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What Is Bone Marrow Transplantation

What Is Bone Marrow Transplantation

Executive Summary

Bone marrow transplantation is considered the specific protocol in medical science. It is also known as hematopoietic stem cell transplantation (HSCT) in the medical domain. It is categorized into two significant subtypes: autologous, where a patient donates the marrow stem cells to themselves, and allogeneic, which is a complex process of bone marrow transplantation where a patient receives the stem cell graft from a healthy donor. The patients undergoing bone marrow transplantation are recommended for regular follow-ups under the observation of qualified management by a multidisciplinary team. This medical treatment involves preparing and caring for a healthy donor volunteer who must undergo a medical procedure for stem cell collection.

Haematopoietic stem cells (HSCs) are adult stem cells that represent almost 0.05 to 0.5% of the cellular density of the normal bone marrow. HSCs are characterized by in vitro culture techniques such as immunofluorescence and flow cytometry. Hematopoietic stem cell transplantation (HSCT) involves the regeneration of haematopoiesis, and the recipient’s immune system is found within the bone marrow. Aphaeresis is a process of collecting peripheral blood with the aid of specific cytokines. Around 47% of the autologous HSCT is performed in case of multiple myeloma, 30% for non-Hodgkin lymphoma, 11% for Hodgkin lymphoma, and 3% for leukaemia. Other indications for autologous HSCT include autoimmune diseases such as multiple sclerosis, systemic sclerosis, and Crohn’s disease and solid tumors such as sarcoma, germinal tumors, and neuroblastoma.

Approximately 50% of the transplants in case of acute myeloid leukaemia and ALL account for allogeneic HSCT. Other indications for allogeneic HSCT include lymphoma, myeloma, and hematologic disorders like aplastic anaemia and thalassemia. Integrating bone marrow transplantation involves the action mechanism of stem cell transplant against malignancy. It entirely depends upon the effect of the graft and donor immunity against malignant cells in recipients. Bone marrow transplantation is considered an effective procedure for treating different cancer types. Some involve leukaemias, bone marrow failures, hemoglobinopathies (thalassemia, sickle cell disease), immunodeficiencies, and other HSC transplant-based treatments for solid tumors and other genetic disorders such as lysosomal storage disease along with autoimmunity.

Introduction

Bone marrow transplantation is considered the specific protocol in medical science. It is also known as hematopoietic stem cell transplantation (HSCT) in the medical domain. In today’s era, bone marrow transplantation has become standard care for hematologic malignancies and congenital or acquired disorders of the hematopoietic system. It is mainly integrated as a therapeutic option in case of the occurrence of solid tumors. The expansion in the integration of bone marrow transplantation for different diseases across the globe while evolving modern techniques. Bone marrow transplantation is employed for novel indications in treating autoimmune and inherited metabolic disorders (Daikeler et al., 2009; Hirano et al., 2006). It includes administering healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow. It helps increase the bone marrow function that depends upon the treatment of the disease in eliminating the tumor cells with malignancy or generating the functional cells that replace the dysfunctional cells in certain disorders such as immune deficiency syndromes, hemoglobinopathies, and other diseases. 

Bone marrow transplantation is categorized into two significant subtypes: autologous, where a patient donates the marrow stem cells to themselves, and allogeneic, which is a complex process of bone marrow transplantation where a patient receives the stem cell graft from a healthy donor. As per the European Registry of Hematopoietic Stem Cell Transplantations reports in 2012, approximately 42% of all the cases of bone marrow transplantation were found to be allogeneic (Passweg et al., 2012). The allogenic bone marrow transplantation involves the process of stem cell transplantation where a stem cell donor is matched with their related siblings or any other family member who is closely related (haploidentical). The stem cell grafts are obtained from non-related volunteers and cryopreserved cord blood units. This is the reason for the increased risk of the volunteer donors and the availability of cord blood units.

The allogeneic stem cell transplantation is performed by qualified medical staff while providing appropriate conditions with the patient’s environmental isolation, cellular processing transplantation laboratory, and apheresis unit. The patients undergoing bone marrow transplantation are recommended for regular follow-ups under the observation of qualified management by a multidisciplinary team. This medical treatment involves preparing and caring for a healthy donor volunteer who must undergo a medical procedure for stem cell collection. Allogeneic stem cell transplantation is concerned with an increased mortality and morbidity rate along with high costs (Khera et al., 2014).

Hematopoietic stem cells and transplantation

Haematopoietic stem cells (HSCs) are adult stem cells that represent almost 0.05 to 0.5% of the cellular density of the normal bone marrow. HSCs are characterized by in vitro culture techniques such as immunofluorescence and flow cytometry. Hematopoietic stem cell transplantation (HSCT) involves the regeneration of haematopoiesis, and the recipient’s immune system is found within the bone marrow. Aphaeresis is a process of collecting peripheral blood with the aid of specific cytokines. The hematopoietic stem cells from umbilical cord blood are used successfully. 

Historical aspect of bone marrow transplantation

Bone marrow transplantation was initially studied among humans in the year the 1950s and is derived from the study done on mice models that represented the infusion of healthy bone marrow components into a myelosuppressive bone marrow which has the chances of inducing recovery of its function in the recipient (Barnes et al., 1956). The clinical application of these animal-based models was generated in humans by performing the first bone marrow transplantation in monozygotic twins in New York in 1957 (syngeneic transplant) suffering from acute leukaemia (Thomas et al., 1957). The first successful allogeneic bone marrow transplant was reported in Minnesota in 1968 for a paediatric patient having severe combined immunodeficiency syndrome (Gatti et al., 1968). Hence, the allogeneic and autologous stem cell transplants were integrated globally. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogeneic transplants were performed in the United States in 2016, with a higher number of autologous transplants with a steady and higher increase of autologous compared to allogenic (Pasquini et al., 2010). 

Current indications for Hematopoietic stem cell transplantation

Approximately 58% of the transplants done in Europe are autologous HSCT. Around 47% of the autologous HSCT is performed in case of multiple myeloma, 30% for non-Hodgkin lymphoma, 11% for Hodgkin lymphoma, and 3% for leukaemia. Other indications for autologous HSCT include autoimmune diseases such as multiple sclerosis, systemic sclerosis, and Crohn’s disease and solid tumors such as sarcoma, germinal tumors, and neuroblastoma. Approximately 50% of the transplants in case of acute myeloid leukaemia and ALL account for allogeneic HSCT. Other indications for allogeneic HSCT include lymphoma, myeloma, and hematologic disorders like aplastic anaemia and thalassemia. These indications of HSCT have tended to change over time. The current movements may also change when new therapies are integrated, resulting in recent appearances. The current indications for autologous and allogeneic stem cell transplantation are represented in the below table:

Autologous transplantationAllogeneic transplantation
MalignanciesMultiple myelomaAcute myeloid leukaemia
Non-Hodgkin lymphomaAcute lymphoblastic leukaemia
Hodgkin diseaseChronic myeloid leukaemia
Acute myeloid leukaemiaMyelodysplastic syndromes
NeuroblastomaMyeloproliferative neoplasms
Ovarian cancerNon-Hodgkin lymphoma
Germ-cell tumorsHodgkin disease
Multiple myeloma
Juvenile chronic myeloid leukaemia
Non-malignant disordersAutoimmune diseaseAplastic anaemia
AmyloidosisParoxysmal nocturnal hemoglobinuria
Fanconi’s anaemia
Diamond-Blackfan anaemia
Thalassemia major
Sickle cell anaemia
Severe combined immunodeficiency
Wiskott–Aldrich syndrome
Inborn errors of metabolism
Congenital neutropenia syndromes

Table 1: Current indications for autologous and allogeneic stem cells transplantation

Technique of bone marrow transplantation

Integrating bone marrow transplantation involves the action mechanism of stem cell transplant against malignancy. It entirely depends upon the effect of the graft and donor immunity against malignant cells in recipients. It is explained by depicting the study that involved 2000 patients having different types of leukaemia. These patients have undergone stem cell transplantation, resulting in the lowest rate of relapses among those who received non-T-cell-depleted bone marrow cells and those who developed GVHD compared with those receiving T-cell-depleted stem cells did not develop GVHD, and patients who received syngeneic grafts. These results reveal that donor cellular immunity plays a vital role in engraftment against tumor cells. The action mechanism among patients with autoimmune diseases is considered secondary to the increase in T-cell regulatory function, which promotes immune tolerance. In the case of hemoglobinopathies, the transplanted stem cells produce functional cells after engraftment that replaces the diseased cells. 

Efficacy of bone marrow transplantation in cancer treatment

The blood-forming cells and leukocytes are damaged in case of aggressive tumors among cancer patients. The damage is possible due to integrating a high dose of chemotherapy to remove all types of cancer cells. Hence, the patient requires an intravenous infusion of autologous or allogeneic hematopoietic stem cells in this condition. These HSCs evolve a process that results in the quick migration of stem cells that niches within the bone marrow. The transplanted HSCs undergo an engraftment process after encountering the bone marrow and produce specialized blood cells. Hence, bone marrow transplantation is considered an effective procedure for treating different cancer types. Some involve leukaemias, bone marrow failures, hemoglobinopathies (thalassemia, sickle cell disease), immunodeficiencies, and other HSC transplant-based treatments for solid tumors and other genetic disorders such as lysosomal storage disease along with autoimmunity. The prevalence and severity of Graft versus host disease (GvHD) reduction is observed after integration to bone marrow transplantation. 

One of the effectiveness of using bone marrow transplantation in cancer treatment has evolved the contribution of appropriate donors with better outcomes in the treatment (McCurdy et al., 2016). The techniques used in bone marrow transplantation have benefited the patients in terms of prolonged survival rates (McCurdy et al., 2018). The bone marrow cells are the source of hematopoietic stem cells, which have been modified in different ways to reduce the prevalence of Graft versus host disease (GvHD). It integrates the complete removal of the T cells showing efficacy. Decreasing the number of contaminating T cells is effective in cancer patients. It further helps mitigate the risk of relapse by inducing donor lymphocyte infusions through HSC transplantation (Dazzi et al., 2000). It works by providing long-term curative treatment. 

Complications in bone marrow transplantation

The significant complications of bone marrow transplantation occur due to various factors involving toxicity associated with the conditioning treatment, the release of specific cytokines that cause cell damage, immunological processes associated with all-HSCT (especially GVHD) and the effect of immunosuppressive drugs. Some side effects are observed among the patients undergoing bone marrow transplantation. It appears in the form of signs and symptoms that result due to early toxicity from the conditioning treatment. Nausea, sickness, diarrhoea, mucositis, haemorrhagic cystitis (generally associated with the administration of cyclophosphamide or due to certain viral infections) and alopecia are some of the common side effects which occur in the form of complications in some of the patients. Also, various multifactorial complications are observed among the patients that majorly involve infections that range from standard to severe, hepatic veno-occlusive disease, thrombotic microangiopathy and idiopathic interstitial lung disease. Immunological complications are also observed in some patients involving graft rejection which is not so common, along with GVHD that occurs due to the pathophysiological bases of the transplantation. These complications are exclusive to allo-HSCT. Autoimmune disorders can also develop, in particular cytopenia. Also, late complications are observed among the patients, majorly involving endocrine diseases such as thyroid, growth disorders, osteoporosis, etc.), sterility, neurological disorders, leukoencephalopathy, cataracts, or the development of secondary tumours.

References

  1. Daikeler T, Hügle T, Farge D, et al. Allogeneic hematopoietic SCT for patients with autoimmune diseases. Bone Marrow Transplant. 2009;44:27–33. doi: 10.1038/bmt.2008.424. 
  2. Hirano M, Martí R, Casali C, et al. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE. Neurology. 2006;67:1458–60. doi: 10.1212/01.wnl.0000240853.97716.24.
  3. Passweg JR, Baldomero H, Peters C, et al. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant. 2014;49:744–50. doi: 10.1038/bmt.2014.55.
  4. Khera N, Emmert A, Storer BE, Sandmaier BM, Alyea EP, Lee SJ. Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens. Oncologist. 2014;19:639–44. doi: 10.1634/theoncologist.2013-0406.
  5. BARNES DW, CORP MJ, LOUTIT JF, NEAL FE. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J. 1956 Sep 15;2(4993):626-7. 
  6. THOMAS ED, LOCHTE HL, LU WC, FERREBEE JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957 Sep 12;257(11):491-6. 
  7. Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968 Dec 28;2(7583):1366-9.
  8. Pasquini MC, Wang Z, Horowitz MM, Gale RP. 2010 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. Clin Transpl. 2010:87-105.
  9.  McCurdy SR, Fuchs EJ. Selecting the best haploidentical donor. Semin Hematol. (2016) 53:246. 10.1053/j.seminhematol.2016.08.001
  10. McCurdy SR, Zhang M-J, St. Martin A, Al Malki MM, Bashey A, Gaballa S, et al.. Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide. Blood Adv. (2018) 2:299. 10.1182/bloodadvances.2017014829 
  11. Dazzi F, Szydlo RM, Craddock C, Cross NCP, Kaeda J, Chase A, et al.. Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood. (2000) 95:67–71. 

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