and sequential CTLA4
(Abatacept) primed DLI starting at day+7 of PTCy based haplo-HCT in 30
patients with relapsed/refractory leukemia. Prophylactic use of DLIs had
been successfully used in the setting of advanced haematological
malignancies to attenuate the possibility of disease progression (DP).
This was based on the principle that NK cell mediated anti-leukemia
effect could be exploited without an increase in T cell-mediated
alloreactivity. They showed promising results with an incidence of aGVHD
of only 6.7%, limited cGVHD in 20.8%, NRM 4.5% and a progression free
survival (PFS) of 75.8% (35). This is particularly striking as the
reported PFS of 372 patients with high disease risk index after PTCy
based haplo-HCT was reported to be 22% by the Baltimore group (36).
Abatacept represents a unique approach to immunomodulation where
prevention of early severe aGVHD is not associated with a delay in
overall immune reconstitution. Patients treated with abatacept have been
shown to accumulate significantly fewer proliferating and activated
CD4+ T cells with a reduction in effector memory CD4 T
cell expansion, early after transplantation (17, 27). That effect was
not similarly demonstrated in CD8+ function and
therefore combining T cell blockade with another signaling pathway may
be necessary to control CD 4 and CD8 alloreactivity (37, 38). Similar to
other studies, reconstitution of NK cells occurred more rapidly compared
to other lymphocyte subsets. In the phase 1 trial (NCT01917708), no
differences were seen in granulocyte or B cell recovery in non-malignant
disease patients compared to Aba2 groups (Aba2; NCT01743131). Patients
treated with abatacept have experienced transient T cell and NK
depletion, where similar counts are seen by day +100, and therefore may
be less likely to experience T cell dependent immunocompromise (28).
An additional vital aspect with the introduction of new immunomodulating
agents is the added risk of infectious complications. There is in vitro
evidence that T cells exposed to CTLA4Ig and cyclosporine still retain
virus specific immunity (39). The use of abatacept in patients with
severe aplastic anemia resulted in lower incidence of CMV and other
viral infections which may be explained by the relative lack of effect
of abatacept on anti-viral memory T cells as well as the demonstrated
improved recovery of Tregs (30). Ngwube et al also showed T cell subsets
gradually recovered after day +100 to the normal range by 1 year.
Although the rates of viral reactivations are non-negligible, majority
of the patients in the previous studies were asymptomatic, and treated
successfully with antiviral therapy. No incidence of post-transplant
lymphoproliferative disorder (PTLD) was reported in the aforementioned
studies. Careful routine monitoring for viral activation and immune
recovery is needed post-transplant to guide interventions.
Although our study has a small cohort of four patients, it is the only
pediatric report to describe outcomes with abatacept in the unique
setting where administration of PTCy may be contraindicated. Our report
highlights the concept of achieving acceptable GVHD rates with the
addition of abatacept to GVHD prophylaxis without compromising the risk
of relapse or increasing infectious complications.