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Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Socié, G., Aljurf, M., Salmenniemi, U., Labussière-Wallet, H., Srour, M., Kröger, N., Zahrani, M. A., Lioure, B., et al
Bone marrow transplantation. 2023
Abstract
In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy + Cy was used in 2105 cases while TBI 12 Gy + Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with a reduced risk of relapse (HR = 0.69, p = 0.049) and increased risk of grade 2-4 acute graft-versus-host disease (GVHD, HR = 1.57, p = 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBI/Cy as compared to TBI/Flu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p = 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBI/Cy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBI/Flu and therefore should probably be considered a preferable regimen.
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Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Angelucci, E., Arat, M., Aljurf, M., Sica, S., Pavlu, J., Socié, G., Bernasconi, P., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
PICO Summary
Population
Adults with acute lymphoblastic leukemia (ALL) treated with haploidentical (n=haematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide (n=236)
Intervention
Fludarabine + total body irradiation conditioning (Flu-TBI, n=117)
Comparison
Thiotepa + iv. busulfan + fludarabine conditioning (TBF, n=119)
Outcome
In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%). There was a tendency towards reduced incidence of relapse after TBF. Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34) but an increased risk of relapse (HR = 2.59) without significant effect on survival and graft-versus-host disease.
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Improved Outcomes of Haploidentical Hematopoietic Cell Transplantation with Total Body Irradiation-Based Myeloablative Conditioning in Acute Lymphoblastic Leukemia
Dholaria, B., Labopin, M., Angelucci, E., Tischer, J., Arat, M., Ciceri, F., Gülbas, Z., Ozdogu, H., Sica, S., Diez-Martin, J. L., et al
Transplantation and cellular therapy. 2021;27(2):171.e1-171.e8
Abstract
The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI)-based versus chemotherapy (CT)-based MAC regimens in patients with acute lymphoblastic leukemia (ALL). The study included 427 patients who underwent first haplo-HCT with post-transplantation cyclophosphamide (PTCy), following TBI-based (n = 188; 44%) or CT-based (n = 239; 56%) MAC. The median patient age was 32 years. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most frequently used TBI- and CT-based regimens, respectively. In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% versus 37% (P = .05), overall survival (OS) was 51% versus 47% (P = .18), relapse incidence (RI) was 34% versus 32% (P = .44), and nonrelapse mortality (NRM) was 21% versus 31% (P < .01). In the multivariate analysis, TBI was associated with lower NRM (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33 to 0.86; P = .01), better LFS (HR, 0.71; 95% CI, 0.52 to 0.98; P =.04), and increased risk for grade II-IV acute graft-versus-host disease (GVHD) (HR, 1.59; 95% CI, 1.08 to 2.34; P = .02) compared with CT-based MAC. The type of conditioning regimen did not impact RI, chronic GVHD, OS, or GVHD-free, relapse-free survival after adjusting for transplantation-related variables. TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo-HCT/PTCy.
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Bone marrow versus mobilized peripheral blood stem cell graft in T-cell-replete haploidentical transplantation in acute lymphoblastic leukemia
Nagler, A., Dholaria, B., Labopin, M., Savani, B. N., Angelucci, E., Koc, Y., Arat, M., Pioltelli, P., Sica, S., Gulbas, Z., et al
Leukemia. 2020
Abstract
The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.
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Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Dholaria, B., Finke, J., Brecht, A., Schanz, U., Niittyvuopio, R., Neubauer, A., Bornhauser, M., Santarone, S., et al
British journal of haematology. 2019
Abstract
Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34.6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.
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Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)
Kansagra, A. J., Frey, N. V., Bar, M., Laetsch, T. W., Carpenter, P. A., Savani, B. N., Heslop, H. E., Bollard, C. M., Komanduri, K. V., Gastineau, D. A., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
PICO Summary
Population
Children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia
Intervention
Expert opinion on clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia
Comparison
None
Outcome
An initial roadmap for navigating common clinical practice scenarios since the approval of the first commercially available CAR-T product for B-ALL.
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Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research
Lazaryan, A., Dolan, M., Zhang, M. J., Wang, H. L., Kharfan-Dabaja, M. A., Marks, D. I., Bejanyan, N., Copelan, E., Maijhail, N., Waller, E. K., et al
Haematologica. 2019
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Editor's Choice
Abstract
Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia. To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. Patients with abnormal cytogenetics had 40% leukemia-free survival and 42% overall survival at 5-years post-transplant, which was similar to those with normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (p=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse (hazard ratio=2.11; 95% confidence interval, 1.04-4.27) and treatment failure (hazard ratio=1.97; 1.20-3.24). Complex karyotype was prognostic for relapse (hazard ratio=1.69; 1.06-2.69), whereas t(8;14) predicted treatment failure (hazard ratio=2.85; 1.35-6.02) and overall mortality (hazard ratio=3.03; 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse (monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy), intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (p=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities of acute lymphoblastic leukemia can be overcome by transplant, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
PICO Summary
Population
Adults with Philadelphia-negative acute lymphoblastic leukemia in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to CIBMTR registry (n=1731)
Intervention
Patients with abnormal conventional metaphase cytogenetics (n=632)
Comparison
Patients with normal cytogenetics (n=1099)
Outcome
Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival. In the multivariable analysis, monosomy 7 predicted post-transplant relapse and treatment failure. Complex karyotype was prognostic for relapse, whereas t(8;14) predicted treatment failure and overall mortality.
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The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia
Yeshurun, M., Weisdorf, D., Rowe, J. M., Tallman, M. S., Zhang, M. J., Wang, H. L., Saber, W., de Lima, M., Sandmaier, B. M., Uy, G., et al
Blood advances. 2019;3(4):670-680
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Abstract
Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.
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Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia: a CIBMTR Analysis
Wood, W. A., Brazauskas, R., Hu, Z. H., Abdel-Azim, H., Ahmed, I. A., Aljurf, M., Badawy, S., Beitinjaneh, A., George, B., Buchbinder, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
BACKGROUND For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions upon post-transplant outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. METHODS Using data from the Center for Blood and Marrow Transplant Research (CIBMTR), we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross National Income per capita (GNI), Health Expenditure per Capita (HEPC), and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. RESULTS In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (N=697) were associated with increased hazard for mortality (HR 2.42, 95% CI 1.64-3.57, p<0.001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile vs 88% for all other quartiles). CONCLUSION Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation.