Submitting Author: Hatem, Joseph, MD
Institution: University of Pennsylvania
Additional authors:Noelle Frey, MD / Martin Carroll, MD / Adam Bagg, MD
Session: AML with myelodysplasia-related changes

A 70-year-old woman with no significant past medical history presented in October 2011 with fatigue and palpitations. The presence of severe anemia prompted a bone marrow biopsy that showed acute myeloid leukemia (AML) with monosomy 7, best classified as AML, with myelodysplasia-related changes (AML-MRC). She did not respond to either standard (exact therapy not known) or salvage chemotherapy with mitoxantrone, etoposide, cytosine arabinoside, and sirolimus (MEC-sirolimus). Based upon this, therapy with eltrombopag (ET) was initiated; the use of and response to this novel therapy is the reason for the submission of this case.

The bone marrow submitted to the workshop is from 12/21/2011, which was performed just prior to the initiation of therapy with ET. However, the chronology of the findings in the series of marrows (both prior to, and, more importantly subsequent to this one) are much more relevant, and are detailed in the accompanying PowerPoint. This bone marrow biopsy, fixed in B5 and decalcified in HCl showed residual AML, with 25% blasts that were medium-sized with fine chromatin, irregularly nuclear contours, prominent nucleoli, scant cytoplasm.

The tandem Wright-Giemsa stained bone marrow aspirate was hemodilute, but did reveal 22% medium-sized blasts with fine chromatin, irregularly nuclear contours, prominent nucleoli, scant to moderate blue agranular cytoplasm. The background myeloid elements where overall left-shifted with cytologic atypia (abnormal lobation and granulation).

Flow cytometry studies were not performed on this submitted biopsy. However, at initial diagnosis (10/14/2011), there was reportedly an expansion of blasts (19%) with the following immunophenotype: CD13(moderate)+ CD33(dim)+ CD34(moderate)+ CD117(moderate)+ HLA-DR(moderate to bright)+ cMPO(partial, 10%)+ CD19(partial, 53%, dim)+ sCD22(partial 20%, dim)+ and TdT(partial 51%, dim)+.

45,XX,-7[14]/46,XX[1]). Refer to the accompanying PowerPoint for studies at other time points.

By report, molecular studies performed by the referring institution were negative for FLT3 ITD as well as NPM1 mutations.

This case shows a dramatic morphologic and genetic response to a novel single agent therapy.

Eltrombopag (ET) is a small-molecule non-peptide thrombopoietin receptor agonist, previously shown to be useful in the treatment of persistent thrombocytopenia and was approved by the FDA for use in adult patients with chronic idiopathic thrombocytopenia purpura. Subsequent studies demonstrated that ET could inhibit the in vitro proliferation of acute myeloid leukemia cells, although the exact mechanism remains unclear.

The patient had no significant clinical side effects on the study drug aside from developing “gray skin” which was attributed to a darkening of the plasma that was evident in specimens submitted to the clinical laboratory. An upward trend in platelet count was noted from late January to March 2012, at which point the platelet count was 539 x 103/L, requiring a decrease in ET dose from 300 to 200 mg. Silver stains on the bone marrow biopsy demonstrated a progressive increase in reticulin fibrosis during ET therapy (grade 0 to grade 2-3, modified Bauermeister scale) with a concurrent increase in megakaryocytes with morphologic atypia (hypo- and atypically lobated forms with focal clustering), but without development of collagen fibrosis on a trichrome stain.

Acute myeloid leukemia with a dramatic morphologic and genetic response to single agent therapy with eltrombopag.

Acute myeloid leukemia with myelodysplasia-related chanages (morphologic and genetic response to single agent therapy with eltrombopag)

Case 241