CASE DESCRIPTION
A previously healthy 2-year-old male presented with lethargy, pallor,
and bruising whilst visiting family in Iran. He had marked
hepatosplenomegaly, and his full blood picture demonstrated anaemia
(5.6g/L), thrombocytopaenia (58 x 109/L), and marked
leucocytosis (540 x 109/L). Immunophenotyping of
peripheral blood confirmed a diagnosis of T-ALL. Bone marrow cytogenetic
analysis revealed a normal karyotype with no chromosomal abnormalities.
He first received chemotherapy as per the Berlin-Frankfurt-Muenster 2009
study (Protocols IA and IB). He tolerated these cycles with minimal
toxicity and was subsequently transferred to our unit for ongoing
treatment. Day 15 and day 33 bone marrow flow cytometry minimal residual
disease (FCM-MRD) results were documented as high at 16.48% and 0.38%
respectively. Bone marrow examination following completion of BFM
Protocol IB had FCM-MRD level of 0.887%. In view of this result, he
received three high-risk intensification chemotherapy blocks as per the
Children’s Oncology Group AALL1231 protocol. Bone marrow assessment
following these cycles demonstrated morphological remission, with an
improved MRD level of 0.062%.
At this juncture, he was considered for an allogeneic haematopoeitic
stem cell transplant (HSCT) with his 5-year-old sibling identified as an
optimal donor. With the aim of achieving MRD remission priot to HSCT, he
went on to receive a further cycle of chemotherapy including nelarabine
(to which he was naïve). Unfortunately, despite this, his leukaemia
burden worsened with bone marrow examination confirming morphological
relapse. The immunophenotype indicated additional new clonal evolution
with preservation of normal cytogenetics. MRD of the initial clone was
0.043%, with its persistence indicative of treatment-refractory
leukaemia.
Soon after, the child developed a vesicular rash to his upper limb
confirmed to be varicella zoster infection, and he was commenced on
anti-viral therapy. He was noted to have increasing hepatosplenomegaly
with a rising white cell count (WCC) and peripheral blast count.
Multiple discussions were had with his parents who understood the dismal
prognosis but were keen to explore further therapies, still with the aim
of receiving HSCT. He was not fit to receive further intensive
myelosuppressive chemotherapy given the risk of varicella dissemination.
Daratumumab was offered as a bridging agent with the aim of reducing
tumour burden and providing recovery time from his acute infection.
With provision made on compassionate grounds, the child received 2 doses
of daratumumab 1 week apart. The prescribed dose was 16mg/kg based on an
ongoing phase II clinical trial. Both doses were well tolerated, except
for the development of a grade I rash during the first infusion which
resolved with anti-histamine therapy. There were no other features of
cytokine toxicity. Over the next 48 hours, he showed signs of
improvement with a steep drop in his WCC from 34.33 (x
109/L) to 3.31 (x 109/L) and
peripheral blast count from 82% to 7% pre and post daratumumb
respectively (Fig. 1). Concurrently, his lactate dehydrogenase level
rose from 3510 U/L pre-daratumumab to 7030 U/L 24 hours later, and fell
progressively to 944 U/L on day 8 indicating initial tumour lysis and
subsequent reduced tumour burden. On serial examination, he demonstrated
significant reduction in the degree of hepatosplenomegaly and
improvement in his overall clinical condition. His WCC remained low
until 4 days after the second dose of daratumumab after which he was
found to have an increase in his peripheral blast count and increasing
hepatosplenomegaly. By this time, the zoster infection was under control
and he proceeded to receive a course of fludarabine, high-dose
cytarabine, idarubicin chemotherapy (FLA-Ida). Unfortunately, 3 weeks
later his bone marrow showed persistent disease and he died at home the
following week.