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.