scholarly journals Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 209 ◽  
Author(s):  
Lucio Luzzatto
Keyword(s):  
Stem Cells ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Treatment Options ◽  
Surface Membrane ◽  
Allogeneic Bone Marrow Transplantation ◽  
Thrombosis Prophylaxis ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Complement Regulatory Proteins ◽  
Inactivating Mutation

Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disease that has been investigated for over one century and has revealed unique aspects of the pathogenesis and pathophysiology of a hemolytic anemia. PNH results from expansion of a clone of hematopoietic cells that, as a consequence of an inactivating mutation of the X-linked genePIG-A, are deficient in glycosylphosphatidylinositol (GPI)-linked proteins: since these include the surface membrane complement-regulatory proteins CD55 and CD59, the red cells arising from this clone are exquisitely sensitive to lysis by activated complement. Until a decade ago, the treatment options for PNH were either supportive treatment – often including blood transfusion, anti-thrombosis prophylaxis, and sometimes thrombolytic therapy – or allogeneic bone marrow transplantation. Since 2007, PNH has received renewed and much wider attention because a new form of treatment has become available, namely complement blockade through the anti-C5 monoclonal antibody eculizumab. This brief review focuses on two specific aspects of PNH: (1) response to eculizumab, variability of response, and how this new agent has impacted favorably on the outlook and on the quality of life of patients; and (2) with respect to pathogenesis, new evidence supports the notion that expansion of the PNH clone results from T-cell-mediated auto-immune damage to hematopoietic stem cells, with the GPI molecule as target. Indeed, GPI-specific CD8+ T cells – which have been identified in PNH patients – would spare selectively GPI-negative stem cells, thus enabling them to re-populate the marrow of a patient who would otherwise have aplastic anemia.

Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation

2001 ◽  
Vol 19 (16) ◽  
pp. 3675-3684 ◽  
Author(s):  
Alberto Bosi ◽  
Daniele Laszlo ◽  
Myriam Labopin ◽  
Josy Reffeirs ◽  
Mauricette Michallet ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Leukemia ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Cooperative Group ◽  
Hematopoietic Stem ◽  
Blood And Marrow Transplantation

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade ≥ 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.

Human Cord Blood Progenitors Sustain Thymic T-Cell Development and a Novel Form of Angiogenesis

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3928-3940 ◽  
Author(s):  
Laura Crisa ◽  
Vincenzo Cirulli ◽  
Kent A. Smith ◽  
Mark H. Ellisman ◽  
Bruce E. Torbett ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cord Blood ◽  
Allogeneic Bone Marrow Transplantation ◽  
In Vivo Model ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
T Cell Progenitors

There is growing interest in using human umbilical cord blood (CB) for allogeneic bone marrow transplantation (BMT), particularly in children. Thus, CB has been identified as a rich source of hematopoietic progenitors of the erythroid, myeloid, and B-cell lineages. Whether CB blood cells engrafting in the BM space also comprise T-cell progenitors capable of trafficking to the thymus and reconstituting a functional thymopoiesis in young recipients is presently unknown. Here, we show that CB progenitors, engrafted in the BM of immunodeficient mice, sustain human thymopoiesis by generating circulating T-cell progenitors capable of homing to and developing within a human thymic graft. Surprisingly, development of CB stem cells in this in vivo model extended to elements of the endothelial cell lineage, which contributed to the revascularization of transplants and wound healing. These results demonstrate that human CB stem cell transplantation can reconstitute thymic-dependent T-cell lymphopoiesis and show a novel role of CB-derived hematopoietic stem cells in angiogenesis.

scholarly journals The myelodysplastic syndromes: diagnosis, prognosis and therapy

2013 ◽  
pp. 90-97
Author(s):  
Cristina Clissa ◽  
Carlo Finelli ◽  
Antonio De Vivo
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Allogeneic Bone Marrow Transplantation ◽  
Clinical Signs ◽  
The Elderly ◽  
International Prognostic Scoring System ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Risk Class

The authors conducted a systematic review of the medical literature published in the past 15 years on the myelodysplastic syndromes (MDSs). The MDSs are typically seen in the elderly, and primary and secondary forms can be distinguished. This heterogeneous group of hematologic diseases is caused by clonal disorders of pluripotent hematopoietic stem cells. The pathogenesis of the syndromes appears to be multifactorial. Genetic damage, spontaneous or induced by environmental or iatrogenic factors, leads to abnormal proliferation and apoptosis of bone marrow stem cells. The most common presentation is anemia, alone or associated with thrombocytopenia and / or neutropenia, accompanied by the related symptoms and clinical signs (asthenia, fatigue, bleeding, recurrent infections). The diagnosis involves the exclusion of other causes of cytopenia and is based on well-defined, internationally recognized criteria, which are mainly morphologic and cytogenetic. Accurate diagnosis of MDS is essential for prognostic evaluation and for estimating the risk of progression to acute myeloid leukemia (AML). The risk is rated according to the International Prognostic Scoring System (IPSS), which includes 4 levels (low, intermediate-1, intermediate-2, and high). The risk class is a major determinant of the therapeutic approach. Apart from supportive care (transfusions), the main therapeutic tools are erythropoiesis-stimulating agents (ESAs), iron-chelating agents, immunomodulatory drugs, demethylating agents and, in selected cases, allogeneic bone marrow transplantation.

scholarly journals Response of Paroxysmal Nocturnal Hemoglobinuria Clone with Aplastic Anemia to Rituximab

2012 ◽  
Vol 2012 ◽  
pp. 1-5
Author(s):  
Radha Raghupathy ◽  
Olga Derman
Keyword(s):  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Cell Clone ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
First Case ◽  
Life Threatening ◽  
Anti Cd20 ◽  
Pnh Clone

Paroxysmal nocturnal hemoglobinuria is caused by expansion of a hematopoietic stem cell clone with an acquired somatic mutation in the PIG-A gene. This mutation aborts the synthesis and expression of the glycosylphosphatidylinositol anchor proteins CD55 and CD59 on the surface of blood cells, thereby making them more susceptible to complement-mediated damage. A spectrum of disorders occurs in PNH ranging from hemolytic anemia and thrombosis to myelodysplasia, aplastic anemia and, myeloid leukemias. Aplastic anemia is one of the most serious and life-threatening complications of PNH, and a PNH clone is found in almost a third of the cases of aplastic anemia. While allogeneic bone marrow transplantation and T cell immune suppression are effective treatments for aplastic anemia in PNH, these therapies have significant limitations. We report here the first case, to our knowledge, of PNH associated with aplastic anemia treated with the anti-CD20 monoclonal antibody rituximab, which was associated with a significant reduction in the size of the PNH clone and recovery of hematopoiesis. We suggest that this less toxic therapy may have a significant role to play in treatment of PNH associated with aplastic anemia.

scholarly journals Origin of human mast cells: development from transplanted hematopoietic stem cells after allogeneic bone marrow transplantation

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 2954-2959 ◽  
Author(s):  
M Fodinger ◽  
G Fritsch ◽  
K Winkler ◽  
W Emminger ◽  
G Mitterbauer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Mast Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Donor Genotype

Although mast cells are hematopoietic cells, little is known about the origin of their precursors in vivo. In this study, the origin (donor v recipient genotype) of human mast cells (MCs) was analyzed in a patient who underwent allogeneic bone marrow transplantation (BMT). The patient presented with secondary acute myeloid leukemia (French-American- British classification, M2) arising from refractory anemia with excess of blast cells and bone marrow (BM) mastocytosis. Transplantation was performed in chemotherapy-induced complete remission. On days 88, 126, 198, and 494 after BMT, mast cells were enriched to homogeneity from bone marrow mononuclear cells (BM MNCs) by cell sorting for CD117+/CD34- cells. Purified mast cell populations were CD117(c-kit)+ (> 95%), CD34- (< 1%), CD3- (< 1%), CD14- (< 1%), and virtually free of contaminating cells as assessed by Giemsa staining. The genotype of MCs was analyzed after amplification by polymerase chain reaction (PCR) of a variable number tandem repeat (VNTR) region within intron 40 of the von Willebrand factor (vWF) gene. Unexpectedly, on days 88 and 126 after BMT, sorted MCs displayed recipient genotype as shown by vWF.VNTR-PCR. However, on days 198 and 494, PCR analysis showed a switch to donor genotype in isolated mast cells. Peripheral blood (PB) and BM MNC as well as highly enriched (sorted) CD3+ T cells (PB, BM), CD4+ helper T cells (PB), CD8+ T cells (PB), CD19+ B cells (PB), CD14+ monocytes (PB, BM), and CD34+ precursor cells (BM) showed donor genotype throughout the observation period. Together, these results provide evidence that human MCs developed in vivo from transplanted hematopoietic stem cells. Engraftment and in vivo differentiation of MCs from early hematopoietic progenitor cells may be a prolonged process.

scholarly journals Polyclonal reconstitution of human marrow after allogeneic bone marrow transplantation

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2031-2037 ◽  
Author(s):  
R Nash ◽  
R Storb ◽  
P Neiman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
X Chromosome ◽  
Marrow Transplantation ◽  
Autologous Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Marrow Transplant ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Allogeneic Marrow

Abstract Clonal dominance suggestive of reconstitution of marrow from small numbers of pluripotent hematopoietic stem cells has been noted in different experimental and clinical situations. Recipients of human allogeneic marrow transplants have not been previously studied to determine if clonal dominance occurs in this clinical setting. Clonal analysis of 20 allogeneic marrow transplant recipients was performed on DNA from peripheral blood neutrophils using restriction fragment length polymorphisms on the X chromosome. Similar studies were performed on 16 of the donors. To analyze the results further, recipients were paired with their respective donors. There was no evidence of shifts in cell populations contributing to the X chromosome inactivation patterns in recipient marrow grafts when compared with their respective donors. A mathematical model based on binomial statistics was adapted to estimate the numbers of reconstituting pluripotent hematopoietic stem cells. There was no evidence of clonal dominance suggestive of oligoclonal reconstitution in marrow grafts after allogeneic marrow transplantation. This does not preclude the possibility of oligoclonal reconstitution in other marrow transplant settings such as autologous transplantation.

Human Cord Blood Progenitors Sustain Thymic T-Cell Development and a Novel Form of Angiogenesis

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3928-3940 ◽  
Author(s):  
Laura Crisa ◽  
Vincenzo Cirulli ◽  
Kent A. Smith ◽  
Mark H. Ellisman ◽  
Bruce E. Torbett ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Cord Blood ◽  
Allogeneic Bone Marrow Transplantation ◽  
In Vivo Model ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
T Cell Progenitors

Abstract There is growing interest in using human umbilical cord blood (CB) for allogeneic bone marrow transplantation (BMT), particularly in children. Thus, CB has been identified as a rich source of hematopoietic progenitors of the erythroid, myeloid, and B-cell lineages. Whether CB blood cells engrafting in the BM space also comprise T-cell progenitors capable of trafficking to the thymus and reconstituting a functional thymopoiesis in young recipients is presently unknown. Here, we show that CB progenitors, engrafted in the BM of immunodeficient mice, sustain human thymopoiesis by generating circulating T-cell progenitors capable of homing to and developing within a human thymic graft. Surprisingly, development of CB stem cells in this in vivo model extended to elements of the endothelial cell lineage, which contributed to the revascularization of transplants and wound healing. These results demonstrate that human CB stem cell transplantation can reconstitute thymic-dependent T-cell lymphopoiesis and show a novel role of CB-derived hematopoietic stem cells in angiogenesis.

scholarly journals Polyclonal reconstitution of human marrow after allogeneic bone marrow transplantation

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2031-2037 ◽  
Author(s):  
R Nash ◽  
R Storb ◽  
P Neiman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
X Chromosome ◽  
Marrow Transplantation ◽  
Autologous Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Marrow Transplant ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Allogeneic Marrow

Clonal dominance suggestive of reconstitution of marrow from small numbers of pluripotent hematopoietic stem cells has been noted in different experimental and clinical situations. Recipients of human allogeneic marrow transplants have not been previously studied to determine if clonal dominance occurs in this clinical setting. Clonal analysis of 20 allogeneic marrow transplant recipients was performed on DNA from peripheral blood neutrophils using restriction fragment length polymorphisms on the X chromosome. Similar studies were performed on 16 of the donors. To analyze the results further, recipients were paired with their respective donors. There was no evidence of shifts in cell populations contributing to the X chromosome inactivation patterns in recipient marrow grafts when compared with their respective donors. A mathematical model based on binomial statistics was adapted to estimate the numbers of reconstituting pluripotent hematopoietic stem cells. There was no evidence of clonal dominance suggestive of oligoclonal reconstitution in marrow grafts after allogeneic marrow transplantation. This does not preclude the possibility of oligoclonal reconstitution in other marrow transplant settings such as autologous transplantation.

scholarly journals Origin of human mast cells: development from transplanted hematopoietic stem cells after allogeneic bone marrow transplantation

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 2954-2959 ◽  
Author(s):  
M Fodinger ◽  
G Fritsch ◽  
K Winkler ◽  
W Emminger ◽  
G Mitterbauer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Mast Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Donor Genotype

Abstract Although mast cells are hematopoietic cells, little is known about the origin of their precursors in vivo. In this study, the origin (donor v recipient genotype) of human mast cells (MCs) was analyzed in a patient who underwent allogeneic bone marrow transplantation (BMT). The patient presented with secondary acute myeloid leukemia (French-American- British classification, M2) arising from refractory anemia with excess of blast cells and bone marrow (BM) mastocytosis. Transplantation was performed in chemotherapy-induced complete remission. On days 88, 126, 198, and 494 after BMT, mast cells were enriched to homogeneity from bone marrow mononuclear cells (BM MNCs) by cell sorting for CD117+/CD34- cells. Purified mast cell populations were CD117(c-kit)+ (> 95%), CD34- (< 1%), CD3- (< 1%), CD14- (< 1%), and virtually free of contaminating cells as assessed by Giemsa staining. The genotype of MCs was analyzed after amplification by polymerase chain reaction (PCR) of a variable number tandem repeat (VNTR) region within intron 40 of the von Willebrand factor (vWF) gene. Unexpectedly, on days 88 and 126 after BMT, sorted MCs displayed recipient genotype as shown by vWF.VNTR-PCR. However, on days 198 and 494, PCR analysis showed a switch to donor genotype in isolated mast cells. Peripheral blood (PB) and BM MNC as well as highly enriched (sorted) CD3+ T cells (PB, BM), CD4+ helper T cells (PB), CD8+ T cells (PB), CD19+ B cells (PB), CD14+ monocytes (PB, BM), and CD34+ precursor cells (BM) showed donor genotype throughout the observation period. Together, these results provide evidence that human MCs developed in vivo from transplanted hematopoietic stem cells. Engraftment and in vivo differentiation of MCs from early hematopoietic progenitor cells may be a prolonged process.

scholarly journals Successful combination chemotherapy involving clofarabine, cyclophosphamide, and etoposide for pediatric relapsed acute myeloid leukemia: A case report

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110155
Author(s):  
Sachio Fujita ◽  
Ryosuke Matsuno ◽  
Naoko Kawabata ◽  
Yumiko Sugishita ◽  
Ryota Kaneko ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Gemtuzumab Ozogamicin ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Positive Effects ◽  
Refractory Acute Myeloid Leukemia ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Limited salvage chemotherapies are available for relapsed/refractory acute myeloid leukemia. Herein, we described successful reinduction chemotherapy, involving a combination of clofarabine, cyclophosphamide, and etoposide, in a 12-year-old male with relapsed acute myeloid leukemia prior to allogeneic bone marrow transplantation from his father. Although treatment with a combination of fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin, and gemtuzumab ozogamicin had no positive effects, the aforementioned clofarabine-based chemotherapy induced complete remission and allowed the transplantation to go ahead. The abovementioned regimen may be useful for induction chemotherapy prior to hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia.

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