Optimal TBI Dose to Improve the Survival in Unrelated Matched Marrow Transplantation for Adult Patients with Severe Aplastic Anemia: Prospective De-Escalation Study of TBI Dose.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2770-2770
Author(s):  
Jong-Wook Lee ◽  
Ki Seong Eom ◽  
Yoon Hee Park ◽  
Yoo Jin Kim ◽  
Seok Lee ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Adult Patients ◽  
Severe Aplastic Anemia ◽  
Fixed Dose ◽  
Unrelated Donor ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background and Objectives: Patients with severe aplastic anemia (SAA) who do not have suitably HLA-matched related donor generally receive immunosuppressive therapy (IST) as first-line treatment and are considered for transplantation from matched unrelated donor (MUD) if they fail to respond to IST. To determine the optimal total body irradiation (TBI) dose as conditioning regimen in unrelated marrow transplantation for adult SAA patients, we conducted a prospective study to evaluate minimal dose of TBI sufficient to achieve sustained engraftment when it is used in combination with fixed dose of cyclophosphamide (CY). Methods: Between May 1998 and December 2003 twenty-eight patients were enrolled with a median age of 23 years old (20–44). All patients were multiply transfused and had received 1 or 2 course of intensive IST. Conditioning regimen consisted of CY (120mg/kg) plus TBI and they were divided into 3 group according to the fractionated TBI dose: group 1 (1200 cGy, n=5), group 2 (1000 cGy, n=9), and group 3 (800 cGy, n=14). Donor/recipient pairs were matched for HLA-A, -B by serology and -DRB1 by low-resolution DNA typing (n=15) or HLA-A, -B, and -DRB1 by high-resolution typing (n=13). Patients received CsA+MTx (n=4) or FK506+MTx (n=24) as GVHD prophylaxis. Results: All patients except one (group 2) achieved sustained engraftment. The incidence of acute GVHD more than grade II was not significantly different (60% in group 1, 38% in group 2, and 43% in group 3), but chronic GVHD developed more frequently in group 1 and 2 (60% & 80%, respectively) compared to group 3 (15%). Patients who received 800 cGy (group 3) had significantly better survival than those 1000 and 1200 cGy (93% in group 3, 44% in group 2, and 40% in group 1; group 3 vs group 1 and 2, p<0.02). Conclusions: Thus, a TBI dose of 800 cGy in combination with CY (120mg/kg) was sufficient to allow for engraftment in adult patients with SAA who received MUD BMT. Outcome in patients who received 800 cGy of TBI was superior to survival that among patients 1000 and 1200 cGy.

Decreased Rejection and Improved Survival of First and Second Marrow Transplants for Severe Aplastic Anemia (A 26-Year Retrospective Analysis)

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2742-2749 ◽  
Author(s):  
Anne Stucki ◽  
Wendy Leisenring ◽  
Brenda M. Sandmaier ◽  
Jean Sanders ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Graft Rejection ◽  
Marrow Transplant ◽  
Severe Aplastic Anemia ◽  
Probability Of Survival ◽  
Gvhd Prophylaxis ◽  
Group 3 ◽  
Group 2 ◽  
American Society ◽  
Group 1

Abstract Between 1970 and 1996, 333 patients with severe aplastic anemia underwent HLA-matched related marrow transplant after conditioning with cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group 3 v 2). In group 3, 92% of rejecting patients underwent a second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas group 3 patients received MTX combined with cyclosporine (CSP). Over the three time periods studied, first graft rejection decreased from 35% to 9%, and the proportion of rejecting patients undergoing second transplants increased from 77% to 92%. The 10-year probability of survival after second transplants increased from 5% to 83%. Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a significant factor accounting for the increase in patient survival after second transplant. © 1998 by The American Society of Hematology.

Decreased Rejection and Improved Survival of First and Second Marrow Transplants for Severe Aplastic Anemia (A 26-Year Retrospective Analysis)

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2742-2749
Author(s):  
Anne Stucki ◽  
Wendy Leisenring ◽  
Brenda M. Sandmaier ◽  
Jean Sanders ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Graft Rejection ◽  
Marrow Transplant ◽  
Severe Aplastic Anemia ◽  
Probability Of Survival ◽  
Gvhd Prophylaxis ◽  
Group 3 ◽  
Group 2 ◽  
American Society ◽  
Group 1

Between 1970 and 1996, 333 patients with severe aplastic anemia underwent HLA-matched related marrow transplant after conditioning with cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group 3 v 2). In group 3, 92% of rejecting patients underwent a second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas group 3 patients received MTX combined with cyclosporine (CSP). Over the three time periods studied, first graft rejection decreased from 35% to 9%, and the proportion of rejecting patients undergoing second transplants increased from 77% to 92%. The 10-year probability of survival after second transplants increased from 5% to 83%. Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a significant factor accounting for the increase in patient survival after second transplant. © 1998 by The American Society of Hematology.

scholarly journals Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment

2018 ◽  
Vol 2 (15) ◽  
pp. 2020-2028 ◽  
Author(s):  
George E. Georges ◽  
Kris Doney ◽  
Rainer Storb
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Severe Aplastic Anemia ◽  
Unrelated Donor ◽  
Line Treatment ◽  
First Line ◽  
Matched Unrelated Donor ◽  
First Line Treatment

Abstract Treatment of severe aplastic anemia has improved significantly over the past 4 decades. This review will summarize the key areas of progress in the use of allogeneic hematopoietic cell transplantation and nontransplant immunosuppressive therapy (IST) for the treatment of aplastic anemia and then summarize the recommendations for first-line treatment. Based on recent data, we argue that guidelines for the initial treatment of patients with newly diagnosed severe aplastic anemia require revision. At the time of diagnosis, before beginning treatment, HLA typing should be done to identify a marrow donor among family members or in the unrelated donor registries, and a marrow transplant should be considered first-line therapy. The priority order of donor source for bone marrow transplantation is: (1) HLA-identical sibling, (2) HLA-matched unrelated donor, and (3) HLA-haploidentical donor if an HLA-matched unrelated donor is not rapidly available. Each of these donor marrow sources may be preferable to nontransplant IST. We make this recommendation because of the long-term persistent risk for disease relapse and secondary myelodysplastic syndrome or acute myeloid leukemia with the use of nontransplant IST for patients with aplastic anemia. In contrast, marrow transplantation is associated with high cure rates of aplastic anemia and a relatively low risk for graft-versus-host disease, with many patients now living for decades without the risk for disease recurrence or the development of clonal disorders. Implementation of this first-line treatment strategy will provide patients with severe aplastic anemia the best chance of long-term disease-free survival.

scholarly journals Bone marrow transplantation for children with severe aplastic anemia: use of donors other than HLA-identical siblings

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1852-1857 ◽  
Author(s):  
B Camitta ◽  
R Ash ◽  
J Menitove ◽  
K Murray ◽  
C Lawton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Pneumocystis Pneumonia ◽  
Severe Aplastic Anemia ◽  
High Dose ◽  
Gvhd Prophylaxis

Abstract Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T- cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical- related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow- up.

Safe Out-of-Hospital Treatment of Chest Pain Without Direct Medical Control

1996 ◽  
Vol 11 (1) ◽  
pp. 16-19 ◽  
Author(s):  
Mara McErlean ◽  
Nancy Raccio-Robak ◽  
Joel M. Bartfield ◽  
Daniel Hermes
Keyword(s):  
Chest Pain ◽  
Adult Patients ◽  
Categorical Variables ◽  
Hospital Treatment ◽  
Time Interval ◽  
Medical Control ◽  
Physician Contact ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

AbstractIntroduction:The use of direct medical control (DMC) in the out-of-hospital setting often is beneficial, but has the disadvantage of consuming emergency medical services (EMS) resources.Hypothesis:Uncomplicated, nontrauma, adult patients with chest pain can be treated safely and transported by paramedics without DMC.Methods:Retrospective chart review of all nontrauma, adult patients with chest pain treated in a combined rural and suburban EMS system during a 2-year period (December 1990 through November 1992) was conducted. Before November 1991, DMC was mandatory for all patients with chest pain. Beginning 01 November 1991, if a patient had resolution of pain either spontaneously, with administration of oxygen, or after a single dose of nitroglycerin, DMC was at the discretion of the paramedic. Using the above criteria for inclusion, three study groups were defined: Group 1, before protocol change; Group 2, after protocol change without DMC; and Group 3, after protocol change when physician contact was obtained, but not required. These groups were compared for the following parameters: 1) scene time; 2) time to administration of first dose of nitroglycerin; 3) time interval between measurement of vital signs; 4) oxygen use; 5) intravenous access; and 6) electrocardiographic monitoring. Continuous and categorical variables were analyzed by multivariate and univariate analysis of variance and chi-square tests, respectively.Results:Of 308 nontrauma, adult patients with chest pain, 71 met inclusion criteria in Group 1, 40 in Group 2, and 34 in Group 3. No statistically significant differences were identified in any of the study parameters.Conclusion:Adult patients with chest pain who have no other symptoms or complicating conditions can be treated appropriately by paramedics without DMC.

Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia

2020 ◽  
Vol 55 (8) ◽  
pp. 1570-1579 ◽  
Author(s):  
Seung Hwan Shin ◽  
Sung Soo Park ◽  
Jae Ho Yoon ◽  
Seung Ah Yahng ◽  
Sung Eun Lee ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Adult Patients ◽  
Severe Aplastic Anemia ◽  
Unrelated Donor ◽  
Matched Sibling ◽  
Acquired Severe Aplastic Anemia

scholarly journals Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia [see comments]

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 277-279 ◽  
Author(s):  
G Socie ◽  
M Henry-Amar ◽  
JM Cosset ◽  
A Devergie ◽  
T Girinsky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Marrow Transplantation ◽  
Malignant Tumors ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Male Patients

Abstract From May 1980 to December 1989, 107 consecutive patients with non- constitutional severe aplastic anemia underwent bone marrow transplantation at our institution using cyclophosphamide and thoraco- abdominal irradiation as conditioning regimen. During the same period, 40 patients with Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean follow- up of 64 months, four male patients developed a solid malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general population = 41, P less than .001). These results should be considered as a warning to clinicians who follow these successfully grafted long-term patients.

NPM1, IDH1/2 and DNAH11 Gene Mutations Can Improve a Prognostic Stratification of Acute Myeloid Leukemia Patients with Normal Karyotype but Not Harboring FLT3/ITD Mutation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2534-2534
Author(s):  
Yeo-Kyeoung Kim ◽  
Il-Kwon Lee ◽  
Dennis Dong Hwan Kim ◽  
Chul Won Jung ◽  
Jun-Ho Jang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Npm1 Mutation ◽  
Group 3 ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

Abstract Abstract 2534 Background: Acute myeloid leukemia with normal karyotype (AML-NK) is known to be heterogeneous in the molecular level. Accordingly, it has become more critical to dissect this group of patients according to their prognosis using a molecular genetic technology. We attempted to analyze the incidence and prognostic implication of genetic abnormalities on survival in 426 adult patients with AML-NK. Methods: A total of 67 AML-NK patients achieved complete remission (CR), candidate mutations in 21 genes were identified by whole exome sequencing which has 41–89× coverage and by single-nucleotide polymorphism array analysis using marrow mononuclear cells at diagnosis of AML-NK. Subsequently, mutation analysis of 11 genes (i.e. FLT3/ITD, NPM1, DNMT3a, IDH1, IDH2, TET2, NRAS, WT1, DNAH11, SF3B1, and PHF6) which are known to be involved in the pathogenesis of hematologic diseases, were performed using Sanger sequencing in another subset of 359 AML-NK patients as a validation cohort. Results: Of 426 patients in total (median age: 51, ranges: 15–85), FLT3/ITD, NPM1, and DNMT3a mutations were associated with higher leukocytes counts at presentation of AML-NK. In 284 patients who received standard remission induction (RI) chemotherapy (excluding 119 patients with conservative treatment and 22 early death/1 follow-up loss after RI chemotherapy), those with FLT3/ITD mutation were significantly associated with a higher risk of relapse (p=0.02), a shorter leukemic-free survival duration (LFS)(p<0.01) or overall survival (OS) (p=0.01). Accordingly, we divided the patients into FLT3/ITD+ and FLT3/ITD− population, and analyzed their treatment outcomes according to the other mutations. In the FLT3/ITD− group (n=200), those with NPM1 mutation showed a higher CR rates after one or two cycles of RI chemotherapy (p<0.01) and a longer OS duration (p<0.01), hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.25–0.73, adjusted by other clinical variables including age, leukocyte counts at diagnosis, and transplantation (Figure 1). In the FLT3/ITD+ patients (n=84), NPM1 mutation was found to be a favorable prognostic factor showing a lower relapse rate (p=0.00), a longer LFS duration (p<0.01, HR 0.35, 95% CI 0.18–0.70), and OS duration (p=0.04, HR 0.55, 95% CI 0.31–0.98) in NPM1 mutated patients. In addition, OS was significantly different in favor of those with IDH2, especially R140Q IDH2 mutation, (p=0.04, HR 0.30, 95% CI 0.09–0.99), whereas DNAH11 mutation was associated with inferior OS (p<0.01, HR 5.78, 95% CI 1.65–20.25). Accordingly, we stratified the FLT3/ITD+ patients into three subgroups according to the NPM1, IDH1/2 and DNAH11 mutation status, Group 1: NPM1 mutation and IDH1 or 2 mutations (n=16), Group 2: isolated DNAH11 mutation (n=4) and Group 3: all mutations were negative (n=64). The group 1 showed significantly better OS than group 2 (p<0.01, HR 16.90, 95% CI 3.48–82.15) or group 3 (p<0.01, HR 3.40, 95% CI 1.20–9.55) (Figure 2). In a subgroup analysis of younger patients less than 60 years of age, similar outcomes were also observed in favor of group 1 in terms of OS (data not shown). Conclusion: Our study confirmed that NPM1 mutation is an independent prognostic factor in adult patients with AML-NK not harboring FLT3/ITD mutation. In addition, several other genetic markers were identified as prognostic including IDH1/2 or DNAH11 mutations as well as NPM1 mutation in a subgroup of AML-NK patients with FLT3/ITD mutation. Disclosures: No relevant conflicts of interest to declare.

Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5755-5755
Author(s):  
Hiroshi Okamura ◽  
Mitsutaka Nishimoto ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
Yasuhiro Nakashima ◽  
...  
Keyword(s):  
Risk Factors ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Adult Patients ◽  
Allogeneic Hsct ◽  
History Of ◽  
Group 3 ◽  
Group 2 ◽  
Prophylactic Use ◽  
Group 1

Abstract Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

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