Discussion
In the past decades treatment of ALL at childhood became more and more successful reflected by survival rates achieving greater than 90 % in high-resource developed countries . To further improve outcome in the rather small patient group with poor treatment response and a high risk of relapse, one aim of CoALL-08-09 trial was to find a new therapeutic option by adding a second line or salvage therapy element. As such, we implemented amsacrine into the frontline treatment of ALL and examined the efficacy and toxicity profile in combination with methylprednisolone and etoposide in late consolidation of patients with high EOI MRD (≥10-3).
In comparison to an MRD-matched historical control group of ALL patients recruited in trial CoALL-07-03, AEP treatment increased overall survival without impact on pEFS in HR-I patients under the CoALL-08-09 protocol. Time to relapse of matched patients did not differ between CoALL-07-03 and CoALL-08-09 cohorts but HSCT-related mortality was lower in the successor CoALL-08-09 trial likely accounting for the improvement of OS . A refined HSCT procedure including more precise donor selection, improved graft-versus-host disease prophylaxis and a more efficacious antifungal therapy might have contributed to this effect . In a T-ALL subgroup with high MRD burden AEP could have exerted an immediate effect on the risk of relapse by more efficacious eradication of residual leukemic clones as suggested by an improved pEFS. However, T-ALL subgroups in both trials are too small to draw firm conclusions.
In general, persistence of MRD throughout chemotherapy is associated with a poor prognosis, whereas early MRD negativity improves outcome significantly . The impact of MRD response to a single treatment element in consolidation treatment appears to be disputable. Yet, the level of MRD load prior to stem cell transplantation is a strong predictor of relapse . In the chemoresistant patient population with IF and a persistent MRD load the AEP block as part of a bridging-to-transplant procedure was shown to lower the MRD burden in a large proportion of patients without severe toxicity. Also in patients treated in the HR-I arm the side effects reported after the AEP block were rather moderate. Moreover, the average duration until the next therapeutic element as a surrogate parameter for myelosuppression was similar to other intensive therapy elements. By contrast, many study groups made the observation that very intensive chemotherapy was associated with an unusually high rate of side effects and increased treatment-related mortality .
The advances in immunotherapies offer alternative, potentially better treatment options for patients with refractory or relapsed leukemia compared to second-line chemotherapeutic agents such as amsacrine. CD19- and CD22-directed therapeutic antibodies have been licensed for several years. For instance, blinatumomab, a CD3/CD19-directed bispecific T cell engager, has been successfully used as a bridging-to-transplant approach leading to MRD-negativity in a substantial proportion of patients. Therapeutic antibodies exhibit a distinct toxicity profile mostly associated with a cytokine release syndrome or neurological side effects which could preclude their application in some patients . In those patients and under conditions of very limited resources AEP-based intensification or bridging treatment could be a viable alternative to control MRD in HR-ALL patients, particularly in patients without CD19 surface expression on B-lymphoblasts that are not eligible for anti-CD19 directed therapies .
In conclusion, AEP is a well-tolerated and effective treatment element that can be applied as a part of the HR therapy or as an option in the process of bridging to HSCT in patients with ALL.