Presented in September 2021 with history of fatigue and weight loss of 10kgs over 2 months.
Comorbidities: Type 2 Diabetes Mellitus since 2018.
O/E: Liver palpable 6cms BCM, Spleen palpable 12cms below left costal margin. Rest of the clinical examination normal.
He was started on Dasatinib in view of high-risk EUTOS.
Did not tolerate due to Grade 3/4 cytopenia despite dise reduction.
Switched to Imatnib.
Failure as per 3m RQPCR milestone (April 2022).
Defaulted therapy.
July 2022: Progressed to CML blast crisis : Medullary and CNS involvement.
Flow cytometry shows presence of 2 population of blasts with no specific lineagae specificity.
However, IHC shows presence of strong expression of B cell markers (PAX-5, CD10) and 50% cells expressing CD19.
TKD mutation analysis shows presence of compound mutation as follows:
Positive for compound mutation in exon 4 (G250E) & exon 8 (A424G, E459K) of the ABL1 gene (p210 transcript) along with a nonsense mutation in exon 6 of the RUNX1 gene.
1. What should be the preferred modality to get the patient into a remission prior to transplant?
2. What should be the preferred TKI strategy considering the compound mutation?
Bone marrow 9/6/22:
Hypercellular bone marrow aspirate smears reveal near complete replacement by blasts (84%) Two types of blast population is seen.
One type of blasts have intermediate to large size with a high N:C ratio, open chromatin, conspicuous nucleoli, and moderate cytoplasm.
Other type of blast population are small in size, with a high N:C ratio, open chromatin, inconspicuous nucleoli and scant cytoplasm. Normal hematopoietic elements are markedly reduced.
Megakaryocytes are occasionally seen. Blasts are cytochemical MPO stain negative.
REMARKS Bone marrow aspirate is consistent with CML in blast crisis.
Bone marrow biopsy:
Markedly hypercellular marrow with near complete replacement by blasts. On IHC these blasts are positive for CD34, TdT, CD10, PAX5 and negative for cMPO and CD117. CD19 is positive in a subset of blasts ~50%. CD117 highlights scattered myeloid precursors and cMPO highlights cells of myeloid series.
Impression: Hypercellular Bone marrow trephine biopsy is consistent with B Lymphoid blast crisis in a known case of CML.
Modal Karyotype (ISCN 2016): 46,XY,t(9;22) (q34;q11.2)[18]/46,XY[2]
Immunophenotype : The 63% gated cells in the blast window CD34, CD10, HLADR, TdT, CD38 and CD56. These gated cells are negative for cMPO, CD117,CD13, CD14, CD15, CD33, CD64, CD11b, CD11c, cCD79a, CD19, CD20, cCD22, cCD3, CD7, CD2, CCD41a, CCD61, cCD71, cCD235a.
The immunophenotype of these gated cells is suggestive of Blasts with Ambigous Lineage (in view of no expression of lineage specific markers).
In addition another subset of 24% cells is noted in blast window moderate SSC and dim CD45 expression which are positive for CD34, TdT, CD117, CD19(dim), CD10 (in a subset), CD13, CD33, HLA- DR, CD56 (subset), CD38. These gated 24% cells are negative for cMPO, CD14, CD15, CD64, CD11b, CD123, CD11c, CD20, cCD22, cCD79a, cCD3, CD7, CD2, CCD41a, CCD61, cCD71, cCD235a.
Impression: The immunotype findings are suggestive of Acute Leukemia with Ambigous Lineage favoring Acute Undifferentiated Leukemia. These features are consistent with Blast crisis of Ambigous lineage in a known case of Chronic Myeloid Leukemia.
TKI Domain Mutation Analysis: NGS:
Positive for compound mutation in exon 4 (G250E) & exon 8 (A424G, E459K) of the ABL1 gene (p210 transcript)
1)Positive for nonsense mutation in exon 6 of the RUNX1 gene, NM_001754.5:c.601C>T; p.(Arg201*) [VAF: 46.03%]
2)Positive for missense mutation in exon 8 of the ABL1 gene, NM_005157.6: c.1271C>G; p.(Ala424Gly) [VAF: 35.19%]
3)Positive for missense mutation in exon 8 of the ABL1 gene, NM_005157.6: c.1375G>A; p.(Glu459Lys) [VAF: 5.5%]