Philadelphia Positive Acute Undifferentiated Leukaemia

a Previously Unreported Entity

Xu, Ke ;
1 Motum, P;
1 Harvey, M;
1 Lickiss J;
2 Blombery, P;
2 Getta, B.
1
1. Haematology Unit, Liverpool hospital NSW 2170
2. Peter MacCallum Cancer Centre

Abstract Results
Acute Undifferentiated leukaemia is rare leukaemia which has neither lymphoid Case 1 received Dasatinib/dexamethasone with clearance of circulating blasts;
or myeloid markers. We report the clinical and laboratory characteristics of however, with 45% marrow blasts and BCR-ABL of 39% at d30. Treatment was
Philiadelphia positive AUL. changed to ponatinib which attained CR1 at 6 months with karyotype 46XX and
BCR-ABL 2.45%. She succumbed to Covid-19 at 9 months post diagnosis.
Lymphoid features including TCR rearrangement, EBF1 deletion, STAT5 and Crlk
Introduction activation were identified. Case 1 has no extramedullary disease.

Acute undifferentiated leukaemia (AUL, ICD-O 9801/3) is a group of rare
leukaemia that do not express defining markers for either myeloid of lymphoid
lineages. Such diseases are associated with complex cytogenetics, molecular
abnormalities and poor prognosis. A range of phenotypical variation were
described of this group of disease in recent publications. (Weinberg, 2019) . To
our knowledge, Philadelphia chromosome (Ph) has not been reported.
Here we report two cases of Philadelphia positive acute undifferentiated
leukaemia diagnosed at our institution.
Methods and Materials
Investigations included morphology of bone marrow aspiration and trephine, flow
cytometry, IHC, targeted NGS, FISH and RT-PCR. IHC and flow were both used
to determine presence of lineage defining markers according to WHO 2017
(Swerdlow SH, 2017).
Case 2 has a complex karyotype on diagnosis , 46,XY, t(9;22),
del(16(q13),i(17)(q10)/49,idem,+8,+der(9)t9;22),+10/92-94,idemx2,+8,+10,-13,-
19,+der(22)t(9;22)/46,XY. Both TP53 and EZH2 mutation were identified by next
generation sequencing.
Biopsy of mediastinal mass demonstrated identical immunophenotype
comparing to bone marrow aspiration.
Case 2 was induced with FLAG-IDA-Dasatinib which attained a haematological
CR, normal karyotype, BCR-ABL 9% and resolution of mediastinal mass.
Subsequently he received FLAG/Dasatinib consolidation and progressed to
received haploidentical allogeneic stem cell transplantation at the time of this
report.
Immunophenotype
Case CD19 CD34 CD3s/c CD7 TdT HLA-DR CD13 CD33 CD117 MPO

1 - + - - - + + - - -
Case 1 Case 2
Demographics 2 - - - + - + - + dim -
Age 85 26 Table 2. immunophenotype of cases
Sex Female Male
Comorbidities
ECOG
Diabetes, Hypertension Nil
2 0
Discussion
Follow up duration 9 months 5 months We identified two cases of Philadelphia positive acute undifferentiated
leukaemia, which had not been previously reported in literature.
Pathologic characteristics
WBC (x10^9/L) 75.4 17.5 Both cases were found to have minor BCR-ABL (p190) transcript, which is
Marrow blasts 87% 38% mostly seen in acute lymphoblastic leukaemia. Using extended molecular
LDH (U/L) 634 958 techniques, key mutations and karyotypical abnormalities in commonly seen in
both myeloid and lymphoid disease were revealed in both cases.
Extramedullary No Mediastinal mass
Cytogenetics t(9;22), del(5) Complex The presence of heterogenous molecular pathways highlighted the exceedingly
BCR-ABL Type p190 p190 variable nature of pathological drivers of acute undifferentiated leukaemia. These
Molecular Findings underlying pathways were not able to be detected by conventional flow
cytometry or immunohistochemistry. Therefore advanced molecular techniques
TCR/IGH TCR beta Not performed
are required to obtain deeper understanding and subclassification of this group or
Targeted NGS No Variants identified TP53, EZH2
rare acute leukaemia.
Phospho-flow Stat5, Crkl activation NA
Table 1. Demographics and pathological characteristics Each case in our report demonstrated significant response to oral tyrosine kinase
inhibitor therapy with or without concomitant chemoimmunotherapy. Despite
PB smear BM aspirate BM Trephine sample size, we have shown such therapies could be effective in obtaining
disease remission.

Conclusions
This report identifies an unreported type of AUL and effective treatment. We
identify shortcomings of conventional lineage assignment and benefits of
ancillary techniques.
Figure 1. Morphological features of case 1 at diagnosis

Contact References
1. Swerdlow SH, C. E. (2017). WHO Classification of Tumours of
Dr Ke Xu
Haematopoietic and Lymphoid Tissues. Lyon
Department of Haematology, Liverpool hospital
2. Weinberg, O. H. (2019). Clinical, immunophenotypic, and genomic findings
Elizabeth Drive Liverpool 2170
of acute undifferentiated leukemia and comparison to acute myeloid
Email: ke.xu@health.nsw.gov.au
leukemia with minimal differentiation: a study from the bone marrow
Phone: 87385176
pathology group. Mod Pathol, 32, 1373-1385