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.