A six-month-old with a week of coughing: KMT2A::AFF1 pro-B ALL presenting with extreme hyperleukocytosis

Not with a lump, not with a rash, and not with anything that looks like cancer. The report records one week of paroxysmal coughing without obvious cause and difficulty clearing sputum, then wheezing that worsened with activity the day before admission. He was given nebulised treatment and intramuscular dexamethasone, and the wheeze improved - which is what a viral wheeze does, and is part of why this diagnosis gets missed. What changed the direction of the case was a complete blood count: white cells 1,560 x 10^9/L, haemoglobin 49 g/L, platelets 32 x 10^9/L 1.

That combination - the anaemia (concept-pallor-and-fatigue-anaemia), the thrombocytopenia (concept-bruising-petechiae-thrombocytopenia) and the white count - is the blood-count picture described in concept-blood-film-and-blood-count-leukemia. Here it arrived inside a presentation that a general paediatric service sees many times a week and which almost never turns out to be leukaemia.

On examination the liver was palpable 4 cm and the spleen 5 cm below the costal margin, firm - the hepatosplenomegaly of concept-hepatosplenomegaly-infant-leukemia, present but not what brought him in.

The white count on the day after admission was 1,755 x 10^9/L with 94% blasts. Marrow was hypercellular with small, regular primitive cells showing nuclear indentation and clefting, scanty agranular cytoplasm and negative peroxidase 1.

The immunophenotype was pro-B and CD10-negative: CD34+, CD19+, cCD79a+, TdT+, CD9+, HLA-DR+, CD123+, CD38+, with CD10, CD20, CD22, CD13, CD33, CD117 and MPO all negative. That is the phenotype concept-flow-cytometry-immunophenotype-kmt2a-r describes, and it was present in the CSF too: 21.16% of nucleated cells in the cerebrospinal fluid were CD19+CD38+CD34+ abnormal B lymphoblasts, that is, CNS involvement at diagnosis (concept-cns-involvement-at-diagnosis).

Karyotype was 46,XY,t(4;11)(q21;q23) - the classic finding of concept-cytogenetics-karyotype-kmt2a. A 57-gene fusion panel and whole-transcriptome sequencing independently called KMT2A::AFF1, and the transcriptome also called the reciprocal AFF1::KMT2A at lower confidence (concept-molecular-confirmation-fusion-transcript). Immunoglobulin-repertoire sequencing found no dominant clonal IGH, IGK or IGL rearrangement - consistent with a clone arrested before the point at which the B-cell receptor is assembled 1.

Transcutaneous oxygen saturation fell to 75-78% with sudden dyspnoea and he was intubated and ventilated. He received two leukaphereses, of 70 and 100 minutes, on a continuous-flow separator through a 6.5 F femoral catheter, with low-dose dexamethasone (3.2 mg/m2, then 6 mg/m2) given around the procedures to begin cytoreduction and limit tumour lysis. The white count fell 1,755 to 946.52 to 493.47 to 55.63 x 10^9/L, a 96% reduction, with no tumour lysis syndrome and no apheresis complication recorded. Between the two procedures he had a fever to 38.5 C and one seizure, managed with sedation and osmotherapy 1.

He was weaned from the ventilator on the third post-procedure day and left intensive care on the fifth. He was then treated on the Chinese Children's Cancer Group infant ALL 2022 protocol with high-dose methotrexate for about half a year, and the report states that MRD fell below the assay threshold, the KMT2A::AFF1 transcript became undetectable, and the repeat karyotype was 46,XY with no tumour-associated abnormality. At the time of writing he was 1 year 1 month old, with normal counts and growth and development comparable to his peers 1.

The report describes remission at roughly seven months from diagnosis. It does not describe cure. KMT2A-rearranged infant ALL relapses predominantly in the first two years, so a child in remission at thirteen months of age is at the beginning of the risk period, not past it.

Seventeen clinical concept entries in this graph describe signs, tests and emergencies in the abstract. None of them can tell you that the sign which brings a baby to hospital may be a cough.

Three things this case teaches that a category entry cannot:

1. The presenting complaint and the diagnosis need not resemble each other. A week of wheeze, improved by a nebuliser, over a white count of 1,560 x 10^9/L.
2. CNS disease can be present at diagnosis and silent. A fifth of the CSF nucleated cells were blasts; nothing in the presentation pointed at the CNS.
3. Hyperleukocytosis is a mechanical emergency before it is an oncological one. What nearly killed him in the first days was viscosity and leukostasis, treated with a centrifuge, not with anything directed at the fusion.

It also instantiates the commonest lesion in the whole graph. Roughly half of infant ALL is KMT2A::AFF1, and this is what one of those children looked like on the day they arrived.