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.