G-CSF Primed Bone Marrow Is Not Superior to Unprimed Bone Marrow as a Source of Stem Cells in HLA Matched Related Allogeneic SCT for β Thalassaemia Major.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5052-5052
Author(s):  
Reena Rajasekar ◽  
Vikram Mathews ◽  
Kavitha M. Lakshmi ◽  
Auro Viswabandya ◽  
Biju George ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Survival Curve ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
T Cell Subsets ◽  
Thalassaemia Major ◽  
Class Iii ◽  
Gvhd Prophylaxis

Abstract G-CSF stimulated BM (G-BM) offers a source of stem cells that has been reported to be associated with faster engraftment and decreased risk of GVHD. It is possible that these differences are related to the immunological composition of these grafts. We compared G-BM and unprimed bone marrow as a source of stem cells in 33 consecutive thalassaemia major patients who underwent a matched related allogeneic SCT treated with a similar conditioning and GVHD prophylaxis regimen. Twenty patients received G-BM from HLA matched donors primed with G-CSF 10ug/Kg/day for 2 days prior to BM harvest and the rest received unprimed BM. Lymphocyte subsets and progenitor cells contained in the grafts was assessed using FACSCalibur and monoclonal antibodies directed against B, NK and T cell subsets. The median age of the cohort was 7 years (range: 2–14) and there were 22 (67%) males. All patients received Bu/Cy/ATG as conditioning regimen. Cyclosporine and short course Methotrexate were used as GVHD prophylaxis. 88% of patients achieved sustained engraftment. The mean follow up was 37 months. Patient and graft characteristics were similar in both HSC sources (Table 1). The target cell dose of 3x108 TNC/Kg could be achieved with smaller volume of the graft in the G-BM group. Time to neutrophil engraftment (median: 16 days, p= 0.260) and platelet engraftment (median: 30 Vs 26 days, p= 0.163) was identical in both the groups. The incidence of acute GVHD (grade II–IV, 10% vs. 15%) and chronic GVHD (12% vs. 9%) were similar in both the groups. 9 patients rejected their graft, six (30%) in G-BM and three (23%) in BM. There were 4 transplant-related deaths within the first 100 days (two in each group). Survival curve analysis showed no difference in overall and event free survival between the two groups. In this cohort of patients, G-BM resulted in rates of engraftment, GVHD, rejection and TRM that were similar to those produced by unprimed BM. G-BM as a HSC source may not add selective advantage to patients with thalassaemia major undergoing a matched related allogeneic SCT. Comparison of Graft Source Characteristics BM (n=13) G-BM (n=20) P Age (median years: range) 6 (2–14) 8 (2–13) 0.22 Male (%) 9 (69) 13 (65) 1.00 Lucarelli Class III (%) 5 (39) 9 (45) 0.71 Harvest TNC/mm3 23430±9007 39045±13457 0.000 Harvest Volume 417±173 290±98 0.012 TNC / 10e8/kg 4 (2.9–7.6) 4.8 (2.4–8.8) 0.083 CD34 x 10e6/kg 6.89 (3.3–12.9) 8.3 (1.2–16.4) 0.439 Total CD3 cells x 10e6/kg 45.6 (12.7–120.1) 40.4 (26.2 – 139.8) 0.912 NK cells x 10e6/kg 4.71 (0.9–49.8) 6.7 (0.1–15.2) 0.580 Total B cells x 10e6/kg 19 (0.3 – 47.2) 24.3 (0.8 – 62.2) 0.32 Helper T cells x 10e6/kg 20.8 (7.2 – 48.7) 13.7 (15.4 – 77.8) 0.556 Cytotoxic T cells x 10e6/kg 24.8 (7 – 91) 10.6 (8.8 – 51.2) 0.39

Peripheral Blood Stem Cells Vs Bone Marrow: Stem Cell Source Comparison for Patients Acute Myeloid Leukemia and Myelodysplastic Syndrome Receiving an Allogeneic Stem Cell Transplantation from a 10/10 Matched Donor. Study from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2552-2552 ◽  
Author(s):  
Aurélie Ravinet ◽  
Aurélie Cabrespine ◽  
Gerard Socie ◽  
Noel Milpied ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
French Society ◽  
Peripheral Blood Stem Cells ◽  
Cell Therapies ◽  
Gvhd Prophylaxis

Abstract Introduction: Peripheral blood stem cells (PBSC) are increasingly used for unrelated donor (UD) hematopoietic stem cell transplantation (HSCT). A recent randomized prospective trial did not detect significant survival differences between PBSC and bone marrow (BM) transplantation from a UD. The use of PBSC reduced the risk of graft failure, whereas BM reduced the risk of chronic graft versus host disease (GVHD) (Anasetti & al, NEJM 2012). However, HLA matching was based on HLA-A, HLA-B, HLA-C &HLA-DRB1 (8/8 but also 7/8), some of the patients (pts) received a reduced intensity conditioning regimen (22%) and diseases consisted of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but also other hematological malignancies. We thus conducted this study to compare mobilized PBSC with BM for matched 10/10 UD HSCT after standard conditioning regimen (MAC) in pts with AML and MDS only. Patients and methods: We included all consecutive pts in France who received a first HSCT for AML or MDS with PBSC or BM from a matched 10/10 UD after a MAC (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=165 or Endoxan-Cy, n=203) between 2000 and 2013. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). HLA typing data were collected from the SFHI (French Society of Histocompatibility and Immunogenetic) and the ABM (French Biomedical Agency). This study is in accordance with Helsinki declaration for clinical research. Results: We included368 adults pts (221 [60%] received BM; 147 [40%] received PBSC). Median follow-up was of 16.5 months [0-156]. The BM and PBSC groups were well balanced with respect to age, diagnosis, disease risk, use of antithymocyte globulins (ATG) (67 [30%] BM and 52 [35%] PBSC recipients,) and cytomegalovirus (CMV) recipient and donor status. PBSC recipients were more likely to be male and received less TBI-based regimen. GVHD prophylaxis mainly combined cyclosporine A (CSA) and methotrexate (MTX) (82%). The median number of nucleated cell dose infused was higher in the PBSC group compared with the BM group: CD34+ cells, 6.96 x10⁶/kg [1.2-37.8] vs 2,78 x10⁶/kg [0.6-89] p<0.01) and total nucleated cells, 9.8 x10⁸/kg [1.3-663] vs 2.3 x10⁸/kg [0.3-305.3] p<0.01). Two hundred and seven (90%) pts engrafted after BM and 144 (99.3%) after PBSC HSCT (p=0.1). Among pts who received PBSC as compared with those who received BM, the median time to neutrophils engraftment (> 0.5 x 109 /L) was 6 days shorter and 8 days shorter to platelets engraftment (>20x109 /L) (p<0.01). The cumulative incidence (CI) for severe acute GVHD III-IV was 21.1% and 16.3% in the PBSC and the BM group, respectively (p=0.18). CI of chronic GVHD was higher after PBSC (47.1% vs 34.3% for BM, p=0.05). By multivariate analysis, the absence of ATG in the conditioning regimen (HR 0.4 95%CI [0.22-0.72] p<0.01) and PBSC as stem cells source (HR 0.6 95%CI [0.34-0.97] p=0.04) were associated with an increased chronic GVHD. At 2-years, the CI of non relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, better OS was associated with complete remission (CR) disease status (HR 0.5 95%CI [0.32-0.69] p<0.01) and pts’s age<38.1 years (HR 0.67 95%CI [0.48-0.93] p=0.02) at time of HSCT, and the use of CSA-MTX as GVHD prophylaxis (HR 0.6 95%CI [0.41-0.95] p=0.03). Conclusion: OS, NRM and relapse rates are similar with PBSC and BM after HLA 10/10 matched UD for AML or MDS using MAC, but engraftment is better with PBSC and the CI of chronic GVHD is lower with BM. Better results are obtained for pts <38 years old with a disease in CR at time of HSCT using CSA-MTX as GVHD prophylaxis. The absence of ATG with PBSC was associated with chronic GVHD. This study thus favors the use of ATG in the setting of matched 10/10 PBSC. However, the role of ATG in the context of BM after HLA 10/10 matched UD MAC HSCT remains unclear and warrants further investigation. Table 1: 2-year CI of NRM*, relapse, DFS** and OS*** Parameters BM % (95% CI) PBSC % (95%CI) p value NRM 23 (20-26) 18 (15-21) 0.8 Relapse 30 (27-33) 28 (25-31) 0.83 DFS 47.1 (44-51) 54.4 (50-58) 0.2 OS 54 .4 (50.8-57.9) 60.2 (55.7-64.6) 0.31 *NRM: non-relapse mortality **DFS: disease free survival ***OS: overall survival Disclosures No relevant conflicts of interest to declare.

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.

A Report of Transplantation of 224 Patients with Beta Thalassemia Major in Tehran, 1991– 2004.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3772-3772
Author(s):  
Ardeshir Ghavamzadeh ◽  
Mohamad Jahani ◽  
Kamran Alimoghaddam ◽  
Masoud Iravani ◽  
Babak Bahar ◽  
...  
Keyword(s):  
Single Gene ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Thalassemia Major ◽  
Class I ◽  
Beta Thalassemia ◽  
Class Iii ◽  
Beta Thalassemia Major ◽  
Gvhd Prophylaxis

Abstract Introduction: Beta Thalassemia Major is one of the most common single gene disorders and the most common type of hemoglobinopathies in Iran, with more than 20,000 patients. North and South parts of Iran have the highest prevalence, although it exists all over the country. In Iran, the first thalassemic patient was transplanted in our center, in 1991. Methods and patients: Till now (August 2004) 224 Beta Thalassemia Major Patients have been transplanted in this center. Age range =2–17 years, M/F=123/101, Class I=99, class II=81 and class III= 44. 124 patients (55.4%) received Bone Marrow, 94 (42%) Peripheral Blood stem cell and 6 (2.7%) Cord Blood for transplantation. Their conditioning regimen in class I and II included Busulfan 3.5mg/kg for 4days, Cyclophosphamide (CY) 50mg/kg for 4 days and their GVHD prophylaxis regimen was Cyclosporine (CYX) 3mg/kg (IV from day −2 till day +5) and 12.5mg/kg (PO after then) and in class III, included Busulfan 4mg/kg for 4days and CY 40mg/kg for 4days and their GVHD prophylaxis regimen was CYX plus MTX 10mg/m2 on day +1 and 6mg/m2 on days +3 and +6. Results:188 (84%) patients are alive and 36(16.1%) deceased.188 (84%) patients have passed 100 days after transplantation.168 (75%) patients had developed clinical acute GVHD after transplantation (grade II–IV= 57.1%). 67(35.6%) patients developed chronic GVHD (44 limited, 23 extensive). Three to ten year overall survival was 81% and disease free survival was 70 %. Conclusion: Blood and marrow transplantation (based on other documented studies and our experience) is the treatment of choice for class I& II and is indicated in class III thalassemic patients.

Fludarabine Based Conditioning for Allogeneic Transplantation in Severe Aplastic Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2029-2029
Author(s):  
Mammen Chandy ◽  
Biju George ◽  
Auro Viswabandya ◽  
Vikram Mathews ◽  
Ashish Bajel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Severe Aplastic Anemia ◽  
Peripheral Blood Stem Cells ◽  
Allogeneic Bmt ◽  
Gvhd Prophylaxis ◽  
Blood Stem Cells

Abstract Patients with severe aplastic anemia (SAA) who are multiply transfused or septic have a poor outcome after allogeneic stem cell transplantation. Forty three patients (31 males and 12 females) with SAA underwent allogeneic BMT using a fludarabine based conditioning regimen between 1998 and 2005. The median age was 20 years (range: 4–38) with 11 children and 32 adults. All donors were 6 antigen matched HLA identical sibling or family donors. Co morbidities seen included bacterial sepsis in 15 patients, fungal pneumonia in 4 and a recent intracranial bleed in 5 patients. Seven patients had failed Antithymocyte or antilymphocyte globulin (ATG/ALG) and two patients had failed their first transplant. The median time from diagnosis to transplant was 12 months (range: 2 – 96) and the median transfusions prior to BMT was 28 (range: 2 – 380). Conditioning therapy consisted of: Fludarabine (Flu) 180 mg/m2 over 6d + Busulfan (Bu) 8 mg/kg over 2d + ATG 40 mg/kg/day over 4 d in 17 patients, Flu 180 mg/m2 over 6d + Cyclophosphamide (Cy) 120 mg/kg over 2d ± ATG 40 mg/kg/day over 4d in 17 patients, Flu/TBI/OKT3 in 4, and Cy 120 + Flu 150mg/m2 in 5 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and mini methotrexate. Graft source was peripheral blood stem cells in 39 patients and G-CSF stimulated bone marrow in 4. The median cell dose was 5.2 x 108 MNC/kg (range: 2.1 – 13.6) for PBSC and 5.2 x 108 TNC/kg (range: 3.7 – 6.8) for bone marrow. Five patients expired within the first 10 days due to sepsis. Thirty seven patients engrafted with a mean time to ANC > 500 of 11.6 days (range: 8 – 18) and median platelet engraftment time of 13 days (range: 8 – 32). One patient had primary graft failure and expired on day 64 due to fungal pneumonia despite a second transplant. Acute GVHD was seen in 14 patients (38%) with Grade III–IV GVHD in 4 (10.5%). Chronic GVHD was seen in 10 patients with 6 having limited and 4 with extensive GVHD. Two patients had secondary graft rejection on day + 24 and +60 respectively and expired due to fungal pneumonia. At a median follow up of 17 months (range: 5 – 78); 29 patients (67.7%) are alive and well. Among patients treated with Flu/Bu/ATG, 12/17 (70.5%) are alive and well while the DFS is 82% (14/17) in patients treated with Flu/Cy ± ATG. Comparison with patients conditioned with Cy/ATG during 1990–2004 is given in the table. This comparison suggests that a fludarabine based conditioning regimen may be better, with less rejection, than Cy/ATG for allogeneic BMT in sick patients with SAA who are infected and multiply transfused at the time of BMT. Comparative data Fludarabine Cy/ATG Number 43 26 Rejection 3 (7%) 7 (27%) DFS 29(67.7%) 11 (46%)

Immunosupressive Property of Mesenchymal Stem Cells (MSCs) in Mixed Lymphocyte Reactions In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4313-4313 ◽  
Author(s):  
Jianyong Li ◽  
Lijuan Meng ◽  
Yu Zhu ◽  
Hua Lu ◽  
Changgeng Ruan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Subsets ◽  
Bone Marrow Mscs ◽  
Human Bone Marrow Mscs ◽  
Mixed Lymphocyte Reactions ◽  
Activation Phase

Abstract Meesnchymal stem cells (MSCs) were successfully used in the prevention and treatment of graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. To further explore the immunosuppressive property of human bone marrow (MSCs) in alloantigen-induced mixed lymphocyte reactions (MLRs) in vitro, human bone marrow MSCs and lymphocytes were prepared from healthy volunteers. MSCs were expanded in vitro in Mesencult serum free media. MSCs were cocultured with one-way MLRs and bidirectional MLRs, responder cells were labeled with carboxyfluorescein diacetate- succinimidyl ester (CFSE) in bidirectional MLRs. Cell Counting Kit-8(CCK-8)kit was used in cell proliferation detection, T-cell subsets were analyzed by flow cytometry (FCM). The results showed that MSCs were positive for CD105, CD73, CD13, CD90 and were negative for hematopoietic cell markers. In one-way MLRs, MSCs down-regulated alloantigen-induced lymphocyte expansion in a dose-dependent and MHC-independend manner. In two-way MLRs, MSCs suppressed proliferation of CFSE positive cells. T cell subsets were changed: Th2 and Tc2 were down-regulated. Th2 was reduced from 1.70% to 0.65%, and Tc2 reduced from 1.10% to 0.47%, while Th1 and Tc1 were unaffected. T cells that became CD69+, which was an early activation marker, were significantly up-regulated from 7.14% to 26.12% and CD4+CD25+T regulatory cells (CD4+CD25+Tr) were up-regulated from 4.04% to 6.19%, which indicating that suppression did not interfere with activation phase of T cells and might be mediated by CD4+CD25+Tr partly. We conclede that MSCs down-regulated alloantigen-induced lymphocyte expansion. The immunosupressive effect might involve in post-activation phase of T cells. CD4+CD25+Tr might contribute to the suppressory activity of MSCs.

Long-Term Outcome After Matched Allogeneic Hematopoietic Stem Cell Transplantation for Fanconi Anemia On Behalf of the FA Committee of the Severe Aplastic Anemia Working Party (SAA WP) and the Pediatric Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 325-325
Author(s):  
Régis Peffault de Latour ◽  
Raphael Porcher ◽  
Jean-Hugues Dalle ◽  
Mahmoud Aljurf ◽  
Elisabeth T Korthof ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cells ◽  
Bone Marrow ◽  
Clonal Evolution ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Working Party ◽  
Secondary Malignancies ◽  
Hematopoietic Stem

Abstract Abstract 325 Background: Fanconi anemia (FA) is a rare, genetically and phenotypically heterogeneous inherited disorder. The natural history of FA is characterized by progressive bone marrow failure (BMF) and an increased risk for development of malignancies. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is considered the treatment of choice for FA patients with BMF or clonal evolution (acute myeloid leukemia or MDS). Most deaths related to HSCT occur within the first year after HSCT. Risk factors for the development of malignancies after HSCT are still incompletely defined in patients with FA. Our objectives were to evaluate risk factors for late mortality and secondary malignancies in 1-year survivors in the largest cohort of FA patients post-HSCT ever studied, so far. Patients and methods: Patients with FA reported to the European Blood and Marrow Transplant (EBMT) Group alive 1 year after a matched allogeneic HSCT were reviewed. Donor and recipient were matched if HLA A and B were identical at the generic level and HLA DRB1 at the allelic level. Cord blood as source of stem cells was excluded because of a few number of FA patients with very long-term follow-up (FU). Data was analyzed using proportional hazards and proportional cause-specific hazards models. Results: Between May 1972 and January 2009, 789 patients with FA who underwent first SCT were reported to the EBMT registry. 509 patients were alive 1 year post-HSCT and were included in the present study. 273 patients were male. Median age at HSCT was 9 years (range, 10 months to 44 years). The majority (77%) of patients had received stem cells from a related donor and bone marrow (80%) was the main source of stem cells. Irradiation was used as part of the conditioning regimen in 27% of the cohort, while fludarabine-based regimen was used in 29%. T-cell depletion (ex vivo and in vivo) was used in 41%. In January 2010, 15% (n=74) of the patients had died. Median age at death was 19 years. With a median FU of 6 years (1 to 28 years), the probability for survival after HSCT was 49% at 20 years (95%CI 38–65). The main causes of death were secondary malignancies in 52% of cases and treatment related mortality in 21%. Solid tumor represented 89% of the secondary malignancies. Cumulative incidence of death and secondary cancer are presented in Figure 1. A worse survival was observed in patients transplanted before year 2000 (Hazard ratio - HR: 2.24; 95%CI 1.06–4.71; p=0.034), in those transplanted because of clonal evolution (acute myeloid leukemia or MDS) (HR: 3.88; 95%CI 2.03–7.41; p<0.0001), in patients older than 10 years at SCT (HR: 2.00; 95%CI 1.26–3.18; p<0.004), and in patients transplanted more than a year after FA diagnosis (HR: 1.98; 95%CI 1.10–3.54; p=0.02). Without taking into account transplant period, HSCT after the age of 10 (HR 1.88 [1.17 to 3.03], P=0.009), clonal evolution before HSCT (HR 3.31 [1.72 to 6.39], P=0.0004) and previous chronic GVHD (HR 2.72 [1.65 to 4.46], P<0.0001) were associated with decreased survival. After adjustment for these factors, patients transplanted before 2000 still showed a worse survival (HR 2.09 [0.99 to 4.41], P=0.052). Using occurrence of a secondary malignancy as a time-dependent covariate, the hazard of death after this event was extremely high (HR 17.3 [9.70 to 30.7], P<0.0001). Independent risk factors for secondary malignancies included HSCT after the age of 10 (HR 2.89 [1.53 to 5.45], P=0.001), peripheral blood as source of stem cells (HR 3.06 [1.18 to 5.45], P=0.001) and previous chronic GVHD (HR 2.89 [1.53 to 5.45], P=0.001). Irradiation in the conditioning regimen and donor type (related versus unrelated) did not correlate with outcomes (both late survival and secondary malignancies). Conclusion: We found improved outcomes for patients with FA post-HSCT in recent years (>2000). However, long-term survival in FA patients after HSCT is still mainly affected by secondary malignancies (89% of solid tumors). Patients should be transplanted before the age of 10 with bone marrow as source of stem cells to try to avoid this complication. Moreover, chronic GvHD still emerges as a major cause for both secondary malignancies and mortality. Clearly improved method for prevention, early diagnosis and treatment of this complication are urgently needed. This study also highlights the need for very long-term FU for FA patients after HSCT. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

Direct Intra-Bone Injection of Unrelated Cord Blood Cells Overcomes the Problem of Delayed Engraftment and Improves the Feasibility of Hematopoietic Transplant in Adult Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 334-334 ◽  
Author(s):  
Adalberto Ibatici ◽  
AnnaMaria Raiola ◽  
Marina Podesta ◽  
Francesca Gualandi ◽  
Nadia Sessarego ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Significant Proportion ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Seeding Efficiency

Abstract Background. Cord blood transplants (CBT) are associated with delayed or failed engraftment in a significant proportion of patients (pts). Two of our previous observations suggested (i) that, in the animal model, direct intra-bone (i.b.) injection improves seeding efficiency and (ii) that the delayed engraftment was not related to an insufficient number of hematopoietic stem cells but rather to some difficulties to differentiate and maturate. Methods. Unrelated CB cells were selected for 29 consecutive pts (18 CB units were 4/6 HLA antigen matched, 10 were 5/6 and one 3/6 antigen matched). Median cell dose infused was 2.3 x10^7/kg (range 1.4 – 4.2). CB cells were concentrated in 4 syringes of 5 ml each and injected in the supero-posterior iliac crest (SPIC) under rapid general anesthesia (10 min. with propofol). Pts’ median age was 38 years (18–63); 25 had acute leukaemia (21 with refractory or relapsed disease and 4 high risk first remission leukemia); 2 chronic myeloid leukemia in advanced phase; 2 refractory Hodgkin’s disease. Most pts (n=24) were prepared with conventional conditioning regimen (TBI-cyclophosphamide). Results. The infusion of cells i.b. in SPIC (11 pts bilaterally; 18 pts monolaterally) was uneventful. Five pts are not evaluable because they died within 14 days from transplant. All pts surviving more than 14 days engrafted (100%). Median time for PMN (>0.5x10^9/l) and platelets (>20x10^9/l) engraftment was day +23 (14–40) and +38 (range 22–60) respectivelly. Four pts died of infection; one patient died of PTLD on day +140. Four patients relasped and 3 died of relapse. Fifteen out of 16 alive patients are in hematologic or molecular remission at a median follow up of 7.5 months (range 2–17). From day +30 full donor chimerism was documented in CD3, bone marrow cells and progenitor cells from both the injected and in non-injected SPIC; from day +30, CFC progenitors had already reached the lower values of the range of normal individuals in bilateral sites. These findings document the colonization of the hematopoietc system and the recovery of stem cell reservoir possibly due to an improvement of seeding efficiency. Only 3 pts (8%) experienced acute GvHD (2 grade II and 1 grade I); 4 pts. have moderate chronic GVHD. It is known that lymphocyte trafficking is one of the crucial factor in immunity. Two combined factors might contribute to the low incidence of acute GvHD: few of the transplanted T cells do not reach/circulate primarily in the lymphatic organs, where they would be immediately confronted with host antigen presenting cells as probably occurs after i.v. injection; injected T cells come immediately in contact with mesenchymal stem cells (MSC) and osteoblasts, known to be potent immunosuppressants. Conclusion. Direct intra-bone transplant of CB cells overcomes the problem of graft failure and is associated with reduced incidence of acute GvHD even when low numbers of HLA mismatched CB cells are transplanted. Nearly all patients searching for a CB unit were able to undergo CBT. This approach may change our policy of hemopoietic cell transplants.

Tacrolimus, Mini-Methotrexate and Mycophenolate Mofetil Is Safe and Effective as Acute Gvhd Prophylaxis for Non-Myeloablative Unrelated Donor Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1172-1172
Author(s):  
Sanghee Hong ◽  
Thomas Martin ◽  
Lloyd E. Damon ◽  
Lawrence Kaplan ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mycophenolate Mofetil ◽  
Liver Toxicity ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Disease Relapse ◽  
Eligibility Criteria ◽  
Gvhd Prophylaxis

Abstract Abstract 1172 Poster Board I-194 Introduction: Acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) cause significant morbidity and mortality following nonmyeloablative unrelated donor transplantation (NMUDT). The incidence of severe aGVHD (grades II-IV) following non-myeloablative transplant and standard GVHD prophylaxis (cyclosporine or tacrolimus plus mini-methotrexate or mycophenolate mofetil (i.e. two drug prophylaxis)) ranges between 40-70%. The incidence of cGVHD ranges between 50-70%. In order to decrease the incidence and severity of acute and chronic GVHD following NMUDT, consecutive patients were given triple prophylaxis therapy with tacrolimus (TAC), mycophenolate mofetil (MMF) and mini-methotrexate (MTX). In addition, patients were given anti-thymocyte globulin (ATG, thymoglobulin 10 mg/kg) as part of preparative therapy. Patients and Methods: Thirty-five consecutive patients meeting eligibility criteria for NMUDT were prospectively enrolled. The majority of patients had advanced disease; 9AML, 4 MDS, 2CML, 2MPD, 4 MM, 3CLL, 9 Lymphoma and 2 with aplastic anemia. The mean age was 53 years (26-68); 18 males and 17 females. Preparative therapy consisted of Fludarabine (F) 150mg/m2, Busulfan (Bu) 6.4mg/kg IV and ATG. All patients received stem cells from allele-matched unrelated donors; 9/10 (n= 13) or 10/10 (n= 22) at HLA A, B, C, DR and DQ. Thirteen patients received bone marrow and 22 patients received G-CSF mobilized blood stem cells. All patients received TAC (target 5-10 ug/L), MTX (5mg/m2 d1,3,6,11) and MMF (15mg/kg bid day 0 to 60) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results: The F/Bu/ATG non-myeloablative regimen was well tolerated. On average, patients experienced little or no mucositis (15% > grade 1), enteritis (3%> grade 1), skin toxicity (3% >grade 1) or liver toxicity (29% > grade 1). No VOD was seen. The median total bilirubin, alkaline phosphatase, ALT, and AST values post-transplant were 1.4 mg/dL, 153 U/L, 91 U/L and 77 U/L, respectively. The incidence of Grades II-IV and III-IV aGVHD were 26% and 6% respectively. No difference in aGVHD for 9/10 vs. 10/10 allele matched donors or those receiving stem cells vs. bone marrow was detected. The 100 day non-relapse mortality (NRM) was 11% (2 GVHD, 1 infection, 1 neurotoxicity). The incidence of cGVHD was 52% (80% extensive cGVHD). The majority of these patients required immunosuppression for >1 year. The 1 year NRM was 20% (2 GVHD, 2 infection, 2 neurotoxicity). Disease relapse was the most common cause of mortality; 37% overall and 17% within the first year of transplantation. The overall survival at 4 years is 41%. Conclusions: In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the GVHD prophylaxis regimen of TAC/MTX/MMF is safe and effective. The low incidence of aGVHD (26%) compares favorably to published results. Only two patients experienced Grade IV aGVHD within 100 days of transplantation. Chronic GVHD and disease relapse remain problematic. Better strategies to prevent and treat cGVHD and disease relapse are needed. Disclosures: No relevant conflicts of interest to declare.

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

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.

Tacrolimus and Sirolimus as GVHD Prophylaxis for HLA-MRD Allogeneic HCT Conditioned with 3 Regimens: Toxicity and Efficacy in 70 Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2867-2867
Author(s):  
Roberto Rodriguez ◽  
Joycelynne Palmer ◽  
Ryotaro Nakamura ◽  
Pablo Miguel Parker ◽  
Auayporn P. Nademanee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Gvhd ◽  
Opportunistic Infections ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Conditioning Regimens ◽  
Study Support

Abstract Based on encouraging phase 2 data, we are prospectively testing the combination of tacrolimus and sirolimus (tacro/siro) as GVHD prophylaxis in patients undergoing HLA-MRD HCT. Seventy patients evaluable for this report (>100 days post-HCT) were stratified according to preparative regimen as follows: Fludarabine/melphalan (38), FTBI/VP-16 (23), and Bu/Cy (9). Regimens were given through day -4; tacro/siro was started on day -3 and dosed as published (Cutler et al, BBMT 10 (5), 328–336, 2004). Median age was 50 years (range, 10–67). Diagnoses by regimen were flu/mel: AML (16), NHL (7), MPD (4), HD (4), MM (3), MDS (2), ALL (1), CLL (1); FTBI/VP-16: ALL (12), AML (10), NHL (1); and Bu/Cy: CML (5), MDS (3), AML (1). Stem cell source was PB (n=66) and bone marrow (n=4). Donor gender F:M was 34:36. Median CD34+ cell dose was 5.1 x 106/kg. Median time to neutrophil >500/ml was 15 days (range, 10–26); median day 30 bone marrow MNC chimerism was 100% (65–100%). CTC toxicities >3 were low (2 DAH, 1 ARDS, 1 IP, 1 mucositis); as expected, mucositis was more common with FTBI/VP-16; however, therapeutic sirolimus level was similarly achieved with all conditioning regimens (median level 6.5 ng/ml, range 2.1–61 in the FTBI/VP-16 arm). Opportunistic infections included CMV reactivation (6), Aspergillus pneumonia (2), candidemia (3) and parainfluenza pneumonia (1). Reversible TTP/HUS (IWG definition) was diagnosed in 14 patients (20%) and was more common with Bu/Cy (55%) than with FTBI/VP-16 (22%) or flu/mel (11%); median tacro and siro level in patients with TTP was 9.8 and 15 ng/ml, respectively. Six patients died before day 100 from relapse (2), DAH (2) and multi-organ failure MOF (2), for a day 100 non-relapse mortality of 6%. With a median follow-up of 6 months, 60 patients are alive and 10 patients have died from progressive disease (6), MOF (2) and DAH (2). Disease-free and overall survival at day 100 are 88% and 91%, and at 1 year are 72% and 75%, respectively, with no significant differences by regimen. Acute GVHD grade 2–4 and 3–4 was observed in 25 (36%) and 13 patients (19%), respectively; by conditioning regimen, grade 2–4 acute GVHD incidence was: flu/mel, 11/38 (29%); FTBI/VP-16, 9/23 (39%); and Bu/Cy, 5/9 (56%). A temporal relationship between GVHD and TTP could not be established, with some patients developing GVHD before and others after TTP. Chronic GVHD has been diagnosed in 17/45 evaluable patients. This study shows a low TRM when tacro/siro is given with 3 different conditioning regimens; adequate sirolimus levels can be achieved even in patients with significant mucositis; a high incidence of TTP in patients conditioned with Bu/Cy suggests synergistic endothelial toxicity with this combination. Acceptable rates of acute GVHD in this study support plans for a national phase 3 study comparing tacro/siro with tacro/methotrexate.

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