DISCUSSION
Daratumumab is a human monoclonal antibody that specifically binds a
unique isotope on the CD38 molecule, and exerts its anti-tumour activity
through various complement- and antibody-dependent cytotoxic
mechanisms.8 It has demonstrated a favourable toxicity
profile, and is currently U.S. Food and Drug Adminisration (FDA)
approved for the treatment of adults with relapsed or refractory
multiple myeloma.8,9 Daratumumab has now emerged as a
potential agent to be used in the treatment of T-ALL given its efficacy
demonstrated in mouse models.7,10 In a preclinical
study it was tested in a large panel of paediatric T-ALL patient-derived
xenografts (PDX) where it was found to be efficacious in 14 of 15 the
different PDXs as measured by reduction in leukaemia burden in blood and
spleen.7 The single PDX that failed to respond had low
expression of CD38. In another study in mice, daratumumab was found to
eradicate MRD in 7 of the 8 T-ALL PDX mice who had been
treated.10 There is also evidence that daratumumab can
be combined with conventional cytotoxic chemotherapy with minimal
toxicity in adults with multiple myeloma giving hope for its translation
to leukaemia therapy. Off-label use has been reported in three adult
patients from a single centre, all heavily pre-treated, one with
relapsed high-risk B-ALL and two with relapsed T-ALL who achieved MRD
remission for at least 10 months by using daratumumab in combination
with vincristine or nelarabine with minimal
toxicity.11,12
This unprecedented case documents the use of daratumumab in paediatric
T-ALL and suggests its potential benefit for the treatment of this
disease. For our patient, daratumumab was used as monotherapy to tide
over the crisis in the setting of an active varicella infection and a
high tumour burden. Although complete remission was not achieved, there
was a significant response as demonstrated by a rapid reduction in the
patient’s WCC and peripheral blast counts, as well as clinical
improvement. It may be inferred that his reponse was only partial due to
the inherently aggressive nature and late stage of his disease with
failure to respond to FLA-Ida chemotherapy. However, notwithstanding his
refractory leukaemia, it could also be hypothesised that a partial and
less sustained response was achieved as daratumumab was used as
monotherapy. Based on our patient’s leukaemia resurgence 2 weeks later
and prior case reports,11,12 daratumumab will likely
to be more effective when used in combination with other chemotherapy
agents.
It is clear that larger clinical studies are required to further
investigate daratumumab in paediatric T-ALL. Currently there is an open
phase II clinical study (NCT03384654) evaluating daratumumab in
combination with chemotherapy in children and young adults (less than 30
years) with relapsed and/or refractory T- or B-ALL.13Hopefully, further studies will be able to answer some of these
questions surounding daratumumab’s role in paediatric T-ALL, and in turn
bring a novel approach to what is ordinarily a devastating disease in
the relapse/refractory setting.