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1.
Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia
Ishida, H., Arakawa, Y., Hasegawa, D., Usami, I., Hashii, Y., Arai, Y., Nishiwaki, S., Keino, D., Kato, K., Sato, M., et al
Annals of hematology. 2023
Abstract
Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.
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2.
Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Houhou, M., Caillot, D., Finke, J., Blaise, D., Fegueux, N., Ethell, M., Cornelissen, J. J., Forcade, E., et al
Bone marrow transplantation. 2023;58(4):393-400
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.
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3.
Thiotepa-based regimens are a valid alternative to total body irradiation-based reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia: a retrospective study on behalf of the Acute Leukemia Working Party of the EBMT
Battipaglia, G., Labopin, M., Mielke, S., Ruggeri, A., Nur Ozkurt, Z., Henri Bourhis, J., Rabitsch, W., Yakoub-Agha, I., Grillo, G., Sanz, J., et al
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, where reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI- or chemotherapy-based approach is better, is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The aim of the current study is to compare transplant outcomes after RIC with TBI- or thiotepa-based regimens in ALL. METHODS Included were patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000-2020, receiving a RIC regimen containing either TBI- (4-6 Gray, Gy) or thiotepa. RESULTS We identified a total of 265 patients, including 117 receiving TBI- and 148 receiving a thiotepa-based RIC regimen. In univariate analysis, no differences were observed in transplant outcomes (for TBI versus thiotepa: relapse, 23% versus 28%, p=0.24; non-relapse mortality, 20% versus 26%, p=0.61; leukemia-free survival, 57% versus 46%, p=0.12; overall survival, 67% versus 56%, p=0.18; graft-versus-host disease [GVHD]/relapse-free survival, 45% versus 38%, p=0.21; grade II-IV acute GVHD, 30% in both groups, p=0.84; grade III-IV acute GVHD, 9% versus 10%, p=0.89) except for chronic GVHD which was higher for TBI-based regimens (43% versus 29%, p=0.03). However, on multivariate analysis no differences in transplant outcomes were observed. CONCLUSION In patients ≥40 years receiving a RIC regimen, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens as no differences were observed in the main transplant outcomes.
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4.
Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40 years old - a secondary analysis of a CIBMTR database
de Oliveira Fernandes Junior, I., Arcuri, L. J.
Annals of hematology. 2023
Abstract
Few studies have addressed the role of reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens in older adults with Philadelphia acute lymphoblastic leukemia (Ph + ALL). The objective of this current study was to compare the outcomes of RIC/NMA versus TBI-based myeloablative (MAC) regimens in Ph + ALL patients older than 40 years old who underwent hematopoietic cell transplantation (HCT) in CR1. We used a freely available database from the CIBMTR. Transplants were performed between 2013 and 2017. With a median follow-up of 37.6 months, we have included 629 patients. We used propensity score weighting. Three-year OSs were 64% in the TBI-MAC group and 66% in the RIC/NMA group. OS was not different (HR = 0.92; p = 0.69). Three-year relapse incidences were 21.6% and 27.6% in the TBI-MAC and RIC/NMA groups. RIC/NMA was not associated with an increase in relapse rate (HR 1.02; p = 0.91). Three-year NRMs were 24.3% in the TBI-MAC group and 20.3% in the RIC/NMA group. RIC/NMA was not associated with superior NRM (HR 0.88; p = 0.57). In summary, we have shown that RIC/NMA regimens achieve outcomes comparable to TBI-based MAC in Ph+ ALL older patients in CR1 who may tolerate a TBI-based MAC regimen.
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5.
Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning
Sijs-Szabo, A., Dinmohamed, A. G., Versluis, J., van der Holt, B., Bellido, M., Hazenberg, M. D., van Gelder, M., Schaap, N. P. M., Meijer, E., van der Wagen, L. E., et al
Transplantation. 2023
Abstract
BACKGROUND The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL. METHODS In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation. RESULTS Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001). CONCLUSIONS Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.
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6.
ALL-RIC trial protocol: a comparison of reduced dose total body irradiation (TBI) and cyclophosphamide with fludarabine and melphalan reduced intensity conditioning in adults with acute lymphoblastic leukaemia (ALL) in complete remission
Marks, D. I., Castleton, A., Olavarria, E., Gilleece, M., Fielding, A., Mikhaeel, G., Beasley, M., Diez, P., Jackson, A., Hodgkinson, A., et al
BMJ open. 2023;13(6):e067790
Abstract
INTRODUCTION The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL. METHODS AND ANALYSIS The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality. ETHICS AND DISSEMINATION The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER EudraCT Number: 2017-004800-23.ISRCTN99927695.
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7.
Intensity of induction regimen and outcomes among adults with Ph+ALL undergoing allogeneic hematopoietic stem cell transplantation
Raman, H. S., Kim, S. E., DeAngelo, D. J., Stevenson, K. E., Neuberg, D., Winer, E. S., Wadleigh, M., Garcia, J. S., Kim, A. S., Stone, R. M., et al
Leukemia research. 2022;125:107004
Abstract
Tyrosine kinase inhibitors (TKIs) are essential for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and have allowed for effective, low intensity induction regimens including no or minimal chemotherapy. Whether the use of low intensity induction regimens impacts outcomes after allogeneic hematopoietic stem cell transplant (alloHCT) is less understood. We identified consecutive adult patients with Ph+ ALL undergoing alloHCT in first complete remission (CR1) at our center from 2010 to 2021 and examined the impact of pre-transplant induction intensity on outcomes. Among the 87 identified patients, 44 (51%) received low intensity induction and 43 (49%) received induction with high intensity chemotherapy. Patients receiving low intensity induction were older (median age 60 vs. 47 years, p < 0.01). Following induction, measurable residual disease (MRD) negativity by BCR::ABL1 RT-PCR was similar in the low and high intensity induction cohorts (54% and 52% respectively). Receipt of reduced intensity transplant conditioning was not associated with intensity of induction regimen (39% vs. 19% in low vs. high, respectively, p = 0.06). At a median follow-up of 21 months from transplant, there was no difference between low and high intensity induction with respect to 2-year disease-free survival (58% vs. 56%), 2-year overall survival (62% vs. 63%), 2-year cumulative incidence of relapse (9% vs. 17%), and 2-year non-relapse mortality (33% vs. 29%). We also found no difference in outcomes when patients were segmented by both induction and conditioning regimen intensities. Our retrospective analysis suggests that induction intensity does not impact post-transplant outcomes among patients with Ph+ ALL transplanted in CR1.
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8.
Reduced-Intensity Conditioning with Busulfan and Fludarabine for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Lymphoblastic Leukemia
Lee, S. S., Jung, S. H., Do, Y. R., Kim, D. S., Lee, J. H., Park, H. S., Moon, J. H., Yi, J. H., Park, Y., Koh, Y., et al
Yonsei medical journal. 2020;61(6):452-459
Abstract
PURPOSE Allogeneic hematopoietic stem cell transplantation (HSCT) with optimal conditioning has helped better long-term survival in acute lymphoblastic leukemia (ALL). This study investigated the efficacy and safety of reduced-intensity conditioning (RIC) with busulfan and fludarabine in adult ALL patients unfit for myeloablation. MATERIALS AND METHODS Records of 78 patients who underwent HSCT with RIC consisting of 3.2 mg/kg/day of busulfan for 2 or 3 days and 30 mg/m(2)/day of fludarabine for 5 or 6 days were analyzed. RESULTS The median age at diagnosis was 49 years. Over a median follow-up of 22 months, 2-year estimates of relapse-free survival (RFS) and overall survival were 57.4% and 68.7%, respectively. Multivariate analysis showed a trend of improved RFS in patients with chronic graft-versus-host disease (GVHD) (hazard ratio, 0.53; 95% confidence interval, 0.26-1.08; p=0.080). The cumulative incidences of relapse and non-relapse mortality were 42.9% and 19.6%, respectively and one case of central nervous system relapse was noted. No hepatic veno-occlusive disease was reported. Grade II-IV acute GVHD and any grade chronic GVHD occurred in 21.1% and 41.7%, respectively. CONCLUSION RIC with busulfan and fludarabine is an effective and safe conditioning regimen for adult ALL patients unfit for myeloablation.
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9.
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.
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10.
Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation-a retrospective study by the Acute Leukemia Working Party of EBMT
Peric, Z., Labopin, M., Peczynski, C., Polge, E., Cornelissen, J., Carpenter, B., Potter, M., Malladi, R., Byrne, J., Schouten, H., et al
Bone marrow transplantation. 2020
Abstract
The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients > 45 years with ALL in first complete remission who underwent a matched sibling or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n = 127), fludarabine/melphalan (FLUMEL, n = 190), and fludarabine-TBI (FLUTBI, n = 100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p = 0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p = 0.09); overall survival (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p = 0.62) or leukemia-free survival (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p = 0.99), but GVHD-relapse-free survival was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p = 0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05-3.72, p = 0.04). We conclude that the three most popular RIC regimens yield similar transplant outcomes.