Daniel H. Fowler

Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population

A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 microg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34(+) cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/microL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34(+) cell counts than donors who did not (94 vs 79 cells/microL, P < .001). In multivariate analysis, higher post-G-CSF CD34(+) cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre-G-CSF platelet count, pre-G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post-G-CSF CD34(+) cell counts.

Association of Serum Interleukin-7 Levels With the Development of Acute Graft-Versus-Host Disease

PURPOSEnMorbidity from acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic stem-cell transplantation (HSCT) to treat malignancy. Interleukin-7 (IL-7), the principal homeostatic cytokine for T cells, is required for acute GVHD in murine models. In contrast to inflammatory cytokines (eg, IL-2, tumor necrosis factor alpha), IL-7 has not been studied extensively in the clinical transplant setting relative to its relationship with acute GVHD.nnnPATIENTS AND METHODSnWe evaluated the association of serum IL-7 levels with acute GVHD in 31 patients who were uniformly treated in a prospective clinical trial with reduced-intensity allogeneic HSCT from human leukocyte antigen-identical siblings. GVHD prophylaxis consisted of cyclosporine and methotrexate. Serum IL-7 levels and lymphocyte populations were determined at enrollment, the day of transplantation before the allograft infusion, and at specified intervals through 12 months post-transplantation.nnnRESULTSnAs expected, IL-7 levels were inversely correlated with T-cell populations (P < .00001). Acute GVHD was significantly associated with higher IL-7 levels at day +7 (P = .01) and day +14 (P = .00003) post-transplantation as well as with the allograft CD34(+) cell dose (P = .01). IL-7 levels at day +14 also correlated with the severity of acute GVHD (P < .0001). In logistic regression models, these factors were highly sensitive (up to 86%) and specific (100%) for classifying whether patients developed acute GVHD.nnnCONCLUSIONnThese data support preclinical observations that IL-7 plays a critical role in inducing acute GVHD and provide a rational basis for novel approaches to prevent and treat acute GVHD through modulation of the IL-7 pathway.

EPOCH-FR: A novel salvage regimen for patients with lymphoid malignancies being considered for reduced-intensity allogeneic hematopoietic stem cell transplantation.

6536 Background: There is no standard chemotherapy regimen for patients (pts) with lymphoid malignancies being considered for reduced intensity allogeneic hematopoietic stem cell transplantation (RI-alloHSCT). The ideal regimen would result in disease control and recipient lymphocyte depletion and have limited toxicity. We developed a novel regimen consisting of continuous infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus fludarabine ± rituximab, depending on CD20+ expression (EPOCH-FR). Methods: 147 pts, median age 50 yrs (range 21-71), with high-risk lymphoid malignancies (47% with chemo-resistant disease to last regimen, median 3 prior regimens [range 1-13]) were given EPOCH-FR (74% dose-adjusted) prior to RI-alloHSCT. Pts received 1 (48%), 2 (21%), or 3 (31%) cycles of EPOCH- FR until they were lymphodepleted (CD4+ count DLBCL/HL>TCL (p = 0.047...

Natural killer cell receptor repertoire following HLA-matched allogeneic hematopoietic stem cell transplantation

6635 Background: Following hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells are among the first lymphocytes to recover, returning to normal levels within six weeks after HSCT. NK cells may mediate anti-tumor effects and regulate graft versus host disease (GVHD); modulation of the relative frequency and intensity of expression of the cytotoxic NK receptors may influence NK activity post transplant.nnnMETHODSnWe compared the NK receptor expression in seven patients at one month following non-myeloablative HLA-matched allogeneic HSCT with that of donors and healthy volunteers. NK cells were divided into two subsets based on expression of CD56 and CD16. Both subsets were assessed for three main classes of receptors that trigger or inhibit cytotoxicity: natural cytotoxicity receptors (NCR), killer immunoglobulin-like receptors (KIR) and C-type lectin receptors.nnnRESULTSnCompared to donors, the expression of the NCR NKp46 increased significantly in all patients, whereas NKp30 increased in the CD 56+ bright subset only in patients that developed acute GVHD. Expression of KIR receptors (CD158A, CD158B) did not change or decreased slightly. In contrast the C-type lectin receptor CD 94 was upregulated on most NK cells. The heterodimeric partners of CD94, NKG2A and NKG2C, were also increased, but the increase in frequency of cells expressing the inhibitory receptor NKG2A was greater than that of the activating receptor NKG2C. The homodimeric activating receptor NKG2D increased in all patients. No significant differences in NK receptor expression between the donors and healthy volunteers was observed Conclusions: These results demonstrate changes in the NK receptor repertoire during the early post-transplant period that may have an impact on NK cells mediated cytotoxicity. No significant financial relationships to disclose.