A Fludarabine Based Conditioning Regimen Associated with A Good Survival Following HLA Identical Sibling/Family Donor Transplants in Patients with Aplastic Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1194-1194 ◽  
Author(s):  
Mammen Chandy ◽  
Biju George ◽  
Vikram Mathews ◽  
Shashikant Apte ◽  
Velu Nair ◽  
...  
Keyword(s):  
Overall Survival ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Group ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Transplant Recipients ◽  
Primary Graft Failure ◽  
Family Donor

Abstract Abstract 1194 Poster Board I-216 Between January 2001 and June 2009, 120 patients with aplastic anemia underwent HLA identical sibling or family donor transplants using a combination of Fludarabine 150-180 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days as the conditioning regimen. Antithymocyte globulin (ATG) 10 mg/kg x 4 days in addition was used in 34 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine with low dose Methotrexate. Graft source included peripheral blood stem cells (PBSC) in 108 and G-CSF stimulated bone marrow in 12. Seventy patients (58.3%) were considered as high risk (presence of fever/infection at time of HSCT or >20 transfusions prior to HSCT or failed previous immunosuppressive therapy). There were 79 males and 41 females with a median age of 22 years (range: 2 - 51) including 36 children (age <15 years). PBSC was used in 108 while BM was the graft source in 12. The median cell dose infused was 7.1 × 108 MNC/Kg for PBSC (range: 1.9 – 19.6) and 4.9 × 108 TNC/Kg for bone marrow (range: 2.1 to 9.9). One hundred and thirteen patients (94.1%) engrafted while 2 (1.6%) had primary graft failure and 5 expired within the first 2 weeks due to infection. The median time to neutrophil engraftment (ANC > 0.5 × 109/L) was 12 days (range: 7-19) while platelet engraftment (Platelet count > 20 × 109/L) occurred at a median of 13 days (range: 0 -30). Acute GVHD occurred in 38 patients (33.3%) with grade III-IV GVHD in 13.1%. Acute GVHD was not significantly lower in patients where ATG was used in conditioning (21.8% with ATG vs 38.2% without ATG; p = 0.129). Nine patients (7.5%) had veno-occlusive disease of the liver while 11 (9.1%) had hemorrhagic cystitis; all responded well to supportive therapy. Bacterial infections were documented in 28% of transplant recipients while fungal infections (both probable and definite) occurred in 23%. CMV reactivation was seen in <5%. Chronic GVHD occurred in 32.6% of evaluable transplant recipients and was limited in a majority of patients. At a median follow up of 30 months (range: 1 – 105), 88 patients (73.3%) are alive and well. Causes of death included sepsis in 19, acute GVHD in 7, chronic GVHD in 4, primary graft failure in 1 and road traffic accident in 1 patient. The overall survival was similar among children (75%) and adults (72.6%). The overall survival was significantly lower in the high risk group (60%) compared to the low risk group (92%; p = 0.0001). Conclusion: A combination of fludarabine and cyclophosphamide as conditioning for aplastic anemia is associated with good engraftment, a very low incidence of primary or secondary graft failure and good overall survival. Toxicity is low but acute and chronic GVHD remain significant problems. Sepsis continues to remain the major cause of death in these patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia: (FluCAB-Prime)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Raheel Iftikhar ◽  
Qamar Un Nisa Chaudhry ◽  
Syed Kamran Mahmood ◽  
Tariq Ghafoor ◽  
Nighat Shahbaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Marrow Transplant ◽  
Free Survival ◽  
Post Transplant ◽  
Primary Graft Failure

Introduction Allogeneic hematopoietic stem cell transplant (HSCT) is the standard treatment for patients younger than 40 years with Severe and Very Severe Aplastic Anemia (AA) who have a Matched Related Donor (MRD). For patients lacking a MRD, treatment options include immunosuppressive therapy (IST), matched unrelated donor (MUD) or alternate donor (haploidentical/cord blood) transplant. Pakistan has a population of around 23 million but there is no donor registry for MUD transplants and horse antithyomcyte globulin (hATG) is not available. Over past decade, results of haploidentical transplants have improved remarkably with use of post-transplant cyclophosphamide. However, most of these protocols incorporate total body irradiation (TBI) to improve engraftment and reduce graft failure. TBI is not available in most of the transplant centres across Pakistan. We have developed a novel TBI free conditioning regimen (NCT03955601) for haploidentical HSCT in acquired AA patients lacking a MRD. Materials and Methods We conducted a prospective, single centre, interventional trial (NCT03955601) using novel TBI free conditioning at AF bone marrow transplant centre (AFBMTC)/ National institute of blood and marrow transplant (NIBMT) for patients with acquired severe and very severe AA. Between July 2018 and March 2020, a total of 10 patients received related haploidentical transplant.Study inclusion criteria was diagnosis of severe and very severe AA, patients of both genders, age 2-60 years, Karnofsky performance status&gt;70%. Exclusion criteria was presence of donor specific antibodies (DSA), inherited bone marrow failure syndrome, prior HSCT and severe sepsis. Conditioning regimen used was Fludarabine (Flu) 30 mg/m2 IV daily from day -7 to -3, Cyclophosphamide (Cy) 14.5 mg/kg IV daily on day -6 and -5 , rabbit Antithymocyte globulin (rATG) 5 mg /kg/day from day -6 to day-3; Busulphan (Bu) IV 3.2 mg per kg/day in 04 divided doses on day -3 and day-2, Granulocyte Colony Stimulating factor (GCSF) primed Bone marrow harvest (BMH) and/or PBSC graft on day 0 and day +1 respectively. Graft versus host disease (GVHD) prophylaxis used was post-transplant cyclophosphamide (PTCy) administered at a dose of 50mg/kg/day given daily on days +3 and +5 post-transplant, cyclosporine (CsA) from day +5 and mycophenolate mofetil (MMF) from day+5 to +35. Primary outcome measure was overall survival (OS) while secondary outcome measures included graft failure, treatment related mortality (TRM), disease free survival (DFS), GVHD free relapse free survival (GRFS), acute and chronic GVHD. Results: Ten patients were transplanted, 5 (50%) female and 5 (50%) male (table 1). Median age was 15.5 years (range 5-41 years). Median duration from diagnosis to transplant was 14 months (range 4-51 months). One patient received ATG prior to transplant. Median number of red cell concentrate (RCC) transfusions before transplant were 27 (8-90) and platelet transfusions 100(6-150). Median donor age was 23 years (10-41 years). Donor-recipient major ABO mismatch was present in 2(20%) while four (40%) had minor ABO mismatch. Primed bone marrow harvest (BMH) was used in 3(30%) while primed BM+PBSC was given in 7(70%) patients. Median CD34 dose given was 8 x 106/kg (range 5.1-16). Seven patients (70%) achieved sustained neutrophil engraftment. One patient had primary graft failure, one patient secondary graft failure at day 35 due to Cytomegalovirus infection and one patient (currently day +118) is having poor graft function. Acute skin GVHD stage-2 developed in 1 patient which settled with topical steroids. None of the patient developed chronic GVHD. Cytomegalovirus reactivation was documented in 8 (80%) patients. All donors and recipients were CMV seropositive pre-transplant. One patient (female, 20 years) had primary graft failure and died on day +31 with sepsis and multiorgan dysfunction syndrome (MODS). One patient (female, 14 years) had secondary graft failure due to CMV infection and died on day +44 with intracranial hemorrhage. Conditioning regimen was well tolerated without any treatment related morbidly and mortality. Median follow-up of study was 13 months (range 4-22 months). Overall survival of study cohort is 80%, DFS 70% and GRFS 70%. Conclusion: Our study shows that for countries lacking TBI, use of FluCAB-Prime protocol is feasible and is associated with low rates of acute and chronic GVHD. Disclosures No relevant conflicts of interest to declare.

National, Retrospective, Multi-Centre Comparison of Alemtuzumab- Versus ATG-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation for Aplastic Anemia: A Study From the British Society for Blood and Marrow Transplantation (BSBMT) (CTCR 09-03)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 52-52
Author(s):  
Judith C. W. Marsh ◽  
Rachel M Pearce ◽  
Mickey B Koh ◽  
Daniel Tang ◽  
ZiYi Lim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Aplastic Anemia ◽  
Median Time ◽  
Research Funding ◽  
Graft Failure ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Conditioning Regimens

Abstract Abstract 52 Background: The ideal conditioning regimen for HSCT in AA is one that achieves engraftment, absence of GVHD and minimal toxicity. Standard conditioning for young patients undergoing matched sibling donor (MSD) HSCT for AA is cyclophosphamide (CY) 200mg/kg and ATG as T-cell depletion (TCD), with ciclosporin (CSA) and methotrexate (MTX) as post graft immunosuppression. For patients who are > 30–40years old receiving MSD HSCT a fludarabine (FLUD)-based regimen with low dose CY (1200mg/m2) and ATG is commonly used. For unrelated donor (UD) HSCT, in Europe, a similar FLUD-based regimen with low dose CY and ATG is commonly used, with addition of low dose TBI (2Gy) for older patients. Long term survival for MSD HSCT is 80–90%, but only 50% for patients aged > 50 years. For UD HSCT, survival is around 75–80%. Chronic GVHD remains a problem, in 30–40% of MSD and up to 50% of UD HSCT. A recent retrospective study of 50 patients transplanted with Alemtuzumab instead of ATG, with CY (1200mg/m2), FLUD, and CSA alone as post graft immunosuppression, showed overall survival at 2 years was 95% for MSD and 83% for UD HCT and only two patients (4%) developed chronic GVHD. Patients: We analyzed data from 159 patients with acquired AA transplanted in the UK, who received either Alemtuzumab or ATG pre-transplant, as part of the conditioning for a first allograft. Patients who received their graft between 1999 and 2009 and had a minimum follow-up of 6months were included in this study. Median age was 20yr (range 1– 67) and M: F ratio was 86: 73. MSD HSCT was performed in 88 (55%) patients, UD HSCT in 65 (41%) including 2 mis-matched, and 6 patients were transplanted from other related donors of which 3 were mis-matched. Source of stem cells was BM in 108 (68%), PB in 39 (25%), BM+PB in 8 (5%) and cord blood in 4 (2%) patients. Conditioning was with Alemtuzumab in 103 (65%) and ATG in 55 (35%), and one patient had received both. CY +/− FLUD was used in 148 and FLUD +/− Melphalan in 11 patients, with addition of TBI in 11 (7%) patients. Median time from diagnosis to HSCT was 6 months (range 0.5–300). Results: Of 159 patients, 137 (86%) are alive at a median follow up of 3.3yr (range 3 months – 10.4 yr). Twenty two patients have died from the following causes of death (not mutually exclusive): infection (n = 15, 68%), GVHD (n = 6, 27%), multi-organ failure (n = 4), lymphoproliferative disorder (n = 1), relapse of breast cancer (n = 1) and one unknown. For all patients, the 1 yr, 5 yr and 10 yr overall survival (OS) were 89% (95% C.I. = 83–93%), 85% (78–90%) and 85% (78–90%), respectively. There was no difference in the 1 yr OS in relation to the method of TCD (Alemtuzumab 91% (84–95%) versus ATG 84% (71–91%), p = 0.1578). Graft failure was observed in 15 (9%) patients. Median time to neutrophil engraftment, defined as ANC > 0.5 × 109/l on first of 3 consecutive days, was 20 days (range 10–89) and platelet engraftment, defined as platelet count > 20 × 109/l on first of 3 consecutive days and no platelet transfusions 7 days prior, was 21 days (range 0–275). Chimerism was full donor in 70 (46%), mixed in 41 (27%), not performed in 37 (24%) and unknown or not evaluable in 2 patients. Acute GVHD grade I-II occurred in 35 (25%) evaluable patients, grade III-IV in 8 (6%). Chronic GVHD was seen in 23 (16%) evaluable patients, limited in 14, extensive in 6 and unknown in 3. Conclusions: From this national study, we report excellent outcomes for HSCT in SAA during the last decade. There was a trend, not significant, for better survival with Alemtuzumab instead of ATG in the conditioning regimen. This is the first reported study comparing outcomes after Alemtuzumab versus ATG based conditioning regimens for SAA. Further analyses, comparing graft failure, acute and chronic GVHD, probability of survival and event - free survival, and patient-related, disease-related and treatment related variables, between Alemtuzumab and ATG-based conditioning regimens, are currently in progress. Disclosures: Marsh: Genzyme: Research Funding. Off Label Use: ATG used as part of conditioning regimen for HSCT in aplastic anaemia. Alemtuzumab used as part of the conditioning regimen for HSCT in aplastic anemia. Pagliuca:Genzyme: Speakers Bureau. Mufti:Celgene: Consultancy, Research Funding.

Unrelated Allogeneic Stem Cell Transplantation for Severe Acquired Aplastic Anemia: Has Outcome Improved?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3105-3105 ◽  
Author(s):  
Sebastien Maury ◽  
M.-Lorraine Balere-Appert ◽  
Zina Chir ◽  
J.-Michel Boiron ◽  
Claire Galambrun ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Young Patients ◽  
Unrelated Donor ◽  
Hla Matching ◽  
The Impact

Abstract We aimed to determine whether outcome of HSCT from an unrelated donor has improved over time for patients with severe acquired aplastic anemia (SAA) and, if so, to determine whether improvement resulted from changes in patient selection, changes in transplantation technique, or both. We thus analyzed the outcome of 89 patients (median age 17 years, range 0–52) who received such transplantations between 1989 and 2004. We compared two cohorts of patients transplanted within two successive time-periods (1989–1998 and 1999–2004) associated with probabilities (± 95% confidence interval) of 5-year survival significantly different: 29% ± 7% and 50% ± 7%, respectively (P<.01, Figure 1). Significant differences between the two cohorts concerned transplant-related, but not patient- and disease-related variables: the use of ATG and of fludarabine within conditioning and HLA matching at the allelic level for the 10 HLA-A, -B, -C, -DRB1 and -DQB1 loci (P=.0004) were more frequent in the recent 1999–2004 period. In multivariate analysis, the only 2 factors influencing survival were HLA allelic matching (P<.01) and younger age of recipient (<17 years, P<.0001). Of note, the impact of HLA matching disappeared in multivariate analysis when it was considered at the antigenic level for HLA-A, -B and -DR antigens, which underlines the importance of considering HLA matching at the allelic rather than the generic level for these transplantations. Survival reached 78% ± 11% at 5-year for the younger patients fully HLA-matched (n=14), which can be compared with survivals obtained for HLA-identical sibling transplants in similar young patients. Cumulative incidences of graft failure, grade II–IV or grade III–IV acute GVHD, and chronic GVHD were: 14% ± 4 % at 2 years, 50% ± 5 % and 24% ± 4 % at 100 days, and 28% ± 5 % at 2 years after HSCT (limited: 17% ± 4 %, extensive: 11% ± 3 %), respectively. In a competing risk analysis, allelic HLA matching - particularly incorporating HLA-C but not -DQB1 matching - but also a high cell-dose injected (> 2,6.108/kg nucleated cells, the median value of the cohort) and the use of fludarabine and/or ATG in the conditioning regimen were found as protective against graft failure and acute GVHD, respectively. Our results suggest that survival after unrelated transplantation for SAA has improved over the past 15 years, due to a better HLA matching at the allelic level for both HLA class I and class II antigens, but also to other transplant-related factors. Figure 1 Figure 1.

Outcomes of 40 Adult Patients after Double Cord Blood Transplantation Using a Reduced Intensity Chemotherapy Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 605-605
Author(s):  
Karen K. Ballen ◽  
Corey Cutler ◽  
Thomas R. Spitzer ◽  
Beow Yeap ◽  
Steve McAfee ◽  
...  
Keyword(s):  
Cord Blood ◽  
Total Dose ◽  
Aplastic Anemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cord Blood Unit ◽  
Reduced Intensity ◽  
Related Mortality

Abstract Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit transplantation in adults is associated with high transplant related mortality, mostly due to infection. In this study, we used a reduced intensity conditioning regimen followed by infusion of two partially matched cord blood units. The conditioning regimen was fludarabine 30mg/m2/day Days -8,-7,-6,-5,-4,-3 (total dose 180mg/m2), melphalan 100mg/m2/day Day -2, and rabbit antithymocyte globulin (thymoglobulin) 1.5 mg/kg/day Days -7,-5,-3,-1 (total dose 6.0 mg/kg). Cord blood units were a 4/6 or better HLA A, B, DR match with each other and with the patient, and contained a minimum combined pre-freeze cell dose of 3.7 x 107NC/kg. GVHD prophylaxis was cyclosporine and mycophenolate mofetil, for the first 21 patients, and tacrolimus and sirolimus for the second cohort of 19 patients. Forty patients, 22 males (55%) and 18 females (45%) with a median age of 48 years (range 19–64 years) were treated. The diagnoses were AML (n=14), ALL (n=1), NHL (n=10), CLL (n=2), MDS (n=5), Hodgkins Disease (n=5), aplastic anemia (n=2), and chronic myelogeneous leukemia (n=1). Thirty-five patients have greater than 100 days of follow-up and are included in this analysis. The cell doses infused were a median of 4.0 x 10 7NC/kg (range 3.0–6.7 x 107) and 1.9 x 10 5 CD34+ cells/kg (range 0.5–10.0 x 105). Two patients (both with MDS complicating aplastic anemia) experienced primary graft failure, and received second cord blood transplants using a different conditioning regimen. Among the remaining patients, the median time to an absolute neutrophil count &gt;500 was 21 days (range 14–70 days). There were two late graft failures. The median time to a platelet count &gt;20,000 unsupported was 43 days (range 21–125 days). The incidence of acute GVHD Grades II–IV was 40% for the patients receiving cyclosporine/MMF and 29% for patients receiving tacrolimus and sirolimus. There were no deaths from acute GVHD in the cyclosporine/MMF group and one death from acute GVHD in the tacrolimus/sirolimus group. Seven patients (20%) developed chronic GVHD. The 100-day transplant related mortality was 14%. Two deaths were related to Epstein Barr virus related lymphoproliferative disorder, and the other deaths were due to a CNS bleed, staphylococcal sepsis, and respiratory failure due to aspergillus infection. Two patients have relapsed and one has progressive disease. With a median follow up of 14 months (range 3–31 months) the overall survival is 74% and the disease-free survival is 67%. Chimerism analysis showed predominance of one cord by Day +100. In 71% of patients, the first cord blood unit infused predominated. In conclusion, engraftment of adult patients appears to be acceptable using double cord blood products and reduced intensity, non TBI conditioning regimen; the risk of serious acute and chronic GVHD is low, survival is excellent in a selected group of patients and relapse rate is low, suggesting preservation of graft versus leukemia effect despite the low T cell dose.

A Randomized, Controlled Trial of Graft-Versus-Host Disease (GVHD) Prophylaxis Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate: Analysis of GVHD, Relapse and Survival.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2235-2235 ◽  
Author(s):  
Janelle Perkins ◽  
Melissa Alsina ◽  
Claudio Anasetti ◽  
Ernesto Ayala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Controlled Trial ◽  
Mycophenolate Mofetil ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Controlled Trial ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Randomized Controlled ◽  
Gvhd Prophylaxis

Abstract The selective IMPDH inhibitor, mycophenolate mofetil (MMF), has entered the clinic with the promise to provide potent immune suppression without the side effects of methotrexate (MTX) or other broad-spectrum immunosuppressants. The use of MMF in the prevention of GVHD after hematopoietic cell transplantation (HCT) has been increasing worldwide, but only one small controlled study comparing cyclosporine + MMF to cyclosporine + MTX has been conducted to date. We compared GVHD prophylaxis with tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF) in a single institution, randomized, controlled trial. Eligible patients were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA-A, B, C, DRB1 and DQB1 matched donors, and have no contraindications to the use of TAC, MTX, or MMF. Randomization was stratified based on conditioning regimen intensity. Ninety-two pts were randomized, 45 to TAC/MMF and 47 to TAC/MTX and were all included in the intent-to-treat (ITT) analysis. Two pts were not transplanted and one pt withdrew consent prior to transplant. These pts were all randomized to TAC/MMF and excluded in the modified ITT (MITT) analysis. Pts received TAC 0.03 mg/kg/24hr as a continuous IV infusion beginning day -3 with doses adjusted to maintain whole blood levels of 5–15ng/ml. Pts were converted to PO therapy as tolerated and tapered after 6 months in the absence of GVHD. MTX was given IV at doses of 15mg/m2 day +1 and 10mg/m2 on days +3, +6 and +11. In pts with renal insufficiency, MTX doses were adjusted per pts’ pretransplant creatinine clearance. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO as tolerated and continued for 12 months. Acute GVHD was graded weekly by Thomas’ criteria, modified per ASBMT consensus criteria; chronic GVHD was scored monthly based on NIH consensus criteria. The groups were balanced with respect to age, diagnosis, disease risk, recipient/donor CMV status, conditioning regimen, donor type and relation. The incidences of grade 2–4 and 3–4 acute GVHD were 79% and 4% in the TAC/MTX arm and 79% and 17% in the TAC/MMF arm (p=1.0 and 0.08, respectively). The incidence of moderate or severe chronic GVHD was 55% in the TAC/MTX arm and 59% in the TAC/MMF arm (p=0.91). By ITT analysis, the cumulative incidence of non-relapse mortality suggested an early difference in favor of TAC/MTX, but at 2 years it was 28% for TAC/MTX arm compared to 32% for the TAC/MMF arm (p=0.41; MITT p=0.33). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% (ITT; 16% MITT) for the TAC/MMF pts (p=0.06; p=0.04 MITT). Overall survival was similar between groups in both the ITT (p=0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year) and MITT analysis (p=0.75; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing acute or chronic GVHD and may perhaps be less effective in preventing more severe forms of acute GVHD. Given the direction of effect we observed in severe acute GVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse of malignancy was more frequent after MTX than MMF, apparently in relation to the drug interference with the graft-vs.-leukemia effect. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.

Fludarabine, Cyclophosphamide, Anti-Thymocyte Globulin, with or without “ 2Gy TBI, for Alternative Donor Transplants in Acquired Aplastic Anemia (SAA): A Report From the EBMT-SAA Working Party.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1207-1207
Author(s):  
Andrea Bacigalupo ◽  
Gerard Socie' ◽  
Edoardo Lanino ◽  
Arcangelo Prete ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Graft Failure ◽  
Causes Of Death ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Working Party ◽  
Lymphoproliferative Disease ◽  
Actuarial Survival ◽  
Alternative Donor ◽  
Family Donor

Abstract Abstract 1207 Poster Board I-229 Patients. Data from 100 patients with acquired severe aplastic anemia (SAA) undergoing an alternative donor transplant, were analyzed. Patients were prepared with a combination of fludarabine (30 mg/m 2×4), cyclophosphamide (300 mg/m 2×4), antithymocyte globulin (3.75 mg/lgx4) (FCA) (n=52, median age 13 years), or FCA supplemented with low dose (2 Gy) total body irradiation (FCA-TBI), but with a lower dose of ATG (total 7.5 mg/kg) (n=48, median age 27 years). The donor was unrelated (n?87) or a one antigen mismatched family donor (n=13). GvHD. Acute graft versus host disease (GvHD) grade III-IV was seen in 13% and 7% ; extensive chronic GvHD was recorded in 1 FCA patient and in 4 patients receiving FCA-TBI. Graft failure. Rejection/graft failure was seen in 17 patients, equally distributed in the two groups: 9/17 patients survive long term, 3 with autologous recovery, and 6 after a second transplant.. As to predictors of graft failure, patients with a longer interval from diagnosis to transplant (> 2 years) had a trend for a higher risk of GF (22%) as compared to patients grafted <1 year (12%) or between 1-2 years (14%) (p=0.3). Chimerism data: within 100 days from BMT the average donor chimerism was 93% and 84% in the FCA and FCA-TBI regimens. Beyond day +100 the average was 89% and 80%. Survival. With a median follow up of 1204 days, the overall actuarial 5 year survival is 75%, respectively 73% for the FCA and 79% for the FCA-TBI. The interval diagnosis-transplant (<1 year, 1-2 years and >2 years) was a significant predictor of survival in univariate and multivariate analysis : actuarial survival was 87%, 86%, 58% respectively (p=0.004). Older age and HLA mismatch was a significant predictor of survival in the FCA group, but not in the FCA-TBI patients. Causes of death. Twentythree patients died, 13/52 in the FCA group and 10/48 in the FCA-TBI group (p=ns): major causes of death were rejection (n=7), post-transplant-lymphoproliferative-disease (n=4) and GvHD (n=4). Conclusions. This study confirms a significantly improved outcome of alternative donor transplants in SAA patients, and suggests that best results are achieved if the transplant is performed within 2 years from diagnosis. FCA seems appropriate only for children with well matched donors, whereas FCA-TBI is preferable in adults, especially when the donor is HLA mismatched. Complications such as rejection and EBV reactivation need to be addressed with modifications of the transplant regimens. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Transplant In Children with Severe Aplastic Anemia – Excellent Outcomes with the Use of a Fludarabine Based Conditioning Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3519-3519
Author(s):  
Biju George ◽  
Vikram Mathews ◽  
Auro Viswabandhya ◽  
Aby Abraham ◽  
Lakshmi M Kavitha ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Antithymocyte Globulin ◽  
Conditioning Regimen ◽  
Allogeneic Transplant ◽  
Graft Versus Host ◽  
Primary Graft Failure

Abstract Abstract 3519 There is limited data on the use of fludarabine based conditioning regimen in children with aplastic anemia though these regimens are increasingly being used in developing countries. Thirty four children (aged < 15 years) including 21 males and 13 females with a median age of 8 years (range: 2–15) underwent allogeneic transplant (HSCT) at our centre between 2004 and 2010 using HLA identical sibling or family donors. The median time from diagnosis to HSCT was 5 months (range: 2–96) and the median number of transfusions prior to HSCT was 10 (range: 3– 64). Five patients (14.7%) had failed treatment with Antithymocyte globulin (ATG) and 4 (11.4%) had an intracranial bleed in the 3 months prior to HSCT. Conditioning regimen consisted of Fludarabine 150 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days. Antithymocyte globulin (ATGAM) [10 mg/kg/day for 4 days] was used in 9 patients. Graft source consisted of either bone marrow [9 patients] or G-CSF stimulated peripheral blood stem cells (PBSC)[25 patients]. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and short course methotrexate. The median cell doses infused were 4.9 × 108 TNC/Kg for bone marrow and 8.5 × 108 MNC/Kg for PBSC. Thirty patients (88.2%) engrafted while 2 (5.8%) had primary graft failure. Two children died on Day 0 and Day +5 respectively due to infection. The median time to neutrophil engraftment was 14 days (range: 8–19) while the median time to platelet engraftment was 12 days (range: 7–24). Two patients (5.8%) developed veno-occlusive disease (VOD) of the liver while none developed hemorrhagic cystitis. Acute graft versus host disease (GVHD) was seen in 7 patients (23.3%) and was grade 1–2 in all patients. Chronic GVHD was seen in 31% of patients who could be evaluated and was limited in nature in a majority of patients. Of the 2 patients with primary graft failure, one was rescued with a second transplant while the second expired due to fungal pneumonia. The Day 100 mortality was 14.1%. Secondary graft failure was seen in 1 patient but was rescued with a second transplant using the same donor. At a median follow up of 30 months (range: 1 –67), 29 patients are alive for a 3 year OS of 85.1%. Fludarabine based conditioning regimens are associated with favorable outcomes in Indian children with aplastic anemia. These results are superior to an OS of 37% with the use of ATG and Cyclosporine in a similar population (George B et al PHO March 2010). Disclosures: No relevant conflicts of interest to declare.

Absence of Graft Failure and Excellent Long Term Survival Following Fludarabine-Based Reduced Intensity Hematopoietic Stem Cell Transplantation In Heavily Transfused Patients with ATG-Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 517-517
Author(s):  
Jeremy Pantin ◽  
Xin Tian ◽  
Nancy Geller ◽  
Catalina Ramos ◽  
Lisa Cook ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Graft Rejection ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Bone Marrow Failure ◽  
Chronic Gvhd ◽  
Abo Incompatibility ◽  
Bone Marrow Failure Syndromes

Abstract Abstract 517 Heavily transfused and alloimmunized patients with bone marrow failure syndromes including aplastic anemia have an increased risk of graft rejection following conventional allogeneic bone marrow transplantation. Results from pilot trials suggest the addition of fludarabine to the conditioning regimen reduces the risk of graft rejection in patients at high risk for this complication. Here we report the results of a fludarabine-based transplant approach in 56 patients with severe aplastic anemia (SAA) or other bone marrow failure syndromes (SAA n=31, MDS-RA n=6, PNH n=16, PRCA n=2, DBA n=1) who were transplanted from May 1999 to November 2008 at the NHLBI. Forty one percent of patients were found to be alloimmunized (median 82% PRA) prior to transplantation as a consequence of prior transfusions. Seventy three percent of patients had received antibody-based immunesuppressive therapy at a median of 303 days (range 21 to 2588) prior to transplantation (horse-ATG n=34, rabbit-ATG n=5, alemtuzumab n=1 and daclizumab n=1). Conditioning with fludarabine (25 mg/m2 × 5 days), ATG (40mg/kg × 4 days) and cyclophosphamide (60mg/kg × 2 days) was followed by infusion of an un-manipulated G-CSF mobilized allograft from an HLA matched (n=52) or single antigen mismatched (n=4) relative. GVHD prophylaxis consisted of cyclosporine (CSA) either alone (n=2) or combined with mycophenolate mofetil (n=10) or mini-dose methotrexate (n=44). The median CD34+ cell dose was 6.6 × 106 cells/kg (range 1.7 to 21.1 × 106 cells/kg) and the median CD3+ cell dose was 2.6 × 108 cells/kg (range 0.5 to 6.9 x108 cells/kg). Nearly half (46 %) of patients received an ABO incompatible allograft (major mismatch n=15; minor mismatch n=11). Despite a high prevalence of pre-transplant alloimmunization, graft rejection and/or graft failure did not occur, with all patients achieving sustained donor engraftment in both myeloid and T-cell lineages. The median time to achievement of full donor (>= 95%) myeloid and T-cell chimerism was 15 and 30 days respectively. Neutrophil and platelet recovery occurred at a median 15 (range 6 to 24) and 12 (range 5 to 168) days respectively. Major ABO incompatibility was associated with delayed donor erythropoiesis; reticulocyte recovery (> 60 K/μ L on two occasions) occurred at a median 17 days in those without major ABO incompatibility and 42 days in the recipients of a major ABO mismatched graft, where clearance anti-donor isohemagglutinins was delayed a median 171 days following transplantation. CMV reactivation occurred in 31/50 (62%) patients at risk although no patients died from CMV related mortality. With a median follow-up of 4.5 years (range 1.8–11 years) in surviving patients, overall survival was 87.1%. There were 5 treatment related deaths with two attributable to steroid refractory acute GVHD and one attributable to extensive chronic GVHD. The cumulative incidence of Grade II-IV, III-IV and steroid refractory acute GVHD was 51.8%, 30.4% and 21.4% respectively. The cumulative incidence of chronic GVHD was 72% (23.2% limited and 48.9% extensive), with 42.5% who developed cGVHD having resolution of symptoms allowing discontinuation of systemic immunosuppressive therapy. Conclusion: Fludarabine-based allogeneic peripheral blood stem cell transplantation achieves excellent donor engraftment and long-term disease free survival in heavily transfused and alloimmunized patients with ATG refractory SAA and other nonmalignant hematological disorders associated with bone marrow failure. Efforts to reduce the high incidence of GVHD associated with this approach without increasing the risk of graft failure by manipulating the cellular content of the allograft are currently being explored. Disclosures: No relevant conflicts of interest to declare.

Outcome of Alternative Donor Transplantation for Severe Aplastic Anemia Can Be Comparable to Outcome with Matched Related Donors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2052-2052
Author(s):  
Alana A. Kennedy-Nasser ◽  
Kathryn Leung ◽  
Steven Gottschalk ◽  
Dean A. Lee ◽  
George Carrum ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Aplastic Anemia ◽  
Pediatric Patients ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Severe Aplastic Anemia ◽  
Unrelated Donor ◽  
Alternative Donor

Abstract Matched related donor (MRD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia; however, only 25% of patients will have an HLA-identical sibling. Alternative donor transplants may be an option for these patients, but such therapies have been associated with greater incidences of graft failures and graft-versus-host disease (GVHD). We retrospectively analyzed 32 pediatric patients who have undergone either bone marrow or peripheral blood stem cell transplant for severe aplastic anemia at our institution from April 1997 to April 2005. These patients had a total of 34 transplants. One patient had a MRD transplant followed by a matched unrelated donor (MUD) transplant eight years later, while another patient had a HLA-mismatched unrelated donor (MMUD) transplant followed by a transplant from a haplo-identical parent. Of the remaining 30 patients, 12 received MRD transplants, whereas 18 patients received alternative donor transplants - 11 MUD, 3 haplo-identical donors, and 4 MMUD. The median age at transplant was 9 years (range 1.5 to 18.4 yrs). All patients who received alternative donor transplants had previously failed therapy, including antithymocyte globulin (ATG) and cyclosporine. For MRD transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days and ATG 30 mg/kg x 3 days. For alternative donor transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days, Campath 3–10 mg x 4 days (dependent upon patient’s weight) or ATG 30 mg/kg x 3 days, and TBI (single fraction 200 cGy for MUD; two fractions 200 cGy for MMUD). Alternative donor recipients who received ATG in their preparative regimen were transplanted between December 1997 and March 2001 (n=9), whereas patients who received Campath were treated between November 2001 and April 2005 (n=11). GVHD prophylaxis was either FK506 or cyclosporine +/− mini-methotrexate. The overall survival for MRD patients was 91.7% versus 80% for alternative donor patients at a median follow-up of 47 months (range 3 to 100 months). Of the 32 patients, there were 5 deaths: pulmonary failure with extensive, chronic GVHD (n=1); poor graft function with infection (n=1); and infection (n=3). For patients receiving alternative donor transplants, the overall survival for the Campath group was 81.8% vs. 77.8% in the ATG group. None of the Campath patients developed extensive, chronic GVHD compared to 3/9 ATG patients. In conclusion, alternative donor transplantation using Campath or ATG in the preparatory regimens can establish donor engraftment and offers a curative therapy for pediatric severe aplastic anemia patients with survival similar to that of patients receiving matched sibling transplants. Although follow-up is shorter, Campath may be associated with a reduced incidence of extensive, chronic GVHD and further investigation is warranted.

Risks and Benefits of Unrelated Donor Peripheral Blood Progenitor Cells (PBPC) in Children and Adolescents with Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 977-977
Author(s):  
Mary Eapen ◽  
Olle Ringden ◽  
Franco Locatelli ◽  
Haydar Frangoul ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Free Survival ◽  
Grade 3

Abstract Although PBPC is an acceptable alternative to bone marrow (BM) for transplanting children with leukemia, there are no published studies describing outcomes after unrelated donor PBPC transplants. We compared the results of 385 unrelated donor BM transplants that were allele-matched (n=186) or mismatched (n=199) at HLA A, B, C, DRB1 and 110 PBPC transplants that were matched (n=60) or mismatched (n=50) at HLA A, B, C, DRB1 in patients younger than 18 years of age. All patients had acute leukemia and were transplanted in 2000–2006. Median follow up of surviving patients was 2 years in both treatment groups. There were no significant differences in patient and disease characteristics, transplant conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and donor-recipient HLA disparity by graft type. Though the early probability of neutrophil recovery (³500/ul) was faster after transplantation of PBPC (31% vs. 10% at day-14, p<0.001) the probability of recovery by day-28 was similar after PBPC and BM transplants (94% and 91%, p=0.391). In contrast, platelet recovery (³20,000/ul) was better after PBPC transplants (86% vs. 76% at day-60, p=0.022). Risks of grade 2–4 (hazard ratio [HR] 1.24, p=0.147) and grade 3–4 (HR 1.07, p=0.785) acute GVHD were similar after PBPC and BM transplants. The risk of developing chronic GVHD was significantly greater after PBPC transplants compared to BM transplants (HR 2.36, p<0.001). After adjusting for disease status, donor-recipient HLA disparity and age, the of transplant-related mortality (TRM) relapse, treatment failure (relapse or death from any cause; inverse of leukemia-free survival and overall survival were similar after PBPC and BM transplants. The Table below shows the day-100 probability of grade 2–4 acute GVHD and the 3-year probabilities of chronic GVHD, TRM, relapse, leukemiafree survival and overall survival by graft type. These results differ from transplantation of PBPC from HLA-matched siblings where higher chronic GVHD translated into higher TRM and lower LFS. It remains to be seen whether the observed higher chronic GVHD after PBPC transplants will eventually result in the long term in higher mortality or fewer leukemia recurrence. PBPC BM Grade 2–4 acute GVHD 53% 49% Chronic GVHD 58% 33% TRM 20% 24% Relapse 34% 28% Leukemia-free survival 46% 48% Overall survival 49% 49%

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