Vu H. Duong

Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy

Abstract We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m2 daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) ≥ 2, and 39 had ≥ 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1–4) courses. The only pretreatment characteristic that differed significantly between responders and non-responders was percent marrow blasts (median 42% vs. 65%; p = 0.01). Median overall survival was 9.0 months; it was 19.4 and 2.3 months for responders and non-responders, respectively (p < 0.001). Thus 10-day decitabine therapy has efficacy in patients with AML considered unfit for chemotherapy, and may serve as a backbone for the addition of other novel agents.

Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer

Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

Treatment of catheter-related deep vein thrombosis in patients with acute leukemia with anticoagulation

Abstract Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge. Twenty-one patients with CVC-related VT received AC, 14 did not. VT resolved in 80% of patients in the AC group (similarly with low-dose and high-dose enoxaparin) and 45% in the non-AC group (p = 0.11). Fourteen (67%) patients in the AC group are alive (median survival not reached), compared to four patients (29%) in the non-AC group (median survival 9 months) (p = 0.015) with a hazard ratio (HR) of 0.32 (95% confidence interval: 0.12–0.85) in favor of AC. HR remained < 1 after adjustments for leukemia type and cytogenetics. Bleeding (< grade 4) occurred in five and one patients in the AC vs. non-AC groups, respectively (p = 0.37).

The effect of iron chelation therapy on overall survival in sickle cell disease and β-thalassemia: A systematic review.

Red blood cell transfusions have become standard of care for the prevention of life‐threatening anemia in patients with β‐thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event‐free survival in patients with β‐thalassemia and SCD. Eighteen articles discussing survival in β‐thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second‐generation oral agents, appears to be associated with improved overall and event‐free survival in transfusion‐dependent patients with β‐thalassemia and patients with SCD.

Cryptic ETV6–PDGFRB fusion in a highly complex rearrangement of chromosomes 1, 5, and 12 due to a chromothripsis-like event in a myelodysplastic syndrome/myeloproliferative neoplasm

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are hematological malignancies characterized by simultaneous presence of both myelodysplastic and myeloproliferative features [1]. C...

High-risk acute promyelocytic leukemia with unusual T/myeloid immunophenotype successfully treated with ATRA and arsenic trioxide-based regimen

We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3-ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation. Our report highlights the complexity and challenge of diagnosis and management of APL due to the variant immunophenotype and genetics and underscores the importance of synthesizing information from all testing modalities. The association of the unusual immunophenotype and FLT3-ITD mutation illustrates the plasticity of the hematopoietic stem cell and the pathobiology of leukemia with mixed lineage or lineage infidelity.

Splenic Artery Embolization as a Bridge to Splenectomy in Severe Transfusion-Refractory Thrombocytopenia Secondary to Myelodysplastic Syndrome

Transfusion-refractory thrombocytopenia is an important clinical challenge in the treatment of patients with myelodysplastic syndrome. Hypersplenism can play a major role in splenic platelet sequestration and transfusion refractoriness, and though rare in myelodysplastic syndrome, it can commonly be seen in a wide range of other benign and malignant conditions. Splenectomy has been an effective approach in management of hypersplenism-induced cytopenias, however those who are unresponsive to platelet transfusions are not surgical candidates making this an unfeasible treatment option. There has been increasing interest in the therapeutic value of the less invasive procedure of splenic artery embolization. Here we report the first case of a patient with myelodysplastic syndrome complicated by hypersplenism and severe transfusion-refractory thrombocytopenia in which a splenic artery embolization was successfully used as a bridge to splenectomy, which resulted in platelet transfusion responsiveness and correction of her thrombocytopenia. Reversal of severe thrombocytopenia has multiple important therapeutic values including allowing patients to safely continue receiving myelosuppressive chemotherapy treatments which are sometimes delayed or dose-adjusted due to cytopenias, safely undergo surgical interventions and also open the door for candidacy for stem cell transplantation. In conclusion, splenic artery embolization with or without subsequent splenectomy is highly recommended as a safe therapeutic option in patients with hematologic malignancies. *Corresponding author: Ashkan Emadi, M.D., Ph.D, Associate Professor of Medicine, Pharmacology and Experimental Therapeutics, Director, Hematology and Medical Oncology Fellowship Program, University of Maryland, School of Medicine, Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 South Greene Street, Room N9E24, Baltimore, Maryland 21201, USA, Tel: 410-328-2596, Fax: 410-328-6896; E-mail: aemadi@umm.edu Received Date: September 30, 2016 Accepted Date: October 28, 2016 Published Date: November 01, 2016

Abstract 2848: Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia

We present here strong preclinical data for a novel, mechanistically based, combinatorial approach to using DNA methyltransferase inhibitors (DNMTi’s), such as decitabine (DAC) and 5-Azacytidine (AzaC), with PARP inhibitors (PARPi’s) as a treatment strategy for acute myelogenous leukemias (AML). AzaC and DAC alone show efficacy in AML but combinatorial approaches will be required to maximize therapeutic responses. PARPi9s have not been well studied as agents for these diseases. The mechanistic rationale for our approach is based upon: 1) data from our group and others showing DNMT9s and PARP co-reside in DNA damage induced protein complexes; 2) the fact that AzaC and DAC trap DNMT9s into DNA via their mechanism of action, led us to hypothesize that these drugs might also increase PARP trapping at DNA damage sites 3) the cytotoxicity of clinically available PARPi’s, and especially the most potent ones, appears to correlate with degree of trapping of PARP1 at DNA damage sites in chromatin. We first find that, indeed, in cultured human AML cells, the DNMTi9s (10 to 20 nM DAC) and PARPi9s (1 to 10 nM BMN 673) alone trap PARP into chromatin and this effect is enhanced when the drugs are combined. Concomitant with this, the combined doses, especially, strongly reduce double strand break (DSB) repair thereby increasing cytotoxic DNA damage. In association with these findings, in methylcellulose cloning assays of both cultured (N = 4) and primary AML cells (N = 9), a combination of the DNMTi9s and PARPi9s strongly decreased colony survival compared to each of the agents alone. Interestingly those cell lines and primary samples expressing poor prognostic FLT3/ITD (Fms-like tyrosine kinase 3 internal tandem duplication) mutations, were particularly sensitive to the combination treatment. Based on all the above results, we developed an in-vivo treatment model, using human FLT3/ITD-positive, MV411-luc xenografts in immunocompromised mice. As opposed to mock treatment, and treatment with AzaC or BMN673, alone, the combined drug treatment, over a 40 day treatment course, starkly and significantly decreases leukemia burden, as measured by luciferase imaging, peripheral blood blast counts and spleen weights. Our data suggest a novel use of both DNMTi9s and PARPi9s in a compelling therapeutic strategy for poor prognosis AML, that will be funded by Van Andel-SU2C for a clinical trial to be based at the University of Maryland. Citation Format: Nidal E. Muvarak, Carine Robert, Pratik K. Nagaria, Khadiza Chowdhury, Eun Yong Choi, Vu Duong, Ashkan Emadi, Maria R. Baer, Rena Lapidus, Stephen Baylin, Feyruz Rassool. Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2848. doi:10.1158/1538-7445.AM2015-2848