Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia

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Abstract

<p id="d16302626e277"> <div class="list"> <a class="named-anchor" id="d16302626e279">  </a> <ul class="so-custom-list"> <li id="d16302626e280"> <div class="so-custom-list-content so-ol"> <p class="first" id="d16302626e281">In a pilot study, the nonanticoagulant heparin derivative CX-01 was well tolerated when combined with chemotherapy for the treatment of AML. </p> </div> </li> <li id="d16302626e283"> <div class="so-custom-list-content so-ol"> <p class="first" id="d16302626e284">Preliminary results show encouraging complete remission rates and rapid platelet recovery.</p> </div> </li> </ul> </div> </p><p class="first" id="d16302626e288">Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women). Three, 5, and 4 patients had good-, intermediate-, and poor-risk disease, respectively. Day 14 bone marrows were available on 11 patients and were aplastic in all without detectable leukemia. Eleven patients (92%) had morphologic complete remission after 1 induction (CR1). Eight patients were alive at a median follow-up of 24 months (4 patients in CR1). Three patients received an allogeneic stem cell transplant in CR1. Median disease-free survival was 14.8 months. Median overall survival was not attained at the maximum follow-up time of 29.4 months. No CX-01-associated serious adverse events occurred. Median day to an untransfused platelet count of at least 20 × 10 <sup>9</sup>/L was 21. CX-01 is well tolerated when combined with intensive therapy for AML and appears associated with enhanced count recovery and treatment efficacy. </p><p id="d16302626e297"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1">  </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/4b9aa3f1-1d98-40ed-b839-3fb9aaaed566/PubMedCentral/image/advances013391absf1"/> </div> <div class="panel-content"/> </div> </p>

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Most cited references 31

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C. J. CLOPPER, E. PEARSON (1934)

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The World Health Organization (WHO) classification of the myeloid neoplasms.

James W Vardiman, Nancy Lee Harris, Richard Brunning (2002)

A World Health Organization (WHO) classification of hematopoietic and lymphoid neoplasms has recently been published. This classification was developed through the collaborative efforts of the Society for Hematopathology, the European Association of Hematopathologists, and more than 100 clinical hematologists and scientists who are internationally recognized for their expertise in hematopoietic neoplasms. For the lymphoid neoplasms, this classification provides a refinement of the entities described in the Revised European-American Lymphoma (REAL) Classification-a system that is now used worldwide. To date, however, there has been no published explanation or rationale given for the WHO classification of the myeloid neoplasms. The purpose of this communication is to outline briefly the WHO classification of malignant myeloid diseases, to draw attention to major differences between it and antecedent classification schemes, and to provide the rationale for those differences.

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Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells.

Meng Zhao, John M Perry, Heather Marshall … (2014)

Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor β1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-β1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-β-SMAD signaling. Indeed, TGF-β1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-β1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-β inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.