Conditioning Regimen, Graft Sources, and Alternative Donor Transplantation

Abstract Abstract 3034 Background: Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for thalassemia patients, However, most candidates for HSCT do not have a suitable family donor. In order to evaluate whether HSCT from an HLA–well -matched alternative donor can offer a probability of cure comparable to that of HSCT from sibling donor. The new conditioning regimen and peripheral blood stem cell transplant (PBSCT) from alternative donor (NF-08-thalassemia protocol) were used for b thalassemia patients. The improved outcome was summarized here. Objective: To evaluate the overall survival (OS), thalassemia-free survival (TFS), rejection (RE) and transplant related mortality (TRM) of NF-08-thalassemia protocol. Patients and Methods: Sixty-one thalassemia patients, 42 male and 19 female (median age, 7 years; age range, 3–15 years), were transplanted from 56 (32 patients were 8/8 and 24 patients 7/8 locus matched at HLA-A, B, Cw and DRB1) unrelated and 5 (1 patient 8/8 and 4 patients 7/8 antigen matched) parents donors from Oct.2008 to Jan.2011(median follow-up time, 14 months; range, 6–31months). NF-08-thalassemia protocol included Cyclosphosphamide (d-10 to d-9), Busulfan (d-7 to d-5), Thiotepa (d-4), Fludarabine (d-8 to d-4) and ATG (d-3 to d-1). PBSCs from unrelated (56 cases) and parents (5 cases) donor were used as only source of stem cells in all patients. GVHD prophylaxis included Cs A, MMF and sMTX. Results: OS, DFS and TRM in the cohort of 61 patients were 91.8%, 90.2% and 8.2%, respectively. Only one rejected his graft two months after transplantation. Acute GVHD III∼IV was 8.2% (5 patients) and none suffered from extensive chronic GVHD. Three patients died of acute GVHD and two died of the infection after transplantation. Discussion: In comparing this alternative donor HSCT with sibling donor HSCT (30 patients, using the same protocol, meanwhile), OS, TFS, RE and TRM were 91.8% vs. 85.9% (P=0.401), 90.2% vs. 79.2% (p=0.147), 1.6% vs. 6.9% (p=0.197) and 8.2%vs.14.1%, respectively. No significant difference was found. Summary: The results of alternative donor HSCT for b thalassemia patients are comparable with sibling donor transplant with using NF-08-thalassemia protocol. Disclosures: Li: Qi fa Liu: Workmates.

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Allogeneic STEM CELL Transplants for Patients with Myelofibrosis: Changes in the Transplant Platform and Improved the Outcome

Blood ◽

10.1182/blood.v126.23.4336.4336 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4336-4336

Author(s):

Stefania Bregante ◽

Alida Dominietto ◽

Anna Ghiso ◽

Anna Maria Raiola ◽

Francesca Gualandi ◽

...

Keyword(s):

Stem Cell ◽

Conditioning Regimen ◽

Older Age ◽

Recent Period ◽

Gvhd Prophylaxis ◽

Donor Type ◽

Recent Group ◽

Alternative Donor ◽

Matched Sibling ◽

Time Periods

Abstract Introduction. Allogeneic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, but is associated with relevant morbidity and mortality, possiby due to the specific nature of the disease. The outcome is significantly worse when alternative donor transplants are compared to matched siblings (MSD): in a recent cooperative study, TRM was 22% in MSD vs 59% in patients receiving unrelated donor grafts (UD) (Blood 2014 124:1183). Aim of the study. This is a retrospective analysis of 95 patients with myelofibrosis (MF) allografted in our Unit between 2001 and 2014. The aim of the study was to assess whether (a) the outcome of alternative donor grafts has improved with time and (b) how this compares with the outcome of identical sibling grafts. Patients were studied in two time intervals-2000-2010 (n=58) and 2011-2014 (n=37). The DIPSS score was comparable in the two time periods, but differences in the most recent group included older age (58 vs 53 years, p=0.004), more family haploidentical donors (54% vs 5%, p<0.0001), and the introduction of the thiotepa- fludarabine- busulfan conditioning regimen (70% of patients vs 2%, p<0.0001). Reduced intensity regimens were used mainly in the first transplant period (85% vs 30% in the most recent period). All patients received unmanipulated grafts (86% bone marrow). GvHD prophylaxis for sibling donor grafts was cyclosporin methotrexate (CsA+MTX), with the addition of ATG for unrelated transplants. Haploidentical grafts were performed with high dose cyclophosphamide post-transplant (PT-CY), CsA and mycophenolate. Results. Acute and chronic GvHD were comparable in the two time periods. Full donor chimerism was >90% in both periods in sibling transplants; on the other hand, in alternative donor transplants it improved from 69% to 95% in the most recent period (p=0.02). The 3 year transplant related mortality (TRM), in the 2011-2014 vs the 2000-2010 period, is 16% vs 38% (p=0.08), the relapse rate 19% vs 43% (p=0.01) and actuarial survival 70% vs 39% (p=0.08). Improved survival was most pronounced in alternative donor grafts (69% vs 21%, p=0.02), as compared to matched sibling grafts (72% vs 45%, p=0.4). The actuarial 3 year survival for high risk DIPSS was 8% in the 2000-2010 period, and it is currently 57% (p<0.01). In multivariate Cox analysis, DIPSS (p=0.001) and transplant score (transfusion requirement and spleen size) (p=0.03) were independent predictor of survival. Donor type was not predictive in multivariate analysis. Conclusions. The outcome of allografts for myelofibrosis has improved in recent years, due to a reduction of both TRM and relapse, despite comparable DIPSS and older age in the more recent group of patients. Improved survival has been more pronounced for alternative donor transplants, such that 3 year survival is currently superimposable to sibling donor grafts. There have been significant changes in the transplant platform, including conditioning regimen, donor type and GvHD prophylaxis, mainly with the introduction of PT-CY. All of our MF patients now receive the thiotepa, busulfan fludarabin conditioning, and, for patients lacking a matched sibling, a family haploidentical donor seems to be an interesting alternative. Disclosures No relevant conflicts of interest to declare.

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Allogeneic HSCT for Patients Aged More Than 55 Years with Myeloid Malignancies: Results of 171 Patients

Blood ◽

10.1182/blood.v126.23.5525.5525 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5525-5525

Author(s):

Tamim Alsuliman ◽

Samia Harbi ◽

Raynier Devillier ◽

Sabine Furst ◽

Catherine Faucher ◽

...

Keyword(s):

Disease Control ◽

Cell Transplantation ◽

Older Patients ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Myeloid Malignancies ◽

Alternative Donor ◽

Very High

Abstract Background: Incidence of most myeloid malignancies increases with age. Although allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative option for most of myeloid diseases, conventional myeloablative regimens are associated with considerable toxicity in older patients and high rate of non-relapse mortality (NRM). Thus, such standard approach is very rarely performed in the setting of older patients. Recent developments and introduction of reduced intensity\toxicity (RIC/RTC) and non-myeloablative (NMAC) regimens have allowed the extension of Allo-HSCT to these older patients. This study aims to report our experience of Allo-HSCT in patients > 55 years of age. Patients and Methods: From 2005 to 2014, 171 patients > 55 years of age with myeloid malignancies underwent first allogeneic HSCT at our center, with a median age of 63 years (56-72 years). Sixty-five patients (38%) had 65 years or more. Data had been double-checked using individual institutional files along with HSCT database of the IPC. Of all patients 117 had AML, 49 had MDS and 5 had MPN. They were conditioned by RIC (120 patients, 70%), RTC (16 patients, 9%) or NMAC (35 patients, 21%) regimens. One hundred and nineteen patients (70%) were transplanted with HLA-identical donor (sibling donor, n=66; unrelated donor; n=53), while 52 patients (30%) received transplantation from alternative donor (mismatched unrelated donor, n=18; cord blood, n=14; haploidentical donor, n=20). We found that 91 patients (53%) have a hematopoietic cell transplantation comorbidity index (HCT-CI) between 0 and 2, while 80 patients (47%) had a HCT-CI ≥ 3. Disease risk index (DRI) was low, intermediate, high and very high in 4 (2%), 108 (63%), 55 (33%) and 4 (2%) patients, respectively. Results: NRM at day+100 and 3 years were 7% and 23%, respectively. Cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 20% and 28%, respectively. With a median follow-up of 32 months (3.3-99.5), 3-years cumulative incidence of relapse (CIR), overall survival (OS) and progression free-survival (PFS) were 32%, 52% and 45%, respectively. Although we found a trend for higher NRM in patients aged above 65 years (< 65 vs. >= 65 years: 20% vs. 28%, p=0.056), no impact of age was found on PFS (< 65 vs. >= 65 years: 44% vs. 46%, p=0.662) and OS (< 65 vs. >= 65 years: 50% vs. 54%, p=0.750). DRI significantly influenced outcome (low + intermediate vs. high + very high: PFS: 53% vs. 28%, p=0.011; OS: 60% vs. 34%, p=0.020) while patients who received NMAC regimens had significantly lower PFS (NMAC vs. RIC vs. RTC: PFS: 26% vs. 50% vs. 50%, p=0.028) and OS (NMAC vs. RIC vs. RTC: PFS: 30% vs. 57% vs. 63%, p=0.031).There were no significant differences of OS or PFS among patients groups classified according to type of donor, sex mismatch, donors' age, donors' sex, donors' CMV antibodies positivity, patients' sex, HCT-CI, disease classification, graft's source or whether they were transplanted before or after 2010. In multivariate analysis model including conditioning type (NMAC vs. RIC vs. RTC), DRI (low + intermediate vs. high + very high), HCT-CI (0-2 vs. >=3), patients' age (continuous) and donors' type (HLA-identical vs. alternative donor), high/very high DRI as well as the use of NMAC regimens were independent poor predictive factor associated with higher CIR and shorter PFS (HR, 95%CI=1.77, 1.16-2.72; p=0.009 for DRI; HR, 95% CI=1.87, 1.11-3.13; p=0.018 for NMAC) and OS (HR, 95% CI=1.75, 1.11-2.75; p=0.016 for DRI; HR, 95% CI=1.98, 1.14-3.45; p=0.016 for NMAC). Patient's age was associated with higher NRM (HR, 95% CI=1.10, 1.01-1.19; p=0.027). Conclusion: Our data shows that though aged patients still generally at a higher risk of NRM, Allo-HSCT using adapted conditioning regimen can provide low NRM and prolonged survival. Beyond the feasibility, disease relapse appears as the major issue after Allo-HSCT. To optimize conditioning regimen for older patients may be a viable option to enhance disease control without raising toxicity. Indeed, the development of RIC/RTC regimens may improve overall outcome of older patients suffering from myeloid diseases. In contrast, truly NMAC regimens may provide insufficient disease control. The optimal conditioning intensity in the setting of older patients with myeloid malignancies remains undefined and should be evaluated in further prospective trials. Disclosures No relevant conflicts of interest to declare.

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Fludarabine-Based Reduced Intensity Regimen for Matched Related Donor Stem Cell Transplantation in Acquired Severe Aplastic Anemia

Blood ◽

10.1182/blood.v128.22.5753.5753 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5753-5753

Author(s):

Khaled M Ghanem ◽

Mohamed A. Kharfan-Dabaja ◽

Hassan El-Solh ◽

Nariman Harris ◽

Nabila Kreidieh ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Aplastic Anemia ◽

Conditioning Regimen ◽

Alternative Donor ◽

Conditioning Regimens ◽

Related Donor ◽

Acquired Severe Aplastic Anemia ◽

Reduced Intensity ◽

Neutrophil Engraftment

Abstract The outcome of severe acquired aplastic anemia (SAA) has improved dramatically over the past few decades due to advances in allogeneic stem cell transplantation (allo-STC). Different conditioning regimens have been tested in matched related donor (MRD) transplants with variant results. Before 2008, we have encountered poor engraftment in our patients using high dose cyclophosphamide (200 mg/kg) and thymoglobulin (ATG). Fludarabine, low dose cyclophosphamide, ATG and total body irradiation (TBI) was used for alternative donor transplants by Bacigalubo and colleagues (1). Since 2008, we have decided to start using this regimen in our MRD transplants to improve engraftment and ultimately overall survival. To our knowledge, this abstract describes the outcome of the largest cohort of patients who received MRD allo-STC for SAA using this regimen. It represents our single institution experience over a period of 10 years. Methods: This is a retrospective chart review of all patients diagnosed with acquired SAA who underwent allo-STC between August 2005 and December 2015 at the American University of Beirut Medical Center (AUBMC) Results: A total of 22 patients underwent transplant with grafts from related HLA-matched donors. Before 2008, three patients received cyclophosphamide 50 mg/kg/day over 4 days and ATG (Fresenius) 30 mg/kg/day over 4 days. Since 2008, nineteen patients received fludarabine 30 mg/m2/day for 4 days (-6, -5, -4 and -3), cyclophosphamide 300 mg/m2/day for 4 days (-6, -5, -4 and -3) and ATG (Genzyme) 3.75 mg/m2/day for 2 days (-4 and -3). TBI at a dose of 2 Gy was added on day -1 for patients more than 15 years of age. Graft versus host disease (GvHD) prophylaxis consisted of cyclosporin A with either mycophenolate mofetil (50%) or a short course of methotrexate (50%). The median age of patients was 21 years (range: 1.7-64 years). The median duration between diagnosis and transplant was 11 months (range: 1-85 months). Seven patients (31%) had failed immunosuppressive therapy before transplant. The stem cell source was bone marrow (BM) for 14 patients (64%) and peripheral blood (PB) for 8 patients (36%). The median CD34 cell dose infused was 5.4 ×106/kg (range: 1 - 19.5 ×106/kg). The 2-year overall survival rate was 82% with trend toward better survival without statistical significance when using fludarabine-based regimen (84% vs 66%, P: 0.42), if both donor and recipient had the same gender (92% vs 66%, P: 0.11), or if PB was the source of stem cells (87% vs 78%, P: 0.58). Engraftment failure was observed in 2 cases (9%). The median time for neutrophil engraftment was 20.3 days (range: 14-38 days). Neutrophil engraftment was faster when the fludarabine-based conditioning regimen was used (18 vs 38 days, P: 0.04), if PB was used as the source of stem cells (17 vs 20 days, P: 0.03) or if TBI was added to the conditioning regimen (18 vs 20 days, P: 0.07). Chimerism studies were available for 18 out of 20 engrafted patients. Two patients had partial engraftment (89% and 76%) and 16 patients had complete engraftment (>90%). The previous use of IST or the duration between diagnosis and transplant (< or > 1 or 2 years) did not affect survival or engraftment. Acute GvHD (grade I-II) occurred in 2 patients (9%). No cases of chronic GvHD or veno-occlusive disease (VOD) were reported. CMV reactivation occurred in 2 cases while CMV disease was reported in another case. EBV reactivated in one case without LPD. Hemorrhagic cystitis occurred in one case. One patient developed donor cell precursor B-cell acute lymphoblastic leukemia 2 years after transplant. Conclusions: Fludarabine-based reduced intensity regimen for MRD transplants in SAA has led to improved engraftment with minimal toxicity. This result was not affected by the previous use of IST or the long duration between diagnosis and transplant as was reported in previous studies with different conditioning regimens or donor types. Thus, this regimen may be particulary useful in countries where patients present late to transplant. References:Bacigalupo A, Locatelli F, Lanino E, et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone marrow transplantation 2005;36:947-50 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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Non-Myeloablative Hematopoietic Transplant with Sirolimus Immunosuppression: Determinants of Outcome.

Blood ◽

10.1182/blood.v106.11.5462.5462 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5462-5462

Author(s):

David F. Claxton ◽

Chuancai Wang ◽

Michelle Carraher ◽

Christopher Ehmann ◽

Witold Rybka

Keyword(s):

Graft Failure ◽

Conditioning Regimen ◽

Disease Free Survival ◽

Unrelated Donor ◽

Logit Analysis ◽

Risk Of Death ◽

Increased Risk ◽

Donor Cells ◽

Alternative Donor ◽

Disease Free

Abstract We added Sirolimus to an established conditioning regimen in an attempt to optimize engraftment and anti-tumor effects while minimizing GVHD. 55 patients patients with advanced hematological malignancies (median age 60) received cyclophosphamide (1gm/m2 days −7 and −6) and fludarabine (25mg/m2 days −7 through −3) prior to peripheral blood cell (51 patients) or marrow (4 patients) transplant. All received sirolimus with tacrolimus, both adjusted to 5–15ng/ml, and methotrexate (5mg/m2 days 1,3, 6) immunoprophyllaxis. Tacrolimus was tapered from days 30–45 in matched siblings (Msib -12 patients) and days 40–100 in (most) alternative donor recipients (AltD- unrelated donor or 5/6 matched related cells - 43 patients) without acute GVHD. Median follow-up is 313 days in AltD patients and 337 days for Msib patients. All Msib cells engrafted, whereas 3/43 AltD recipients showed primary graft failure or secondary graft failure (1/43). Msib recipients engrafted more rapidly than those with AltD transplants (p<0.01). For AltD recipients, the CD34 dose had a positive significant effect on donor engraftment - chimerism (p<0.05 for all points up to D100). Median overall and disease free survival was 287 and 230 days respectively for AltD patients and 303 and 167 days for Msib recipients. Amongst AltD patients, 17/43 survive progression free at D114-1167 (median D416), while in MSib patients only 1/12 survives progression free (p=0.0023 ). Two additional patients are disease free after donor lymphocytes (DLI) or withdrawal of immunosuppression in each group. No patient in the Msib group had transplant related mortality (TRM), but in the AltD group there were nine TRMs, including 7 from GVHD (NS). Multivariate analysis showed CD34 dose and donor types had no significant effect on development of progressive disease (PD). However, in general the odds ratio of any PD decreased exponentially as the level of chimerism increased. For example, at D100 the odds of developing PD decreased by 0.699 times when the level of chimerism increased by 0.1. Multinomial logit analysis showed that compared to GVHD death, the odds ratios for PD death decreased exponentially as the level of chimerism increased. In this series of patients with advanced hematological malignancy, Alternative donor cells provided a higher probability of control of disease, albeit with a trend to higher TRM. Higher CD34 cell doses were associated with improved donor engraftment (chimerism) in AltD recipients. For AltD recipients, risk of PD was reduced by increasing donor chimerism, but increasing chimerism is associated with increased risk of death from GVHD. Efforts to improve control of malignancy via more rapid engraftment of donor cells must be tempered with concern regarding potentially severe GVHD. Figure Figure

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Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now

Blood ◽

10.1182/blood-2011-01-332510 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1197-1207 ◽

Cited By ~ 81

Author(s):

Matthew M. Hsieh ◽

Courtney D. Fitzhugh ◽

John F. Tisdale

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Disease Burden ◽

Conditioning Regimen ◽

Adult Patients ◽

Cell Disease ◽

Hematopoietic Stem ◽

Alternative Donor ◽

Hematopoietic Chimerism ◽

Matched Sibling

Abstract Although sickle cell disease (SCD) has a variable clinical course, many patients develop end-organ complications that are associated with significant morbidity and early mortality. Myeloablative allogeneic HSCT (allo-HSCT) is curative but has been historically performed only in children younger than 16 years of age. Modest modifications in the conditioning regimen and supportive care have improved outcome such that the majority of children with a suitable HLA-matched sibling donor can expect a cure from this approach. However, adult patients have been excluded from myeloablative allo-HSCT because of anticipated excess toxicity resulting from accumulated disease burden. Efforts to use nonmyeloablative transplantation strategies in adults logically followed but were initially met with largely disappointing results. Recent results, however, indicate that nonmyeloablative allo-HSCT in adult patients with SCD allows for stable mixed hematopoietic chimerism with associated full-donor erythroid engraftment and normalization of blood counts, and persistence in some without continued immunosuppression suggests immunologic tolerance. The attainment of tolerance should allow extension of these potentially curative approaches to alternative donor sources. Efforts to build on these experiences should increase the use of allo-HSCT in patients with SCD while minimizing morbidity and mortality.

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