Comparison of Outcomes Between Unrelated Donor and Sibling Donor Transplant in Adult Patients with Severe Aplastic Anemia: A Single Center Retrospective Study

Abstract Abstract 4151 For the patient with severe aplastic anemia (SAA) who do not have a sibling donor and had failed to immunosuppressive therapy, allogeneic stem cell transplantation (SCT) from an unrelated donor is therapeutic option. Although unrelated SCT (u-SCT) has shown less favorable outcomes, there were few studies comparing unrelated donor to sibling donor transplant. The aim of the present study was to evaluate the feasibility of u-SCT in adult SAA patients compared with sibling SCT (s-SCT). This study examined 157 consecutive patients who underwent allogeneic SCT at our institution between April 2001 and December 2011. In this study, for a homogenous cohort, patients who received second allogeneic SCT were excluded. The diagnosis of acute GVHD or chronic GVHD was made as the NIH published consensus criteria. There were 71 male and 86 female patients with a median age of 31 years (range, 13–59 years). The median interval from the diagnosis to transplantation was 24 months (range; 1–346 months). The median transfusions prior to SCT were 47 units (range; 4–680 units). Patients with SAA (n=114) or VSAA (n=43) had received SCT from sibling donor (n=82) or unrelated donor (n=75). The conditioning regimen for s-SCT consisted of fludarabine (180 mg/m2) + cyclophosphamide (CY, 100 mg/kg) + ATG (10 mg/kg), and the conditioning regimen for u-SCT consisted of TBI (fractionated, 800 cGy) + CY (100–120 mg/kg) ± ATG (2.5 mg/kg) (Lee JW, et al, Biol BMT 2011, 17:101). GVHD prophylaxis consisted of CsA + MTX in s-SCT and FK506 + mini-MTX in u-SCT, respectively. After a median follow-up of 45 and 50 months for s-SCT and u-SCT, respectively, the 3-year estimated OS rates were 92.7 and 89 % for s-SCT and u-SCT (P=0.650), respectively. 15 patients (7 in s-SCT, 8 in u-SCT) died of transplant toxicities, including in s-SCT, acute GVHD (n=1), infections (n=4), and occurrence of MDS or AML (n=2) and in u-SCT, acute GVHD (n=4), chronic GVHD (n=1), infection (n=1), thrombotic microangiopathy (n=1). Nine patients (8 in s-SCT, 1 in u-SCT) developed secondary engraftment failure. The cumulative incidence of acute GVHD (≥grade II) was 4.9% in s-SCT and 44.0% in u-SCT (P<0.001). The cumulative incidence of chronic GVHD also showed higher in u-SCT than s-SCT (4.2% vs 44.4%, P<0.001). This study showed that survival of u-SCT is comparable to that of s-SCT. Therefore, early application of u-SCT should be considered in patients with SAA/VSAA in case of availability of well matched donor. Because the incidence of GVHD is significantly higher in u-SCT than s-SCT, further study is mandatory to reduce the incidence of GVHD in u-SCT setting. Disclosures: No relevant conflicts of interest to declare.

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HLA-Haploidentical HSCT with Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Blood ◽

10.1182/blood.v120.21.4510.4510 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4510-4510

Author(s):

Yuelin He ◽

Chunfu Li ◽

Xuedong Wu ◽

Xiaohui Zhou ◽

Xiaoqin Feng ◽

...

Keyword(s):

Aplastic Anemia ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Donor Lymphocyte Infusion ◽

Severe Aplastic Anemia ◽

Platelet Recovery ◽

Graft Versus Host

Abstract Abstract 4510 Objective To investigate the effect of pretransplantation donor lymphocyte infusion (DLI) and posttransplantation cycolphosphamide (CY) to prevent graft rejection and graft-versus-host disease (GVHD) after bone marrow transplantation plus peripheral blood stem cell transplantation from HLA-haploidentical mismatched related donors. Methods Four patients (median age, 11 years; range, 8–15 years) with severe aplastic anemia and all of them had HLA-haploidentical donors more than or equal to 2/8 HLA (HLA-A, B, C and DRB1) mismatched at antigen level. The conditioning regimen consisted of pretransplantation DLI (Lymphocytes, 1×10e7/kg at day -9); 40mg/m2/day of fludarabine (day-6 to -2); 3.2mg/kg/day of Busulfex (day-6 and -5); 10mg/kg/day of Thiotepa (day -4) and 50mg/kg/day of Cy on day -7, 14.5mg/kg on day-3,-2 and 40mg/kg on day +3,+4, respectively. The prophylaxis of acute GVHD consisted of tacrolimus and mycophenolate mofetil. The median follow-up time is 5 (rang: 3–6) months. Results The median times to neutrophil (>500/ÌL) and platelet recovery (>20,000/ÌL) were 21 and 23.5 days, respectively. No acute GVHD and Chronic GVHD were, so far, observed for all patients and were survive without SAA. Conclusion Posttransplantation cyclophosphamide for the prophylaxis of acute GVHD was safe and effective. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v106.11.2052.2052 ◽

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.

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Allogeneic Hematopoietic Peripheral Blood Stem-Cell Transplantation From HLA-Identical Siblings Versus Allelic-Matched Unrelated Donors (10/10 high resolution) in Patients with Acute Myeloid Leukemia and Myelodyplasic Syndrome After Reduced Intensity Conditioning,

Blood ◽

10.1182/blood.v118.21.4132.4132 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4132-4132

Author(s):

Marie Robin ◽

Raphael Porcher ◽

Lionel Ades ◽

Emmanuel Raffoux ◽

Nicolas Boissel ◽

...

Keyword(s):

Cumulative Incidence ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Disease Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Sibling Donor ◽

Matched Sibling

Abstract Abstract 4132 Introduction: Although precise matching of the donor/recipient pairs has been made easier by HLA typing at the allelic level, several issues with respect to unrelated transplantation remain to be addressed. In particular, the impacts of allelic HLA matching in patients with Acute Myeloid Leukemia (AML) and myelodysplasic syndrome (MDS) who receive allogeneic Peripheral Blood Stem cells (PBSC) after a reduced intensity conditioning (RIC) regimen is still unclear. In the present study, we aim to compare the impact of the donor type in this setting: HLA identical sibling versus HLA matched 10/10 (high resolution) unrelated donor (MUD). Method and transplantation characteristics: From 01/2001 to 12/2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from HLA identical sibling (n=69) or MUD (n=39). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis consisted in cyclosporine plus mycophenolate in 79% of patients. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate and overall survival (OS) at 3 years were compared according to type of donor: HLA identical sibling donor and MUD. Disease characteristics: WHO classification for MDS at time of hematopoietic stem cell transplantation (HSCT) was RAEB1 (24%), RAEB2 (36%), MDS transformed into secondary AML (20%), CMML2 (9%), RA (4%), or other (7%). Disease risk was assumed by cytogenetic (MRC for AML, IPSS for MDS) and EBMT score (good risk: CR1 for AML or MDS or untreated MDS, intermediate risk: CR2 for AML, CR2 or partial remission for MDS, poor risk: all other status). Cytogenetic (no missing data) was poor, intermediate or good for 21, 74 and 5% of AML and 24, 36 and 40% of MDS, respectively. EBMT score at time of HSCT was poor, intermediate or good for 29, 7, 64% of MDS and 11, 21, 68% of AML, respectively. Results of the comparison: Patients characteristics according to type of donor were similar for age (median 57 years), gender and disease distribution. Particularly, disease risks were comparable in 2 groups. Conversely, conditioning regimen (more ATG in MUD: 69 vs. 43%, p=0.016), donor age (younger for MUD: 30 vs. 52 years, p<0.0001) and number of CD34+ cells infused (higher in MUD: 7 vs. 6.5 × 106/kg, p=0.022) were different. The median follow-up was 36 months (range 2 to 72). All patients engrafted. The cumulative incidence of acute GvHD was 40% with HLA matched sibling donor and 44% for MUD (p=0.58). The cumulative incidence of chronic GvHD at 3 years was 49% with HLA matched sibling donor and 45% with MUD (p=0.66). No risk factor was associated with acute GvHD but chronic GvHD was less frequent in patients with AML vs. MDS (41% vs. 59%, p=0.077) and in those patients who received ATG in conditioning regimen (54% vs. 43%, p=0.067). During follow-up, 47 patients died. The 3-year cumulative incidence of TRM was 17% and 22% with HLA matched sibling donor and MUD, respectively (p=0.55). Adjusting for age, MDS was the only factor increasing TRM (HR 3.4; 95% CI 1.2 to 9.5; p=0.02). The 3-year cumulative incidence of relapse was 46% with HLA matched sibling donor and 30% with MUD (p=0.28) knowing that there was no difference between both groups regarding disease risk (cytogenetic and EBMT score). The 3-year OS was 44% with HLA matched sibling donor (95%CI: 33–61) and 50% with MUD (95%CI: 35–71) (Figure 1). Disclosures: Fenaux: Celgene: Honoraria, Research Funding. Peffault de Latour:Alexion: Consultancy, Research Funding.

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Influence of recipient's Age On the Outcome of HLA-Matched Sibling Transplants in Adult Patients with Severe Aplastic Anemia Who Conditioned with Fludarabine-Based Regimen

Blood ◽

10.1182/blood.v120.21.1921.1921 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1921-1921 ◽

Cited By ~ 2

Author(s):

SeungHwan Shin ◽

JaeHo Yoon ◽

SeungAh Yahng ◽

SungEun Lee ◽

ByungSik Cho ◽

...

Keyword(s):

Stem Cell ◽

Aplastic Anemia ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Adult Patients ◽

Severe Aplastic Anemia ◽

Age Group ◽

Increased Risk ◽

Significant Difference

Abstract Abstract 1921 Background: There is a controversy concerning upper age limit of recipient in allogeneic stem cell transplantation (allo-SCT) of severe aplastic anemia (SAA) because older patients have an increased risk of transplant-related mortality (TRM). Recently, a less toxic regimen comprising reduced dose of cyclophosphamide (CY), fludarabine (Flu), and ATG (Flu/CY/ATG) was introduced for conditioning the patients with SAA scheduled for HLA-identical sibling allo-SCT. We analyzed the outcome of these patients after conditioning with Flu/CY/ATG regimen according to recipient's age. Method: We analyzed 82 consecutive adult patients transplanted from March 2002 to June 2011, followed conditioning with CY (50 mg/kg/day × 2 days), Flu (30 mg/m2/day × 6 days), and ATG (2.5 mg/kg/day × 4 days). Results: The median age of patients was 39 years (range, 13–58 years). 29 (35.4%) patients were very SAA at the time of allo-SCT. Stem cell sources were bone marrow (BM, n=59), peripheral blood stem cell (PBSC, n=12), and BM+PBSC (CD34+ cell selection, n=11). The conditioning regimen was well tolerated, with low TRM (4.9%). Neutrophil engraftment was observed in all patients; the median time to engraftment of neutrophils and platelets was 12 and 17 days, respectively. The 100-day cumulative incidence (CI) of acute graft-versus-host disease (GVHD, grade °Ã2) was 3.7% and 2-year CI of chronic GVHD was 4.4%. With a median follow-up of 3 years, overall survival (OS) and failure-free survival was 93% and 83%, respectively. Seven patients (8.5%) developed delayed graft failure and 6 patients of them have successful durable engraftment after second allo-SCT without TRM. Seven patients died of veno-occlusive disease (n=1), cytomegalovirus pneumonia (n=2), sepsis (n=2), clonal evolution after allo-SCT (n=2, 1 acute myeloid leukemia and 1 myelodysplastic syndrome), respectively. 3-year probability of OS by age group were 88% at less than 20 years old (n=8), 97% at 20–39 (n=34), 92% at 40–49 (n=26), 86% at 50–59 (n=14). There is no significant difference in OS according to age group (p=0.426). Conclusion: These data indicate that the Flu/CY/ATG conditioning regimen is well tolerable with low TRM and CI of GVHD in all age group. Similar OS according to 4-divided age group suggest that patient's age more than 50 years old might be possible candidate for allo-SCT in SAA with Flu/CY/ATG conditioning regimen. Disclosures: No relevant conflicts of interest to declare.

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Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies

Blood ◽

10.1182/blood.v122.21.5544.5544 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5544-5544

Author(s):

El-Cheikh Jean ◽

Devillier Raynier ◽

Fürst Sabine ◽

Crocchiolo Roberto ◽

Granata Angela ◽

...

Keyword(s):

Elderly Patients ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Reduced Intensity

Abstract Objectives The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older. Patients and methods We retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available. Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1. Results No patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years. The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively. Conclusions This retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v108.11.3105.3105 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3105-3105 ◽

Cited By ~ 2

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.

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Current Outcome Of HLA Identical Sibling Vs Unrelated DONOR Transplants In Severe Aplastic Anemia : An EBMT Analysis

Blood ◽

10.1182/blood.v122.21.707.707 ◽

2013 ◽

Vol 122 (21) ◽

pp. 707-707 ◽

Cited By ~ 1

Author(s):

Andrea Bacigalupo ◽

Gérard Socié ◽

Rose-Marie Hamljadi ◽

Mahmoud Aljurf ◽

A Mashan ◽

...

Keyword(s):

Stem Cell ◽

Aplastic Anemia ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Treatment Strategies ◽

Severe Aplastic Anemia ◽

Unrelated Donor ◽

Stem Cell Source ◽

Cell Source ◽

Risk Patients

Abstract Background Unrelated donor (UD) transplants for patients with acquired severe aplastic anemia (SAA) have been known to yield inferior results when compared to transplants from HLA identical siblings (SIB). With the significant improvement of UD transplants over the past decade, on may ask whether this is still true. Aim of the study To compare the outcome of UD with SIB transplants in recent cohort of patients reported to the European Group for Blood and Marrow Transplantation (EBMT) Aplastic Anemia Registry. Patients We have analyzed 1500 patients with acquired aplastic anemia (SAA), who received a first bone marrow (BM) or peripheral blood (PB),. HLA matched transplant between 2005 and 2009, from identical siblings (n=975) or unrelated donors (n=525). Excluded were cord blood grafts. Clinical characteristics of the two groups were different: although SIB vs UD grafts had comparable age (20 vs 21 years median age , p=0.1), SIB grafts were performed earlier (152 vs 607 median days from diagnosis, p<0.00001), had less frequently anti-thymocyte globulin (ATG) in the conditioning regimen (50% vs 61%, p<0.0001), had less frequently radiation based conditioning (5% vs 31%, p<0.00001), and more frequently received marrow as a stem cell source (61% vs 53%, p=0.002). Results The cumulative incidence (CI) of engraftment was 91% for both SIB and UD transplants; and the CI of acute GvHD grade II-IV was11% in SIB and 25% in UD grafts (p<0.0001). Infection was the leading cause of death (10% UD, 8% SIB), followed by GvHD (6% UD vs 3% SIB) and rejection (1,7% and 1,4% respectively). In multivariate COX analysis the strongest negative predictors of survival was the use of PB as a stem cell source (RR 2, p<0.00001), followed by patient age >20 years (RR 2.0, p<0.0001), an interval diagnosis-transplant (Dx-Tx) >180 days (RR 1.3, p=0.006) and no anti-thymocyte globulin (ATG) in the conditioning (RR 1.6, p=0.002). The use of an UD as compared to a SIB was not statistically significant (RR 1.2, p=0.4). When stratified for negative predictors, the actuarial 5 year survival of SIB and UD transplants was 91% vs 81% in low risk patients (n=541, 0-1 negative predictors, p=0.052), 74% vs 72% for the largest group of intermediate risk patients (n=829, 2-3 negative predictors, p=0.4) and 53% vs 50% for a small group of high risk patients (n=130, 4 negative predictors, p=0.8). Conclusions This study suggests that the outcome of UD and SIB transplant for SAA is currently comparable, if one corrects for confounding variables, and especially time to transplant. This information warrants the activation of an unrelated donor search for all patients lacking an HLA matched sibling, up to the age of 60, and this may be relevant for treatment strategies. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplantation Cyclophosphamide for Gvhd Prophylaxis in Related and Unrelated Allogeneic Hematopoietic Cell Transplantation: Study from the SFGM-TC Registry

Blood ◽

10.1182/blood-2021-151989 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2883-2883

Author(s):

Mauricette Michallet ◽

Tereza Coman ◽

Stephane Morisset ◽

Mohamad Sobh ◽

Raynier Devillier ◽

...

Keyword(s):

Cell Transplantation ◽

Lower Incidence ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Gvhd Prophylaxis ◽

Significant Difference

Abstract Rational: The significant increase in haplo-identical allogeneic cell transplantation (Allo-HCT) has led to the more frequent use of cyclophosphamide (Cy) after transplantation for graft-versus-host disease (GVHD) prophylaxis (PT-Cy). This strategy has subsequently been used in related and unrelated allogeneic HCT settings as well with some controversial results. Patients and Methods: We analyzed all consecutive Allo-HCTs from matched related (MR) and unrelated donors (HLA matched and mismatched: MUD and MMUD) reported to the SFGM-TC registry from January 2014 to December 2019 and who have received PT-Cy alone or in combination with other immunosuppressive molecules (IS). We therefore performed a pair-matched analysis (1/2) with transplantations using classic GVHD prophylaxis with (w) or without (wo) anti-thymocyte globulins (ATG). The primary objective was to evaluate the incidence and severity of acute and chronic GVHD in PT-Cy compared to other strategies. Secondary objectives included: modalities of PT-Cy and IS, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), overall survival (OS), GVHD and relapse free-survival (GRFS), infection rates. Results: We analyzed a total of 1190 patients (pts), 386 (32%) received PT-Cy and matched with 804 (68%) pts who received classic GVHD prophylaxis (no PT-Cy). Among PT-Cy patients, 59% were males with a median age of 55.3 years (3.4-75.5), 49% were AML, 14% ALL, 20% MDS and MPS, 12.5% NHL and HL, and 4.5% Multiple Myeloma. Before transplantation, 61% of pts were in complete remission (CR), 34% not in CR, 2% in stable disease and 3% were not treated. Conditioning regimen was myeloablative in 35% of patients, 86% received peripheral blood stem cells, 31% were CMV negative pairs, 58% were sex-matched and 51% were ABO compatible. There was no significant difference between the PT-Cy and no PT-Cy groups regarding all the variables. We identified four groups: group 1: PT-Cy + IS (n=259), group 2: PT-Cy + ATG + IS (n=120), group 3: ATG w or wo IS (n=651) and group 4: other IS (n=160). We observed significant differences between the 4 groups for age (p<0.001), type of disease (p<0.001), disease status (p=0.016), conditioning intensity (p=0.002), HC source (p<0.001), HLA matching (p<0.001) and ABO compatibility (p<0.001). The cumulative incidence of acute GVHD grades II, III/IV, chronic GVHD, relapse and NRM, the probability of OS and GRFS are shown in Table 1. The results of multivariate analysis (Table 2) showed a significant lower incidence of acute GVHD gr II, III, IV and chronic GVHD after PT-Cy + IS and a significant higher TRM after ATG ± IS. In addition, other well-known parameters were found to have a significant impact as age on OS and GRFS, use of unrelated donor on OS and CIR and PBSC on chronic GVHD. Regarding severe infections after HCT, there was no difference between PT-cy and pair-matched patients except for pneumonia (12.5% vs. 8% respectively, p=0.08) and septicemia (12% vs. 1.7% respectively, p<0.001). In conclusion, there was a significant lower incidence and severity of acute and chronic GVHD in the PT-Cy group after related, HLA matched and mismatched unrelated Allo-HCT compared to matched patients with other GVHD prophylaxis with a higher NRM when patients received ATG. We did not observe significant translation into GRFS improvement probably due to the higher toxicity of PT-Cy. Figure 1 Figure 1. Disclosures Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huynh: Jazz Pharmaceuticals: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

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Reduced Intensity Conditioning for Haploidentical Transplantation Using Double Source of Hematopoietic Stem Cells and Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-131578 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5745-5745

Author(s):

Ana Rojas Fonseca ◽

Vivian Aparecida Zanao ◽

Katya Parisio ◽

José Salvador Rodrigues de Oliveira

Keyword(s):

Aplastic Anemia ◽

Conflicts Of Interest ◽

Jc Virus ◽

Ex Vivo ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Hematopoietic Stem ◽

Post Transplant ◽

Haploidentical Transplantation

Significant improvements in haploidentical stem cell transplantation (haplo-SCT) have confirmed its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms. However, the optimal conditioning regimen for haplo-SCT for SAA remains undefined. A recent review demonstrated haplo-SCT using NMA and RIC, engraftment between 75 to100% and OS one year of 75-100%. In our Institutions we started a double source since Jan 2017 using a RIC protocol that is the objective of this presentation. There were nine haplo-SCT in eight patients in two Brazilian centers, Hospital Santa Marcelina (n=5) and Hospital São Paulo (n=3). All patients were male, median age 26 years old (14-39), nocturnal paroxysmal hemoglobinuria clonality in five (62,5%); treated with Cyclosporine, Thymoglobulin (n=4), Eltrombopag (n=1), Eculizumab (n=2) and/or Alemtuzumab (n=1). Median time disease to transplant was 15,7 months (3.8-192). All patients submitted more than 20 RBC transfusions, and median of ferritin was 2,283 ng/mL (753-3,486). One patient had carbapenem-resistant gram-negative bacilli (CRNGB: Escherichia coli, Klebsiella pneumoniae and/or Pseudomonas aeruginosa). Panel reactive antibody was negative in all patients. The donor was a sibling in 44% (n=4), father and mother 22% each (n=2) and one patient received cells from his cousin after an early failure of engraftment from mother first transplant. The cause of this failure was a JC virus and adenovirus acute infections. The second haplo-SCT conditioning was Fludarabine, Cyclophosphamide and 600 cGy TLI. There were seven male donors. RIC was consisted of Fludarabine, Cyclophosphamide and total body irradiation (TBI) 200 cGy. The source was G-CSF primed bone marrow (G-BM) grafts in combination with PBSC no ex-vivo T cells depleted, and Cyclophosphamide 50 mg/Kg/day IV on days +3 and +4 post-transplant (PTCy), as well as graft versus host disease (GvHD) prophylaxis. The median of G-BM MNCs was 5.4 x 10⁸/Kg (2.3-8.7), and PBSC was 10 x 10⁶CD34+/Kg (4-18.7). One (11%) patient died for sepsis at day +13, he was the only with a confirmed CRGNB colonization before transplant. The ANC recovery was at day +17 (13-24). No one had Sinusoidal Obstructive Syndrome. Acute GvHD grade II and moderate chronic GvHD was observed in two patients (25%). Two patients had engrafting failure: the first at day +30 and received a successfully new haplo-SCT; the second at day +60, with a partial donor reconstitution without dependence of transfusion after immunosuppressive therapy. These two patients had female donors. The OS and DFS at two years were 87.5% and 75%, respectively. In conclusion, with a median follow-up of 30 months, haplo-SCT, PTCy with double source keep the 87.5% overall survival, with no one severe chronic GvHD. Our data suggests an excellent results for haplo-SCT, PTCy, RIC, double source in the SAA treatment. However, prospective well-designed trials need to confirm these results. Disclosures No relevant conflicts of interest to declare.

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Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽

10.1182/blood.v128.22.4655.4655 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4655-4655 ◽

Cited By ~ 1

Author(s):

Kavita Raj ◽

Eduardo Olavarria ◽

Diderik-Jan Eikema ◽

Liesbeth C de Wreede ◽

Linda Koster ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Graft Failure ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Cell Source ◽

Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

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