Case Presentation Hematopathology Robert P Hasserjian - - PowerPoint PPT Presentation

Case Presentation Hematopathology

Robert P Hasserjian Massachusetts General Hospital Harvard Medical School

Clinical history

• 24 year‐old man presented with unintentional weight

loss (10‐15 lb) and was found to splenomegaly and marked leukocytosis

• WBC 456.2 x 109/L
• HGB 7.5 g/dL
• PLT 564 x 109/L

Peripheral blood smear

31% polys, 5% bands, 1% lymphs, 1% monos, 4% eos, 4% basos, 16% metas, 30% myelos, 2% promyelos, 6% blasts

Bone marrow biopsy

Bone marrow aspirate: myeloid‐predominant and left‐shifted with 5% blasts

Results of ancillary studies

• Flow cytometry of bone marrow aspirate

– 1% myeloid blasts

• Cytogenetics

– 46, XY, t(9;22)(q34;q11.2)[20]

• BCR‐ABL1 RT‐PCR

– BCR‐ABL1 rearrangement (B2/A2, p210 BCR‐ABL1 fusion protein)

• NGS panel (SnapShot, 54 myeloid‐associated genes)

– No reportable variants

Diagnosis: Chronic myeloid leukemia, BCR‐ABL1+, in chronic phase

The Philadelphia chromosome and BCR‐ABL1 rearrangement

p230 p210 p190 BCR‐ABL fusion proteins

Most quantitative RT‐PCR tests can

• nly detect p210 BCR‐ABL1 transcript

99% <1% <1%

Clinical course‐1

• Treated initially with

hydroxyurea, then switched to imatinib

• After 3 weeks he developed a

syncopal episode

– WBC 2.9 x 109/L, HGB 6.7 g/dL, PLT 24 x 109/L

• Imatinib was stopped due to

the pancytopenia and he was discharged home

Imatinib started HU started

Clinical course‐2

• 10 days after stopping

imatinib, a CBC showed WBC

• f 13.2 x 109/L with “other

cells” suspicious for blasts

• Imatinib was restarted and a

bone marrow biopsy was performed 3 days later

• WBC at time of biopsy was

49.6 x 109/L with 8% blasts

Imatinib held Imatinib restarted 2nd bone marrow biopsy

Bone marrow biopsy

Bone marrow aspirate 68% myeloids 13% erythroids 6% lymphocytes 4% eosinophils 1% basophils 4% promyelocytes 5% blasts

Flow cytometry

9% myeloid blasts CD33+ CD13+CD117+/‐CD34+ HLADR+ 4% B‐lymphoblasts CD19+CD20‐CD10+TdT+CD34+/‐CD38dim

CD34 MPO CD117 TdT

What is your diagnosis?

• CML in chronic phase
• CML in accelerated phase
• CML in lymphoid blast crisis
• CML in myeloid blast crisis
• Unsure; await cytogenetics

CML‐AP criteria

4% marrow, 8% blood 13%

Results of ancillary studies

• Karyotype

46,XY,t(9;22)(q34;q11.2)[16]/46,idem,inv(16)(p13.1q22)[4]

Now what is your diagnosis?

• CML in chronic phase
• CML in accelerated phase
• CML in lymphoid blast crisis
• CML in myeloid blast crisis
• Unsure; await cytogenetics

PML‐RARA inv(16) or t(16;16) CBFB‐MYH11 t(8;21) RUNX1‐RUNX1T1 t(15;17) CML‐BP criteria:

• Certain cytogenetic abnormalities define AML

irrespective of the blast percentage

• ≥20% blasts (myeloid or lymphoid) in blood or marrow
• Extramedullary blast proliferation

However:

Results of ancillary studies

• Karyotype

46,XY,t(9;22)(q34;q11.2)[16]/46,idem,inv(16)(p13.1q22)[4]

• FISH: nuc ish(CBFBx2)(5'CBFB sep 3'CBFBx1)[12/100]
• NGS assay for fusion of

myeloid‐associated genes

– BCR‐ABL1 fusion – CBFB‐MYH11 fusion

• ABL1 mutation assay: No

TKI‐resistance mutations

Imatinib held Imatinib restarted 2nd bone marrow biopsy

Clinical Course‐4

• Diagnosed with CML in

myeloid blast crisis

• Patient was switched from

imatinib to dasatinib

– WBC rapidly declined to normal levels – Circulating blasts disappeared

• Allogeneic bone marrow

transplant planning was initiated

Dasatinib started

100 50

Peripheral blood blasts WBC

Clinical Course‐5

• 10 weeks later, the patient presented with low back and knee

pain and was noted to have recurrent splenomegaly

• CBC results

– WBC 13.7 x 109/L

• 58% polys, 32% lymphs, 3% monos, 2% eos, 3% basos, 1% metas, 2% myelos

– HGB 15.1 g/dL – PLT 85 x 109/L

• Another bone marrow biopsy was performed. . .

Peripheral smear

Rare blasts seen on scanning

Bone marrow biopsy Bone marrow aspirate Bone marrow aspirate: 56% blasts

Flow cytometry

Results of ancillary studies

• Karyotype:

46,XY,t(9;22)(q34;q11.2)[15]/46,idem,del(9)(p13p22)[16]/46,XY[1]

• NGS assay for fusion of myeloid‐associated genes

– BCR‐ABL1 fusion – CBFB‐MYH11 fusion (very low level)

• ABL1 mutation assay: ABL1 kinase domain T315I mutation

Diagnosis: Chronic myeloid leukemia, BCR‐ABL1+, in B‐lymphoid blast crisis

• Imatinib
• Dasatinib
• Nilotinib
• Bosutinib
• Ponatinib

Tyrosine kinase inhibitors

Clinical followup

• Patient was treated with HAM ALL induction regimen and

ponatinib

• Achieved remission 1 month later, with no evidence of leukemia

in post‐therapy bone marrow

– BCR‐ABL1 quantitative RT‐PCR: 0.0095%

• Underwent allogeneic stem cell transplant
• 3 months after SCT, bone marrow showed 2% B‐lymphoblasts

and RT‐PCR showed BCR‐ABL1 transcript (13.9%), consistent with relapsed disease

Diagnosis: Chronic myeloid leukemia, BCR‐ABL1+, in myeloid blast crisis followed by lymphoid blast crisis Take home points:

Beware of lymphoblasts in CML! AML‐associated translocations can rarely occur in the setting of CML blast crisis and in this context do not convey a favorable prognosis