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Umbilical cord blood or HLA-haploidentical transplantation: Real world outcomes vs randomized trial outcomes
O'Donnell, P. V., Brunstein, C. G., Fuchs, E. J., Zhang, M. J., Allbee-Johnson, M., Antin, J. H., Leifer, E. S., Elmariah, H., Grunwald, M. R., Hashmi, H., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND Randomized clinical trials offer the highest quality data for modifying clinical practice. Results of a phase III randomized trial of non-myeloablative transplantation for adults with high- risk hematologic malignancies with two umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM) (n=154) revealed 2-year progression-free survival (PFS) of 41% and 35% after Haplo-BM and two-unit UCB transplantation, respectively (p=0.41); overall survival was 57% and 46%, respectively (p=0.04), BMT CTN 1101; NCT01597778. OBJECTIVES We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's pre-specified 2-year outcomes. All transplantation occurred between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial will be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM to those after haploidentical peripheral blood (Haplo-PB). STUDY DESIGN The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select non-trial subjects. Extended follow up of trial subjects was obtained from this data source. Three separate analyses were performed: 1) trial subjects beyond the trial's 2-year endpoint 2) comparison of trial subjects to a contemporaneous cohort of non-trial subjects (195 two-unit UCB, 358 Haplo-BM, 403 Haplo-PB) and 3) comparison of non-trial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. RESULTS With longer follow up of the trial cohorts, 5-year PFS (37% versus 29%, p=0.08) and overall survival (42% versus 36%, p=0.06) were not significantly different between treatment groups. We then compared the trial results to comparable real-world transplantations. Five-year overall survival after trial and non-trial two-unit UCB (36% versus 41%, p=0.48) and trial and non-trial Haplo-BM (42% versus 47%, p=0.80) transplantation were not different confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in progression-free survival. With substantially larger numbers of non-trial Haplo-BM transplantations, 5-year survival was higher after non-trial Haplo-BM compared to trial two-unit UCB (47% versus 36%, p=0.012). Non-trial patients who received Haplo-PB transplantation had higher 5-year survival (54%) compared to trial (HR 0.76, p=0.044) and non-trial (HR 0.78, p=0.026) Haplo-BM. Similarly, survival was higher after Haplo-PB compared to trial (HR 0.57, p<0.0001) and non-trial UCB (HR 0.63, p=0.0002). CONCLUSION When considering alternative donor low intensity conditioning regimen transplantation, a haploidentical relative is preferred. Further, PB is the preferred graft.
PICO Summary
Population
Patients enrolled on the BMT CTN 1101 trial (n=337), and non-trial patients identified from the CIBMTR database (n=956), who met the criteria for BMT CTN 11001 but were not enrolled (total n=1293)
Intervention
two umbilical cord blood (UCB) units (trial: n=183, non-trial: n=195; total n=378)
Comparison
HLA-haploidentical relative bone marrow (Haplo-BM, trial: n=154, non-trial: n=358; total n=512); Non-trial cohort undergoing peripheral blood haploidentical transplant (Haplo-PB, n=403)
Outcome
With longer follow up of the trial cohorts, 5-year PFS (37% versus 29%, p=0.08) and overall survival (42% versus 36%) were not significantly different between treatment groups. We then compared the trial results to comparable real-world transplantations. Five-year overall survival after trial and non-trial two-unit UCB (36% versus 41%) and trial and non-trial Haplo-BM (42% versus 47%) transplantation were not different confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in progression-free survival. With substantially larger numbers of non-trial Haplo-BM transplantations, 5-year survival was higher after non-trial Haplo-BM compared to trial two-unit UCB (47% versus 36%). Non-trial patients who received Haplo-PB transplantation had higher 5-year survival (54%) compared to trial (HR 0.76) and non-trial (HR 0.78) Haplo-BM. Similarly, survival was higher after Haplo-PB compared to trial (HR 0.57) and non-trial UCB (HR 0.63).
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HLA Informs Risk Predictions after Haploidentical Stem Cell Transplantation with Post-transplantation Cyclophosphamide
Fuchs, E. J., McCurdy, S. R., Solomon, S. R., Wang, T., Herr, M. M., Modi, D., Grunwald, M. R., Nishihori, T., Kuxhausen, M., Fingerson, S., et al
Blood. 2021
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Editor's Choice
Abstract
Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence and survival after haploidentical donor transplantation with post-transplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.
PICO Summary
Population
Patients undergoing transplant for acute leukaemia or myelodysplastic syndrome at centres reporting to the CIBMTR (n=1434)
Intervention
The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods.
Comparison
None
Outcome
Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics.
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Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial
Fuchs, E. J., O'Donnell, P. V., Eapen, M., Logan, B., Antin, J. H., Dawson, P., Devine, S., Horowitz, M. M., Horwitz, M. E., Karanes, C., et al
Blood. 2021;137(3):420-428
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Editor's Choice
Abstract
Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.
PICO Summary
Population
Patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukaemia in remission (n=368)
Intervention
Cord blood transplantation (UCB, n=186)
Comparison
Haploidentical transplantation (n=182)
Outcome
Two-year PFS was 35% after UCB compared with 41% haploidentical transplant. Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB: 18%, compared with 11% for haploidentical transplantation. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% and 57%, respectively. The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources.
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Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis
Goldsmith, S. R., Abid, M. B., Auletta, J. J., Bashey, A., Beitinjaneh, A., Castillo, P., Chemaly, R. F., Chen, M., Ciurea, S. O., Dandoy, C. E., et al
Blood. 2021
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Editor's Choice
Abstract
Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
PICO Summary
Population
Patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or myelodysplastic synrome (n=2765)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (HaploCy, n=757),
Comparison
Sibling donor with post-transplant cyclophosphamide (SibCy, n=403), or Sibling donor with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605)
Outcome
Cumulative incidences of CMV infection by day 180 were 42% (HaploCy), 37% (SibCy), and 23% (SibCNI), respectively. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3; SibCy (n=279): HR 47.7; SibCNI (n=1065): HR 24.4. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD. PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy.
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HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis
Gooptu, M., Romee, R., St Martin, A., Arora, M., Al Malki, M., Antin, J. H., Bredeson, C. N., Brunstein, C. G., Chhabra, S., Fuchs, E. J., et al
Blood. 2021;138(3):273-282
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Editor's Choice
Abstract
Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate 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 from 2011 through 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% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and 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.
PICO Summary
Population
Patients reported to the CIBMTR registry, undergoing transplantation for acute leukaemia or myelodysplastic syndrome (n=2320)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (PTCy) (Haplo, n=2036)
Comparison
Matched unrelated donor transplantation with PTCy prophylaxis (MUD, n=284)
Outcome
Recipients of myeloablative and reduced-intensity regimens were analysed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazard ratio [HR], 0.70), acute grades 3 and 4 GVHD (HR, 0.41), and nonrelapse mortality (HR, 0.43) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; 55% vs 41%) and overall (HR, 0.65; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39) and chronic GVHD (HR, 0.66) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens.
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HLA Haploidentical versus Matched Unrelated Donor Transplants with Post-Transplant Cyclophosphamide based prophylaxis
Gooptu, M., Romee, R., St Martin, A., Arora, M., Al Malki, M. M., Antin, J. H., Bredeson, C. N., Brunstein, C. G., Chhabra, S., Fuchs, E. J., et al
Blood. 2021
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Editor's Choice
Abstract
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.
PICO Summary
Population
Adults with acute leukaemia or myelodysplastic syndrome, undergoing transplantation with post-transplant cyclophosphamide (n=2320)
Intervention
Matched unrelated donor transplantation (n=284)
Comparison
Haploidentical transplantation (n=2036)
Outcome
Among recipients of reduced intensity regimens, 2-year graft failure (3% versus 11%), acute grade II-IV GVHD (HR 0.70), acute grade III-IV GVHD (HR 0.41) and non-relapse mortality (HR 0.43) were lower after MUD compared to Haplo transplantation. Consequently, disease-free (HR 0.74 55% versus 41%) and overall survival (HR 0.65, 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) and chronic GVHD (HR 0.66) 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.
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Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients
Brunstein, C. G., DeFor, T. E., Fuchs, E. J., Karanes, C., McGuirk, J. P., Rezvani, A. R., Eapen, M., O'Donnell, P. V., Weisdorf, D. J.
Transplantation and cellular therapy. 2021;27(10):879.e1-879.e3
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Editor's Choice
Abstract
To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P = .64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.
PICO Summary
Population
Adults aged up to 70 years with acute leukaemia or lymphoma, enrolled in BMT CTN 1101 trial, and who received a double cord blood (dUCB) graft (n=179)
Intervention
Total body irradiation (TBI) conditioning 200 cGy (n=161)
Comparison
Total body irradiation (TBI) conditioning 300 cGy (n=18)
Outcome
The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy, which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality.
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Shortened-duration immunosuppressive therapy after nonmyeloablative, related HLA-haploidentical or unrelated peripheral blood grafts and post-transplantation cyclophosphamide
DeZern, A. E., Elmariah, H., Zahurak, M., Rosner, G. L., Gladstone, D. E., Ali, S. A., Huff, C. A., Swinnen, L. J., Imus, P., Borrello, I., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IS) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but, given the higher rates of GVHD with PB, excessive GVHD becomes an increased concern. We present a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB transplantation. Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BM transplantation and PTCy, received NMA PB allografts on trial. The primary objective was to evaluate the safety and feasibility of reduced-duration IS (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2). Of the 117 patients (median age 64 years, range 22-78), the most common diagnoses were myelodysplastic syndrome (33%), acute myeloid leukemia (with minimal residual disease or arising from antecedent disorder) (32%), myeloproliferative neoplasms (19%) myeloma (9%), and chronic lymphocytic leukemia (7%). Shortened IS was feasible in 75 pts (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 pts), followed by early relapse (11 pts), non-relapse mortality (NRM) (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned. Of the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV GVHD was 21 days and 32 days in the day 90 and day 60 cohorts respectively, with almost all cases developing within 40 days. Approximately one-third of these patients did restart IS. All outcome measures were similar in the 2 cohorts and to our historical outcomes with 180 days of IS. The cumulative incidence of grade 3-4 acute GVHD were low at 2 and 7% in D90 and D60, respectively. Severe chronic GVHD was 9% (D90) and 5% (D60) at 2 years. The two year overall survival was 67% for both the D90 and D60 cohorts, The two year progression free survival was 47% for the Day 90 cohort and 52% for the Day 60 cohort with the GVHD-free relapse-free survival less than 35% for both cohorts. These data suggest that reduced-duration IS in pts receiving NMA PB grafts with PTCy is feasible and carries an acceptable safety profile.
PICO Summary
Population
Patients with hematologic malignancies associated with higher rates of graft failure (n=117)
Intervention
Non-myeloablative haploidentical transplant with immunosuppression days 5-90 (D90 cohort, n=57)
Comparison
Non-myeloablative haploidentical transplant, with immunosuppression days 5-60 (D60 cohort, n=60)
Outcome
Shortened immunosuppression (IS) was feasible in 75 pts (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 pts), followed by early relapse (11 pts), non-relapse mortality (NRM) (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned. Of the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV GVHD was 21 days and 32 days in the day 90 and day 60 cohorts respectively, with almost all cases developing within 40 days. Approximately one-third of these patients did restart IS. All outcome measures were similar in the 2 cohorts and to our historical outcomes with 180 days of IS. The cumulative incidence of grade 3-4 acute GVHD were low at 2 and 7% in D90 and D60, respectively. Severe chronic GVHD was 9% (D90) and 5% (D60) at 2 years. The two year overall survival was 67% for both the D90 and D60 cohorts, The two year progression free survival was 47% for the Day 90 cohort and 52% for the Day 60 cohort with the GVHD-free relapse-free survival less than 35% for both cohorts.
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9.
Double unrelated umbilical cord blood versus HLA-haploidentical bone marrow transplantation (BMT CTN 1101)
Fuchs, E. J., O'Donnell, P. V., Eapen, M., Logan, B. R., Antin, J. H., Dawson, P., Devine, S. M., Horowitz, M. M., Horwitz, M. E., Karanes, C., et al
Blood. 2020
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Editor's Choice
Abstract
Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).
Clinical Commentary
Dr. Julia Wolf, University Hospitals Bristol and Weston NHS Foundation Trust
What is known?
Allogeneic stem cell transplant is a potentially curative treatment option for patients with poor risk or relapsed acute leukaemia or lymphoma. Transplant outcomes are, amongst other factors, dependent on optimal donor selection; despite recent advances, donor availability remains an area of unmet need for many patients. Fully HLA matched sibling donors are the preferred choice but are available in <30% of patients, while fully matched unrelated donor (MUD) transplants are available in <20% of non-Caucasian patients. For patients who lack a HLA matched donor, alternative stem cell sources include double umbilical cord transplant (DUCT) and haploidentical haematopoietic stem cell transplant (HaploSCT). DUCT is associated with low immunogenicity and non-invasive harvesting, but utility is limited by lack of further cell availability, e.g. for donor lymphocyte infusions, as well as cost. A small (n = 45) randomised trial (Sanz, J. et al, 2020) comparing DUCT and HaploSCT in the myeloablative setting showed increased non-relapse mortality in the DUCT group but no significant difference in terms of relapse rates or overall survival (OS). While other data is extensive it is often registry based and retrospective. Prospective data in the reduced intensity setting is limited.
What did this paper set out to examine?
This randomised multi-centre phase III trial set in the United States is the first randomised trial to compare DUCT and HaploSCT for the treatment of leukaemia and lymphoma in adults in the setting of reduced intensity conditioning. It aims to compare the two donor sources in terms of 2-year progression free survival (PFS) as primary endpoint and engraftment, acute and chronic Graft versus Host Disease (GvHD), non-relapse mortality, relapse/progression and OS as secondary endpoints.
What did they show?
The authors compared data from 368 patients (DUCT = 186 vs HaploSCT = 182) enrolled from 33 centres over a 6-year period from 2012 to 2016. The cohort represents 90% of the planned accrual of 410 patients – the trial closed early due to slow accrual. Patients aged 18-70 years with high risk acute leukaemia and lymphoma with good performance score, adequate organ function and available haploidentical donor or double umbilical cord unit were included. Exclusion criteria were fairly selected. Patients were well matched in terms of age, sex, self-reported ethnic origin, performance status, disease and disease status at randomisation. Reduced intensity conditioning comprised cyclophosphamide and fludarabine with total body irradiation for both donor types. GvHD prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil (MMF) and PtCy, tacrolimus and MMF for HaploSCT.
RESULTS: DUCT and HaploSCT were comparable for the primary endpoint of 2-year PFS (35% vs 41%; p=0.41). Analysis of secondary endpoints reached statistical significance for some of the chosen parameters: DUCT was associated with higher 2-year non-relapse mortality (18% vs 11%; p=0.04) and lower OS (46% vs 57%; p=0.04). Death was most commonly attributed to recurrent disease and relapse rates were comparable in both groups (47% in DUCT vs 48% in HaploSCT; p=0.968). HaploSCT showed higher cumulative incidence of neutrophil recovery at day 56 while no difference was seen in platelet recovery. Similar rates of acute and chronic GvHD were observed.
What are the implications for practice and for future work?
While this study didn’t demonstrate a significant difference in its’ primary end point, it showed an OS benefit and lower non-relapse mortality in the HaploSCT arm. Higher non-relapse mortality associated with DUCT may be explained by lack of immunologic memory and associated higher rates of infection, especially in the early post-transplant period. A recent meta-analysis (Poonsombudlert, et al. 2019) concurs that HaploSCT is associated with improved OS but also demonstrated lower relapse rates, lower rates of acute GvHD and higher rates of chronic GvHD in HaploSCT compared with DUCT. These findings were not replicated in this study. Lower non-relapse mortality and improved OS were also reported in a retrospective study of patients with Hodgkin lymphoma (Kosuri, S. et al, 2017) which also demonstrated improved 4-year PFS in HaploSCT compared with DUCT.
While both donor sources improve access to reduced intensity transplantation, improved overall survival and lower non-relapse mortality with comparable GvHD rates shown in this study make HaploSCT an increasingly attractive option for patients without matched sibling transplant.
PICO Summary
Population
Patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukaemia in remission (n=368)
Intervention
Cord blood transplantation (n=186)
Comparison
Haploidentical transplantation (n=182)
Outcome
Two-year progression-free survival was 35% compared to 41% after cord blood and haploidentical transplants, respectively. Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% compared to haploidentical transplantation, 11%. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% and 57%, respectively. The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources.
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10.
Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide
Webster, J. A., Luznik, L., Tsai, H. L., Imus, P. H., DeZern, A. E., Pratz, K. W., Levis, M. J., Gojo, I., Showel, M. M., Prince, G., et al
Blood advances. 2020;4(20):5078-5088
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Editor's Choice
Abstract
Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
PICO Summary
Population
Adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing allogeneic transplantation (n=76)
Intervention
Myeloablative conditioning in first complete remission (CR1 MAC, n=26); Non-myeloablative conditioning in first complete remission (CR1 NMAC, n=43)
Comparison
Patients in second or subsequent remission (CR2+, n=12)
Outcome
For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%.