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356 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 357

no late effects of G-CSF administration or donation—in particular, On the basis of these and other results, most transplantation centers use
no increased risk of cancer, autoimmune disease, or stroke. Detailed mobilized PBPCs for autologous HCT and have adopted a minimum
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white cell subset analysis by fluorescent-activated cell sorting of healthy CD34+ cell of 2 × 10 CD34+ cells/kg. 61
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donors at 1 year after donation shows no changes in B, T, and natural In the allogeneic setting, the situation is considerably more com-
killer (NK) cells or monocytes and neutrophils compared with analysis plex. PBPC grafts contain approximately 10-fold more T cells com-
before G-CSF administration. 60 pared to marrow grafts, leading to concern over a potentially increased
The adequacy of PBPC products is generally measured through incidence and severity of GVHD. At the same time, G-CSF can induce
the absolute number of CD34+ cells per kg of recipient body weight. functional immune tolerance in healthy individuals, and T cells from
Most laboratories measure CD34+ cell content by fluorescent-activated G-CSF–mobilized PBPC grafts show a predominantly immune-tolerant
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cell sorting. A threshold of greater than 2 × 10 CD34+ cells/kg is often profile with upregulation of genes related to T-cell helper type 2 (Th2)
considered the minimum acceptable dose for PBPC products, although and T cells, and downregulation of genes associated with Th1 cells,
reg
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successful engraftment can occur with lower doses. Platelet recovery cytotoxicity, antigen presentation, and GVHD. 71
appears most impacted by low PBPC CD34+ cell dose. Higher CD34+ A number of randomized clinical trials have compared PBPC and
cell doses are associated with more rapid engraftment, and thus a dose marrow grafts in the setting of allogeneic HCT. 72–75 These studies have
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of equal to or greater than 4 × 10 CD34+ cells/kg is considered opti- consistently reported similar or better overall and disease-free survival
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mal. The impact of very high CD34+ cells doses in allogeneic HCT with PBPCs compared to marrow allografts. Most, although not all,
is somewhat unclear; some studies have associated doses greater than of these randomized trials found a higher risk of chronic GVHD with
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8 × 10 CD34+ cells/kg with a higher risk of extensive chronic graft- PBPCs compared to marrow allografts, and one reported a longer dura-
versus-host disease (GVHD) in matched-related-donor HCT, although tion of immunosuppression in patients receiving a PBPC graft. PBPC
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this association was not confirmed in unrelated-donor allogeneic HCT. allografts were also associated with faster engraftment and a lower risk
Because there is no evidence of benefit for CD34+ cell doses greater than of graft failure. Systematic reviews and meta-analyses have similarly
8 × 10 /kg in allogeneic HCT, this threshold is sometimes, although not reached varying conclusions. 76–78 A 2014 systematic review performed by
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universally, used as a maximum. 61 the Cochrane Library found that overall survival was similar with PBPC
Although inadequate mobilization of healthy donors is rare, and marrow allografts, and that PBPC allografts were associated with
patients with malignancies undergoing mobilization for autologous faster engraftment but also a higher incidence of chronic GVHD. The
HCT often have difficulty collecting adequate numbers of CD34+ cells effects of stem cell source on relapse and on acute GVHD were unclear. 76
because of marrow damage from previous chemotherapy or radiation Currently, the choice between PBPCs and marrow allografts is gen-
therapy. Approximately 10 to 20 percent of patients preparing for autol- erally individualized and depends on patient, donor, and institutional
ogous HCT do not mobilize sufficient numbers of CD34+ cells using considerations. Patients with advanced or high-risk hematologic malig-
G-CSF alone or in combination with chemotherapy. Unfortunately, it has nancies may preferentially be given PBPC grafts to reduce their risk
proven difficult to identify these individuals prospectively. For patients of relapse, a strategy with some support in the literature. Conversely,
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with NHL, Hodgkin lymphoma (HL), and myeloma who fail mobiliza- patients with standard-risk malignancies are often given marrow allografts
tion with G-CSF alone, the majority proceed to collect a transplantable to reduce their risk of chronic GVHD. Likewise, patients transplanted for
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dose of CD34+ cells (>2 × 10 cells/kg) when remobilized with plerixa- nonmalignant diseases such as aplastic anemia are typically given marrow
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for plus G-CSF. Studies of allogeneic HCT using plerixafor-mobilized allografts to reduce their risk of chronic GVHD, as they derive no benefit
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grafts have also confirmed prompt and stable donor cell engraftment. from T-cell–mediated graft-versus-malignancy effects. In settings where
Animal models suggest that plerixafor-mobilized PBPCs have a dif- the risk of GVHD is particularly high—for example, with human leuko-
ferent phenotype and cytokine profile than G-CSF–mobilized PBPCs cyte antigen (HLA)-mismatched unrelated donors—many institutions
and may be associated with a higher risk of acute GVHD; however, the prefer to use marrow allografts to mitigate this risk. For patients receiving
relevance of these findings to human allogeneic HCT is unclear. For reduced-intensity conditioning (RIC), most centers use PBPC allografts
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patients who are thought to be at high risk of poor mobilization, strate- exclusively, as engraftment in this setting is largely dependent on the pres-
gies include the upfront use of plerixafor and/or chemotherapy to sup- ence of donor T cells in the allograft. Donor factors also play a role in the
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plement G-CSF mobilization, as well as large-volume leukapheresis. choice of allograft product, as some donors may specifically decline either
In 2014, the American Society for Blood & Marrow Transplantation marrow donation or PBPC mobilization and collection. Finally, with the
(ASBMT) published guidelines on the mobilization and collection of recent predominance of PBPC as a graft source, institutional resources for
PBPCs for autologous and allogeneic HCT. 61 and expertise in marrow collection have decreased, sometimes limiting
There is some evidence that circadian activity in the hypothalamus the availability of marrow allograft products.
regulates the cyclic release of HSCs by altering the expression of CXCL12
in the marrow microenvironment, with the peak time for HSC release in
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humans in the evening. Preliminary clinical data suggest that CD34+ ALTERNATIVE SOURCES OF HEMATOPOIETIC
yield is higher in donors collected in the later afternoon compared to STEM CELLS
the morning, and more abundant PBPC collections were reported from One of the most significant advances in allogeneic HCT in the past
healthy donors when apheresis was performed at 8:00 PM as opposed 10 years is the increasing experience with alternative donors for
to 8:00 AM. Efforts to exploit this circadian rhythm dependence to patients who lack HLA-identical siblings or suitably HLA-matched
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increase HSC yield in PBPC products have thus far been inconclusive. 67 unrelated donors. Each full sibling has a 25 percent chance of being
HLA-identical with another, so the likelihood of finding an HLA-iden-
Mobilized Peripheral Blood Progenitor Cells versus Marrow tical sibling donor is proportionate to the number of siblings available.
In the setting of autologous HCT, the superiority of PBPCs over marrow HLA-matched unrelated donors can be identified for approximately
as a stem-cell source is clear. Randomized trials have shown that PBPC 75 percent of patients of northern European ancestry, but the odds of
autografts in this setting are associated with more rapid engraftment, finding a suitable unrelated donor are much lower for patients who
better quality of life, and lower costs compared to marrow autografts. 68–70 belong to ethnic groups that are underrepresented in donor registries,

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