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Allogeneic bone marrow transplantation
Allogeneic Bone Marrow Transplantation Theresa Franco and D. Allen Gould
VER THE past 15 years, allogeneic bone marrow transplantation has evolved from an experimental therapy to a standard treatment for several diseases. The number of allogeneic bone marrow transplants (BMTs) performed has increased dramatically. In 1979, less than 400 allogeneic BMTs were performed worldwide. By 1990, the number was more than 14,000.1 Continued use of transplantation can be attributed to many factors. The expanding knowledge of the HLA system, biologic enhancements, refined nursing care practices, and significant developments in patient support systems have improved transplant care. Changes in broad spectrum antibiotics, total parenteral nutrition, and transfusion therapy have augmented both the management and safety associated with allogeneic transplantation. 2 More effective preparative regimens and improved strategies for treating graft-versus-host disease (GVHD), cytomegalovirus (CMV) infection, and disease relapse have also spurred transplant growth. To meet the demand for services, new allogeneic programs are increasing by 25 per year with an average annual increase of 615 patients. 1 Allogeneic bone marrow grafting has become an attractive therapy for several disease states, many of which have limited treatment options.
O
DISEASES TREATED WITH ALLOGENEIC BMT
A variety of disease states can be treated with allogeneic transplantation. Most commonly, allogeneic BMT has been used in the treatment of malignant entities, particularly the leukemias. However, some nonmalignant states also have been treated successfully with transplantation (Table 1).
individuals in their first complete remission, it is not clear whether BMT is the preferred treatment because standard chemotherapeutic regimens offer excellent survival rates. 4's However, 60% survival rates have been achieved with aUogeneic marrow grafting in first remission. 6'7 In circumstances where patients present with a high leukocyte count at diagnosis and in those with certain chromosomal abnormalities, a transplant in first remission is clearly beneficial. 8"9 Persons in second or subsequent complete remission or transplants performed at the time of relapse have a significant survival advantage (20%) over chemotherapy. The patient's age and stage of the disease influence the outcome. In general, earlier treatment and a younger age are advantageous to long-term survival. 3"~GA~ Many children with ALL are cured with chemotherapeutic induction and maintenance therapy and thus are not candidates for BMT. However, children who relapse while receiving chemotherapy or within 18 months of starting therapy are obtaining longer remissions and are potentially cured with marrow transplantation. 12 Allogeneic BMT may offer a cure to individuals with specific subtypes, such as Philadelphia chromosome-positive and B-cell immunophenotype, where there is an increased risk of relapse. 9a3 AML. Controversy surrounds the use of allogeneic BMT in AML patients in first remission. Many believe that intensive chemotherapy offers an equal, if not greater, potential for cure than transplantation. However, several randomized studies have shown improved results with BMT.14-~6 IBMTR reports that leukemia-free survival rates with chemotherapy range from 20% to 50% in contrast to rates of 35% to 60% with a
Malignant States According to reports from the International Bone Marrow Transplant Registry (IBMTR), 83% of all allogeneic BMTs in recent years were for malignancies. 1 Acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML) are the disorders most commonly treated.3 ALL. Allogeneic BMT has been used to treat remission and relapse states in ALL. For those Seminars in Oncology Nursing, Vol 10, No 1 (Februaryl, 1994: pp 3-11
From the Oncology-Hematology Special Care Unit, University of Nebraska Medical Center, Omaha, NE. Theresa Franr RN, MSN: Patient Care Manager, Oncology; D. Alien Gould, RN, MSN: Clinical Nurse Specialist, Oncology-Hematology Special Care Unit, University of Nebraska Medical Center. Address reprint requests to Theresa Franco, RN, MSN, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-2405. Copyright 9 1994 by W.B. Saunders Company 0749-2081/94/1001-000255.00/0
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FRANCO AND GOULD Table 1. Diseases Treated With AIIogeneic BMT and Survival Rates
Disease Malignant states ALL
AML
CML
Nonmalignant states Aplastic anemia SCIDS Thalassemia
Stage
First remission Second/subsequent remission Relapse First remission Second/subsequent remission Relapse Chronic phase Accelerated phase Blast phase Nontransfused Transfused
Disease-Free Long-term Survival (%)
60 20 20 45-60 20-30 20-30 35-45 25-35 6-18 70-80 45-50 50-60 70
Abbreviation: SCIDS, severe combined immunodeficiency syndrome.
transplant. 8 Younger patients are at an advant a g e - t h o s e under the age of 40 in first complete remission experience a 45% to 60% survival rate. 17 For those in second or subsequent remission or relapse, allogeneic BMT offers the best opportunity for disease-free survival with rates as high as 20% to 30%. 2 CML. Transplantation for CML has become the preferred treatment for those patients under 55 with an HLA identical donor because this provides the only hope for a cure. 18 The timing of the transplant is critical. IBMTR reports that in the chronic phase, the probability for leukemia-free survival was highest at 40% +- 4%, next in the accelerated phase at 31% --- 6%, and lowest in the blast phase at 12% --+ 6%. 3 Younger age and absence of GVHD were cited as the two variables that affected superior outcomes in those transplanted in the chronic phase. Because the results of transplantation are poor once blast transformation has occurred, efforts to identify suitable candidates, especially younger individuals who have an HLA identical match, should begin early.
Nonmalignant States Seventeen percent of the total number of aUogeneic BMTs performed in 1988 to 1990 were done for nonmalignant diseases. 1 This is an increase from previous years and signifies a continu-
ing effort to explore the use of BMT in a variety of different disease states. Immunodeficiency states. The goal of transplanting marrow in immunodeficiency states is to replace deficient or defective cell populations with normal cells. In infants with severe combined immunodeficiency syndrome, there has been a 50% to 60% chance of long-term survival with the restoration of immune function by normal donor cells. ~3 Knowledge of immune cell development in bone marrow has also led to the use of allogeneic BMT in Wiskott-Aldrich syndrome. Here, transplantation is the treatment of choice in patients who have an HLA identical donor. 19'2~ Osteopetrosis also can be treated with BMT, offering the only chance for a cure in this fatal disorder. 21 Hematopoietic states. Hematopoietic diseases, such as aplastic anemia, have been successfully treated with allogeneic BMT. A disease-free survival rate of 70% to 80% has been reported with complete reconstitution of normal hematopoiesis in individuals who have not been previously transfused with blood products. 22 In transfused individuals who have been sensitized, the rate of survival is 45% to 50%. 22 The development of host immunity to minor transplant antigens on donor cells in these individuals appears to increase the possibility of rejection. In addition, age is a factor in the outcome with increased success noted in patients who receive a transplant at a younger age. Graft failure in aplastic anemia occurred more commonly in patients who did not have radiation in their preparative regimen, in those who received T-cell depleted marrow, and in those given methotrexate (MTX) instead of cyclosporine-A (CSA) to prevent GVHD. 3'23 Other entities such as Fanconi's anemia, 24 Blackfan-Diamond syndrome, 25 and thalassemia 26 have been treated with allogeneic BMT. In addition, treatment of lysosomal storage states such as Hurler's syndrome z7 has seen limited success. The use of allogeneic BMT in these areas will require further exploration before substantiated conclusions can be drawn about its efficacy. OVERVIEW OF HLA TYPING AND GVHD
Allogeneic BMT provides a method for the replacement of a malignant or otherwise defective marrow with a healthy, normal marrow. Successful bone marrow transplantation (BMT) depends
ALLOGENEIC BMT
on a suitable source of healthy, malignancy-free hematopoietic stem cells and prevention and treatment of GVHD. In the bone marrow, the pluripotent stem cells replicate and differentiate into committed cell lines, which are necessary for survival. 28,29 An allogeneic transplant, the most common type of BMT, is a transplant from someone other than an identical twin and is often a sibling. 3~ Because the chance of an individual having a compatible sibling donor is only 30%, 31 transplants from another relative32 or from an unrelated donor33 are viable alternatives. Matched unrelated donor transplants are discussed in detail later.
HLA Typing Determining compatibility between the marrow donor and the recipient is a key component in allogeneic BMT. The degree of compatibility is determined by HLA typing, a histocompatibility system. This system includes at least six antigen groups that are located on the sixth chromosome: HLA-A, B, C, DR, DQ, and DP. 28'32 Because the HLA system is highly varied with at least 100 different antigens identified, 34 the specific combination of antigens makes an individual's cells distinguishable from most other cells. This HLA " c o d e " or "fingerprint" allows the body's immune system to differentiate between cells that are " s e l f " and "nonself" and to mount an immune reaction against cells that are noted as "nonself."32 In the current practice of typing, HLA-A, -B, and -DR antigens from the patient and potential donor are determined using serological methods.32 The ideal donor is identical to the recipient at all three loci resulting in a six-antigen match. A mixed lymphocyte culture (MLC) also is performed to observe interaction between the potential donor's cells and the recipient's cells. Low MLC reactivity indicates compatibility between the potential donor and the recipient. 29
Graft-Versus-Host Disease Careful HLA typing is crucial in reducing GVHD and thus the morbidity and mortality of allogeneic BMT. The severity of GVHD, a frequent and often fatal complication of allogeneic BMT, depends on the degree of HLA incompatibility. 35 GVHD occurs when the T lymphocytes produced by the donor's marrow recognize the
cells of their new host as foreign tissue and initiate a cytotoxic response against them. 34'36 This process can manifest itself in an acute and/or chronic manner. Because T lymphocytes mediate GVHD, several investigators have attempted to decrease its incidence and severity by removing T cells from transplanted marrow. T-cell--depleted transplants have resulted in higher relapse rates and thus show less promise as an effective method for treating leukemias. 37 The higher relapse rate is believed to result from the absence of the "graft-versus-leukemia" (GVL) effect. GVL occurs when the transplanted marrow mounts a response against residual leukemic cells (GVL) as well as the host tissues (GVHD). 2 This effect has been reported in several studies that have demonstrated a decreased leukemia relapse rate in patients who developed GVHD. 38'39 This GVL effect is regarded as one of the advantages of allogeneic BMT compared with other types of marrow transplants. THE TRANSPLANT PROCESS
Bone marrow transplantation is a lengthy process that takes several months from initial consideration to complete recovery. Although each patient's experience of the transplant is unique, a brief overview of patient care issues and potential problems involved in BMT will help facilitate understanding of this complex treatment.
Pretransplant Phase Because BMT is associated with many risks and costs, the decision to undergo a marrow transplant requires careful consideration. Factors in the decision-making process include demonstrated success in treating the individual's disease with BMT, limited alternate therapies, and the absence of preexisting conditions that could jeopardize patient survivalfl~ Sufficient information must be provided to the patient and family for an informed decision to be made. If the patient wishes to pursue the option of a transplant, the search for a suitable donor begins. HLA compatibility between donor and recipient must be ensured to prevent or minimize the development of GVHD as discussed earlier. Because there is a one-in-four chance that any two siblings will have the same HLA type, a BMT candidate's siblings are screened first. Only 30% of candidates have a matched sibling donor and, therefore, a
FRANCO AND GOULD
Table 2. Sample Preparative Regimen Protocol: Treatment of Leukemia or Lymphoma with Cyclophosphamide, Etoposide, and Total Body Irradiation Followed by AIIogeneic BMT BMT Day
Procedure/Therapy
- 8 -7
Admission Etoposide (VP-16), 1,800 mg/M 2 iV over 4 hours Cyclophosphamide, 60 mg/kg IV over 3-4 hours Continue cyclophosphamide Rest TBI 200 rads twice a day Continue irradiation Continue irradiation BMT
- 6 - 5 - 4 -3 - 2 - 1 0
Abbreviation: IV, intravenous.
partially matched or matched donor may be sought among the candidate's extended family.3~ If no donor is available within the family, a search for a unrelated donor may be undertaken through the National Marrow Donor Program. 32 While the availability of a donor is assessed, an extensive medical work-up of the candidate is performed. Confirmation of the diagnosis and staging of the disease and a thorough history of previous treatments are necessary to develop an individualized plan of care. A comprehensive examination and tests to determine current level of functioning of major organ systems also are necessary for planning care during treatment. 28"29'4z A final step in preparation for BMT is the placement of one or more multilumen tunneled right atrial catheters. These catheters will be used to sample venous blood and to deliver intravenous fluids and medications.
The Preparative Program The goals of the preparative regimen in BMT are to eradicate malignant cells, create space in the marrow to allow engraftment, and to destroy the patient's immune system to prevent graft rejection. 29'30 Because this high-dose therapy produces severe neutropenia, strict infection control measures are instituted. Laminar air flow or a highefficiency particulate air-filtering system, diligent handwashing practices, decontamination regimens, and prophylactic antibiotics are methods used to reduce the patient's risk of infection.28"42 To prevent the development of CMV pneumonia, a critical complication of allogeneic BMT, the ad-
ministration of intravenous immunoglobulin may begin before the transplant. 43 The treatment protocol is disease specific and will include a combination of high-dose chemotherapeutic agents and possibly total body irradiation (TBI) (see Table 2). 30 Busulfan and intravenous cyclophosphamide, cytosine arabinoside, etoposide (VP-16), and carmustine (BCNU) are commonly used agents in allogeneic BMT. 41'44 Both chemotherapy and TBI produce several predictable side effects including nausea, vomiting, diarrhea, and severe mucositis. Infection of the oral cavity with herpes simplex, Candida, or other local opportunistic infections can exacerbate the mucositis. Fluid and electrolyte replacement, meticulous oral and skin care, pain control, and management of infections are critical priorities for the BMT nurse. At the end of the preparative regimen, the patient may begin a GVHD prophylaxis protocol to retard the growth of the T lymphocytes from the donor's marrow (see Table 3). 45 Before the transplant and for several months after, the patient will receive a combination of immunosuppressive medications such as CSA and MTX. Other agents used in the prevention of GVHD include antithymocyte globulin and prednisone. 38
The Transplant The marrow infusion occurs 2 or 3 days after the chemotherapy is administered or on the last day of TBI. The donor is admitted to the hospital the day before or the day of the marrow harvest and undergoes a routine preoperative evaluation in preparation for general anesthesia. Through multiple aspirates of the posterior iliac crests, marrow is harvested, filtered to remove fat and bone particles, heparinized, and placed in a blood transfuTable 3. Sample GVHD Prophylaxis Protocol BMT Day(s) -3 - 1 , 1, 3, 5, and then every Monday and Thursday 0
1,3,6,11,18
Procedure/Therapy
Begin CSA, 2 mg/kg IV over 2 hours every 12 hours CSA trough level Methylprednisolone, 100 mg IV just before marrow infusion MTX 5 mg/M 2 IV
Note: CSA should be decreased by 25% for a 25% increase over baseline creatinine. Reduce CSA by 50% for a creatinine 50% greater than baseline. Hold CSA for a creatinine that is
twice the baseline,
ALLOGENEIC BMT
sion bag. Postoperatively, the donor is observed for signs of bleeding from the harvest sites and for complications of anesthesia. With an unrelated transplant, the harvesting occurs near the donor's home and the marrow is transported to the recipient's facility. 29 The marrow infusion itself is a technically simple procedure, resembling a blood transfusion28 and is often described as anticlimactic. Side effects, which are infrequent, include signs of a mild allergic reaction such as fever, chills, shortness of breath, chest pain, rash, and hives. A severe reaction to the transplanted marrow rarely occurs. 41 Frequent monitoring of the patient's vital signs and lung sounds is necessary because the hypertonic marrow may cause fluid overload.
Posttransplant/Engraftment Phase After the marrow infusion, the stem ceils migrate to marrow spaces, and within 7 to 14 days, they begin to reestablish normal bone marrow functions. 41 During this interval, the patient has no functional immune system and is susceptible to infection and other potentially serious complications. As a result, this phase is the most critical time in the process and requires astute assessments and prompt interventions by expert BMT nurses. Because of the risk of infections, broadspectrum antibiotic coverage is usually initiated when neutropenia develops or when the patient spikes a fever. 29 With recurrent or persistent fever, an antifungal agent is usually added to ensure adequate coverage. 29 Despite antimicrobial support and infection control practices, septic shock syndrome may ensue. Treating septic shock may require the administration of large volumes of fluid and multiple vasopressors. Hemodynamic monitoring is useful in guiding such treatments. 46 Extensive research has focused on decreasing the time during which the BMT patient is susceptible to infection. The use of hematopoietic growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colonystimulating factor, shows promise as a means of decreasing the neutropenic period. 47'4s Infectious complications of BMT are discussed in greater detail elsewhere in this issue. Pulmonary complications are the leading cause of death in patients undergoing BMT. 49 Interstitial pneumonitis, 5~ diffuse alveolar hemorrhage, 51 and pneumonia49 are associated with mortality rates as
high as 95% 52 necessitating consistent monitoring of pulmonary status throughout the treatment process. Other complications of BMT include bleeding, renal failure, and veno-occlusive disease (VOD). The nose is the most common site for hemorrhage although oral and gastrointestinal bleeding occur frequently.29 Multiple transfusions of blood products are necessary during the period of aplasia to maintain adequate counts. Packed red blood cells and platelets are irradiated to prevent GVHD produced by transfused lymphocytes.47 Renal failure may develop from a number of factors associated with BMT, including hypovolemia, the use of nephrotoxic agents and vasopressors, and ischemic episodes. 53'54 VOD is caused by obstruction of hepatic venules and results in reduced hepatic function manifested by increased bilirubin, decreased metabolism of ammonia, and decreased synthesis of clotting factors. 53 Renal failure and VOD are discussed later in this issue. Recognizing and implementing appropriate treatments for the myriad of acute complications of BMT is a tremendous responsibility and challenge for the transplant nurse. Increasingly, critically ill BMT patients remain in the transplant unit where the consistent delivery of comprehensive nursing care is the standard. Management of transplantassociated complications requires astute assessments, expert skills, and a thorough understanding of the physiology underlying the complications and associated treatments. Use of complex treatment modalities including mechanical ventilation, electrocardiogram and hemodynamic monitoring, hemodialysis, and the administration of vasoactive medications is well within the scope of transplant nursing. 52,55 Side effects and complications begin to diminish 2 to 3 weeks after marrow infusion as the body recovers from the toxic effects of the preparative regimen and the new marrow begins to engraft. The increasing function of the marrow is reflected by an increase in white cell counts and a reduced need for blood product support. Increased numbers of circulating white cells are likely to resolve infectious complications that developed during the aplastic period. However, white cells from the transplanted marrow can initiate the cytotoxic response that characterizes acute GVHD. 3s The recovery of marrow function signals the need for discharge education and preparation for dismissal,
FRANCO AND GOULD
and this should begin long before the actual discharge. 56 Education focuses on teaching the patient and/or significant others care of the right atrial catheters, fever monitoring, and signs and symptoms of infection and bleeding.
Discharge~Outpatient Support Although specific criteria for discharge from the inpatient BMT unit differ between institutions, there is general agreement of the following guidelines: (1) the patient is afebrile without intravenous antibiotics; (2) the patient is able to maintain adequate fluid and caloric intake; (3) hemoglobin and platelet counts are stable and maintained with no more than one transfusion per day; and (4) GVHD and other complications are resolving or can be managed on an outpatient basis. 56"ss The management of higher acuity patients in an outpatient environment and the increasing use of home intravenous therapy to deliver fluids and drugs has made it feasible for patients to be safely discharged earlier in the BMT process. These factors, along with the impact of growth factors on the length of neutropenia, have shortened the inpatient stay of BMT patients. 48 Leaving the inpatient unit is both exciting and anxiety producing for the patient and for those closely associated with the patient. 59 Consistent communication between the inpatient and outpatient caregivers facilitates uninterrupted care despite the change in setting. Continued support in the outpatient arena requires assessing and monitoring of delayed complications and long-term effects of the preparative regimen. Chronic GVHD is a late development that carries substantial risk for the allogeneic BMT survivor. Because the immune system is not fully reconstituted for up to a year after the transplant, 6~ late infections are another significant risk.
Long-Term Considerations The overall success of an allogeneic BMT is difficult to assess because of the complex issues that surround the treatment process and its sequelae. Certainly, eradication of the disease is primary. However, confounding issues, such as quality of life for the recipient, impact on significant others, and feelings of the donor must be considered when discussing factors related to outcome. Fear of graft failure, loss of functional status, the possibility of chronic GVHD and/or CMV pneumonia, growth
and development delays, and sexual dysfunction are significant threats to the BMT s u r v i v o r . 61'62 Few studies have focused on the psychosocial issues or functional status of the BMT survivor. A study of the physical and psychosocial functioning of survivors reported a wide range in the functional status of posttransplant patients, which prompted some to question their decision to undergo transplant. 63 Little is known about the specific impact of BMT on the quality of life (QOL). A study that explored the meaning of the QOL identified common themes central to this issue for the BMT patient. 64"65 These results can provide direction to caregivers discussing QOL issues with BMT patients and can serve as a basis for additional research. Family members and the donor (related or unrelated) also are affected by the entire process of BMT. Psychological, financial, and social changes all can be consequences of transplantation. ~9 Allaying anxieties and promoting understanding of the broader implications of BMT can assist families and individuals in making an informed consent to proceed with the transplant. FUTURE DEVELOPMENTS
The future in allogeneic BMT will be stimulated by advances in molecular biology, genetics, clinical trials, and nursing care. The entire approach to BMT will be improved by expanding our current knowledge of the immune system. Further, defining genetic transfer and use of antisense oligonucleotides to block genetic code expressions will add an entirely new dimension to transplantation. 66 Investigative endeavors will continue to focus on the development of new preparative regimens. Achieving greater antitumor effects while decreasing the risk of GVHD and exposing the individual to less toxicity is critical. The availability of hematopoietic growth factors, immunotoxins, and lymphokines will shift emphasis from cytotoxic drugs alone to the addition of biologic agents to prolong remission and potentiate cure. 67 Advances in identifying methods to treat the acute and chronic complications of the transplant process are crucial to successful outcomes. Sepsis, GVHD, and CMV infection remain serious and often fatal consequences. Clinical trials in drug therapies, such as thalidomide to treat chronic GVHD 6s and monoclonal antibodies to treat sepsis, 69 hold the promise of new methods to reduce transplant-related morbidity and mortality.
ALLOGENEIC BMT
Increasing the pool of available donors in the transplant registries would extend the availability of BMT to many individuals who currently have no suitable donor. Improving the method in which marrow is collected and providing education that highlights the value of marrow donation could increase the number of candidates in the donation pool. Other promising alternate sources f0r transplantation include the use of peripheral blood cells, umbilical cord blood, 7~ and cadaver donors. 71 Capital constraints will balance improvements in allogeneic transplantation. Critical questions that ask who will pay, what a fair price is, and how resources will be allocated are yet to be answered. 72 Research that addresses outcomes of comparative treatments, cost per year of life saved,
and dollars spent in follow-up care is essential to future planning. This will provide a means for weighing the benefits of BMT in this era of heightened cost consciousness. SUMMARY
From highly investigational to standardized therapy, allogeneic BMT has established its role in the treatment of selected diseases. Continued refinements in bone marrow transplantation will increase the number of potential candidates, reduce associated risks, and improve disease-free survival rates. With further exploration into its efficacy, allogeneic BMT will bring new challenges and opportunities for patients, families, and health care providers.
REFERENCES
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10 Graft failure following bone marrow transplantation for severe aplastic anemia: Risk factors and treatment results. Blood 73: 606-613, 1989 24. Gluckman E, Berger R, Dutreix J: Bone marrow transplantation for Fanconi anemia. Semin Hematol 21:20-26, 1984 25. Iriondo A, Garijo J, Baro J, et al: Complete recovery of hemopoiesis following bone marrow transplant in a patient with unresponsive congenital hypoplastic anemia (BlackfanDiamond Syndrome). Blood 64:348-351, 1984 26. Lucarelli G, Galimberti M, Polchi P, et al: Bone marrow transplantation in patients with thalassemia. N Engl J Med 322: 417-421, 1990 27. Hobbs JR, Hugh-Jones K, Barrett AJ, et al: Reversal of clinical features of Huder's disease and biochemical improvement after treatment by bone marrow transplantation. Lancet 2:709-712, 1981 28. Buchsel PC, Kelleher J: Bone marrow transplantation. Nurs Clin North Am 24:907-938, 1989 29. Wujcik D, Downs S: Bone marrow transplantation. Crit Care Nurs Clin North Am 4:149-166, 1992 30. Freedman S: An overview of bone marrow transplantation. Semin Oncol Nurs 4:3-8, 1988 31. Gale RP: Potential utilization of a national HLA-typed donor pool for bone marrow transplantation. Transplantation 42:54-58, 1986 32. Weinberg PA: The human leukocyte antigen (HLA) system, the search for a matching donor, national marrow donor program development, and marrow donor issues, in Whedon MB (ed): Bone Marrow Transplantation: Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 105-131 33. Beatty PG, Hansen JA, Anasetti C, et al: Marrow transplantation from unrelated HLA-matched volunteer donors. Transplant Proc 21:2993-2994, 1989 34. Freedman S, Shivnan J, Tilles J, et al: Bone marrow transplantation: Overview and nursing implications. Crit Care Nurs Q 13(2):51-62, 1990 35. Parr MD, Messino MJ, Mclntyre W: Allogeneic bone marrow transplantation: Procedures and complications. Am J Hosp Pharm 48:127-137, 1991 36. Cogliano-Shutta NA, Broda EJ, Gress JS: Bone marrow transplantation: An overview and comparison of autologous, syngeneic, and allogeneic treatment modalities. Nurs Clin North Am 20:49-66, 1985 37. Butturini A, Gale RP: T cell depletion in bone marrow transplantation for leukemia: current results and future directions. Bone Marrow Transplant 3:185-192, 1988 38. Caudell K: Graft-versus-host disease, in Whedon MB (ed): Bone Marrow Transplantation: Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 160181 39. Sullivan KM, Fefer A, Witherspoon R, et al: Graftversus-leukemia in man: Relationship of acute and chronic graft-versus-host disease to relapse of acute leukemia following allogeneic bone marrow transplantation. Prog Clin Biol Res 244:391-399, 1987 40. Weinstein HJ, Rappeport JM, Ferrara JLM: Bone marrow transplantation, in Nathan DG, Oski FA (eds): Hematology of Infancy and Childhood. Philadelphia, PA, Sannders, 1993, pp 317-344 41. Whedon MB: Allogeneic bone marrow transplantation:
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Clinical indications, treatment process, and outcomes, in Whedon MB (ed): Bone Marrow Transplantation: Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 20-48 42. Oncology Nursing Society: 1992 Bone Marrow Transplant Nursing Resource Directory (ed 3). Pittsburgh, PA, ONS, 1992 43. Winston D J, Gale RP: Prevention and treatment of cytomegalovirus infection and disease after bone marrow transplantation in the 1990s. Bone Marrow Transplant 8:7-11, 1991 44. Ford R, Eisenberg S: Bone marrow transplant: Recent advances and nursing implications. Nurs Clin North Am 25: 405-422, 1990 45. Champlin RE, Gale RP: Bone marrow transplantation for acute leukemia: Recent advances and comparison with alternate therapies. Semin Hematol 24:55-67, 1987 46. Rice V: Shock, a clinical syndrome: An update. Part 4. Nursing care of the shock patient. Crit Care Nurse 11(7):28-39, 1991 47. Anderson K, Braine H: Specialized cell component therapy. Semin Oncol Nurs 6:140-149, 1990 48. Aurer A, Ribas A, Gale RP: What is the role of recombinant colony stimulating factors in bone marrow transplantation? Bone Marrow Transplant 6:79-87, 1990 49. Wikle TJ: Pulmonary and cardiac complications of bone marrow transplantation, in Whedon MB (ed): Bone Marrow Transplantation: Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 182-205 50. Weiner RS, Bortin MM, Gale RP: Interstitial pneumonitis after bone marrow transplantation. Ann Intern Med 104: 168-175, 1986 51. Robbins RA, Linder J, Stahl MG, et al: Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am J Med 87:511-518, 1989 52. Afessa B, Tefferi A, Hoagland HC, et al: Outcome of recipients of bone marrow transplants who require intensivecare unit support. Mayo Clin Proc 67:117-122, 1992 53. Ford R, Ballard B: Acute complications after bone marrow transplantation. Semin Oncol Nurs 4:15-24, 1988 54. Ballard B: Renal and hepatic complications, in Whedon MB (ed): Bone Marrow Transplantation Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 240-261 55. O'Quin T, Moravec C: The critically ill bone marrow transplant patient. Semin Oncol Nurs 4:25-30, 1988 56. McGarigle CJ: Long-term follow-up of bone marrow transplant patients. Yale Biol Med 63:503-508, 1990 57. Chielens D, Herrick E: Recipients of bone marrow transplants: Making a smooth transition to an ambulatory care setting. Oncol Nurs Forum 17:857-862, 1990 58. Buchsel PC: Ambulatory care: Before and after BMT, in Whedon MB (ed): Bone Marrow Transplantation: Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 295-311 59. Buchsel PC, Parchem C: Ambulatory care of the bone marrow transplant patient. Semin Oncol Nurs 4:41-46, 1988 60. Lum LG: Immune recovery after bone marrow transplantation. Hematol/Oncol Clin North Am 4:659-675, 1990 61. Nims JW, Strom S: Late complications of bone marrow transplant recipients: Nursing care issues. Semin Oncol Nurs 4:47-54, 1988
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62. Ostroff JS, Lesko LM: Psychosexual adjustment and fertility issues, in Whedon MB (ed): Bone Marrow Transplantation Principles, Practice, and Nursing Insights. Boston, MA, Jones & Bartlett, 1991, pp 312-333 63. Andrykowski MA, Henslee PJ, FarraU MG: Physical and psychosocial functioning of adult survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 4:7581, 1989 64. Ferrell B, Grant M, Schmidt G, et al: The meaning of quality of life for bone marrow transplant survivors. Part 1: The impact of bone marrow transplant on quality of life. Cancer Nurs 15:153-160, 1992 65. Ferrell B, Grant M, Schmidt G, et al: The meaning of quality of life for bone marrow transplant survivors. Part 2: Improving quality of life for bone marrow transplant survivors. Cancer Nurs 15:247-253, 1992 66. Riordan ML, Martin JC: Oligonucleotide-based therapeutics. Nature 350:442-444, 1991
11 67. Mayer RJ: Acute leukemias in adults: An overview of recent strategies. J Cancer Res Clin Oncol 116:94-96, 1990 68. Vogelsang GB, Farmer ER, Hess AD, et al: Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J IVied 326:1055-1058, 1992 69. Greenberg RN, Wilson KM, Keene AY, et al: Observations using antiendotoxin (E5) as adjuvant therapy in humans with suspected serious gram negative sepsis. Crit Care Med 20:730-735, 1992 70. Gluckman E, Broxmeyer HE, Auerbach AD, et al: Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 321:1174-1178, 1989 71. Blazar BR: Successful donor cell engraftment in a recipient of bone marrow from a cadaveric donor. Blood 67: 1655-1660, 1986 72. Durbin M: Bone marrow transplantation: Economic, ethical and social issues. Pediatrics 82:774-783, 1988
VER THE past 15 years, allogeneic bone marrow transplantation has evolved from an experimental therapy to a standard treatment for several diseases. The number of allogeneic bone marrow transplants (BMTs) performed has increased dramatically. In 1979, less than 400 allogeneic BMTs were performed worldwide. By 1990, the number was more than 14,000.1 Continued use of transplantation can be attributed to many factors. The expanding knowledge of the HLA system, biologic enhancements, refined nursing care practices, and significant developments in patient support systems have improved transplant care. Changes in broad spectrum antibiotics, total parenteral nutrition, and transfusion therapy have augmented both the management and safety associated with allogeneic transplantation. 2 More effective preparative regimens and improved strategies for treating graft-versus-host disease (GVHD), cytomegalovirus (CMV) infection, and disease relapse have also spurred transplant growth. To meet the demand for services, new allogeneic programs are increasing by 25 per year with an average annual increase of 615 patients. 1 Allogeneic bone marrow grafting has become an attractive therapy for several disease states, many of which have limited treatment options.
O
DISEASES TREATED WITH ALLOGENEIC BMT
A variety of disease states can be treated with allogeneic transplantation. Most commonly, allogeneic BMT has been used in the treatment of malignant entities, particularly the leukemias. However, some nonmalignant states also have been treated successfully with transplantation (Table 1).
individuals in their first complete remission, it is not clear whether BMT is the preferred treatment because standard chemotherapeutic regimens offer excellent survival rates. 4's However, 60% survival rates have been achieved with aUogeneic marrow grafting in first remission. 6'7 In circumstances where patients present with a high leukocyte count at diagnosis and in those with certain chromosomal abnormalities, a transplant in first remission is clearly beneficial. 8"9 Persons in second or subsequent complete remission or transplants performed at the time of relapse have a significant survival advantage (20%) over chemotherapy. The patient's age and stage of the disease influence the outcome. In general, earlier treatment and a younger age are advantageous to long-term survival. 3"~GA~ Many children with ALL are cured with chemotherapeutic induction and maintenance therapy and thus are not candidates for BMT. However, children who relapse while receiving chemotherapy or within 18 months of starting therapy are obtaining longer remissions and are potentially cured with marrow transplantation. 12 Allogeneic BMT may offer a cure to individuals with specific subtypes, such as Philadelphia chromosome-positive and B-cell immunophenotype, where there is an increased risk of relapse. 9a3 AML. Controversy surrounds the use of allogeneic BMT in AML patients in first remission. Many believe that intensive chemotherapy offers an equal, if not greater, potential for cure than transplantation. However, several randomized studies have shown improved results with BMT.14-~6 IBMTR reports that leukemia-free survival rates with chemotherapy range from 20% to 50% in contrast to rates of 35% to 60% with a
Malignant States According to reports from the International Bone Marrow Transplant Registry (IBMTR), 83% of all allogeneic BMTs in recent years were for malignancies. 1 Acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML) are the disorders most commonly treated.3 ALL. Allogeneic BMT has been used to treat remission and relapse states in ALL. For those Seminars in Oncology Nursing, Vol 10, No 1 (Februaryl, 1994: pp 3-11
From the Oncology-Hematology Special Care Unit, University of Nebraska Medical Center, Omaha, NE. Theresa Franr RN, MSN: Patient Care Manager, Oncology; D. Alien Gould, RN, MSN: Clinical Nurse Specialist, Oncology-Hematology Special Care Unit, University of Nebraska Medical Center. Address reprint requests to Theresa Franco, RN, MSN, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-2405. Copyright 9 1994 by W.B. Saunders Company 0749-2081/94/1001-000255.00/0
3
FRANCO AND GOULD Table 1. Diseases Treated With AIIogeneic BMT and Survival Rates
Disease Malignant states ALL
AML
CML
Nonmalignant states Aplastic anemia SCIDS Thalassemia
Stage
First remission Second/subsequent remission Relapse First remission Second/subsequent remission Relapse Chronic phase Accelerated phase Blast phase Nontransfused Transfused
Disease-Free Long-term Survival (%)
60 20 20 45-60 20-30 20-30 35-45 25-35 6-18 70-80 45-50 50-60 70
Abbreviation: SCIDS, severe combined immunodeficiency syndrome.
transplant. 8 Younger patients are at an advant a g e - t h o s e under the age of 40 in first complete remission experience a 45% to 60% survival rate. 17 For those in second or subsequent remission or relapse, allogeneic BMT offers the best opportunity for disease-free survival with rates as high as 20% to 30%. 2 CML. Transplantation for CML has become the preferred treatment for those patients under 55 with an HLA identical donor because this provides the only hope for a cure. 18 The timing of the transplant is critical. IBMTR reports that in the chronic phase, the probability for leukemia-free survival was highest at 40% +- 4%, next in the accelerated phase at 31% --- 6%, and lowest in the blast phase at 12% --+ 6%. 3 Younger age and absence of GVHD were cited as the two variables that affected superior outcomes in those transplanted in the chronic phase. Because the results of transplantation are poor once blast transformation has occurred, efforts to identify suitable candidates, especially younger individuals who have an HLA identical match, should begin early.
Nonmalignant States Seventeen percent of the total number of aUogeneic BMTs performed in 1988 to 1990 were done for nonmalignant diseases. 1 This is an increase from previous years and signifies a continu-
ing effort to explore the use of BMT in a variety of different disease states. Immunodeficiency states. The goal of transplanting marrow in immunodeficiency states is to replace deficient or defective cell populations with normal cells. In infants with severe combined immunodeficiency syndrome, there has been a 50% to 60% chance of long-term survival with the restoration of immune function by normal donor cells. ~3 Knowledge of immune cell development in bone marrow has also led to the use of allogeneic BMT in Wiskott-Aldrich syndrome. Here, transplantation is the treatment of choice in patients who have an HLA identical donor. 19'2~ Osteopetrosis also can be treated with BMT, offering the only chance for a cure in this fatal disorder. 21 Hematopoietic states. Hematopoietic diseases, such as aplastic anemia, have been successfully treated with allogeneic BMT. A disease-free survival rate of 70% to 80% has been reported with complete reconstitution of normal hematopoiesis in individuals who have not been previously transfused with blood products. 22 In transfused individuals who have been sensitized, the rate of survival is 45% to 50%. 22 The development of host immunity to minor transplant antigens on donor cells in these individuals appears to increase the possibility of rejection. In addition, age is a factor in the outcome with increased success noted in patients who receive a transplant at a younger age. Graft failure in aplastic anemia occurred more commonly in patients who did not have radiation in their preparative regimen, in those who received T-cell depleted marrow, and in those given methotrexate (MTX) instead of cyclosporine-A (CSA) to prevent GVHD. 3'23 Other entities such as Fanconi's anemia, 24 Blackfan-Diamond syndrome, 25 and thalassemia 26 have been treated with allogeneic BMT. In addition, treatment of lysosomal storage states such as Hurler's syndrome z7 has seen limited success. The use of allogeneic BMT in these areas will require further exploration before substantiated conclusions can be drawn about its efficacy. OVERVIEW OF HLA TYPING AND GVHD
Allogeneic BMT provides a method for the replacement of a malignant or otherwise defective marrow with a healthy, normal marrow. Successful bone marrow transplantation (BMT) depends
ALLOGENEIC BMT
on a suitable source of healthy, malignancy-free hematopoietic stem cells and prevention and treatment of GVHD. In the bone marrow, the pluripotent stem cells replicate and differentiate into committed cell lines, which are necessary for survival. 28,29 An allogeneic transplant, the most common type of BMT, is a transplant from someone other than an identical twin and is often a sibling. 3~ Because the chance of an individual having a compatible sibling donor is only 30%, 31 transplants from another relative32 or from an unrelated donor33 are viable alternatives. Matched unrelated donor transplants are discussed in detail later.
HLA Typing Determining compatibility between the marrow donor and the recipient is a key component in allogeneic BMT. The degree of compatibility is determined by HLA typing, a histocompatibility system. This system includes at least six antigen groups that are located on the sixth chromosome: HLA-A, B, C, DR, DQ, and DP. 28'32 Because the HLA system is highly varied with at least 100 different antigens identified, 34 the specific combination of antigens makes an individual's cells distinguishable from most other cells. This HLA " c o d e " or "fingerprint" allows the body's immune system to differentiate between cells that are " s e l f " and "nonself" and to mount an immune reaction against cells that are noted as "nonself."32 In the current practice of typing, HLA-A, -B, and -DR antigens from the patient and potential donor are determined using serological methods.32 The ideal donor is identical to the recipient at all three loci resulting in a six-antigen match. A mixed lymphocyte culture (MLC) also is performed to observe interaction between the potential donor's cells and the recipient's cells. Low MLC reactivity indicates compatibility between the potential donor and the recipient. 29
Graft-Versus-Host Disease Careful HLA typing is crucial in reducing GVHD and thus the morbidity and mortality of allogeneic BMT. The severity of GVHD, a frequent and often fatal complication of allogeneic BMT, depends on the degree of HLA incompatibility. 35 GVHD occurs when the T lymphocytes produced by the donor's marrow recognize the
cells of their new host as foreign tissue and initiate a cytotoxic response against them. 34'36 This process can manifest itself in an acute and/or chronic manner. Because T lymphocytes mediate GVHD, several investigators have attempted to decrease its incidence and severity by removing T cells from transplanted marrow. T-cell--depleted transplants have resulted in higher relapse rates and thus show less promise as an effective method for treating leukemias. 37 The higher relapse rate is believed to result from the absence of the "graft-versus-leukemia" (GVL) effect. GVL occurs when the transplanted marrow mounts a response against residual leukemic cells (GVL) as well as the host tissues (GVHD). 2 This effect has been reported in several studies that have demonstrated a decreased leukemia relapse rate in patients who developed GVHD. 38'39 This GVL effect is regarded as one of the advantages of allogeneic BMT compared with other types of marrow transplants. THE TRANSPLANT PROCESS
Bone marrow transplantation is a lengthy process that takes several months from initial consideration to complete recovery. Although each patient's experience of the transplant is unique, a brief overview of patient care issues and potential problems involved in BMT will help facilitate understanding of this complex treatment.
Pretransplant Phase Because BMT is associated with many risks and costs, the decision to undergo a marrow transplant requires careful consideration. Factors in the decision-making process include demonstrated success in treating the individual's disease with BMT, limited alternate therapies, and the absence of preexisting conditions that could jeopardize patient survivalfl~ Sufficient information must be provided to the patient and family for an informed decision to be made. If the patient wishes to pursue the option of a transplant, the search for a suitable donor begins. HLA compatibility between donor and recipient must be ensured to prevent or minimize the development of GVHD as discussed earlier. Because there is a one-in-four chance that any two siblings will have the same HLA type, a BMT candidate's siblings are screened first. Only 30% of candidates have a matched sibling donor and, therefore, a
FRANCO AND GOULD
Table 2. Sample Preparative Regimen Protocol: Treatment of Leukemia or Lymphoma with Cyclophosphamide, Etoposide, and Total Body Irradiation Followed by AIIogeneic BMT BMT Day
Procedure/Therapy
- 8 -7
Admission Etoposide (VP-16), 1,800 mg/M 2 iV over 4 hours Cyclophosphamide, 60 mg/kg IV over 3-4 hours Continue cyclophosphamide Rest TBI 200 rads twice a day Continue irradiation Continue irradiation BMT
- 6 - 5 - 4 -3 - 2 - 1 0
Abbreviation: IV, intravenous.
partially matched or matched donor may be sought among the candidate's extended family.3~ If no donor is available within the family, a search for a unrelated donor may be undertaken through the National Marrow Donor Program. 32 While the availability of a donor is assessed, an extensive medical work-up of the candidate is performed. Confirmation of the diagnosis and staging of the disease and a thorough history of previous treatments are necessary to develop an individualized plan of care. A comprehensive examination and tests to determine current level of functioning of major organ systems also are necessary for planning care during treatment. 28"29'4z A final step in preparation for BMT is the placement of one or more multilumen tunneled right atrial catheters. These catheters will be used to sample venous blood and to deliver intravenous fluids and medications.
The Preparative Program The goals of the preparative regimen in BMT are to eradicate malignant cells, create space in the marrow to allow engraftment, and to destroy the patient's immune system to prevent graft rejection. 29'30 Because this high-dose therapy produces severe neutropenia, strict infection control measures are instituted. Laminar air flow or a highefficiency particulate air-filtering system, diligent handwashing practices, decontamination regimens, and prophylactic antibiotics are methods used to reduce the patient's risk of infection.28"42 To prevent the development of CMV pneumonia, a critical complication of allogeneic BMT, the ad-
ministration of intravenous immunoglobulin may begin before the transplant. 43 The treatment protocol is disease specific and will include a combination of high-dose chemotherapeutic agents and possibly total body irradiation (TBI) (see Table 2). 30 Busulfan and intravenous cyclophosphamide, cytosine arabinoside, etoposide (VP-16), and carmustine (BCNU) are commonly used agents in allogeneic BMT. 41'44 Both chemotherapy and TBI produce several predictable side effects including nausea, vomiting, diarrhea, and severe mucositis. Infection of the oral cavity with herpes simplex, Candida, or other local opportunistic infections can exacerbate the mucositis. Fluid and electrolyte replacement, meticulous oral and skin care, pain control, and management of infections are critical priorities for the BMT nurse. At the end of the preparative regimen, the patient may begin a GVHD prophylaxis protocol to retard the growth of the T lymphocytes from the donor's marrow (see Table 3). 45 Before the transplant and for several months after, the patient will receive a combination of immunosuppressive medications such as CSA and MTX. Other agents used in the prevention of GVHD include antithymocyte globulin and prednisone. 38
The Transplant The marrow infusion occurs 2 or 3 days after the chemotherapy is administered or on the last day of TBI. The donor is admitted to the hospital the day before or the day of the marrow harvest and undergoes a routine preoperative evaluation in preparation for general anesthesia. Through multiple aspirates of the posterior iliac crests, marrow is harvested, filtered to remove fat and bone particles, heparinized, and placed in a blood transfuTable 3. Sample GVHD Prophylaxis Protocol BMT Day(s) -3 - 1 , 1, 3, 5, and then every Monday and Thursday 0
1,3,6,11,18
Procedure/Therapy
Begin CSA, 2 mg/kg IV over 2 hours every 12 hours CSA trough level Methylprednisolone, 100 mg IV just before marrow infusion MTX 5 mg/M 2 IV
Note: CSA should be decreased by 25% for a 25% increase over baseline creatinine. Reduce CSA by 50% for a creatinine 50% greater than baseline. Hold CSA for a creatinine that is
twice the baseline,
ALLOGENEIC BMT
sion bag. Postoperatively, the donor is observed for signs of bleeding from the harvest sites and for complications of anesthesia. With an unrelated transplant, the harvesting occurs near the donor's home and the marrow is transported to the recipient's facility. 29 The marrow infusion itself is a technically simple procedure, resembling a blood transfusion28 and is often described as anticlimactic. Side effects, which are infrequent, include signs of a mild allergic reaction such as fever, chills, shortness of breath, chest pain, rash, and hives. A severe reaction to the transplanted marrow rarely occurs. 41 Frequent monitoring of the patient's vital signs and lung sounds is necessary because the hypertonic marrow may cause fluid overload.
Posttransplant/Engraftment Phase After the marrow infusion, the stem ceils migrate to marrow spaces, and within 7 to 14 days, they begin to reestablish normal bone marrow functions. 41 During this interval, the patient has no functional immune system and is susceptible to infection and other potentially serious complications. As a result, this phase is the most critical time in the process and requires astute assessments and prompt interventions by expert BMT nurses. Because of the risk of infections, broadspectrum antibiotic coverage is usually initiated when neutropenia develops or when the patient spikes a fever. 29 With recurrent or persistent fever, an antifungal agent is usually added to ensure adequate coverage. 29 Despite antimicrobial support and infection control practices, septic shock syndrome may ensue. Treating septic shock may require the administration of large volumes of fluid and multiple vasopressors. Hemodynamic monitoring is useful in guiding such treatments. 46 Extensive research has focused on decreasing the time during which the BMT patient is susceptible to infection. The use of hematopoietic growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colonystimulating factor, shows promise as a means of decreasing the neutropenic period. 47'4s Infectious complications of BMT are discussed in greater detail elsewhere in this issue. Pulmonary complications are the leading cause of death in patients undergoing BMT. 49 Interstitial pneumonitis, 5~ diffuse alveolar hemorrhage, 51 and pneumonia49 are associated with mortality rates as
high as 95% 52 necessitating consistent monitoring of pulmonary status throughout the treatment process. Other complications of BMT include bleeding, renal failure, and veno-occlusive disease (VOD). The nose is the most common site for hemorrhage although oral and gastrointestinal bleeding occur frequently.29 Multiple transfusions of blood products are necessary during the period of aplasia to maintain adequate counts. Packed red blood cells and platelets are irradiated to prevent GVHD produced by transfused lymphocytes.47 Renal failure may develop from a number of factors associated with BMT, including hypovolemia, the use of nephrotoxic agents and vasopressors, and ischemic episodes. 53'54 VOD is caused by obstruction of hepatic venules and results in reduced hepatic function manifested by increased bilirubin, decreased metabolism of ammonia, and decreased synthesis of clotting factors. 53 Renal failure and VOD are discussed later in this issue. Recognizing and implementing appropriate treatments for the myriad of acute complications of BMT is a tremendous responsibility and challenge for the transplant nurse. Increasingly, critically ill BMT patients remain in the transplant unit where the consistent delivery of comprehensive nursing care is the standard. Management of transplantassociated complications requires astute assessments, expert skills, and a thorough understanding of the physiology underlying the complications and associated treatments. Use of complex treatment modalities including mechanical ventilation, electrocardiogram and hemodynamic monitoring, hemodialysis, and the administration of vasoactive medications is well within the scope of transplant nursing. 52,55 Side effects and complications begin to diminish 2 to 3 weeks after marrow infusion as the body recovers from the toxic effects of the preparative regimen and the new marrow begins to engraft. The increasing function of the marrow is reflected by an increase in white cell counts and a reduced need for blood product support. Increased numbers of circulating white cells are likely to resolve infectious complications that developed during the aplastic period. However, white cells from the transplanted marrow can initiate the cytotoxic response that characterizes acute GVHD. 3s The recovery of marrow function signals the need for discharge education and preparation for dismissal,
FRANCO AND GOULD
and this should begin long before the actual discharge. 56 Education focuses on teaching the patient and/or significant others care of the right atrial catheters, fever monitoring, and signs and symptoms of infection and bleeding.
Discharge~Outpatient Support Although specific criteria for discharge from the inpatient BMT unit differ between institutions, there is general agreement of the following guidelines: (1) the patient is afebrile without intravenous antibiotics; (2) the patient is able to maintain adequate fluid and caloric intake; (3) hemoglobin and platelet counts are stable and maintained with no more than one transfusion per day; and (4) GVHD and other complications are resolving or can be managed on an outpatient basis. 56"ss The management of higher acuity patients in an outpatient environment and the increasing use of home intravenous therapy to deliver fluids and drugs has made it feasible for patients to be safely discharged earlier in the BMT process. These factors, along with the impact of growth factors on the length of neutropenia, have shortened the inpatient stay of BMT patients. 48 Leaving the inpatient unit is both exciting and anxiety producing for the patient and for those closely associated with the patient. 59 Consistent communication between the inpatient and outpatient caregivers facilitates uninterrupted care despite the change in setting. Continued support in the outpatient arena requires assessing and monitoring of delayed complications and long-term effects of the preparative regimen. Chronic GVHD is a late development that carries substantial risk for the allogeneic BMT survivor. Because the immune system is not fully reconstituted for up to a year after the transplant, 6~ late infections are another significant risk.
Long-Term Considerations The overall success of an allogeneic BMT is difficult to assess because of the complex issues that surround the treatment process and its sequelae. Certainly, eradication of the disease is primary. However, confounding issues, such as quality of life for the recipient, impact on significant others, and feelings of the donor must be considered when discussing factors related to outcome. Fear of graft failure, loss of functional status, the possibility of chronic GVHD and/or CMV pneumonia, growth
and development delays, and sexual dysfunction are significant threats to the BMT s u r v i v o r . 61'62 Few studies have focused on the psychosocial issues or functional status of the BMT survivor. A study of the physical and psychosocial functioning of survivors reported a wide range in the functional status of posttransplant patients, which prompted some to question their decision to undergo transplant. 63 Little is known about the specific impact of BMT on the quality of life (QOL). A study that explored the meaning of the QOL identified common themes central to this issue for the BMT patient. 64"65 These results can provide direction to caregivers discussing QOL issues with BMT patients and can serve as a basis for additional research. Family members and the donor (related or unrelated) also are affected by the entire process of BMT. Psychological, financial, and social changes all can be consequences of transplantation. ~9 Allaying anxieties and promoting understanding of the broader implications of BMT can assist families and individuals in making an informed consent to proceed with the transplant. FUTURE DEVELOPMENTS
The future in allogeneic BMT will be stimulated by advances in molecular biology, genetics, clinical trials, and nursing care. The entire approach to BMT will be improved by expanding our current knowledge of the immune system. Further, defining genetic transfer and use of antisense oligonucleotides to block genetic code expressions will add an entirely new dimension to transplantation. 66 Investigative endeavors will continue to focus on the development of new preparative regimens. Achieving greater antitumor effects while decreasing the risk of GVHD and exposing the individual to less toxicity is critical. The availability of hematopoietic growth factors, immunotoxins, and lymphokines will shift emphasis from cytotoxic drugs alone to the addition of biologic agents to prolong remission and potentiate cure. 67 Advances in identifying methods to treat the acute and chronic complications of the transplant process are crucial to successful outcomes. Sepsis, GVHD, and CMV infection remain serious and often fatal consequences. Clinical trials in drug therapies, such as thalidomide to treat chronic GVHD 6s and monoclonal antibodies to treat sepsis, 69 hold the promise of new methods to reduce transplant-related morbidity and mortality.
ALLOGENEIC BMT
Increasing the pool of available donors in the transplant registries would extend the availability of BMT to many individuals who currently have no suitable donor. Improving the method in which marrow is collected and providing education that highlights the value of marrow donation could increase the number of candidates in the donation pool. Other promising alternate sources f0r transplantation include the use of peripheral blood cells, umbilical cord blood, 7~ and cadaver donors. 71 Capital constraints will balance improvements in allogeneic transplantation. Critical questions that ask who will pay, what a fair price is, and how resources will be allocated are yet to be answered. 72 Research that addresses outcomes of comparative treatments, cost per year of life saved,
and dollars spent in follow-up care is essential to future planning. This will provide a means for weighing the benefits of BMT in this era of heightened cost consciousness. SUMMARY
From highly investigational to standardized therapy, allogeneic BMT has established its role in the treatment of selected diseases. Continued refinements in bone marrow transplantation will increase the number of potential candidates, reduce associated risks, and improve disease-free survival rates. With further exploration into its efficacy, allogeneic BMT will bring new challenges and opportunities for patients, families, and health care providers.
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