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.

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.

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>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.

scholarly journals HLA-Matched Related Donor Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Conditioned with a Combination of Cyclophosphamide and Fludarabine : A Study on Behalf of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4391-4391 ◽  
Author(s):  
Lina Benajiba ◽  
Clementine Salvado ◽  
Jean-Hugues Dalle ◽  
Charlotte Jubert ◽  
Claire Galambrun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
French Society ◽  
Cell Therapies ◽  
Related Donor ◽  
Grade 3

Abstract Background. Fanconi anemia (FA) is a rare, phenotypically heterogeneous, inherited disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF) and a predisposition to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is the only curative option for FA patients. However, finding the best conditioning regimen is still challenging for clinicians. To reduce toxicities, we used progressively lower doses of cyclophosphamide (CY) for conditioning through non-irradiation based regimens. A reduced conditioning regimen based on CY 60mg/kg alone was proposed by Bomfim et al (BBMT, 2007). Survival rates were excellent but some patients experienced primary (n=1) or late (n=4) graft failure (11% of the patients). Mucositis was a major problem as 25 patients (60%) presented grade 3 / 4 mucositis. The rate of Chronic graft versus host disease (GvHD) was 29%. We hypothesized that tapering the dose of CY to 40mg/Kg and adding fludarabine (FLU) at 90mg/m2 might improve engraftment, decrease GvHD rates and eventually improve overall toxicity in FA patients transplanted with HLA matched siblings. Method. In 2004, the French reference centre for aplastic anemia and the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) recommended to use FLU 90mg/m2 (30mg/m2 days -4, -3, -2) and CY 40mg/kg (10mg/kg days -5, -4, -3, -2) for FA patients transplanted from matched family donor. Indication for transplantation was based on hematological complications (transfusions and/or infections). FA patients with morphologic signs of clonal evolution (myelodysplastic syndrome or acute myeloid leukemia) were excluded. All patients in France who received a first Allo-HSCT for FA from a matched related donor between October 2004 and January 2013 using this approach were analyzed (n=20). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centres. All patients received uromitexan. Ciclosporin A and micophenolate mofetil were used as GVHD prophylaxis. Six patients received an in vivo T cell depletion using antithymocyte globuline because of local policy at their centre. The guidelines were approved by Saint-Louis hospital ethical committee. Results. The median age at transplant was 9 years (range: 6-19). Stem cell source was bone marrow in 16 cases and matched related cord blood in the remaining transplants. None of the patients received peripheral blood stem cells. All patients had severe or moderate BMF (median hemoglobin: 8.9g/dl, median platelets: 31 103/ul, median neutrophils: 0.88 103/ul) at time of transplant. Two patients had chromosomal abnormalities (47,XX,i(1)(q10)[10]/48,idem,+8[3] and 47,XX,+der(1;3)(q10;q10)[14]/46,XX[6]); however, none of them developed overt myelodysplasia/leukemia before transplant. Patients belonged to complementation groups FANC-A (n=17) and FANC-G (n=2). Transplantation was performed within a median of 30 months from FA diagnosis (range: 7-143). A median of 3.8. 108 nucleated marrow cells were infused (range: 0,65-8,97). Within a median follow up of 2 years (range: 0.2-7.4), overall survival was 95% (figure 1). Only one patient with an atypical form of FA associated with severe immunodeficiency prior to transplant died subsequently due to uncontrolled cerebral toxoplasmosis. Engraftment rate was 100% with a median time to neutrophils and platelets recovery of 16.5 (11-28) and 15 (4-29) days, respectively. No grade 3/4 regimen related toxicity was observed and only 1 patient experienced mucositis (grade 2) using this conditioning regimen. Total acute GvHD grade 3 / 4 was only observed in 3 patients (15%) and chronic GvHD was extensive in 2 patients (10%) and limited in 3 patients (15%). Median alive patients karnofsky scored 100% (range 90 – 100%). No secondary malignancy was observed in our cohort so far. Conclusion. The combination of low dose CY (40mg/Kg) plus FLU (90mg/m2) in HLA-matched donor HSCT in patients with FA resulted in an excellent engraftment rate (100%) with no secondary graft failure, low rates of acute and chronic GvHD, low rates of regimen related toxicity, eventually resulting in an excellent overall survival (95% at 2 years). A longer follow-up in this cohort is needed to confirm such excellent results long-term, namely the continued absence of secondary cancer. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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 Conditioning Regimens and Outcomes after Allogeneic Hematopoietic Cell Transplant for Hyperinflammatory Inborn Errors of Immunity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Rebecca A. Marsh ◽  
Soyoung Kim ◽  
Kyle Hebert ◽  
Christopher C. Dvorak ◽  
Victor Aquino ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Graft Failure ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Event Free Survival ◽  
Inborn Errors ◽  
Free Survival ◽  
Inborn Errors Of Immunity ◽  
Conditioning Regimens

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged &lt;21 years with HLH (n=263) and CGD (n=102) were transplanted in the US between 2005-2018. Included are recipients of HLA-matched sibling (n=58; 16%) and HLA-matched (n=149; 41%) and mismatched unrelated (n=158; 43%) donor HCT. The analysis considered 3 conditioning regimen intensity groups: 1) fully myeloablative conditioning with busulfan (Bu; median dose 16 mg/kg [IQR 13-17]), cyclophosphamide (Cy) ± anti-thymocyte globulin (ATG) or alemtuzumab, n=142; 2) reduced intensity conditioning consisting of fludarabine (Flu), melphalan (Mel; 140mg/m2 [60%], 100 mg/m2 [40%]) ± alemtuzumab or ATG, n=131; and 3) reduced toxicity myeloablative conditioning consisting of either Flu, Mel (140mg/m2 [75%], 100 mg/m2 [25%]), and thiotepa (TT; 8 mg/kg or 10 mg/kg), or Flu, Bu (12mg/kg, IQR 9-15) ± alemtuzumab or ATG, n=92. The cumulative incidence rates of veno-occlusive disease (VOD) and infections were calculated. The probabilities of overall survival and event-free survival were calculated using Kaplan-Meier estimator. For event-free survival, an event was defined as the first occurrence of any of the following: primary graft failure, secondary graft failure, cellular product intervention for mixed chimerism, donor chimerism &lt;5%, second transplant, or death. The Fine and Gray method for acute and chronic GVHD and Cox regression analysis for event-free and overall survival were used to determine factors affecting outcomes. Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p&lt;0.001). The 6-month incidence of bacterial infection was higher after Bu/Cy (50%) and Flu/Mel (58%) compared to Flu/Mel/TT or Flu/Bu (43%) regimens (p=0.013). Viral infections were higher in Flu/Mel group (72%) compared to Bu/Cy (44%) and Flu/Mel/TT or Flu/Bu (56%), p&lt;0.001. There were no differences in overall survival (Figure 1A), but event-free survival (Figure 1B) was lowest with the Flu/Mel regimen, after adjusting for donor type (Table 1). Compared to matched sibling, survival was lower with matched (HR 2.41, p=0.05) and mismatched (HR 2.89, p=0.01) unrelated donor HCT. Chronic GVHD but not grade II-IV acute GVHD was lower with Flu/Mel regimen. Table 2 shows the results of multivariate analysis for HLH disorders and findings consistent with the main analysis. Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

scholarly journals Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-47
Author(s):  
Josu de la Fuente ◽  
Dirk-Jan Eikema ◽  
Paul Bosman ◽  
Robert F Wynn ◽  
Miguel Díaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Response To Treatment ◽  
Variable Response ◽  
Advisory Committees ◽  
Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment &gt;20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Outcome of Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Severe Aplastic Anemia (SAA) above the Age of 40 Years.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3019-3019
Author(s):  
Dario Sangiolo ◽  
Rainer Storb ◽  
Wendy Leisenring ◽  
George Georges
Keyword(s):  
Median Time ◽  
Immune Suppression ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
Conditioning Regimen ◽  
Term Survival ◽  
Allogeneic Hct ◽  
Number Of Patients ◽  
Clinical Records

Abstract Allogeneic HCT for SAA is definitive curative therapy for this otherwise fatal hematologic disease. For younger SAA patients, long-term survival of approximately 90% can be expected after HCT from HLA-identical siblings with cyclophosphamide/ antithymocyte globulin (CY/ATG) conditioning and post-grafting methotrexate/cyclosporine (MTX/CSP) immunosuppression. Most transplant center guidelines and many published reports restrict allogeneic HCT to SAA patients under the age of 40 years, due to concern of increased morbidity and mortality from HCT in older patients. We reviewed the clinical records of all 20 patients with a diagnosis of SAA who were treated with HCT from an HLA-identical sibling at the Fred Hutchinson Cancer Research Center from July 1988 to January 2006 and were above the age of 40 years at the time of HCT. The conditioning regimen consisted of CY/ATG for all but 2 patients who did not receive ATG. MTX and CSP were used as post grafting immunosuppression. The median age of the 10 men and 10 women was 47 (40–63) years. The median time from diagnosis to HCT was 2.7 (0.8–48.5) months. Ten patients had previously received immunosuppressive treatment and all 20 patients had received multiple red blood cell and platelet transfusions before HCT. The median follow-up of surviving patients was 86 (range, 17–194) months after HCT. One patient had graft rejection on day 28 and is alive and well following reconditioning and repeat marrow grafting from original donor. The incidence of acute grades II and III graft-versus-host-disease (GVHD) was 41% and 6%, respectively, the incidence of chronic GVHD (cGVHD) was 37% (6 patients). Overall survival was 70% (fig. 1). Three patients died before engraftment: from preexisting disseminated aspergillosis (n=1), congestive heart failure likely related to CY toxicity (n=1) and preexisting disseminated candidiasis (n=1) on days 2, 3 and 6, respectively. Three patients died from infections on days 83, 179 and 223; in the latter 2 cases, the infections were related to cGVHD and its treatment. The median time to discontinuation of immune suppression was 6 (range, 6–46) months (fig. 1). At last follow-up, 2 patients remain on immune suppression for treatment of cGVHD at 24 and 41 months, respectively. Three patients experienced avascular joint necroses 3, 6 and 9 years after HCT; they had cGVHD (n=2) and/or received extensive steroid treatment before HCT (n=2). Two patients developed superficial basal cell carcinoma at 5.5 and 15 years after HCT. Our data suggest that allogeneic HCT from sibling donor can be successfully extended to SAA patients older than 40 years. Although the number of patients are limited, survival after HLA-identical sibling HCT appears superior to published results of immune suppression therapy for patients >40 years of age. Pre-HCT cardiac screening is indicated to minimize the risk of conditioning related toxicity. Improved treatment to effectively treat or prevent cGVHD and associated infections remain important issues. Figure Figure

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.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4326-4326
Author(s):  
Malek Benakli ◽  
Redhouane Ahmed nacer ◽  
Amina Talbi ◽  
Rachida Belhadj ◽  
Farih Mehdid ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Late Onset ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Lymphoid Leukaemia ◽  
Autologous Transplant

Abstract Abstract 4326 Background Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methods Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). Results Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. Conclusion This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using Alemtuzumab and Cyclophosphamide as Conditioning Regimen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3198-3198
Author(s):  
Fernanda Lodi ◽  
Gustavo Teixeira ◽  
Antonio Vaz Macedo ◽  
Rosana Lamego ◽  
Simone Silva Magalhaes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Median Number ◽  
Off Label Use ◽  
Hematopoietic Stem ◽  
Off Label

Abstract Abstract 3198 Poster Board III-135 Introduction Cyclophosphamide (Cy) with/without antithymocyte globulin (ATG) as conditioning regimen for allogeneic hematopoietic stem cell transplantation (AlloHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). In developing countries, and particularly in Brazil, ATG costs limit its use in AlloHSCT for SAA patients. Alternative low-cost regiments, like busulfan (BU) with Cy as conditioning regimen is still associated with a significant rate of rejection, especially in heavily transfused patients, and long-term infertility. Alemtuzumab (Cam) was reported as an alternative to ATG for SAA patients, with similar activity and a lower cost. Material and Methods In order to study the effect of the combination of Cy and Cam, we reviewed all AlloHSCT performed for SAA using this conditioning regimen. Between April 2007 and Mai 2009, fifteen patients with SAA (defined by Camitta criteria) underwent an AlloHSCT in our institution. Median age at transplantation was 25 (range 5-42) years. All but one patient had positive CMV serology. Median number of transfusions was 20 (range 10-67). One patient received a second AlloHSCT due to a late (> 4 years) graft rejection. Patients received an unmanipulated bone marrow (n=11) or peripheral blood (n=4) graft as stem cell source and all but one patient were transplanted with an HLA-identical sibling. Median number of nucleated cell infused was 2.86 (range 1.65-6.50)x10 8/kg. Cyclosporin alone (n=10) or in combination with methotrexate (n=5) was used as GVHD prophylaxis. Results Thirteen out of 15 patients presented neutrophil recovery with a median time to > 0.5×10 9 neutrophil/L of 23 (range 13-30) days. Platelet recovery (> 20×10 9 platelets/L) occurred in thirteen patients with a median time of 16.5 (range 9-45) days. Acute graft versus host disease (GVHD) was observed in just one patient (grade II). None of 12 patients alive 100-days after AlloHSCT presented chronic GVHD. Seven patients presented CMV reactivation. One patient did not engrafted and other presented a late (14 months) rejection. One patient became pregnant after alloHSCT and gave birth to a healthy child. With a median follow-up of 315(range 4-782) days, two patients died and the estimate 1-year overall survival rate is 87%. One patient died due to complications of a CNS bleeding that occurred hours before marrow infusion and the other of GI infection while still on neutropenia. Conclusion Use of cyclophosphamide and alemtuzumab as conditioning regimen is a valid option in SAA patients undertaking AlloHSCT, with significant lower rates of acute and chronic GVHD. Nevertheless, a longer follow-up is required to properly evaluate rejection incidence. Disclosures Off Label Use: Drug: Alemtuzumab Off-label Use: Aplastic Anemia.

Sign in / Sign up

Export Citation Format

Share Document