A five-year-old with KMT2A::USP2 ALL whose MRD would not clear until blinatumomab, then transplant, then more blinatumomab
also called Li 2026 KMT2A-USP2 blinatumomab DLI case · KMT2A-USP2 post-transplant relapse prophylaxis
A five-year-old boy's leukaemia kept showing traces after standard treatment. One course of an antibody drug cleared those traces, he had a transplant from a half-matched donor, and then more of the same antibody plus donor immune cells to stop it coming back. He stayed in remission with only mild side effects.
The same thing, for a scientist
A 5-year-old boy diagnosed with early pro-B ALL, KMT2A::USP2 fusion positive. After induction on the SCCLG-ALL-2016 protocol, minimal residual disease by flow cytometry, by quantitative PCR for the KMT2A::USP2 fusion transcript and by NGS-based IGH sequencing all remained persistently positive. One cycle of blinatumomab turned flow and RQ-PCR MRD negative; two further weeks of blinatumomab bridged to haploidentical HSCT. Because NGS IGH MRD was still 0.0311% before transplant, he received three post-transplant cycles of blinatumomab and two prophylactic donor-lymphocyte infusions. Toxicity was grade 1 cytokine release syndrome with no neurotoxicity, hypoxaemia or hypotension, and remission was sustained [E1]. **The case is worth recording for three specific reasons**: it is the most detailed treatment account that exists for this genotype; it demonstrates that fusion-transcript RQ-PCR MRD monitoring is achievable for KMT2A::USP2, which the founding report argued was the point of characterising these breakpoints [E2]; and it is a CD19-directed course in a fusion whose cohort contains 24% B/myeloid MPAL, i.e. exactly the setting in which lineage switch is a documented failure mode.
The MRD story, which is the substance of the case1 deeper
Three MRD assays disagreed at different points, and the disagreement drove every decision:
| timepoint | flow MRD | RQ-PCR (KMT2A::USP2) | NGS IGH |
|---|---|---|---|
| after induction | positive | positive | positive |
| after 1 cycle blinatumomab | negative | negative | not stated as negative |
| pre-HSCT | - | - | 0.0311% |
The residual NGS IGH signal after both other assays had turned negative is what prompted the post-transplant blinatumomab plus DLI 1. That is a real, generalisable observation about assay discordance in a high-MRD genotype - 76% of KMT2A::USP2 patients in the founding series were MRD-positive at day 33 2 - and it is the kind of detail a cohort paper never carries.
RQ-PCR on the fusion transcript is possible here
The 2019 discovery paper's stated translational purpose was to enable MRD monitoring in exactly these patients by giving their genomic breakpoint sequences 2. This case shows the downstream reality: a quantitative PCR assay for the KMT2A::USP2 fusion was available and was used to make decisions. The caveat is that this case's assay appears to be transcript-based rather than genomic-breakpoint-based, and the two are not interchangeable - a transcript assay is more sensitive to expression and less to clone size.
What a single favourable case can and cannot support
Can: that blinatumomab plus prophylactic DLI is deliverable in this genotype with acceptable acute toxicity; that fusion-directed MRD monitoring works; that multi-modality MRD can disagree and that the disagreement is actionable.
Cannot: anything about efficacy. The authors say so themselves - larger prospective trials are needed to verify safety, efficacy and optimal dosing 1. Blinatumomab and DLI were given together and their contributions cannot be separated. Follow-up duration after the last DLI is not stated in the abstract. And single case reports of salvage are published when they succeed.
The risk nobody in the case discussion raises
CD19-directed therapy in KMT2A-rearranged leukaemia carries a documented risk of myeloid lineage switch, which this graph holds as risk-lineage-switch-cd19-directed-therapy. KMT2A::USP2 is a genotype in which 4 of 17 patients in the founding series were already B/myeloid mixed-phenotype acute leukaemia before any therapy 2. A lineage with demonstrated myeloid capacity, put under sustained CD19 pressure across five blinatumomab exposures plus two DLIs, is the textbook setup for escape by lineage switch.
This patient did not switch. The point is not that the treatment was wrong - it worked - but that the reported outcome does not retire the risk, and a second patient with the same genotype might. Nothing in the source addresses it.
| age at dx | 5 years |
|---|---|
| fusion | fusion-kmt2a-usp2 |
| course | One cycle of blinatumomab cleared flow and RQ-PCR MRD; two further weeks of blinatumomab as a bridge; haploidentical HSCT with pre-transplant NGS IGH MRD 0.0311%; three post-transplant blinatumomab cycles plus two prophylactic donor-lymphocyte infusions. |
| outcome | Sustained remission after HSCT; grade 1 cytokine release syndrome, no neurotoxicity, hypoxaemia or hypotension. Follow-up duration not stated. |
| source type | case report |
| consent note | public source only, no PHI; no identifying detail beyond age, sex and diagnosis as published |
| mrd discordance | flow and fusion RQ-PCR turned negative while NGS IGH remained at 0.0311%, and that residual signal drove the decision to give post-transplant blinatumomab and DLI |
| unaddressed risk | CD19-directed pressure in a genotype where 4 of 17 patients had B/myeloid MPAL before therapy; lineage switch is a documented escape route in KMT2A-rearranged disease and is not discussed in the source |
| why it matters | The most detailed treatment account that exists for KMT2A::USP2, and a demonstration that fusion-directed MRD monitoring - the stated purpose of characterising these breakpoints - actually reaches the bedside. |
presentation
[ "acute lymphoblastic leukaemia, early pro-B immunophenotype", "KMT2A::USP2 fusion gene positive", "persistently positive MRD after SCCLG-ALL-2016 induction by flow cytometry, fusion RQ-PCR and NGS IGH" ]
mrd assays used
[ "multiparametric flow cytometry", "quantitative PCR for the KMT2A::USP2 fusion", "NGS-based IGH sequencing" ]
- Five separate blinatumomab exposures plus two DLIs in a genotype containing 24% B/myeloid MPAL is sustained CD19 pressure on a lineage with demonstrated myeloid capacity. Lineage switch is the expected escape route and the source does not mention it.
- Prophylactic DLI after haploidentical transplant carries graft-versus-host disease risk that the abstract reports only as absence of CRS-related toxicity. Absence of reported GvHD in one patient is not evidence of safety.
- A favourable single case in a rare genotype is exactly the evidence most likely to be over-weighted, because it is the only detailed account available. It should inform what is feasible, not what is advisable.
- How long has the remission lasted? The abstract does not state follow-up duration after the final DLI, and without it the case supports deliverability but not durability.
- Was the RQ-PCR assay built on the fusion transcript or the genomic breakpoint? The distinction matters for whether the 2019 paper's MRD purpose was actually realised as intended.
- Why did NGS IGH remain positive when flow and fusion RQ-PCR were negative? Assay discordance in a genotype with 76% day-33 MRD positivity is worth a systematic look, not a single anecdote.
- Has any KMT2A::USP2 patient undergone lineage switch on CD19-directed therapy? Three reported patients have now received blinatumomab and none is reported to have switched, which is reassuring at n = 3 and no more.
- E1weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper
A 5-year-old boy with KMT2A::USP2-positive early pro-B ALL had persistently positive MRD by flow cytometry, fusion-transcript RQ-PCR and NGS IGH after SCCLG-ALL-2016 induction; one cycle of blinatumomab turned flow and RQ-PCR MRD negative; two further weeks bridged to haploidentical HSCT; with NGS IGH MRD at 0.0311% pre-transplant he received three post-transplant blinatumomab cycles and two prophylactic donor-lymphocyte infusions, developing only grade 1 CRS and maintaining remission.
Case Report: Safety and efficacy of blinatumomab in combination with donor lymphocyte infusion for the prophylaxis of relapse following allogeneic hematopoietic stem cell transplantation in a pediatric patient with acute lymphoblastic leukemia. · Li YT, Li Y, Wang LN, Huang LB · Frontiers in Immunology 2026What this evidence cannot show
One patient. Follow-up duration after the last DLI is not stated in the abstract. Blinatumomab and DLI were given together so their contributions cannot be separated, and the authors explicitly call for larger prospective trials. Single-centre. Whether the RQ-PCR assay targeted the fusion transcript or the genomic breakpoint is not specified. Abstract read in full; body not read.
Evidence that argues against this (1)
- Publication bias runs strongly toward successful salvage in single case reports, and the cohort picture for this genotype is unfavourable - 76% MRD-positive at day 33, frequent CNS disease, poor prednisone response in 42% of those assessed. One good outcome does not revise that. Meyer C et al. 2019
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In the founding 17-patient KMT2A::USP2 series, 13 of 17 (76%) were MRD-positive at day 33, 4 of 17 had B/myeloid mixed-phenotype acute leukaemia, 5 of 17 had CNS disease, and the authors' stated translational purpose was to supply genomic breakpoint sequences for MRD monitoring.
Human MLL/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions. · Meyer C, Lopes BA, Caye-Eude A, Cavé H, Arfeuille C, et al., Marschalek R · Leukemia 2019What this evidence cannot show
n = 17, so each percentage moves by roughly 6 points per patient; median follow-up 1.2 years; patients treated on diverse protocols with no comparator arm. The cohort was assembled from samples referred after other assays failed, which may select for particular disease characteristics. Full text read (PMC6756029).
Evidence that argues against this (1)
- Day-33 MRD positivity in 76% is a striking figure but has no matched comparator in the paper - KMT2A-rearranged infant ALL in general has high early MRD, so the number may not be specific to USP2 at all. Blackburn PR et al. 2020
the most detailed treatment account that exists for this genotype; fusion-transcript RQ-PCR MRD used to drive decisions
- treated by →Blinatumomab in infant KMT2A-rearranged ALL — the largest single outcome gain in thirty years
five exposures total: one cycle to clear MRD, two weeks as a transplant bridge, three post-transplant cycles with two prophylactic DLIs; grade 1 CRS only
- related to →Lineage switch as antigen escape from CD19-directed therapy in KMT2A-rearranged leukemia
sustained CD19 pressure in a genotype where 4 of 17 patients had B/myeloid MPAL before any therapy; the source does not discuss the risk
a clinical use of the graft-versus-leukaemia principle (donor lymphocyte infusion) in a KMT2A-rearranged patient