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1.
Biol Blood Marrow Transplant ; 25(3): 515-521, 2019 03.
Article in English | MEDLINE | ID: mdl-30315941

ABSTRACT

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.


Subject(s)
CCR5 Receptor Antagonists/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Maraviroc/therapeutic use , Receptors, CCR5/deficiency , Transplantation Conditioning/methods , Adult , Aged , Female , Hematologic Neoplasms/complications , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/mortality , Hematopoietic Stem Cell Transplantation/standards , Humans , Male , Maraviroc/pharmacology , Middle Aged , Survival Analysis , Treatment Outcome , Unrelated Donors
2.
Biol Blood Marrow Transplant ; 24(6): 1203-1208, 2018 06.
Article in English | MEDLINE | ID: mdl-29408506

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a curative option for patients with hematologic malignancies who are unable to undergo myeloablative conditioning, but its success is limited by high rates of relapse. Several studies have suggested a role for T cell doses in peripheral blood stem cell grafts in RIC HSCT. Because T cell dose is typically not known until after the collection, and apheresis blood volume is easily modifiable, we hypothesized that higher donor apheresis blood volumes would improve transplantation outcomes through an effect on graft composition. Thus, we analyzed the relationships between apheresis volume, graft composition, and transplantation outcomes in 142 consecutive patients undergoing unrelated donor allogeneic RIC HSCT. We found that apheresis volume ≥15 L was associated with a significantly decreased risk of relapse (adjusted hazard ratio [aHR], .48; 95% confidence interval [CI], .28 to .84]; P = .01) and improved relapse-free survival (aHR, .56; 95% CI, .35 to .89; P = .02) and overall survival (aHR, .55; 95% CI, .34 to .91; P = .02). A high apheresis volume was not associated with increased rates of acute or chronic graft-versus-host disease. These results demonstrate that an apheresis volume of at least 15 L is independently predictive of improved transplantation outcomes after RIC allogeneic HSCT.


Subject(s)
Blood Component Removal/standards , Blood Volume , Hematopoietic Stem Cell Transplantation/standards , Prognosis , Unrelated Donors , Adult , Aged , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Recurrence , Risk , Survival Analysis , Transplantation, Homologous/methods , Transplantation, Homologous/standards , Treatment Outcome
3.
Biol Blood Marrow Transplant ; 24(3): 594-599, 2018 03.
Article in English | MEDLINE | ID: mdl-29061535

ABSTRACT

Blocking lymphocyte trafficking after allogeneic hematopoietic stem cell transplantation is a promising strategy to prevent graft-versus-host disease (GVHD) while preserving the graft-versus-tumor response. Maraviroc, a CCR5 antagonist, has shown promise in clinical trials, presumably by disrupting the migration of effector cells to GVHD target organs. We describe a phosphoflow assay to quantify CCR5 blockade during treatment with maraviroc and used it to evaluate 28 patients in a phase II study. We found that insufficient blockade of CCR5 was associated with significantly worse overall survival (HR, 10.6; 95% CI, 2.2 to 52.0; P = .004) and higher rates of nonrelapse mortality (HR, 146; 95% CI, 1.0 to 20,600; P = .04) and severe acute GVHD (HR, 12; 95% CI, 1.9 to 76.6; P = .009). In addition, we found that pretransplant high surface expression of CCR5 on recipient T cells predicted higher nonrelapse mortality and worse GVHD- and relapse-free survival. Our results demonstrate that pharmacodynamic monitoring of CCR5 blockade unravels interpatient variability in the response to therapy and may serve as a clinically informative biomarker.


Subject(s)
CCR5 Receptor Antagonists , Graft vs Host Disease , Maraviroc , Receptors, CCR5 , Aged , CCR5 Receptor Antagonists/administration & dosage , CCR5 Receptor Antagonists/pharmacokinetics , Disease-Free Survival , Female , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Male , Maraviroc/administration & dosage , Maraviroc/pharmacokinetics , Middle Aged , Survival Rate
4.
Blood ; 129(7): 906-916, 2017 02 16.
Article in English | MEDLINE | ID: mdl-28057639

ABSTRACT

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.


Subject(s)
CCR5 Receptor Antagonists/therapeutic use , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Lymphocyte Activation/drug effects , Receptors, CCR5/immunology , T-Lymphocytes/drug effects , Adult , Aged , Antigens, Neoplasm/analysis , Antigens, Neoplasm/immunology , Biomarkers, Tumor/analysis , Biomarkers, Tumor/immunology , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunity, Cellular/drug effects , Interleukin-15/analysis , Interleukin-15/immunology , Lectins, C-Type/analysis , Lectins, C-Type/immunology , Male , Middle Aged , Pancreatitis-Associated Proteins , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transplantation, Homologous , Treatment Outcome , Young Adult
5.
Biol Blood Marrow Transplant ; 22(11): 1961-1967, 2016 11.
Article in English | MEDLINE | ID: mdl-27478011

ABSTRACT

To determine the association of somatic mutations in acute myeloid leukemia (AML) with risk of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), we retrospectively studied pre-transplantation genetic profiles obtained from next-generation sequencing of 26 genes in 112 adult patients with AML who underwent alloHSCT. Univariable and multivariable regression analyses were used to assess the association between the presence of a pathogenic mutation and risk of relapse after alloHSCT. Eighty-six percent (96 of 112) of patients had at least 1 pathogenic mutation. Mutations in TP53, WT1, and FLT3-internal tandem duplication (ITD) were associated with an increased risk of relapse after alloHSCT (adjusted hazard ratio [aHR], 2.90; P = .009; aHR, 2.51; P= .02; and aHR, 1.83; P = .07, respectively). DNMT3A mutation in the absence of FLT3-ITD and NPM1 mutations was associated with a lower relapse risk (aHR, .22; P = .04). Comparison of pre-alloHSCT and post-alloHSCT genetic profiles showed clonal evolution in 6 of 6 patients, including acquisition of actionable mutations in 4 patients. In summary, genetic profiling is useful for assessing relapse risk in patients with AML undergoing alloHSCT and may identify patients in need of strategies to reduce this risk. Clonal evolution is present at post-alloHSCT relapse and repeat genetic profiling may uncover acquired actionable mutations.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , High-Throughput Nucleotide Sequencing/methods , Leukemia, Myeloid, Acute/genetics , Mutation , Adult , Aged , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , Female , Humans , Male , Middle Aged , Nuclear Proteins/genetics , Nucleophosmin , Recurrence , Retrospective Studies , Transplantation, Homologous , Tumor Suppressor Protein p53/genetics , WT1 Proteins/genetics , Young Adult , fms-Like Tyrosine Kinase 3/genetics
6.
Am J Hematol ; 91(9): 883-7, 2016 09.
Article in English | MEDLINE | ID: mdl-27197602

ABSTRACT

Reduced intensity allogeneic stem cell transplantation (RI alloSCT) is a potentially curative treatment approach for patients with myelodysplastic syndrome (MDS). It is currently unclear if older related donors are better than younger unrelated donors for patients with MDS undergoing RI alloSCT. We retrospectively studied 53 consecutive MDS patients who underwent RI alloSCT between April 2007 and June 2014 and evaluated associations between donor type and outcomes with adjustment for significant covariates. 34 patients (median age: 64 years) and 19 patients (median age: 60 years) received allografts from unrelated and related donors, respectively. Unrelated donors were younger than related donors (median age: 32 vs. 60 years, P < 0.0001). There were no significant differences in baseline disease characteristics of patients receiving allografts from related or unrelated donors. Patients who received allografts from unrelated donors had a lower relapse risk (adjusted hazard ratio [aHR] = 0.35, P = 0.012) and improved relapse-free survival (aHR = 0.47, P = 0.018). HLA mismatched unrelated donors were associated with a higher risk of grade 2-4 acute graft versus host disease (GVHD) (HR = 4.64, P = 0.002) without an accompanying increase in the risk of non-relapse mortality (P = 0.56). Unrelated donors provided a higher mean CD8 cell dose (P = 0.014) and were associated with higher median donor T cell chimerism at day 60 (P = 0.003) and day 100 (P = 0.03). In conclusion, patients with MDS who received allografts from unrelated donors had a lower risk of relapse and improved relapse-free survival when compared to patients who received allografts from related donors. These findings should be confirmed in a prospective study. Am. J. Hematol. 91:883-887, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Blood Donors , Hematopoietic Stem Cell Transplantation/methods , Myelodysplastic Syndromes/therapy , Adult , Age Factors , Aged , Aged, 80 and over , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Histocompatibility , Humans , Male , Middle Aged , Myelodysplastic Syndromes/mortality , Recurrence , Retrospective Studies , Transplantation, Homologous , Unrelated Donors , Young Adult
7.
J Immunol ; 196(3): 1070-80, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26712946

ABSTRACT

Notch signaling regulates multiple helper CD4(+) T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease in mice. However, the human counterpart of murine DLL4(+) DCs has yet to be examined. We report the identification of human DLL4(+) DCs and their critical role in regulating Th1 and Th17 differentiation. CD1c(+) DCs and plasmacytoid DCs (pDCs) from the peripheral blood (PB) of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation had a 16-fold more DLL4(+)CD1c(+) DCs than healthy donors. Upon activation of TLR signaling, healthy donor-derived CD1c(+) DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4(+) DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing Ab decreased Notch signaling in T cells stimulated with DLL4(+) DCs, and it reduced the generation of Th1 and Th17 cells. Both NF-κB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, autoimmunity, and tumor immunity.


Subject(s)
Cell Differentiation , Dendritic Cells/immunology , Intercellular Signaling Peptides and Proteins/immunology , Lymphocyte Activation/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Adaptor Proteins, Signal Transducing , Allografts/immunology , Blotting, Western , Calcium-Binding Proteins , Cell Differentiation/immunology , Flow Cytometry , Hematopoietic Stem Cell Transplantation , Humans , Lymphocyte Culture Test, Mixed , Real-Time Polymerase Chain Reaction , Th1 Cells/cytology , Th17 Cells/cytology
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