scholarly journals Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 337-345 ◽  
Author(s):  
A Tichelli ◽  
A Gratwohl ◽  
C Nissen ◽  
E Signer ◽  
C Stebler Gysi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Peripheral Blood ◽  
Clonal Evolution ◽  
Cumulative Risk ◽  
Fetal Hemoglobin ◽  
Severe Aplastic Anemia ◽  
Antilymphocyte Globulin ◽  
Probability Of Survival ◽  
Patients At Risk

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in “remission,” ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in “remission.” Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during “remission.” Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

scholarly journals Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 337-345 ◽  
Author(s):  
A Tichelli ◽  
A Gratwohl ◽  
C Nissen ◽  
E Signer ◽  
C Stebler Gysi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Peripheral Blood ◽  
Clonal Evolution ◽  
Cumulative Risk ◽  
Fetal Hemoglobin ◽  
Severe Aplastic Anemia ◽  
Antilymphocyte Globulin ◽  
Probability Of Survival ◽  
Patients At Risk

Abstract One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in “remission,” ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in “remission.” Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during “remission.” Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

Perfect Engraftment after Fludarabine, Cyclophosphamide Plus Thymoglobulin Conditioning Regimen for Unrelated Transplantation in Severe Aplastic Anemia: Phase II Prospective Multi-Center Study in Korea

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3003-3003
Author(s):  
Hyoung Jin Kang ◽  
Hee Young Shin ◽  
Jun Eun Park ◽  
Young Tak Lim ◽  
Nak Gyun Chung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Phase Ii ◽  
Peripheral Blood ◽  
Promising Result ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Once Daily ◽  
Donor Type ◽  
Mobilized Peripheral Blood

Abstract Anti-thymocyte globulin (ATG) has been used in severe aplastic anemia (SAA) as a part of the conditioning regimen. Among the many kinds of ATG preparations, thymoglobulin had been found to be more effective in preventing graft-versus-host disease (GVHD) and rejection of organ transplants. After the promising result of the pilot study (Bone Marrow Transplant. 2004. 34; 939), phase II prospective multi-center clinical trial was performed with fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen to allow good engraftment in unrelated transplantation for SAA. Twenty-eight patients underwent bone marrow (N=15) or mobilized peripheral blood (N=13) transplantation with cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m^2 once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) from HLA matched unrelated donors. GVHD prophylaxis regimen was composed of cyclosporine (or tacrolimus), methotrexate, with or without low dose thymoglobulin (1.25 mg/kg once daily i.v. on days 7, 9 and 11). The median infused cell dose of nucleated cells and CD34 positive cells were 6.8×10^8/kg (1.3– 39.9×10^8/kg) and 5.2×10^6/kg (1.2–27.0×10^6/kg), respectively. The median number of days required for ANC of more than 0.5×10^9/l and 1.0×10^9/l were 14 days (10–35 days) and 15 days (11–40 days), respectively. The spontaneous platelet recovery to more than 20×10^9/l required a median of 22 days (22–182 days). Donor type hematologic recovery (donor type chimerism more than 90%) was achieved in all patients. Fourteen patient developed grade II–IV acute GVHD. The event free survival (EFS) was 73% and all events were transplantation related mortality (TRM) which included coagulopathy (N=3), PTLD (N=2), pneumonia (N=1), and myocardiac infarction (N=1). The EFS of patients who received bone marrow (65%) was not different from that of patients who received mobilized peripheral blood (82%) (P=0.37), but the EFS of patients who received immunosuppressive therapy (IST) previously (55%) was lower than that of patients who didn’t receive IST (92%), significantly (P=0.04). Fludarabine, cyclophosphamide plus thymoglobulin conditioning allows for the promising result of very good engraftment, although serious events occurred in some patients. We are now planning to start new multicenter study to decrease TRM by reducing the dose of cyclophosphamide.

A Retrospective Evaluation of the Effects of Severe Aplastic Anemia Treatment in Children with Horse and Rabbit ATG.Polish Pediatric Hematology Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4375-4375 ◽  
Author(s):  
Katarzyna Pawelec ◽  
Michal Matysiak ◽  
Malgorzata Salamonowicz ◽  
Jerzy Kowalczyk ◽  
Walentyna Balwierz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Severe Aplastic Anemia ◽  
Retrospective Evaluation ◽  
Pediatric Hematology ◽  
Probability Of Survival ◽  
Anemia Treatment

Abstract Abstract 4375 Antithymocyte horse globulin (hATG) or rabbit (rATG) is used to treat children with severe aplastic anemia (SAA) in the absence of a compatible bone marrow family donor’s. We presenting (viewing) retrospective evaluation of the effects of SAA therapy using hATG and rATG. 49 children (20 girls and 29 boys, aged 1.2–17) were treated between 1993 and 2000 - hATG (15mg/kg/day for 5 days with cyclosporine 5mg/kg/day for 12–24 mths). On day 180 day of treatment there was a complete response (CR) in 22 of 49 children (44.5%) and a partial response (PR) in 12 children (24.4%). 34 of 49 children (69,4%) responded to treatment. There was no remission (NR) in 15 of 49 children (30.6%). In the whole group there were 7 deaths during the first 6 months. There were no relapses within 5 years of observation. The 5-year probability of survival in this group was 84%. 55 children (22 girls and 33 boys, aged 3,5–17,7 years) were treated in the years 1996–2009 using rATG (3.75 mg/kg/day for 5 days and cyclosporine 5mg/kg/day for 12–24 mths). On day 180 of treatment 5 patients (9%) achieved a CR, 23 children (41.8%) had a PR. 28 of 55 children (50.9%) responded to treatment. NR was found in 27 children (49%).In the rATG group 15 deaths (27%) were recorded, 4 patients (7%) had relapses. In one child paroxysmal nocturnal hemoglobinuria was noted.The 5-year survival in the rATG.group was 63.54%. Our results show the greater effectiveness of treatment with horse globulin than rabbit globulin in terms of hematological response and overall survival. Disclosures: No relevant conflicts of interest to declare.

Germline and Somatic Genetic Characterization of Shwachman-Diamond Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2681-2681
Author(s):  
Kasiani C. Myers ◽  
Adam S. Nelson ◽  
Brian Sheehan ◽  
Maggie Malsch ◽  
Gwendolyn Towers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Diagnostic Criteria ◽  
Congenital Anomalies ◽  
Clonal Evolution ◽  
Severe Aplastic Anemia ◽  
Splice Donor ◽  
Shwachman Diamond Syndrome ◽  
Intron 2

Abstract The North American Shwachman-Diamond Syndrome Registry (SDSR) opened in 2008 to improve our understanding of the natural history of Shwachman-Diamond Syndrome (SDS), improve medical outcomes, and facilitate research. The diagnosis of SDS was defined by either biallelic SBDS gene mutations or by the clinical combination of exocrine pancreatic dysfunction with bone marrow failure. Median age of study subjects is 11.2 years (range, 0.6-52.8). SBDS genetic reports were available for 168 subjects. Eighty-one had biallelic SBDS mutations, while 48 individuals lacked SBDS mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of SDS individuals meeting clinical diagnostic criteria as outlined above, as well as a more heterogenous subgroup with features of SDS but in whom a clinical diagnosis could not be confirmed by classic diagnostic criteria. Amongst those with biallelic SBDS mutations, cytopenias were noted in all but 1 subject. Intermittent neutropenia was noted in 97% (n=70/72) and was the most frequent hematologic abnormality. Anemia was noted in 53% (n=39/73) and thrombocytopenia in 64% (n=48/75). Congenital anomalies were seen in 50% (n=39/78). The mutational spectrum of SBDS was explored. In 80 of 81 patients harboring biallelic SBDS mutations, the c.258+2 T>C intron 2 splice donor mutation was found in at least one of the two mutant SBDS alleles. In these cases, the mutation spectrum of the second mutant SBDS allele included missense mutations, splice site mutations, and truncating mutations. The one patient lacking the intron 2 splice donor mutation had a c.183_184delTAinsCT mutation together with a c.523 C>T mutation in SBDS confirmed to be in trans. This results in the combination of a truncating p.Lys62X mutation with a p.R175W missense mutation at a conserved residue predicted to be deleterious. This patient presented with neonatal severe aplastic anemia requiring platelet and red cell transfusions with neutrophil counts of 0-200 unresponsive to G-CSF. The marrow showed irregular islands of cartilage surrounded by osteoid consistent with a disorder of bone formation. A low level of SBDS protein is expressed by the c.258+2T>C variant, so the absence of this hypomorphic allele may have contributed to this exceptionally severe phenotype. Bone marrow reports were available for 67 subjects with biallelic SBDSmutations. Marrow hypocellularity was noted in 79% (n=49/62). Mild morphologic marrow dysplasia was observed in 58% (n=35/60). Clonal abnormalities developed in 36%. The most common clonal abnormality was del20q in 16% (n=10/64). Isochromosome 7 was noted in 2% (n=1/64). Three individuals developed AML at ages 19.5, 38, and 39 years. Eleven (14%) have undergone hematopoietic stem cell transplantation (HSCT), 10 for MDS or AML and 1 for severe aplastic anemia. Given the frequency of del20q clones in SDS, we studied clinical features of the 10 SDSR subjects with del20q clones. Median age of this group was 17 years (range, 10.8-29.3). Congenital anomalies were noted in 80% (n=8/10). Frequency of cytopenias was similar to that of non-del20q subjects, with neutropenia, anemia and thrombocytopenia seen in 90%, 50%, and 80% respectively. Bone marrow pathology reports were available for 9 subjects. All were noted to have hypocellular marrows as well as mild marrow dysplasia. In many patients, the clone was persistent or grew over time, with longest duration of 14.6 years. Progression to MDS was reported in 3 subjects who initially had an isolated del20q clone. Two developed an additional loss of chromosome 7. Progressive marrow dysplasia and falling blood counts were seen in two subjects. All three were treated with HSCT at 5.4, 5.7 and 7 years. Deletion of 20q in SDS has been hypothesized to result in a milder hematologic phenotype due to compensatory deletion of eIF6. eIF6 binds to the nascent 60S ribosomal subunit and sterically inhibits joining of the 60S to the 40S ribosomal subunits. SBDS functions to facilitate release of eIF6 thus promoting assembly of the mature 80S ribosome. These data from the SDSR suggest that SDS patients with del20q clones remain at risk for clonal evolution. Higher patient numbers are needed to quantitate risk of MDS in SDS patients with del20q. The SDSR continues to expand and mature as a resource for biological and clinical studies in this rare disorder advancing our understanding of marrow failure and clonal evolution. Disclosures Davies: Novartis: Honoraria. Dale:Amgen: Consultancy, Honoraria, Research Funding.

Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1931-1934 ◽  
Author(s):  
A. Bacigalupo ◽  
B. Bruno ◽  
P. Saracco ◽  
E. Di Bona ◽  
A. Locasciulli ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Clonal Evolution ◽  
Severe Aplastic Anemia ◽  
Granulocyte Colony Stimulating Factor ◽  
Antilymphocyte Globulin ◽  
Colony Stimulating Factor ◽  
Actuarial Survival ◽  
First Line Therapy ◽  
Stimulating Factor ◽  
Median Interval

Abstract One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 × 109/L (range, 0-0.5 × 109/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 × 109/L (P = .001) and 88% versus 87% for patients aged less than versus more than 16 years (P = .8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 × 109/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF.

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