Advertisement

How I treat patients who mobilize hematopoietic stem cells poorly

L. Bik To, Jean-Pierre Levesque and Kirsten E. Herbert

Article Figures & Data

Figures

  • Figure 1

    Model of HSC niche regulation in steady state. (A) Perivascular niches harboring active HSCs that regenerate the hematopoietic system. Active HSCs are in contact with perivascular nestin+ MSCs and sinusoidal endothelial cells. Both MSCs and sinusoidal endothelial cells express SDF-1, transmembrane SCF, and VCAM-1 that retain HSCs within the niche via adhesive and chemotactic interactions. (B) Endosteal niches harboring quiescent HSCs. Quiescent HSCs are in contact with nestin+ MSCs or osteoprogenitors or both. (C) Interactions between niches cells, HSCs, and adrenergic neurons. CD68+ CD169+ macrophages and osteomacs forming support function of nestin+ MSCs, osteoprogenitors and osteoblasts which in turn maintain HSCs in steady state (stimulating feed-back illustrated by green arrow). Sympathetic β3 adrenergic nerves inhibit SDF-1 secretion by MSCs and osteoblasts after a circadian pulse (negative pulse illustrated by dotted red bars).

  • Figure 2

    G-CSF deregulates niches and causes HSC mobilization. (A) G-CSF activates CD68+ CD169+ macrophages in perivascular niches. This suppresses macrophage supportive function for MSCs. Consequently, expression of CXCL12, SCF, and VCAM-1 is down-regulated. Complement cascade is activated, leading to erythrocyte lysis and release of S1P in the blood, creating a chemotactic counter gradient. Active HSCs are mobilized. (B) G-CSF suppresses osteomacs in endosteal niches. Osteoblasts are lost, bone formation stops, and expression of CXCL12, SCF, and VCAM-1 by MSCs and osteoprogenitors is down-regulated. Dormant HSCs are mobilized. (C) Schematic representation of interactions in response to G-CSF. β-adrenergic neuron activation by G-CSF inhibits SDF-1 production by MSCs, osteoprogenitors, and osteoblasts and inhibits bone formation by osteoblasts (solid red bars). Stimulation of osteomacs and CD169+ macrophages by G-CSF (solid red bars) suppresses their supportive function for MSCs and osteoblasts. Consequently, expression of SDF-1, Kit ligand, and VCAM-1 by osteoprogenitors and MSCs is down-regulated. Complement cascade is activated by G-CSF, resulting in S1P release into the blood.

  • Figure 3

    Example of a proposed risk-adapted protocol for ISP in the case of suboptimal mobilization response to a conventional regimen. Triggers for ISP can be based on peripheral blood CD34+ counts (PB CD34) or on the daily yield from the first day's apheresis.

Tables

  • Table 1

    Risk factors, mechanisms, and strategies to optimize collection in predicted poor mobilizer patients

    Risk factorPostulated mechanismMobilization strategy
    Low steady-state platelet counts and PB CD34+ levelReflects overall HSC reserveRegimen promoting HSC proliferation, eg, SCF, cyclophosphamide
    Low steady-state TNF-α levelMay reflect niche dysfunction, including the macrophage response to G-CSFRegimen bypassing the macrophage-dependent pathways, eg, plerixafor-containing regimen
    Increasing ageReduced HSC reserve because of the following:
    • Age-related HSC senescence

    • Age-related loss or dysfunction of HSC niche

    • Age-related bone loss or altered bone metabolism

    Regimen promoting HSC proliferation, eg, SCF, cyclophosphamide
    Add risk-adapted plerixafor to augment niche response to G-CSF
    Bisphosphonate treatment continued throughout collection PTH of interest in experimental models
    Underlying diseaseParaneoplastic niche dysfunction Loss of niche to mass effect of tumorAim to clear BM of disease before collection
    Prior extensive radiotherapy (RT) to red marrowDirect HSC toxicity
    Toxicity to HSC niche
    Rainy day collection before extensive RT when possible
    Risk-adapted plerixafor
    Regimen promoting HSC proliferation, eg, SCF, cyclophosphamide
    Prior chemotherapy
        MelphalanDirect HSC toxicityAvoid melphalan until autologous cells collected
        FludarabineDirect HSC toxicity, niche damageCollect HSCs early, after < 4 cycles of fludarabine
        Intensive chemotherapy (eg, hyper-CVAD)Dose-dense cycles may cause niche damage, and HSCs forced into cell cycle may not engraft as wellUse SCF or preemptive risk-adapted plerixafor for fludarabine-exposed and heavily pretreated patients
    Prior lenalidomidePossible effects on HSC motility
    Possible dysregulated HSC niche because of antiangiogenic effects
    Collect HSC early, after < 4 cycles of treatment
    Temporarily withhold lenalidomide during collection.