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1.
Unrelated cord blood transplantation with myeloablative conditioning for pediatric acute lymphoblastic leukemia in remission: prognostic factors
Kawahara, Y., Morimoto, A., Inagaki, J., Koh, K., Noguchi, M., Goto, H., Yoshida, N., Cho, Y., Hori, T., Hiwatari, M., et al
Bone Marrow Transplantation. 2021;56(2):357-367
Abstract
The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.
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Increased overall and bacterial infections following myeloablative allogeneic HCT for patients with AML in CR1
Ustun, C., Kim, S., Chen, M., Beitinjaneh, A. M., Brown, V. I., Dahi, P. B., Daly, A., Diaz, M. A., Freytes, C. O., Ganguly, S., et al
Blood advances. 2019;3(17):2525-2536
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Abstract
Presumably, reduced-intensity/nonmyeloablative conditioning (RIC/NMA) for allogeneic hematopoietic cell transplantation (alloHCT) results in reduced infections compared with myeloablative conditioning (MAC) regimens; however, published evidence is limited. In this Center for International Blood and Marrow Transplant Research study, 1755 patients (aged ≥40 years) with acute myeloid leukemia in first complete remission were evaluated for infections occurring within 100 days after T-cell replete alloHCT. Patients receiving RIC/NMA (n = 777) compared with those receiving MAC (n = 978) were older and underwent transplantation more recently; however, the groups were similar regarding Karnofsky performance score, HCT-comorbidity index, and cytogenetic risk. One or more infections occurred in 1045 (59.5%) patients (MAC, 595 [61%]; RIC/NMA, 450 [58%]; P = .21) by day 100. The median time to initial infection after MAC conditioning occurred earlier (MAC, 15 days [range, <1-99 days]; RIC/NMA, 21 days [range, <1-100 days]; P < .001). Patients receiving MAC were more likely to experience at least 1 bacterial infection by day 100 (MAC, 46% [95% confidence interval (CI), 43-49]; RIC/NMA, 37% [95% CI, 34-41]; P = .0004), whereas at least a single viral infection was more prevalent in the RIC/NMA cohort (MAC, 34% [95% CI, 31-37]; RIC/NMA, 39% [95% CI, 36-42]; P = .046). MAC remained a risk factor for bacterial infections in multivariable analysis (relative risk, 1.44; 95% CI, 1.23-1.67; P < .0001). Moreover, the rate of any infection per patient-days at risk in the first 100 days (infection density) after alloHCT was greater for the MAC cohort (1.21; 95% CI, 1.11-1.32; P < .0001). RIC/NMA was associated with reduced infections, especially bacterial infections, in the first 100 days after alloHCT.
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Busulfan based myeloablative conditioning regimens for haploidentical transplantation in high risk acute leukemias and myelodysplastic syndromes
Gayoso, J., Balsalobre, P., Kwon, M., Herrera, P., Bermudez, A., Sampol, A., Jimenez, S., Lopez-Corral, L., Serrano, D., Pinana, J. L., et al
European journal of haematology. 2018
Abstract
BACKGROUND High-risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical related donor transplantation based on a myeloablative conditioning regimen (HAPLO-MAC) and post-transplant cyclophosphamide (PT-Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available. OBJECTIVE To evaluate the results of HAPLO-MAC with PT-Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH). PATIENTS AND METHODS We report our multicenter experience using an IV busulfan-based HAPLO-MAC regimen and PT-Cy for treatment of 65 adults with-high risk AL and MDS. RESULTS Engraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow-up of 31 months for survivors, the cumulative incidence of non-relapse mortality and relapse at 2 years was 18.8% and 25%, respectively. Estimated 30-month event-free survival and overall survival were 56% and 54.5%. CONCLUSION HAPLO-MAC comprising an IV busulfan-based conditioning regimen enabled long-term disease control with acceptable toxicity in high-risk AL and MDS. This article is protected by copyright. All rights reserved.
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Comparison of conditioning regimens for autologous stem cell transplantation in children with acute myeloid leukemia: A nationwide retrospective study in Japan
Sakaguchi, H., Muramatsu, H., Hasegawa, D., Kudo, K., Ishida, H., Yoshida, N., Koh, K., Noguchi, M., Shiba, N., Tokimasa, S., et al
Pediatric blood & cancer. 2018;:e27459
Abstract
BACKGROUND Indications for hematopoietic stem cell transplantation (HSCT) have decreased with the improvement in chemotherapy for pediatric acute myeloid leukemia (AML) in the last decade. We conducted reevaluation of autologous HSCT (AHSCT) to compare myeloablative conditioning (MAC) regimens for pediatric AML without the need for consideration of toxicities caused by allogeneic immune reactions. PROCEDURE This retrospective study analyzed the clinical outcomes of 220 children with AML who underwent consecutive AHSCT between 1989 and 2002 in Japan by the national prospective registry. The transplantation outcomes of various conditioning regimens were compared. RESULTS The median follow-up period of the survivors was 160 months. The clinical outcomes of busulfan + cyclophosphamide +/- etoposide or busulfan + melphalan regimens were significantly superior compared with other busulfan-based and total body irradiation-based regimens (leukemia-free survival [LFS]: 68% vs 42% and 55%, P = 0.001; overall survival [OS]: 74% vs 49% and 61%, P < 0.001). Multivariate analysis showed that busulfan + cyclophosphamide +/- etoposide and busulfan + melphalan regimens were independent favorable factors for LFS (hazard ratio: 0.46; P < 0.001) and OS (hazard ratio: 0.40; P < 0.001) compared with the other busulfan-based regimen, and both age 2 years or older and advanced stage at AHSCT were independent poor predictors for LFS and OS, simultaneously. CONCLUSION Busulfan + cyclophosphamide +/- etoposide and busulfan + melphalan regimens exhibited superior antileukemic effects compared with other BU-based myeloablative regimens.
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Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor-Enriched Cord Blood, to Double Cord Blood Unit Transplantation
Stiff, P. J., Montesinos, P., Peled, T., Landau, E., Rosenheimer Goudsmid, N., Mandel, J., Hasson, N., Olesinski, E., Glukhman, E., Snyder, D. A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Umbilical cord blood transplantation (UCBT) has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20-50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the un-manipulated fraction after myeloablative conditioning. The primary endpoint was 100 day survival which was compared to a contemporaneous double-unit cord blood transplant (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n = 295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34+ cell dose/kg were 306 x 10(7) and 164 x 10(5). Median NC and CD34+ fold expansion were 400 and 77, with a mean total CD34/kg infused of 9.7 x 10(5)/kg. The 100 day survival was 84.2% for the carlecortemcel-L study group vs 74.6% for the DUCBT group [odds ratio 0.50 (95% CI 026-0.95); p = 0.035]. Survival at day 180 was similar for the two groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 vs 28 days; p < 0.0001), and platelet (54 vs 105 days; p =0.008) engraftment was seen in the carlecortemcel-L study group; acute and chronic GVHD rates were similar. In this multi-national comparative study, transplanting expanded CD34+ stem cells from a portion of a single UCB unit, with the remaining un-manipulated fraction improved 100 day survival compared to DUCBT controls while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729.
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Haploidentical transplantation is associated with better overall survival when compared to single cord blood transplantation: an EBMT-Eurocord study of acute leukemia patients conditioned with thiotepa, busulfan, and fludarabine
Giannotti, F., Labopin, M., Shouval, R., Sanz, J., Arcese, W., Angelucci, E., Sierra, J., Santasusana, J. R., Santarone, S., Benedetto, B., et al
Journal of hematology & oncology. 2018;11(1):110
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Editor's Choice
Abstract
BACKGROUND Thiotepa-busulfan-fludarabine (TBF) is a widely used conditioning regimen in single umbilical cord blood transplantation (SUCBT). More recently, it was introduced in the setting of non-T cell depleted haploidentical stem cell transplantation (NTD-Haplo). Whether TBF based conditioning provides additional benefit in transplantation from a particular alternative donor type remains to be established. METHODS This was a retrospective study based on an international European registry. We compared outcomes of de-novo acute myeloid leukemia patients in complete remission receiving NTD-Haplo (n = 186) vs. SUCBT (n = 147) following myeloablative conditioning (MAC) with TBF. Median follow-up was 23 months. Treatment groups resembled in baseline characteristics. RESULTS SUCBT was associated with delayed engraftment and higher graft failure. In multivariate analysis no statistically significant differences were observed between the two groups in terms of acute or chronic graft-versus-host disease (GvHD) (HR = 1.03, p = 0.92 or HR = 1.86, p = 0.21) and relapse incidence (HR = 0.8, p = 0.65). Non-relapse mortality (NRM) was significantly higher in SUCBT as compared to NTD-Haplo (HR = 2.63, p = 0.001); moreover, SUCBT did worse in terms of overall survival (HR = 2.18, p = 0.002), leukemia-free survival (HR = 1.94, p = 0.007), and GvHD relapse-free survival (HR = 2.38, p = 0.0002). CONCLUSIONS Our results suggest that TBF-MAC might allow for a potent graft-versus-leukemia, regardless of the alternative donor type. Furthermore, in patients receiving TBF-MAC, survival with NTD-Haplo may be better compared to SUCBT due to decreased NRM.
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Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission
Page, K. M., Labopin, M., Ruggeri, A., Michel, G., Diaz de Heredia, C., O'Brien, T., Picardi, A., Ayas, M., Bittencourt, H., Vora, A. J., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1350-1358
Abstract
For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n=257, 40%) or second complete remission (CR2; n=383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (>=30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.
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Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party
Bento, L., Boumendil, A., Finel, H., Le Gouill, S., Amorim, S., Monjanel, H., Bouabdallah, R., Bay, J. O., Nicolas-Virelizier, E., McQuaker, G., et al
Bone Marrow Transplantation. 2017;52(8):1120-1125
Abstract
Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.
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Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Gorin, N. C., Labopin, M., Czerw, T., Pabst, T., Blaise, D., Dumas, P. Y., Nemet, D., Arcese, W., Trisolini, S. M., Wu, D., et al
Cancer. 2017;123(5):824-831
Abstract
BACKGROUND Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. METHODS From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P=.02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P=.02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. RESULTS Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P=.003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P=.005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P=.0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P=.01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P=.03). CONCLUSIONS In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society. Copyright © 2016 American Cancer Society.
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Thiotepa-based versus total body irradiation-based myeloablative conditioning prior to allogeneic stem cell transplantation for acute myeloid leukaemia in first complete remission: a retrospective analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation
Eder, S., Labopin, M., Arcese, W., Or, R., Majolino, I., Bacigalupo, A., de Rosa, G., Volin, L., Beelen, D., Veelken, H., et al
European Journal of Haematology. 2016;96(1):90-7
Abstract
Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukaemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n = 121) or a cyclophosphamide/total body irradiation-based (TBI; n = 358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (P = 0.06). The 2-yr cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (P = 0.98). At 2 yrs, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) vs. 22.4% (TBI; P = 0.66) and 17.2% (thiotepa) vs. 23.3% (TBI; P = 0.77), respectively. The probabilities of leukaemia-free and overall survival at 2 yrs were not significantly different between the thiotepa and TBI groups, at 58.9% vs. 54.2% (P = 0.95) and 61.4% vs. 58% (P = 0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes, but the optimal conditioning remains unclear for the individual patient in this setting. Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.