Early Tapering of Immunosuppressive Agents to Immunomodulation to Improve Survival of AML Patients

Although 60-80% of AML patients can achieve complete remission through conventional chemotherapy, relapse is still a common problem. For patients unlikely to respond, re-induction attempts may be dismal, leading to more organ toxicity and increased tumor resistance. In addition, 10% to 40% of patients are primary induction failure (PIF) or resistant disease. AML with PIF or relapse still represents one of the most poor outcomes. In such settings, allogeneic transplantation(allo-HSCT) remains the best prospect of curative potential in a small percentage of patients.

However, several retrospective studies have reported long-term survival rates only of 10% to 40% for patients with AML not in remission at the time of allo-HSCT. Michel Duval et al reported that leukemia progression was the single most frequent cause of failure( 42% for AML) for these patients with advanced disease. It is widely accepted that advanced disease status at transplantation is a significant adverse-risk factor for post-HSCT relapse. Thus, how to improve the recurrence rate of these advanced patients after transplantation is still the main problem.

Dose intensity is a main cause for relapse. In order to improve the outcome of allo-HSCT for advanced leukemia, many scholars design the intensified conditioning or the sequential strategy of cytoreductive chemotherapy followed immediately by intensified myeloablative conditioning (MAC) regimens.With increasing dosage, the chance of relapse decreases but the incidence of acute graft-versus-host disease (GvHD) and non-relapse mortality(NRM) increase. How to well-balance NRM versus relapse is still the subject of much debate and investigation. So many centers developed reduced intensity conditioning(RIC) regimens based on the combination of alkylating agents with a purine analog and TBI, whereby the dose of TBI or the alkylating agent is usually reduced by at least 30% compared with a conventional ablative regimen. And an increased dose of alkylating agents as part of RIC may be associated with better leukemia free survival and the lower NRM.

Apart from the conditioning regimen, curative potential of allo-HSCT is largely based on immune-mediated graft-versus-leukemia(GvL)effects caused by donor T cells contained in the graft. The occurrence of GvHD is thought to be associated with a GvL effect. Since 1990, it has been known that leukemic relapses after allo-HSCT can be successfully treated by the induction of a GvL reaction. Strategies of adoptive immunotherapy such as donor lymphocyte infusion (DLI) and withdrawal of immunosuppression are proved to be able to enhance GvL effects. Many results show that the clinical benefit is limited to a minority of patients relapsed posttransplant, so new strategies such as prophylactic DLI (pDLI) before overt relapse is used in many center. But the results is varied from each centers. Liga M et reported that Patients with leukemia who received low-dose pDLI after allo-HSCT is associated with a relatively high incidence of severe GvHD. Furthermore, finding matched unrelated donors(MUD) again in a timely manner may be difficult and limit access to this treatment and the DLI process itself is more complicated.

Cyclosporine(CsA) withdrawal is generally accepted as first-line treatment in patients with relapse after allo-HSCT. In some studies, the early withdrawal of immunosuppression even in the absence of DLI, can prevent overt morphologic relapse in advanced patients.. AH Elmaagacli et al studied the immunomodulating effect of withdrawal of immunosuppression, the result showed that a probability of 10% for achieving and remaining in remission with AML 3 years after relapse posttransplant, patients with advanced CML and ALL had no chance of achieving and remaining in remission in the same time period. The best results have been seen in CML in early relapse. F Rosenow et al showed that low-tumor burden, defined by the blast count in BM aspirates, is one of the important prognostic factors for successful immune intervention. In a retrospective analysis, Sairafi et al also demonstrated that early immune intervention in case of impending relapse was more effective compared with late intervention after overt relapse. Since withdrawing immunosuppression allows for increased GvL effects, prevention may be the most feasible and effective means of managing relapse after allo-HSCT. On the basis of these results, we designed a prospective clinical study to decrease relapse risk in patients achieving CR with early reduction of immunosuppressive agents.As usual,during the first month, blood CsA levels were kept at 100-150 ng/mL in patients with sibling donors and 200-300 ng/mL in patients with a matched unrelated donors (MUD) and mismatched related donors(haplo-SCT). In the absence of GVHD, CsA was discontinued after 3-4 months when HLA-identical sibling donors were used and after 6 months when unrelated donors were used.In this clinical study,immunosuppressive agents were adjusted according to the schedule. Usually in the absence of GvHD, immunosuppressive agents were gradually reduced by 6 weeks and discontinued in three months after transplant in the advanced patients even if complete donor chimerism (CDC) achieved in matched unrelated donors(MUD) while immunosuppressive agents were gradually reduced by 2 months and discontinued in four months after transplant in the advanced patients in haploidentical SCT. If donor chimerism had not achieved CDC with no significant acute GVHD at four weeks after HSCT, immunosuppressive agents were gradually reduced. If GvHD was present during the time of immunosuppressive agents reduction, CsA was added again and tapering was done over longer periods. Immunosuppressive agents were regularly reduced by 3 months and discontinued in the 5 months without GvHD in the CR group. We used the result of chimerism as the reference. The key point in this clinicaltrial was emphasizing the early reduction of immunosuppressive agents according to the time point after transplant and the clinical symptoms. The ultimate goal of therapy is to minimize GvHD while maintaining GvL effects in order to enhance long-term disease control in the advanced patients.