Bone Marrow Transplantation

Bone Marrow Transplantation
Theodore Moore, MD, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine; President of University of California at Los Angeles Department of Pediatrics Group Practice


Updated: Mar 28, 2008

Background
Over the past 40 years, bone marrow transplantation and hematopoietic stem cell transplantation have been used with increasing frequency to treat numerous malignant and nonmalignant diseases. Post?World War II "Cold War" fears of nuclear warfare stimulated interest in the effects of radiation on the human body.

Early studies with animals quickly revealed that bone marrow was the organ most sensitive to the damaging effects of radiation. The reinfusion of marrow cells was subsequently used to rescue lethally irradiated animals. In the 1950s, patients were given lethal doses of radiation to treat leukemia. Although many had hematologic recovery following this treatment, all patients eventually succumbed to relapse of their malignancies or to infections. In the 1950s and 1960s, almost 200 allogeneic marrow transplants were performed in humans, with no long-term successes. However, during this time, transplantation using identical twin donors brought a fair amount of success and provided a crucial foundation to continued clinical research in the field.

Bone marrow

In 1968, the first major landmark in bone marrow transplantation occurred with successful allogeneic transplantations performed for an infant with X-linked lymphopenic immune deficiency and for another with Wiskott-Aldrich syndrome.1,2 These successes were followed by reports of effective transplantation for aplastic anemia and, later, for leukemia. Advances in histocompatability testing and development of marrow donor registries, such as the National Marrow Donor Program (NMDP), have facilitated the use of unrelated donors, thus expanding the number of patients who can receive transplants.

Cord blood

In 1988, successful transplantation occurred in a young boy with Fanconi anemia using umbilical cord blood collected at the birth of his sibling.3 The patient remains alive and well to this date. In 1992, a patient was successfully transplanted with cord blood instead of bone marrow for the treatment of leukemia. Over the past decade, the use of cord blood has rapidly expanded;4 more than 2000 transplants have been performed using cord blood as a stem cell source. Cord blood has been used to transplant in any disease state for which bone marrow can be used (see Cord blood advantages and disadvantages).

The 5-year leukemia-free survival rate in 503 children with acute lymphoblastic leukemia (ALL) who received a transplant of umbilical cord blood that was mismatched for either one or two human leukocyte antigens (HLA) was similar when compared with the survival rate of 282 children who received bone marrow transplants.5 The limited number of cells in cord blood traditionally restricted its use to children and small adults. Research into cord blood expansion and the use of multiple units for a single patient may allow this source to become routinely available to all patients.

Peripheral blood stem cells

In addition to bone marrow and cord blood, peripheral blood stem cells (PBSCs) have gained popularity as a source of stem cells since their initial introduction in the 1980s. Transplants using PBSCs are discussed in detail elsewhere (see Hematopoietic Stem Cell Transplantation).


Basic Information
Stem cell sources

The most important cell needed for successful transplantation is the hematopoietic stem cell. Currently, the major sources of stem cells for transplantation include bone marrow, peripheral blood, and cord blood. These can be obtained from various donors. When they are obtained from the recipient, they are called autologous. When they come from someone other than the recipient, they are termed allogeneic.

The 3 types of allogeneic donors are syngeneic, related, and unrelated. When the donor is an identical twin, donation is termed syngeneic. As the names imply, related allogeneic donors are relatives, and unrelated donors are identified through a donor registry or from a cord blood bank. A summary is as follows:

Stem cell sources
Autologous
Allogeneic
Syngeneic (identical twin)
Related
Unrelated
Stem cell type
Bone marrow
Cord blood
PBSC
Cord blood advantages and disadvantages
Cord blood can be used to transplant in any disease state for which bone marrow can be used. However, the following factors limit or enhance cord blood use:

The small number of cells collected in each unit typically limits the size of the recipient, although successful transplantations in patients weighing more than 100 kg have been reported. Current clinical trials exploring the use of multiple cord units for a single patient may overcome this limitation.
Typically, fewer cells are needed per kilogram of weight when using cord blood.
A larger percentage of primitive cells are present in cord blood than in bone marrow.
In addition, more cells are in a highly proliferative state in cord blood, and these typically would be in a quiescent state in bone marrow.
Despite these characteristics, engrafting with a cord blood unit can be attempted only once, whereas bone marrow donors can give again if the first transplant fails to engraft.
Cord blood is associated with a higher rate of nonengraftment. This is especially evident in the bone marrow failure diseases, especially aplastic anemia.
In addition, delayed engraftment of neutrophils is common with cord blood (23 d, compared to 10-14 d for marrow and 7-12 d with PBSCs).
Advantages of cord blood appear to include a shorter time to procure it, fewer issues with graft versus host disease (GVHD), and a smaller number of cells needed to obtain engraftment.


Indications for Transplantation
Nonmalignant diseases



Inherited metabolic disorders - Adrenoleukodystrophy, Hurler syndrome, metachromatic leukodystrophy, osteopetrosis, and others
Inherited immune disorders -Severe combined immunodeficiency, Wiskott-Aldrich syndrome, and others
Inherited red cell disorders - Pure red cell aplasia, sickle cell disease, beta-thalassemia, and others
Marrow failure states - Severe aplastic anemia, Fanconi anemia, and others
Autoimmune diseases (experimental) - Systemic sclerosis, severe systemic juvenile rheumatoid arthritis, lupus, multiple sclerosis, and others
Malignant/premalignant diseases


Acute lymphoblastic leukemia (ALL)
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia (CML)
Juvenile myelomonocytic leukemia
Myelodysplastic syndromes
Plasma cell disorders
Hodgkin and non-Hodgkin lymphoma

The Search Process
Once a disease process has been identified and transplant is considered as a possible therapy, an appropriate donor must be identified. The best possible match results in the least complications. For allogeneic transplants, HLA histocompatability typing is performed for immediate family members initially using serologic typing. Fully matched family members provide the most compatible matches because they often share minor HLA antigens not usually included in testing. Class I and class II HLA antigen compatibility is tested and compared. Class I includes HLA-A, HLA-B, and HLA-C. Class II includes HLA-DR, HLA-DP, and HLA-DQ. A 6-of-6 match refers to testing of HLA-A, HLA-B, and HLA-DR, each of which has 2 alleles. Routine testing involves checking for these 6 antigens among family members.

If the donor and recipient are not a 6-of-6 match, they are said to be mismatched. When only 3 of 6 mismatch, the term of haplotypic donor applies. Unrelated-donor searches generally look for 6-of-6 matches also, although information on all 12 of the above-mentioned alleles is often provided.

This information helps the transplant physician determine the risks of nonengraftment and GVHD (for more information, see Hematopoietic Stem Cell Transplantation). In addition, donor age (younger is better), sex (female stem cells given to a male is less favorable), cytomegalovirus (CMV) serology (CMV-negative has better outcome), pregnancy and transfusion history, and body weight are considered.

Unrelated-donor search registries

When a related donor cannot be identified, a search for an unrelated donor is often initiated. This usually consists of a search of marrow donor registries and cord blood banks. The largest donor registry is the NMDP, which is responsible for providing marrow and stem cells for more than 9000 recipients to date. More than 260,000 cord units are currently stored in banks worldwide. The largest cord blood bank in the United States is the New York Cord Blood Bank, which has collected more than 32,000 units. The cord blood bank in Spain now has more than 25,000 specimens collected and processed, and the Australian cord registry has more than 17,000 specimens. Several additional cord blood banks are organized throughout the United States, Europe, and Asia, which are collecting units much like a blood bank solicits volunteer blood donations.

The NMDP contains typing information on over 4 million potential donors. Also, the NMDP can search more than 14 international registries through cooperative agreements with those registries. Bone Marrow Donors Worldwide (BMDW) is a collective database of 59 registries in 43 countries and 37 cord blood registries from 21 countries; 11,386,999 potential donors and cord units were available as of July 2007. Preliminary searches through the NMDP routinely also explore the BMDW.

In addition, private for-profit cord blood banks often solicit funds from expectant mothers to pay for the collection and storage of cord blood following delivery. Typically, an upfront processing fee and an ongoing storage fee are charged. To date, autologous stored cord blood from private banks has rarely been used. Calculations suggest that, of the individuals who store cord blood, fewer than 1 in 20,000 would use autologous stored cord blood. Therefore, common recommendations suggest that individuals donate cord blood to public banks, if that option is available.

Unrelated-donor search process

The process begins by performing DNA-HLA typing of the recipient, a more accurate method of typing than the serologic method. This is followed by a preliminary search that explores the registry databases. The preliminary search is performed free of charge, and the results are usually available within 24 hours. When a potential donor is requested, a formal search is begun, including class II typing of potential donors and subsequent confirmatory typing of selected matches. This incurs a cost to the recipient or their insurer. When donors are requested, they undergo a workup that includes laboratory testing and viral screening, physical examination, and an informational session.

When donor approval has been obtained, a date is set for the collection. Bone marrow or PBSCs are harvested on the same day of transplantation with the intent to infuse the recipient within 24 hours of the harvest. Generally, cord blood is shipped to the transplant center prior to the onset of the recipient's conditioning regimen. Donors are kept anonymous from the recipient until one year after transplant. At this time, identifying information can be exchanged if mutually desired.


The Transplant Process
The transplant process generally is divided into the following 5 phases: (1) conditioning, (2) stem cell infusion, (3) neutropenic phase, (4) engraftment phase, and (5) postengraftment period.

Conditioning

The conditioning period typically lasts 7-10 days. The purpose is to deliver chemotherapy, radiation, or both to eliminate malignancy, prevent rejection of new stem cells, and create space for the new cells. The most common conditioning regimens include total body irradiation (TBI) and cyclophosphamide or busulfan (Myleran, Busulflex) and cyclophosphamide. Numerous other combinations are also used and commonly include drugs such as fludarabine, etoposide, melphalan, cytarabine, and thiotepa in addition to the above-mentioned agents. Also, anti?T-cell agents, such as antithymocyte globulin (ATG), may be added to the regimen in certain cases to prevent rejection of the graft. Patients generally tolerate conditioning well, although antiemetic therapy is used to prevent the significant nausea that can occur.

Stem cell processing and infusion

The stem cell infusion is usually performed over about an hour, but this period varies depending on the volume infused. The stem cells may be processed before infusion, if indicated. Depletion of T cells can be performed to decrease GVHD. This is often performed before haplotype-matched transplants or other transplants that may have a significant degree of mismatch. Stem cell CD34+ selection may be performed, either for depletion of T cells or for tumor-purging purposes. In addition, many centers are investigating ex vivo expansion of a portion of the cells before transplant in order to improve engraftment.

Before infusion, the patient is premedicated with acetaminophen and diphenhydramine to prevent reaction. The cells then are infused through a central venous catheter, much like a blood transfusion. Anaphylaxis, volume overload, and a transient GVHD are the major potential complications involved.

Also, stem cell products that have been cryopreserved contain dimethyl sulfoxide (DMSO), a preservative, and can potentially cause renal failure in addition to the unpleasant smell and taste.

Neutropenic phase

During this period (2-4 wk), the patient essentially has no effective immune system. Healing is poor, and the patient is susceptible to infection. Supportive care and empiric antibiotic therapy are the mainstays of successful passage through this phase. Early in this period, herpes simplex virus (HSV) is an important potential pathogen. Usually, this is acquired from reactivation of a previous infection. Also during this period, endogenous flora, such as skin and gut organisms, are the most frequently encountered organisms. Hospital-acquired nosocomial infections perhaps pose the biggest risk because they are frequently more resistant to the standard antibiotic regimens used. During initiation of widespread antibacterial therapy, fungal selection can occur.

Typically, fever manifests 5-7 days following the start of broad-spectrum antibiotic therapy and is treated empirically with antifungal agents; amphotericin is the mainstay. The use of gut sterilizers (oral antibiotics to reduce gut flora) is controversial. They have been shown to reduce the number of positive blood cultures obtained but have had no significant impact on outcomes. In addition to infection risks, nutrition is also a key problem. Oral intake is usually severely reduced because of the severe mucositis that most patients develop. Total parenteral nutrition is provided and is usually quite necessary, especially for children.

Engraftment phase

During this period (several weeks), the healing process begins with resolution of mucositis and other acquired lesions. In addition, fever begins to subside, and infections often begin to clear. The greatest challenges at this time include management of GVHD and prevention of viral infections (especially CMV). In solid organ transplants, rejection of the organ is the major hurdle. However, in hematopoietic cell transplantation, the immune system is part of the transplanted organ; therefore, the new immune system can attack the entire body. When this occurs, it is termed GVHD.

GVHD generally involves the skin, GI tract, and the liver, causing a rash and blistering, diarrhea, and hyperbilirubinemia, respectively. This is discussed in detail in another article (see Graft Versus Host Disease). Patients receiving allogeneic hematopoietic stem cell transplants are typically placed on one or more immunosuppressive medications to protect against the development of GVHD.

The good side of GVHD is the graft versus leukemic (GVL) effect that may also be present. In addition, patients can develop an entity called venoocclusive disease (VOD). The etiology and the most effective management of VOD are unclear. VOD consists of the triad of weight gain, platelet transfusion refractoriness, and hyperbilirubinemia. The process includes damage to the liver with the deposition of thrombotic elements throughout the liver microcirculation. Supportive care and careful fluid management are essential. Antifibrinolytic therapy has unproven benefit.

Postengraftment phase

This period lasts for months to years. Hallmarks of this phase include the gradual development of tolerance, weaning off of immunosuppression, management of chronic GVHD, and documentation of immune reconstitution. Transplants using T-cell depletion or from mismatched or haplotypic sources often have delayed or incomplete immune reconstitution. Patients who received TBI as part of their conditioning regimen often have significant splenic dysfunction.

Most patients need reimmunization, usually beginning one year posttransplantation. Typically, this is begun using tetanus (DT), with titers obtained before and at least one month following to document a response. The use of the DT immunization is age dependent. In addition to the DT, immunization also can be given with the inactivated poliovirus vaccine (IPV). Oral polio vaccine should not be administered. Influenza vaccination should be administered to all patients every year. If a protective titer is obtained from the tetanus vaccine, proceed with the Haemophilus influenzae, pneumococcal, and hepatitis B series.

Typically, after 2 years, immunization may be given with the measles, mumps, and rubella (MMR) vaccine only if the patient is successfully immunized with the above vaccines, the patient is off immunosuppressants for more than 6 months, and the patient does not have chronic GVHD. If the patient has adequate rubella titers, immunization may be withheld. All other live virus vaccines should be avoided if at all possible. Please refer to the American Academy of Pediatrics' Red Book Report of the Committee on Infectious Diseases for further information regarding immunizations in the posttransplant patient.6


Outcomes
Improvements in supportive care, antibiotic regimens, and DNA-HLA typing have had significant impact on improving survival and quality of life following transplant. In general, patients with stable disease or disease in remission have better outcomes than those transplanted during a later disease phase or with relapsed disease. Young age at time of transplant also leads to more favorable outcomes. CMV-negative status of recipient and donor enhance the likelihood of survival. A larger hematopoietic cell dose given at time of transplant may hasten engraftment and improve outcome but may also increase the risk of GVHD.

Transplants for nonmalignant diseases generally have more favorable outcomes, with survival rate of 70-90% if the donor is a matched sibling and 36-65% if the donor is unrelated. Transplants for acute leukemias (eg, ALL, AML) in remission at the time of transplant have survival rates of 55-68% if the donor is related and 26-50% if the donor is unrelated.

The outcome statistics of autologous transplant for solid tumors are somewhat disappointing for the pediatric malignancies, except for relapsed lymphomas and certain brain tumors. Autologous transplant may offer some advantage over chemotherapy alone in patients with relapsed germ cell tumors, Wilms tumor, or Ewing sarcoma. Autologous transplant provides superior results than chemotherapy alone in the 3-year disease-free survival rate for stage IV neuroblastoma, although the survival rate does not exceed 35%.7 In patients in first remission for metastatic alveolar rhabdomyosarcoma or metastatic Ewing sarcoma, no significant advantage has been demonstrated to date for autologous transplant over chemotherapy alone. Some recent transplant regimens use strategies designed to induce autologous GVHD in order to elicit a graft-versus-tumor effect in hopes of improving outcomes.8

Various regimens have been explored in an attempt to improve survival rates in these diseases, including the use of novel conditioning regimens, the use of several courses of high-dose therapy with stem-cell support, and the use of donor-lymphocyte infusions. Likewise, treatment of brain tumors has yielded similarly disappointing results, with the exception of medulloblastoma. Current transplant regimens for treatment of solid tumors emphasize introduction of promising new agents into the regimen or the use of sequential rounds of high-dose therapy followed by stem cell support.


Future Directions
The emphasis of current research is primarily directed at decreasing toxicity and GVHD while increasing the pool of potential donors by developing techniques to cross the traditional HLA histocompatability barriers more successfully. Transplants are performed with increasing degrees of mismatch. Efforts to reduce the toxicity and transplant-related mortality are being made using strategies such as nonmyeloablative therapy with increased peritransplant immune suppression and posttransplant immune suppression to obtain a partial graft. This is then followed with donor leukocyte infusions to achieve complete chimerism. In addition, donor leukocyte infusions are used with increasing frequency for the treatment of patients with leukemia that relapses following transplant.

Cord blood remains a promising source of hematopoietic stem cells. The use of multiple cord blood units for the transplant of larger individuals continues to be explored in the context of a nationwide Bone Marrow Transplant-Clinical Trials Network (BMT-CTN) study exploring the efficacy of double cord transplants. The potential plasticity of stem cells in cord blood hold promise for regeneration of various cell types such as cardiac, endocrine, and neuro tissue without the ethical controversies that surround embryonic stem cells.

Expanded indications for transplant continue to be explored. Preliminary data suggest a possible role for transplant in the treatment of autoimmune diseases such as lupus, multiple sclerosis, systemic sclerosis, and juvenile rheumatoid arthritis. In addition, in utero transplant holds promise for early correction of genetic disease, with some success already demonstrated with the immunodeficiency syndromes.

The use of gene therapy with the targeting of cord blood may also hold promise for the correction of genetic disease. Recently, hematopoietic stem cells and other primitive cell types have been shown to retain the ability to differentiate into various mature cells when they receive the proper cytokine cues. This may hold potential for use in restoring function to ailing hearts or regenerating damaged nervous tissue. The transplant of hematopoietic stem cells continues to be an advancing field in the treatment of human disease.


References
Gatti RA, Meuwissen HJ, Allen HD, et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. Dec 28 1968;2(7583):1366-9. [Medline].

Bortin MM. A compendium of reported human bone marrow transplants. Transplantation. Jun 1970;9(6):571-87. [Medline].

Gluckman E, Broxmeyer HA, 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. Oct 26 1989;321(17):1174-8. [Medline].

Rubenstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1998;339:1565-77. [Medline].

Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. Jun 9 2007;369(9577):1947-54. [Medline].

American Academy of Pediatrics. Red Book 2000 - Report of the Committee on Infectious Diseases. 25th ed. American Academy of Pediatrics; 2000.

Matthay KK, Edeline V, Lumbroso J, et al. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol. Jul 1 2003;21(13):2486-91. [Medline].

Porter DL, Antin JH. The graft-versus-leukemia effects of allogeneic cell therapy. Annu Rev Med. 1999;50:369-86. [Medline].

[Best Evidence] Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. Sep 21 2006;355(12):1199-209. [Medline].

Kline RM. Pediatric Hematopoietic Stem Cell Transplantation. Informa Healthcare USA, Inc; 2006.

Thomas E, Storb R, Clift RA, et al. Bone-marrow transplantation (first of two parts). N Engl J Med. Apr 17 1975;292(16):832-43. [Medline].

Thomas ED, Blume KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 1999;5(6):341-6. [Medline].

Thomas ED, Storb R, Fefer A, et al. Aplastic anaemia treated by marrow transplantation. Lancet. Feb 5 1972;1(7745):284-9. [Medline].

Keywords
bone marrow transplantation, BMT, stem cell transplantation, SCT, cord blood transplantation, leukemia, allogenic bone marrow transplantation, umbilical cord blood, peripheral blood stem cells, PBSCs, human leukocyte antigen, HLA, histocompatibility typing, X-linked lymphopenic immune deficiency, Fanconi anemia, acute lymphoblastic leukemia, aplastic anemia, nonengraftment, graft versus host disease, GVHD, adrenoleukodystrophy, Hurler syndrome, metachromatic leukodystrophy, osteopetrosis, severe combined immunodeficiency, pure red cell aplasia, sickle cell disease, thalassemia, marrow failure, systemic sclerosis, severe systemic juvenile rheumatoid arthritis, lupus, multiple sclerosis, acute myelogenous leukemia, AML, chronic myelogenous leukemia, CML, juvenile myelomonocytic leukemia, myelodysplastic syndromes, plasma cell disorders, Hodgkin lymphoma, non-Hodgkin lymphoma

Contributor Information and Disclosures
Author
Theodore Moore, MD, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine; President of University of California at Los Angeles Department of Pediatrics Group Practice
Theodore Moore, MD is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor
Casimir F Firlit, MD, PhD, Consulting Staff, Department of Urology, Cardinal Glennon Children's Hospital
Casimir F Firlit, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Medical Association, American Society of Transplant Surgeons, American Urological Association, and Illinois State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor
Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor
Nicholas A Shorter, MD, Professor of Clinical Surgery and Clinical Pediatrics, State University of New York-Downstate University; Division Chief, Department of Surgery, Division of Pediatric Surgery, State University of New York-Downstate Medical Center
Disclosure: Nothing to disclose.

CME Editor
Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center
Ron Shapiro, MD is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, and Society of University Surgeons
Disclosure: Astellas Honoraria Speaking and teaching; Brystol Meyer Squibb StemCell Data Monitoring Committee Consulting fee Review panel membership

Chief Editor
Stuart M Greenstein, MD, Professor of Surgery, Albert Einstein College of Medicine; Consulting Surgeon, Department of Surgery, Division of Transplantation, Montefiore Medical Center
Stuart M Greenstein, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Surgeons, American Society of Transplant Surgeons, American Society of Transplantation, Association for Academic Surgery, International College of Surgeons, Medical Society of New Jersey, National Kidney Foundation, New York Academy of Sciences, and Southeastern Surgical Congress
Disclosure: Nothing to disclose.

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