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Diseases treated with blood cell transplants
Diseases Treated With Blood Cell Transplants Linda H. Yoder Objectives: To provide an overview of the vast amount of clinical and research data concerning the diseases treated with blood cell transplants. Data sources: Research studies, abstracts, book chapters, and articles pertaining to diseases treated with blood cell transplantation (BCT). Conclusions: The potential for the expanded use of BCT in cancer and other diseases appears unlimited. This type of transplantation is gaining widespread use and the
number of centers offering this treatment for hematologic and solid tumors is increasing. Implications f o r nursing practice: Nurses working in acute care, outpatient, and home care settings need to familiarize themselves with the rapidly expanding role of this treatment to provide the most state-of-the-art care to their patients.
N 1986, SUCCESSFUL blood cell transplantation (BCT) for patients with diseases other than chronic myelogenous leukemia (CML) were reported. 1 Peripheral blood (PB) stem cells procured from the mononuclear fraction of PB leukocytes are capable of producing full hemopoietic reconstitution after marrow ablation with high-dose therapy. 2 With advances in the technology supporting blood stem cell harvesting and transplantation there is increasing use of BCT as an alternative to autologous bone marrow transplantation (BMT) after high-dose chemotherapy and/or total body irradiation. Such enthusiasm has been generated regarding the use of stem cells in hematopoietic transplantation that it has called into question whether there will be any long-term future role for autologous BMT. 3 Holyoake and Franklin 4 stated that the use of stem cells "will transform medical oncology within the next few years." Based on published reports, more than 1,000 patients have already received BCT for treatment of acute and chronic leukemias, non-Hodgkin's and Hodgkin's lymphomas, multiple myeloma, and a
variety of solid tumors such as breast and ovarian cancers. 5-7 The diseases presented in Table 1 are those most commonly treated with BCT. The number of centers offering BCT for hematologic and solid tumors is increasing. I PB stem ceils have been most commonly used in patients with marrow contaminated by tumor cells, hypocellular marrow due to previous cancer therapy, or in patients who are viable candidates for high-dose therapy, but who do not have a suitable donor. 2 Additionally, the predominant message from the Third International Symposium on advances in stem cell transplantation was that the traditional concept of very intensive, myloablative radio-chemotherapy to consolidate patients in complete or good partial response is being gradually replaced, s Clinicians are now favoring the concept of early onset, high-dose, multimodal, sequential therapy instead of conventional-dose induction and consolidation before conditioning, s This may, in part, be related to factors found by Bensinger et al 9 that influence collection and engraftment of stem cells. These investigators used linear regression analysis and found that disease status and prior treatment influence the ability to mobilize stem cells. Additionally, the CD34+ cell dose is an important predictor of engraftment kinetics after BCT, regardless of disease or mobilization technique. Other factors such as a diagnosis of breast cancer, disease free marrow, limited chemotherapy exposure, and no prior history of radiation were associated with larger numbers of CD34+ cells. Relapse of disease and lack of engraftment have been the most common causes of treatment failure. Oncologists indicate a need for more randomized trials to determine whether positive outcomes from
I
From Nursing Research & Outcomes Management, Brooke Army Medical Center, Fort Sam Houston, TX. Linda H. Yoder, RN, MBA, PhD, OCN®: Lieutenant Colonel, Army Nurse Corps, Director, Nursing Research & Outcomes Management, Brooke Army Medical Center, Fort Sam Houston, TX. The views of the author are her own and do not purport to reflect the position of the Army Medical Department, Department of the Army, or the Department of Defense. Address reprint requests to Linda H. Yoder, RN, MBA, PhD, OCN®, 13322 E1Mirador, San Antonio, TX. This is a US government work. There are no restrictions on its use. 0749-2081/97/1303-000350.00 164
This is a US government work. There are no restrictions on its use.
Seminars in Oncology Nursing, Vo113, No 3 (August), 1997: pp 164-171
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Table 1. Diseases Treated With Peripheral Stem Cell Transplantation Hematologic Malignancies
Solid Tumors
ALL Acute nonlymphocytic leukemia Chronic granulocytic leukemia Hodgkin's disease NHL
Breast cancer Small-cell lung cancer Neuroblastoma Ovarian cancer Testicular cancer Melanoma Multiple myeloma Ewing's sarcoma
BCTs are due to more effective treatment, subject selection and if in vitro removal of tumor cells from the stem cell collection is necessary or effective. 1°,11 In the past, many investigators thought that stem cells were relatively free of tumor cell contamination and used this assumption as the rationale for BCTs over conventional BMTs. Currently, there are insufficient data to evaluate the significance of minimal residual disease in BCT for solid tumors. 12 Recently, investigators showed that stem cells from patients with neuroblastoma, breast cancer, nonHodgkin's lymphoma (NHL), acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), multiple myeloma, and CML are contaminated with tumor cells. Mobilization of stem cells may, in fact, be associated with concomitant tumor cell mobilization.lZ, 13 Dose-intensification followed by BCT has not been conclusively shown to improve cure rates, but promising clinical data have emerged from nonrandomized studies of patients with poor-prognosis lymphoma, metastatic breast cancer, stage II/III breast cancer, and poor risk germ cell tumors. 14 Clinical trials are ongoing to determine the efficacy of BCT in AML, ALL, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, and germ cell tumors. These studies focus on measuring and determining the best timing for BCT, tumor chemosensitivity, and tumor bulk as it relates to disease response? 5 Other purposes of ongoing studies address the use of BCT in conjunction with autologous BMT, the efficacy of tandem or double transplants in breast cancer, and the comparison of BCT versus BMT in relation to disease response, a Although current studies rarely report survival rates for BCT, long-term follow-up is needed to determine if cures have resulted from BCT. However, treatment-related toxicity and mortality is decreased, 2,14,16,17 while quality of life may be increased surrounding the immediate transplant
period. 18 Because BCT is associated with less morbidity and more rapid recovery of hematopoietic function than conventional BMT, 14 patients have shorter lengths of stay and costs may be reduced.19-e1 Although there is a large body of literature concerning the use of BCT, it is difficult to draw conclusions from the data because of the lack of prospective randomized trials in most of the cancers in which BCT has been used. Clearly as more data is forthcoming, more questions arise from clinicians. The purpose of this article is to provide a broad overview of the vast amount of clinical and research data concerning the use of BCT. It is beyond the scope of this article to discuss the intricacies of the various studies cited. However, the reference list provides an extensive array of literature the clinician can use to gain more specific information about a particular topic presented. MULTIPLE MYELOMA
Achieving a complete response in the bone marrow (BM) of patients with multiple myeloma using conventional-dose chemotherapy is difficult. Median survival generally ranges from 2 to 3 years. 22 This problem led to investigators examining high-dose therapy with hematopoietic support as a treatment optionY Dose-intensity studies of people with multiple myeloma showed that drug resistance in myeloma cells can be overcome and patients with poor prognosis can achieve remission. However, patients treated with high-dose therapy early in the course of their disease (less than 1 year of prior chemotherapy) may achieve prolonged disease-free remissions, although survival rates are unavailable for many of these patients at this time.24, 25
The use of stem cells as hematologic support in multiple myeloma clearly reduces treatmentrelated toxicity, although treatment regimens vary and can include both chemotherapy and radiation therapy. 2a,26-28Any antitumor effect depends on the conditioning regimen used, the stage of myeloma at presentation, presence of resistance to prior standard therapy, and possibly the source of hematopoieric stem cells and the use of growth factors for stem cell mobilization. 26 Many questions remain regarding myeloma tumor cell contamination in the blood stem cell collection and the relationship of these cells to
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relapse. The use of various immunologic or pharmacologic purging methods has not been sufficiently investigated, but reports of studies using various methods are beginning to appear in the literature. 29 More research involving innovative approaches for BCT with multiple myeloma are needed to determine the ultimate value of this treatment. 23 LYMPHOMAS
Patients recently diagnosed with intermediate or high-grade NHL or Hodgkin's disease (HD) have a 40% to 70% cure rate when treated with conventional chemotherapy or radiotherapy. Patients who do not achieve a complete remission or who relapse are, for the most part, incurable with conventional salvage therapies. None of the conventional regimens in use show superiority when compared to each other. However, the patients may have the potential for cure with high-dose therapy followed by BeT. 3° Kessinger and Armitage 31 stated that more than 200 lymphoma patients treated with BCT have been reported and while follow-up is still too brief to ascertain the curative potential of this treatment, clearly long-term survival has resulted for a number of patients. Findings from a retrospective study of intermediate NHL patients with bone marrow involvement showed a significantly better outcome after BCT compared with those who received autologous BMT. 32 As with other metastatic solid tumors, stem cell collections may harbor occult lymphoma cells, although fewer than in marrow collections. 3° In regard to both NHL and HD, researchers have nonetheless pointed out that many questions concerning BCT remain unresolved, including definitive proof that BCT improves overall survival. Clinicians and researchers at a recent Consensus Conference on the use of marrow transplantation were unwilling to characterize BCT as the standard of care for relapsed lymphomas in the absence of randomized data showing an overall survival advantage. Optimal high-dose regimens, quality of the stem cell product, the role of total body irradiation, and ex vivo purging clearly require further study. 33 NHL
Most of the patients reported to date had relapsed or had refractory disease at the time of BCT, where
the risks associated with the procedure were justified in light of the potential for cure. However, some patients with poor risk disease received high-dose therapy as consolidation after achieving a complete remission with conventional therapy? 1 A primary issue concerning the use of BCT in NHL is the timing of the transplant. Cohen and KriegeP ° stated that perhaps high-dose therapy with BCT should be used earlier in newly diagnosed NHL patients. BCT has not been used extensively with poor prognosis patients because of the risks associated with any type of transplantation and the fact that outcomes are not clearly better than those achieved with conventional therapy. As with other solid tumors, survival for patients transplanted for NHL correlates with responsiveness to conventional therapy and with bulky disease before transplant. Patients who have non-bulky disease have twice the remission rate and survival than patients who have bulky disease present at the time of transplant. Bulky disease pretransplant may reflect chemoresistance or relapse. The question of whether there is any benefit of "debulking" with conventional therapy before transplant has not been resolved? ° Although there is little data regarding long-term outcomes, it appears that long-term responses to high-dose chemotherapy and BCT are similar to those obtained after marrow infusion, although fewer toxicities, shorter lengths of hospitalization and reduced costs have been reported. 3° HD
The majority of BMTs for HD have been performed using autologous marrow, however transplants for HD may be performed using stem cells. At least 123 relapsed HD patients treated with high-dose therapy and BCT have been reported in the literature. 31 The vast majority of these patients received this therapy because they had an underlying marrow abnormality that precluded a traditional bone marrow harvest. The ability to harvest the necessary quantity of autologous bone marrow may be limited in these patients because of fibrosis, prior pelvic irradiation, or hypocellularity due to extensive chemotherapy. Additionally, the reinfusion of stem cells may nearly half the period of pancytopenia. 3° Kessinger et a134achieved excellent results in 73 HD patients using cyclophosphamide, carrnustine, etoposide (CBV) and BCT. These patients could
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not undergo conventional marrow transplant due to marrow involvement or prior pelvic irradiation. Nearly half of them achieved a complete remission, and actuarial progression-flee survival at 46 months was 33%. Results from the University of Nebraska Medical Center (Omaha) showed that a favorable outcome is possible in patients with histologic evidence of HD in their marrow at the time of stem cell collecfionY Kessinger et a136 reported a 27% actuarial event-free survival in a group of 26 Hodgkin's patients with diseased marrow. This survival rate was comparable to historical results from patients at the University of Nebraska Medical Center (Omaha) with normal marrow who had received autologous BMT. 35 Although the use of BCT does not negate the potential for infusing malignant cells, it is important to note that BCT in patients with histologic evidence of disease in their marrow provides a transplant option in patients that would otherwise not be considered for transplant. Despite the advantages of the graft versus leukemic effect for those receiving allogeneic transplantation, comparative trials have shown no better long-term outcomes than with autologous BMT. The use of BCT is likely to replace the need for allogeneic transplants in patients not otherwise eligible for autologous BMTY Questions regarding the superiority of BCT over autologous BMT remain to be answered via randomized clinical trials. However, early results from several centers do appear promising (see Table 2). LEUKEMIA
Initial interest in BCT for the treatment of AML was based on the premise that there might be less malignant contamination of stem cells than in bone marrow. The additional benefit of rapid hematopoietic reconstitution also was quickly recognized. 4° Most research involved myeloid leukemia but studies have not been extensively performed in advanced acute myeloid leukemia and it is important to note that no prospective randomized studies are currently available.
Juttner 4° reviewed three studies that showed possible advantages with BCT in terms of more rapid granulocyte reconstitution when compared to purged and unpurged conventional BMT. However, Mehta et al41 speculated that unpurged stem cells for acute leukemia may result in higher relapse rates than unpurged BM due to reinfusion of a higher number of malignant cells, simply because of the large cell doses needed for successful BCT. Future research in BCT for leukemia should determine if there is a correlation between cell dose and the risk of relapse. Additionally, preliminary conclusions that can be drawn are that BCT offers no advantage in leukemia-free survival over conventional BMT. Korbling's study 4; of 43 patients showed a disease-free survival of 35% at 2 years in the BCT group (n = 20) and 51% for the 23 patients that received autologous BMT. Szer et al43 showed that a clear advantage for BCT in leukemia may be that this technique allows a greater number of patients of advanced age to be treated. Twenty-five percent of the patients in his study were over the age of 60 and 42% were over the age of 50 years. However, too many critical questions about the overall benefit of BCT in acute leukemia have yet to be answered. Kessinger et a144 did provide a case report of an allogeneic T-cell depleted BCT performed on an 18 year old with ALL in third remission. His brother was reluctant to undergo general anesthesia for BM harvesting and opted to undergo 10 apheresis procedures. A BM biopsy of the patient on day + 27 showed trilineage engraftment. Unfortunately the patient died on day +32 from a systemic aspergillosis infection. On autopsy all cell lineages were present in the bone marrow. Large, prospective, randomized trials are needed to compare chemotherapy regimens, cellular components of BCT versus autologous BMT with careful assessment of mononuclear cell numbers, colony forming units-granulocyte/macrophage counts and CD34+ cell numbers. Additionally, follow-up assessment should include duration of hematopoietic reconstitution, tumor contamination,
Table 2. Results of BCT for HD Investigator
No. Patients
Regimen
Early Deaths
Follow-Up
Lasky et aW Korbling et al 3~ Kessinger et al 3~ Haas et aP9
7 12 56 28
CBV CBV CBV CBV
0 1 (8%) 3 (5%) 4 (14%)
Relapse or progression in 5 patients Continuous complete remission in 7 patients 37% event-free survival at 3 years 55% projected event-free survival
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morbidity and mortality during the transplant period, duration of hospitalization with resultant costs, extent of support required, and endpoints of relapse and long-term disease-free survival. CML
CML cannot be cured with conventional chemotherapy and there is little evidence to support prolongation of life with high doses of chemotherapy in the chronic phase of disease. Interferon (IFN~x-2a) allows approximately 70% of patients to achieve a complete hematologic response and 20% to 40% will achieve a level of cytogenic reversion. 45 The value of autografting and BCT remains speculative. Patients for whom an HLA-matched donor cannot be found, whose performance status is too poor to tolerate general anesthesia and conventional BMT, or who are advanced in age, may derive some benefit from BCT. 46 If allogeneic BMTs improve substantially over the next several years for clinicians to safely transplant older individuals and those lacking HLA-identical siblings, any type of autografting will have little role in the treatment of this disease. However, if graft versus host disease (GVHD) and opportunistic infections remain major complicating factors, any approach to the management of CML that offers the prospect of prolongation of life would be an important option. 45 EPITHELIAL OVARIAN CANCER
Seventy-five percent to 80% of women with ovarian cancer have advanced disease (stage III/IV) at the time of diagnosis. The 5-year survival for all cases combined is less than 40% and ovarian cancer is fifth among causes of cancer death in women. Several randomized clinical trials testing the idea of dose-intensive therapy provide conflicting results. Some trials showed a significant survival advantage with greater toxicity for the high-dose treatment arm, while other trials failed to show a difference in response rate or median survival in stage III/IV patients with suboptimal debulking. 47 For a less chemo-sensitive tumor, such as ovarian cancer, multiple cycles of high-dose chemotherapy with repetitive cytoreduction may be needed to produce a cure. The increasing use of stem cells has made such an approach technically possible. Several studies using BCT with multiple cycles of
chemotherapy in ovarian cancer patients are available in the literature. 7,47 It is uncertain as to whether multiple BCTs will eventually provide a curative option in women for whom long-term disease-free survival is currently not possible. Investigators are also exploring whether highdose chemotherapy with BCT may be more effective if used earlier in the course of ovarian cancer treatment, before the advent of resistant disease, and at a time of minimal tumor burden. As with other solid tumors, prospective randomized trials are needed to determine which treatment approaches are superior to current standard therapy in ovarian cancer. 47 BREAST CANCER
Various stages (II, IIIa, IIIb, and IV) of breast cancer have been treated with BCT, using multiple treatment regimens. 7,48-5° Metastatic breast cancer remains an essentially incurable disease and presents continuing challenges for health care providers. Few studies of women with stage IV breast cancer have reported disease-free survival rates of greater than 3 years. Spitzer et al7 stated that a preliminary analysis of 80 women with estrogen receptor negative or hormone refractory stage IV disease suggests that the patients who experience a positive outcome after BCT have the following characteristics: only one site of disease (minimal disease); a disease-free interval from mastectomy of greater than 12 months; no prior adjuvant therapy; absence of liver involvement; and responsiveness to conventional doses of therapy. Even in this select subset of patients with metastatic breast cancer, at best 30% to 40% will maintain a complete remission beyond 2 years. 48 It is not clear that using high-dose chemotherapy as initial therapy leads to different results compared to high-dose chemotherapy used for consolidation in chemotherapy-sensitive disease. Some investigators also are examining ways of purging tumor cells from the apheresis product in hopes of decreasing the chances of reinfusing breast cancer cells during BCTJ 8 Information regarding high-dose therapy and BCT in women with stage II breast cancer is difficult to interpret in terms of deciding the best approach for best outcome. Many of these women have been treated with high quality radiation therapy and tamoxifen, which serve as confounding
DISEASES TREATED WITH BCT
variables when attempting to determine the true increase in survival produced by high-dose therapy approaches. Whether women treated with highdose therapy thus far will remain in complete remission at 10 or more years after high-dose chemotherapy and are "cured" is unknown. 48 Ongoing randomized trials are of fundamental importance to assist physicians in advising women with stage II breast cancer] ALLOGENEIC STEM CELL INFUSIONS
There is an increasing interest in the value of allogeneic stem cell transplantation. The potential advantages are the same as those seen with autologous BCT, such as the accelerated rate of engraftment and the avoidance of general anesthesia for the donor. 11 Recently, allogeneic peripheral stem cells were used in conjunction with bone marrow in a pilot study of six patients with AML, HD, ALL, and CML. The investigators concluded that transfusion of stem cells to patients undergoing HLA-matched sibling-donor BMT was welltolerated during the early recovery period. Stable, rapid hematopoietic cell recovery also was observed. However, the late development of chronic GVHD in the majority of cases raised concerns about the transfusion of unmanipulated stem cells to allogeneic recipients. These results suggested the need for prolonged follow-up in future clinical trials and perhaps the need for T-cell depletion or CD34+ cell selection of transfused stems cells. 51 Patients with graft failure after allogeneic BMT also have been treated with allogeneic stem cells from the donor. 52,53 From clinical use in two patients, Arseniev et aP 2 concluded that CD34+ cells immunoselected from the stem cells of an HLA-identical sibling donor are appropriate for the treatment of bone marrow graft failure. However, the risk of severe GVHD prompted by such an infusion is still unknown. To determine whether allogeneic T-cell depleted immunoselected CD34 + or unmanipulated stem cells produce full hematopoietic recovery requires clinical trials with larger numbers of patients. FUTURE DIRECTIONS
The ability to harvest and manipulate stem cells has only begun to be used in terms of potential clinical value. This technology cannot only be used in the treatment of malignancies, but also in the
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therapy of other inheritable and acquired disorders. Given the current state-of-the-art it seems likely that: (1) There will be an increasing use of CD34+ selected stem cells that will reduce the toxicity of BCT and tumor cell contamination. (2) Randomized controlled studies will take place to compare autologous BCT versus BMT in selected malignancies. The idea that BCT may reduce relapse by providing antitumor immune cells and rapid immune reconstitution will be tested. (3) Repetitive sequential transplants (double and triple autografts) will become more common. Reduced morbidity in BCT will stimulate earlier application of dose-intensive therapy to high-risk cancer patients. (4) Allogeneic BCTs will become more common as the benefits of infusions with known quantities of CD34 + selected cells, selected T cells, and other cellular components become more obvious. (5) Gene insertion therapy will be used in BCT. This will allow novel strategies for attacking resistant cancers, such as insertion of the multidrug resistance (MDR) gene into stem cells to prevent cytopenias after chemotherapy. 54 (6) Harvested stem cells will serve as the cell population to produce ex vivo expanded hematopoietic progenitor cells, precursor ceils, and stem cell grafts. (7) BCT will be used for in utero transplantation. (8) Use of umbilical cord stem cells for BCT will expand. 55 These and other applications for stem cells will change the way cancer treatments take place in the future.6,13,56 Additionally, stem cells may be a key in correcting genetic defects of the marrow by insertion of a normal gene into the hematopoietic stem cell of the affected person. 57-59 Recent advances in gene cloning have made it possible to contemplate this "somatic gene therapy." Also, the transfer of genes that confer resistance to antineoplastic agents might increase the therapeutic index of chemotherapy by making a patient's marrow more resistant to the effects of anticancer drugs. 8,58,60 The potential for expanded use of BCT in cancer and other diseases appears unlimited. While
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researchers and clinicians are calling for randomized clinical trials to fully test hypotheses regarding the efficacy of BCT, consumers are demanding to receive this therapy sooner in the course of their disease. Because of such a trend, and the unwillingness of some patients to enter clinical trials where they may be randomized to conventional therapy arms of treatment, clinicians may never have corn-
plete scientific information about the efficacy of BCT. Oncology nurses can act as powerful advocates to guide selected patients to appropriate clinical trials. ACKNOWLEDGMENT The author thanks Denyse Pettersson for her secretarial assistance with the preparation of this manuscript.
REFERENCES 1. McCarthy DM, Goodman JM: Transfusion of circulating stem cells. Crit Rev Lab Sci 20:1-24, 1989 2. Crouch MA, Ross JA: Current concepts in autologous bone marrow transplantation. Semin Oncol Nurs 10:12-19, 1994 3. Spitzer G, Adldns DR, Burger SR: Peripheral blood stem cells: Possibilities & limitations, in Levitt D, Mertelsmann R (eds): Hematopoietic Stem Cells: Biology and Therapeutic Applications. New York, NY, Dekker, 1995, pp 391-401 4. Holyoake TL, Franklin LM: Bone marrow transplant from peripheral blood. Br Med J 309:4-5, 1994 5. Gratwohl A, Hermans J, Baldomero H: Indications for haemopoietic precursor cell transplants in Europe. Br J Haematol 92:35-43, 1996 6. Mangan K: Peripheral blood stem cell transplantation: From laboratory to clinical practice. Semin Oncol 22:202-209, 1995 7. Spitzer G, Dunphy FR, Bowers CE, et al: High-dose therapy with stem cell support in solid tumors. Med Oncol 11:53-61, 1994 8. Ghielmini M: Third International Symposium on recent advances in hematopoietic stem cell transplantation. Ann Oncol 6:533-536, 1995 9. Bensinger W, Appelbaum E RowIey S, et al: Factors that influence collection and engraftment of autologous peripheralblood stem cells. J Clin Oncol 13:2547-2555, 1995 10. Gale RP, Henon P, Juttner C: Blood stem cell transplants come of age. Bone Marrow Transplant 9:151-155, 1992 11. Demuynck H, Defforge M, Zachee P, et al: An update on peripheral blood progenitor cell transplantation. Ann HematoI 71:29-33, 1995 12. Sharp JG, Kessinger A: Minimal residual disease and blood stem cell transplants, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 75-86 13. Hoffman R: Human hematopoietic stem cells: Potential use as tumor-free autografts after high-dose myeloablative cancer therapy. Am J Med Sci 309:254-259, 1995 14. Juttner CA, Fibbe WE, Nemunaitis J, et al: Blood cell transplantation: Report from an international consensus meeting. Bone Marrow Transplant 14:689-693, 1994 15. Keating A: Autologous bone marrow transplantation, in Armitage JO, Antman KH (eds): High Dose Chemotherapy. Baltimore, MD, Williams & Wilkins, 1992, pp 162-181 16. King CR: Peripheral stem cell transplantation: Past, present, and future, in Buchsel PC, Whedon MB (eds): Bone Marrow Transplantation. Boston, MA, Jones and Bartlett, 1995, pp 187-211 17. Atkinson K, Dodds A, Milliken S, et al: Autologous blood stem cell transplantation for haematological malignancy:
Treatment-related mortality of 2%. Aust NZ J Med 25:483-489, 1995 18. Crilley P, Goldstein LJ: Peripheral blood stem cell transplantation in breast cancer. Semin Onco122:238-249, 1995 19. Faucher C, le Corroller AG, Blaise D, et al: Comparison of G-CSF-primed peripheral blood progenitor cells and bone marrow auto transplantation: Clinical assessment and costeffectiveness. Bone Marrow Transplant 14:895-901, 1994 20. Henon PR: Autologous blood stem-cell versus bone marrow transplantation: Comparison of cost-effectiveness and of clinical benefits, in Buckner CD, Cliff RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 421-434 21. Uyl-de Groot CA, Richel DJ, Rutten FFH: Peripheral blood progenitor cell transplantation mobilised by r-metHuGCSF (Filgrastim): A less costly alternative to autologous bone marrow transplantation. Eur J Cancer 30A:1631-1635, 1994 22. Alegre A, Lamana M, Arranz R: Busulfan and melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma. Br J Haematol 91:380-386, 1995 23. Topolsky D, Biggs D: Transplantation in multiple myeloma. Semin Onco122:230-237, 1995 24. Marit G, Boiron JM, Pico JL, et al: Autologous blood stem cell transplantation (ABSCT) in high risk myeloma (MM). Bone Marrow Transplant 7:29, 1991 (abstr, suppl 2) 25. Vesole DH, Barlogie B, Jagannath S, et al: High dose therapy for refractory multiple myeloma: Improved prognosis with better supportive care and double transplants. Blood 84:950-956, 1994 26. Barlogie B, Fermand JP, Henon R et al: Blood stem cell transplants in myeloma, in Gale RP, Juttner C, Henon P (eds): Blood Stem Ceil Transplants. New York, NY, Cambridge University, 1994, pp 150-163 27. Dimopoulos MA, Alexanian R, Przepiorka D, et al: Thiotepa, busulfan, and cyclophosphamide: A new preparative regimen for autologons marrow or blood stem cell transplantation in high-risk multiple myeloma. Blood 82:2324-2328, 1993 28. Dimopoulos MA, Hestler J, Huh Y, et al: Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma. Br J Haematol 87:730-734, 1994 29. Gazitt Y, Tian E, Barlogie B, et al: Differential mobilization of myeloma cells and normal hematopoietic stem cells in multiple myeloma after treatment with cyclophosphamide and granulocyte-macrophage colony-stimulating factor. Blood 87:805-811, 1996 30. Cohen SC, Kriegel RL: High-dose therapy with stem cell infusion in lymphoma. Semin Onco122:218-229, 1995 31. Kessinger A, Armitage JO: Blood stem cell transplants in
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lymphomas, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 75-86 32. Vose JM, Anderson JR, Kessinger A, et al: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11:1846-1851, 1993 33. Coiffer B, Phillip T, Burnett AK, et al: Consensus conference on intensive chemotherapy plus hematopoietic stem-cell transplantation in malignancies: Lyon, France, June 4-6, 1993. J Clin Oncol 12:226-231, 1994 34. Kessinger A, Voss JM, Bierman PJ, et al: High dose cyclophosphamide, etoposide and carmustine and peripheral stem cell transplantation for patients with relapsed Hodgkin's disease and bone marrow abnormalities. Int J Cell Cloning 10:135-137, 1992 (suppl 1) 35. Bierman PJ, Armitage JO: Role of autotransplantation in Hodgkin's disease. Hematol Oncol Clin North Am 7:591-611, 1993 36. Kessinger A, Bierman PJ, Voss JM, et al: High dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease. Blood 77:2322, 1991 37. Lasky LC, Hurd DD, Smith JA, et al: Peripheral blood stem cell collection and use in Hodgkin's disease: Comparison with marrow in autologous transplantation. Transfusion 29:323, 1989 38. Korbling M, Holle R, Haas R, et al: Autologous blood stem-cell transplantation in patients with advanced Hodgkin's disease and prior radiation to the pelvic site. J Clin Oncol 8:978, 1990 39. Haas R, Hohaus S, Egerer G, et al: Antologous blood stem cell transplantation in relapsed Hodgkin's Disease. Int J Cell Cloning 10:138, 1992 (snppl 1) 40. Juttner CA: Blood stem cell transplants in acute leukemia, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 102-116 41. Mehta J, Powles R, Singhal S, et al: Peripheral blood stem cell transplantation may result in increased relapse of acute myeloid leukaemia due to reinfusion of a higher number of malignant cells. Bone Marrow Transplant 15:652-653, 1995 42. Korbling M, Fliedner TM, Holle R, et al: Autologous blood stem cell (ABSCT) versus purged bone marrow transplantation (pAUTOLOGOUS BMT) in standard risk AML: Influence of source and cell composition of the autograft on hematopoietic reconstitution and disease-free survival. Bone Marrow Transplant 7:343-349, 1991 43. Szer J, Juttner CA, To LB, et al: Post-remission therapy for acute myeloid leukemia with blood-derived stem cell transplantation: Results of a collaborative Phase II trial. Int J Cell Cloning 10:114-117, 1992 (suppl 1) 44. Kessinger A, Smith DM, Strandjord SE, et al: Allogeneic transplantation of blood-derived, T cell-depleted hemopoietic stem cells after myeloablative treatment in a patient with acute
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lymphoblastic leukemia. Bone Marrow Transplant 4:643-646, 1989 45. Hoyle C, Goldman JM: Blood stem cell transplants in chronic myelogenous leukemia, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 117-127 46. Viele CS: Chronic myelogenous leukemia and acute promyelocytic leukemia: New bone marrow transplantation options. Oncol Nurs Forum 23:488-493, 1996 47. Kotz KW, Schilder RJ: High-dose chemotherapy and hematopoietic progenitor cell support for patients with epithelial ovarian cancer. Semin Onco122:250-262, 1995 48. Myers SE, Williams SF: Role of high-dose chemotherapy and autologous stem cell support in treatment of breast cancer. Hematol Oncol Clin North Am 7:631-645, 1993 49. Spitzer TR, Cirenza E, McAfee S, et al: Phase I-II trial of high-dose cyclophosphamide, carboplatin and autologous bone marrow or peripheral blood stem cell rescue. Bone Marrow Transplant 15:537-542, 1995 50. Weaver CH, Bensinger WI, Applebanm K, et al: Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies. Bone Marrow Transplant 14:813-819, 1994 51. Nemunaitis J, Rosenfeld C, Collins R, et al: Allogeneic transplantation combining mobilized and bone marrow in patients with refractory hematologic malignancies. Transfusion 35:666-673, 1995 52. Arseniev L, Tischler HJ, Battmer K, et al: Treatment of poor marrow graft function with allogeneic CD34+ cells immunoselected from G-CSF-mobilized peripheral blood progenitor ceils of the marrow donor. Bone Marrow Transplant 14:791-797, 1994 53. Gurman G, Kahveci G, Akan H, et al: Allogeneic peripheral blood stem cell transplantation as a second transplant for severe aplastic anemia. Bone Marrow Transplant 15:465486, 1995 54. Giles RE, Hanania EG, Fu S, et al: Genetic therapy using bone marrow transplantation, in Buckner CD, Clift RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 271-280 55. Wagner JE: Umbilical cord blood stem cell transplantation, in Buckner CD, Clift RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 195-213 56. Moolten DN: Peripheral blood stem cell transplant: Future directions. Semin Onco122:271-290, 1995 57. Hong D, Deeg JH: Hemopoietic stem cells: Sources and applications. Med Oncol 11:63-68, 1994 58. Dunbar CE, Emmons RVB: Gene transfer into hematopoietic progenitor and stem cells: Progress and problems. Stem Cells 12:563-576, 1994 59. Thomas ED: History, current results, and research in marrow transplantation. Perspect Biol Med 38:230-237, 1995 60. Storb R, Torok-Storb B: Hematopoietic stem cells: Animal models and human transplantation. Curr Top Microbiol Immunol 177:xi-xiii, 1992
number of centers offering this treatment for hematologic and solid tumors is increasing. Implications f o r nursing practice: Nurses working in acute care, outpatient, and home care settings need to familiarize themselves with the rapidly expanding role of this treatment to provide the most state-of-the-art care to their patients.
N 1986, SUCCESSFUL blood cell transplantation (BCT) for patients with diseases other than chronic myelogenous leukemia (CML) were reported. 1 Peripheral blood (PB) stem cells procured from the mononuclear fraction of PB leukocytes are capable of producing full hemopoietic reconstitution after marrow ablation with high-dose therapy. 2 With advances in the technology supporting blood stem cell harvesting and transplantation there is increasing use of BCT as an alternative to autologous bone marrow transplantation (BMT) after high-dose chemotherapy and/or total body irradiation. Such enthusiasm has been generated regarding the use of stem cells in hematopoietic transplantation that it has called into question whether there will be any long-term future role for autologous BMT. 3 Holyoake and Franklin 4 stated that the use of stem cells "will transform medical oncology within the next few years." Based on published reports, more than 1,000 patients have already received BCT for treatment of acute and chronic leukemias, non-Hodgkin's and Hodgkin's lymphomas, multiple myeloma, and a
variety of solid tumors such as breast and ovarian cancers. 5-7 The diseases presented in Table 1 are those most commonly treated with BCT. The number of centers offering BCT for hematologic and solid tumors is increasing. I PB stem ceils have been most commonly used in patients with marrow contaminated by tumor cells, hypocellular marrow due to previous cancer therapy, or in patients who are viable candidates for high-dose therapy, but who do not have a suitable donor. 2 Additionally, the predominant message from the Third International Symposium on advances in stem cell transplantation was that the traditional concept of very intensive, myloablative radio-chemotherapy to consolidate patients in complete or good partial response is being gradually replaced, s Clinicians are now favoring the concept of early onset, high-dose, multimodal, sequential therapy instead of conventional-dose induction and consolidation before conditioning, s This may, in part, be related to factors found by Bensinger et al 9 that influence collection and engraftment of stem cells. These investigators used linear regression analysis and found that disease status and prior treatment influence the ability to mobilize stem cells. Additionally, the CD34+ cell dose is an important predictor of engraftment kinetics after BCT, regardless of disease or mobilization technique. Other factors such as a diagnosis of breast cancer, disease free marrow, limited chemotherapy exposure, and no prior history of radiation were associated with larger numbers of CD34+ cells. Relapse of disease and lack of engraftment have been the most common causes of treatment failure. Oncologists indicate a need for more randomized trials to determine whether positive outcomes from
I
From Nursing Research & Outcomes Management, Brooke Army Medical Center, Fort Sam Houston, TX. Linda H. Yoder, RN, MBA, PhD, OCN®: Lieutenant Colonel, Army Nurse Corps, Director, Nursing Research & Outcomes Management, Brooke Army Medical Center, Fort Sam Houston, TX. The views of the author are her own and do not purport to reflect the position of the Army Medical Department, Department of the Army, or the Department of Defense. Address reprint requests to Linda H. Yoder, RN, MBA, PhD, OCN®, 13322 E1Mirador, San Antonio, TX. This is a US government work. There are no restrictions on its use. 0749-2081/97/1303-000350.00 164
This is a US government work. There are no restrictions on its use.
Seminars in Oncology Nursing, Vo113, No 3 (August), 1997: pp 164-171
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DISEASES TREATED WITH BCT
Table 1. Diseases Treated With Peripheral Stem Cell Transplantation Hematologic Malignancies
Solid Tumors
ALL Acute nonlymphocytic leukemia Chronic granulocytic leukemia Hodgkin's disease NHL
Breast cancer Small-cell lung cancer Neuroblastoma Ovarian cancer Testicular cancer Melanoma Multiple myeloma Ewing's sarcoma
BCTs are due to more effective treatment, subject selection and if in vitro removal of tumor cells from the stem cell collection is necessary or effective. 1°,11 In the past, many investigators thought that stem cells were relatively free of tumor cell contamination and used this assumption as the rationale for BCTs over conventional BMTs. Currently, there are insufficient data to evaluate the significance of minimal residual disease in BCT for solid tumors. 12 Recently, investigators showed that stem cells from patients with neuroblastoma, breast cancer, nonHodgkin's lymphoma (NHL), acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), multiple myeloma, and CML are contaminated with tumor cells. Mobilization of stem cells may, in fact, be associated with concomitant tumor cell mobilization.lZ, 13 Dose-intensification followed by BCT has not been conclusively shown to improve cure rates, but promising clinical data have emerged from nonrandomized studies of patients with poor-prognosis lymphoma, metastatic breast cancer, stage II/III breast cancer, and poor risk germ cell tumors. 14 Clinical trials are ongoing to determine the efficacy of BCT in AML, ALL, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, and germ cell tumors. These studies focus on measuring and determining the best timing for BCT, tumor chemosensitivity, and tumor bulk as it relates to disease response? 5 Other purposes of ongoing studies address the use of BCT in conjunction with autologous BMT, the efficacy of tandem or double transplants in breast cancer, and the comparison of BCT versus BMT in relation to disease response, a Although current studies rarely report survival rates for BCT, long-term follow-up is needed to determine if cures have resulted from BCT. However, treatment-related toxicity and mortality is decreased, 2,14,16,17 while quality of life may be increased surrounding the immediate transplant
period. 18 Because BCT is associated with less morbidity and more rapid recovery of hematopoietic function than conventional BMT, 14 patients have shorter lengths of stay and costs may be reduced.19-e1 Although there is a large body of literature concerning the use of BCT, it is difficult to draw conclusions from the data because of the lack of prospective randomized trials in most of the cancers in which BCT has been used. Clearly as more data is forthcoming, more questions arise from clinicians. The purpose of this article is to provide a broad overview of the vast amount of clinical and research data concerning the use of BCT. It is beyond the scope of this article to discuss the intricacies of the various studies cited. However, the reference list provides an extensive array of literature the clinician can use to gain more specific information about a particular topic presented. MULTIPLE MYELOMA
Achieving a complete response in the bone marrow (BM) of patients with multiple myeloma using conventional-dose chemotherapy is difficult. Median survival generally ranges from 2 to 3 years. 22 This problem led to investigators examining high-dose therapy with hematopoietic support as a treatment optionY Dose-intensity studies of people with multiple myeloma showed that drug resistance in myeloma cells can be overcome and patients with poor prognosis can achieve remission. However, patients treated with high-dose therapy early in the course of their disease (less than 1 year of prior chemotherapy) may achieve prolonged disease-free remissions, although survival rates are unavailable for many of these patients at this time.24, 25
The use of stem cells as hematologic support in multiple myeloma clearly reduces treatmentrelated toxicity, although treatment regimens vary and can include both chemotherapy and radiation therapy. 2a,26-28Any antitumor effect depends on the conditioning regimen used, the stage of myeloma at presentation, presence of resistance to prior standard therapy, and possibly the source of hematopoieric stem cells and the use of growth factors for stem cell mobilization. 26 Many questions remain regarding myeloma tumor cell contamination in the blood stem cell collection and the relationship of these cells to
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relapse. The use of various immunologic or pharmacologic purging methods has not been sufficiently investigated, but reports of studies using various methods are beginning to appear in the literature. 29 More research involving innovative approaches for BCT with multiple myeloma are needed to determine the ultimate value of this treatment. 23 LYMPHOMAS
Patients recently diagnosed with intermediate or high-grade NHL or Hodgkin's disease (HD) have a 40% to 70% cure rate when treated with conventional chemotherapy or radiotherapy. Patients who do not achieve a complete remission or who relapse are, for the most part, incurable with conventional salvage therapies. None of the conventional regimens in use show superiority when compared to each other. However, the patients may have the potential for cure with high-dose therapy followed by BeT. 3° Kessinger and Armitage 31 stated that more than 200 lymphoma patients treated with BCT have been reported and while follow-up is still too brief to ascertain the curative potential of this treatment, clearly long-term survival has resulted for a number of patients. Findings from a retrospective study of intermediate NHL patients with bone marrow involvement showed a significantly better outcome after BCT compared with those who received autologous BMT. 32 As with other metastatic solid tumors, stem cell collections may harbor occult lymphoma cells, although fewer than in marrow collections. 3° In regard to both NHL and HD, researchers have nonetheless pointed out that many questions concerning BCT remain unresolved, including definitive proof that BCT improves overall survival. Clinicians and researchers at a recent Consensus Conference on the use of marrow transplantation were unwilling to characterize BCT as the standard of care for relapsed lymphomas in the absence of randomized data showing an overall survival advantage. Optimal high-dose regimens, quality of the stem cell product, the role of total body irradiation, and ex vivo purging clearly require further study. 33 NHL
Most of the patients reported to date had relapsed or had refractory disease at the time of BCT, where
the risks associated with the procedure were justified in light of the potential for cure. However, some patients with poor risk disease received high-dose therapy as consolidation after achieving a complete remission with conventional therapy? 1 A primary issue concerning the use of BCT in NHL is the timing of the transplant. Cohen and KriegeP ° stated that perhaps high-dose therapy with BCT should be used earlier in newly diagnosed NHL patients. BCT has not been used extensively with poor prognosis patients because of the risks associated with any type of transplantation and the fact that outcomes are not clearly better than those achieved with conventional therapy. As with other solid tumors, survival for patients transplanted for NHL correlates with responsiveness to conventional therapy and with bulky disease before transplant. Patients who have non-bulky disease have twice the remission rate and survival than patients who have bulky disease present at the time of transplant. Bulky disease pretransplant may reflect chemoresistance or relapse. The question of whether there is any benefit of "debulking" with conventional therapy before transplant has not been resolved? ° Although there is little data regarding long-term outcomes, it appears that long-term responses to high-dose chemotherapy and BCT are similar to those obtained after marrow infusion, although fewer toxicities, shorter lengths of hospitalization and reduced costs have been reported. 3° HD
The majority of BMTs for HD have been performed using autologous marrow, however transplants for HD may be performed using stem cells. At least 123 relapsed HD patients treated with high-dose therapy and BCT have been reported in the literature. 31 The vast majority of these patients received this therapy because they had an underlying marrow abnormality that precluded a traditional bone marrow harvest. The ability to harvest the necessary quantity of autologous bone marrow may be limited in these patients because of fibrosis, prior pelvic irradiation, or hypocellularity due to extensive chemotherapy. Additionally, the reinfusion of stem cells may nearly half the period of pancytopenia. 3° Kessinger et a134achieved excellent results in 73 HD patients using cyclophosphamide, carrnustine, etoposide (CBV) and BCT. These patients could
DISEASES TREATED WITH BCT
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not undergo conventional marrow transplant due to marrow involvement or prior pelvic irradiation. Nearly half of them achieved a complete remission, and actuarial progression-flee survival at 46 months was 33%. Results from the University of Nebraska Medical Center (Omaha) showed that a favorable outcome is possible in patients with histologic evidence of HD in their marrow at the time of stem cell collecfionY Kessinger et a136 reported a 27% actuarial event-free survival in a group of 26 Hodgkin's patients with diseased marrow. This survival rate was comparable to historical results from patients at the University of Nebraska Medical Center (Omaha) with normal marrow who had received autologous BMT. 35 Although the use of BCT does not negate the potential for infusing malignant cells, it is important to note that BCT in patients with histologic evidence of disease in their marrow provides a transplant option in patients that would otherwise not be considered for transplant. Despite the advantages of the graft versus leukemic effect for those receiving allogeneic transplantation, comparative trials have shown no better long-term outcomes than with autologous BMT. The use of BCT is likely to replace the need for allogeneic transplants in patients not otherwise eligible for autologous BMTY Questions regarding the superiority of BCT over autologous BMT remain to be answered via randomized clinical trials. However, early results from several centers do appear promising (see Table 2). LEUKEMIA
Initial interest in BCT for the treatment of AML was based on the premise that there might be less malignant contamination of stem cells than in bone marrow. The additional benefit of rapid hematopoietic reconstitution also was quickly recognized. 4° Most research involved myeloid leukemia but studies have not been extensively performed in advanced acute myeloid leukemia and it is important to note that no prospective randomized studies are currently available.
Juttner 4° reviewed three studies that showed possible advantages with BCT in terms of more rapid granulocyte reconstitution when compared to purged and unpurged conventional BMT. However, Mehta et al41 speculated that unpurged stem cells for acute leukemia may result in higher relapse rates than unpurged BM due to reinfusion of a higher number of malignant cells, simply because of the large cell doses needed for successful BCT. Future research in BCT for leukemia should determine if there is a correlation between cell dose and the risk of relapse. Additionally, preliminary conclusions that can be drawn are that BCT offers no advantage in leukemia-free survival over conventional BMT. Korbling's study 4; of 43 patients showed a disease-free survival of 35% at 2 years in the BCT group (n = 20) and 51% for the 23 patients that received autologous BMT. Szer et al43 showed that a clear advantage for BCT in leukemia may be that this technique allows a greater number of patients of advanced age to be treated. Twenty-five percent of the patients in his study were over the age of 60 and 42% were over the age of 50 years. However, too many critical questions about the overall benefit of BCT in acute leukemia have yet to be answered. Kessinger et a144 did provide a case report of an allogeneic T-cell depleted BCT performed on an 18 year old with ALL in third remission. His brother was reluctant to undergo general anesthesia for BM harvesting and opted to undergo 10 apheresis procedures. A BM biopsy of the patient on day + 27 showed trilineage engraftment. Unfortunately the patient died on day +32 from a systemic aspergillosis infection. On autopsy all cell lineages were present in the bone marrow. Large, prospective, randomized trials are needed to compare chemotherapy regimens, cellular components of BCT versus autologous BMT with careful assessment of mononuclear cell numbers, colony forming units-granulocyte/macrophage counts and CD34+ cell numbers. Additionally, follow-up assessment should include duration of hematopoietic reconstitution, tumor contamination,
Table 2. Results of BCT for HD Investigator
No. Patients
Regimen
Early Deaths
Follow-Up
Lasky et aW Korbling et al 3~ Kessinger et al 3~ Haas et aP9
7 12 56 28
CBV CBV CBV CBV
0 1 (8%) 3 (5%) 4 (14%)
Relapse or progression in 5 patients Continuous complete remission in 7 patients 37% event-free survival at 3 years 55% projected event-free survival
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morbidity and mortality during the transplant period, duration of hospitalization with resultant costs, extent of support required, and endpoints of relapse and long-term disease-free survival. CML
CML cannot be cured with conventional chemotherapy and there is little evidence to support prolongation of life with high doses of chemotherapy in the chronic phase of disease. Interferon (IFN~x-2a) allows approximately 70% of patients to achieve a complete hematologic response and 20% to 40% will achieve a level of cytogenic reversion. 45 The value of autografting and BCT remains speculative. Patients for whom an HLA-matched donor cannot be found, whose performance status is too poor to tolerate general anesthesia and conventional BMT, or who are advanced in age, may derive some benefit from BCT. 46 If allogeneic BMTs improve substantially over the next several years for clinicians to safely transplant older individuals and those lacking HLA-identical siblings, any type of autografting will have little role in the treatment of this disease. However, if graft versus host disease (GVHD) and opportunistic infections remain major complicating factors, any approach to the management of CML that offers the prospect of prolongation of life would be an important option. 45 EPITHELIAL OVARIAN CANCER
Seventy-five percent to 80% of women with ovarian cancer have advanced disease (stage III/IV) at the time of diagnosis. The 5-year survival for all cases combined is less than 40% and ovarian cancer is fifth among causes of cancer death in women. Several randomized clinical trials testing the idea of dose-intensive therapy provide conflicting results. Some trials showed a significant survival advantage with greater toxicity for the high-dose treatment arm, while other trials failed to show a difference in response rate or median survival in stage III/IV patients with suboptimal debulking. 47 For a less chemo-sensitive tumor, such as ovarian cancer, multiple cycles of high-dose chemotherapy with repetitive cytoreduction may be needed to produce a cure. The increasing use of stem cells has made such an approach technically possible. Several studies using BCT with multiple cycles of
chemotherapy in ovarian cancer patients are available in the literature. 7,47 It is uncertain as to whether multiple BCTs will eventually provide a curative option in women for whom long-term disease-free survival is currently not possible. Investigators are also exploring whether highdose chemotherapy with BCT may be more effective if used earlier in the course of ovarian cancer treatment, before the advent of resistant disease, and at a time of minimal tumor burden. As with other solid tumors, prospective randomized trials are needed to determine which treatment approaches are superior to current standard therapy in ovarian cancer. 47 BREAST CANCER
Various stages (II, IIIa, IIIb, and IV) of breast cancer have been treated with BCT, using multiple treatment regimens. 7,48-5° Metastatic breast cancer remains an essentially incurable disease and presents continuing challenges for health care providers. Few studies of women with stage IV breast cancer have reported disease-free survival rates of greater than 3 years. Spitzer et al7 stated that a preliminary analysis of 80 women with estrogen receptor negative or hormone refractory stage IV disease suggests that the patients who experience a positive outcome after BCT have the following characteristics: only one site of disease (minimal disease); a disease-free interval from mastectomy of greater than 12 months; no prior adjuvant therapy; absence of liver involvement; and responsiveness to conventional doses of therapy. Even in this select subset of patients with metastatic breast cancer, at best 30% to 40% will maintain a complete remission beyond 2 years. 48 It is not clear that using high-dose chemotherapy as initial therapy leads to different results compared to high-dose chemotherapy used for consolidation in chemotherapy-sensitive disease. Some investigators also are examining ways of purging tumor cells from the apheresis product in hopes of decreasing the chances of reinfusing breast cancer cells during BCTJ 8 Information regarding high-dose therapy and BCT in women with stage II breast cancer is difficult to interpret in terms of deciding the best approach for best outcome. Many of these women have been treated with high quality radiation therapy and tamoxifen, which serve as confounding
DISEASES TREATED WITH BCT
variables when attempting to determine the true increase in survival produced by high-dose therapy approaches. Whether women treated with highdose therapy thus far will remain in complete remission at 10 or more years after high-dose chemotherapy and are "cured" is unknown. 48 Ongoing randomized trials are of fundamental importance to assist physicians in advising women with stage II breast cancer] ALLOGENEIC STEM CELL INFUSIONS
There is an increasing interest in the value of allogeneic stem cell transplantation. The potential advantages are the same as those seen with autologous BCT, such as the accelerated rate of engraftment and the avoidance of general anesthesia for the donor. 11 Recently, allogeneic peripheral stem cells were used in conjunction with bone marrow in a pilot study of six patients with AML, HD, ALL, and CML. The investigators concluded that transfusion of stem cells to patients undergoing HLA-matched sibling-donor BMT was welltolerated during the early recovery period. Stable, rapid hematopoietic cell recovery also was observed. However, the late development of chronic GVHD in the majority of cases raised concerns about the transfusion of unmanipulated stem cells to allogeneic recipients. These results suggested the need for prolonged follow-up in future clinical trials and perhaps the need for T-cell depletion or CD34+ cell selection of transfused stems cells. 51 Patients with graft failure after allogeneic BMT also have been treated with allogeneic stem cells from the donor. 52,53 From clinical use in two patients, Arseniev et aP 2 concluded that CD34+ cells immunoselected from the stem cells of an HLA-identical sibling donor are appropriate for the treatment of bone marrow graft failure. However, the risk of severe GVHD prompted by such an infusion is still unknown. To determine whether allogeneic T-cell depleted immunoselected CD34 + or unmanipulated stem cells produce full hematopoietic recovery requires clinical trials with larger numbers of patients. FUTURE DIRECTIONS
The ability to harvest and manipulate stem cells has only begun to be used in terms of potential clinical value. This technology cannot only be used in the treatment of malignancies, but also in the
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therapy of other inheritable and acquired disorders. Given the current state-of-the-art it seems likely that: (1) There will be an increasing use of CD34+ selected stem cells that will reduce the toxicity of BCT and tumor cell contamination. (2) Randomized controlled studies will take place to compare autologous BCT versus BMT in selected malignancies. The idea that BCT may reduce relapse by providing antitumor immune cells and rapid immune reconstitution will be tested. (3) Repetitive sequential transplants (double and triple autografts) will become more common. Reduced morbidity in BCT will stimulate earlier application of dose-intensive therapy to high-risk cancer patients. (4) Allogeneic BCTs will become more common as the benefits of infusions with known quantities of CD34 + selected cells, selected T cells, and other cellular components become more obvious. (5) Gene insertion therapy will be used in BCT. This will allow novel strategies for attacking resistant cancers, such as insertion of the multidrug resistance (MDR) gene into stem cells to prevent cytopenias after chemotherapy. 54 (6) Harvested stem cells will serve as the cell population to produce ex vivo expanded hematopoietic progenitor cells, precursor ceils, and stem cell grafts. (7) BCT will be used for in utero transplantation. (8) Use of umbilical cord stem cells for BCT will expand. 55 These and other applications for stem cells will change the way cancer treatments take place in the future.6,13,56 Additionally, stem cells may be a key in correcting genetic defects of the marrow by insertion of a normal gene into the hematopoietic stem cell of the affected person. 57-59 Recent advances in gene cloning have made it possible to contemplate this "somatic gene therapy." Also, the transfer of genes that confer resistance to antineoplastic agents might increase the therapeutic index of chemotherapy by making a patient's marrow more resistant to the effects of anticancer drugs. 8,58,60 The potential for expanded use of BCT in cancer and other diseases appears unlimited. While
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researchers and clinicians are calling for randomized clinical trials to fully test hypotheses regarding the efficacy of BCT, consumers are demanding to receive this therapy sooner in the course of their disease. Because of such a trend, and the unwillingness of some patients to enter clinical trials where they may be randomized to conventional therapy arms of treatment, clinicians may never have corn-
plete scientific information about the efficacy of BCT. Oncology nurses can act as powerful advocates to guide selected patients to appropriate clinical trials. ACKNOWLEDGMENT The author thanks Denyse Pettersson for her secretarial assistance with the preparation of this manuscript.
REFERENCES 1. McCarthy DM, Goodman JM: Transfusion of circulating stem cells. Crit Rev Lab Sci 20:1-24, 1989 2. Crouch MA, Ross JA: Current concepts in autologous bone marrow transplantation. Semin Oncol Nurs 10:12-19, 1994 3. Spitzer G, Adldns DR, Burger SR: Peripheral blood stem cells: Possibilities & limitations, in Levitt D, Mertelsmann R (eds): Hematopoietic Stem Cells: Biology and Therapeutic Applications. New York, NY, Dekker, 1995, pp 391-401 4. Holyoake TL, Franklin LM: Bone marrow transplant from peripheral blood. Br Med J 309:4-5, 1994 5. Gratwohl A, Hermans J, Baldomero H: Indications for haemopoietic precursor cell transplants in Europe. Br J Haematol 92:35-43, 1996 6. Mangan K: Peripheral blood stem cell transplantation: From laboratory to clinical practice. Semin Oncol 22:202-209, 1995 7. Spitzer G, Dunphy FR, Bowers CE, et al: High-dose therapy with stem cell support in solid tumors. Med Oncol 11:53-61, 1994 8. Ghielmini M: Third International Symposium on recent advances in hematopoietic stem cell transplantation. Ann Oncol 6:533-536, 1995 9. Bensinger W, Appelbaum E RowIey S, et al: Factors that influence collection and engraftment of autologous peripheralblood stem cells. J Clin Oncol 13:2547-2555, 1995 10. Gale RP, Henon P, Juttner C: Blood stem cell transplants come of age. Bone Marrow Transplant 9:151-155, 1992 11. Demuynck H, Defforge M, Zachee P, et al: An update on peripheral blood progenitor cell transplantation. Ann HematoI 71:29-33, 1995 12. Sharp JG, Kessinger A: Minimal residual disease and blood stem cell transplants, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 75-86 13. Hoffman R: Human hematopoietic stem cells: Potential use as tumor-free autografts after high-dose myeloablative cancer therapy. Am J Med Sci 309:254-259, 1995 14. Juttner CA, Fibbe WE, Nemunaitis J, et al: Blood cell transplantation: Report from an international consensus meeting. Bone Marrow Transplant 14:689-693, 1994 15. Keating A: Autologous bone marrow transplantation, in Armitage JO, Antman KH (eds): High Dose Chemotherapy. Baltimore, MD, Williams & Wilkins, 1992, pp 162-181 16. King CR: Peripheral stem cell transplantation: Past, present, and future, in Buchsel PC, Whedon MB (eds): Bone Marrow Transplantation. Boston, MA, Jones and Bartlett, 1995, pp 187-211 17. Atkinson K, Dodds A, Milliken S, et al: Autologous blood stem cell transplantation for haematological malignancy:
Treatment-related mortality of 2%. Aust NZ J Med 25:483-489, 1995 18. Crilley P, Goldstein LJ: Peripheral blood stem cell transplantation in breast cancer. Semin Onco122:238-249, 1995 19. Faucher C, le Corroller AG, Blaise D, et al: Comparison of G-CSF-primed peripheral blood progenitor cells and bone marrow auto transplantation: Clinical assessment and costeffectiveness. Bone Marrow Transplant 14:895-901, 1994 20. Henon PR: Autologous blood stem-cell versus bone marrow transplantation: Comparison of cost-effectiveness and of clinical benefits, in Buckner CD, Cliff RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 421-434 21. Uyl-de Groot CA, Richel DJ, Rutten FFH: Peripheral blood progenitor cell transplantation mobilised by r-metHuGCSF (Filgrastim): A less costly alternative to autologous bone marrow transplantation. Eur J Cancer 30A:1631-1635, 1994 22. Alegre A, Lamana M, Arranz R: Busulfan and melphalan as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma. Br J Haematol 91:380-386, 1995 23. Topolsky D, Biggs D: Transplantation in multiple myeloma. Semin Onco122:230-237, 1995 24. Marit G, Boiron JM, Pico JL, et al: Autologous blood stem cell transplantation (ABSCT) in high risk myeloma (MM). Bone Marrow Transplant 7:29, 1991 (abstr, suppl 2) 25. Vesole DH, Barlogie B, Jagannath S, et al: High dose therapy for refractory multiple myeloma: Improved prognosis with better supportive care and double transplants. Blood 84:950-956, 1994 26. Barlogie B, Fermand JP, Henon R et al: Blood stem cell transplants in myeloma, in Gale RP, Juttner C, Henon P (eds): Blood Stem Ceil Transplants. New York, NY, Cambridge University, 1994, pp 150-163 27. Dimopoulos MA, Alexanian R, Przepiorka D, et al: Thiotepa, busulfan, and cyclophosphamide: A new preparative regimen for autologons marrow or blood stem cell transplantation in high-risk multiple myeloma. Blood 82:2324-2328, 1993 28. Dimopoulos MA, Hestler J, Huh Y, et al: Intensive chemotherapy with blood progenitor transplantation for primary resistant multiple myeloma. Br J Haematol 87:730-734, 1994 29. Gazitt Y, Tian E, Barlogie B, et al: Differential mobilization of myeloma cells and normal hematopoietic stem cells in multiple myeloma after treatment with cyclophosphamide and granulocyte-macrophage colony-stimulating factor. Blood 87:805-811, 1996 30. Cohen SC, Kriegel RL: High-dose therapy with stem cell infusion in lymphoma. Semin Onco122:218-229, 1995 31. Kessinger A, Armitage JO: Blood stem cell transplants in
DISEASES TREATED WITH BCT
lymphomas, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 75-86 32. Vose JM, Anderson JR, Kessinger A, et al: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11:1846-1851, 1993 33. Coiffer B, Phillip T, Burnett AK, et al: Consensus conference on intensive chemotherapy plus hematopoietic stem-cell transplantation in malignancies: Lyon, France, June 4-6, 1993. J Clin Oncol 12:226-231, 1994 34. Kessinger A, Voss JM, Bierman PJ, et al: High dose cyclophosphamide, etoposide and carmustine and peripheral stem cell transplantation for patients with relapsed Hodgkin's disease and bone marrow abnormalities. Int J Cell Cloning 10:135-137, 1992 (suppl 1) 35. Bierman PJ, Armitage JO: Role of autotransplantation in Hodgkin's disease. Hematol Oncol Clin North Am 7:591-611, 1993 36. Kessinger A, Bierman PJ, Voss JM, et al: High dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease. Blood 77:2322, 1991 37. Lasky LC, Hurd DD, Smith JA, et al: Peripheral blood stem cell collection and use in Hodgkin's disease: Comparison with marrow in autologous transplantation. Transfusion 29:323, 1989 38. Korbling M, Holle R, Haas R, et al: Autologous blood stem-cell transplantation in patients with advanced Hodgkin's disease and prior radiation to the pelvic site. J Clin Oncol 8:978, 1990 39. Haas R, Hohaus S, Egerer G, et al: Antologous blood stem cell transplantation in relapsed Hodgkin's Disease. Int J Cell Cloning 10:138, 1992 (snppl 1) 40. Juttner CA: Blood stem cell transplants in acute leukemia, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 102-116 41. Mehta J, Powles R, Singhal S, et al: Peripheral blood stem cell transplantation may result in increased relapse of acute myeloid leukaemia due to reinfusion of a higher number of malignant cells. Bone Marrow Transplant 15:652-653, 1995 42. Korbling M, Fliedner TM, Holle R, et al: Autologous blood stem cell (ABSCT) versus purged bone marrow transplantation (pAUTOLOGOUS BMT) in standard risk AML: Influence of source and cell composition of the autograft on hematopoietic reconstitution and disease-free survival. Bone Marrow Transplant 7:343-349, 1991 43. Szer J, Juttner CA, To LB, et al: Post-remission therapy for acute myeloid leukemia with blood-derived stem cell transplantation: Results of a collaborative Phase II trial. Int J Cell Cloning 10:114-117, 1992 (suppl 1) 44. Kessinger A, Smith DM, Strandjord SE, et al: Allogeneic transplantation of blood-derived, T cell-depleted hemopoietic stem cells after myeloablative treatment in a patient with acute
171
lymphoblastic leukemia. Bone Marrow Transplant 4:643-646, 1989 45. Hoyle C, Goldman JM: Blood stem cell transplants in chronic myelogenous leukemia, in Gale RP, Juttner C, Henon P (eds): Blood Stem Cell Transplants. New York, NY, Cambridge University, 1994, pp 117-127 46. Viele CS: Chronic myelogenous leukemia and acute promyelocytic leukemia: New bone marrow transplantation options. Oncol Nurs Forum 23:488-493, 1996 47. Kotz KW, Schilder RJ: High-dose chemotherapy and hematopoietic progenitor cell support for patients with epithelial ovarian cancer. Semin Onco122:250-262, 1995 48. Myers SE, Williams SF: Role of high-dose chemotherapy and autologous stem cell support in treatment of breast cancer. Hematol Oncol Clin North Am 7:631-645, 1993 49. Spitzer TR, Cirenza E, McAfee S, et al: Phase I-II trial of high-dose cyclophosphamide, carboplatin and autologous bone marrow or peripheral blood stem cell rescue. Bone Marrow Transplant 15:537-542, 1995 50. Weaver CH, Bensinger WI, Applebanm K, et al: Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies. Bone Marrow Transplant 14:813-819, 1994 51. Nemunaitis J, Rosenfeld C, Collins R, et al: Allogeneic transplantation combining mobilized and bone marrow in patients with refractory hematologic malignancies. Transfusion 35:666-673, 1995 52. Arseniev L, Tischler HJ, Battmer K, et al: Treatment of poor marrow graft function with allogeneic CD34+ cells immunoselected from G-CSF-mobilized peripheral blood progenitor ceils of the marrow donor. Bone Marrow Transplant 14:791-797, 1994 53. Gurman G, Kahveci G, Akan H, et al: Allogeneic peripheral blood stem cell transplantation as a second transplant for severe aplastic anemia. Bone Marrow Transplant 15:465486, 1995 54. Giles RE, Hanania EG, Fu S, et al: Genetic therapy using bone marrow transplantation, in Buckner CD, Clift RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 271-280 55. Wagner JE: Umbilical cord blood stem cell transplantation, in Buckner CD, Clift RA (eds): Technical and Biological Components of Marrow Transplantation. Norwell, MA, Kluwar Academic, 1995, pp 195-213 56. Moolten DN: Peripheral blood stem cell transplant: Future directions. Semin Onco122:271-290, 1995 57. Hong D, Deeg JH: Hemopoietic stem cells: Sources and applications. Med Oncol 11:63-68, 1994 58. Dunbar CE, Emmons RVB: Gene transfer into hematopoietic progenitor and stem cells: Progress and problems. Stem Cells 12:563-576, 1994 59. Thomas ED: History, current results, and research in marrow transplantation. Perspect Biol Med 38:230-237, 1995 60. Storb R, Torok-Storb B: Hematopoietic stem cells: Animal models and human transplantation. Curr Top Microbiol Immunol 177:xi-xiii, 1992