scholarly journals Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4743-4748 ◽  
Author(s):  
Nada Jabado ◽  
Elizabeth R. de Graeff-Meeder ◽  
Marina Cavazzana-Calvo ◽  
Elie Haddad ◽  
Françoise Le Deist ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Rejection ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Disease Free

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

scholarly journals Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4743-4748 ◽  
Author(s):  
Nada Jabado ◽  
Elizabeth R. de Graeff-Meeder ◽  
Marina Cavazzana-Calvo ◽  
Elie Haddad ◽  
Françoise Le Deist ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Graft Rejection ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Marrow Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Disease Free

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare genetic disorder associated with the onset early in life of overwhelming activation of T lymphocytes and macrophages invariably leading to death. Allogeneic bone marrow transplantation (BMT) from an HLA-identical related donor is the treatment of choice in patients with this disease. However, fewer than 20% of patients have a disease-free HLA-identical sibling. BMT from HLA-nonidentical related donors has previously met with poor results, with graft rejection a major obstacle in all cases. We describe BMTs from HLA-nonidentical related donors (n = 13) and from a matched unrelated donor (n = 1) performed in two centers in 14 consecutive cases of FHL. Remission of disease was achieved before BMT in 10 patients. Marrow was T-cell–depleted to minimize graft-versus-host disease (GVHD). Antiadhesion antibodies specific for the α chain of the leukocyte function–associated antigen-1 (LFA-1, CD11a) and the CD2 molecules were infused pre-BMT and post-BMT to help prevent graft rejection, in addition to a conditioning regimen of busulfan (BU), cyclophosphamide (CP), and etoposide (VP16) or antithymocyte globulin (ATG). Sustained engraftment was obtained in 11 of 17 transplants (3 patients had 2 transplants) and disease-free survival in 9 patients with a follow-up period of 8 to 69 months (mean, 33). Acute GVHD greater than stage I was not observed, and 1 patient had mild cutaneous chronic GVHD that resolved. Toxicity due to the BMT procedure was low. Results obtained using this protocol are promising in terms of engraftment and event-free survival within the limitations of the small sample. We conclude that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell–depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetically identical donor.

Treatment of Familial Hemophagocytic Lymphohistiocytosis with Bone Marrow Transplantation : A Single Center Experience of 48 Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2158-2158
Author(s):  
Marie Ouachée-Chardin ◽  
Francoise Le Deist ◽  
Genevieve De Saint Basile ◽  
Marina Cavazzana-Calvo ◽  
Alain Fischer
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cyclosporin A ◽  
Median Time ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Marrow Transplantation ◽  
Mixed Chimerism ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Donor Cells

Abstract Familial Hemophagocytic Lymphohistiocytosis (FHLH) is a rare genetically heterogeneous autosomal recessive disease, curable only by bone marrow transplantation (BMT).We retrospectively analysed 48 children undergoing BMT between May 1982 and May 2004. Fourteen patients received BMT from matched sibling donor (MSD), 29 from family haploidentical donor and 5 from unrelated donor. The 48 patients had a total of 60 transplants. Genetic studies of perforin and Munc13, the two known genes, have been performed in 29 children: 7 had a perforin defect, 10 a Munc13 defect and 12 were not linked to perforin or Munc13. Median age at diagnosis was 3 months. Central nervous system involvement (CNS) was present at diagnosis in 30 patients (62%) and during the course prior to BMT in 38 patients (80%). Initial treatment before BMT was a chemotherapy regimen consisting of VP16, steroids, cyclosporin A and intrathecal methotrexate (IT) for 15 patients (31%). Thirtythree patients (69%) received an alternative treatment, based on the primary role of T cell activation in FHLH, including steroids, cyclosporin A, IT, and for 26 patients rabbit anti-thymocytes globuline (ATG). Twenty-seven children (56%) had a complete resolution before BMT, 14 (30%) a partial remission, 5 (10%) a unstable active disease and 2 a CNS involvement.Conditioning regimen consisted of Busulfan, Cyclophosphamide and ATG for 32 transplants and Busulfan, Cyclophosphamide and VP16 for 18 transplants. Marrow was T cell depleted for all transplants except MSD. Median age at BMT was 6 months and median time from diagnosis to BMT was 3,5 months. Donor cell engraftment was achieved in 37 children (77%). Seven patients (18%) had a acute GVHD of grade II-IV. The major regimen related toxicities were VOD in 14 children (29%) and severe infections (n=30). In the 19 deceased patients, death occured prior to day+100 in 15, caused by BMT complication (n=7) or reactivation of HLH (n=8). Four children died after day+100, 2 by GVHD and 2 by HLH. The median follow-up was 6 years. Twenty-nine children (60%) are alive at the time of evaluation, without recurrence of HLH. One child is alive with slight psychomotric retardation and 1 with a moderate spasticity. Survival with regard to donor was 100% in MUD, 57% in MSD, and 55% in haplo-identical donor. Among alive patients, 17 had a donor chimerism and 12 a mixed chimerism. Five patients had late disease relapse after 8 to 46 months of mixed chimerism. All these 5 children had mismatch BMT and relapse occured with less than 10% of donor cells, supporting the hypothesis that a certain amount of donor cells are needed to control T lymphocytes activation in HLH. Severe neurological involvement is associated with a lower survival (36%). Survival for patients with perforin, Munc13, no perforin or Munc defect were respectively 72%, 80% and 67%. With a pretreatment by immunotherapy 68% of patients survived, compared to 47% with chemotherapy. Survival for patients younger than 3 months was 61%, 66% for them between 3 months and 2 years, and 50% for older ones. Survival if BMT was performed early or late, using the median time to BMT as the cut-off time were 64% and 55%. We report the largest series of allogenic BMT in HLH from one center. Immunotherapy as pretreatment allows fast CR and short delay between diagnosis and BMT. Results of this non myeloablative approach are very encouraging with a great improvement of the survival.

A critical comparison of allogeneic bone marrow transplantation and conventional chemotherapy as treatment for acute nonlymphocytic leukemia.

1984 ◽  
Vol 2 (5) ◽  
pp. 369-378 ◽  
Author(s):  
C B Begg ◽  
P B McGlave ◽  
J M Bennett ◽  
P A Cassileth ◽  
M M Oken
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Disease Free Survival ◽  
Acute Nonlymphocytic Leukemia ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Critical Comparison ◽  
Selection Factors ◽  
Disease Free

Published data from two centers conducting bone marrow transplantation on patients with acute nonlymphocytic leukemia in first remission were pooled and compared with results from an Eastern Cooperative Oncology Group (ECOG) study in which patients were treated with conventional chemotherapy. A series of adjustments were made to the ECOG sample to account for selection factors that restrict access of patients to transplantation. The transplant sample exhibits considerably higher disease-free survival when compared to the adjusted ECOG series (53% versus 21% at three years). The transplant series is somewhat younger than the ECOG series (median, 24 years versus 28 years). The impact of age on the disease-free survival results is difficult to assess because of the relatively small samples in the different age groups. However, by defining a suitable control group, methodology for making a critical comparison between the two modalities is presented which, if applied to larger samples of patients, should help to resolve the issue. In the absence of data from a large, prospective randomized study, a critical retrospective comparison of available data is essential in the assessment of treatment options.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

1992 ◽  
Vol 10 (1) ◽  
pp. 41-46 ◽  
Author(s):  
G J Schiller ◽  
S D Nimer ◽  
M C Territo ◽  
W G Ho ◽  
R E Champlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Disease Free Survival ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
First Remission ◽  
Disease Free

PURPOSE Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

scholarly journals Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 2256-2262 ◽  
Author(s):  
John E. Wagner ◽  
Mary Eapen ◽  
Margaret L. MacMillan ◽  
Richard E. Harris ◽  
Ricardo Pasquini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Fanconi Anemia ◽  
Marrow Transplantation ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Donor Bone Marrow ◽  
The Impact

AbstractBone marrow transplantation (BMT) is the only known cure for the hematologic manifestations of Fanconi anemia (FA). Potential benefits of unrelated donor BMT for FA, however, have been severely limited by graft rejection and treatment-related mortality with resultant poor survival. Therefore, we evaluated the impact of potential prognostic factors on hematopoietic recovery, graft-versus-host disease (GVHD), and mortality in 98 recipients of unrelated donor BMT who received transplants between 1990 and 2003. Probabilities of neutrophil (89% vs 69%; P = .02) and platelet (74% vs 23%; P < .001) recovery were higher after fludarabine-containing regimens than nonfludarabine-containing regimens. Risks of acute GVHD (relative risk [RR], 4.29; P < .001) were higher with non–T-cell–depleted grafts. The day-100 mortality rate was significantly higher after nonfludarabine-containing regimens than fludarabine-containing regimens (65% vs 24%, respectively; P < .001). Corresponding 3-year adjusted overall survival rates were 13% versus 52% (P < .001). In addition, mortality was higher in recipients who were older (> 10 years), who were cytomegalovirus (CMV) seropositive, and who received more than 20 blood product transfusions before BMT. Based on these results, significant practice changes are suggested: use of a fludarabine-containing conditioning regimen in the context of T-cell–depleted marrow allografts, and earlier referral for transplantation prior to excessive transfusions in patients with marrow failure.

Taperring Treatment According Minimal Residual Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4960-4960 ◽  
Author(s):  
Ihab A. Eldessouki ◽  
Eman Z Kandeel ◽  
Shady Adnan ◽  
Mohammed Ghareeb ◽  
Ola Gaber ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Disease Free ◽  
Minimal Residual

Abstract In spite its established prognostic role in ALL and being a powerful method for patient stratification, Minimal residual disease in AML is still an area of research need to be investigated to decide its value in AML treatment. In this is a retrospective study, 388 adult AML patients from period 2009-2014 in NCI Cairo University were included, comparing minimal residual disease to other prognostic factors to determine its value as an independent prognostic factor to stratify AML patients and to assess possibility of treatment tapering according MRD. We divided patients in to 3 groups according cytogenetics: favorable, intermediate, poor risk. (We considered patients having negative MRD: those having day 28 and day 42 BMA free for MRD less than 0.01) All patients with FLT3 were excluded prior start this study because we proved by other study its grave prognosis and it outweigh MRD as independent prognostic factor, and eventually those patients will relapse within a short period of time. 5 years disease free survival First group patient with favorable cytogenetics: included 156 patients. We found that 76 patients who become MRD negative post first cycle induction had significantly better disease free survival 64% and overall survival 61.7% compared to those having persistence MRD ( 80 patient) post first cycle of induction 24%, 14% respectively with p value 0.02. Out of 76 patients had negative MRD, 29 patients just took 2 cycles of chemotherapy one induction chemotherapy and one consolidation. Those patients continued to maintain CR in spite receiving 2 cycles of chemotherapy which confirm powerful prognostic impact of MRD with DFS : 61, OS 59.3% which showed no significant difference from those who completed their chemotherapy (p value : 0.07) Those patients didn't continue treatment due to medical problems or non compliance or insurance coverage problems. Those who had persistence MRD post first cycle of induction had prognosis resembling those of poor cytogenetics. Out of 80 patients having persistent MRD, 9 died prior relapse due to medical problems. 64 relapsed and took salvage chemotherapy then kept under follow up. 23 patient did allogenic bone marrow transplantation, 9 were in CR and were done due to persistence MRD and 14 patient did due to relapse and transplantation were done in second CR. patients who had did allogenic transplantation had better disease free survival and overall survival. Second group intermediate risk: 103 patients. We had 40 patients with negative MRD, whose DFS and OS were 59% and 55% respectively. Of those patients, 14 received only 2 cycles of chemotherapy and also showed favorable prognosis in spite being intermediate risk and retained CR. DFS : 57%, OS 55% with no statistical difference between those continued chemotherapy or not. 63 Patients had positive MRD, out of them 5 patients had lost follow up. DFS was13% and OS was 11%. 47 patients relapsed took salvage chemotherapy and kept under follow up out of which 16 patients did bone marrow transplantation. 11 patients did bone marrow transplantation due to persistence MRD and they had longer disease free survival compared to those had salvage chemotherapy and kept under follow up. Same disease free survival overall survival to those did BMT post second CR. Third group with poor risk cytogenetic included 127 patients. 32 patients got MRD negative (DFS: 38% OS: 8%). Out of which 9 didn't receive further chemotherapy post 2 cycles. Again with no significant p value between both groups (P: 0.08) We had 95 patients with persistent MRD post induction. 11 patients lost follow up. 65 relapsed and received salvage chemotherapy DFS 29% and OS: 5%. 19 patients did allogenic bone marrow transplantation. 8 patients did allogenic bone marrow transplantation due to persistence MRD. We found that poor risk cytogenetic outweighs MRD and only patients did BMT had favorable outcome regarding disease free survival 42% and overall survival 11%. Finally we conclude that minimal residual disease can be used as independent prognostic factor. Also MRD can be used as in stratifying patients and tailoring the treatment plan allowing the possibility to stop treatment at a less number of cycles and preventing further chemotherapy complications. Disclosures No relevant conflicts of interest to declare.

scholarly journals T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3380-3387 ◽  
Author(s):  
JW Young ◽  
EB Papadopoulos ◽  
I Cunningham ◽  
H Castro-Malaspina ◽  
N Flomenberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
De Novo ◽  
Remission Induction ◽  
Allogeneic Bone ◽  
Acute Nonlymphocytic Leukemia ◽  
Free Survival ◽  
First Remission

We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC- compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval [CI], 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.

scholarly journals Prevention of graft rejection following bone marrow transplantation

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 9-12
Author(s):  
RP Gale ◽  
W Ho ◽  
S Feig ◽  
R Champlin ◽  
A Tesler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Aplastic Anemia ◽  
Total Body Irradiation ◽  
Graft Rejection ◽  
Marrow Transplantation ◽  
Low Dose ◽  
Conditioning Regimen ◽  
Actuarial Survival ◽  
Total Body

Bone marrow transplantation from an HLA-identical sibling is increasingly used in the treatment of severe aplastic anemia. One major problem with this approach is graft rejection that occurs in 25%-60% of patients conditioned for transplantation with cyclophosphamide. At most transplant centers it has been difficult to accurately identify patients at high risk for graft rejection. We studied a conditioning regimen of cyclophosphamide (200 mg per kg) and low-dose total body irradiation (3 Gy; equivalent to 300 rad) in 23 consecutive unselected patients with aplastic anemia followed for a minimum of 6 mo. There was only one episode of graft rejection. Graft-versus-host disease and interstitial pneumonitis were not increased by the more intensive conditioning regimen. Actuarial survival was 61% at 1 yr and 49% at 2.5 yr. Cyclophosphamide and low-dose total body irradiation is an effective conditioning regimen in patients with aplastic anemia. It may be particularly useful when accurate predictive tests of graft rejection are not available as is the case in most transplant centers.

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