Correlation of Clinical and Molecular Response to Imatinib in Polycythemia Vera (PV) Patients with Bone Marrow Morphologic and Immunophenotypic Changes.
Authors: Hyjek Elizabeth , Chadburn Amy , Cross Nicholas C.P. , Jones Amy V. , Sun Su-Chieh P. , Mathew Susan , Chiu April , Young April , Knowles D.M. , Silver Richard T. 
Published: April 2020

Abstract
Imatinib, a tyrosine kinase inhibitor, is effective in treating erythrocytosis and splenomegaly in many PV patients (pts), but is less effective controlling thrombocytosis or splenomegaly in others. Imatinib in PV pts may inhibit c-kit signaling, essential for erythroid progenitor proliferation and/or PDGF-R signaling. The JAK2 V617F mutation is present in most PV pts. We found imatinib therapy in PV pts resulted in a modest molecular response based on %V617F that correlated with hematologic improvement/clinical response; however, those who achieved complete hematological remission had initially lower %V617F. Here we correlate bone marrow (BM) morphology and immunophenotype with clinical/molecular response to imatinib in 10 pts fulfilling criteria for PV (8 men, 2 women; 28–72 yr) treated with imatinib (400–800 mg/day) for 5–31 mo. Cytogenetics in 1 pt showed +9; 4 were normal. CR was defined as phlebotomy-free within18 mo. of treatment (Tx), HCT level &lt;45% for men/&lt;42% for women, platelet count &lt;400×109/L and no splenomegaly. PR was similarly defined except the platelet count &gt; 400×109/L and &lt;50% reduction of palpable spleen size. %JAK2V617F was determined by pyrosequencing on pre-tx BM (5 pts) and post-tx PBL samples (all pts). Morphologic evaluation was done on sequential BM biopsies based on H&E/reticulin/trichrome stains and available BM aspirate smears. IHC was used to identify progenitors (CD34, CD117), megakaryocytes (MK; CD61), erythoid precursors (GlycoC), granulocytic precursors (MPO); MK c-mpl expression; proliferation (Ki-67). 2 pts showed CR, 6 PR and 2 NR. Median %V617F in CR was 15% (range 8–21%), in PR 57% (range 19–83%) and in NR 58% (range 44–72%). Both CR pts had 2–3-fold decrease in %V617F, whereas 3/6 PR pts had an increase (1–1.5 fold) in %V617F on tx. The 2 CR pts had in the pre-tx BM increased cellularity (60–80%), normal M:E ratio, moderate increase in MKs (10–15/20x). Imatinib tx resulted in normalization of cellularity, decreased erythropoiesis, a lesser decrease in granulopoiesis/megakaryopoiesis, and decreased proliferation in 1 pt (57% to 20%); the other the proliferation was stable at 24%. Reticulin fibrosis was minimal/mild. The PR/NR pre-tx BMs had markedly increased cellularity (80–100%), moderate/marked erythroid hyperplasia, increased granulopoiesis and moderate/marked increase in polymorphic MKs (10 to &gt;30/20x). Imatinib Tx resulted in decreased erythroid cells; less granulopoiesis; and no change/increased MKs with clustering and shedding of CD61+ platelets clumps into stroma. 2 cases progressed to fibrosis.The proliferation was variable (15–30%) with no change on Tx. C-mpl expression in MKs decreased with disease progression. The % cells expressing CD34 and/or CD117 was low and did not change. We found BM morphologic and immunophenotypic changes correlate with clinical/molecular response to imatinib in PV pts. Thus, BM evaluation may be helpful in assessing severity/disease progression and identifying pts who may benefit from imatinib Tx. The findings also suggest heterogeneity of hematopoietic stem cell proliferation. Targeting JAK2/other pathways involved in MK proliferation/migration may be beneficial in PV pts with large numbers of MKs who likely progress to fibrosis.