A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 – tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 – tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 – tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001)

Biodistributions, Myelosuppression and Toxicities in Mice Treated with an Anti-CD45 Antibody Labeled with the α-Emitting Radionuclides Bismuth-213 or Astatine-211

We previously investigated the potential of targeted radiotherapy using a bismuth-213- labeled anti-CD45 antibody to replace total body irradiation as conditioning for hematopoietic cell transplantation in a canine model. While this approach allowed sustained marrow engraftment, limited availability, high cost and short half-life of bismuth-213 induced us to investigate an alternative α-emitting radionuclide, astatine-211, for the same application. Biodistribution and toxicity studies were conducted with conjugates of the anti-murine CD45 antibody 30F11 with either bismuth-213 or astatine-211. Mice were injected with 2-50 μCi on 10 μg or 20 μCi on 2 or 40 μg 30F11 conjugate. Biodistribution studies showed that the spleen contained the highest concentration of radioactivity, ranging from 167±23 to 417±109 % injected dose/gram (%ID/g) after injection of the astatine-211 conjugate and 45±9 to 166±11 %ID/g after injection of the bismuth-213 conjugate. The higher concentrations observed for astatine-211- labeled 30F11 were due to its longer half-life, which permitted better localization of isotope to the spleen before decay. Astatine-211 was more effective at producing myelosuppression for the same quantity of injected radioactivity. All mice injected with 20 or 50 μCi astatine-211 but none with the same quantities of bismuth-213 had lethal myeloablation. Severe reversible acute hepatic toxicity occurred with 50 μCi bismuth-213, but not with lower doses of bismuth-213 or with any dose of astatine-211. No renal toxicity occurred with either radionuclide. The data suggest that smaller quantities of astatine-211-labeled anti-CD45 antibody are sufficient to achieve myelosuppression and myeloablation with less non-hematological toxicity compared with bismuth-213-labeled antibody

Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in first or second remission after myeloablative conditioning (MAC; n = 515) or non-MAC (n = 295) who underwent multiparameter flow cytometry–based MRD testing before as well as 20 to 40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85 of 104; 81.7%) than non-MAC (33 of 57; 57.9%) regimen (P = .002). Although non-MAC regimens were less likely to clear MRD, if they did, the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and “MRD conversion” for relapse (P = .020), RFS (P = .002), and OS (P = .001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared with the isolated use of pre-HCT MRD status or post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments in patients with AML

Conditioning Intensity, Pre-Transplant Flow Cytometric Measurable Residual Disease, and Outcome in Adults with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

How conditioning intensity is related to outcomes of AML patients undergoing allografting in morphologic remission is an area of great ongoing interest. We studied 743 patients in morphologic remission and known pre-transplant measurable residual disease (MRD) status determined by multiparameter flow cytometry (MFC) who received a first allograft after myeloablative, reduced intensity, or nonmyeloablative conditioning (MAC, RIC, and NMA). Overall, relapse-free survival (RFS) and overall survival (OS) were longer after MAC than RIC or NMA conditioning, whereas relapse risks were not different. Among MRD(pos)patients, 3-year estimates of relapse risks and survival were similar across conditioning intensities. In contrast, among MRD(neg)patients, 3-year RFS and OS were longer for MAC (69% and 71%) than RIC (47% and 55%) and NMA conditioning (47% and 52%). Three-year relapse risks were lowest after MAC (18%) and highest after NMA conditioning (30%). Our data indicate an interaction between conditioning intensity, MFC-based pre-transplant MRD status, and outcome, with benefit of intensive conditioning primarily for patients transplanted in MRD(neg)remission. Differing from recent findings from other studies that indicated MAC is primarily beneficial for some or all patients with MRD(pos)pre-HCT status, our data suggest MAC should still be considered for MRD(neg)AML patients if tolerated

Relative impact of residual cytogenetic abnormalities and flow cytometric measurable residual disease on outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia

Measurable residual disease (MRD) before hematopoietic cell transplantation (HCT) is an independent established prognostic factor in patients with acute myeloid leukemia (AML). Several methods exist to evaluate the presence of residual leukemia cells, but how these are used best in combination is unclear. In order to examine how residual cytogenetic abnormalities and MRD testing by multiparameter flow cytometry (MFC) may refine risk assessment before HCT, we analyzed 506 adults with cytogenetically abnormal AML who underwent both routine karyotyping and MFC MRD testing before receiving a first allograft while in morphologic remission. Testing for residual cytogenetic abnormalities and MFC MRD identified four groups of patients with differential relapse-free survival (RFS) (hazard ratio [HR]=1.63 for Cytoabnormal/MFCnegative [P=0.01, n=63], HR=3.24 for Cytonormal/MFCpositive [P<0.001, n=60], and HR=5.50 for Cytoabnormal/MFCpositive [P<0.001, n=56] with Cytonormal/MFCnegative as reference [n=327]) and overall survival (OS) (HR=1.55 for Cytoabnormal/MFCnegative [P=0.03], HR=2.69 for Cytonormal/MFCpositive [P<0.001], and HR=4.15 for Cytoabnormal/MFCpositive [P<0.001] with Cytonormal/MFCnegative as reference). Results were similar for patients who received myeloablative or non-myeloablative conditioning. C-statistic values were higher, indicating higher accuracy, when using pre-HCT cytogenetic and MFC MRD information together for prediction of relapse, RFS, and OS, rather than using either test result alone. This study indicates that residual cytogenetic abnormalities and MFC MRD testing provide complementary prognostic information for post- HCT outcomes in patients with cytogenetically abnormal AML undergoing allogeneic HCT

Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors

Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM), we studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) scores. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval ≤6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.Research reported in this publication was supported by grants P01-CA078902, P01-CA018029, and P30-CA015704 from the National Cancer Institute/National Institutes of Health (NCI/NIH), Bethesda, MD, USA. E.R.-A. is funded by a Juan Rodés clinician scientist grant (JR23/00067) from the Instituto de Salud Carlos III (ISCIII).Peer reviewe

allogeneic hematopoietic cell transplantation hct in the eighth decade of life how much does age matter

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