INTRODUCTION
Despite improvement in survival of children with acute leukemia (AL), a
significant number of such patients still experience primary or
secondary resistance to treatment.1,2 Children failing
to achieve remission and those relapsing after previous allogeneic
hematopoietic stem cell transplantation have a short life expectancy,
and palliative treatment remains the only reasonable option, because in
many cases escalation of conventional chemotherapy is no longer
effective. Thus far, cell/immune therapies are applied primarily in B
precursor acute lymphoblastic leukemia (ALL), whereas refractory T-cell
acute lymphoblastic leukemia (T-ALL) and acute myeloblastic leukemia
(AML) still represent an unmet challenge.3 Allogeneic
hematopoietic stem cell transplantation (HSCT) seems to improve survival
in children with high-risk acute leukemia. Better survival can in part
be mediated by the graft-versus-leukemia (GvL) effect together with the
anti-leukemic effect of the conditioning regimen. However, the efficacy
of allogeneic HSCT is inversely correlated to the tumor burden. In
patients without at least morphological remission at the time of
transplantation, the risk of subsequent relapse is very high.
Clofarabine has been shown to potently induce remissions in refractory
cases of pediatric acute leukemia, both when given as a single drug and
in combination with etoposide and cyclophosphamide. In the Nordic
countries, clofarabine has not been incorporated in the primary
treatment of acute leukemia in children, thus leukemic cells from
patients who are refractory to multiple multidrug regimes have usually
not been exposed to clofarabine. Still, responses induced by
clofarabine-containing drug combinations are often transient in
character. Nevertheless, even a temporary decrease in tumor load before
an allogeneic HSCT could theoretically increase the potency of the GvL
effect in reducing the risk of relapse, making this treatment modality a
potential consolidation of clofarabine-induced responses. The short
duration of clofarabine-elicited responses requires precise timing of
the allogeneic HSCT. Transplantation with haploidentical donors offers
such precision and may also lead to an enhanced GvL effect due to the
HLA disparity between the donor and recipient.4-6 Our
aim was to evaluate the safety and toxicity of intensified
clofarabine-based multidrug remission induction for heavily pretreated
children with r/r AL, and also determine the potential of this approach
to bridge these patients to a promptly timed haploidentical HSCT.