Bone Marrow Transplantation

Published on 09/02/2015 by admin

Filed under Allergy and Immunology

Last modified 09/02/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1120 times

Bone Marrow Transplantation

Stem cell transplantation is currently being used to treat patients with malignant and nonmalignant diseases (e.g., chronic myelogenous leukemia, severe combined immunodeficiency disease, non-Hodgkin’s lymphoma). The goal of transplanting bone marrow or peripheral blood progenitor cells is to achieve a potential cure or help patients recover from high-dose chemotherapy that has destroyed stem or marrow cells, a condition known as myeloablation.

Cancers Treated with Progenitor Cell Transplants

Leukemia

In most types of leukemia, the body produces large numbers of immature white blood cells (WBCs) that do not function properly. Under appropriate conditions, bone marrow transplantation may be useful in treating certain types of leukemia (Box 32-1).

Acute lymphoblastic leukemia is the most common type of leukemia in young children but may also affect adults, especially those age 65 years and older. It is a rapidly progressive malignant disorder involving the production of immature WBCs (blasts), which often results in the replacement of normal bone marrow with blast cells. Acute myeloid leukemia, also referred to as nonlymphoblastic leukemia, occurs in adults and children.

Although chronic lymphocytic leukemia most often affects adults older than 55 years, it sometimes occurs in younger adults, but rarely affects children. Chronic myeloid leukemia occurs mainly in adults and affects a very small number of children.

Non-Hodgkin’s and Hodgkin’s Lymphoma

In Hodgkin’s disease and non-Hodgkin’s lymphoma, cells in the lymphatic system become abnormal. They divide too rapidly and grow without any order or control, and old cells do not die as cells normally do. Because lymphatic tissue is present in many parts of the body, Hodgkin’s disease and non-Hodgkin’s lymphoma can start almost anywhere. These diseases may occur in a single lymph node, in a group of lymph nodes, or sometimes in other parts of the lymphatic system (e.g., bone marrow, spleen).

For patients with lymphoma, chances of survival depend on the grade and stage of cancer, overall patient health, and response to treatment. Hodgkin’s lymphoma is one of the most curable forms of cancer. Patients diagnosed with stage I disease have more than a 90% chance of living 10 years or longer. Of interest, higher grade aggressive types are more likely to be cured with chemotherapy. Lower-grade lymphoma often can have longer average survival times, with a mean survival of 10 years in some cases. Most children respond well to treatment, even though children tend to have the higher grades of lymphoma. From 70% to 90% of these children survive 5 years or longer (Table 32-1).

Table 32-1

Estimated 5-Year Survival Rates after Transplantation

Disease Allogeneic (%) Autologous (%)
Severe combined immunodeficiency 90 N/A
Aplastic anemia 90 N/A
Thalassemia 90 N/A
Acute myeloid leukemia    
 First remission 55-60 50
 Second remission 40 30
Acute lymphocytic leukemia    
 First remission 50 40
 Second remission 40 30
Chronic myeloid leukemia    
 Chronic phase 70 ID
 Blast crisis 15 ID
Chronic lymphocytic leukemia 50 ID
Myelodysplasia 45 ID
Multiple myeloma 30 35
Non-Hodgkin’s lymphoma, first relapse, second remission 40 40
Hodgkin’s disease, first relapse, second remission 40 50

ID, Insufficient data; N/A, not applicable.

These estimates are based on data reported by the International Bone Marrow Transplant Registry.

What Are Progenitor Blood Cells?

Progenitor cells have the ability to evolve into different types of cells. Bone marrow and peripheral blood progenitor cells are capable of reconstituting a person’s immune system because they contain the precursor to the cells that make up the blood: lymphocytes, granulocytes, macrophages, and platelets. Progenitor cells that circulate in the bloodstream are called peripheral blood stem cells (PBSCs). PBSCs are found in much smaller quantities in the circulating blood than in the bone marrow. Hematopoietic stem cells are found in very small numbers in the peripheral blood and greater numbers in the marrow.

The hematopoietic stem cell population is not fully characterized, but the cell marker, CD34+ antigen, identifies a population of stem cells that can repopulate the bone marrow after chemotherapy. The required minimal dose of CD34+ cells is difficult to define, but most transplantation centers will infuse a minimal dose of 2 × 106 CD34+ cells/kg patient weight in the autologous and allogeneic PBSC setting.

Historically, the dose of bone marrow has been based on the nucleated cell (NC) count (i.e., 2 to 4 × 108 NC/kg recipient weight). There is no established amount of CD34+ bone marrow stem cells to infuse because there may be more primitive cells, and therefore likely to be CD34− cells, in the marrow that are capable of reconstituting the recipient’s marrow.

Traditional Treatment Options

To understand why bone marrow and PBSCs are used and how they work, it is helpful to understand how chemotherapy and radiation therapies affect these cells. Chemotherapy and radiation target rapidly dividing cells. These therapies are used to treat cancers because cancer cells divide more rapidly than healthy cells. Bone marrow cells also divide at a rapid rate and can be severely damaged or destroyed by high-dose treatment. Without healthy bone marrow, the patient cannot make the blood cells that are able to fight off infections, carry oxygen, and prevent bleeding.

Treatment for cancer includes chemotherapy, radiation therapy, surgery, hormone therapy, and/or immunotherapy. These therapies may be administered alone or in combination to eliminate malignant cells most effectively.

Chemotherapy

Chemotherapy may involve one drug or a combination of two or more drugs, depending on the type of cancer and its rate of progression.

Chemotherapeutic drugs can be divided into the following:

1. Agents that are active against both dividing and nondividing cells

2. Drugs that are active against dividing cells and affect a particular phase of cell division

3. Agents that affect all or most of the phases of the cell cycle (Box 32-2)

Box 32-2   Cancer Chemotherapy Agents

Direct DNA-Interacting Agents Indirect DNA-Interacting Agents
Alkylators
Cyclophosphamide
Chlorambucil
Melphalan
BCNU (carmustine)
CCNU (lomustine)
Ifosfamide
Procarbazine
Cisplatin
Carboplatin
Antimetabolites
Deoxycoformycin
6-Mercaptopurine
2-Chlorodeoxyadenosine
Hydroxyurea
Methotrexate
5-Fluorouracil (5-FU)
Cytosine arabinoside (ARA-C)
Gemcitabine
Fludarabine phosphate
Asparaginase
Antitumor Antibiotics
Bleomycin
Actinomycin D
Mithramycin
Mitomycin C
Etoposide (VP-16)
Topotecan
Doxorubicin and daunorubicin
Idarubicin
Mitoxantrone
Antimitotic Agents
Vincristine
Vinblastine
Paclitaxel
Estramustine phosphate

Whatever the mode of action of these drugs, they destroy malignant cells in the same proportion of cells that is killed for each dose of chemotherapeutic agent.

Alkylating Agents, Antimetabolites, and Alkaloids

The first chemotherapeutic agents to be used in bone marrow transplantation were alkylating agents such as cyclophosphamide and busulfan. Their common mechanism of action is that on entering the cells, the alkyl groups bind to the electrophilic sites in DNA and other biologically active molecules. This bifunctional alkylation of DNA results in efficient cross-linking of the DNA, leading to strand breakage and ultimately cell death.

Antimetabolites such as 5-fluorouracil (5-FU), cytarabine, and fludarabine induce cytotoxicity by serving as false substrates in biochemical pathways. Many are nucleoside analogues that are incorporated into DNA and RNA and therefore inhibit nucleic acid synthesis. They are cell cycle active and are specific mainly for cells in the S phase.

The vinca alkaloids, vincristine and vinblastine, which were isolated from the periwinkle plant, inhibit microtubule assembly by binding to tubulin. This microtubule stabilization prevents the cells from dividing; thus these alkaloids are cytotoxic predominantly during the M phase of the cell cycle. Bleomycin, an antitumor antibiotic, induces single-strand and double-strand breaks through free radical generation and is cytotoxic mainly during the G2 and M phases of the cell cycle.

Evaluation of Candidates for Peripheral Blood Stem Cell and Bone Marrow Transplantation

Factors that influence the eligibility for bone marrow transplantation include age, disease status, performance status for the recipient, organ function (i.e., heart, lung, liver, and kidney function), infectious disease status, compatibility of the donor and recipient, and psychosocial status. Patients who undergo high-dose chemotherapy and hematopoietic stem cell transplantation require a careful evaluation of all body systems to ensure that they are able to tolerate the aggressive therapy and the isolation of their hospital stay, which can last days to months.

Pretransplantation evaluation and testing (Fig. 32-1) may include HLA tissue typing, bone marrow biopsy and aspiration, electrocardiography, echocardiography, complete history and physical examination, chest x-ray study, pulmonary function tests, dental cleaning, blood tests such as complete blood count (CBC) and blood chemistries, and screening for viruses such as hepatitis, human T lymphotropic virus I and II, cytomegalovirus (CMV), herpes, and human immunodeficiency virus (HIV).

At some point before transplantation, a central venous catheter is usually placed in a large vein to help in drawing blood samples, infusing medications during and after the transplantation, and actually infusing bone marrow or PBSCs.

ABO Blood Group and Human Leukocyte Antigen Matching

The donor and recipient may be incompatible. HLA matching is the primary consideration in assessing whether a donor is acceptable for a given patient and overshadows any other non-HLA factors, including ABO incompatibility.

HLA matching is important because a close HLA match does the following:

There are a number of HLA markers. Some markers, such as HLA-A, HLA-B, HLA-C, and HLA-DRB1 are most important to the success of transplantation. The HLA-DQ is used for evaluation by some transplant centers but not by others. The impact of DQ is minimal.

Minimum matching levels must be met before a donor or unit of cord blood cells can be transplanted. The National Marrow Donor Program (NMDP) program requires that at least a 6 out of 8 match exist. However, some transplant centers set more stringent requirements for a 7 out of 8 match between patient and donor (Fig. 32-2).

For adult donors, a match of at least six of these eight HLA markers is required. For cord blood units, which require less strict matching criteria, a match of at least four of six markers is required at HLA-A, HLA-B, and HLA-DRB1.

Obtaining Cells for Transplantation

Bone Marrow

In the procedure for harvesting bone marrow, the donor is given general or regional anesthesia and marrow is usually aspirated with large needles from the posterior iliac crest; the anterior crest can also be used in certain cases (Fig. 32-3). The goal of the procedure is to collect 10 to 15 mL of marrow/kg of recipient weight. Approximately 600 to 900 mL of marrow is collected. The aspirated marrow is collected in bags containing a buffered isotonic solution and heparin to prevent coagulation.

Buy Membership for Allergy and Immunology Category to continue reading. Learn more here