HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis

Blood ◽  
2021 ◽  
Author(s):  
Mahasweta Gooptu ◽  
Rizwan Romee ◽  
Andrew St. Martin ◽  
Mukta Arora ◽  
Monzr M. Al Malki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Failure ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Conditioning Regimens ◽  
Disease Free ◽  
Reduced Intensity ◽  
Grade Iii

Post transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has allowed haploidentical (Haplo) transplantation to be performed with results similar to that after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD versus Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate containing GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults between 2011 and 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced intensity regimens were analyzed separately. Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70, p=0.022), acute grade III-IV GVHD (HR 0.41, p=0.016) and non-relapse mortality (HR 0.43, p=0.0008) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74, p=0.008; 55% versus 41%) and overall survival (HR 0.65, p=0.001; 67% versus 54%) were higher after MUD compared to Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% versus 88%) was higher and grade III-IV acute (HR 0.39, p=0.07) and chronic GVHD (HR 0.66, p=0.05) were lower after MUD compared to Haplo transplantation. There were no differences in graft failure, relapse, non-relapse mortality, disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced intensity conditioning regimens.

Influence of Graft Versus-Host Disease Prophylaxis Regimen On T-Cell Repertoire Diversity Following Reduced-Intensity HLA-Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3054-3054 ◽  
Author(s):  
Rachel B. Salit ◽  
Frances T. Hakim ◽  
Michael R. Bishop ◽  
Thea M. Friedman ◽  
Robert Korngold ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Cell Repertoire ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Repertoire Diversity ◽  
Reduced Intensity

Abstract Abstract 3054 Background: A clearly superior graft-versus-host disease (GVHD) prophylaxis regimen has not been established for patients undergoing reduced intensity allogeneic hematopoetic stem cell transplantation (HSCT) from matched unrelated donors (URD). Encouraging results have been reported with both the combination of alemtuzumab and cyclosporine (AC) and the regimen of tacrolimus, methotrexate, and sirolimus (TMS) in the URD setting. These two regimens work by biologically distinct mechanisms and may have markedly different effects on immune reconstitution. T-cell receptor (TCR) spectratyping analysis, which provides information on antigen receptor diversity, is a valuable method for monitoring post-transplant immune reconstitution. As part of a randomized pilot study, we prospectively assessed the effects of AC vs. TMS on TCR Vb repertoire diversity in patients undergoing reduced intensity HLA-matched unrelated donor transplantation. Methods: Twenty patients (median age 53 yrs; range 24–70 yrs) with hematologic malignancies received reduced intensity conditioning (fludarabine 30 mg/m2/day and cyclophosphamide 1200 mg/m2/day IV Day -6 to -3) followed by a 10/10 HLA-matched unrelated donor T-cell replete mobilized peripheral blood allograft. Patients were randomized to receive either: AC (n=10): alemtuzumab 20 mg/day IV over 8 hours Days -8 to -4 and cyclosporine starting at Day -1 with a 10% per week taper starting at Day +100 or TMS (n=10): tacrolimus and sirolimus starting at Day -3 with a 33% taper at Day +63 and Day +119 and methotrexate 5 mg/m2 IV, Days +1, +3, +6, and +11. Blood samples were collected from the donor and patient at baseline and the patient at 1, 3, 6 and 12 months post-transplant for TCR spectratyping analysis. All comparisons are based on an exact Wilcoxon rank sum test; p values < 0.01 were significant because of multiple comparisons. Results: Patients on the AC arm had significantly fewer T-cells on Day +14 compared with the TMS arm (median CD3+ = 1 cells/μl vs 356 cells/μl; CD4+ = 0 cells/μl vs 243 cells/μl; CD8+ = 0 cells/μl vs. 59 cells/μl; each p<0.0001); there was less disparity at Day +28 (median CD3+ = 45 cells/μl vs. 398 cells/μl; CD4+ = 36 cells/μl vs. 218 cells/μl; CD8+= 5 cells/μl vs 152 cells/μl; each p 0.002). By Day +100, lymphocyte recovery was not appreciably different between the two arms (median CD3+ = 242 cells/μl vs. 445 cells/μl (p = 0.095): CD4+ = 106 cells/μl vs. 212 cells/μl (p=0.28); CD8+ = 72 cells/μl vs. 135 cells/μl (p = 0.03). NK-cell recovery was slightly less in the AC vs. TMS arm at Day +14 (median NK = 27 cells/μl vs. 70 cells/μl; p = 0.01) and at Day +28 (median NK = 29 cells/μl vs. 150 cells/μl; p=0.02). There was no difference by Day +100 (median NK = 124 cells/μl vs. 88 cells/μl; p=0.31). B-cell reconstitution was negligible in both arms through Day +100. Assessment of CD4+ TCR Vb repertoire diversity by spectratyping demonstrated significantly lower diversity in patients receiving AC at 1 (p = 0.0003), 3 (p = 0.0003) and 6 (p=0.003) months post transplant compared with patients receiving TMS. CD8+ TCR spectratyping similarly revealed significantly reduced diversity in the AC arm at 3 (p = 0.001) and at 6 months (p = 0.003), and a trend toward significance at 12 months (p = 0.07). On each of the 2 arms, 2 of 10 patients developed acute Grade II-IV GVHD. Of the 5 patients on the AC arm who were seropositive for CMV, all 5 reactivated CMV by PCR within the first 60 days and reactivated 2–5 times in the first year. In contrast, only 3 of 5 seropositive patients reactivated CMV on the TMS arm and only one reactivated in the first 60 days. Conclusions: Two factors may have contributed to the loss of repertoire diversity in the AC arm. First, the alemtuzumab regimen may have severely depleted the infused donor T-cells. Second, stimulation by reactivating virus may have induced expansion of CMV-specific memory and effector T-cells, resulting in a skewed and oligoclonal T-cell repertoire. Especially in CD8+ T-cells, CMV has been shown to produce significant oligoclonal expansion (including CD4+: CD8+ ratio inversion). The loss of T-cell numbers and repertoire may in turn have contributed to the prevalence of early CMV reactivation. Thus, despite the similarities in frequency of acute GVHD in this small sample, it appears that these two commonly used GVHD prophylaxis regimens have very different effects on post-transplant immune reconstitution in the first 6 months after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

Defining The Optimal Dose Of Alemtuzumab In Unrelated Donor Reduced Intensity Allografts: A UK Retrospective Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4540-4540
Author(s):  
Kile Green ◽  
Rob Sellar ◽  
Laura Jardine ◽  
Janice Ward ◽  
Paul Ferguson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Study ◽  
High Risk ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Reduced Intensity ◽  
Grade Iii

Acute and chronic graft versus host disease (GVHD) represent major causes of morbidity and mortality following reduced intensity unrelated donor allografts, particularly in older patients. Alemtuzumab (AL, humanised anti-CD52 antibody) is highly effective at reducing the incidence of both forms of GVHD. There are a number of reported schedules used in this setting, with doses of between 50-100mg AL administered over 2-5 days. The timing of AL administration relative to stem cell return is also likely to have a significant impact on the depletion of donor T cells, but comparative data for unrelated donor transplants are lacking and the optimal dose and schedule remain unknown. In this three-centre retrospective study, we compared the post-transplant outcomes of patients receiving the same chemotherapeutic backbone of fludarabine 150mg/m2 and melphalan 140mg/m2 (flu-mel) along with the originally described AL regimen (100mg administered as 20mg/day, day -7 to -3, n=79), with those of patients receiving flu-mel and one of two alternative AL schedules: 60mg administered as 30mg/day, day -4 and -2, n=72; or 50mg administered as 10mg/day, day -7 to -3, n=107. In keeping with prior pharmacokinetic studies of de-escalating schedules in sibling donor cohorts, the day 1 serum AL levels in the 60mg cohort (median 4.7 mcg/ml, range 1.75-8.02 mcg/ml, n=14), did not differ significantly from historical data for the 100mg schedule. Donor lymphocyte infusions were given for mixed chimerism in all centres according to similar schedules starting at 6 months post transplantation. Median age at transplantation differed significantly between cohorts at 52, 45 and 56 years for the 100mg, 60mg and 50mg cohorts respectively (p = 0.005). Other statistically significant differences between cohorts were CMV status (p = 0.006) and disease indication (p = 0.0005); with AML patients constituting a majority in the 50mg cohort and lymphoproliferative disorder patients a majority in the 100mg cohort. No significant differences were detected between cohorts for HLA matching status (mismatched in 21/79 [27%], 12/72 [17%] and 33/107 [31%] respectively, p = 0.11), graft type (p = 0.06), or disease status at transplantation (p = 0.09). The incidences of acute grade II-IV GVHD were 35%, 32%, and 38% (p = 0.6) for the 100mg, 60mg and 50mg cohorts respectively, whilst those for grade III-IV GVHD were 4%, 6%, and 15% (p = 0.02). The corresponding incidences of chronic GVHD at 2 years were 29%, 28% and 39% respectively (p = 0.38). A trend towards a higher incidence of chronic GVHD in the 50mg cohort was confirmed by comparison with the combined data for the other 2 cohorts (29% vs 39%, p = 0.17). In the high-risk CMV cohort (seropositive recipient), reactivation requiring anti-viral therapy occurred in 97%, 77% and 76% respectively (p = 0.02). The incidences of full donor T-cell chimerism (>97% donor according to assay sensitivity) at day 100 were 56%, 29% and 44% respectively (p = 0.02). There were no significant differences with respect to non-relapse-related mortality at two years post-transplant (28%, 27% and 29% respectively, p = 0.57). Although univariate analyses of relapse rates and overall survival were confounded by the differences in patient characteristics between cohorts, no significant differences were observed (relapse rate at 3 years 20%, 20%, and 26%, p = 0.39; overall survival at 3 years 59%, 64% and 37%, p = 0.05). In conclusion, this study represents the first attempt to define an optimal dosing schedule for AL in unrelated donor allograft recipients, and suggests that significant reduction in AL dose is achievable for patients receiving flu-mel conditioning with unrelated donor grafts. There was evidence of more acute grade III-IV GVHD with the 10mg/day x5 schedule, and a trend towards a higher incidence of chronic GVHD, whilst the 30mg/day x2 schedule delivered similar results to the 20mg/day x5 schedule, perhaps in keeping with the comparable day 1 serum AL levels. Lower alemtuzumab doses were associated with a modest reduction in the risk of CMV reactivation in high-risk patients. Whilst the usual caveats associated with retrospective cross-institutional comparative studies apply, the data suggest that reduction to 30mg/day x2 is not associated with any significant detrimental impact and may be preferable on economic grounds. Disclosures: No relevant conflicts of interest to declare.

Survival after T-Cell Replete Haplo-Identical Related Donor Transplant Using Post-Transplant Cyclophosphamide Compared with Matched Unrelated Donor Transplant for Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 679-679 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Mei-Jie Zhang ◽  
Andrea Bacigalupo ◽  
Asad Bashey ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Treatment Groups ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity ◽  
Donor Transplant

Abstract Background: Increasing numbers of haplo-identical transplants are being performed and the most common approach in the United States includes transplantation of an unmanipulated graft with tacrolimus, mycophenolate and post-transplant cyclophosphamide for GVHD prophylaxis. In this analysis we compare the early outcomes after haplo-identical transplantation with this GVHD prophylaxis with that after conventional HLA-matched unrelated donor transplant approaches (MUD). Methods: Included are 2174 patients with AML aged 21-70 years and transplanted between 2008 and 2012. Cox regression models were built for recipients of myeloablative (N=1245 MUD compared with N=104 haplo-identical) and reduced intensity (N=737 MUD compared with 88 haplo-identical) conditioning transplants. Primary endpoint was 2-year overall survival. With median follow-ups of 2-3 years, surviving patients in all treatment groups were censored at 2-years. Results: Characteristics of recipients of myeloablative transplantation were similar across the two treatment groups except peripheral blood (PB) was the predominant graft with calcineurin inhibitor (CNI) with methotrexate the predominant GVHD prophylaxis for the MUD group compared to predominantly BM grafts with CNI, mycophenolate and post-transplant cyclophosphamide for the haplo-identical group. Most regimens were non-irradiation containing, 74% for MUD and 78% for haplo-identical transplants. Characteristics of recipients of reduced intensity conditioning transplants differed by treatment groups; recipients of MUD transplants were older (median age 62 vs. 57 years), more likely to report performance score 80 or lower, be in first complete remission at transplantation and shorter interval from diagnosis to transplantation. PB was the predominant graft for MUD and BM, for haplo-identical transplants. The conditioning regimen for reduced intensity haplo-identical transplants was uniform (TBI 200 cGy, cyclophosphamide, fludarabine) and for MUD transplants, it was predominantly an alkylating agent and fludarabine (79%). Day-30 cumulative incidence of neutrophil recovery was higher after myeloabative MUD compared with haplo-identical transplants (97% vs. 90%, p=0.01). Neutrophil recovery was not different after MUD and haplo-identical reduced intensity conditioning transplants (96% vs. 93%, p=0.25). Table 1 shows the results of multivariate analysis for non-relapse mortality (NRM), relapse and overall survival. Overall survival is not significantly different after haplo-identical and MUD transplants with either the myeloablative or reduced intensity conditioning approaches. The 2-year survival rates adjusted for age, disease status and interval from diagnosis to transplant after myeloablative MUD and haplo-identical transplantation were 54% (95% CI 51-57) and 47% (95% CI 37-57), respectively (p=0.22). The corresponding 2-year survival rates after reduced intensity conditioning transplantation were 49% (95% CI 45-53) and 53% (95% CI 42-63), p=0.25. We also explored for difference in survival with in vivo T-cell depletion in the myeloablative (HR 0.81, p=0.19) and reduced intensity (HR 1.18, p=0.33) MUD groups compared with the corresponding haplo-identical groups (baseline HR 1.00) and found none. We tested for a transplant center effect on survival and found none. Conclusion: With the available data, 2-year survival rates for AML after myeloablative or reduced intensity conditioning transplants are comparable after conventional MUD transplant approaches and haplo-identical transplant with the post-transplant cyclophosphamide approach. Longer follow-up of haplo-identical transplant recipients as well as confirmation of these findings in a larger population, are needed before wide spread adoption of selecting haplo-identical donors over HLA-matched unrelated donors. Table Transplant Conditioning Regimen Outcomes Myeloablative Hazard Ratio Reduced intensity Hazard Ratio NRM Haplo-identical 1.00 1.00 MUD 1.07; p=0.82 2.35; p=0.03 Relapse Haplo-identical 1.00 1.00 MUD 0.88; p=0.40 0.76; p=0.09 Survival Haplo-identical 1.00 1.00 MUD 0.93; p=0.61 1.13; p=0.46 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Reduced Intensity Allogeneic Tranplants Are Well Tolerated In Patients Over the Age of 60: Identification of Factors Predicting Overall Survival

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2361-2361
Author(s):  
Emmanouil Nikolousis ◽  
Sandeep Nagra ◽  
Janice Ward ◽  
Fiona L Dignan ◽  
Bronwen E. Shaw ◽  
...  
Keyword(s):  
Overall Survival ◽  
Older Patients ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Post Transplant ◽  
Comorbidity Index ◽  
Bed Days ◽  
Disease Free ◽  
Reduced Intensity

Abstract Abstract 2361 Introduction: Reduced intensity allogeneic transplants represent a potentially curative therapy in older patients with haematological malignancies. However the upper age limit for transplantation using a sibling or unrelated donor is unclear and few studies have addressed this important issue. In the UK in vivo T cell depletion utilising alemtuzumab is commonly used as a strategy to reduce the risk of acute and chronic graft-versus-host disease (GVHD) but this manoeuvre impairs immune reconstitution and may pose a particular problem in older patients. Aim: We analysed the outcome of patients over the age of 60 after an alemtuzumab based reduced intensity allograft from five UK Transplant Centres with the aim of identifying factors determining long term outcome and also factors affecting the duration of inpatient admission during the first 100 days post transplant. A modified Charlson's comorbidity index score (Sorror modified HCT comorbidity index) was applied to analyse the transplant outcomes of these patients according to the presence of transplant co-morbidities. Patients and Methods: We have studied the outcome of 161 patients (89 male, 72 female) after an alemtuzumab conditioned reduced allograft allograft for a haematological malignancy. The median age of the patients was 62 years(range 60–72). 115 patients had a transplant for myeloid malignancies (87 acute myeloid leukaemia, 21 myelodysplastic syndrome, 2 chronic myeloid leukaemia, 5 myelofibrosis) and 46 for lymphoid malignancies (18 Non_Hodgkin's lymphoma, 14 chronic lymphocytic leukaemia, 4 T-prolymphocytic leukaemia, 7 multiple myeloma and 3 acute lymphoblastic leukaemia). 93 patients received an unrelated donor transplant and 68 had a sibling transplant. The great majority of patients were transplanted using a Fludarabine/Melphalan conditioning regimen(n=118) whilst 13 received a combination of fludarabine and busulphan, 21 BEAM (BCNU, cytarabine, etoposide, melphalan) and 9 a combination of BEAM and fludarabine. The median follow up was 19.1 months (range 2–94 months). Results: The one year overall survival for the whole group was 52% and the predicted two year OS 46%. The transplant related mortality (TRM) was 19% in the first 100 days post transplant and 23% in the first year post transplant. 40 patients (25%) relapsed. 25 patients (21%) developed Grade III-IV acute GvHD and 16 (10%) patients developed chronic extensive GvHD. There was a weakly negative correlation between Age and Bed Days(p:0.05843) but the correlation between high comorbidity index (3 or greater than 3) and increased bed days is significant(P:0.0013). Transplant outcomes were affected by Sorror modified comorbidity index for HCT.A score of 3 and above was significantly associated with decreased overall survival (P:0.001) and interestingly with decreased disease free survival (P:0.02). CMV status and stem cell dose did not have any impact on overall survival and disease free survival and CR1 at transplantation was showed a trend towards increased overall survival(P:0.05). Conclusions: Reduced intensity alemtuzumab based stem cell transplant can be delivered safely in patients above the age of 60. It appears that a Sorror comorbidity score of 3 and above has a negative impact on overall survival and disease free survival of these patients and significantly increases inpatient days.These observations require confirmation in a larger cohort of patients but suggest that the selection of patients above the age of 60 for a reduced intensity transplants will be facilitated by incorporation of the Sorror HCI comorbidity index into a transplant algorithm. 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.

Donor Characteristics Affecting Graft Failure and Survival after Unrelated Donor Transplantation with Reduced Intensity Conditioning Regimens (RIC) for Hematologic Malignancies.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1968-1968
Author(s):  
Jakob R. Passweg ◽  
Fangyu Kan ◽  
Mei-Jie Zhang ◽  
Vanderson Rocha ◽  
Luis M. Isola ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Resolution ◽  
Graft Versus Host Disease ◽  
Graft Failure ◽  
Unrelated Donor ◽  
Neutrophil Recovery ◽  
Graft Versus Host ◽  
Donor Characteristic ◽  
Conditioning Regimens ◽  
Donor Characteristics

Abstract Impact of donor characteristics is well described for standard intensity unrelated donor and matched sibling donor transplants but may differ in recipients of unrelated donor RIC transplants. Less immunosuppressive regimens at transplantation may lead to higher graft failure rates. We examined risk factors affecting graft failure, acute and chronic graft-versus-host disease (GVHD) and survival after RIC unrelated donor transplants in 715 patients with acute (n=394) and chronic leukemia (n=74), myelodysplastic syndrome (n=70) and non-Hodgkin lymphoma (n=177). Graft failure was defined as &lt;5% donor chimerism within 3 months after transplantation. 159 patients received bone marrow (BM) and 556 peripheral blood (PB) grafts. All transplantations occurred in 1999–2006 in the US. Median follow-up of surviving patients was 36 months (range 6–92). All donors and recipients were typed for HLA A, B, C and DRB1 using high resolution molecular methods. Mismatches at low resolution (antigen) and high resolution (allele) were considered together and are described collectively as mismatches. The day-28 incidence of neutrophil recovery (≥ 0.5 x 109/L) was 96%. After initial neutrophil recovery most patients (n=506) had &gt;95% donor chimerism. 63 patients had &lt;5% donor cells and the remaining 146 patients, 5–95% by 3-months post-transplant. In multivariate analysis, the only factor associated with graft failure was transplantation of BM vs. PB grafts (odds ratio 2.36, p=0.002). We specifically looked for an effect of donor-recipient sex match on graft failure and female donor parity on GvHD and found none. As expected risks of acute graft-versus-host disease (GVHD) were higher after mismatched transplants (p=0.015). No donor characteristic was associated with chronic GVHD. The only donor characteristic affecting overall survival was donor-recipient HLA disparity: 3-year overall survival rates were significantly lower at 23% after mismatched transplants compared to 42% after HLA-matched transplants (p=0.008). Additionally, mortality rates were significantly higher in patients older than 50 years (p=0.005), performance score &lt;90 (p=0.002) and when transplantation occurred with active disease (p&lt;0.001). As seen in recipients of myeloablative conditioning regimens, the only donor characteristic associated with survival is donor-recipient HLA disparity. Donor age, donor-recipient sex match, donor parity and donor cytomegalovirus serostatus were not associated graft failure or survival after unrelated donor RIC transplants.

scholarly journals Haploidentical Vs. Matched Unrelated Donor Transplants Using Post-Transplant Cyclophosphamide for Lymphoma: A Joint CIBMTR/EBMT Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 174-174
Author(s):  
Alberto Mussetti ◽  
Abraham S. Kanate ◽  
Tao Wang ◽  
Meilun He ◽  
Mehdi Hamadani ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Retrospective Studies ◽  
Cell Lymphoma ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Reduced Intensity

Abstract Introduction: Post-transplant cyclophosphamide (PTCy) is a standard GVHD prophylactic approach for haploidentical hematopoietic cell transplantation (haploHCT). Retrospective studies in patients with lymphoma showed lower chronic GVHD in haploHCT with PTCy-based GVHD prophylaxis compared to matched unrelated donor (MUD) HCT with calcineurin-based GVHD prophylaxis (+/- ATG). Recent retrospective studies showed that using MUD donors was better than haplo donors when PTCy and reduced-intensity conditioning are used for ALL, AML or MDS. However, no studies to date have compared haploHCT and MUD HCT when PTCy is used in the setting of lymphomas. Methods: 2155 adults (730 CIBMTR, 1425 EBMT) aged =/&gt;18 years who received their first haploHCT or MUD HCT (8/8 match at HLA-loci A, B, C and DRB1) using PTCy from 2010-2019 for lymphoma were included. The majority of both MUD (n=312; 14%) and haplo (n=1843; 86%) HCTs received reduced intensity/non-myeloablative conditioning (n=1655; 77%) using a peripheral blood stem cell graft (n=1379; 64%) and a three-drug GVHD prophylaxis (PTCy + calcineurin inhibitor + MMF, n=1805; 84%). Hodgkin's lymphoma was the most common indication (n=899; 42%) followed by diffuse large B-cell lymphoma (n=525; 24%), T-cell lymphomas (n=328; 15%), mantle cell lymphoma (n=234; 11%) and follicular lymphoma (n=169; 8%). Most had chemosensitive disease at transplant (n=1781; 83%). Some main characteristics of the two cohorts are shown in Figure 1. Median follow-up among survivors was longer for haplo-HCT (36 and 31 months for the CIBMTR and EBMT cohort, respectively) than MUD-HCT (24 and 17 months, respectively). Cox proportional hazards models were built using stepwise forward and backward selection with a selection/retention threshold of 0.05. Any clinical variables that did not meet the proportional hazard assumption were adjusted for by stratification, and regression models were built to compare outcomes between donor types. Center effect was adjusted in all the models. Results: Figures 2 and 3 show the multivariate analysis results. Overall survival was 73% (71-75%) at 1 year and 65% (63-67%) at 2 years. Relapse was 21% (20-23%) at 1 year and 26% (24-28%) at 2 years. All outcomes favored MUD over haplo donors with the use of PTCy-based GVHD prophylaxis for both. Conclusions: Patients with lymphoma receiving PTCy HCT from MUDs demonstrated better outcomes than those with haplo donors in this retrospective study of CIBMTR and EBMT data Future prospective studies are needed to confirm and clarify the reasons for these differences. Figure 1 Figure 1. Disclosures Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Glass: Novartis: Consultancy; Riemser: Research Funding; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Dreger: Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Sureda: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau.

scholarly journals Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3285-3285
Author(s):  
Rebeca Bailén ◽  
Mi Kwon ◽  
Maria Jesus Pascual-Cascon ◽  
Anna Torrent ◽  
Christelle M Ferra ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cumulative Incidence ◽  
High Dose ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation (SCT) with Fludarabine and Intravenous Busulfan Is Associated with Improved Toxicity Profile and Longer Survival Than Conditioning with Fludarabine and Melphalan in Patients with Chemo-Sensitive Hematological Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2002-2002
Author(s):  
Avichai Shimoni ◽  
Izhar Hardan ◽  
Avital Rand ◽  
Noga Shem-Tov ◽  
Ronit Yerushalmi ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Graft Failure ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Organ Toxicity ◽  
Increased Risk ◽  
Reduced Intensity ◽  
Grade Iii

Abstract Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic SCT. They are more effective when the underlying malignancy is in remission at the time of SCT. Various RIC regimens have been designed, yet there is no defined data as to whether any of the regimens has an advantage over the others. To answer this question we retrospectively analyzed SCT outcomes in 100 consecutive patients (pts) given RIC for various hematological malignancies including AML/MDS (n=45), ALL (n=8), CML (n=6), multiple myeloma (MM, n=18), various lymphomas (n=19), others (n=4). All pts were considered not eligible for myeloablative conditioning and were required to have chemo-sensitive disease at SCT. The median age was 56 years (23–75). Donors were HLA-matched siblings (n=53) or matched unrelated (n=47). RIC consisted of fludarabine with intravenous busulfan (6.4 mg/kg; FB, n=62) or with melphalan (100–140 mg/m2; FM, n=38). The FB group included older pts; median age 59(23–75) compared with 51(27–66) years in the FM group (p&lt;0.001). The FB group included more pts with acute leukemia (66% vs 32%) while the FM group included more pts with MM (42% vs 2%, p&lt; 0.0001) and also more pts with a prior autologous SCT (42% vs. 21%, p=0.02). Donor type was not different between the regimens. 93 pts engrafted, 2 died early and 5 had primary graft failure, 3 after FB and 2 after FM (p=NS). The median time to engraftment was not different among groups. NCI grade III–IV organ toxicity occurred in 13 (21%) and 17 pts (45%) after FB and FM, resulting in 4 and 1 deaths, respectively (p=0.04). The cumulative incidence of acute GVHD grade II–IV were 20% and 43% (p=0.004) and the rates of grade III–IV were 6% and 19% (p=0.03), respectively. The cumulative incidence of chronic GVHD was 44%; not different between the regimens. The 1-year non-relapse mortality (NRM) rate was 10% after FB (6 pts; 1 graft failure, 1 organ toxicity, 2 GVHD, 2 infections) and 27% after FM (10 pts; 1 graft failure, 4 organ toxicity, 4 GVHD, 1 infection)(p=0.03). Relapse rate was not statistically different between the regimens; 38% and 50% after FB and FM, respectively (p=NS). With a median follow-up of 28 months (1–80), 58 pts are alive and 42 have died (18 NRM including 2 late events in the FB group, 24 of relapse). 43 FB and 15 FM recipients are alive with an estimated 3-yr survival rate of 59%(95CI, 43–75) and 26%(95CI, 8–44, p=0.007). Disease-free survival rates were 46%(95CI, 31–61) and 28%(95CI, 12–43, P=0.03), respectively. Multivariable analysis determined that FM conditioning was associated with shorter survival (HR, 2.9 (1.2–7.0), p=0.02) while SCT from an unrelated donor was of borderline significance (HR, 1.8 (1.0–3.3), p=0.06). Age, disease type and prior autologous SCT were not predictive of survival in this cohort. In conclusion, there are marked differences in SCT outcomes between RIC regimens that are theoretically equivalent in dose intensity. The FM regimen in the doses used is more toxic. It was associated with higher incidence of NRM due to increased risk of both organ toxicity and acute GVHD. FM offered no advantage in disease control in pts with chemo-sensitive disease, thus reduced toxicity with FB translated into improved survival. These observations merit further study in more homogeneous pt population and in prospective studies.

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