Addition of Plerixafor Overcomes Poor Mobilization in Autologous and Allogeneic Stem Cell Grafts and Leads to Efficient and Sustained Engraftment

Abstract

▪Poor hematopoietic stem cell (HSC) mobilization upon granulocyte-colony stimulating factor (G-CSF) remains a significant problem for autologous and allogeneic hematopoietic cell transplantation (HCT). In up to 20% of patients, no sufficient autografts can be collected. The chemokine receptor CXCR4 plays a pivotal role in the homing of HSCs to the bone marrow. CXCR4 inhibition by the bicyclam derivative plerixafor can lead to improved HSC yields. We here evaluated the effects of plerixafor supported HSC apheresis in order to enable otherwise impossible HCT and with regard to graft quality and transplantation outcomes in both the autologous and allogeneic setting.Data retrospectively obtained from all 2,257 leukaphereses between 2014 and 2017 (588 for autologous and 1,669 for allogeneic transplantation) were analyzed. 48 individuals (31 male and 17 female, median age 52 years, range 31-72 years) were identified who received plerixafor due to insufficient HSC mobilization upon G-CSF stimulation. 44 patients (non-hodgkin lymphoma n=19, multiple myeloma n=19, systemic sclerosis n=3, Ewing sarcoma n=2, germinal cell cancer n=1) collected HSC for autologous, 4 HLA-identical siblings for allogeneic transplantation representing a low rate of poor mobilizers of 7% (44/588) and 0.2% (4/1669) autologous and allogeneic donors, respectively.A median of 1 dose plerixafor (range, 1-3 doses) was applied. Aphereses after addition of plerixafor were performed at a median of 2 days (range, 1-651 days) after insufficient attempts (median CD34+ cells 13/µl; range, 0-46/µl). 4 patients received a second mobilization chemotherapy before plerixafor application. 2 donors received plerixafor despite collection of >3.0x106 HSC per kilogram recipient body weight (kg BW) to enable in vitro graft manipulation or more than one HCT.Patients collecting HSC for autologous HCT received a median of 7 therapy cycles (range, 3-25 cycles) before HSC mobilization. Allogeneic donors tended to be older (median age of 54 years; range, 49-69 years).HSC mobilization was improved in 38/44 patients and 4/4 allogeneic donors. Before and after plerixafor application, median CD34+ cell counts were 0.6x106 (0.1-4.1 x106) cells/kg BW in 51 aphereses (range, 1-3 per patient) and 2.0x106 (range, 0.1-23.3 x106) cells/kg BW in 94 aphereses (range, 1-4 per patient), respectively (p<0.0001).Autologous HCT was performed in 32/44 patients. In the remaining, no HCT was performed due to further insufficient HSC mobilization despite plerixafor application (n=6), death due to progressive disease (n=3) or due to infection (n=1) before HCT. Two recent patients did not undergo autologous HCT, yet. All patients received G-CSF during autologous HCT. Median neutrophil (>500/µl) and platelet (>20,000/µl) engraftment was reached on day 12 (range, days 9-21) and 14 (range, days 10-23), respectively. No primary or secondary graft failure or poor graft function (PGF) was observed.The collected allogeneic grafts were applied to the patients in all 4 cases. Allogeneic HCT patients did not receive G-CSF. Median neutrophil and platelet engraftment was noted on days 13 (range, days 11-20) and 15 (range, days 11-23), respectively. Again, neither primary or secondary graft failure nor PGF was noted.Median overall survival after HCT for patients receiving autologous and allogeneic grafts was 31 (range, 1-72) and 7 (range, 5-53) months, respectively.For both autologous and allogeneic grafts, addition of plerixafor improved HSC yields in most poor mobilizers and therefore enabled for an otherwise impossible HCT including in vitro manipulation of allogeneic grafts and repetitive HCT. Of note, using G-CSF and plerixafor mobilization resulted in insufficient cell counts in only 0.3% of donors (6/2,257; for patients 6/588: 1%; for allogeneic donors 0/1,669: 0%) allowing HCT for almost every patient. Of note, poor mobilizers overall appeared to be seldom. Since plerixafor application was successful in most patients, these data might also help to reduce G-CSF application especially to patients who should not suffer from additional pulmonal toxicity (e.g. in systemic sclerosis). Hematopoietic engraftment after HCT of plerixafor mobilized grafts was rapid and sustained without observation of graft failure or PGF. The time to engraftment was comparable to G-CSF mobilized grafts showing that the quality of plerixafor mobilized grafts is to be estimated equal. DisclosuresBethge:Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.