Impact of renal impairment on light chain amyloidosis outcomes after autologous hematopoietic stem cell transplantation
Annals of translational medicine. 2020;8(7):509
Haploidentical Transplants for Patients with Graft Failure After the First Allograft
American journal of hematology. 2020
Cytogenetics and Blast Count Determine Transplant Outcomes in Patients with Active Acute Myeloid Leukemia
Acta haematologica. 2020;:1-8
Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
Idiopathic refractory ascites after allogeneic stem cell transplantation: a previously unrecognized entity
Blood advances. 2020;4(7):1296-1306
At our center, we observed a series of patients who developed transudative refractory ascites secondary to noncirrhotic, non-veno-occlusive disease (VOD)-related portal hypertension after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients were considered to have idiopathic portal hypertension-related refractory ascites (IRA) if they developed ascites secondary to intrahepatic portal hypertension (serum ascites albumin gradient ≥1.1 g/dL or hepatic venous pressure gradient [HVPG] >5 mm Hg), but did not meet the clinical criteria for classical VOD/sinusoidal obstructive syndrome (SOS) and did not have any alternate etiology of portal hypertension. From our institutional database, we identified 40 patients who developed IRA after allo-HSCT between 2004 and 2018. The patients' median age at the time of allo-HSCT was 54 years (range, 21-73 years). The median time to development of IRA after allo-HSCT was 80 days (range, 16-576 days). The median number of paracentesis was 3 (range, 1-11), and 15 (38%) patients had an intraperitoneal catheter placed for continued drainage of the rapidly accumulating ascites. Portal pressures were measured in 19 patients; 6 (15%) had moderate portal hypertension (HVPG 6-9 mm Hg), and 13 (33%) had severe portal hypertension (HVPG ≥ 10 mm Hg). Liver biopsy was performed in 24 patients. None of the patients met the criteria for classical VOD/SOS (clinical/histological) or cirrhosis (histological). The cumulative incidence of nonrelapse mortality was 63%, and the median survival duration after the development of the IRA was 7 months (range, 0.8-125.6 months). IRA is a poorly understood and often fatal complication of allo-HSCT.
Endothelial Activation and Stress Index (EASIX) at Admission Predicts Fluid Overload in Recipients of Allogeneic Stem Cell Transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity, and sought to determine whether the Endothelial Activation and Stress Index (EASIX), (defined as lactate dehydrogenase (U/L) x creatinine (mg/dL)/ platelets (10(9) cells per L), correlates with grade ≥2 FO in two cohorts of recipients of AHCT at our institution. METHODS We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors, and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors transplanted between 2010-2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis, and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on Receiver Operating Characteristics (ROC) curve analysis. RESULTS Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) in the two respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥ 2 FO in the study (cutoff: 4.4, HR=4.8, p<0.001) and in the validation (cutoff: 4.3, HR=4.8, p<0.001) cohorts. The significant effect of EASIX persisted in multivariate CART analysis in the study (HR=6.3, p<0.001) and the validation (HR=28, p=0.002) cohorts. Additional predictors in multivariate analysis included body weight below 80 kg in recipients older than >55 years (HR=4.5, p<0.001) in the study cohort, and diabetes (HR=34, p=0.001) and age >60 years (HR=9.6, p=0.04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% vs 17%, p=0.9) was not different between the diabetics and non-diabetics. CONCLUSIONS EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.
Myeloablative conditioning using timed-sequential busulfan plus fludarabine in older patients with acute myeloid leukemia: long term results of a prospective phase II clinical trial
Haploidentical Transplantation for Acute Myeloid Leukemia Patients with Minimal/ Measurable Residual Disease at Transplantation
American journal of hematology. 2019
There have been conflicting results regarding impact of minimal/measurable disease at transplant on acute myeloid leukemia (AML) outcomes after haploidentical transplantation (haplo-SCT). We assessed the impact of pre-transplant disease status on post-transplant outcomes of 143 patients treated with haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy). With a median follow-up of 29 months, the two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 (95% CI: 2.05-6.1; P < .001) and 2.3 (95% CI: 1.3-3.9; P = 0.002), respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41) (HR 1.85, 95%CI: 0.9-4.0; P = 0.1). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes. Our findings suggest that haplo-SCT with FM conditioning regimen and PTCy-based GVHD prophylaxis has a protective effect, and may potentially abrogate the inferior outcomes of MRD positivity for patients with AML. Patients with positive MRD may benefit from proceeding urgently to a haplo-SCT, as this does not appear to negatively impact transplant outcomes. This article is protected by copyright. All rights reserved.
Patients with acute myeloid leukaemia (n=143)
Haplo-SCT using fludarabine-melphalan (FM) conditioning and post-transplant cyclophosphamide (PTCy).
The two-year PFS for all patients was 41%. Compared to patients in complete remission (CR) at transplant, those with active disease (n = 29) and CR with incomplete count recovery (CRi) (n = 39) had worse PFS. They had hazard ratios (HR) of 3.5 and 2.3 respectively. Among patients who were in CR at transplant, there were no differences in PFS between those who had minimal residual disease (MRD) positive (n = 24), and MRD negative (n = 41). In multivariable analysis for patients in CR, only age was predictive for outcomes, while MRD status at transplant did not influence the treatment outcomes.
Mixed myeloid chimerism and relapse of myelofibrosis after allogeneic stem cell transplantation
Haploidentical vs haplo-cord transplant in adults under 60 years receiving fludarabine and melphalan conditioning
Blood advances. 2019;3(12):1858-1867
Haplo-identical transplant with posttransplant cyclophosphamide (haplo) and umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) are competing approaches to alternative donor transplant. We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions. All received reduced intensity conditioning with fludarabine and melphalan +/- total body irradiation. GVHD prophylaxis for haplo consisted of cyclophosphamide, tacrolimus, and mycophenolate, whereas haplo-cord received antithymocyte globulin, tacrolimus, and mycophenolate. Haplo transplant used mostly bone marrow, and peripheral blood stem cells were used in haplo-cord transplants. Haplo-cord were older and had more advanced disease. Haplo-cord hastened median time to neutrophil (11 vs 18 days, P = .001) and platelet recovery (22 vs 25 days, P = .03). At 4 years, overall survival (OS) was 50% for haplo-cord vs 49% for haplo. Progression-free survival (PFS) was 40% for haplo-cord vs 45% for haplo. In multivariate analysis, the disease risk index was significant for OS (hazard ratio, 1.8; 95% confidence interval, 1.48-2.17; P = .00) and PFS. Total body irradiation was associated with decreased recurrence and improved PFS, age >40 with increased nonrelapse mortality. The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo (P < .0001), but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo (P < .0001). Haplo or haplo-cord results in similar and encouraging outcomes. Haplo-cord is associated with more rapid neutrophil and platelet recovery and lower acute and chronic GVHD. Institutional review board authorization for this retrospective study was obtained at each institution. Some patients participated in trials registered at www.clinicaltrials.gov as #NCT01810588 and NCT01050946.
We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions
Haploidentical transplantation with post-transplant cyclophosphamide (n=170)
Umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) (n=137)
The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo, but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo.
Comparison of Outcomes of Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Three Different Conditioning Regimens
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
BACKGROUND Allogeneic hematopoietic cell transplant (allo-HCT) is a potentially curative therapy for patients with multiple myeloma as it provides graft-versus-myeloma effect alongside a myeloma-free graft. Although reduced-intensity conditioning regimens decrease non-relapse mortality (NRM), there is a paucity of data with regard to the ideal conditioning regimen in myeloma. METHODS We conducted a retrospective comparison of three different preparative regimens used for allo-HCT for multiple myeloma at our institution in recent clinical trials: Busulfan/Fludarabine (BuFlu), Fludarabine /Melphalan 100mg/m2 (FM100), and Fludarabine/Melphalan 140mg/m2 (FM140). NRM, progression-free survival (PFS) at 3 years, and overall survival (OS) at 3 years were the primary endpoints. Secondary endpoints included time to engraftment, and the incidence of grade II-IV acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). RESULTS A total of 73 patients received allo-HCT with these regimens. NRM at 3 years was seen in 3 (21%), 5 (28 %), and 6 (24%) patients in BuFlu, FM100 and FM140, respectively. Three-year PFS in the BuFlu, FM100 and FM140 groups was 16% (HR 1.2; 95% CI 0.6-2.1), 26% (HR 0.6; 95% CI 0.3-1.2), and 11% (ref), respectively. Three-year OS in the BuFlu, FM100 and FM140 groups was 39% (HR 1.1; 95% CI 0.5-2.2), 43% (HR 0.7; 95% CI 0.3-1.4), and 32% (ref), respectively. High-risk cytogenetics and relapsed disease prior to allo-HCT were found to be independent predictors of inferior OS on multivariate analysis, with HR of 2.1 (P=0.02) and 2.6 (P=0.004), respectively. In contrast, the preparative regimen did not emerge as a predictor of PFS or OS. CONCLUSIONS Durable clinical remission can be achieved in 11-25% of patients multiple myeloma with the use of allo-HCT, without any significant difference in the safety or efficacy of the conditioning regimen. High-risk cytogenetics and relapsed disease prior to transplant were associated with inferior PFS and OS.