Submitting Author: Nybakken *, Grant Edward, MD, PhD
Institution: Stanford University* and University of Pennsylvania**
Additional authors:Darshan Roy, MD** Jennifer Morrissette, Ph.D.** Alexander Perl, MD** Martin Carroll, MD** Adam Bagg, MD**
Session: AML with recurrent genetic mutations Part II

The purpose of this case submission is to illustrate one of two distinct responses to the FLT3 inhibitor quizartinib (AC220). The other response (and comparing it with this case) is shown in the submitted images. A 33-year-old woman initially presented with cytogenetically normal AML. Following conventional ltherapy, she attained remission prior to relapse. She was treated with AC220. Pre- and post therapy (interval 29 days) marrow are submitted.

Bone marrow, iliac crest

1. Pretreatment:

A Wright-Giemsa stain of the aspirate smear demonstrates sheets of medium to large-sized blasts (80%) with oval to folded nuclear contours, open chromatin, variably prominent nucleoli and moderate amounts of cytoplasm. In the background there is markedly reduced trilineage hematopoiesis without evident dyspoiesis.

H&E sections of the B5-fixed core biopsy reveal a normocellular marrow for age (70% cellularity). Blasts account for ~80% of cellularity. Trilineage hematopoiesis is markedly reduced without evident dyspoiesis.

2. Posttreatment

A Wright-Giemsa stain of the aspirate smear demonstrates essentially normal trilineage hematopoiesis. Blasts account for <5% of marrow cellularity. There is no evident dyspoiesis.

H&E sections of the B5-fixed core biopsy reveal a normocellular marrow for age (85% cellularity). Blasts account for <5% of cellularity. Orderly trilineage hematopoiesis is present with a myeloid to erythroid ratio of 3:1. There is no evident dyspoiesis.

Flow cytometry:

1. Pretreatment

Blasts: 74% (CD13+ CD33+ CD34+ CD64+ CD117+ HLA-DR+)

Lymphocytes: 2%

Monocytes: 6%

Granulocytes: 13%

2. Posttreatment

Blasts: <5%

Lymphocytes: 5%

Monocytes: 10%

Granulocytes: 81%

46,XX[20] in both specimens

1. Pretreatment FLT3-ITD mutant:WT ratio: 1:1.2

2. Posttreatament FLT3-ITD mutant:WT ratio: 1.25:1

Quizartinib (AC220), a FLT3 inhibitor, demonstrates overall response rates of around 70% in FLT3-ITD positive acute myeloid leukemia. Interestingly, these responses can demonstrate distinct marrow responses, termed cytotoxic and differentiation responses. The submitted case is a differentiation response, characterized by maintenance of marrow cellularity, return of trilineage hematopoiesis and blast clearance. This coincides with reduction in leukemic symptoms and return of peripheral neutrophils. Molecular studies identify retained or increased FLT3-ITD burden in patients with a differentiation response, suggesting marrow cellularity represents maturation of the leukemic clone, not return of normal hematopoiesis. In contrast, those with cytotoxic responses have a marked reduction in marrow cellularity and little evident hematopoiesis. These patients do not recover peripheral counts, but do have reduced leukemic symptoms. Cytogenetics proved a marker for predicting type of response. All responders with normal cytogenetics differentiated (8/8), whereas the majority of responders with abnormal cytogenetics underwent cytotoxic responses (9/10), suggesting response depends on inherent features of the leukemic clone. Patients undergoing cytotoxic responses frequently had cytogenetic remissions and reduction in FLT3-ITD ratio. This submission (including the accompanying images) demonstrates the diverse responses that can be seen with novel anti-leukemic agents.

Acute myeloid leukemia, FLT3-ITD positive.

Treatment response of AC220

Acute myeloid leukemia, with FLT3 ITD mutation

Case 254