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.