FLT3 Inhibitor (FI) Therapy: Morphologic and Phenotypic Findings
Emily Rostlund, Jessica Altman, Olga Frankfurt, Amy Chadburn. Northwestern University Feinberg School of Medicine, Chicago, IL
Background: The success of imatinib, targeting the abnormal tyrosine kinase (TK) generated by t(9;22) in CML, has led to development of other directed TK inhibitors for treatment of myeloid neoplasms. FLT3, a membrane bound receptor TK important in proliferation, survival and differentiation, is often mutated in AML (∼35%). Several FLT3 inhibitors (FIs) have been developed and are in clinical trials. However, the features of FLT3 positive cases, including post-FI therapy, have not been described.
Design: Bone marrows (BM) from 8 patients (pts; 4M/4F; 26-72 yrs) with relapsed/refactory AML were studied (4 BM-Day 14 post-standard induction [SI] chemotherapy, 8 BM-immediately prior to FI therapy [D0], 8 BM-Day 15 or 31 [D15/31] post-FI therapy). All 8 pts had FLT3 ITD mutations; other genetic abnormalities included: del 5q (1), del 20q (1), mutated NPM1 (1). D0 BMs were assessed for blast morphology, percent and phenotype. FI treated D15/31 BMs were compared with D0 and SI-BMs for blast percent (aspirate count/CD34 immunostain), marrow damage (reticulin), presence of normal hematopoiesis, and cytomorphology. The morphologic characteristics were semi-quantitated on a scale of 0-4+.
Results: D0 blasts often had folded nuclei (5 cases 3+), moderate amount of cytoplasm (5 cases 2-3+), variable granulation (0-3+) and rare Auer rods (4 cases). All D0 cases were CD64+, 6/8 CD34+, 6/8 HLA-DR+, 5/7 CD11b+. While 2 FI-BMs resembled SI-treated BMs (severely hypocellular, minimal/no hematopoeisis), most FI-D15/31 BMs were cellular and 6 had erythroid cells, megakaryocytes and/or neutrophils. Seven FI-D15/31 BMs had markedly less blasts in the blood (<5% vs 20-80%) and marrow (0-30% vs 30-90%); 1 case with >80% blasts D0, had >80% blasts after FI therapy. FI-D15/31 blasts were less folded and in 2 cases myeloid cells showed discordant nuclear (immature) - cytoplasmic (more mature; secondary granules) features. 3 hypercellular FI-D15/31 BM cores contained largely myeloid cells with granular cytoplasm and folded/round immature nuclei morphologically distinct from D0 blasts. The number of CD34+ blasts in FI-D15/31 vs SI-BMs was more, less or the same; the amount of reticulin fibrosis was similar.
Conclusions: FLT3 ITD mutated AML blasts are usually CD64 positive, but have variable morphologic features. After FI therapy, most BMs show a decrease in blast count and/or some return of normal hematopoeisis. Cytologically, some cells exhibit discordant nuclear-cytoplasmic features with granular immature myeloid cells seen, a finding that may represent a morphologic manifestation of the impact of FI therapy on mutated FLT3 function.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 231, Monday Morning