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Outcomes following second allogeneic stem cell transplant for disease relapse after T cell depleted transplant correlate with remission status and remission duration after the first transplant.

ABSTRACT: Background:Second allogeneic hematopoietic stem cell transplant (HCT) remains as an option for disease relapse after initial HCT. Methods:We analyzed retrospectively the outcomes of 65 consecutive patients who underwent a second HCT for disease relapse at the University of Chicago. Univariate and multivariate analysis were conducted, and a scoring system was generated to select the patients who would benefit second HCT. Results:All except four patients received T cell depleted (TCD) first HCT. The majority of patients had AML (n?=?47) and high risk MDS (n?=?5). The median age at second HCT was 45 years (11-73). 13 patients (20%) achieved CR before second HCT. 98% (n?=?64) and 72% (n?=?47) patients achieved neutrophil and platelet engraftment at a median interval of 10 and 18 days, respectively, following the second HCT. With a median follow up of 23 (5.5-140) months for survivors after second HCT, the estimated 2 years PFS was 17.5% and the 2 years OS was 22.6%. The day 100 cumulative incidence of non-relapse mortality rate was 23.6%, and the cumulative incidence of aGVHD and cGVHD were 16.9% and 7.7% respectively at 1 year after second HCT. In univariate analysis, patients with remission duration after first HCT of >?12 months and those in CR before second HCT had significantly better PFS and OS. A scoring system using disease status before second HCT (CR?=?0 vs. non-CR?=?1), and remission duration after first HCT (?12 months?=?0) was generated as an approach to classify patients into different risk categories in the purpose to provide guidance to the transplant physician to inform the outcomes to potential patients undergoing 2nd HCT. A score of ?12 months after first HCT with acceptable rates of GVHD and donor engraftment.

SUBMITTER: Fan Y

PROVIDER: S-EPMC6317199 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Outcomes following second allogeneic stem cell transplant for disease relapse after T cell depleted transplant correlate with remission status and remission duration after the first transplant.

Fan Yun Y Artz Andrew S AS van Besien Koen K Stock Wendy W Larson Richard A RA Odenike Olatoyosi O Godley Lucy A LA Kline Justin J Cunningham John M JM LaBelle James L JL Bishop Michael R MR Liu Hongtao H

Experimental hematology & oncology 20190103

<h4>Background</h4>Second allogeneic hematopoietic stem cell transplant (HCT) remains as an option for disease relapse after initial HCT.<h4>Methods</h4>We analyzed retrospectively the outcomes of 65 consecutive patients who underwent a second HCT for disease relapse at the University of Chicago. Univariate and multivariate analysis were conducted, and a scoring system was generated to select the patients who would benefit second HCT.<h4>Results</h4>All except four patients received T cell deple ...[more]

PMID: 30622841

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Project description:ImportanceThe optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date.ObjectiveTo compare overall survival (OS) after an allo-HCT2 or DLI in relapsed AML after a first allo-HCT.Design, setting, and participantsA retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n?=?137) or DLI (n?=?281) for postallograft-relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017.Main outcomes and measuresNumber of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI.ResultsOf the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo-HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P?=?.86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P?<?.001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P?=?.86).Conclusion and relevanceHeterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI.

Project description:To identify favored choice of transplantation in patients with acute promyelocytic leukemia (APL) in second complete remission, we studied 294 patients with APL in second complete remission (CR2) receiving allogeneic (n = 232) or autologous (n = 62) hematopoietic cell transplantation (HCT) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006, including 155 with pre-HCT PML/RAR∝ status (49% of allogeneic and 66% of autologous). Patient characteristics and transplantation characteristics, including treatment-related mortality, overall survival (OS), and disease-free survival, were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous with 63% (49% to 75%), compared with allogeneic at 50% (44% to 57%) (P = .10). OS was 75% (63% to 85%) versus 54% (48% to 61%) (P = .002), for autologous and allogeneic transplantation, respectively. Multivariate analysis showed significantly worse DFS after allogeneic HCT (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.16 to 3.06; P = .011) and age > 40 years (HR, 2.30; 95% CI, 1.44 to 3.67; P = .0005). OS was significantly worse after allogeneic HCT (HR, 2.66; 95% CI, 1.52 to 4.65; P= .0006); age > 40 (HR, 3.29; 95% CI, 1.95 to 5.54; P < .001), and first complete remission < 12 months (HR, 1.56; 95% CI, 1.07 to 2.26; P = .021). Positive pre-HCT PML-RAR∝ status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group. The survival advantage for autografting was attributable to increased treatment-related mortality (TRM) in the allogeneic group of 30% compared to 2% in the autologous group, in addition to the added mortality associated with GVHD. We conclude that autologous HCT yields superior OS for APL in CR2. Long-term DFS in autologous recipients, even with minimal residual disease-positive grafts, remains an important subject for further study.

Project description:ObjectiveType 1 diabetes (T1D) is an autoimmune disorder in which autoreactive T cells destroy insulin-producing β-cells. Interventions that preserve β-cell function represent a fundamental therapeutic goal in T1D and biomarkers that predict and monitor β-cell function, and changes in islet autoantigenic signatures are needed. As proinsulin and neoantigens derived from proinsulin peptides (hybrid insulin peptides, HIPs) are important T1D autoantigens, we analysed peripheral blood CD4+ T-cell autoantigen-specific proliferative responses and their relationship to estimated β-cell function.MethodsWe recruited 72 people with and 42 without T1D, including 17 pre-diabetic islet antibody-positive and 9 antibody-negative first-degree relatives and 16 unrelated healthy controls with T1D-risk HLA types. We estimated C-peptide level at 3-month intervals for 2 years post-diagnosis and measured CD4+ T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay.ResultsWe show that CD4+ T-cell proliferation to any islet peptide and to multiple epitopes were significantly more frequent in pre-diabetic islet antibody-positive siblings and participants with T1D ≤ 3 months of duration, than in participants with T1D > 3 months or healthy controls. Among participants with T1D and first-degree relatives, CD4+ T-cell proliferation occurred most frequently in response to proinsulin33-63 (full-length C-peptide). Proinsulin33-63-specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/DQ8. In children with T1D, proinsulin33-63-specific T-cell proliferation positively associated with concurrent estimated C-peptide and predicted survival in honeymoon.ConclusionCD4+ T-cell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin33-63-specific CD4+ T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.

Project description:Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell-depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.

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Outcomes following second allogeneic stem cell transplant for disease relapse after T cell depleted transplant correlate with remission status and remission duration after the first transplant.

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Outcomes following second allogeneic stem cell transplant for disease relapse after T cell depleted transplant correlate with remission status and remission duration after the first transplant.

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