DISCUSSION
Current treatment protocols for both ALL and AML in children are
effective, and the majority of children can be saved by intensive
conventional chemotherapy with/or without stem cell
transplantation.1,2 Indeed, the newest approaches,
such as use of bispecific antibodies or cell therapy, are successful
even for therapy-resistant ALL.5 It is still an open
question whether immunotherapy alone can suffice to achieve long-lasting
remission particularly in refractory disease.7 A
number of immunotherapies for r/r AML are under investigation, but the
best immunotherapy for this condition that is currently available
entails attempting to control the disease and subsequently performing
stem cell transplantation.8 Thus stem cell
transplantation seems to be the most widely applied and proven curative
procedure for children with refractory AL.9-12 It is
commonly accepted that the better the disease control before
HSCT,13-16 the better the expected outcome. Thus in
r/r AL, the main focus is on effective reduction of blast cell load that
can potentially bridge the patients to a salvage procedure: HSCT alone
or cell therapy with or without subsequent HSCT. Immunotherapy was not
available when we designed and performed our study, and the only
possible approach to bridge the patients to HSCT at that time was
intensified re-induction chemotherapy.17,18Clofarabine, both alone or in combination with other agents, is known to
be effective and is recommended for relapsing AL, with acceptable
toxicity. The salvage therapy is nearly always given to heavily
pretreated children, including those with previous HSCT, and such
patients often have pre-existing organ toxicities. We chose the
combination of clofarabine, etoposide, and cyclophosphamide based on
promising published data showing an acceptable toxicity profile (even in
HSCT).6 However, our results suggest that the
applicability of the protocol for this demanding patient group was
limited by the treating physicians’ pursuit of an individualized
approach, and a lack of confidence in repeating CloEC if the first
course did not result in a substantial response. Two of the seven
patients deviated significantly from the CloEC protocol: one of them was
transplanted already after the first course, and the other one received
a different second course. One patient received the third CloEC off
protocol (despite not fulfilling the required response criteria) and
proceeded to transplantation while not in morphological remission; this
decision reflected the patient’s good clinical condition despite a high
treatment burden, and the treating physician’s hope that the GvL effect
after haploidentical HSCT might overcome a high tumor load at
transplantation. Considering the two CloEC responders (both with
BCP-ALL), one was transplanted already after the first course of CloEC
despite still having a high MRD (> 1%) before
transplantation. The other non-responder was in complete morphological
remission but had 1 x 10-4 positive MRD after the
first course and undetectable MRD after the second course; this is the
only long-term survivor in our cohort. The children with AML and T-ALL
did not respond and progressed, although one of them could be salvaged
by changing chemotherapy from CloEC to FLADx; this patient was finally
transplanted in morphological remission but died in remission of AdV
hepatitis. Our results suggest that CloEC should probably not be
repeated in patients showing no response after the first course, whereas
repeating CloEC may further decrease the pre-transplant tumor load in
responding patients.
No deaths related to CloEC toxicity were observed, and, in all children
who died before being transplanted, death was due to progressive
disease. However, the toxicity of the courses of CloEC was significant
and mainly related to the profound immuno- and myelosuppression. Still,
it is plausible that, together, both CloEC and previous treatments
(including allogeneic HSCT in two patients) contributed to the
immunosuppressive state of the patients. Contrary to some previous
observations,6,17 we found no significant liver
toxicity, neither during induction phase nor after transplantation. In
all cases, the timing of the transplantation could be adjusted to the
changing situations of the children. There was no unnecessary delay in
transplantation due to logistical difficulties, reflecting the
flexibility of this transplant modality. Ex-vivo T-cell depletion
effectively prevented clinically relevant GvHD, even though the
pharmacological prophylaxis was limited, MMF based, and given only
during the first 4 weeks after transplantation.
In conclusion, the combination of clofarabine, etoposide, and
cyclophosphamide did not seem to be a universal treatment for r/r AL:
the only children responding to CloEC in our study were those diagnosed
with BCP-ALL. Nevertheless, this particular group of patients may be
offered salvage immunotherapy with either bi-specific T-cell engaging
CD19 antibodies or chimeric antigen receptor (CAR) T-cells, an approach
that seems more reasonable than exposing such patients to CloEC.
Haploidentical HSCT remains a viable option in cases in which
flexibility in planning the transplantation essential, although further
studies are needed to assess the anti-leukemic potential of such HSCT.