Submitting Author: Paessler, Michele Elizabeth, DO
Institution: Children's Hospital of Philadelphia
Additional authors:Gerald Wertheim, Rebecca King
Session: Therapy-related myeloid neoplasms

This patient is a 12 year old girl who presented in January of 2010 with a history of bone pain. CBC was normal. MRI studies showed bony lesions. Clinical exam was unremarkable. Bone marrow evaluation revealed a diagnosis of primary bone diffuse large B cell lymphoma (details below). She was treated and achieved remission. In April of 2011, she presented to Oncology Clinic and was found to have blasts on her peripheral blood smear. WBC was 6,400 thou/uL with 24% blasts. Bone marrow biopsy and aspirate were performed (details below).

Bone marrow, aspirates and biopsies (decalcified and fixed in AZF).

January 2010: The right side showed a hypercellular marrow (>95%). The marrow is infiltrated by mononuclear cells with medium to large sized nuclei, condensed chromatin and moderate to abundant cytoplasm. The left side showed extensive tumor necrosis with rare viable neoplastic cells. There was virtually no normal trilineage hematopoiesis seen.

April 2011: Sheets of blasts with large irregular to twisted nuclei, fine chromatin, prominent nucleoli, and moderate amounts of cytoplasm with occasional fine azurophilic granules. The blasts had a monocytic/promonocytic morphology.

January 2010: Paraffin immunohistochemistry shows the tumor cells are B cells with the following immunophenotype: positive for CD45, CD20, CD79a, PAX5 and BCL2 while negative for CD3, CD5, CD34, CD10, TdT, CD30, ALK1, and BCL6.

April 2011: 80% blasts with the following immunophenotype: positive for CD13, CD33, CD4, CD14, CD11b, CD38, CD34, CD15, MPO.

January 2010: 82-84,XXXX,?+X,-1,-2,-4,?del(5)(q?),-6,-8,-10,-11,-13,?-15,+21,-22[18]

nuc ish 8q24(MYCx3),8cen(CEP8x3),14q32(IGHx4)[32/100]

nuc ish 14q32(IGHx4)[30/100]

nuc ish 12p13(TELx4),21q22(AML1x5)[25/100]

The karyotypes showed a modal number of 82-84 chromosomes per cell considered to be

near-tetraploid, and the karyotype reflects changes in relation to an

expected copy number of 4. There was no evidence for an IGH translocation, MYC-IGH fusion or TEL-AML fusion. However these studies confirmed that there were 3 copies of 8, 4

copies of 12 and 14, and some cells with 5 copies of 21. Most of the changes were whole chromosome gains or losses, however loss of heterozygosity was noted for chromosome 1p and 6p. There were alternating regions of gain and loss for chromosome 5, ranging from 3 to 5 copies along the length of the chromosome. In summary, these findings are consistent with a near tetraploid leukemia.

April 2011: 46,XX,t(6;11)(q27;q23)[19]nuc ish 11q23(3'MLLx2,5'MLLx2)(3'MLL sep 5'MLLx1)[181/200]

The bone marrow is essentially replaced by a leukemic clone of cells with a single detectable cytogenetic abnormality. There is a balanced translocation between the long arms of chromosome 6 and 11, resulting in an interruption of the MLL locus in 11q23. The t(6;11)(q27;q23) was confirmed by FISH using a commercially available probe set for the MLL gene. The leukemia at diagnosis was near-tetraploid clone with a large number of cytogenetic changes, with no t(6;11). The results are therefore consistent with a secondary AML, and in the setting of a MLL translocation, a poor prognosis.

SNP array

January 2010:

Whole Genome SNP Array Results:

Chromosome/Arm Start End Abnormality/Notes

1pterp22.1 742,429 93,425,533 Dup/4 copies w/LOH

1p22.1p11.2 93,461,549 121,013,322 Dup/3 copies

1q Dup/3 copies

2 WC Dup/3 copies

3 WC Dup/4 copies

4 WC Dup/3 copies

5pterp15.32 91,139 5,747,586 Dup/5 copies

5p15.32p14.3 5,766,635 21,908,049 Dup/4 copies

5p14.3p14.1 21,908,653 27,203,395 Dup/5 copies

5p14.1pcen 27,209,030 46,384,240 Dup/4 copies

5q11.1q14.3 49,618,507 83,999,082 Dup/4 copies

5q14.3q21.3 84,010,157 107,658,952 Dup/3 copies

5q21.3q33.2 107,699,831 155,104,413 Dup/4 copies

5q33.2qter 155,125,888 180,623,543 Dup/3 copies

6pterp21.31 110,391 34,061,624 Dup/4 copies w/LOH

6p21.31pcen 34,068,589 58,762,701 Dup/3 copies

6q Dup/3 copies

7 WC Dup/4 copies

8 WC Dup/3 copies

9 WC Dup/4 copies

10 WC Dup/3 copies

10q23.2q23.31 89,537,028 90,410,295 Del PTEN

11 WC Dup/3 copies

12 WC Dup/4 copies

13 WC Dup/3 copies-4 copies

14 WC Dup/4 copies

16 WC Dup/? 5 copies

17 WC Dup/4 copies

18 WC Dup/4 copies

19 WC Dup/4 copies

20 WC Dup/4 copies

21 WC Dup/? 4 copies-5 copies

22 WC Dup/3 copies

The results are therefore consistent with a near-tetraploid leukemia.

April 2011 :

Whole Genome SNP Array Results:

Chromosome/Arm Start End Abnormality

9p23 11,391,387 11,519,226 Htz del

High resolution SNP array studies confirmed a small deletion in 9p that does not have any gene content, and is likely a non-contributory germline alteration.

The patient presented with a diffuse large B cell lymphoma, best classified as a primary bone lymphoma. The cytogenetic studies showed a large number of cytogenetic changes and was signed out as a near tetraploid leukemia. Review of the case confirmed it was indeed a primary B cell lymphoma of bone. The patient was treated. Fifteen months later the patient presented with a secondary therapy related AML with a t(6;11). The t(6;11) was not present in the diagnostic specimen.

Therapy-related acute myeloid leukemia, after treatment for primary bone lymphoma.

Therapy-related myeloid neoplasm, acute myeloid leukemia with t(6;11)(q27;q23)

Case 379