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We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/ host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P ‫؍‬ .003) and natural killer (NK) cell (P ‫؍‬ .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P ‫؍‬ .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progressionfree survival (P ‫؍‬ .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression. (Blood.

. Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P ‫؍‬ .11), viremia (P ‫؍‬ .16), and disease (P ‫؍‬ .08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P ‫؍‬ .01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P ‫؍‬ .02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and preemptive ganciclovir treatment similar to that of myeloablative HSCT patients. (Blood. 2002;99:1978-1985

Peripheral-blood mononuclear cells (PBMCs) mobilized with AMD3100, a CXCR4 antagonist, combined with granulocyte colony-stimulating factor (G-CSF) have reconstituted autologous hematopoiesis in cancer patients following myeloablative conditioning. The engraftment potential of PBMCs mobilized with AMD3100 alone, however, has remained unproven. We therefore studied AMD3100-mobilized PBMCs in a canine model. Four dogs received 920 cGy total body irradiation (TBI) before infusion of autologous AMD3100-mobilized PBMCs (median CD34 cell count, 3.9 ؋ 10 6 /kg). Neutrophil (> 0.5 ؋ 10 9 /L [500/L]) and platelet (> 20 ؋/10 9 /L [> 20 000/L]) recoveries occurred at medians of 9 (range, 7-10) days and 25 (range, 23-38) days, respectively, after TBI, and all dogs had normal marrow function at 1 year after transplantation. To evaluate the long-term engraftment potential of AMD3100-mobilized PBMCs, 5 dogs were given 920 cGy TBI followed by infusion of AMD3100-mobilized PBMCs (median CD34 cell dose, 4.7 ؋ 10 6 /kg) from their dog leukocyte antigen (DLA)-identical littermates. Neutrophil and platelet recoveries occurred at medians of 8 (range, 8-10) days and 26 (range, 26-37) days, respectively, after TBI. With a median follow-up of 53 (range, 33-61) weeks, recipients' marrow function was normal, and blood-donor chimerism levels were 97% to 100%. In summary, both autologous and allogeneic AMD3100- IntroductionUnder steady-state conditions, CD34 ϩ hematopoietic progenitor and stem cells circulate in the blood of animals and humans at frequencies too low to allow for efficient collection of numbers sufficient to ensure timely hematopoietic reconstitution after myeloablative therapy. The frequencies of CD34 ϩ cells in the blood are considerably increased both in response to various growth factors and during the recovery phase following myelosuppressive chemotherapy. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral-blood mononuclear cells (PBMCs) are routinely used as a source of hematopoietic stem cells for transplantation and, owing to the earlier neutrophil and platelet engraftments and shortened hospital stay associated with the use of this product, are often preferred over bone marrow. [1][2][3][4][5][6][7][8] In the setting of autologous hematopoietic cell transplantation (HCT), difficulties in mobilizing and harvesting sufficiently large numbers of hematopoietic stem cells may occur, particularly in patients who have been exposed to repetitive cycles of myelotoxic chemo-and/or radiation therapy. 9 Alternative strategies aimed at improving CD34 ϩ cell mobilization including use of novel growth factors or growth factor combinations have been explored in clinical studies. [10][11][12][13][14][15] With respect to efficacy and/or safety of the mobilization procedure, however, none of these strategies has proven superior to G-CSF used alone or in combination with chemotherapy.Recently, several studies have demonstrated the importance of the interaction between stromal-cell-derived factor-1␣ (SDF-1␣) and its rece...

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fludarabine or autologous HCT predicted higher early T-cell chimaerism (P ¼ 0AE001), while advanced donor age predicted lower chimaerism (P £ 0AE02). Patients with aggressive diseases were at higher risk for relapse/ disease progression, and shorter progression-free and overall survival (P < 0AE01). These results suggest that the dosing of certain cellular subsets of PBSC products can influence important outcomes post-HCT after nonmyeloablative conditioning.

We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3-11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning.

Systemic chemotherapy induces remissions; however, most dogs succumb to disease recurrence because of multidrug resistance. Outcome of allogeneic hematopoietic cell transplantation in dogs can be excellent because of improved donor-recipient selection by use of molecular dog leukocyte antigen typing, compared with early attempts, and better prevention of graft versus host disease, better supportive care, and substitution of peripheral blood mononuclear cells for bone marrow.