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CML in Medullary and CNS Blast crisis with compound mutation

  • Arijit Nag
  • Arijit Nag's Avatar Topic Author
1 year 6 months ago #1879 by Arijit Nag
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%]
  • Jeff Lipton
  • Jeff Lipton's Avatar Topic Author
1 year 6 months ago - 1 year 6 months ago #1880 by Jeff Lipton
This is a very sad case with a very poor prognosis. There is probably going to be a single chance for a long-term, disease free period and possible cure, so no holds barred with the therapy.

Information on things like age, donor availability and type are not provided and obviously will impact the plan. As both a CML treater and an allografter, I can offer the following.

There is a lot of information provided here about the disease, both early on and after transformation. Although for the most part very interesting, we need to cut to the bottom line. This patient has myeloid blast crisis CML with CNS and extramedullary disease. All the markers and molecular tests are really icing on the diagnosis. Unless the patient gets a good response to treatment, and by this I mean at least a second chronic phase with disappearance of the extramedullary disease and clearance of the CSF, attempting an allograft even with an excellent donor is probably futile. Transplant in blast crisis is not recommended as per the ELN 2020 recommendations, and personally I have never had a success doing this.

For arguments sake, I will assume that you have a relatively young patient with no co-morbidities other than the DM. I would treat with AML-type induction plus ponatinib as the best chance. Aggressive intrathecal therapy, triple preferred, needs to be done in parallel, and if there is evidence of fixed CNS lesions, make cranial spinal radiation part of the transplant conditioning. If CP2 is achieved, I would proceed right to allografting regardless of the molecular response. Given the presentation, a myeloablative regimen such as CyTBI or VP16TBI should be used with the 1200cGy built into the cranial spinal if given. Stem cell source should be PBSC for the potential of more GVH/GVL than bone marrow. Reduction of immunosuppression should be prompt and early, starting at around 45-60 days post allograft in the absence of acute GVHD. Life long ponatinib maintenance starting at day 60 or once immunosuppression is finished, initially at 30mg daily and reducing to 15mg if MR4.5 is achieved and sustained for at least 6 months. If cranial spinal radiation is not needed, then I would give an additional 6 IT treatments, once every 2-3 weeks depending on counts, starting at around 60 days.

Without knowing what is available to the treating physician, this is a suggested road map to be adapted. Toxicity will be high, but I believe that trying to minimize this, will only compromise the outcome. Even with everything going very well and a very fit patient, a very and I mean very optimistic success rate is no better than 10-20%.

I wish the treating physician the best with patient discussion and if they proceed. Needless to say, a discussion about palliative therapy needs to be included as an option.
Last edit: 1 year 6 months ago by arlene.
Moderators: Nicolaarlene