scholarly journals Easix before Conditioning Therapy Predicts Sepsis after Allogeneic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1774-1774
Author(s):  
Felix Korell ◽  
Nicholas Schreck ◽  
Axel Benner ◽  
Tobias Liebregts ◽  
Stefan Schönland ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Cox Regression ◽  
Working Party ◽  
Fold Increase ◽  
Serum Markers ◽  
Time Dependent ◽  
Training Cohort ◽  
Conditioning Therapy ◽  
Early Sepsis

Abstract Purpose: Endothelial complications are principal causes of non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). Sepsis is a dysfunctional endothelial response to harmful microorganisms with increased risk of microvascular damage and organ failure. We hypothesized that the endothelial activation and stress index (EASIX) predicts risk of sepsis after alloSCT. Methods: In this retrospective evaluation, 1290 patients (random 1:1 allocation into a training cohort and a validation cohort while balancing for sepsis events) were assessed for presence of neutropenic fever, sepsis and infectious pathogens within 50 days after alloSCT. Sepsis and septic shock were defined according to the modified Sepsis-3 guidelines by the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO) for neutropenic cancer patients. EASIX and additional serum markers were assessed longitudinally before and after transplantation and correlated with outcome. Established clinical risk scores (EBMT, HCT-CI and VOD-CIBMTR) were raised and compared to EASIX. Results: Within the full cohort of 1290 patients transplanted since 01/2004, neutropenic fever episodes until day+50 after alloSCT were reported in 989 (76.7%), sepsis in 93 (7.2%), catecholamine use in 35 (2.7%), and mechanical ventilation in 31 (2.4%) patients. Patients who developed sepsis until day+50 differed from patients without early sepsis in more frequently having a higher disease score (58% vs 33%, p<0.001), more often receiving ATG prophylaxis (77% vs 64%, p=0.007), myeloablative or aplasia conditioning (44% vs 20%, p<0.001), and less likely receiving MTX prophylaxis (33% vs 43%, p=0.06). Prior to conditioning therapy, EASIX(-pre) was the only marker to predict the hazard of early sepsis irrespective of pathogen detection in time-dependent ROC (AUC 0.85 at day 50) and multivariable cause-specific Cox regression analyses (HR per two-fold increase 2.3 (1.9-2.8, p<0.001). The prognostic value of uni- and multivariable models were evaluated in the second cohort. An optimized cutoff for EASIX defined in the training cohort (2.32) strongly predicted sepsis in multivariable cause-specific Cox regression in the second cohort (HR 16.3 (7.0-37.5), p<0.001). Although Ferritin significantly predicted time to death without sepsis (HR per two-fold increase 1.11 (1.03-1.19), p=0.008), EASIX performed superior to other scores in univariate analysis when predicting time to early sepsis with respect to predictive accuracy measured by the time-dependent Brier score (Figure 1). Accordingly, EASIX was the strongest pre-transplantation score to predict early non-relapse mortality (NRM) within 6 months after alloSCT. Pre-conditioning leukocyte counts, CRP or endothelial serum markers did not associate with early sepsis. After transplantation starting with day 0, sepsis associated with EASIX at any time point until day+28, and in addition with suppressor of tumorigenicity (ST)2 and interleukin-18. Conclusions: EASIX is a powerful predictor of early sepsis and 6-months NRM, irrespective of detected pathogens. Patients with EASIX-pre>2.32 represent a high-risk cohort requiring intensive prophylaxis and endothelial protective treatment strategies. Figure 1 Figure 1. Disclosures Schönland: Pfizer: Honoraria; Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding; Takeda: Honoraria, Other: Travel grants. Hegenbart: Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Alnylam: Honoraria; Akcea: Honoraria; Prothena: Research Funding. Schmitt: Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company. Dreger: Novartis: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

Absence or Blockage of E-Selectin-Mediated Cell Adhesion Delays Hematopoietic Stem Cell (HSC) Turn-Over and Enhances Chemoresistance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 564-564
Author(s):  
Ingrid G Winkler ◽  
Valerie Barbier ◽  
Bianca Nowlan ◽  
Theodore Smith ◽  
John T Patton ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Adhesion ◽  
Hematopoietic Stem Cell ◽  
Adhesion Molecule ◽  
Research Funding ◽  
Fold Increase ◽  
Brdu Incorporation ◽  
Adhesive Interaction ◽  
Hematopoietic Stem

Abstract Abstract 564 The behaviour of a hematopoietic stem cell (HSC) is regulated by its immediate micro-environment or niche. We have identified a novel function for the adhesion molecule E-selectin which is constitutively expressed on bone marrow (BM) vasculature. Using mice knocked-out for E- (E-/-) or P-selectin (P-/-) genes, we investigated whether selectin absence alters HSC behaviour in vivo. We found HSC cycling in the absence of E-selectin to be significantly delayed 2.5-fold in BrdU incorporation assays compared to either P-/- or WT (mice were administered BrdU for 3d then BrdU incorporation in BM Lineage-KIT+Sca1+(LKS+)CD34- or LKS+CD48-CD150+cells measured). To confirm these findings, LKS+ cells were stained with rhodamine123, a vital dye retained by metabolically active cells but not quiescent HSC. More LKS+ cells from E-/- mice were rhodamine dull (34±2%) than WT (23±1%; p=0.037) confirming that a greater proportion of HSC from E-/- mice are quiescent. We then determined whether administration of E-selectin antagonists alone could similarly delay HSC turnover. Mice were administered the glycomimetic E-selectin antagonist GMI-1070, for set periods of time before harvest. We found HSC turnover to be significantly delayed following GMI-1070 administration (1.4 fold less BrdU incorporation, p=0.011) with a concomitant 1.4-fold increase in the number of Rho123 dull LSK+ quiescent HSC per femur (p=0.020). Non-cycling, quiescent HSC are known to be more resistant to chemotherapy and irradiation. Indeed 7 days following 5-FU administration, we found that E-/- mice had faster BM HSC recovery / less HSC damage compared to WT mice, both by phenotype analysis and in a competitive long-term reconstituting assay. Following 5-FU administration the number of reconstituting units/femur in WT mice decreased 5.1-fold but only decreased 2.3-fold in similarly treated E-/- mice. Interestingly, when mice were pre-treated with GMI-1070 before 5-FU, there was significantly enhanced blood neutrophil recovery compared to mice administered 5-FU alone (blood neutrophils were 710±205 ×103/mL with GMI-1070, compared to 234±141 ×103/mL without, at day 9 post-5-FU, p=0.0001). Similarly when mice were severely irradiated and test bleeds performed weekly, a more rapid haematopoietic recovery was observed in E-/- compared to WT mice. In summary, we have identified a novel function for the adhesion molecule E-selectin. HSC turnover is dramatically reduced in E-/- mice an effect that can be replicated by transient administration of E-selectin antagonist mimetics. Furthermore blood leukocyte and HSC numbers recover faster following cytotoxic or irradiation injury in the absence or blockage of E-selectin-mediated cell adhesion. Thus E-selectin may well be a crucial component of the proliferative HSC niche regulating HSC turnover. Blockage of E-selectin adhesive interaction by GMI-1070, a novel E-selectin antagonist that has completed phase I clinical trails, may represent a promising treatment for the protection of HSC during chemotherapy. Disclosures: Winkler: Glycomimetics Inc: Research Funding. Smith:GlycoMimetics, Inc: Employment. Patton:GlycoMimetics, Inc: Employment. Magnani:GlycoMimetics, Inc.: Employment. Levesque:Glycomimetics Inc.: Research Funding.

SWOG S0120 Observational Trial for MGUS and Asymptomatic Multiple Myeloma (AMM): Imaging Predictors of Progression for Patients Treated At UAMS,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3955-3955
Author(s):  
Christoph Heuck ◽  
Rachael Sexton ◽  
Madhav Dhodapkar ◽  
Qing Zhang ◽  
Saad Usmani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Research Funding ◽  
Cox Regression ◽  
Time Dependent ◽  
M Protein ◽  
Risk Scores ◽  
Imaging Studies ◽  
Focal Lesions ◽  
Pet Ct

Abstract Abstract 3955 Background: MGUS counts for the majority of monoclonal gammopathies and can be found in approximately 3% of adults older than 50 years. MGUS progresses to active Multiple Myeloma (MM) at a rate of 1–2% per year, thus imparting an average risk of 25% for progression (PRO) over a lifetime once diagnosed. Unfortunately no single laboratory, molecular or imaging variable can reliably predict PRO. S0120 accrued 363 patients at 69 sites across the US between January 1, 2004 and November 1, 2011, of whom 166 had MGUS and 190 AMM, defined according to IMWG criteria, on whom laboratory, gene expression and imaging studies were collected in a prospective fashion. Here we report the results of imaging studies as predictors of progression. Methods: 262 patients with evaluable follow-up were enrolled at the University of Arkansas for Medical Sciences (UAMS) site. MRI and PET-CT studies were performed at baseline and serially thereafter until PRO to symptomatic MM defined by standard variables of M-protein, bone marrow findings and CRAB criteria, according to protocol. Lab studies were performed at three months, six months and one year after registration, then every 12 months for a total of 5 years from registration as well as within 14 days of decision to discontinue observation or within 14 days of progression. MRI parameters included the number of focal lesions (FL) recognized by short TI inversion recovery (STIR) analysis of the axial bone marrow along with an account of bone marrow background intensity compared to adjacent muscles (hypo-, iso-, hyper-intense). PET-CT parameters included number of FDG-avid focal lesions (PET-FL), SUVmax of PET-FL, presence of extra-medullary disease (EMD) as well as the FDG avidity score at L5 (SUV-L5). Evaluable baseline MRI and PET studies were available for 235 and 224 patients, respectively. Results: In the 262 eligible patients enrolled and followed at UAMS, the two subgroups of MGUS and AMM differed by definition in M-protein and bone marrow plasmacytosis; in addition, IgA subclass and Hyperdiploidy molecular subgroup were overrepresented in the AMM group. Patients in the AMM group also had higher risk scores defined by the GEP 70-gene risk model (GEP70). At 24 months from study entry, 18.8% of all patients had progressed to MM (25.6% of AMM patients and 8.2% of MGUS patients) and 11.5% had begun MM therapy (15.8% of AMM patients and 4.5% of MGUS patients). Univariate Cox regression strongly indicated that age ≥ 65, serum albumin <3.5g/dL, B2M >+3.5mg/L, detection of any cytogenetic abnormalities (CA), and suppression of uninvolved light chains were adversely associated with time to PRO. The AMM-constituting features, bone marrow plasmacytosis >10%, M-protein >30g/L, and abnormal K/L ratio also conferred greater hazard of PRO. Risk scores > −0.26 and >1.5 for GEP70 and GEP80, respectively, as well as detection of focal lesions by MRI at baseline carried an elevated HR for PRO. A multivariate Cox regression showed only elevated M-protein, abnormal K/L ratio and GEP70 risk scores > =0.26 to be strongly associated with time to PRO. In the context of this MV model, disease subtype (AMM v MGUS) was insignificant. Inclusion of development of MRI-FL or and PET-FL as time-dependent variables showed that they were associated with time to PRO with HRs of 27.12 and 32.18 respectively. Abnormal K/L ratio and elevated M-protein were lost in this MV model. Analyzing variables linked to initiation of MM therapy, abnormal K/L ratio, elevated BM plasmacytosis, elevated M-protein, GEP70 risk scores >-0.26 as well as detection of MRI-FL at baseline (≥1 FL: HR=4.90; ≥3FL: HR=10.00) were univariately significant. On multivariate analysis, abnormal K/L ratio, elevated M-protein and GEP70 risk scores > – 0.26 were associated with time to treatment for MM. Inclusion of development of MRI-FL or PET-FL as a time dependent variable were associated with time to treatment with HRs of 29.12 and 36.50 respectively. Conclusion: To our knowledge, this is the first comprehensive effort that has used available imaging modalities along with established laboratory and pathology investigations in an attempt to distinguish features predictive of PRO from MGUS to active MM. In addition to the established “high-risk” MGUS/AMM features, we found that presence of MRI-FL at baseline, presence of CA and GEP70 scores >-0.26 carry a higher risk of PRO. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Impact of Donor-Recipient Histocompatibility and CMV-Mismatch on Outcome of Allogeneic Stem Cell Transplantation for AML and MDS: A Retrospective Registry Study of the German Stem Cell Transplant Registry (DRST) of the German Working Group for Blood and Marrow Transplantation (DAG-KBT)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2304-2304 ◽  
Author(s):  
Francis A. Ayuk ◽  
Dietrich W. Beelen ◽  
Martin Bornhäuser ◽  
Matthias Stelljes ◽  
Tajana Zabelina ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Cox Regression ◽  
Negative Impact ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
T Cell Depletion ◽  
Cox Regression Analysis

Abstract Introduction Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions. Patients and methods: We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST), 2) age >/= 18 years, 3) availability of high-resolution typing for HLA-A, -B, C, DRB1 and DQB1 in case of unrelated donor. Patients with ex-vivo T cell depletion were excluded. 3215 patients with AML (n = 2648) or MDS (n = 567) were included in the study. Donors were matched related (MRD, n =872), matched unrelated (MUD, n = 1553) or mismatched unrelated (9/10 MMUD, n= 620; 8/10 MMUD n = 137; <8/10 MMUD n = 33). Remission status at transplant was CR (49%), not in CR (40%) or untreated (11%). The vast majority of patients (96%) received peripheral blood stem cell grafts. Conditioning was reduced intensity (51%) or myeloablative (49%) according to EBMT criteria. ATG (56%) or alemtuzumab (8%) were used for in vivo T cell depletion. Median patient age was 56 (18-79) years. Median donor age was 38 (12-80) years. Median follow-up was 54 months (34-81 months). Primary endpoint was overall survival (OS) at 3 years. Results: Kaplan-Meier estimates for OS at 3 years was similar after transplants from MRD = 55% (95%CI 51-59%) compared to MUD = 53% (95%CI 51-59%), p = 0.26. OS at 3 years was worse for 9/10 MMUD with 45% (95% CI 41-49%, p<0.001), for 8/10 MMUD with 35% (95% CI: 27%-43%, p < 0.001) and for <8/10 MMUD with 29% (95% CI 13%-45%, p = 0.005) (figure 1). In recipients of unrelated donor transplants, multivariate cox regression analysis revealed significant negative impact of increasing patient age, increasing donor age, sex-mismatch (male patient/female donor), CMV-mismatch (patient pos/ donor neg), diagnosis of AML or sAML compared to MDS, lack of complete remission at transplant, abnormal cytogenetics and HLA-mismatching (table 1a). In a subgroup analysis restricted to patients transplanted from unrelated donors after myeloablative conditioning and T cell depletion, 3 years OS was better after 10/10 MUD: 60% (55-65%) compared to 9/10 MMUD: 49% (41-57%), p = 0.02. This was also true after reduced intensity conditioning and T cell depletion with ATG, with 3 year OS after 10/10 MUD: 49% (45-53) compared to 9/10 MMUD: 37% (31-43%), p = 0.001. Excluding HLA-DQB1-mismatches and HLA-C0303/0304-mismatches from the 9/10 MMUD group did not significantly alter results. Acknowledging the negative impact of both HLA and CMV-mismatching, we sought to determine which of these two parameters is of higher relevance for donor selection. For this purpose subgroup analyses were performed including only CMV-positive patients who received transplants from an unrelated donor (10/10 MUD or 9/10 MMUD). HLA-DQB1-mismatches and HLA-C0303/0304-mismatches were excluded. For this subgroup of n = 1167 patients multivariate cox regression analysis revealed better outcome after 10/10 MUD from CMV neg. donors compared to 9/10 MMUD from a CMV pos. donors (RR: 1.31, p = 0.04, table 1b and figure 2). Restricting the analysis only to patients who received T cell depletion with ATG did not significantly alter these findings. Conclusions: In this large multicenter cohort of recently transplanted patients, we find similar survival outcomes for matched related and fully matched unrelated donor transplants. We confirm the negative impact of HLA-mismatching on survival outcome, irrespective of conditioning intensity. Our results show that though CMV-mismatching is associated with poorer outcome, its relevance is secondary to HLA-mismatching. Acknowledgments: This work was supported by a research grant of the DKMS-Stiftung to FA and WB. Disclosures Stelljes: Pfizer: Consultancy. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

The Percentage of Cytotoxic T-Cells in Mantle Cell Lymphoma (MCL) Biopsies Predicts Response to Rituximab.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2923-2923
Author(s):  
Stephen Opat ◽  
Pedro Farinha ◽  
Merrill Boyle ◽  
Nathalie Johnson ◽  
Hilary OLeary ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
B Cells ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Cox Regression ◽  
Cytotoxic T Cells ◽  
Response To Therapy ◽  
Cell Transplant ◽  
Treatment Regimens

Abstract Abstract 2923 Poster Board II-899 Background: MCL is characterized by the presence of the t(11;14) translocation that juxtaposes the cyclin D1 gene downstream of the immunoglobulin heavy-chain gene promoter resulting in enhanced G1μS phase transition leading to cellular proliferation. Despite the common genetic lesion, patients exhibit considerable heterogeneity in their clinical behavior and response to therapy. The clinical significance of the microenvironment in follicular lymphoma has been highlighted by gene expression studies demonstrating that a T-cell response signature correlates with a superior outcome compared to that seen with a macrophage signature. In contrast, the significance of the non-malignant cellular component in MCL biopsies remains unknown. We report the results of a retrospective study examining flow cytometry (FCM) of MCL diagnostic tissue biopsies, focusing on the non-malignant lymphoid cells. Method: Patients were included in the study if they had MCL diagnosed according to the 2008 WHO criteria, had FCM performed on their diagnostic nodal or tissue biopsy and had adequate clinical information that included baseline clinical characteristics, treatment regimens and clinical outcome. Patients were excluded if they were too frail to receive chemotherapy or if FCM was only performed on peripheral blood or bone marrow. 122 patients met the criteria for inclusion in the study; of which 56 were also assessable by tissue microarray (TMA). FCM data were re-analyzed for expression of CD3, CD4, CD8, CD19, CD20 and kappa and lambda light chains on cells gating on lymphoid populations. Estimates of the non-neoplastic B-cells were derived from total CD19/CD20 positive B cells excluding the light chain restricted population. ‘High' and ‘low' expressers for each marker were determined by examining frequency histograms for a trough. TMAs were prepared from diagnostic paraffin-embedded blocks according to established protocols. Sections were immunostained for CD3, CD4, CD8, CD68, CD34, TIA-1, CD163, FOXP3, PD-1, CD57, CD21, P53 and Ki67. Survival correlates were assessed by Cox regression using SPSS. Results: The median age was 67 y (range 22-94) with 69% being male. 88% had advanced-stage disease with 16% having a high IPI (4/5). 50 (41%) patients received rituximab as part of initial or subsequent therapy. Primary and secondary treatment regimens included: observation (19); single agent alkylators (33); CHOP-like with rituximab (39); CHOP-like without rituximab (32); CVP-like (11); higher intensity regimens (9); fludarabine-based (19); gemcitabine-based (9); bortezimib (4); flavopiridol (2); autologous stem cell transplant (12); allogeneic stem cell transplant (2); radiation (45); and therapeutic splenectomy (6). The median follow up of the living patients was 30 months. The 5-y OS for the group was 21%. FCM median tumor content was high at 84% (range 21-100%) with median CD3, CD4, CD8 and non-tumor CD20 populations of 12%, 7%, 4% and 1%, respectively. Univariate analysis revealed CD8<8% (p=0.009), IPI (p<0.001) and rituximab therapy (p<0.001) as predictive of favorable OS while Cox regression analysis identified only IPI (p<0.001) and rituximab therapy (p<0.001) to be independent predictors of OS. Restricting analysis to those who received rituximab revealed a survival advantage for patients with <8% CD8+ T cells in their biopsies which was independent of the IPI (5-y OS with CD8<8% (37) 49%; CD8≥8% (13) 0%, p=0.023). The number of CD3, CD4 and the non-neoplastic B cells did not appear to significantly predict survival. TMA analysis confirmed the adverse impact of elevated CD8+ lymphocytes (<1% versus ≥1%) in patients who received rituximab (p=0.004) and suggested that many CD8 cells were cytotoxic with increased TIA-1+ expression predicting an inferior outcome (p=0.009). Ki-67 expression >35% was also adversely associated with OS (p=0.028). Conclusion: While the non-neoplastic cellular infiltrate often constitutes only a minor fraction of the tumor mass in MCL, it appears to significantly influence response to rituximab therapy. Further studies are required to validate this observation prospectively and define the mechanism by which the cytotoxic T-cells exert their influence. Disclosures: Connors: Roche Canada: Research Funding. Gascoyne:Roche Canada, Genentech, Lilly, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Salvage Therapy with Azacitidine Increases Regulatory T Cells in Patients with AML or MDS and Early Relapse After Allogeneic Blood Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1964-1964
Author(s):  
Thomas Schroeder ◽  
Julia Fröbel ◽  
Ron Patrick Cadeddu ◽  
Akos G. Czibere ◽  
Ariane Dienst ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Fold Increase ◽  
Absolute Number ◽  
Advisory Committees ◽  
Early Relapse

Abstract Abstract 1964 Introduction: Treatment with azacitidine (Aza) and donor lymphocyte infusions (DLI) can induce sustained remissions in some patients (pts) with AML or MDS relapsing after allogeneic stem cell transplantation (allo-SCT). Meanwhile incidence and severity of GvHD seems to be relatively low when compared to historical data using DLI alone. As a potential mechanism murine models have suggested that Aza upregulates the transcription factor FoxP3 thereby expanding CD4+ regulatory T cells (Tregs). This has also been recently shown in 17 AML pts receiving Aza maintenance therapy following allo-SCT (Goodyear et al., 2012). Patients and Methods: To confirm and expand this knowledge we monitored CD4+CD25+FoxP3+ Tregs and lymphocyte subsets (CD3+; CD3+/CD4+; CD3+/CD8+; CD3−/CD56+; CD20+) by flow cytometry in 46 pts during salvage therapy with Aza (up to 8 cycles either 100 mg/m2/day d1-5 or 75 mg/m2/d d1-7) and DLI (envisaged on day 34/90/146) for relapse following allo-SCT. PB samples were obtained prior treatment (d0), after the 1st (d6), 2nd (d34), 4th (d90) and 6th cycle (d146). To assure a serial measurement only pts who had received at least 4 Aza cycles were eligible. Thereby 13 pts could be included, while 33 pts were excluded as a consequence of early drop-of resulting from progression or death (n=21), or due to missing samples (n=12). Results: Relapse of AML (n=8) or MDS (n=5) occurred in median 446 d (range:19–1688) following allo-SCT in these 13 pts. They received a median of 6 Aza cycles (range: 4–8). DLI were administered in all patients with a median number of 2 DLI per patient (range:1–4) resulting in a median total T cell dose of 5.0×106CD3+ cells/kg per patient (range:1–119). A CR rate of 62% (n=8) was observed in these 13 pts being overestimated in comparison to a CR rate of 33% (n=15) in the whole group due to positive selection of pts. Prior to relapse 6 pts (46%) had suffered from aGvHD (Io 1 pt, IIo 1 pt, IIIo 3 pts, IVo 1 pt) and 2 pts (15%) from cGvHD (limited 1 pt, extensive 1 pt). At the beginning of Aza treatment 3 pts were still on immunosuppresion which could be tapered in all cases without GvHD flare. Following treatment with Aza aGvHD was observed in 5 pts (overall 38%, Io 3 pts, IIIo2 pts) in median 129 d (range: 20 – 253) following the 1st DLI, while cGvHD developed in 6 pts (overall 46%, limited 5 pts, extensive 1 pt). In concordance with this rather mild presentation of GvHD, a 1.5-fold increase of Tregs was observed after 4 Aza cycles (d0: 8.23/μl vs. d90: 13.26/μl, p=0.0479). By grouping the pts on the basis of the median time to relapse (day 446), we observed a 3.2-fold increase of the absolute number (d0: 4.7/μl vs. d90: 14.8/μl, p=0.031) as well as an 1.9-fold increase of the frequency of Tregs (d0: 6.7% vs. d90: 12.9% of CD3+CD4+ cells, p=0.06) during treatment with Aza in the group of patients who relapsed early. On the other hand, in those patients who relapsed late the absolute number of Tregs (d0: 12.2/μl vs. d90: 11.9/μl, n. s.) was already higher and remained together with the Treg frequency (d0: 4.7% vs. d90 3.9%, n. s.) unchanged during treatment. Of interest, in those patients with early relapse only 1 pt developed aGvHD (Io), in contrast to 4 pts with aGvHD in those with late relapse. No significant changes were observed with regard to other lymphocyte subpopulations. Conclusions: We here demonstrate an intra-individual Treg expansion, which might be induced by Aza and may explain the low rate and mild presentation of GvHD observed following the combination of Aza and DLI. In line with the data of Goodyear et al. Aza-induced expansion of Tregs seems to be restricted to patients relapsing early after allo-SCT where the Treg repertoirs is still immature. Disclosures: Schroeder: Celgene: Travel support Other. Platzbecker:Celgene: Honoraria, Research Funding, Speakers Bureau. Bug:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, Travel support Other. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kröger:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

Total Therapy (TT) Studies For Gene Expression Profiling (GEP)-Defined High-Risk Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 126-126
Author(s):  
Christoph Heuck ◽  
Frits van Rhee ◽  
Alan Mitchell ◽  
Adam Rosenthal ◽  
Sarah Waheed ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Research Funding ◽  
Cox Regression ◽  
Time Dependent ◽  
P Value ◽  
Chi Square ◽  
Stepwise Selection ◽  
Response Status ◽  
Chi Square Test

Abstract Little progress has been made in the management of the 15% of patients presenting with GEP-70-defined high risk MM. Successive TT protocols (TT3, TT5) were reviewed and clinical endpoints (CR, CR duration, PFS, OS) compared and prognostic models developed for this high-risk entity. Altogether 127 patients were identified (TT3a, 40; TT3b, 37; TT5, 50), whose baseline characteristics were similar with regard to age, B2M, CRP, creatinine, hemoglobin, platelet count, LDH, metaphase-based cytogenetic abnormalities and the recently introduced GEP-5 risk designation (Table 1Table 1Patient characteristics, TT3 vs. TT5FactorTT3TT5P-valueAge >= 65 yr21/77 (27%)14/50 (28%)0.929Albumin < 3.5 g/dL44/77 (57%)25/49 (51%)0.501B2M >= 3.5 mg/L57/77 (74%)40/49 (82%)0.323B2M > 5.5 mg/L41/77 (53%)22/49 (45%)0.361CRP >= 8 mg/L35/77 (45%)18/49 (37%)0.334Creatinine >= 1.5 mg/dL18/77 (23%)11/49 (22%)0.904Hb < 10 g/dL41/77 (53%)28/49 (57%)0.668LDH >= 190 U/L37/77 (48%)17/49 (35%)0.140Platelet Count < 150 x 10^9/L24/77 (31%)17/49 (35%)0.681Cytogenetic abnormalities57/76 (75%)33/49 (67%)0.352GEP-5 High-Risk58/77 (75%)34/50 (68%)0.367n/N(%): n- Number with Factor, N-Number with Valid Data for FactorN/A:All Positive or All Negative for Factor, P-value not available* Fisher Exact Test, otherwise Chi-Square Test). Compared to TT3a/b combined, TT5 resulted in improved OS (2-yr estimate 92% v 68%, p=0.02) with no difference noted for PFS and CR duration. GEP-5-defined high-risk MM fared significantly worse for OS (p=0.02) and PFS (p=0.04), without difference in CR duration (p=0.4). Univariate Cox regression analysis was performed on standard prognostic factors as well as time-dependent indicators for achieving CR and disease progression; the interaction term for achieving CR and disease progression (i.e. relapse from CR) was also considered for the multivariate model (Table 2). A stepwise selection algorithm identified age >=65yr and disease progression as independent adverse variables, while TT5 had a HR=0.31 (p=0.002). The results from this model highlight the importance of improving the rate of progression in high-risk MM. The importance of sustained CR or progression-free survival for at least 2 years is demonstrated in Figure 1. Patients relapsing within 2 years from CR or lower response level survived a subsequent median of less than 1 year.Table 2Multivariate Cox Regression AnalysisOverall SurvivalVariablen/N (%)HR (95% CI)P-valueMultivariate ModelTT548/124 (39%)0.29 (0.14, 0.60)<.001Disease Progression ***13.13 (7.47, 23.10)<.001Age >= 65 yr34/124 (27%)2.44 (1.38, 4.31)0.002Multivariate Model with Additional Term for Achieving CRTT550/127 (39%)0.30 (0.14, 0.64)0.002Achieved CR ***0.63 (0.35, 1.11)0.110Disease Progression ***11.99 (6.85, 21.00)<.001Age >= 65 yr35/127 (28%)2.50 (1.41, 4.43)0.002HR-Hazard Ratio, 95% CI- 95% Confidence Interval, P-value from Wald Chi-Square Test in Cox Regression. All univariate pvalues reported regardless of significance.Multivariate model uses stepwise selection with entry level 0.1 and variable remains if meets the 0.05 level.A multivariate p-value greater than 0.05 indicates variable forced into model with significant variables chosen using stepwise selection.*** Indicates Time-dependent variable. Figure 1 Overall Survival by Response Status at 2 year Landmark Figure 1. Overall Survival by Response Status at 2 year Landmark Thus, GEP-70-defined high-risk MM has not yet benefited from therapeutic advances observed in low-risk disease. The superior OS in TT5 may be due to the availability of additional new agents, pomalidomide and carfilzomib, which will be incorporated into the front line management of such patients. A plateau-like shape of the PFS curve emerged at 4 years supporting previous observations in TT2 that GEP-defined high-risk MM can be cured in a fraction of patients. The GEP-5 model points to the detrimental role of a limited number of genes which, when targeted, may offer means of controlling this disease entity. We are also applying exomics to identify, in high-risk MM, early on actionable mutations for personalized therapy of such patients. Disclosures: van Rhee: Jansen & Jansen: Research Funding. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; Myeloma Health, LLC: Patents & Royalties.

scholarly journals Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1958-1958
Author(s):  
Donal McLornan ◽  
Richard Szydlo ◽  
Anja van Biezen ◽  
Linda Koster ◽  
Evgeny Klyuchnikov ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Working Party ◽  
Active Management ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Number Of Patients ◽  
Significant Difference

Abstract Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode. Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded. The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019). Conclusions : This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Bmi-1 Overexpression Synergizes with p210-BCR-ABL to Induce Stem Cell and Progenitor Transformation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3251-3251
Author(s):  
Amitava Sengupta ◽  
Jorden Arnett ◽  
Susan Dunn ◽  
Jose Cancelas
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Research Funding ◽  
Chronic Phase ◽  
Fold Increase ◽  
Myelogenous Leukemia ◽  
Leukemic Stem Cells ◽  
Blastic Transformation ◽  
Bmi1 Expression ◽  
Blastic Phase

Abstract Abstract 3251 Poster Board III-1 Chronic myelogenous leukemia (CML) is a hematopoietic stem cell (HSC) malignancy induced by p210-BCR-ABL and characterized by myeloproliferation followed by poor-prognosis acute blastic transformation. Persistence of BCR-ABL+ HSCs in patients under tyrosine kinase inhibitor therapy suggests that inhibition of ABL-kinase alone is not sufficient to completely eliminate the leukemic stem cells and progenitor (LSC/P) population and a group of patients continue developing accelerated/blastic phase despite therapy. Expression of p210-BCR-ABL is necessary and sufficient to develop CML but the molecular mechanisms necessary for its blastic transformation remain elusive. The polycomb group gene Bmi1 plays an essential role in regulating the proliferative capacity of both normal and leukemic stem cells (Lessard J, et al. Nature 2003). Recently, expression of Bmi1 has been found significantly elevated in CD34+ cells of patients with advanced phases compared with patients in chronic-phase CML (Mohty M et al. Blood 2007). We therefore intend to determine whether Bmi1 expression in CML stem cells and progenitors, isolated from Scl/p210-BCR-ABL-expressing mice, is sufficient to accelerate significantly the development of blastic phase. Since simultaneous co-expression of Bmi1 and BCR-ABL in normal HSC/P may not faithfully recapitulate the progression events in CML transformation, we have over-expressed Bmi1 in a model of stem cell-dependent chronic phase CML. This model is based on the tetracycline-dependent expression of p210-BCR-ABL driven by the Scl promoter (Scl-tTA x TRE-BCR-ABL, Koschmieder S et al. Blood 2005), where expression of BCR-ABL is restricted to the HSC/P compartment. Scl-driven expression of BCR-ABL is predominantly active in HSC (Lin-/Sca1+/c-kit+; LSK) and progenitors (Lin-/c-kit+; LK) and is transplantable into secondary recipients (Sengupta A et al., ASH 2008). Expression of Bmi1 into Scl/p210-BCR-ABL-expressing cells significantly increases the HSC/P proliferation (2.5 fold) and also increases the frequency of colony forming cells (CFU-Cs) after serial propagation in liquid culture, compared to Bmi1 (4.6-fold) or BCR-ABL-expressing CML cells alone (517-fold). Furthermore, Bmi1 expression into Scl/p210 leukemic progenitors increases the hypermigratory phenotype of leukemic progenitors (3-fold increase over 5.5-fold increase induced by BCR/ABL alone; P<0.005) in response to CXCL12. Although, Bmi1 overexpression in Scl/p210 cells does not decrease further the reduced adhesion to fibronectin of BCR/ABL-transformed CML HSC/P, leukemic progenitors co-expressing Bmi1 and SCL/p210 have significantly reduced homing in bone marrow compared to Bmi1-expressing HSC/P (7.7 fold, P≤0.005). Altogether, these data indicate that Bmi-1 synergistically enhances the transformation phenotype of p210-BCR-ABL-expressing HSC/P and emphasize the role of epigenetic changes inducing overexpression of self-renewal genes in the pathogenesis of CML. These data suggest that Bmi-1 may represent a novel therapeutic target for CML LSC/P. Disclosures: Cancelas: CERUS CO: Research Funding; CARIDIAN BCT: Research Funding; HEMERUS INC: Research Funding.

scholarly journals Allogeneic Stem Cell Transplantation in Myelodysplastic Syndrome; A More Favorable Outcome after Fludarabine and Treosulfan Conditioning. a Survey on Behalf of the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1216-1216
Author(s):  
Avichai Shimoni ◽  
Arnon Nagler ◽  
Simona Iacobelli ◽  
Anja van Biezen ◽  
Dietrich Beelen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Working Party ◽  
Unrelated Donor ◽  
Refractory Disease ◽  
Predicting Factors ◽  
History Of ◽  
Relapse Rates

Abstract Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for patients with myelodysplastic syndrome (MDS). So far, there is no proven advantage for any conditioning regimen over the others. Prior studies have shown that reduced-intensity conditioning (RIC) is associated with lower non-relapse mortality (NRM) compared with myeloablative conditioning (MAC), however, relapse rates are increased, resulting in similar survival. Novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal anti-leukemia effect will be of benefit. Fludarabine combined with treosulfan (FT) has been shown, in relatively small phase II studies, to be a reduced-toxicity regimen with intense anti leukemia activity and limited toxicity in patients with myeloid malignancies and possibly in particular in MDS. In this analysis we performed a retrospective analysis of all SCTs for MDS, performed between 2000 and 2011 and reported to the chronic malignancies working party (CMWP) of the EBMT (n=2516). We identified 480 patients given FT and compared their outcomes to patients given various MAC (n=1090) and RIC (n=946) regimens. FT and RIC recipients were older than MAC recipients, median age 59, 60 and 50 years, respectively (p=0.001). They were also more likely to have an unrelated donor, 56%, 57% and 50%, respectively (p=0.001) and to be given peripheral blood stem cell rather than bone marrow grafts, 92%, 94% and 79%, respectively (p=0.001). More FT recipients had previously untreated MDS at SCT, 33%, 20% and 24% while less had chemosensitive disease, 42%, 51% and 51%, respectively (p=0.001). The proportion of patients with chemo-refractory disease and with more than 10% marrow or peripheral blood blasts at SCT was similar in the three groups. More FT recipients had a prior history of transformation to AML, 15%, 9% and 9%, respectively (p=0.03). The proportion of patients with high and intermediate-risk cytogenetics was 13%, 21% and 18%, respectively (p=0.01). With a median follow-up of 21 months (range, 1-150), 1364 patients are alive, 456 patients died of relapse and 696 of NRM causes. The estimated 5 year overall (OS) and disease-free (DFS) rates for the entire group were 40% (95%CI, 37-43) and 35% (95%CI, 33-38), respectively. The 5-year OS rate of FT recipients was 47% (95%CI, 41-52). OS after the various RIC and MAC regimens was similar, 39% (95%CI, 34-43) and 38% (95%CI, 33-42), respectively, significantly shorter than after FT (p=0.02). DFS rates were 42% (95%CI, 37-47), 31% (95%CI, 27-36) and 35% (95%CI, 30-39), respectively (p=0.002). Relapse rates were similar after FT and MAC, 25% (95%CI, 21-30) and 29% (95%CI, 25-33), respectively, significantly lower than after RIC, 37% (95%CI, 33-41) (p=0.001). NRM was lower after FT and RIC than after MAC, 33% (95%CI, 28-38) and 32% (95%CI, 28-35), Vs. 36% (95%CI, 33-40), respectively (p=0.14). Multivariate analysis identified age> 55 years (HR 1.7, P=0.01), marrow blasts at SCT > 10% (HR 1.5, p=0.02), a history of transformation to AML (HR 1.7, p=0.01) and MDS refractory to prior therapy (HR 1.8, p=0.001) as poor prognostic factors for survival, while FT conditioning was protective (HR 0.6, p=0.02). Gender, cytogenetics, time from diagnosis to SCT, donor type and stem cell source were not predictive for survival. The predicting factors for increased relapse risk were RIC (HR 1.6, p=0.03), chemorefractory disease (HR 1.6, p=0.05), marrow blasts at SCT > 10% (HR 1.6, p=0.04), poor risk cytogenetics (HR 2.2, p=0.003) and prior transformation to AML (HR 1.8, p=0.0001). The predicting factors for increased NRM were MAC (HR 1.6, p=0.004), age > 55 years (HR 1.5, p=0.008), unrelated donor (HR 1.4, p=0.004), chemo-refractory disease (HR 1.5, p=0.05), marrow blasts > 10% (HR 1.6, p=0.01) and positive patient serology for CMV (HR 1.4, p=0.04). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved outcome over both RIC and MAC regimens. FT might be the preferred regimen for SCT in MDS. These observations merit further study in randomized prospective trials. Disclosures Nagler*: MEDAC, Germany: Honoraria, Research Funding. Beelen:MEDAC, Germany: Research Funding. Ciceri:MEDAC, Germany: Honoraria, Research Funding. Kröger:MEDAC, Germany: Research Funding.

Pharmocokinetic (PK)-Directed High Dose Intravenous Busulfan, Cyclophosphamide and Etoposide Produces Predictable Drug Exposure and Durable Long Term Survival In Lymphoma Patients Undergoing Autologous Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1359-1359
Author(s):  
Hongzheng Zhang ◽  
Michael Graiser ◽  
Donald Hutcherson ◽  
M. Olufemi Dada ◽  
Stephanie McMillan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Research Funding ◽  
Regression Models ◽  
Cox Regression ◽  
Disease Status ◽  
High Dose ◽  
Treatment Groups

Abstract Abstract 1359 Background: Improved survival has been observed after replacing oral with intravenous (iv) busulfan in autologous stem cell transplantation (ASCT) for lymphoma conditioned with busulfan (Bu), cyclophosphamide (Cy) and etoposide (VP-16; Dean et al., Br J Hematol. 2010), but it is unknown whether PK-directed iv Bu dosing is associated with additional improvements in safety or efficacy. To address this issue we performed an IRB-approved retrospective cohort study to compare the efficacy of PK-directed oral and iv Bu in lymphoma patients undergoing ASCT from 2000–2010 at Emory University. Methods: Patients included for analysis received oral Bu (1.0mg/kg every 6 hours × 16, n=97), or iv Bu (0.9mg/kg every 6 hours × 16, n=199) followed by Cy (60mg/kg qd × 2), etoposide (10 mg/kg qd x3) and infusion of previous collected autologous stem cells. Baseline demographic, lymphoma subtype, disease status, body weight (kg), body surface area (BSA), body mass index (BMI; kg/m2), stem cell dose, and other clinical and ASCT parameters were compared for oral and iv groups. Bu area under the curve (AUC), maximum bilirubin, and overall survival (OS) were compared for oral and iv groups using Chi-squared statistics and Cox regression models. Results: Diagnosis was comparable across two treatment groups except the oral treatment group had slightly higher number of NHL (58%) than iv group (43%, p=0.04). The median age and percentage of males were 43 (range 19–66) and 45 (17-69), 67% and 62.3% for oral and iv groups, respectively. Patients who received oral and iv Bu did not differ by race, mean weight, BMI, stem cell dose and disease status. BSA was greater in the iv busulfan group (p=0.03). Pharmacokinetic-directed dosing was performed in both treatment groups with a total target AUC of 20,000μMol-min. Following the initial Bu dose, the Bu half-life (mean ± std., oral: 225.8 ± 104.4, iv: 189.4 ± 47.5; p=0.0026) and total targeted AUC (oral: 20,534 ± 2,969, iv: 19,695 ± 1,434; p=0.01) were significantly different between two treatment groups. 44% of patients in oral group (n=94) and 88% of patients in the iv group (n=178) achieved targeted AUC between 18,000-22,000μMol-min. PK-directed Bu dosing generated a narrower AUC range in the iv treatment groups compared with that in the oral groups (Figure 1). Regimen-related toxicities, including VOD, were similar between patients in the oral and iv groups, with 100-day mortality of 3% and 4%, respectively (p=NS). With a mean follow-up of 1,521 and 789 days for oral and iv Bu groups, 58% and 72% patients were alive in each group respectively (Figure 2). In multivariate Cox regression models, age (HR=1.03, CL 1.01–1.05, p=0.001) significantly influenced survival, but route of Bu administration did not. Oral and iv PK-directed Bu had 2-year OS of 77% and 92% in this cohort. Conclusion: PK-directed iv Bu improves the consistency of delivering target AUC over oral PK-directed Bu with similar survival outcomes for lymphoma patients undergoing ASCT. The narrow CI for final AUC among patients receiving PK-directed iv Bu may safely permit dose-escalation of busulfan administered as part of high-dose conditioning to improve transplant efficacy. Disclosures: Flowers: Genentech/Biogen-Idec (unpaid): Consultancy; Celgene, Intellikine: Consultancy; Millennium: Research Funding; Otsuka: Research Funding. Waller:Otsuka: Research Funding.

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