Blood cell transplantation: Concepts and concerns

Blood Cell Transplantation: Concepts and Concerns Pamela M. Kapustay Objectives: To provide a review of the concepts and concerns for each phase of blood cell transplantation (BCT). Data sources: Review articles, research studies, abstracts, and book chapters related to BCT. Conclusions: The evolution of BCT as a major treatment option for a growing number of diseases will challenge nursing professionals. BCT is a complex pro-

cess that requires conceptual knowledge as well as technical skills. Implications for nursing practice: Comprehending specific concepts related to patient eligibility, mobilization, apheresis, cryopreservation, dose-intensive therapy, reinfusion, and marrow engraftment is essential to providing quality nursing care to patients undergoing BCT. Copyright © 1997 by W.B. Saunders Company

HE USE OF blood cell transplantation (BCT) in the treatment of selected leukemias and solid tumors has evolved rapidly over the past 10 years. Recently reported data from the International Bone Marrow Transplant Registry (IBMTR) and the newly formed Autologous Blood & Marrow Transplant Registry (ABMTR) shows explosive growth in the use of blood stem cells over those collected from bone marrow (BM). In 1991, bone marrow constituted 60% of stem cells used in autologous transplantation while blood was the source of only 20%. Four years later, in 1995, blood became the primary source of stem cells surpassing BM by 10% (Fig 1). 1 Allogeneic BCT is becoming a treatment option for carefully selected patients who are not eligible for bone marrow transplantation (BMT). However, numbers are small and efficacy cannot yet be determined until further research shows clear advantages of allogeneic BCT over BMT. The evolution of BCT as a major treatment option for a growing number of diseases will challenge nursing professionals to keep pace with the clinical concepts and technical advances associated with this therapy. The primary purpose of this article is to provide a discussion of the underlying concepts for each phase of BCT.

doxorubicin and nephrotoxicity with cisplatin administration, continue to have dose-limiting effects. 2 If these toxicities could be eliminated, administration of dose-intensive therapy would hold promise of cure for thousands who would otherwise die of their disease. 3 Intensive research in this area is ongoing. For example, the molecular manipulation of cisplatin to formulate carboplatin has produced a less nephrotoxic agent without compromising tumor kill. 4 Marrow toxicity causing pancytopenia remains a major hurdle and patients receiving second generation agents will continue to be "rescued" by reinfusion of stem cells to repopulate and restore marrow function.

T

OVERVIEW OF BCT Rationale Administration of conventional doses of chemotherapy and/or irradiation are accepted treatments for cancer. Dose-intensive therapy may cure or offer quality life years gained for selected oncologic and hematologic diseases but profound immunosuppression and organ toxicities are limiting factors. Organ toxicities secondary to chemotherapy agents such as, cardiomyopathy with

Hematopoiesis One of the pivotal premises of BCT is new understanding of the hematopoietic process. Hematopoiesis is the process by which circulating blood cells are produced in adequate numbers, under normal conditions and in times of increased demand (ie, in response to infection, after chemotherapy). 5 The origin of all blood cells are derived from the pluripotent stem cell primarily found in the bone marrow (Fig 2): The important characteristics of pluripotent stem cells are their unlimited ability to replicate repeatedly and differentiate to either myeloid or lymphoid stem cells. Only a small

From Clinical Services, SHC Specialty Hospital, Westlake Village, CA. Pamela M. Kapustay, RN, MN: Director, Clinical Services, SHC Specialty Hospital, Westlake Village, CA. Address reprint requests to Pamela M. Kapustay, RN, MN, 1118 Monte Serene Dr, Thousand Oaks, CA 91360. Copyright © 1997 by W.B. Saunders Company 0749-2081/97/1303-000255.00

Seminars in OncologyNursing, Vo113, No 3 (August), 1997: pp 151-163

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population is required to accomplish this process. Once a cell begins to differentiate it is known as a progenitor cell. These cells further differentiate and become committed to following a specific cell lineage resulting in the various mature blood and lymphocyte cells. 6

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The success of BCT lies in the ability to identify appropriate blood cells to reinfuse to assure durable engraftment. Stem cell identification is difficult because they are nondescript, small lymphoid mononuclear cells with no unique identifying morphological features. 6 Currently there are no means to detect and measure accurately the earliest pluripoteut stem cell. However, the use of culture assay systems to detect colony-forming unit-granu-

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Fig 1. Stem cell source for autotransplants. The most common source of cells used for hematopoietic recovery in autotransplants has shifted from BM to blood. (Reprinted with permission from IBMTR [July 1995]).

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BCT: CONCEPTS AND CONCERNS

locyte, erythrocyte, macrophage, and megakarayocyte (CFU-GEMM), CFU-grannlocyte macrophage (CFU-GM) and burst forming unit-erythrocyte (BFU-E) units are being used to detect early progenitor cells expressing the CD34 antigen on their surface. 3 The two methods currently used and accepted in clinical settings to identify stem cells are CFU-GM quantitative assay and CD34 count. 7 Controversy prevails over which provides a more accurate stem cell count. 8 The CFU-GM assay identifies the number of mononuclear cells collected during apheresis so that an adequate yield can be determined to ensure reestablishment of the hematopoietic system following dose-intensive chemotherapy regimens. Doses of 4 to 8 × 108/kg mononuclear cells have been reported to be sufficient to provide for adequate engraftment. 9 Accuracy of this assay is a concern as there is no consistency among laboratories as to how the test is performed. In addition, the CFU-GM assay requires up to 14 days to complete delaying further aphereses and/or the initiation of dose-intensive chemotherapy. I° Identifying the number of CD34+ cells in the harvested product is a more timely method to determine hematopoietic capability. In 1984, a monoclonal antibody (MoAB), known as Civin's antibody, was isolated and found to be useful in identifying stem cells. This antibody reacts with a cell protein marker or antigen, known as CD34, which is present on all committed hematopoietic progenitor cells and pluripotent stem cells. 6,1I CD34+ cells can now be readily identified and isolated from the masses of other cells in the circulation by using flow cytometry and MoABs. During the normal maturation of blood cells, the expression of the CD34 antigen on the cell surface diminishes and therefore, they are no longer identified as progenitor cells. 6 Since the CD34+ cell count can be determined within hours of an apheresis, the need for excessive collections can be eliminated. Identification of a stem cell and/or progenitor cell is essential to ensure that sufficient numbers are collected to enable marrow engraftment after BCT. The higher the yield the more likely that a rapid, sustained marrow engraftment after myeloablative therapy will occur. A total stem cell harvest with a CD34+ cell count of 5 X 106/kg is considered sufficient to provide for rapid engraftment and marrow recovery following myeloablative chemotherapy, a,12

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It is now known that the number of CFU-GM or CD34 + cells infused during BCT is directly related to the rate of recovery for neutrophils and platelets.l° For this reason it is vital that the optimal number of stem cells be collected to ensure a rapid and enduring marrow engraftment. The data collected to date is inconclusive as to the accuracy of one cell measurement assay over the other. 8 Both are somewhat variable and the need to standardize them is crucial to ensure accurate measurements of stem and progenitor cells.13 There is considerable interest in the possibility of expanding the number of stem and/or progenitor cells with ex vivo stem cell manipulation. These techniques allow stem cells to be procured, treated with colony-stimulating factors (CSFs), grown in an incubator, and subsequently reinfused after the patient has received dose-intensive therapy (Fig 3). To date, successful ex vivo expansion has been achieved using various combinations of growth factors. Its application to BCT is that stem cell collection and subsequent isolation of CD34 + cells enable ex vivo expansion to increase rapidly the population of committed progenitor cells. Although infusion of these cells has been found to be safe, the clinical benefits are still to be proven. ~4 The major goal of ex vivo expansion is to provide reinfusion of functional mature cells within days to decrease the number and length of apheresis procedures, decrease the potential for tumor contamination, increase the absolute number of progenitor cells, and shorten the period of pancytopenia following BCT.13,14

Types of BCT Like BMT, there are several types of BCT. Patients either receive stem cells procured from themselves (autologous), an identical twin (syngeneic), or a matched related or unrelated donor (allogeneic). Currently most BCTs are autologous and they have proven to be a safe and effective alternative to BMT. Table 1 describes several advantages to autologous BCT over BMT.15 Allogeneic BCT is an area of major interest and research. At present, data regarding the efficacy, cost versus benefit, and/or long-term disease survival rates for allogeneic and syngeneic BCT are limited. Only a small number of these transplants have been performed to date and it is premature to predict outcomes. Bensinger et al, 8 showed earlier engraftment in BCT compared to BMT but

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long-term durable recovery is yet to be determined. In addition, there appears to be no difference in the rate of graft versus host disease (GVHD) between allogeneic blood and marrow transplantation. Allogeneic BCT opens an array of research areas to be pursued such as the development and improvement of short-term peripherally inserted venous

access apheresis devices, stem cell mobilization and collection techniques eliminating the need for additional apheresis procedures, the effects of recombinant CSFs on healthy donors, and its application to volunteer donor pools. Large randomized, controlled studies comparing allogeneic BCT and BMT need to address issues such as the

Table 1. Advantages and Disadvantages of BCT Versus BMT Issue

BCT

Care facility Granulocyte recovery Morbidity and mortality Platelet recovery Long-term engraftment Tumor contamination Cost Product collection or harvest

Largely performed in outpatient area 8-12 days Less 10 days Not yet determined Yes $60,000-100,000 No general anesthesia Multiple apheresis Primarily limited to autographs May be used as an adjuvant therapy in breast cancer (investigational) Approximately 4-6 wk Caregiver burden may be more intense, but of shorter duration Less available than BMT due to "experimental nature" Large double-bore catheter None or short hospitalizations Approximately 65%

Patient and family time Commitments Insurance coverage Venous access Hospitalization Readmission rate

Reprinted with permission. 15

BMT Hospital/acute care setting 10-24 days More 14-21 days Determined. Long-term survivors to more than 30 yr Yes $90,000-250,000 Marrow harvest under general anesthesia Autologous, allogeneic, and unrelated BMTs Not used as an adjuvant therapy Approximately 6-12 mo Caregiver burden intense over longer duration More available, but exceptions exist Standard multilumen catheter Longer hospitalizations Approximately 50%

BCT: CONCEPTS AND CONCERNS

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incidence of acute and chronic GVHD, rate and duration of sustained engraftment, long-term disease-free survival rates, and cost analysis data. 8

don of BCT in these and other diseases are discussed by Yoder elsewhere in this issue.

Tandem Blood Cell Transplants

Patient Eligibility

In breast cancer, administration of doseintensive chemotherapy followed by BCT has shown a significantly higher initial tumor response rate over conventional dosing protocols. However, high rates of relapse in this patient population following BCT, particularly in previous sites of metastatic disease, continue to be of concern and are thought to be attributed to drug-resistant tumor ceils that remain and multiply after treatment. 16 Rapid marrow engraftment and recovery following BCT has enabled research to be conducted in the application and efficacy of multiple consecutive courses of myeloablative therapy with stem cell rescue. Drug resistance in tumor cells may be affected by a dual assault of dose-intensive therapy if given in rapid succession following acceptable marrow recovery from BCT. Ghalie et al, I7 studied 44 women with metastatic breast cancer after administration of two equal high-dose chemotherapy regimens each followed by BCT. Although rapid hematological engraftment was achieved from BCT between courses of myeloablative therapy, additional organ and nonhematological adverse effects prevented rapid sequential administration of dose-intensive therapy. Delays between therapy were, on the average, greater than 3 months and the antitumor effect was not found to be significantly higher compared to standard single B C T . I7 Clinical trials enlisting large numbers of patients and extensive follow-up are needed to determine the efficacy of tandem and other types of BCT.

Evaluation to determine eligibility for BCT can be lengthy, tedious, and anxiety-producing for patients and their families already under the threat of advanced disease. Often this process is initiated after multiple courses of conventional chemotherapy and/or irradiation have been unsuccessful in controlling malignancy. Patient eligibility is often determined initially between the primary referring oncologist and the transplant physician after discussion of the patient's present disease state, progression and response to conventional therapy. Before any additional work-up, verification of insurance coverage and benefits as they pertain to BCT is initiated. Initial contact is generally with case managers who identify the documentation requirements and review process for obtaining authorization for BCT, which differ among third party payors. Letters of medical necessity outlining the individual's disease history, previous chemotherapy, response, and test results are all that is required by some third-party payors. Others provide a prepared packet that lists the required documentation to be submitted. This information may necessitate multiple pretransplant laboratory and radiographic studies to further document the stage of disease and physiological status of the patient. Unfortunately, the patient is responsible for payment of these tests if authorization for BCT is denied. Appropriateness for BCT is determined by the medical director or review committee according to institutional guidelines. Review committees are generally comprised of physicians with expertise in blood and marrow transplantation and are either internal to the institution or outside contracted services. Unfortunately, the review, denial, and subsequent appeals process can be the most tedious and timeconsuming phase of BCT. Patients often choose to go forward with transplantation, liquidating their assets to pay for the procedure, while continuing to appeal denial of benefits.

Diseases Currently Treated With BCT Those diseases currently being treated with BCT are acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and some solid tumors such as breast and, more recently, ovarian. In diseases such as multiple myeloma, where tumor cells are identified less frequently in the blood as compared to the BM, autologous BCT has significantly improved disease-free survival rates. 6,18 Stem cells obtained from cord blood have been used for a number of noncancer related conditions, such as Fanconi's anemia, thalassemia, and aplastic anemia, with early positive results. 19 The applica-

THE BCT PROCESS

Mobilization Mobilization is a process of stimulating the BM resulting in the proliferation of pluripotent stem cells in the marrow and their subsequent rapid expression into the peripheral circulation for

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collection, l° The most common agents to accomplish mobilization are alkylating agents and CSFs used alone or in combination. The most common alkylating agent used is cyclophosphamide 2 to 4 g/m2. m The rationale for administering a single high-dose alkylating agent is to increase the numbers of progenitor cells in the peripheral circulation resulting in a higher yield of stem cells. Conceptually, the BM, under normal conditions, has a concentration of stem cells 10 to 100 times higher than the peripheral blood. However, after a chemotherapy-induced nadir there is a dramatic hematopoiesis phase during which the numbers of CFU-GM in the peripheral circulation are increased by 100-fold. 2° An additional advantage to the administration of a single dose alkylating agent for mobilization is to further enhance tumor cytoreduction before BCT. 1°'20 The second agent for mobilization of stem cells is human recombinant growth factor and includes granulocytemacrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF). There are some studies that suggest a combination of cytokines and chemotherapy actually result in higher numbers of circulating progenitor cells than the single agent use of either chemotherapy or cytokines. Others disagree and suggest that a single dose of chemotherapy, in combination with CSFs, does not significantly increase the overall numbers of proliferating stem cells. 7,9,13 The need for large studies in which comparative data is generated are essential before this can be substantiated. Additional areas that need further research are determination of optimal time for mobilization, the role of stem cell factor and interleukin-3 (IL-3) either alone or in sequence with G-CSF and GM-CSF, the ideal combination and/or sequence of cytokines, and the design of protocols that enhance the mobilization of progenitor cells while minimizing tumor cell mobilization. Further research is significant as the number of stem and progenitor cells reinfused after dose-intensive chemotherapy and/or irradiation is directly related to the longterm hematopoietic recovery and survival. Improved mobilization techniques, that increase the number of circulating progenitor cells will decrease the number of apheresis procedures required. 21

PAMELA M. KAPUSTAY

(approx. 13.5 French), double lumen central venous catheter (Fig 4) is surgically placed in the patient. The large internal diameter of each lumen is essential because of the high flow rates that must be maintained during apheresis. Because the majority of BCTs are autologous, surgical placement of a long-term apheresis catheter is appropriate as it can be used throughout the phases of BCT for administration of hydration, blood products, medications, and collection of blood samples. The use of healthy donors for allogeneic BCT stem cell procurement has resulted in the development and evaluation of short-term apheresis catheters that can be inserted at the bedside and/or in radiology under fluoroscopy thus eliminating an aggressive surgical approach. Apheresis is the method for stem cell procurement using commercial cell separators that are programmed to collect either lymphocytes or low-density leukocytes. The most commonly used apheresis machines are the COBE Spectra (COBE Laboratories, Lakewood, CO) (Fig 5), Fenwall

Collection/Apheresis To facilitate collection of stem cells from the peripheral circulation by apheresis, a large bore

Fig 4. Double lumen apheresis catheter. (Reprinted with permission from Bard Access Systems, Salt Lake City, UT.)

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BCT: CONCEPTS AND CONCERNS

located between the red blood cells on the outer wall and the plasma at the inner wall. The white cell layer is made up of mononuclear cells, monocytes, lymphocytes, and polymorphonuclear cells. Desired stem ceils lie in the mononuclear cell layer and the "interface" is the point of desired collection. Collection of platelets and/or polymorphonuclear cells that lie on either side of the mononuclear cell layer can have an adverse effect on the patient and/or viability of the collection. The apheresis machine operator or automated procedures continually set and reset the interface throughout the procedure by defining the pump flow rates, run time, and centrifuge speed to ensure maximum collection of mononuclear cells. Once the collection is complete, plasma, red blood cells, platelets, and the remaining white cells are returned to the individual via the catheter's second lumen. There is little documented difference that one machine has the ability to collect a higher number of mononuclear cells over the others. Generally, equipment preference is related to the ease of use and cost factors. The COBE Spectra requires more involvement by the operator while the Baxter Fenwall CS-3000 is more automated.l°

Large Volume Apheresis

Fig 5. COBE Spectra. (Reprinted with permission from COBE Laboratories, Lakewood, CO.)

CS-3000 (Baxter, Round Lake, IL), and Haemonetics V-50 (Haemonetics Corp, Brainier, MA). The equipment design is based on the principle of a centrifuge. The patient's whole blood enters the machine from one lumen of an apheresis catheter, mixes with anticoagulant citrate dextrose solution USE is pumped into the centrifuge and separated out into its fluid and cellular components. The centrifugal action causes the component of highest density (red blood cells) to migrate to the outer wall of the centrifuge, with layers of the remaining blood components progressing toward the inner wall where the lowest density component (plasma) gravitates. The white cell and platelet layers are

Multiple stem cell collections, patient comfort, and allocation of nursing and laboratory personnel represents a significant barrier to cost-effective BCT. Research to develop a method of collecting sufficient cells for BCT in one collection is intense. Until recently, the generally accepted daily blood volume to be processed for harvest from a patient was 10 L and 3 to 5 collections were needed to achieve this amount. 9,1° Under normal circumstances during apheresis of stem cells a small amount of platelets are collected with the mononuclear cells due to their proximity to each other within the centrifuge. A major disadvantage of processing higher blood volumes (up to 40 L) is a decrease in circulating platelets due to the increased frequency of contact between the platelets and mononuclear cells resulting in the inadvertent collection of platelets with stem ceils causing thrombocytopenia requiring subsequent transfusion support. 1°,21-23 However, platelets can now be extrapolated from the final stem cell product and reinfused to the patient to prevent this problem. ~3 Pettengell et al 2I documented sufficient harvest of stem cells for marrow reconstitution with a single

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apheresis of a median of 14 L of chemotherapy and growth factor mobilized blood. Although patients experienced a decrease in platelets after collection, no platelet transfusions were necessary. Single large volume collections are a safe and costeffective method to harvest stem cells and decrease apheresis time. 21,23

Tumor Contamination and Optionsfor Purging Two important concepts to be considered are tumor contamination and purging options. The prevention of tumor contamination decreases the hypothetical risk of relapse that limits the utility of BMT. There is a significant risk to reinfusion of tumor cells that may contribute to relapse of disease in patients who might have otherwise achieved tumor-free status following dose-intensive chemotherapy and/or irradiation. 24,25An important step in stem cell processing is the ability to detect tumor cells during the collection so that minimal residual disease can be identified. Although patients may be in complete clinical remission, circulating tumor cells may be present in small but undetectable numbers. Morphologic and immunocytochemical techniques are used to detect the presence of tumor cells in stem cell collections and do not differ from those used in marrow harvests. 26 There is much discussion as to the prognostic significance of transplanting tumor contaminated stem cells and their relationship to relapse and disease-free survival rates. Some researchers believe that these cells may not have the potential to grow and metastasize. 13,24,26-28 However, studies have shown that tumor cells are able to grow and survive in vitro suggesting that contamination can contribute to relapse. 13,24-26 Researchers are attempting to develop more effective purging techniques before stem cell reinfusion to prevent tumor contamination. Purging techniques fall into two categories: (1) negative cell, and (2) positive cell selection techniques. Negative cell selection techniques attempt to eradicate tumor cells via methods such as, chemotherapeutic agents (eg, etoposide), antibodies that bind to tumor cells and subsequently eliminate them, electrical charges, phototherapeutic compounds, and gene transfer. Positive selection techniques include the use of CD34+ antibody binding techniques. 29,3° Most of these technologies are in various stages of investigation; consequently, important questions remain unanswered.

PAMELA M. KAPUSTAY

Cryopreservation The average stem cell life is 3 to 7 days; consequently, cryopreservation is important to prevent stem cell damage and assure viability at the time of BCT. 15 Cryopreservation is a process by which cells are frozen and stored at temperatures below 0°C while still maintaining an adequate rate of viability. 31 At temperatures between - 7 9 ° C and - 1 9 6 ° C cell metabolism is in a resting state and movement of enzymes across the cell membrane is blocked. There is a direct correlation between the number of viable stem cells recovered at time of thawing and the temperatures in which they are stored. The lower the temperature, the higher the rate of cell viability. 29 After stem cell collection, the product is weighed and the concentration of cells per milliliter is calculated. If the concentration exceeds 2 × 108 nucleated cells/mL, additional plasma may be collected at the completion of apheresis and used to adjust the volume to the optimal freezing concentration of 2 × 108 nucleated cells/mL. The collection is tested for tumor and/or other outside contamination, total CD34+ and mononuclear cell counts, and viability of the stem cells. The cells are then prepared for cyropreservation with one of two methods, and there is no data suggesting one method is more effective than the other. Selection is based on cost concerns rather than efficacy. The most recent technique of cryopreservation is the use of Medium 199, deoxyribonuclease I (DNase), and dimethyl sulfoxide (DMSO) which, when combined, form a freezing medium used for cryopreservation of stem cells. The most critical period for preserving cell viability during stem cell processing occurs during the freezing and thawing process. As cells lyse during the freeze/thaw process, deoxyribonucleic acid (DNA) is released producing a sticky substance that may cause severe clumping of the remaining intact cells. DNase is an enzyme that breaks apart the free DNA, preventing clumping and protects the product as it thaws. During the freezing process cell injury is related to the rate of freezing and results from intracellular ice crystal formation and cellular dehydration. DMSO at a concentration of 10% by volume is a cryoprotectant agent that diffuses rapidly into stem cells and increases intracellular solute concentration. At rapid rates of cooling, the increased solute concentration results in a decreased intracellular ice crystal formation and prevents cell lysis. During

BCT: CONCEPTS AND CONCERNS

slower rates of cooling, cellular dehydration is minimized because of the decreased osmotic gradient between the inside and outside of the cell. 29 The cells are cooled in a controlled-rate freezer and stored in the vapor phase of liquid nitrogen. The second method uses DMSO at a concentration of 5% by volume combined with hydroxyethyl starch, which does not penetrate the cell, for cryoprotection. In the later and older method, the cells are placed in a - 80°C freezer for cooling and placed in the freezer for storage. For allogeneic BCT, the collected product may be infused the same day or it may be refrigerated at 4°C for a maximum of 24 hours until reinfusion without the addition of DMSO. 31

Dose-Intensive Therapy Chemotherapy. Established dose-intensive conditioning clinical protocols are being used in most facilities performing BCT and research continues in the study of those chemotherapeutic agents that affect cure without causing permanent adverse sequelae. However, much controversy exists as to the specific and total number of chemotherapeutic agents administered. Administration of an alkylating agent in the regimen is universally agreed upon since the goal of dose-intensive chemotherapy is to obliterate the patient's marrow. Additional chemotherapeutic agents are then added based on their effect on the particular cancer to achieve tumor cytoreduction, more durable disease control, and possible cure. Use of single alkylating agents, such as melphalan, are being investigated because of decreased side-effects such as nausea, vomiting, and stomatitis, as compared to combination chemotherapy. 32 Furthermore, melphalan is administered over 30 minutes for 2 days in an outpatient setting. This concept of a single "universal" alkylating agent in BCT needs further investigation to determine its efficacy and long-term effects on the primary cancer cell type. In a changing health care environment, emphasis on decreasing cost is mandated. Minimal infusion time, ease of administration and fewer dose-intensive related side effects will facilitate the care of BCT patients in an outpatient setting. Total body irradiation (TBI). Institutions vary in the inclusion of TBI in BCT protocols. The role of TBI in addition to dose-intensive chemotherapy in BCT remains controversial. TBI in combination

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with high-dose chemotherapy for BMT is wellestablished and has two essential roles. The first is to ensure eradication of malignant ceils refractory to high-dose chemotherapy and responsible for disease relapse and, second, to ablate the immune system to decrease the risk of graft rejection. 33 Evidence that TBI plays no significant role in BCT is based on the hypotheses that blood stem cells are less contaminated by tumor cells in comparison to stem cells obtained from the BM, and that tumor contaminated stem cells expressed from a tumor and/or its metastatic sites are thought to be less capable of re-establishing a tumor then those cells procured from the marrow. 26 The possible advantages of BCT without TBI may be a treatment option for patients denied BMT because they cannot withstand the associated toxicities. For example, older, more debilitated patients, those with marrow metastasis, or those who have had previous BM irradiation. 34 Current studies are limited but research continues to investigate whether the addition of TBI to high-dose chemotherapy with blood stem cell support can improve the disease-free survival and quality of life in patients with hematological malignancies and BM involvement.

Reinfusion The majority of reactions experienced during the reinfusion of stem cells are due to the preservative, DMSO, and free hemoglobin that is inadvertently collected during multiple apheresis procedures. 21 Compared to BM harvesting, large quantities of cells are collected during apheresis following CSFs and/or chemotherapy mobilization techniques. These higher cell yields require greater concentrations of DMSO to ensure viability during freezing and thawing to prevent cells from clumping. 31 Toxicities related to DMSO during reinfusion are mild and include nausea and vomiting, abdominal cramping, chilling, and unusual taste of garlic or oysters. The administration of anti-emetics, antihistamines, and steroids immediately before the reinfusion may allay the severity of these side effects and help relax patients. More severe reactions are related to volume with symptoms of fluid overload or pulmonary emboli. 15 Washing of cells before reinfusion, concentrating cells after thawing, and freezing higher concentrations of cells are among the options being explored in an attempt to improve cryopreservation techniques in

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relation to the high concentrations of stem cells. 31 Renal toxicities such as, hematuria and increases in serum bilirubin and creatinine, are directly related to red cell contamination and can necessitate hemodialysis. 15 Secondary centrifugation has been used in an attempt to remove red cells from the stem cell product and reduce the final volume with no adverse effects noted from routine freezing or thawing procedures. Techniques for the administration of stem cells, such as split reinfusions over 2 to 3 days, need further investigation. 31 The stem cell reinfusion phase of BCT requires astute clinical coordination, observation, and interventions.

Engraftment~Recovery Generally speaking, hematopoietic recovery after BCT is similar to autologous BMT. However, platelet recovery in BCT, is inconsistent for reasons that remain unclear. It is thought that the phenomena may be secondary to megakaryocyte fragility caused during apheresis, cryopreservation, or thawing processes causing a decrease in sufficient megakaryocyte precursors to be reinfused into the peripheral circulation. 27 CSFs in clinical trials that hasten megakaryocyte engraftment hold promise for speedier engraftment with subsequent reductions in cost and risks of multiple platelet transfusions. 35 Parameters of hematopoietic recovery differ slightly among institutions. Minimal criteria are an absolute neutrophil count >500 mm 3, platelet count 50,000 mm 3 with no active bleeding, and a hematocrit of 25% for 1 to 2 weeks. 36 Patients usually remain near the transplant center for 3 to 4 weeks after treatment to be monitored for febrile fever episodes, viral pneumonia, dehydration, persistent nausea, suspected veno-occlusive disease and thrombocytopenia. Prophylactic antibiotics may prevent or diminish episodes of fever and sequential once-daily antibiotic therapy simplifies febrile neutropenia occurrences. The ability to deliver daily 24-hour care is imperative and a cadre of medical, nursing, pharmacy and laboratory personnel need to be available. Hospital admissions/re-admissions peak during this period and provisions for smooth transition between in-patient, outpatient, and home care are essential. Particular attention must be paid to family caregiver stamina to withstand possible multiple therapies and transportation to clinical treatment areas. 15 For the allogeneic recipient, similar but more

PAMELA M. KAPUSTAY

intense complications can occur secondary to more intensive chemotherapeutic regimens. The appearances or exacerbation of acute GVHD, usually managed in a hospital setting, are being increasingly managed in ambulatory care settings. These symptoms often confound already existing problems and nausea, vomiting, diarrhea, fever, chills, and skin disorders will require differential diagnosis and management. Nurses, who are usually the first to assess these patients, will require intensive education in the pathophysiology, clinical manifestation, and management of acute GVHD. As allogeneic BCTs increase, nurses will require more education in this area. 15

Prevention and Treatment of GVHD for Allogeneic BCT With the recent increase in allogeneic BCT, the incidence of GVHD in BCT compared to BMT has been the subject of discussion and investigation. 37 Higher levels of T-cell concentration are found in stem cells collected from blood as compared to those found in marrow harvests. For this reason it is thought that a higher incidence of GVHD will occur in BCT. However, Bensinger et al, 8 in a study of 73 recipients of HLA matched allogeneic BCT, reported that there was no statistically significant difference between BMT and BCT in regards to incidence of either acute or chronic GVHD. Presently, GVHD prophylaxis in allogeneic BCT consists of cyclosporine-A in combination with either short-term methotrexate or prednisone. This differs very little from the standard protocol used in GVHD for allogeneic BMT. 37 However, the administration of specific cytokines (ie, 1L-4, IL-10, IL-13) to increase immunosuppression are thought to have a prophylactic effect against GVHD. 38 This indicates a potential role for cytokines in GVHD prophylaxis, but clearly, this is an area that needs further investigation. NEW DEVELOPMENTS

New Sources of Stem Cells Stem cells procured from the umbilical cord or placenta, at the time of birth, stored, and later transplanted to a related or unrelated matched recipient is a growing area of transplant technology. Rapid marrow reconstitution following cord blood transplantation has been well-documented over the past 6 years in malignant as well as nonmalignant conditions. 39,4° In unrelated recipi-

BCT: CONCEPTS AND CONCERNS

ents, the incidence of GVHD may be less than in traditional marrow and/or blood stem cell transplants since cord blood T cells are immature and not yet fully functional. This is promising for individuals who are unable to locate a matched donor. 4I However, this remains controversial and further research is needed. 39 In addition, long-term enduring engraftment and disease-free survival rates are yet to be determined and will require continued follow-up of recipients. Along with the increasing interest and application of cord/placenta stem cell harvest and transplantation, ethical issues have begun to emerge. Specific issues concern the ownership of stem cells stored and their future disposition, the establishment of appropriate informed consent, security of donor's future identity, medical records and results of laboratory testing, and measures to ensure equal access and availability to stem cell distribution. 4° These issues are complex and will be in a state of constant evolution as social mores and legal decisions redefine the scope of transplant medicine. Multidisciplinary ethical review boards at institutions involved in cord stem cell transplant need to address these issues and develop practice protocols for ongoing evaluation and redesign.

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BMT and suggest that BCT has potential for lower overall cost due to outpatient stem cell collection and processing, shorter periods of neutropenia and resulting use of antibiotics, and fewer inpatient days. Advanced technologies in the collection, processing, storage, and delivery of care in the outpatient setting for BCT shows a savings of $13,000 to $15,000 over autologous BMT. Early studies such as these demonstrate the need for measuring the cost-effectiveness of BCT in direct relation to clinical outcomes.

Gene Therapy The significance of stem cell isolation technology is far reaching in its clinical application for BCT. For instance, the collection, identification, and isolation of desired CD34+ cells allows for the application of gene therapy. Studies are underway in which stem cells are marked with a recognizable gene before transplant to determine the source of malignant cells that may cause relapse or treatment failure. Other studies, involving the insertion of a therapeutic gene, are being done in individuals undergoing BCT for ovarian, breast, and other a d v a n c e d c a n c e r s . 44 Gene therapy is discussed, in more detail, by Cuaron and Gallucci elsewhere in this issue.

Cost Analysis of Risks Versus Benefits At perhaps no other time in history has cost of various therapies been so influential in dictating health care practices and sites of care delivery. Administrators and financial officers no longer analyze expenditures without involving clinicians in strategies to deliver cost-effective, quality care. Third-party payors grant exclusive provider contracts based on such cost containment strategies, which translate into higher revenue income and drive product lines for institutions. 41 Emerging technologies and changing clinical practices have resulted in an emphasis on calculation and cost analysis of BCT in relation to overall risks versus benefits. Very little is available in the literature specific to direct and/or indirect costs incurred with BCT. There are only a few studies that have been conducted with BMT. Welch and Larsen 42 compared cost of care and quality of life years gained in leukemia patients receiving either BMT or standard chemotherapy. They concluded that BMT offered more cost-effective care and greater quality of life years gained when compared to standard therapy. Smith et a143 compared costs of autologous BCT to

Areas for Nursing Research Rapid advances in medical technology and the demands of a changing health care delivery system have resulted in challenges and endless opportunities for administrators, clinicians, educators, and researchers to become involved in the evolution of care for patients undergoing BCT. The shift in care from inpatient services to the outpatient setting presents nurses with a very different work environment as outpatient facilities expand hours of operation and manage patients on an emergency basis. As a result, nursing administrators need to develop innovative staffing patterns to use and allocate staff in the most cost-effective manner. Caregiver burden, development of clinical protocols and care pathways to effectively administer dose-intensive therapy, manage and treat the side effects on an outpatient basis are areas for nursing research. CONCLUSION Initial data show that autologous BCT in combination with dose-intensive therapy is an acceptable alternative to BMT. Basic concepts of

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hematopoiesis, stem cell expression, and isolation support the rationale for various types o f B C T and its application in certain diseases. C o n t i n u e d l o n g - t e r m patient f o l l o w - u p is n e e d e d to substantiate these early findings. Questions related to each phase o f B C T still r e m a i n and require continued investigation before answers can be assertained. Issues related to concepts i n v o l v i n g stem cell mobilization, collection, cryopreservation, and reinfusion are in a constant state of e v o l u t i o n as n e w m e t h o d s are found to i m p r o v e and e n h a n c e the processes. R e s e a r c h studies to d e t e r m i n e appropriate agents, used alone or in combination, to p r o d u c e m y e l o a b l a t i v e effects, efficient m a n a g e m e n t o f their side effects, and rapid m a r r o w e n g r a f t m e n t and r e c o v e r y are essential to ensuring the safety and efficacy o f BCT. Durability o f m a r r o w engraftment, effects o f t u m o r contamination and purging techniques are additional areas in w h i c h recent research studies h a v e b e e n focused. E x p l o r a t i o n in finding n e w sources o f stem cells, p r e v e n t i n g and treating G V H D in allogeneic BCT,

g e n e manipulation, and analysis o f risks versus benefits will direct future research and clinical applications of BCT. Rapidly c h a n g i n g d e m a n d s are b e i n g p l a c e d on care delivery systems by thirdparty payors as w e l l as health care consumers. Institutions are b e i n g c h a l l e n g e d to p r o v i d e h i g h l y technical and intense treatment protocols, such as BCT, driven by m e a s u r a b l e quality o u t c o m e s and cost-effective m e t h o d s increasingly d e l i v e r e d in alternate sites o f care. Nursing must be ready to m e e t the c h a l l e n g e o f developing, revising, and i m p l e m e n t i n g change to systems presently being used in the care o f patients u n d e r g o i n g BCT. Basic understanding and k n o w l e d g e o f those concepts specifically related to B C T will formulate the foundation o f e x p a n d e d and a d v a n c e d nursing practice roles as B C T e v o l v e s o v e r the n e x t f e w years. ACKNOWLEDGMENT

The author thanks Lisa Matthews for her secretarial assistance with the preparation of this manuscript.

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