Ronald Hoffman

A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction

In the past decade, we have studied four unrelated children with what we believe is a previously unreported disorder affecting the bone marrow and exocrine pancreas. During infancy these patients had the onset of severe, transfusion-dependent, macrocytic anemia plus a variable degree of neutropenia and thrombocytopenia. Their bone marrows had normal cellularity but were characterized by remarkable vacuolization of erythroid and myeloid precursors, hemosiderosis, and ringed sideroblasts. The vacuoles probably represented manifestations of cellular degeneration and death. In two patients, in vitro bone marrow cultures showed abnormal erythroid and myeloid progenitor cell growth and, in one child, abnormal vacuolated erythroid colonies. Family histories were unrevealing, parents were hematologically normal, and both sexes were involved. There was no evidence of specific nutritional deficiencies or exposure to agents associated with marrow vacuolization. A number of therapeutic interventions produced no effect. One child had clinical malabsorption. This child and one other had extensive pancreatic fibrosis at autopsy. The other two patients had findings indicating exocrine pancreatic dysfunction. Two children had splenic atrophy. This new syndrome, with associated bone marrow and exocrine pancreatic dysfunctions, differs in several respects from the syndrome of pancreatic liposis and neutropenia described by Shwachman et all and Bodian et al, and from other conditions with vacuolization of the marrow or sideroblastosis.

Assay of an Activity in the Serum of Patients with Disorders of Thrombopoiesis That Stimulates Formation of Megakaryocytic Colonies

We have recently described an in vitro clonal assay system for human megakaryocyte-progenitor cells or megakaryocytic colony-forming units (CFU-M). Serum specimens from patients with quantitative platelet disorders were screened for the capacity to alter in vitro megakaryocyte-colony formation. Serum from 11 patients with hypomegakaryocytic thrombocytopenia significantly enhanced the formation of CFU-M-derived colonies (200 to 1840 per cent). Neither serum from eight patients with thrombocytopenia and normal or increased numbers of marrow megakaryocytes nor serum from 11 patients with thrombocytosis altered colony formation. This stimulatory activity has been termed megakaryocytic-colony-stimulating activity (Meg-CSA). The number of megakaryocytic colonies formed was directly proportional to the quantity of stimulatory serum added. Meg-CSA levels appeared to be inversely related to marrow megakaryocyte numbers. The variations in Meg-CSA levels that were detected in different disease states suggest that alterations in the production of this stem-cell regulator have physiologic importance.

Antibody-Mediated Aplastic Anemia and Diffuse Fasciitis

IT has been suggested that aplastic anemia may be due to either a deficiency of hematopoietic stem cells or an adverse interaction between stem cells and factors in the marrow microenvironment.1 Th...

Mechanisms of abnormal erythropoiesis in malignancy

In order the investigate mechanisms of diminished red cell production in malignancy, we assayed erythroid progenitor cell proliferative responses to erythropoietin in plasma cloth cultures of bone marrow cells from 34 cancer patients. Erythroid colony growht by marrow cells of 11 healthy donors (means of 58 CFU‐E and 19 BFU‐E derived colonies/6 × 104 cells) was similar to that in cultures of cells from patients either with (means of 44 CFU‐E and 22 BFU‐E derived colonies/6 × 104 cells) or without was normal at all erythropoietin concentrations tested, indicating that both the CFU‐E and BFU‐E retin normal erythropoietin sensitivity in vitro. CFU‐E proliferation correlated negatively (r = − 0.56; P < 0.001) with the level of hemoglobin. In contrast to marrow cell proliferative responses to erythropoeitin, serum erythropoietin levels were inappropriately reduced in all 19 patients in whom they were measured, a finding which may be important in the pathogenesis of anemia in patients with cancer.

Ruxolitinib: The First FDA Approved Therapy for the Treatment of Myelofibrosis

The BCR-ABL1–negative myeloproliferative neoplasms (e.g., essential thrombocythemia, polycythemia vera, and primary myelofibrosis) are a group of heterogeneous hematologic malignancies that involve a clonal proliferation of hematopoietic stem cells. Thrombosis, bleeding, and transformation to acute leukemia reduce the overall survival of patients with myelofibrosis, a disease typified by progressive splenomegaly and disease-related symptoms such as fatigue, pruritus, and bony pains. Hematopoietic stem cell transplant offers the only potential for cure in a minority of eligible patients, leaving a serious unmet need for improved therapies. Recent advances in our understanding of the pathogenetic mechanisms underlying these diseases have led to an explosion of clinical trials evaluating novel therapies. The discovery of an activating mutation in the Janus-activated kinase 2 (JAK2) gene provided a therapeutic target to downregulate this activated signaling pathway, which influences the phenotype of these diseases. Ruxolitinib (Jakafi; Incyte) is a small-molecule inhibitor of JAK1/2 that has proved to be effective at reducing splenomegaly and ameliorating symptoms in myeloproliferative neoplasms. Based on the results of 2 pivotal randomized phase III clinical trials, ruxolitinib has become the first therapeutic to be approved by the U.S. Food and Drug Administration for treatment of patients with myelofibrosis. Ruxolitinib offers a well-tolerated oral therapeutic option for patients with myelofibrosis with symptomatic splenomegaly and debilitating disease-related symptoms, but it does not seem to be effective at eliminating the underlying hematological malignancy. Clin Cancer Res; 18(11); 3008–14. ©2012 AACR.

Therapeutic options for patients with myelofibrosis in blast phase

Myelofibrosis (MF) is a clonal stem cell disorder with the potential to transform to acute leukemia, referred to as myelofibrosis in blast phase (MF-BP). The outcome of patients with MF-BP is grave with a median survival of only 2.7 months. MF-BP is largely refractory to conventional chemotherapy and intensive induction therapy fails to have a significant impact with a median survival of 3.9 months. Eleven consecutive patients were treated at our institution with MF-BP over a 2-year period. Eligible patients with an available donor received an allogeneic stem cell transplant (ASCT) and those that were not eligible or without a donor were treated with Decitabine (DEC). The median time for follow up for the entire group was 9 months (range 5-21 month). At 9 months (range 5-45 months), 67% of the patients treated with DEC were alive and at 20 months (range 9-23 months), 53% of patients treated with ASCT remain alive. Reduced intensity conditioning allogeneic stem cell transplantation (RIC-ASCT) is a viable option that offers the potential for prolonged survival and the possibility of cure for patients with MF-BP. DEC is a tolerable outpatient chemotherapeutic regimen for MF-BP patients ineligible for transplant and deserves further prospective study.

Autoimmune Hemolytic Anemia and Periodic Pure Red Cell Aplasia in Systemic Lupus Erythematosus

A patient with systemic lupus erythematosus and autoimmune hemolytic anemia complicated by periodic episodes of red cell hypoplasia is described. Using a plasma clot culture system a serum inhibitor of erythropoiesis was detected. In addition, heat eluates of the red cells of this patient were capable of impairing erythroid colony formation. The possibility that the autoantibodies of acquired autoimmune hemolytic anemia might influence the proliferation and/or maturation of erythroid progenitor cells is raised by these findings.

Lymphoblastic-like Leukemic Transformation of Polycythemia Vera

Excerpt Polycythemia vera terminates in acute leukemia in 0 to 30% of cases, depending on the series cited (1). The nature of this leukemic transformation has not been well characterized but is gen...

Humoral suppression of erythropoiesis in systemic lupus erythematosus (SLE) and rheumatoid arthritis

Anemia due to inadequate red cell production often accompanies systemic lupus erythematosus and rheumatoid arthritis. We investigated its pathogenesis in 17 patients with these disorders, using a plasma clot culture system. In serum from normal donors and nonanemic patients CFU-E derived colony formation was not significantly altered by normal marrow cells (mean 74 +/- 12 colonies/6 x 10(4) cells), whereas colony formation was inhibited (mean 36 +/-6 colonies/6 x 10(4) cells) in serum from 10 anemic patients. In serum from anemic patients proliferation of the more primitive BFU-E was also reduced in three cases. In two patients with a humoral inhibitor, colony growth was suppressed by autologous marrow cells. In another patient without an inhibitor, colony formation was not suppressed by autologous bone marrow. The physical properties of this inhibitor are compatible with those of an immunoglobulin. Moreover, its presence is related to disease activity and it can be removed by successful therapy with either corticosteroids or plasma exchange. Circulating inhibitors of erythropoiesis may play an important role in causing severe anemia in patients with these rheumatic diseases.

Anti-transforming growth factor-β therapy in patients with myelofibrosis

Bone marrow fi brosis (BMF), in the myeloproliferative neoplasm (MPN) myelofi brosis (MF), is the result of a complex and yet not fully understood interaction between megakaryocytes, monocytes, fi broblasts, endothelial cells, cytokines and marrow stroma [1]. Th ere are substantial data to support the clonal nature of MPNs from primitive progenitor hematopoietic cells which then secrete factors that activate polyclonal fi broblasts in the bone marrow [2]. BMF is not an irreversible process, and morphologic evidence of reversal can be achieved after hematopoietic stem cell transplant and occasionally drug therapy [3 – 5]. Transforming growth factorβ (TGFβ ) is a pleiotropic cytokine implicated in the promotion of angiogenesis, tumor growth, collagen fi brosis, metastatic spread and down-regulation of antitumor immunity, and paradoxically, tumor-suppressive eff ects [6]. TGFβ likely plays a dual role in promoting myelofi brosis and myeloproliferation, both of which are the morphologic hallmarks of MF [2]. Degree of BMF can be correlated with a variety of clinical features such as anemia, thrombocytopenia, leukopenia, splenomegaly and peripheral blood blasts, and can be predictive of survival in patients with MF [7,8]. Preclinical studies support a pathobiological role of TGFβ in MF [9 – 11]. Th e development of BMF in GATA-1 low and TPO high murine models of MF is associated with high levels of TGFβ expression in extracellular fl uids and spaces within the bone marrow and spleen [10]. A working hypothesis linking abnormal megakaryocyte/neutrophil interaction with enhanced TGFβ expression in MF has been developed based on these observations [11]. Para-apoptosis leading to the release of TGFβ from megakaryocyte alpha-granules may be the result of impaired neutrophil emperipolesis due to abnormal P-selectin localization on the demarcation membrane of MF megakaryocytes [10]. Additionally, TGFβ mRNA levels are signifi cantly elevated in megakaryocytes of patients with MF and correlate with the degree of BMF [9]. We hypothesized that inhibiting the TGFβ signaling pathway in MF would decrease the fi brogenic stimuli leading to BMF and concomitantly interrupt myeloproliferation. GC1008 is a human immunoglobulin G4 (IgG4) kappa monoclonal antibody capable of neutralizing each of the mammalian isoforms of TGFβ (i.e. β 1, β 2 and β 3). Animal toxicology studies of TGFβ antibodies in normal rodents and primates have shown that administration of inhibitory antibodies to TGFβ is well tolerated, and a phase 1 clinical trial of GC1008 in advanced melanoma and renal cell carcinoma has also proven to be well tolerated in humans [12]. A total of 29 patients were enrolled in this study, and doses up to 15 mg/kg were found to be safe without the development of dose limiting toxicities (DLTs). Th e most frequently reported drug-related adverse events (AEs) were gingival bleeding and fatigue, and the most serious AEs were skin rashes (including keratocanthomas and squamous cell carcinoma) that were noted in sun-exposed areas of patients with melanoma only. Based on an existing preclinical rationale, we conducted an investigator-initiated, single institution, open label, phase 1, dose escalation study investigating the tolerability and safety of GC1008 (Fresolimumab; Genzyme) in patients with intermediate-1 or higher primary myelofi brosis (PMF) or post-polycythemia vera/essential thrombocythemia myelofi brosis (post-PV/ET MF) [13]. Th is trial was registered at www.ClinicalTrials.gov (NCT01291784), approved by the Mount Sinai School of Medicine Program for the Protection for Human Subjects (PPHS), and informed written consent was obtained in accordance with the Declaration of Helsinki. Patients were eligible if they had documented BMF of MF-2 or higher as assessed by the European consensus grading score and grade 3 or higher by modifi ed Bauermeister scale [14 – 16]. Th e primary objective of this study was to determine the safety and tolerability of GC1008 treatment in patients with MF. Secondary objectives included treatment response assessment by International Working Group for Myelofi brosis Research and Treatment (IWG-MRT) criteria; assessment of degree of change in BMF grade measured by the modifi ed Bauermeister scale and European consensus grading system after six and 12 cycles; evaluation of exploratory markers for their potential to predict treatment response; and assessment of symptom response using the Myeloproliferative L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y N yu M ed ic al C en te r on 0 7/ 24 /1 5