Showing papers by "Vinod Pullarkat published in 2014"

Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis

Abstract: Purpose Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.

Pharmacokinetics-Based Integration of Multiple Doses of Intravenous Pegaspargase in a Pediatric Regimen for Adults With Newly Diagnosed Acute Lymphoblastic Leukemia

Abstract: Purpose Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults. Patients and Methods Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m 2 per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses.

Proteasome Inhibition Induces Both Antioxidant and Hb F Responses in Sickle Cell Disease Via the Nrf2 Pathway

Abstract: Oxidant stress is implicated in the manifestations of sickle cell disease including hemolysis and vascular occlusion. Strategies to induce antioxidant response as well as Hb F (α2γ2) have the potential to ameliorate the severity of sickle cell disease. Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) is a transcription factor that regulates antioxidant enzymes as well as γ-globin transcription. The Nrf2 in the cytoplasm is bound to its adapter protein Keap-1 that targets Nrf2 for proteasomal degradation, thereby preventing its nuclear translocation. We examined whether inhibiting the 26S proteasome using the clinically applicable proteasome inhibitors bortezomib and MLN 9708 would promote nuclear translocation of Nrf2, and thereby induce an antioxidant response and as well as Hb F in sickle cell disease. Proteasome inhibitors induced reactive oxygen species (ROS) and thereby increased Nrf2-dependent antioxidant enzyme transcripts, elevated cellular glutathione (GSH) levels and γ-globin...

Iron Toxicity in Hematopoietic Stem Cell Transplantation: Strike while the Iron Is Labile

Abstract: normal when transferrin saturation is >85%. LPI can be measured in serum by a fluorescence-based assay (FeROS, Aferrix Ltd, Tel Aviv, Israel), with levels >0.5 μmol/l being considered elevated. Profound alterations in iron metabolism occur during HSCT; it is therefore important to study the kinetics of various iron parameters during HSCT rather than simply measure body iron stores prior to transplantation. NTBI (of which LPI is a component) has been shown to rise immediately upon initiation of the conditioning regimen and to remain elevated until engraftment [3, 4] . The major cause of this spike in NTBI and LPI during the period from the initiation of conditioning until engraftment is the lack of utilization of iron by the erythron, although other factors like the release of iron from dying malignant cells may also contribute [2] . This is consistent with the drop in NTBI that coincides with a rise in the reticulocyte count. Hepcidin, the major iron regulatory hormone, is induced by inflammation and its level peaks at around day 7 after HSCT [5] . By preventing iron release from storage sites as well as absorption from the gut, hepcidin may counteract the rise in LPI to some extent. By providing readily available iron for bacterial and fungal growth, the elevation in NTBI and LPI may be a major determinant of such infections that occur early after HSCT. The study by Naoum et al. [6] in this issue of Acta Haematologica sheds important light on the pathophysiology Iron overload has been associated with adverse outcomes after hematopoietic stem cell transplantation (HSCT) in various studies [1, 2] . Besides reduced overall survival and increased nonrelapse mortality, iron overload has been implicated in predisposing to an increased risk of infections and regimen-related toxicity including sinusoidal obstruction syndrome. The role of iron overload as a major determinant of HSCT outcome is not controversial in thalassemia syndromes where it is defined by measurement of liver iron concentration in liver biopsy specimens or by magnetic resonance imaging. On the contrary, the majority of the studies examining the impact of iron overload on outcomes of HSCT for nonthalassemia indications have used pretransplant serum ferritin as a measure of iron stores for practical reasons. Hence, there has been interest in performing more direct measurement of tissue or serum iron parameters and correlating them with HSCT outcomes and complications. Iron toxicity results from generating tissue-damaging free radicals that are produced by the catalytic activity of free iron. The majority of plasma iron is bound by the carrier protein transferrin, thereby protecting tissues from iron toxicity. The small fraction of iron that is not bound to transferrin is termed non-transferrin-bound iron (NTBI). Labile plasma iron (LPI) refers to the redox-active, cell-penetrating component of NTBI in the plasma that is directly chelatable. LPI levels generally rise above Received: September 17, 2013 Accepted: September 19, 2013 Published online: December 3, 2013

The Combination of Fludarabine, Cytarabine and Etoposide Is an Active and Well-Tolerated Regimen in Relapsed/Refractory Acute Myeloid Leukemia

Abstract: We retrospectively reviewed the outcome of 20 consecutive subjects with refractory/relapsed acute myeloid leukemia (AML; 9 refractory and 11 relapsed) treated at our institution with a fludarabine, cytarabine and etoposide (FCE) salvage regimen. Of 20 patients with refractory/relapsed AML, 15 (75%) achieved complete remission (CR)/CR with incomplete peripheral blood count recovery (CRi), including 14 CR and 1 CRi. The 4- and 8-week treatment-related mortality (TRM) for all patients during reinduction was 0 and 5%, respectively. Eight of 15 patients (53%) who successfully achieved CR were able to undergo allogeneic hematopoietic stem cell transplantation with a 0% non-relapse mortality rate. FCE is a new, well-tolerated, anthracycline-free regimen, which has a promising activity in relapsed/refractory AML and is associated with low TRM in this high-risk population.

Nodular regenerative hyperplasia causing portal hypertension in a patient with chronic graft versus host disease: response to sirolimus.

Abstract: was complicated by hypogammaglobulinemia, iron deficiency anemia and cGVHD involving the oral mucosa, the skin and the gastrointestinal tract. Three years after HSCT, the patient presented with new-onset ascites. He had no history of viral hepatitis, excessive alcohol use, hepatic sinusoidal obstruction syndrome (SOS) or GVHD involving the liver. There was no history of jaundice, encephalopathy or gastrointestinal bleeding. Physical examination showed an ill-appearing, wasted man with moderate abdominal distension. No hepatosplenomegaly, peripheral edema or stigmata of chronic liver disease was noticed. Laboratory values are reported in table 1 . Viral hepatitis studies were negative. His immunosuppressive regimen at the time of presentation consisted of tacrolimus (1 mg daily) and prednisone (4 mg daily). Abdominal CT scan showed subtle liver surface nodularity with relative enlargement of the lateral left hepatic and caudate lobes and moderate ascites. Ascitic fluid was straw-colored, with a serum-ascites albumin gradient of 0.3, consistent with PH. Esophagoduodenoscopy showed grade II medium-sized esophageal varices and portal hypertensive gastropathy. Biopsies from the stomach and duodenum were negative for GVHD, infiltration or malignancy. A transjugular liver biopsy with hepatic vein pressure measurements was obtained. Normal right atriNodular regenerative hyperplasia (NRH) of the liver is a rare, noncirrhotic liver disease characterized by diffuse replacement of normal hepatic parenchyma by multiple small nodules composed of regenerating hepatocytes with minimal or no fibrosis [1, 2] . In the Western world, it accounts for 14–27% of noncirrhotic portal hypertension (PH) cases [3] . NRH is most commonly seen in association with rheumatologic diseases, exposure to chemotherapy, radiation and immunosuppressive therapy, and prothrombotic conditions including myeloproliferative and lymphoproliferative disorders [4, 5] . In the organ transplantation setting, NRH is mostly associated with solid organ transplantation and has rarely been reported as a complication of allogeneic hematopoietic stem cell transplant (HSCT). We report the development of PH secondary to NRH in a patient with chronic graft versus host disease (cGVHD) 3 years after allogeneic HSCT and review the literature on NRH associated with HSCT. We further demonstrate the rapid resolution of clinical features of PH in this patient after initiation of sirolimus therapy. A 61-year-old man with relapsed mantle cell lymphoma underwent allogeneic HSCT from a matched unrelated donor with reduced-intensity conditioning using fludarabine and melphalan. His posttransplant course Received: July 29, 2013 Accepted: October 8, 2013 Published online: January 15, 2014