Stem Cells, Vol. 14, No. 2, 185-195,
March 1996
© 1996 AlphaMed Press
Peripheral Blood Progenitor Cell Transplantation: A Replacement for Marrow Auto- or Allografts
Martin Körbling,
Richard Champlin
University of Texas MD Anderson Cancer Center, Division of Medicine, Department of Hematology, Section of Blood and Marrow Transplantation, Houston, Texas, USA
Key Words. CD34+ • Blood stem cells • Apheresis • Autologous stem cell transplantation • Allogenic stem cell transplantation • Hematologic malignancies • Breast/ovarian cancer • Stem cell mobilization • Gene therapy
Dr. Martin Körbling, University of Texas MD Anderson Cancer Center, Division of Medicine, Department of Hematology, Section of Blood & Marrow Transplantation, Box 68, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
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Abstract
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Circulating hematopoietic progenitor cells include pluripotent stem cells expressing indefinite self-renewal capacity and, therefore, can be used for restoring hematopoiesis following myeloablative treatment. A transient shifting of progenitor cells from extravascular sites into the circulation by chemopriming and/or cytokine treatment enables the collection by apheresis of a sufficient number of progenitor cells to guarantee engraftment. The addition of new cytokines (e.g., thrombopoietin) and large volume apheresis will increase peripheral blood progenitor cell (PBPC) procurement efficiency, whereas the risk of concurrently mobilizing clonogenic tumor cells in patients with solid tumors and hematologic malignancies remains to be carefully evaluated. As compared with bone marrow (BM) progenitor cells, the use of PBPCs significantly shortens the recovery of WBC and platelets following transplantation. Most recently, successful allogeneic transplantation of PBPCs has been reported without increasing the incidence and severity of acute graft-versus-host-disease. Due to the more than one log higher number of lymphoid subsets contained in a PBPC allograft, one might expect a more pronounced graft-versus-leukemia effect in the transplant patient. Similar to BM cells, ex vivo manipulation of mobilized apheresis products is used or being developed (ultralight density percoll gradient, CD8 depletion, selection of graft facilitating cells, CD34+ cell purification and others). The transduction and long-term expression of marker genes and, most recently, therapeutic genes (e.g., MDR–1) in PBPCs have been successfully demonstrated by several groups in patients with hematologic malignancies and selected solid tumors. It is expected that, based on the easier procurement of hematopoietic stem cells and advantageous engraftment characteristics, PBPCs in both autologous and allogeneic transplant situations will eventually replace BM-derived progenitor cells.
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Circulating Hematopoietic Progenitor Cells
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Bone marrow (BM) and blood stem cell pools are in dynamic equilibrium to each other allowing hematopoietic progenitor cells migrating from extravascular marrow sites into circulation and vice versa [1]. Both stem cells and their progeny express CD34, a cell surface protein present on 1–4% of low density BM mononuclear cells (MNC) [2]. Greater than 90% of CD34+ cells express antigens that are characteristic of commitment to the lymphoid, myeloid or erythroid lineages, and, therefore, are not considered stem cells with pluripotent reconstitutive potential [2]. Cells that initiate long-term marrow cultures (long-term culture initiating cells [LTC-IC]), express CD34 and do not express lineage antigens such as CD3, CD4, CD8, CD10, CD14, CD15, CD19, CD20, CD33, CD38 and CD71 (CD34+ Lin– cells) [3, 4]. Cell surface molecules that appear to be useful in selecting primitive and multipotential stem cells against committed progenitor cells include HLA class II (DR) antigens [5], CD38 [6], and Thy-1 (CDw90) [7]. Only 1% of the CD34+ cells does not express the CD38 antigen [6]. These CD34+ CD38– cells appear as a homogenous primitive blast cell population with self-renewing potential. As reported by Terstappen et al. [6], during 120 days of culturing sorted CD34+ CD38– cells up to five sequential generations of colonies were obtained after replating of the first generation primitive colonies. CD34+ Thy-1dim cells are particularly enriched for high proliferative potential colony-forming cells (HPP-CFC) [7], LTC-IC [3] and cobblestone area-forming cells, and are capable of long-term multilineage engraftment in severe combined immunodeficiency (SCID) human (hu) mice [8].
CD34+ cells and subsets are found in the unperturbed circulating blood from normal blood stem cell donors in a concentration of approximately 4 x 106/l [9]. The more primitive CD34+ subsets such as CD34+ Thy-1dim and CD34+ Thy-1dim CD38– encompass 30% and 2.5%, respectively, of the unperturbed circulating CD34+ cell pool [9].
For complete and sustained hematopoietic engraftment after myeloablative chemo- or chemo/radiotherapy, patients must receive a sufficient number of early and pluripotent hematopoietic progenitor cells with indefinite self-renewal potential. As shown by Spangrude et al. [10] and later Uchida et al. [11], in mice as few as 100 primitive BM Thy-1.1lo Lin– Sca-1+ cells are sufficient to radioprotect 95–100% of animals. In humans, the minimum number of early progenitor cells that guarantees complete and permanent engraftment is unknown.
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Initial Use of Peripheral Blood Progenitor Cells for Transplantation
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The initial successful use of peripheral blood progenitor cell (PBPC) autotransplants was in patients with advanced stage chronic myelogenous leukemia (CML), a disease in which hematopoietic progenitors, although predominantly Philadelphia chromosome (Ph)+, are known to circulate [12]. The first attempt to transplant "normal" PBPCs was made by collecting stem cells in the chemotherapy-induced Ph– phase of chronic CML followed by transplantation in the accelerated phase with resulting Ph– hematopoietic reconstitution [13]. Subsequently, autologous transplantation of PBPCs was applied to patients with lymphoma [14, 15], particularly in patients in whom marrow harvest was not possible because of prior radiotherapy or involvement by malignant cells [16, 17]. Autologous PBPC transplants have also been performed for patients with acute leukemia using cells collected during the recovery phase from chemotherapy, also serving as an in vivo purging procedure [18, 19]. Those first clinical studies demonstrated that autologous PBPCs can indeed replace BM-derived progenitor cells with a similar outcome for treatment of these disorders.
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Mobilization of Hematopoietic Progenitor Cells from Extravascular Marrow Sites or Marginal Pools into the Circulation
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The total amount of steady-state progenitor cells circulating at any given time is usually too low to be collected by one or two continuous-flow leukaphereses to result in a safe transplant dose [20]. As first shown under clinical conditions by Richman et al. [21], the circulating stem cell pool markedly expands during the recovery phase after high-dose bolus cyclophosphamide treatment [22]. Other chemopriming regimens, often as part of intensification treatments, (including ifosfamide, cisplatin, etoposide, and paclitaxel) are also effective if stem cell toxic drugs are not employed.
Systemic treatment with recombinant human (rHu) G-CSF expands the circulating stem cell pool as well, exceeding the pretreatment level by approximately 10-fold [23, 24]. Stem cell peripheralization with rHuGM-CSF is less effective in increasing circulating levels of CD34+ cells [25]. Combinations of interleukin 3 and GM-CSF [26] or G-CSF [27] may have synergistic effects on progenitor cell mobilization. Stem cell factor (c-kit ligand) also mobilizes progenitor cells and has synergistic effects with G-CSF in primates [28] and humans [29].
Mobilization is further increased by combining a chemotherapy-induced rebound of PBPC concentration (called chemopriming) with timed cytokine treatment. Ideally, the progenitor cell mobilizing chemopriming regimen would employ non-stem cell toxic agents active and indicated for treatment of the patient's malignancy which may also reduce circulating clonogenic tumor cells (so-called in vivo purging). Usually, cytokine treatment is started 24 h after completion of the chemotherapy, and stem cells are collected when the patient's WBC concentration exceeds 1.0 x 109/l. It is noteworthy, however, that in heavily pretreated patients and in patients with BM tumor cell involvement, the mobilization efficiency varies enormously depending upon the size of the residual marrow stem cell pool. Progenitor yield decreases progressively with cumulative exposure to myelotoxic chemotherapy or radiation. Mobilization efficiency is somewhat variable even in normal donors because of factors that are not understood.
While mobilization of PBPCs from normal donors for allogeneic transplantation cannot utilize chemotherapy, cytokine treatment alone can. rHuG-CSF is considered the preferential cytokine for stem cell peripheralization applied at doses of 10 µg/kg/day [30], 12 µg/kg/day [31], up to 16 µg/kg/day [32]. It has been shown that rHuG-CSF alone peripheralizes CD34+ cells and, to an even higher extent, most primitive CD34+ cell subsets such as CD34+ Thy-1dim and CD34+ Thy-1dim CD38– [9]. Under a four-day exposure to rHuG-CSF (6 µg/kg every 12 h) the WBC and polymorphonuclear (PMN) counts increase by sixfold and eightfold, respectively, whereas the CD34+ cell concentration and primitive subsets increase by between 16-fold and 24-fold. As compared to a marrow harvest, the total number of CD34+ cells collected by apheresis from one donor exceeds, on the average, the CD34+ cells contained in the BM graft by fourfold [9]. The granulocyte-macrophage colony-forming units (CFU-GM) formation and the formation of erythroid burst-forming units (BFU-E) is significantly higher when the same number of G-CSF-mobilized CD34+ cells are cultured compared with BM-derived CD34+ cells [33]. Mobilized PBPCs express a higher clonogenicity as demonstrated by limiting dilution analysis of LTC-IC [34] and by studies involving in vivo transplantation [35].
It is also noteworthy that the mobilization pattern in normal donors is much more uniform than in cancer patients who have previously received myelotoxic chemotherapy. Table 1
shows the percentage of CD34+ cells among total nucleated cells (TNC) in the peripheral blood (PB) of normal donors at steady-state, as compared to the percentage at the peak of G-CSF mobilization prior to apheresis, in the apheresis product and in a single BM harvest from normal donors at steady-state.
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Table 1. Percentage of CD34+ cells among TNC in the PB at steady-state, in G-CSF-mobilized PB, in the apheresis product and in BM from normal stem cell donors
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Mobilization of hematopoietic progenitor cells by rHuG-CSF appears safe in normal donors. Most donors will experience bone pain and headache but other adverse effects are rare. In balance, this discomfort is considerably less than the pain caused by multiple BM aspirations, and long-term adverse effects of rHuG-CSF treatment for stem cell mobilization are not expected. For example, children with congenital neutropenia have received rHuG-CSF treatment for several years without major complications [36].
There are a number of unanswered questions in progenitor cell mobilization such as:
- what cytokine regimen is optimal?
- how do different mobilization regimens affect the quality of the PBPC graft?
- are clonogenic tumor cells recruited and is there a preferred method of mobilization to selectively collect normal hematopoietic progenitor cells?
- can the efficacy of stem cell mobilization be predicted (PB CD34+ cell concentration at steady-state, adhesion molecules, etc.)?
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Continuous-Flow Stem Cell Apheresis
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PBPCs are collected by single or multiple continuous-flow apheresis under cytokine treatment in the recovery phase from prior chemotherapy (autologous situation) or at steady-state. The total blood volume processed per run is between 2 and 3.5 times the donor's blood volume. Large volume stem cell apheresis processing up to 6 times the donor's blood volume has been reported [37–39]. Typically, 3–5 x 108 mononuclear cells per kg are collected per run with MNC encompassing between 60 and 90% of TNC collected. Anticoagulation is performed either with ACD-A alone or in combination with heparin (large volume leukapheresis). Calcium replacement is required when using ACD-A alone in large volume leukapheresis. A central line is placed (subclavian or jugular vein); the return flow is either by peripheral vein (cubital vein) or by central line (double lumen catheter). In normal stem cell donors it is common practice not to place a central line but rather use the peripheral vein needle approach to minimize the risk involved with catheter placement.
The CD34+ cell concentration in the donor's PB is predictive for the yield of CD34+ cells in the apheresis product. Whereas steady-state PB CD34+ cell concentrations in unperturbed hematopoietic condition, being in the range of less than 0.1% of TNC analyzed, are less predictive due to the limited sensitivity of the flow-cytometry technique, the pre-apheresis PB CD34+ cell concentration correlates well with CD34+ cell yield [9]. For example, in normal donors, 40 x 106 CD34+ cells/l PB predict for an apheresis yield of approximately 20 x 106 CD34+ cells/l donor's blood processed. In normal donors under four-day rHuG-CSF treatment at 6 µg/kg every 12 h, the yield is approximately 50 x 104 CD34+ cells/kg recipient and per liter of donor blood processed.
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Cryopreservation of Apheresis-Derived Stem Cell Products
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Apheresis products for autologous transplantation purposes are usually frozen and stored in liquid nitrogen or in a mechanical freezer at temperatures below –120°C. The cryoprotectant used is dimethyl sulfoxide at a final concentration of between 5% and 10%. Cells are frozen at a controlled freezing rate of 1–2°C/min. An alternative approach is to keep the apheresis-derived cells on ice for up to three days, the time needed to administer high-dose treatment to the patient [40]. This latter approach is limited by the loss of stem cell viability over time. Apheresis products from normal donors for allogeneic transplantation are either frozen or transfused fresh. Cryopreserving stem cells has the advantage of being independent from delivering the transplant therapy to the patient. It also has been suggested that there may be a selective loss of alloreactive, graft-versus-host-disease (GVHD)-inducing cells by the cryopreservation and thaw procedures [41].
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Progenitor Cell Dose Requirements for Successful Engraftment after Myeloablative Treatment
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The indicators for hematopoietic progenitor cells with reconstitutive potential contained in the apheresis products are CFU-GM or, more recently, the CD34 surface antigen. Since clonogenic assays are time consuming and difficult to standardize, the immunophenotyping of progenitor cells has widely replaced the CFU assay. The minimal CD34+ cell dose required in the autologous transplant situation for complete three lineage engraftment is not well-defined, but may be in the range of 1 x 106/kg [42]. There is more consistent rapid recovery with higher CD34+ cell doses, and levels between 2–5 x 106/kg have been recommended as the safe engrafting dose by different centers. For complete and sustained allogeneic engraftment among HLA-matched siblings, we propose the transfusion of >3 x 106 CD34+ cells/kg of recipient body weight; the lower threshold engraftment dose has not been determined.
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Blood Stem Cell Engraftment Characteristics
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There are numerous reports of more rapid recovery of hematopoiesis after transplantation of mobilized PBPCs compared to BM [24, 43–46]. The most striking advantage is the more rapid recovery of platelets; patients typically become platelet transfusion independent approximately one week earlier than with BM transplants. The explanation for this difference is not completely understood but could be due to a larger progenitor cell dose or a higher percentage of late, lineage-committed progenitor cells in the apheresis product, requiring less time to transit cell differentiating compartments. Furthermore, the apheresis product is collected under maximum endogenous (following chemopriming) and exogenous cytokine stimulation with a higher percentage of early progenitor cells in cycle than what is expected from a BM harvest. Finally, accessory cells, still poorly defined, might also contribute to the faster kinetics post-transplantation. It is unclear whether similar priming/mobilizing treatment would also increase BM progenitor cells for collection [47].
Nevertheless, despite transplantation of maximal cell doses including progenitor cells, there is an obligate period of profound pancytopenia lasting approximately eight days before hematopoietic recovery occurs. This presumably reflects the interval necessary from initial engraftment of stem cells within the marrow to expand to a critical size where cell proliferation and maturation starts. There have been concerns regarding the reconstitutive capability of circulating stem cells collected by apheresis, i.e., three lineage and sustained engraftment. Clinical studies in patients receiving myeloablative treatment indicate that autologous or syngeneic PBPC transplants have not been associated with an excessive risk of graft failure. The longest follow-up post-myeloablative chemo/radiotherapy and autologous blood stem cell transplantation in a patient with Burkitt's lymphoma exceeds 10 years, showing normal hematopoietic function [14]. More recently, gene marking studies have been initiated using a combination of retrovirally marked autologous hematopoietic progenitor cells from both BM and PB for autotransplantation [48]. Progenitor cells from PB and BM were transduced with a different retroviral vector allowing assessment of the relative contribution of both stem cell sources to short- and long-term engraftment. Evidence of 100% donor chimerism in patients transplanted with mobilized PBPCs from their HLA-matched siblings and followed up to three years [31, 49] confirms the experience coming from autologous PBPC transplantation that mobilized and circulating progenitor cells have the same, if not a better, repopulation potential than BM-derived progenitor cells.
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Potential Risks of Mobilizing Clonogenic Tumor Cells
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Based on the clinical observation that relapses in malignant hematological disorders occur first in the marrow before involving the blood, apheresis products were initially felt to potentially have less tumor cell contamination than BM harvests. This is supported by the fact that patients with CML recovering from intensive chemotherapy preferentially peripheralize nonmalignant diploid cells early in the course of recovery [13, 50]. On the other hand, it has been reported that mobilization procedures involving hematopoietic growth factors in patients with breast cancer increase the level of circulating progenitor cells as well as clonogenic tumor cells [51]. Furthermore, even if the concentration of tumor cells is lower in the circulation, the one log higher total number of cells transfused would offset this advantage.
Using immunocytochemistry, polymerase chain reaction or culture techniques, tumor cells appear to circulate at any stage of the disease as shown in neuroblastoma [52], lymphoma [53] and breast cancer [54]. It seems that the appearance of circulating tumor cells is not necessarily a function of marrow disease although blood involvement appears greatest when there is overt marrow disease [55].
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Ex Vivo Manipulation of the PBPC Graft: Purging Versus Purification
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Negative purging techniques developed for eliminating clonogenic tumor cells from the stem cell autograft were first developed for BM cells and have more recently been applied to PBPC autografts as well. PBPCs depleted of B cells by immunomagnetobead separation have performed without compromise in hematologic recovery in patients with lymphoma [56]. An alternative approach is to positively select hematopoietic progenitor cells necessary for engraftment [42]. This latter approach gains more attention insofar as it avoids the use of less specific monoclonal antibodies or chemotreatment (i.e., mafosfamide). Unfortunately, compared with BM autografts, a significantly greater amount of cells contained in the apheresis product(s) (approximately 5 x 1010 TNC) needs to be processed. Ultralight density gradient techniques to debulk apheresis products have been proposed [57], but separation of normal hematopoietic progenitor cells from malignant clonogenic tumor cells remains a challenge. Some malignant hematopoietic cells are CD34+, and anti-CD34 monoclonal antibodies may label malignant cells in solid tumors [58]. Therefore, the stem cell maturation level at which the stem cell autograft is free of tumor cells has not been defined for various malignant hematological disorders and solid tumors. It is assumed that the highly purified CD34+ Thy-1dim subset might represent a "clean" stem cell product in solid tumors such as breast cancer or ovarian cancer. The technique necessary to accomplish this goal is being developed, in particular "high speed cell sorting" using a fluorescence activated cell sort (FACS) rate of 35,000 per second [59], or sequential immunoadsorption/immunomagnetobead separation followed by FACS [60].
Most recently, gene marking of the autograft using transduction of the NeoR phosphotransferase gene into BM– and/or PBPCs of autografts has provided evidence that in acute myeloid leukemia [61], neuroblastoma [62] and CML [63], malignant cells contaminating the graft contribute to relapse. Despite reduction of clonogenic tumor cells ex vivo, it remains uncertain whether stem cell purging or selection procedures reduce the risk of relapse and improve treatment outcome [64].
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Allogeneic Transplantation of PBPC
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Most recently, allogeneic transplantation of PBPCs from HLA-matched relatives is being reported by several groups, including ours [31, 32, 49]. Whereas, compared to a BM allograft, the average number of CD34+ cells collected in PBPC allotransplants is four times higher, the number of T and natural killer cells in the apheresis product exceeds the BM allograft by 10- to 20-fold [9], leading to concern that PBPC allotransplants could produce more severe GVHD. On the other hand, these cells could favorably affect immune reconstitution, even inducing a graft-versus-malignancy effect [9]. Initial clinical data have indicated encouraging results with rapid engraftment and no increase in the rate of acute GVHD [65]. More extensive follow-up is necessary for evaluation of chronic GVHD or graft-versus-malignancy effect.
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Benefits and Drawbacks of PBPC Transplantation
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Table 2 lists the benefits and disadvantages of PBPC transplantation. In several reports, the more rapid hematopoietic recovery resulted in a shorter length of stay in the hospital and thus fewer days at risk for infection, resulting in a reduction in the overall morbidity and cost of the transplant procedure [66]. This has allowed for the development of outpatient transplant programs in which patients are only admitted to the hospital for high-dose therapy, with transplantation and follow-up performed on an outpatient basis [25]. The cost effectiveness of the PBPC compared to the BM transplantation procedure depends primarily on costs of the chemopriming, growth factors and the number of aphereses needed to collect an engraftment dose of progenitor cells. With one or two aphereses performed, the PBPC transplantation approach is generally less costly [67]. In addition, collection of a sufficient amount of progenitor cells can support multiple courses of dose-intensive chemotherapy as an outpatient (1 x 106 CD34+ cells per course), allowing significant dose escalation on a shorter time period over that achievable with growth factors alone [68].
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Table 2. PB versus BM as a source of hematopoietic progenitor cells for transplantation: advantages and disadvantages of autologous or allogeneic stem cell collection and transplantation
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It is foreseeable that the more convenient collection of blood-derived hematopoietic progenitor cells from the patient as well as from the normal donor will eventually get the upper hand. A discussion has already been initiated as to whether an unrelated PBPC donor program can be set up, similar to the National Marrow Donor Program, reaching by far more potential stem cell donors and offering greater access to minorities [69]. Disadvantages of PBPC transplantation include: 1) the chemopriming of patients for stem cell mobilization; 2) adverse effects of cytokine treatment; 3) variability of stem cell mobilization efficiency among patients and, to a lesser extent, among normal donors, and 4) vascular access.
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Blood-Derived Hematopoietic Progenitor Cells as a Target Population for Gene Transduction
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As mentioned above, ex vivo transduction of marker genes such as NeoR into blood-derived hematopoietic progenitor cells allows us to study their kinetics after autologous transplantation. If combined with a tumor marker such as the Ph chromosomal breakpoint (t 9;22), the fate of malignant cells can be traced as well. Most recently, transduction of a functional gene such as the multidrug resistance gene (MDR-1) into PBPCs has been proposed [70, 71] as a means to confer resistance to drugs such as paclitaxel. Following engraftment of the retrovirally modified PBPCs, patients may then be capable of tolerating repetitive exposure to high-dose paclitaxel. With each cycle paclitaxel, drug resistant progenitor cells would be expected to be selected and the autograft might become progressively more resistant to chemotherapy. This approach has been successful in mice [72], and human trials are ongoing. This so-called in vivo selection of MDR-1-transduced PBPCs can be considered a model for simultaneously introducing therapeutic gene sequences at a high expression rate.
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Outstanding Issues Regarding Transplantation of PBPC
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The clinical value and cost effectiveness of dose intensive therapies requiring stem cell support for the treatment of hematologic malignancies and solid tumors is an area in which misuse or premature translation of technology to community centers is a major concern, particularly in the autologous transplant situation. The role of high-dose chemotherapy and PBPC transplantation is still debated versus standard chemotherapy for many indications. The role and cost effectiveness of outpatient high-dose therapy or multiple course escalated dose chemotherapy with PBPC support require further investigation before it should be widely adopted. Use of PBPC transplants to support standard dose chemotherapy or only modest dose escalation is unlikely to be beneficial and will add considerable expense. Patients receiving high-dose therapies should enter into clinical trials designed to evaluate their therapeutic role or into studies designed to further advance development of this technology.
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Conclusions
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The use of PBPCs for transplantation represents a major advance. The temporary peripheralization of hematopoietic progenitor cells allows collection of large doses of progenitors and has a significant advantage for the donor, avoiding the need for general anesthesia and multiple BM aspiration. PBPC transplantation provides rapid hematologic recovery and in most studies has reduced hospitalization and costs. The optimal dose of cells, means of mobilization and the cellular composition of the stem cell graft (hematopoietic versus nonhematopoietic) need to be further investigated and fine tuned. PBPCs are as effective as BM for autologous transplantation for the same indications as autologous BM transplantation has been proven efficacious. Although promising, it is unproven whether use of PB progenitors to support multiple courses of myelosuppressive therapy will improve outcome. Allogeneic PBPC transplants are promising and do not appear to increase the risk of acute GVHD in preliminary studies, but long-term study of their beneficiary effects is required.
Overall, PBPCs appear at least as effective as BM as a source of hematopoietic stem cells for transplantation. The ease and safety of collection as well as initial data with PBPC allotransplants provide justification for further evaluation. In the long-term, it is likely the PBPCs will replace BM as the preferred source of hematopoietic cells for transplantation.
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Abstract
Circulating Hematopoietic...
