Submitting Author: Gong, Jerald Z, MD
Institution: Thomas Jefferson University
Session: AML with myelodysplasia-related changes

The patient was a 67-year-old female who presented to the doctor’s office with upper respiratory infection. She was subsequently found to have anemia and blasts in peripheral blood. A bone marrow biopsy was performed and showed acute myeloid leukemia (AML). The patient received induction chemotherapy with cytarabine and anthracycline with persistent disease. She was re-induced with mitoxantrone/etoposide and high dose Ara-C. She did not achieve complete remission. Her disease course was complicated by neutropenic fever and deep vein thrombosis. She subsequently received 2-step haplo-identical allogeneic stem cell transplantation from her daughter, and achieved complete engraftment. She had recurrent AML one-year after transplantation. She received donor lymphocyte infusion with no response. SNP array was performed on recurrent AML and showed segmental uniparental disomy (UPD) with likely loss of donor specific HLA loci. She was treated by Azacitidine and did not achieve remission. The disease course was also complicated by neutropenic fever and fungal pneumonia. The decision was made to seek hospice care 7 months after the recurrence.

The initial bone marrow biopsy showed hypercellular bone marrow with extensive replacement by leukemic blasts. The blasts were medium to large in size, with round nuclei, fine chromatin, prominent nucleoli, and scant cytoplasm.

The bone marrow biopsy from the recurrent AML showed normocellular marrow with trilineage hematopoiesis. There was an increase of blasts in interstitium. The blasts constituted 12% by manual different count and showed similar morphology to those from the initial presenting bone marrow.

Flow cytometry from the initial bone marrow detected a blast population (72%) with a myeloid phenotype: CD10-, CD13+, CD14-, CD15+, CD19-, CD20-, CD22+ (aberrant), CD33+, CD38+, HLA-DR+, CD117+, MPO+, and TdT-.

Flow cytometry from the recurrent bone marrow showed 12% blasts with the identical phenotype to that of the original disease.

Karyotype from the presenting AML: 43-46,XX,-5,add(5)(q11.2),-7,-13,-15,-16,-17,-18,-19,-21,+22,add(22)(q11.2),+r,+2-7mar[cp13]/46,XX[4]. FISH showed monosomy 22 and trisomy 22 in separate cell groups, monosomy 16q, deletion 5q, and deletion 7q.

Karyotype from the recurrent AML: 40-44,XX,del(2)(q21q23),-5,-7,+11,del(11)(q13),-13,-16,-18,-19,-22,+3-5mar[8]/46,XX[12].

Whole genome SNP microarray using Affymetrix Cytoscan HD platform was performed on DNA extracted from the bone marrow aspirate of the recurrent AML. The most interesting finding is the detection of acquired uniparental disomy (aUPD) in chromosome 6p. Approximately 50 Mb segment including the entire HLA region was at the 2-copy state but there was loss of heterozygosity of SNP genotypes. This result highly suggests loss of mismatched HLA haplotype and duplication of matched HLA haplotype in the recurrent disease. This finding could explain why the recurrent AML did not respond to the treatment of donor lymphocyte infusion, in contrast with the initial AML.

Additional structural copy number abnormalities included deletion of the short arm of chromosome 2, interstitial deletion of long arm of chromosome 5, loss of the entire chromosome 7, both loss and gain of a portion of chromosome 13, duplication of the short arm of chromosome 16 and deletion of the entire long arm of chromosome 16, loss of part of the short arm of chromosome18, a telomeric loss of the short arm of chromosome 19, telomeric gain of the long arm of chromosome 19 and loss of the proximal long arm of chromosome 22.

Stem cell transplantation using partially matched donor from family members is used to induce long term remission in high risk hematologic malignancy. The mismatched donor T lymphocytes produce strong graft-versus-leukemia effect on residual disease. However, relapse still occurs. Genomic loss of HLA loci through UPD has been observed in some of the relapsed patients. The loss of mismatched HLA loci confers a selective advantage of leukemic cells, which escape the anti-leukemia effect of donor T lymphocytes. Our patients received donor lymphocytes infusion after the relapse with no significant response. Whole genome SNP array analysis of the relapsed leukemia subsequently revealed segmental UPD of HLA loci leading to loss of the patient-specific HLA haplotype. The loss of mismatched HLA loci results in escape of leukemia cells from antileukemic effect of donor T lymphocytes and hence ineffective of donor lymphocytes infusion treatment in these patients.

Acute myeloid leukemia with complex cytogenetics abnormalities, relapsed after haploidentical stem cell transplantation with loss of mismatched HLA resulting from uniparental disomy (UPD).

Acute myeloid leukemia with myelodysplasia-related changes (complex karyotype), relapsed after haploidentical stem cell transplantation with loss of mismatched HLA resulting from uniparental disomy (UPD)

Case 281