-
1.
Cost-Effectiveness of Unrelated Umbilical Cord Blood vs. HLA Haploidentical Related Bone Marrow Transplant: Evidence from BMT CTN 1101
Ramsey, S. D., Bansal, A., Li, L., O'Donnell, P. V., Fuchs, E. J., Brunstein, C. G., Eapen, M., Thao, V., Roth, J. A., Steuten, L.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced intensity conditioning followed by double unrelated umbilical cord blood (UCB) versus HLA-haploidentical related donor bone marrow (haplo-BM) transplantation for patients with high-risk hematologic malignancies. OBJECTIVE The objective of this study is to report the results of a parallel cost-effectiveness analysis. STUDY DESIGN Three hundred sixty-eight patients were randomized to unrelated UCB (n=186) or haplo-BM (n=182) transplant. We estimated healthcare utilization and costs using propensity score-matched BMT patients from the OptumLabs(Ⓡ) Data Warehouse for trial participants <65 years and Medicare claims for participants ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used estimate Quality-Adjusted Life Years (QALYs). RESULTS At 5-year follow-up, survival was 42% for haplo-BM versus 36% for UCB (P=.06). Over a 20-year time horizon, haplo-BM is expected to be more effective (+0.63 QALY) and more costly +$118,953) for persons under 65. For those over 65, haplo-BM is expected to be more effective and less costly. In one-way uncertainty analyses, for persons <65, the cost per QALY result was most sensitive to life years and health state utilities. For persons ≥65, life years were more influential than costs and health state utilities. CONCLUSION Compared to UCB, haplo-BM was moderately cost-effective for patients aged <65 years, and less costly and more effective for persons ≥65 years. Haplo-BM is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BM is a preferred choice when considering costs and outcomes.
-
2.
External validation and extended application of the transplant conditioning intensity score in acute myeloid leukemia
Yanada, M., Shimomura, Y., Mizuno, S., Matsuda, K., Kondo, T., Doki, N., Tanaka, M., Fukuda, T., Ara, T., Uchida, N., et al
Bone marrow transplantation. 2023
Abstract
This study aimed to validate the utility of the transplant conditioning intensity (TCI) score in 1714 patients with acute myeloid leukemia (AML) undergoing allogeneic bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) and assess its applicability to 753 patients with AML undergoing umbilical cord blood transplantation (UCBT) both during first complete remission. Patients classified into a high TCI group accounted for 63% and 56% in the BMT/PBSCT and UCBT cohorts, respectively. In the BMT/PBSCT cohort, the risk of relapse was lower in patients in the high versus intermediate TCI group (P = 0.002), although non-relapse mortality (NRM) did not differ among the three TCI groups. In the UCBT cohort, both relapse and NRM did not differ among the TCI groups. Increasing cutoff points for intermediate and high TCI categories significantly improved the ability to predict relapse and NRM in the BMT/PBSCT cohort (P = 0.030 and 0.006, respectively), and relapse but not NRM in the UCBT cohort (P = 0.005 and 0.364, respectively). These findings highlight the difference in the threshold level of the TCI score for outcome discrimination between European and Japanese cohorts. The TCI scheme appears less effective for UCBT than for BMT/PBSCT.
-
3.
Cord blood transplantation with a reduced-intensity conditioning regimen using fludarabine and melphalan for adult T-cell leukemia/lymphoma
Nakano, N., Takatsuka, Y., Kubota, A., Tokunaga, M., Miyazono, T., Tabuchi, T., Odawara, J., Tokunaga, M., Makino, T., Takeuchi, S., et al
International journal of hematology. 2021
Abstract
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma with a poor prognosis when treated with chemotherapy alone; therefore, allogeneic stem cell transplantation is a consideration. We attempted cord blood transplantation (CBT) using a reduced-intensity conditioning regimen without total body irradiation (non-TBI-RIC) to allow for the best possible timing of transplantation and improve survival outcomes, particularly in older patients. Forty-eight patients (27 male, 21 female) underwent CBT using fludarabine (Flu) 125 mg/m(2) and melphalan (Mel) 140 mg/m(2) as pre-transplant conditioning. The median age was 32 years (range 44-72), and 21 patients were in complete remission (CR) at the time of CBT. The median duration to neutrophil engraftment (NE) was 19.5 days (range 15-50), with a cumulative incidence of NE of 86.7% at day 50 after CBT. The 1- and 3-year overall survival (OS) rates were 40.4% and 37.7%, respectively. The 3-year OS rate in CR patients was 60.8%, compared with 18.8% in non-CR patients. In ATLL patients, CBT with non-TBI-RIC using Flu/Mel is a promising treatment strategy.
-
4.
Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children
Sawada, A., Shimizu, M., Koyama-Sato, M., Higuchi, K., Okada, Y., Goto, K., Inoue, S., Yasui, M., Inoue, M.
International journal of hematology. 2021
Abstract
Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n?=?11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m(2), melphalan (MEL) 210 mg/m(2), and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n?=?10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p?=?0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.
-
5.
Comparison of reduced-intensity/toxicity conditioning regimens for umbilical cord blood transplantation for lymphoid malignancies
Imahashi, N., Terakura, S., Kondo, E., Kako, S., Uchida, N., Kobayashi, H., Inamoto, Y., Sakai, H., Tanaka, M., Ishikawa, J., et al
Bone marrow transplantation. 2020
Abstract
To investigate which reduced-intensity conditioning (RIC)/reduced-toxicity conditioning (RTC) is superior for umbilical cord blood transplantation (UCBT) for lymphoid malignancies, we retrospectively compared three widely used RIC/RTC regimens: fludarabine/melphalan/total body irradiation (FM-TBI, n = 524), fludarabine/cyclophosphamide/total body irradiation (FC-TBI, n = 96), and fludarabine/busulfan/total body irradiation or melphalan (FB-based, n = 159). Among patients with acute lymphoblastic leukemia (ALL) (n = 314), there were no differences in overall survival (OS) by conditioning regimen. Among patients with malignant lymphoma (ML) (n = 465), FM-TBI and FC-TBI regimens had similar OS, whereas FB-based regimen had lower OS (hazard ratio [HR], 1.73; P < 0.01) than did FM-TBI regimen due to higher non-relapse mortality (HR, 1.72; P = 0.02). In addition, mycophenolate mofetil-containing GVHD prophylaxis was associated with better OS than methotrexate-containing GVHD prophylaxis among patients who received FM-TBI (HR, 0.65; P = 0.03) and FC-TBI (HR, 0.25; P < 0.01) regimens due to a decreased relapse risk. In summary, our results suggest that all three RIC/RTC regimens have comparable clinical outcomes in ALL, while the FM-TBI or FC-TBI regimens combined with mycophenolate mofetil-containing GVHD prophylaxis is preferable in RIC/RTC-UCBT for ML. Large prospective studies are warranted to confirm these results.
-
6.
Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders
Vander Lugt, M. T., Chen, X., Escolar, M. L., Carella, B. A., Barnum, J. L., Windreich, R. M., Hill, M. J., Poe, M., Marsh, R. A., Stanczak, H., et al
Blood advances. 2020;4(13):3041-3052
-
-
Free full text
-
Abstract
Children with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. We prospectively evaluated a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa with a single-unit UCB graft in 44 consecutive patients with inborn errors of metabolism, immunity, or hematopoiesis. In addition, 5% of the UCB graft was re-cryopreserved and reserved for cord donor leukocyte infusion (cDLI) posttransplant. All patients engrafted at a median of 15 days posttransplant, and chimerism was >90% donor in the majority of patients at 1-year posttransplant with only 1 secondary graft failure. The incidence of grade II to IV graft-versus-host disease (GVHD) was 27% (95% confidence interval [CI], 17-43) with no extensive chronic GVHD. Overall survival was 95% (95% CI, 83-99) and 85% (95% CI, 64-93) at 1 and 5 years posttransplant, respectively. No significant end-organ toxicities were observed. The use of cDLI did not affect GVHD and showed signals of efficacy for infection control or donor chimerism. This RIC transplant regimen using single-unit UCB graft resulted in outstanding survival and remarkably low rates of graft failure. Implementation of the protocol not requiring pharmacokinetic monitoring would be feasible and applicable worldwide for children with inherited disorders of metabolism, immunity, or hematopoiesis. This trial was registered at www.clinicaltrials.gov as #NCT01962415.
-
7.
Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases
Mayumi, A., Sawada, A., Sato, M., Shimizu, M., Ioi, A., Higuchi, K., Yasui, M., Kawa, K., Inoue, M.
Pediatric blood & cancer. 2020;:e28536
Abstract
The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning "LPAM140 regimen," which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210 mg/m(2) ("LPAM210 regimen"). Patient data (n = 22; LPAM140, n = 7; LPAM210, n = 15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P = .002). Fludarabine combined with melphalan (210 mg/m(2) ) had a favorable impact on engraftment.
-
8.
Reduced-intensity versus myeloablative conditioning in cord blood transplantation for AML (40-60 years) across highly mismatched HLA barriers - On behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT
Sheth, V., Volt, F., Sanz, J., Clement, L., Cornelissen, J., Blaise, D., Sierra, J., Michallet, M., Saccardi, R., Rocha, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
-
-
-
Free full text
-
Editor's Choice
Abstract
The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated with high non-relapse mortality (NRM) in patients >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced intensity conditioning (RIC) and higher GVL associated with greater HLA disparities would expand its use for patients (40-60 years) without compromising efficacy, and compared outcomes between RIC versus MAC regimens. 288 patients aged 40 to 60 years, with de novo AML, receiving UCBT with at least 2 HLA mismatches with RIC (n=166) or MAC (n=122) regimens were included. As compared to RIC, the MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts, and more in vivo T-cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98, p=0.9), NRM (HR-0.68, p=0.2) and relapse (HR- 1.24, p=0.5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients 40-60 years having =2 HLA mismatches are comparable after RIC or MAC regimen.
PICO Summary
Population
Patients with de novo AML aged 40 to 60 years (n=288)
Intervention
Cord blood transplantation with at least 2 mismatches, and reduced intensity conditioning (RIC, n=166)
Comparison
Cord blood transplantation with at least 2 mismatches, and myeloablative conditioning (MAC, n=122)
Outcome
As compared to RIC, the MAC cohort included relatively younger patients. Median time to neutrophil engraftment, infections (bacterial, viral and fungal), as well as grade II-IV acute and chronic graft-versus-host disease were similar in both groups. In the multivariate analysis, overall survival (HR-0.98), NRM (HR-0.68) and relapse (HR- 1.24) were not different between RIC and MAC. Refractory disease was associated with worse survival.
-
9.
Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation
Duinhouwer, L. E., Beije, N., van der Holt, B., Rijken-Schelen, A., Lamers, C. H., Somers, J., Braakman, E., Cornelissen, J. J.
Bone marrow transplantation. 2018
Abstract
Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC(+) T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3-4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3-4 infections.
-
10.
Thiotepa Based Intensified Reduced-Intensity Conditioning Adult Double-Unit Cord Blood Hematopoietic Stem Cell Transplantation Results in Decreased Relapse Rate and Improved Survival Compared to Transplantation Following Standard Reduced-Intensity Conditioning: a Retrospective Cohort Comparison
Sharma, P., Pollyea, D. A., Smith, C. A., Purev, E., Kamdar, M., Haverkos, B., Sherbenou, D., Rabinovitch, R., Hammes, A., Gutman, J. A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
The "Minnesota" reduced intensity conditioning (RIC) cord-blood transplantation (CBT) regimen (standard-RIC) of fludarabine (Flu, 200mg/m(2)), cyclophosphamide (Cy, 50mg/kg), and 200cGy or 300cGy total body irradiation (TBI) is the most published RIC CBT regimen. Though well tolerated, high relapse rates remain a concern with this regimen. Intensification of conditioning may reduce relapse without increasing transplant related mortality (TRM). We performed a retrospective cohort comparison of outcomes in adult patients who underwent first double-unit CBT with standard-RIC as compared to the intensified regimen of fludarabine 150mg/m(2), cyclophosphamide 50mg/kg, thiotepa 10mg/kg and 400cGy TBI (intensified-RIC). Of the 99 patients studied, 47 received intensified-RIC. Acute myeloid leukemia was the major indication for transplant. The median age at transplant was 67 years (range, 24-74) and 54 years (range, 25-67) in standard-RIC and intensified-RIC respectively. Median hematopoietic stem-cell transplant comorbidity-index was 3 (range, 0-5) and 1 (range, 0-6) in standard-RIC and intensified-RIC groups respectively. Median follow-up among survivors was 22 months (range, 3.7- 79) following standard-RIC and 15 months (range, 2.8- 36) following intensified-RIC. The cumulative incidence (CI) of relapse was significantly lower following intensified-RIC compared to standard-RIC (p= 0.0013); this finding maintained significance in multivariate analysis (p= 0.045). TRM was comparable between the two groups (p= 0.99). Overall survival (OS) was significantly improved following intensified-RIC as compared to standard-RIC (p= 0.03). Median OS was 17 months following standard-RIC versus not reached followed intensified-RIC. The CI of grade 2-4 acute graft-versus-host disease (GVHD) was significantly higher in the intensified-RIC cohort than the standard RIC-cohort (p= 0.007) while CI of grade 3-4 acute GVHD, any chronic GVHD, and moderate to severe chronic GVHD was comparable in each cohort (p= 0.20, p= 0.21, and p= 0.61 respectively). This retrospective analysis shows an improvement in OS and decreased relapse without increase in TRM in patients receiving intensified-RIC as compared to standard-RIC. Our data suggest that consideration of thiotepa based intensified-RIC may improve outcomes in fit, older patients undergoing double-unit CBT.