Bone Marrow Transplants, by Erinn Dandley, Max Nowak and Jean Smith

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Overview

Bone marrow transplantation is the process by which bone marrow is harvested from either a donor or the patient himself and administered intravenously to the patient [1]. Nine million potential bone marrow donors around the world are registered in databases that lead to donor-patient matches in over 50% of cases. Due to the time lapse from match to donation—three months—only about half of these matches are actually utilized [6]. Hematopoietic stem cells (HSC), the therapeutic component of bone marrow, are used mainly in the treatment of hematological and lymphoid cancers, with other potential applications in the treatment of HIV. This widespread application of HSCs is the motivation for continued research in bone marrow transplantation [6].

History

Reference 6

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 a 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 for research. 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 needle pierces 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 treat 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].

Human Bone Anatomy

Reference 12

Human bone is composed of compact bone, cancellous (spongy) bone, and myeloid tissue (red and yellow bone marrow) [12]. Yellow marrow contains fatty tissue whereas red marrow is rich in hematopoietic stem cells. At birth humans only possess red marrow, which gradually changes to yellow marrow in the long bones. In adults, most red marrow resides in the ends of the long bones as well as the pelvis, sternum, vertebrae, and skull.

The stem cells in red marrow give rise to various blood cells, including erythrocytes (red blood cells), leukocytes (white blood cells), and megakaryocytes (marrow cells that produce platelets) [12]. Lymphocytes (a type of leukocyte) are the only blood cells that mature outside of marrow in the lymphoid organs. Due to the role of bone marrow in producing cells for the cardiovascular and immune systems, red marrow transplants are useful to treat hematological and immune disorders, especially leukemia. Radiation therapy and chemotherapy easily damage bone marrow, but transplants can restore immunity and blood production after cancer treatment.

Diseases Treated Using Bone Marrow Transplants

Reference 6

Irradiation

High dose irradiation is rapidly fatal. Low dose irradiation damages the intestinal track and central nervous system, resulting in slower death from organ failure. Bone marrow transplants in humans were first conducted to save those that had been accidentally irradiated [6].

Leukemia

Leukemia, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), is a cancer of the blood [13]. Excessive amounts of abnormal white blood cells accumulate in bone marrow but never mature and cannot properly fight infection. The cancerous cells fill up the bone marrow leaving little room for healthy white blood cells, red blood cells, and platelets. Bone marrow transplants are often involved in leukemia treatment depending on the type of cancer [13]. ALL is typically resolved with chemotherapy and radiation therapy. Certain subtypes and relapses of ALL require additional treatment with bone marrow transplants. AML and CML commonly use bone marrow transplants to fight the cancer by inducing an immune reaction against the cancerous cells, along with radiation therapy, chemotherapy, and blood transfusions. This immune reaction, called graft versus leukemia (GVL), is closely related to and possibly inseparable from a potentially dangerous complication of bone marrow transplants called graft-versus-host-disease (GVHD) [14]. Leukemic cells are replenished by leukemic stem cells much as normal cells are renewed from noncancerous stem cells. Chemotherapy attacks fast growing adult cancer cells but cannot attack quiescent cancerous stem cells. GVHD attacks and kills the cancerous stem cells left behind after chemotherapy. 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].

Lymphoma

Lymphoma, including Hodgkins and non-Hodkins lymphoma, is a cancer of the lymphatic system [13]. Abnormal lymphocytes spread from the lymph nodes to other areas of the body including bone marrow, lungs, and liver. Hodgkins lymphoma is characterized by a predictable pattern of progression through the lymphatic system whereas non-Hodgkins lymphoma includes a variety of subtypes of this cancer that spread in less predictable ways. Lymphoma treatment includes radiation therapy and chemotherapy, followed by bone marrow transplants to replace damaged tissue or fight relapses after initial treatment.

Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a rare bone marrow disease that typically affects adults over the age of 60 but can also affect children and younger adults [13]. MDS results in insufficient production of all types of blood cells. Produced cells do not mature or function properly. Bone marrow transplants usually cure MDS.

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

Tyrosinemia type 1 results from a lack of enzymes necessary to metabolize tyrosine, leading to liver and kidney failure. Mice that would normally die from tyrosinemia without intervention had restored liver function following injection of hematopoietic stem cells from bone marrow. A biopsy found that large sections of the liver had been taken over by differentiated hematocytes that could properly metabolize tyrosine. Studies in humans have shown improved liver function in hepatitis C patients [5].

Reference 5

Other Diseases

Autologous bone marrow transplants can be used to treat rheumatoid arthritis and multiple sclerosis. Allograft bone marrow transplants can be used to treat sickle cell anemia, thalassemia, and Wiskott-Aldrich syndrome [6]. Aplastic anemia, and Fanconi anemia can also be treated with bone marrow transplants [13].

Bone Marrow Transplant Procedures

Types of Transplants

Autologous

Cells are harvested from the patient and frozen before cancer treatment, then transfused back into the patient after treatment [4]. Autologous bone marrow transplants carry no risk of rejection or GVHD but cancer cells can be harvested during the donation process. Any harvested cancer cells are selectively removed after incubation with antibodies that bind only to hematopoietic stem cells [15]. Without inducing GVHD, autologous transplants result in increased rates of reoccurrence because the cancer stem cells may not be killed. This type of transplant is currently common due decreased mortality and lack of GVHD, but the risk of relapse may be greater than the benefit [6].

Allogeneic

Cells are harvested from a donor whose tissue is closely matched. Allogeneic transplants carry a high chance of GVHD and infection during the time when the patient is immune-compromised [4].

Cord Blood Transplant

Cord blood may be used for children [6]. Stem cells are harvested from the umbilical cord of a newborn infant, tested, and frozen until needed for a transplant [16]. Umbilical stem cells differentiate into blood cells faster than stem cells harvested from bone marrow. The cells are free of cancer and cause slight GVHD, but are more likely to be attacked and die before engraftment [6]. This technique has been used by thousands of children but generally, not enough stem cells are available for an adult patient. The match can be less exact, and uses a low in volume rich in cells.

Mini-Transplant

When a sick patient cannot sustain a full transplant that would weaken the immune system, a smaller transplant may attack part of the cancer, bone marrow, and immune system. The new cells slowly take over the host cells. This technique is not ideal for treatment of advanced cancer [4].

Donation Process

Bone Marrow Transplant Animation (Reference 17)

Reference 15

Donors register in bone marrow databases so that their marrow can be matched to patients in need of transplants. Matches are determined by the typing of human leukocyte antigens (HLAs) [16]. Of the 100+ known HLAs, only a few are critical to the successful engraftment of bone marrow transplants. HLAs are coded on a single chromosome, so siblings have a 25% chance of being a full match.

Bone marrow is frequently donated via peripheral stem cell harvest [4]. Peripheral blood stem cell harvest is a several day process. In the few days before the procedure, daily shots of filgrastim induce production and release of HSCs into the blood. When the HSCs reach a sufficient level in the blood, they are harvested through apheresis [16]. Blood is drawn from a catheter in a large arm vein or chest vein, circulated through a machine to separate out the stem cells, and returned through another catheter in the opposite arm over a 2-4 hour period [4]. Several sessions are required to obtain enough stem cells for successful engraftment [16].

In some cases a more invasive surgical harvest may be required. The harvest is done under general anesthesia where 10% of the donor’s bone marrow (about 2 pints) is harvested from the pelvis in 1-2 hours [4]. The removed cells will be replaced in 4-6 weeks. The donor can return home in a few hours or the next morning, with a full recovery after 2-3 days. For the donors trouble the recipient’s insurance pays for the expenses.

Transplantation Process

Radiation therapy to destroy cancer, and subsequently bone marrow, is the first step in the process [4]. Cyclophosphamide can be used instead of irradiation to reduce cell growth and decrease the potential immune response after transplantation [6]. Following cancer treatment, the transplant is injected into the recipient’s bloodstream so that the cells can engraft into the bone [4]. Depending on the type of transplant, different preparations must be made to the transplant. An allograft from peripheral blood contains many T-cells and can have an increased instance of GVHD, which is mitigated by the administration of cyclophosphamide [6]. Autologous bone marrow transplants require removal of cancer cells before injection, which is accomplished by tagging the desired HSCs with selective antibodies [15].

The recipient will require a 2-6 week recovery period to return to a normal blood count. During this time, marrow migrates into the bones, engrafts, and begins producing blood cells. Recovering bone marrow transplant recipients are extremely susceptible to infections, which are prevented with the administration of antibiotics [4].

Cost

The cost of the transplant and recovery varies depending on the method used [18]. An autologous transplant may cost around $360,000, comparable to the cost of a single organ transplant. An allogeneic transplant is much more expensive, around $800,000, comparable to the cost of a double lung transplant. The recipient’s insurance pays for the expenses of transplantation and donation [4].

Side effects

Donors who undergo peripheral blood stem cell harvest may experience bone pain and headaches from the filgrastim medication [4]. Donors who undergo surgical harvest experience soreness and weakness but are usually back to normal in 2-3 days [4].

Common side effects for transplant recipients include GVHD, infections, low thyroid function, fatigue, slowed growth and development, infertility, and lung, kidney, liver, or heart problems [4]. GVHD is prevented through the use of the arthritis drug methotrexate, which blocks enzymes involved in the immune system. GVHD decreases the chance of relapse, because the new immune cells attack the cancer cells [6].

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

12. Singh S. (c2014) Bone Marrow. In: Encyclopaedia Britannica. [Internet] Chicago (IL): Encyclopaedia Britannica, Inc.: [cited 2014 Feb 2]. Available from: http://www.britannica.com/EBchecked/topic/72944/bone-marrow

13. Conditions We Treat [Internet]. [updated 2014]. Boston (MA): Dana Farber/Boston Children’s Cancer and Blood Disorders Center; [cited 2014 Feb 2]. Available from: http://www.danafarberbostonchildrens.org/Centers-and-Programs/Stem-Cell-Transplant-Center/Conditions.aspx

14. Slavin, S., A. Ackerstein et.al., The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD? PubMed 1990. 6(3): p.155-61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2252954

15. Singh S. (c2014) Bone Marrow Transplant. In: Encyclopaedia Britannica. [Internet] Chicago (IL): Encyclopaedia Britannica, Inc.: [cited 2014 Feb 2]. Available from: http://www.britannica.com/EBchecked/topic/72962/bone-marrow-transplant

16. Bone Marrow Transplantation [Internet]. Boston (MA): Johns Hopkins Medicine; [cited 2014 Feb 2]. Available from: http://www.hopkinsmedicine.org/healthlibrary/conditions/hematology_and_blood_disorders/bone_marrow_transplantation_85,P00086/

17. Bone Marrow Transplantation - Animation [Internet]. Chennai (India): Medindia; [cited 2014 Feb 2]. Available from: http://www.medindia.net/animation/bone-marrow-transplantation.asp

18. How much does a transplant cost? [Internet]. Memphis (TN): National Foundation for Transplants: [cited 2014 Feb 3]. Available from: http://www.transplants.org/faq/how-much-does-transplant-cost