Discussion
We present a case of refractory KMT2A -r infantile leukemia that
underwent multiple lineage switches during therapy, both with and
without immunotherapeutic pressure. The underlying mechanism by whichKMT2A -r leukemia can lineage switch is not fully understood.
Recent single cell sequencing studies suggest that some patients withKMT2A -r B-ALL harbor subpopulations of blasts that contain
myeloid transcriptional profiles, which can become the dominant clone
under the selective pressure of therapy.2,3 It is also
described that in mixed phenotype acute leukemia, even distinct
phenotypic populations, retain multilineage potential, rather than
simple outgrowth of a minor clone.14 The frequently
shifting leukemia immunophenotype presented a challenge for measuring
MRD using flow-cytometry based methods. In this case, identifying and
sequencing the clonal Ig rearrangements allowed for disease detection
throughout therapy despite lineage switching. However, rearrangements ofKMT2A often occur prior to VDJ recombination and result in
oligoclonal IG/TCR rearrangements15, which limits the
broader utility of this approach for tracking MRD in KMT2A -r
B-ALL. Alternatively, quantitative PCR based approaches for tracking the
underlying KMT2A rearrangements have been
suggested.16
KMT2A rearrangements confer poor prognosis in
B-ALL17 and, when combined with detectable disease
after consolidation, portend high risk of relapse.16Recent genomic analysis suggests that the immature differentiation state
of KMT2A-r blasts may partially explain this poor therapeutic
response through resistance to steroids.3 Our patient
did not achieve remission at any point during initial therapy with
standard cytotoxic agents, nor did she achieve meaningful benefit from
the addition of the BCL-2 inhibitor venetoclax.
Given the lineage infidelity of her disease, she was treated with
combinations of agents to target both the myeloid and lymphoid
compartments. Initially, she received therapy containing blinatumomab
(bispecific CD19/CD3 monoclonal antibody) and gemtuzumab (anti-CD33
monoclonal antibody conjugated to calicheamicin), which has demonstrated
activity in cases of mixed phenotype acute
leukemia.13,18 She did not achieve a clinically
meaningful benefit from this combination, despite her blasts expressing
both CD19 and CD33. However, the dominant blasts emerging from this
therapy lost expression of the CD19 antigen in response to the
blinatumomab and her disease did not regain expression of CD19
throughout the rest of her therapy.
The results of Interfant-06 determined that children with high end of
induction MRD benefit from an intensive myeloid-directed chemotherapy
backbone.19 These results, in combination with our
experiences of frequent lineage switching in this patient, led us to
treat her with a novel combination of liposomal daunorubicin +
cytarabine (CPX-351) in combination with inotuzumab (anti-CD22
monoclonal antibody conjugated to calicheamicin). This was the only
therapy she received that achieved remission, albeit with low level
molecular evidence of disease still present.
The growing list of immunotherapeutic approaches provides opportunities
to explore different combinations to improve disease control in infants
with KMT2A -r B-ALL, potentially with improved safety profile in
this patient group, who have inherently higher risk of treatment related
toxicity. Along these lines, the addition of blinatumomab to the
backbone of interfant-06 therapy showed improved survival in a recently
published trial of KMT2A-r infantile
leukemia20. The rise of single-cell genomic analysis
may eventually lead to better prediction tools to help select which
patients with KMT2A-r leukemia would respond to a lymphoid,
myeloid, or combinatorial directed therapy.
This case highlights the challenges in treating KMT2A -r infantile
B-ALL. The infidelity of KMT2A-r leukemias to either myeloid or
lymphoid lineages presents unique challenges with respect to monitoring
disease response by flow-based analysis. The inherent treatment
resistance and poor prognosis emphasize the need to study novel
combinatorial therapeutic strategies.