Abbreviations and Acronyms: AN = anorexia nervosa; MRI = magnetic resonance imaging; WE = Wernicke encephalopathy

Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/μL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/μL for single or <20/μL for multiple transplantations, or day-1 yield was <1.5 × 10(6) CD34/kg, or any subsequent daily yield was <0.5 × 10(6) CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower.

Background Early versus delayed autologous stem cell transplantation (SCT) results in comparable overall survival in multiple myeloma (MM) with alkylator-based therapies. It is not clear if this paradigm holds true in the context of new therapies such as immunomodulatory agents (IMiDs). Methods We studied 290 patients with untreated MM who received IMiD-based initial therapy; 123 with thalidomide-dexamethasone (TD) and 167 with lenalidomide-dexamethasone (LD) induction prior to SCT. Patients undergoing a stem cell harvest attempt were considered transplant eligible and included. SCT within 12 months of diagnosis and within 2 months of harvest were considered as early-SCT (n=173, 60%). SCT more than 12 months after diagnosis was considered delayed-SCT (n=112, 40%). Results In the delayed-SCT group 42 patients have so far undergone SCT; the median estimated time to SCT was 5.3 and 44.5 months among the early and delayed-SCT groups respectively. The 4-year OS from diagnosis was 73% in both early-SCT and delayed-SCT groups (P=0.3), and was comparable within those receiving TD (68% vs. 64%) or LD (82% vs. 86%) as initial therapy. The time to progression after SCT was similar between the early and delayed-SCT groups (20 vs. 16 months, P=NS). Conclusion We conclude that in transplant eligible patients receiving IMiDs as initial therapy followed by early stem cell mobilization, delayed-SCT results in similar overall survival compared with early-SCT. Importantly, we also demonstrate excellent 4-year survival of over 80% among transplant eligible patients receiving initial therapy with lenalidomide and dexamethasone regardless of the timing of the transplantation.

Vascular endothelial growth factor (VEGF)-induced receptor phosphorylation is the crucial step for initiating downstream signaling pathways that lead to angiogenesis or related pathophysiological outcomes. Our previous studies have shown that the neurotransmitter dopamine could inhibit VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), endothelial cell proliferation, migration, microvascular permeability, and thus, angiogenesis. In this study, we address the mechanism by which VEGFR-2 phosphorylation is regulated by dopamine. Here, we demonstrate that D2 dopamine receptor (D2DR) colocalizes with VEGFR-2 at the cell surface. Dopamine pretreatment increases the translocation and colocalization of Src-homology-2-domain-containing protein tyrosine phosphatase (SHP-2) with D2DR at the cell surface. Dopamine administration leads to increased VEGF-induced phosphorylation of SHP-2 and this increased phosphorylation parallels the increased phosphatase activity of SHP-2. Active SHP-2 then dephosphorylates VEGFR-2 at Y951, Y996 and Y1059, but not Y1175. We also observe that SHP-2 knockdown impairs the dopamine-regulated inhibition of VEGF-induced phosphorylation of VEGFR-2 and, subsequently, Src phosphorylation and migration. Our data establish a novel role for SHP-2 phosphatase in the dopamine-mediated regulation of VEGFR-2 phosphorylation.

Peripheral Blood Stem Cells (PBSC) are usually mobilized using granulocyte colony stimulating factor (G-CSF) with or without chemotherapy. With the emergence of newer mobilizing agents, predicting poor mobilization may allow early intervention and prevent the costs and complications associated with remobilization. We retrospectively evaluated a cohort of 1556 patients seen between January 2000 and December 2008 with Multiple Myeloma (MM) (565; 36%), Non-Hodgkin’s Lymphoma (NHL) (562; 36%), Amyloidosis (345; 22%) or Hodgkin’s disease (HD) (94; 6%) initially mobilized with single agent G-CSF. Sensitivity-specificity analysis was used to identify ideal peripheral blood CD34 count (PB-CD34) cut-points that predicted successful collection. In patients with plasma-cell disorders a PB-CD34 of 11/uL, 17/uL, 21/uL, and 28/uL by day 4 or 5 were required to collect a target of 2, 4, 8 or 12 million/kg respectively. A CD34 yield <0.8 million cells/kg on first apheresis also predicted for <2 million CD34/kg. For patients with NHL or HD, a PB-CD34 <6/uL and <15/uL on day 4 or 5 predicted failure to achieve a target collection of 2 and 4 million/kg respectively. This study suggests that PB-CD34 thresholds should be based on collection target to allow for early intervention and prevent collection failures.