[Show abstract][Hide abstract] ABSTRACT: While B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased BAFF levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B cell receptor (BCR) responsiveness in 48 patients who were > 1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components, BLNK and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared to B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD, and suggest that therapeutic inhibition of the involved kinases may benefit these patients.
[Show abstract][Hide abstract] ABSTRACT: The effectiveness of stem cell mobilization with G-CSF in lymphoma patients is suboptimal. We reviewed our institutional experience using chemomobilization with etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and G-CSF (5 μg/kg twice daily from day +3 through the final day of collection) in 159 patients with lymphoma. This approach resulted in successful mobilization (>2 × 10(6) CD34+ cells collected) in 94% of patients (83% within 4 apheresis sessions). Fifty-seven percent of patients yielded at least 5 × 10(6) cells in 2 days and were defined as good mobilizers. The regimen was safe with a low rate of rehospitalization. Average costs were $14 923 for good mobilizers and $27 044 for poor mobilizers (P<0.05). Using our data, we performed a 'break-even' analysis that demonstrated that adding two doses of Plerixafor to predicted poor mobilizers at the time of first CD34+ cell count would achieve cost neutrality if the frequency of good mobilizers were to increase by 21%, while the frequency of good mobilizers would need to increase by 25% if three doses of Plerixafor were used. We conclude that chemomobilization with etoposide and G-CSF in patients with lymphoma is effective, with future opportunities for cost-neutral improvement using novel agents.Bone Marrow Transplantation advance online publication, 19 November 2012; doi:10.1038/bmt.2012.216.
Bone marrow transplantation 11/2012; 48(6). DOI:10.1038/bmt.2012.216 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD). Patients with cGVHD have delayed B-cell reconstitution and elevated BAFF to B-cell ratios compared to patients without cGVHD. The mechanisms promoting and sustaining B-cell activation in this disease, however, remain unknown. As BAFF increases murine B-cell metabolism and survival and maintains autoreactive B-cell clones, we performed ex vivo analyses of peripheral B cells from 51 patients who either had or did not have active cGVHD and were greater than 1 year from the time of allogeneic hematopoietic stem cell transplantation. We found that B cells from patients with active cGVHD were in a heightened metabolic state and were resistant to apoptosis. Exogenous BAFF treatment amplified cell size and survival in B cells from these patients. We found significantly increased signaling through ERK and AKT that associated with decreased levels of proapoptotic Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell survival. Thus, we identify a role for BAFF in the pathogenesis of cGVHD and define B-cell activation and survival pathways suitable for novel therapeutic development in cGVHD.
[Show abstract][Hide abstract] ABSTRACT: Patients without chronic graft-versus-host disease (cGVHD) have robust B cell reconstitution and are able to maintain B cell homeostasis after allogeneic hematopoietic stem cell transplantation (HSCT). To determine whether B lymphopoiesis differs before cGVHD develops, we examined bone marrow (BM) biopsies for terminal deoxynucleotidyl transferase (TdT) and PAX5 immunostaining early post-HSCT at day 30 when all patients have been shown to have high B cell activating factor (BAFF) levels. We found significantly greater numbers of BM B cell precursors in patients who did not develop cGVHD compared with those who developed cGVHD (median = 44 vs 2 cells/high powered field [hpf]; respectively; P < .001). Importantly, a significant increase in precursor B cells was maintained when patients receiving high-dose steroid therapy were excluded (median = 49 vs 20 cells/hpf; P = .017). Thus, we demonstrate the association of BM B cell production capacity in human GVHD development. Increased BM precursor B cell number may serve to predict good clinical outcome after HSCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2012; 18(6):968-73. DOI:10.1016/j.bbmt.2012.03.005 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The HCT-CI helps to predict non-relapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic cell transplantation (HCT) recipients. The usefulness of this index in a younger, adolescent and young adult (AYA) population is unclear.
We tested the validity of the HCT-CI as a predictor of mortality in a retrospective cohort of 56 AYA recipients between the ages of 16 and 39, using chart abstraction followed by univariable and multivariate analysis.
Only pulmonary dysfunction (46%), hepatic dysfunction (27%), infection (20%), and psychiatric disturbance (11%) had frequencies greater than 5% in this population. HCT-CI scores of 0-2 were present in 54%, and scores of >3 in 46%. The cumulative incidence of NRM at 2 years was 32%, with an OS of 46%; the NRM and OS for patients with an HCT-CI of 0-2 were 24% and 62%, whereas the NRM and OS for patients with an HCT-CI >3 were 38% and 28%. Patients with pulmonary dysfunction prior to transplant had a 29% OS at 2 years, compared to a 61% OS among patients without (P = 0.001). There was no statistically significant difference for patients and a worse NRM (P = 0.08). In multivariable analysis, both an HCT-CI score of >3 and any pulmonary dysfunction remained associated with OS (P = 0.01, P = 0.03), but neither with NRM.
The HCT-CI appears useful in predicting OS in AYAs, though higher scores may reflect prior treatment, with pulmonary dysfunction particularly prevalent. Prospective studies to further validate and explain these findings are warranted.
[Show abstract][Hide abstract] ABSTRACT: This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received ≥ 2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials.
Cancer Investigation 03/2011; 29(3):214-9. DOI:10.3109/07357907.2010.550663 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The optimal mobilization strategy prior to autologous stem cell transplantation for patients with multiple myeloma remains unclear. Mobilization with cytokines alone appears to yield suboptimal results in older patients as well as patients who have received prior lenalidomide. To avoid the marked cytopenias and risks of hemorrhagic cystitis associated with the administration of cyclophosphamide, we investigated the efficacy and safety of chemomobilization with an intermediate dose etoposide (VP-16; 375 mg/m(2) on days +1 and +2) and granulocyte-colony stimulating factor (G-CSF) (5 μg/kg twice daily from day +3 through the final day of collection). We reviewed our institutional experience with 152 myeloma patients mobilized with this regimen. The addition of VP-16 to G-CSF resulted in successful mobilization in 100% of patients, including 143 (94%) who collected successfully in a single day. A total of 99% of patients, including those with prior XRT and/or prior lenalidomide or thalidomide therapy, collected at least 5 × 10(6) cells/kg in 1 or 2 days of apheresis, and the median total number of CD34(+) cells collected in the entire population was 12 × 10(6) cells/kg. Collection was predictable, with 61% of patients collecting on day +11, and the rest between days +7 and +13. There were no variables, including age, prior imid exposure, radiation therapy, or total amount of prior therapy that were associated with suboptimal mobilization. Adverse effects of the regimen included supportive transfusions required in 31 (20%) patients, and fevers requiring hospitalization or intravenous antibiotics in 26 (17%) patients. VP-16 and G-CSF appears to be a safe and effective mobilization regimen for patients with multiple myeloma undergoing autologous stem cell transplantation, producing excellent stem cell yield with the majority of patients requiring 1 day of apheresis.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):141-6. DOI:10.1016/j.bbmt.2010.06.021 · 3.40 Impact Factor