Abstract

Background:

Hematopoietic stem cell release is regulated by the sympathetic nervous system through the β (3) adrenergic receptor [Mendez-Ferrer et al. Nature 2008]. Peripheral sympathetic nerve neurons express the G-CSF receptor and stimulation of peripheral sympathetic nerve neurons with G-CSF reduced norepinephrine (NE) reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability [Lucas et al Blood 2012]. Based on preclinical data, we investigated the NE reuptake inhibitor desipramine in HSC mobilization.

Despite augmentation with Plerixafor (CXCR4 inhibitor), 20% of all patients fail to mobilize 6*10^6 CD34 cells/kg in myeloma and the collection rate with G-CSF alone is 51.1% [Diperiso et al Blood 2012]. The cost of upfront plerixafor is $9,081 per patient while desipramine costs $40. We undertook a feasibility study of adult patients with MM undergoing autologous transplantation (ASCT) to study safety and efficacy of mobilization with desipramine and G-CSF.

Patients & Methods:

From 2013- 2014, 10 patients between the ages of 18-70, eligible for ASCT were enrolled. Desipramine 100mg daily was administered for 7 days, starting 4 days prior to starting G-CSF (D-3) and continue along with G-CSF for a total of 7 days. CBC and CD34 counts were determined on Day+5. If CD34 counts were > 10/ul, stem cell collection was commenced and if < 10/ul, plerixafor was added as salvage therapy. The endpoints were safety and efficacy in mobilizing CD34 cells for ASCT in patients with multiple myeloma. This trial was registered at clinicaltrials.gov as NCT01899326.

Results

Six of ten patients enrolled completed the protocol and underwent stem cell transplantation. Reasons for not completing were 1. Lack of insurance coverage 2. Non-compliance with study treatment 3. Disease relapse prior to ASCT. Five patients did not have any grade 3 or 4 adverse events and 1 had disease-related Grade 4 hypercalcemia and Grade 2 AKI at the time of stem cell mobilization. No patients had significant treatment related adverse effects. All 6 patients who completed the protocol achieved the target collection of 5*10^6 CD34 cells/kg. Four patients achieved 6*10^6 CD34 cells/kg or more and the remaining 2 patients achieved 5.52 and 5.92 *10^6 CD34 cells/kg respectively. Among the 6 patients, 2 patients received salvage plerixafor. The median time to achieve WBC >1000/ul, ANC >500/ul and platelets>20k was 11.5, 11, 13.5 days

Table 1.
 Age Ind.
Regimne 
Disease status PB CD34/ul CD34 collected
*10^6 / kg 
Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine 
     D1 D2 D3 D4 D2 D3 D4  ANC >0.5 Platelets> 20k G1,G2 G3,G4 
62
Free
λ 
VRD VGPR 45.8 66.0   7.01   7.01 12 13 none none 
50
Free
λ 
VRD VGPR 88.0 143.5   12.22   12.22 12 12 none none 
58
IgA 
VCD VGPR 38.0 67.7 31.6  4.22 2.75  6.97 13 17 none none 
70
IgAκ 
VRD VGPR 2.40 40.2 16.6  4.31 1.61  5.92 12 14 none none 
56
IgGκ 
VCD VGPR 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 
70
IgGλ 
VD
RD 
Relapse 76.2 97.1   5.54   5.54 11 20 AKI hypercalcemia 
 Age Ind.
Regimne 
Disease status PB CD34/ul CD34 collected
*10^6 / kg 
Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine 
     D1 D2 D3 D4 D2 D3 D4  ANC >0.5 Platelets> 20k G1,G2 G3,G4 
62
Free
λ 
VRD VGPR 45.8 66.0   7.01   7.01 12 13 none none 
50
Free
λ 
VRD VGPR 88.0 143.5   12.22   12.22 12 12 none none 
58
IgA 
VCD VGPR 38.0 67.7 31.6  4.22 2.75  6.97 13 17 none none 
70
IgAκ 
VRD VGPR 2.40 40.2 16.6  4.31 1.61  5.92 12 14 none none 
56
IgGκ 
VCD VGPR 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 
70
IgGλ 
VD
RD 
Relapse 76.2 97.1   5.54   5.54 11 20 AKI hypercalcemia 

P-Plerixafor; V-Velcade; R-Lenalidomide; D-Dexamethasone; C-Cyclophosphamide

Conclusions

Overall G-CSF + Desipramine combination appears to be safe, well tolerated and shows signs of efficacy. G-CSF and desipramine was successful in 4/6 (66%) and all achieved the stem cell collection in 2 days or less. Desipramine, GCSF and Plerixafor was successful in all (6/6) patients to achieve a target of 5*10^6 CD34 cells/kg. The mean number of CD34 cells collected in the desipramine+ G-CSF mobilisers was 7.24*10^6 CD34 cells/kg which, based on historical data, is higher than what would be expected with G-CSF alone even though 3/4 of these patients had lenalidomide as induction therapy. Based on these results, a phase II clinical study evaluating the efficacy of G-CSF with desipramine with or without salvage plerixafor in multiple myeloma and lymphoma will be initiated.

Disclosures

Barta:Seattle Genetics: Research Funding.

Author notes

*

Asterisk with author names denotes non-ASH members.