-
1.
Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis
Khimani, F., Dutta, M., Faramand, R., Nishihori, T., Perez, A. P., Dean, E., Nieder, M., Perez, L., Mishra, A., Elmariah, H., et al
Transplantation and Cellular Therapy. 2021;27(7):620.e1-620.e9
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
-
2.
Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation
Bejanyan, N., Zhang, M. J., Wang, H. L., Lazaryan, A., de Lima, M., Marks, D. I., Sandmaier, B. M., Bachanova, V., Rowe, J., Tallman, M., et al
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2018;24(5):945-955
-
-
-
Free full text
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received ≥2 (n = 109), 1 (n = 93), or 0 cycles (n = 322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving ≥2, 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk, 1.20, 95% confidence interval, .86 to 1.67; P = .28 for no consolidation; RR, 1.18, 95% confidence interval, .79 to 1.76; P = .41 for 1 cycle versus ≥2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1.
Clinical Commentary
What is known?
NIHMS941192
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
-
3.
Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph-negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation
Czyz, A., Labopin, M., Giebel, S., Socie, G., Apperley, J., Volin, L., Remenyi, P., Yakoub-Agha, I., Orchard, K., Michallet, M., et al
American journal of hematology. 2018
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph-negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia-free survival (60% vs. 50%, P = .04), and improved "graft versus host disease (GVHD) and relapse-free survival" (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end-points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph-negative ALL treated with alloHCT.
-
4.
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.
-
5.
Allogeneic Hematopoietic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Results from a Single Center, 1993-2011
Yonal-Hindilerden, I., Kalayoglu-Besisik, S., Gurses-Koc, N., Hindilerden, F., Sargin, D.
International Journal of Hematology Oncology & Stem Cell Research. 2017;11(1):58-62
Abstract
Background: For adult ALL patients, the indications and appropriate timing of allogeneic hematopoietic stem cell transplantation (AHSCT) continue to be debated. The primary aim of this single-institution study was to compare the results of our adult ALL patients that had been allografted with those reported in the current literature. Subjects and Methods: This study included 53 consecutive adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic stem cell transplantation (AHSCT) with myeloablative (92%) and reduced-intensity (8%) conditioning between 1993 and 2011. Results: Mean patient age was 27 years (SD:8.62) and donor age was 33.7 years (SD:9.47). Fourteen patients were in first remission; 21 in >=2nd remission, 15 in relapse and 3 had primary refractory leukemia. Thirty-four, 15 and 4 patients received busulfan plus cyclophosphamide, cyclophosphamide/total body irradiation and fludarabine-based regimens, respectively. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine plus methotrexate were used. Forty-six donors were related and 7 were unrelated. Thirty patients received granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood and 23 received bone marrow as stem cell source. Twenty-six patients relapsed at a mean duration of 11.3 months (SD:19.1). Forty-four patients succumbed to their disease after a mean follow-up of 13.6 months (SD:19.5). The cause of mortality was relapse (n=24; 54.5%) and transplant-related etiologies (n=20; 45.5%). The estimated five year probabilities of overall survival (OS) and progression-free survival (PFS) were 37% and 12%, respectively. Conclusion: By multivariate analyses, transplantation in first remission was the most important predictor of transplant success.
-
6.
Clofarabine Plus Busulfan is an Effective Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Lymphoblastic Leukemia: Long-Term Study Results
Kebriaei, P., Bassett, R., Lyons, G., Valdez, B., Ledesma, C., Rondon, G., Oran, B., Ciurea, S., Alousi, A., Popat, U., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):285-292
Abstract
We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n=52) or matched unrelated donor (n=55) transplant for ALL in first complete remission (n=62), second complete remission (n=28), or more advanced disease (n=17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n=34), t(4;11) (n=4), or complex cytogenetics (n=7). Clo 40mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32mg/m2. The target daily area under the curve was 5500 micro mol/min for patients aged <60 years and 4000 micro mol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n=7) or CR2 (n=4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.