Systematic Review of Randomized Controlled Trials of Hematopoietic Stem Cell Mobilization Strategies for Autologous Transplantation for Hematologic Malignancies,
Authors: Sheppard Dawn , Tay Jason , Bredeson Christopher , Allan David S. 
Published: October 2019

Abstract
Abstract 4046

Background:
Autologous hematopoietic stem cell transplantation is an effective treatment strategy for a variety of hematologic malignancies. Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation, however a significant proportion of patients will fail to collect the minimum number of stem cells required. There is significant diversity in the mobilization strategies that are currently employed, but the optimal strategy remains unclear. We sought to summarize the efficacy and safety of HSC mobilization strategies to help inform stem collection practice.

Methods:
We performed a systematic review of randomized controlled trials (RCTs) comparing various peripheral blood HSC mobilization strategies prior to autologous transplantation for hematologic malignancies. Our search strategy included Ovid MEDLINE (1950 to week 42 of 2010), EMBASE (1980 to week 42 of 2010) and all EBM reviews (1950 to the fourth quarter of 2010). Our primary outcome was CD34+ cell yield. Secondary outcomes included: number of aphereses required to achieve a minimum CD34+ cell target, proportion of mobilization failures, rate of engraftment, and incidence of adverse events, including febrile neutropenia.

Results:
We identified 27 articles representing 2124 patients, evaluating HSC mobilization within 3 broad strategies: cyclophosphamide with growth factor (n = 479), growth factor (n = 828), and combination or non-cyclophosphamide based chemotherapy with growth factor (n = 817). A heterogeneous group of comparisons were made between different growth factors, dose, and timing, as well as various chemotherapy regimens and doses. A formal meta-analysis could not be performed due to significant trial heterogeneity.
Nine articles reporting on a cyclophosphamide with growth factor based strategy were identified. One study revealed that the addition of growth factor (molgramostim) improves CD34+ cell yield over cyclophosphamide alone (1.4 vs. 0.5 × 106/kg, p = 0.0165). Another study demonstrated improved CD34+ cell yield (12.4 vs. 8.3 × 106/kg, p = 0.007) and fewer aphereses (2 vs. 1, p = 0.008) with the addition of ancestim to cyclophosphamide and filgrastim.
Six studies employing a growth factor based strategy were identified. Two large RCTs demonstrated that the addition of plerixafor improves CD34+ cell yield over filgrastim alone in populations with multiple myeloma (MM) (11.0 vs. 6.2 × 106/kg, p < 0.001) and non-Hodgkin lymphoma (NHL) (5.69 vs. 1.98 × 106/kg, p < 0.01). In patients with MM, plerixafor also reduces the number of aphereses required (4 vs. 1, p < 0.001). There were 12 RCTs that used a non-cyclophosphamide based chemotherapy regimen. Of these, improved CD34+ cell yield was achieved with a higher dose of filgrastim (8.2 vs. 4.7 × 106/kg for 16 vs. 8 mcg/kg daily of filgrastim, respectively, p < 0.0001) and with the addition of rituximab to a strategy of etoposide with filgrastim (9.9 vs. 5.6 × 106/kg, p = 0.021).
More rapid neutrophil engraftment was achieved with filgrastim than molgramostim when used in a cyclophosphamide with growth factor (11 vs. 15 days, p = 0.001) or growth factor alone (13 vs. 15 days, p = 0.01) setting. Increasing the growth factor dose also hastens neutrophil engraftment (9 vs. 12 days for 16 vs. 8 mcg/kg daily of filgrastim, respectively, p < 0.001). In patients with NHL, the addition of plerixafor to filgrastim allows more patients to proceed to transplantation (90 vs. 55%, p < 0.001).

Conclusions:
RCT evidence supports the combined use of cyclophosphamide and growth factor over cyclophosphamide alone. The addition of either ancestim or rituximab to a chemotherapy with growth factor based strategy improves CD34+ cell yield, as does increasing the growth factor dose. Current evidence supports the addition of plerixafor to growth factor alone to improve CD34+ yield, decrease the number of aphereses required and allow more patients to proceed to transplantation. The optimal mobilization strategy remains undefined and the choice is dependent on patient- and centre-specific goals.

Disclosures:
No relevant conflicts of interest to declare.