Bone Marrow Transplants, by Erinn Dandley and Max Nowak

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Overview

Bone marrow transplantation is the process by which bone marrow is harvested from either a donor or the patient themselves and then given intravenously to the patient [1]. Hematopoietic stem cells (HSC) are the therapeutic component of bone marrow. Their main use is the treatment of hematological and lymphoid cancers, but may also have future applications in HIV treatment. There are currently nine million potential donors in databases around the world; matches for bone marrow transplants are found over 50% of the time. Due to the time it takes from match to donation - three months- only about half of those matches are actually utilized [6]. The motivation for continued research in this area is due to the widespread application of HSC that will be covered in detail in the following sections.

History

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1903 – Pianese (Italy) is the first person to take a bone marrow sample for diagnostic purposes. The sample was taken from the femur by a surgical trephine [1].

1922 – Morris and Falconer use a drill to start a marrow biopsy [1].

1922 – Seyfarth makes puncture needle to get bone marrow from rib bones. He recommends the use of gloves and a gown for this procedure but sufficient anesthesia was not used [1].

1927 – Anirkin (Russia) uses a lumbar puncture needle to take marrow from the sternum; his method was also used to diagnose typhus and tuberculosis. He published his results and reported no complications but increased marrow activity [1].

1935 – Klima and Rosegger make needles with guards [1].

1929-1938 – Healthy volunteers give marrow just for the good of science. The procedures were done without anesthesia because many doctors felt it was unnecessary [1].

1943 – The first death due to a bone marrow collection occurs by accident when a sternal puncture goes through the patient’s heart [1].

1950 – The pelvis, which contains 50% of body’s bone marrow, is suggested as a good site for drawing samples [1].

1956 - Dr. E. Donnall Thomas performs the first bone marrow transplant on a leukemia patient using marrow from an identical twin [2].

1959 – Georges Mathe performs the first successful bone marrow transplants not on identical twins to help four accidentally irradiated nuclear researchers [2].

1963 – Georges Mathe announces that he cured a leukemia patient with a bone marrow transplant. This was the first time the patient’s blood type successfully changed to the donor’s, but it was not universally considered a success since the patient died of encephalitis 20 months later [2].

Mid 1960’s- The typing of histocompatibility complexes allows for matching of donors to patients. It’s found that ¼ of all siblings have the same complexes [6].

1968 – Robert A. Good performs the first bone marrow transplant to cure a severe immunal deficiency in a 5 month old. The boy grew into a healthy adult [8].

1990’s – Storb introduces low dose irradiation and immunosuppressive drugs to permit engraftment and prevent graft versus host disease (GVHD). He then went on to decrease rejection rates by adding an antirejection agent before irradiation. It’s a gentle, safe, and effective method but for serious cancers there is the risk of relapse from the lack of GVHD [6].

Health Issues Associated with Bone Marrow Transplants

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Irradiation

High dose irradiation will kill a person rather quickly. A low dose of radiation damages the intestinal track and central nervous system. These people will slowly die of organ failure. Bone marrow transplants in humans were first conducted to save those that had been accidentally irradiated [6].

Cancer

Cancers of the blood, for example leukemia, are prime candidates for bone marrow transplants. Leukemic cells are replenished by leukemic stem cells much as normal cells are renewed from noncancerous stem cells. Chemotherapy only attacks fast growing cells but stem cells are usually quiescent. GVHD attacks the cancerous cells that are left behind and kills them. Minor antigens on the surface of the donated cells from the Y chromosome account for and increase GVHD in male recipients from female donors. This results in more cures/remissions than other treatments but may cause a serious immune reaction that can result in death [6].

Other

Autologous donors are good for the treatment of rheumatoid arthritis and multiple sclerosis. Allograft donors are good for sickle cell anemia, thalassemia, and Wiskott-Aldrich syndrome [6].

AIDS

Thirty-two attempts to cure AIDS with bone marrow transplants were conducted between 1982 and 1996. In two patients HIV was eradicated (test positive to negative). One transient disappearance occurred and many other patients had clinical improvement. This includes a xenotransplantation from a baboon into a human patient as baboons are unable to acquire HIV [7].

The first attempt in 1983 to cure AIDS with a bone marrow transplant was done to two men but they had progressed too far into the disease already and died. In 1984 a second, healthier, male got a bone marrow donation from his identical twin brother and showed immunologic improvement but no clinical improvement and died in 12 months [7].

HIV enters into cells with the help of CD4 surface molecule and co-receptors (mostly CCR5). A homogeneous 32 base pair deletion in the CCR5 gene protects from HIV infection by eradicating this co-receptor. The heterozygous presence of the mutation leads to delayed disease progression. In 2007 a patient, now known as the “Berlin patient,” was treated for acute myeloid leukemia and also had AIDS. His donor was homozygous for a CCR5 deletion, and despite being taken off antiviral drugs during the transplant, the patient became the first person to be cured of an HIV infection [3]. He still shows no signs of HIV [10].

Current therapy for AIDS allows people to live for 2/3 of the life expectancy of the rest of the population. There are side effects associated with these treatments, they are expensive, they have led to resistant strains, and some people still progress to AIDS. Bone marrow transplants could be the ideal treatment for some patients. Mostly Caucasians have the homogeneous mutation, 1-3%, and it is most prevalent in the NE parts of Europe. Current registries offer a theoretical 30% chance of finding a match with homogeneous mutant. As an added bonus this mutation also reduces GVHD [3]!

On July 26th, 2012, Daniel Kuritzkes presented a study of two men with HIV who underwent bone marrow transplants but remained on antiretrovirals. These patients demonstrated a decrease in HIV DNA to the point that it became undetectable as well as a decrease in patient HIV antibody levels. Unlike the “Berlin” patient, the donors were not inherently immune to HIV due to a CCR5 deletion. Although this is promising, studies of HIV in the tissue still need to be conducted to confirm results, and the patients are still on antiretroviral therapy [11].

Tyrosinemia Type 1

Injection of bone marrow into mice that would normally die from tyrosinemia without intervention had restored liver function and survived. (Tyrosinemia type 1 means that you totally lack the enzymes necessary to metabolize tyrosine which leads to liver and kidney failure) It was found that only hematopoietic stem cells gave rise to these changes. Upon the biopsy of these mice it was found that large sections of the liver had been taken over by donor cells that could properly proves tyrosine. Studies in humans have shown improved liver function in hepatitis C patients [5].

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Procedures Involved

Irradiation to destroy cancer and subsequently bone marrow is the first step in the process [4]. The use of cyclophosphamide can be used instead of irradiation; it slows growth of cells and decreases immune response [6]. The transplant is then injected into the blood stream so that the cells can engraft into the bone [4].

The harvest is done under general anesthesia where 10 % of donors bone marrow is taken (about 2 pints) in 1-2 hours. The cells taken will be replaced in 4-6 weeks. The donor will be able to leave in a few hours or next morning. They will be sore and weak but are usually back to normal in 2-3 days. For the donors trouble the recipient’s insurance pays for the expenses [4].

Peripheral blood stem cell harvest is a several day process. For a few days before the procedure a shot is administered of filgrastim which causes the body to make and release stem cells into the blood. This can cause bone pain and headaches. Blood is taken out through a catheter in a large arm vein or chest vein and is put through a machine to separate out the stem cells. This takes 2-4 hours [4]. An allograft from peripheral blood has many T-cells and can have an increased instance of GVHD. The use of the drugs above helps this ratio. The process takes about 25 L in 4 hours [6].

The recipient of the bone marrow transplant will take anywhere from 2-6 weeks to return to a normal blood count. This includes the time required for the marrow to migrate into the bones, establish itself, and begin producing blood cells. During this time they are very susceptible to infections and may be given antibiotics [4].

Types of Transplants

Autologous

Cells are taken from the patient and then frozen. The patient is treated for their disease and then their bone marrow is transfused back into their bodies [4]. There is no risk of rejection but cancer cells may also be harvested. To combat this, the patient may have anticancer treatment first. Because there is no risk of rejection, there is no chance of GVHD, leading to an increase in reoccurrence because the cancer stem cells may not be killed. This type of transplant is more common these days because of decreased mortality and no GVHD, but the risk of relapse from possible contaminated cells and lack of GVHD may be greater than the benefit [6].

Allogeneic

Cells are taken from another person whose tissue is closely matched. For allogeneic transplants from a bone marrow donor there is a high chance of GVHD and infection from the time when the patient is immune-compromised [4].

Cord Blood Transplant

Cord blood may be used for children. The cells are free of cancer, have just enough GVHD, but they are more likely to be attacked and die before engraftment. This technique has been used by thousands of people but there are generally not enough stem cells for an adult patient. The match can be less exact, rich in cells but low in volume [6].

Mini-Transplant

When someone is too sick to wipe out their immune system they do it just enough treatment to kill some of the cancer, bone marrow, and immune system to allow for a donation. The new cells slowly take over hosts cells. This technique is not good for people with tons of cancer cells [4].

Side effects

2% of people will die from autologous transplants, <10% from allogeneic, and 40% from advanced cancer patients [6].

Common side effects are: graft-versus-host disease; infections; lung, kidney, liver, or heart problems; low thyroid function; fatigue, slowed growth and development; and infertility [4].

GVHD is prevented through the use of methotrexate which is also used to help with arthritis, it blocks enzymes involved in the immune system. GVHD decreases the chance of relapse because the new immune cells attack the cancer cells [6].

References

1. Parapia, L. A. (2007). Trepanning or trephines: a history of bone marrow biopsy. British Journal of Haematology.

2. Martin, Douglas (20 October 2010). "Dr. Georges Mathé, Transplant Pioneer, Dies at 88". New York Times.

3. Hutter, G. (2009). Transplantation of selected or transgenic blood stem cells – a future treatment for hiv/aids?.Journal of the International AIDS Society.

4. (2011). Stem cell transplant (peripheral blood, bone marrow, and cord blood transplants). American Cancer Society.

5. Lagasse, E. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature Medicine.

6. Copelan, E. A. (2006). Hematopoietic stem-cell transplantation. The New England Journal of Medicine.

7. Huzicka. (1997). Could bone marrow transplantation cure aids/: review. Medical Hypothesis.

8. Saxon, Wolfgang. (18 June 2003). “Robert A. Good, 81, Founder Of Modern Immunology, Dies”. New York Times.

9. Fernyhough, L. J. et al. (2013). “Relative recovery of haematopoietic stem cell products after cryogenic storage of up to 19 years”. Bone Marrow Transplantation.

10. Knox, Richard. (18 July 2012). “HIV Cure Is Closer As Patient's Full Recovery Inspires New Research.” NPR.

11. (26 July 2012). “New HIV Cure Research Released Today at the XIX International AIDS Conference (AIDS 2012).” International AIDS Society.