Explore the important and growing world of hematopoietic stem cell transplantation in ReFlections. HSCT is the standard of care for many hematological malignancies and has found new utility in the treatment of immunological and hereditary conditions.
Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure which is today the standard of care for many hematological malignancies.
In recent years its purview has expanded: the procedure has found new utility in the treatment of immunological and hereditary conditions; and other novel areas are being explored as well. Because of this broadening scope of applicability and several recent procedural improvements, insurers need to understand HSCT today. This article provides an overview.
Hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, is the procedure wherein hematopoietic stem cells (HSC) that is, blood-forming stem cells 鈥 are transplanted with the intention of repopulating the recipient鈥檚 bone marrow with new, healthy cells. The donor can be the actual patient, a relative, or even an unrelated individual.
The first human allogeneic bone marrow transplant 鈥 transplantation from an outside donor 鈥 was performed in 1957 by physician and cancer researcher Dr. E. Donnall Thomas, who is also known as the father of bone marrow transplantation. Initial results were disappointing, with very high mortality due to graft failure, graft vs. host disease (GVHD), and primary disease relapse.
The procedure did, however, establish that bone marrow infusion could lead to hematological reconstitution in patients with acute leukemia.1 Major progress came in the late 1960s with the discovery of the human leukocyte antigen (HLA) system by immunologists Dr. Jean Dausset, Dr. Johannes Joseph Van Rood, and Rose O. Payne, Ph.D. The HLA is what enables the human immune system to distinguish its own proteins from those of foreign entities.2, 3 Its discovery permitted unrelated donors to be typed and matched to recipients, which increased the success rate of these transplants. In 1980, Dr. Dausset received the Nobel Prize in Physiology or Medicine, together with Baruj Benacerraf and George Davis Snell, for their discoveries of 鈥済enetically determined structures on the cell surface that regulate immunological reactions.鈥 Dr. Dausset was recognized for his identification of human leukocyte antigens and the genes that code for them. In 1990, Dr. Thomas received a Nobel Prize in Physiology or Medicine as well for his work in cell transplantation.
Today, HSCT is standard of care for many hematological malignancies, and hematopoietic stem cells are the most routinely transplanted type of adult stem cell. More than one million HSCTs have reportedly been performed worldwide during the past six decades; this number is steadily rising,6 and survival rates are improving.
Stem cells are nonspecialized (or basic or generic) cells of multicellular organisms. All stem cells have two fundamental characteristics: the ability to duplicate precisely by cell division, known as self-renewal, so that the daughter cells are exactly the same as the parent cells; and differentiation, which refers to the ability of these cells to mature into a wide range of specialized cells.
There are three main types of stem cells:
Multipotent, also known as adult stem cells or somatic stem cells, which are found throughout an organism after cell differentiation and development. Multipotent cells can differentiate into a number of cell types, but only those in closely related cell families. Hematopoietic, neural, and mesenchymal cells are types of multipotent stem cells.
The two types of HSCT procedures utilized today are autologous, where the donor and the patient are the same, and allogeneic, where the donor is other than the patient.
The advantages of autologous transplantation include faster patient cell count recovery, less transplant-related morbidity, shorter hospital stays, and reduced cost compared with allogeneic grafts. Relapse of the underlying malignancy is the major risk.5
Allogeneic transplants consist of hematopoietic stem cells from an external donor. An advantage of an allogeneic graft is that the donor鈥檚 immune system can contribute significantly to the elimination of cancer via graft vs. tumor (GVT) effect.6 The risk of disease relapse is low, but the procedure is associated with graft vs. host disease (GVHD).
Indications for HSCT are constantly being expanded and refined, as research progresses and new efficacies are discovered (Table 1, below). The American Society for Blood and Marrow Transplantation (ASBMT) and the European Blood and Marrow Transplantation Group
(EBMT) have published guidelines that classify the many conditions for which HSCT is an indicated treatment.
The guidelines provide three categories of indications: standard of care, including clinical option; developmental; and not generally recommended.
The majority of HSCTs performed for lymphoid malignancies, are autologous, while most done for myeloid malignancies are allogeneic. Autologous HSCT is also preferred for patients with autoimmune disorders.7, 8, 9
Table 1: Indications for HSCT | |
Category | Indications |
Hematologic malignancies | 64% lymphoid malignancies
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25% myeloid malignancies
| |
Solid tumors | 4% solid tumors
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Nonmalignant disorders | 7% nonmalignant disorders
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The availability of various sources of stem cells as well as alternative donor options have made it possible to offer HSCT as a treatment option for a wider group of patients.
Hematopoietic stem cells can come from three sources: harvested bone marrow, peripheral blood stem cells, and umbilical cord blood.7
Bone marrow cells are harvested from donors in a surgical procedure. They are extracted either from the hip bone (specifically, the posterior iliac crest) or from the sternum. Since the 1990s, scientists have been able to collect stem cells directly from peripheral blood. The procedure involves an injection of granulocyte colony stimulating factor (G-CSF), which causes marrow stem cells to migrate into circulating blood. Peripheral blood stem cells (PBSCs) can then be collected by apheresis, which is a much less invasive procedure than bone marrow collection. Over the past decade, PBSCs have become the preferable stem cell source for many transplant centers, accounting for around 75% of all HSCTs.10
PBSC patients benefit from faster engraftment, but the risk is higher rates of GVHD.10
High-level evidence has shown that there is no difference in overall and disease-free survival between bone marrow and PBSC HSCTs.11
Umbilical cord blood (UCB) cells are an alternative source to bone marrow cells and PBSCs. These cells, as the name implies, are extracted from the umbilical cord after birth. UCB offers several advantages: easier availability, higher tolerable HLA disparity as the cells are naive, and lower risk of GVHD and relapse.
The strongest determinant of outcomes for allogeneic HSCT is donor-recipient human leukocyte antigen (HLA) matching.12 HLA matching identifies the HLA A, B, C (Class I) and DR, DQ, DP (Class II) loci present on donor and recipient cells. Each person has two types of A, B, C, and DR antigens, one inherited from each parent.
The best donor for an allogeneic HSCT is either an HLA-matched sibling or an unrelated donor who is a complete HLA match (8/8 or 10/10). Unfortunately, less than 30% of patients have a sibling who is a complete match.13 If an adult-matched sibling or matched unrelated donor (MURD) cannot be identified, recent advances in HLA research have enabled three alternative donor options:
An exciting new development is the use of either autologous or unrelated UCB cells in therapies for diseases such as cerebral palsy, hypoxic ischemic encephalopathy, and dilated cardiomyopathy.15
HSCT generally requires four steps, depending on the source of the stem cells:
Table 2: Conditioning regimens 鈥 favorable and unfavorable factors | |
Myeloablative | Nonmyeloablative or Reduced Intensity |
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Although outcomes of HSCT tend to be good and patients show considerable improvement over time, the procedure is associated with significant related morbidity, mortality, and long-term health issues.
Major complications include:
Infections are the most important cause of morbidity and mortality during the post-transplant period of neutropenia. In the pre-engraftment period (0-30 days after transplantation) bacterial infections followed by fungal infections (e.g., Candida, Aspergillus) predominate due to low white blood cell counts and the disruption of normal barrier defenses.17 The most important pathogens in the early post-engraftment period (30 to 100 days) are viruses such as cytomegalovirus (CMV) and other pathogens such as Pneumocystis and the previously mentioned Aspergillus.
In later stages (>100 days post transplantation), the immune system recovers, reducing the risk of opportunistic infections. Chronic GVHD (discussed in the next section) and continued immunosuppression can lead to infection with viruses such as CMV, varicella zoster virus (VZV or shingles), and Epstein-Barr virus (EBV), as well as with encapsulated bacteria such as Hemophilus influenzae and Streptococcus pneumoniae.18,19
Graft vs. Host Disease (GVHD), which is the major complication of allogeneic HSCT, is an immunologically mediated reaction of donor cells (the graft) to host (or recipient) cells. GVHD develops in >50% of these patients despite prophylaxis and can be life-threatening.
For GVHD prophylaxis, patients receive immunosuppressive drugs, most commonly a combination of cyclosporine and methotrexate or mycophenolic acid. In contrast to organ transplantation, GVHD prophylaxis can be tapered off and stopped in patients who do not develop GVHD after six to 12 months.20
GVHD can be acute or chronic. Although GVHD has traditionally been classified as acute or chronic based on a cutoff of 100 days after transplantation, it is now widely recognized that there is extensive overlap in the time course at presentation. Each is a clinically distinct entity with very different pathophysiologic mechanisms.
Graft failure/rejection is an uncommon but serious complication of HSCT. It is defined as either lack of initial engraftment of donor cells (primary graft failure) or loss of donor cells after initial engraftment (secondary graft failure). Risk factors include RIC/NMA regimens, UCB transplants, and HLA- mismatched transplants.24
Post-transplant lymphoproliferative disorders (PTLD), which are almost exclusively seen in allogeneic HCT recipients and comprise a heterogeneous group of lymphoid proliferations primarily involving B-lymphocytes, which result from EBV infection.
Hematologic malignancies, such as MDS and AML.
Solid cancers, with lifelong cancer screening recommended for all HCT survivors in accordance with established guidelines.
HSCT outcomes are influenced by the patient鈥檚 age, the nature and stage (if cancer) of the disease, and transplant- specific variables such as donor/recipient histocompatibility and the time interval from diagnosis to transplant.
Disease relapse is the main cause of treatment failure in the first two to four years after transplantation. Patients who do not relapse through this time period have relatively high rates of subsequent survival.
Cumulative chemotherapy and radiation exposures can injure normal tissues, leading to premature onset of chronic health conditions such as subsequent neoplasms, congestive heart failure, coronary artery disease, and endocrine and musculoskeletal abnormalities.
Pediatric HSCT survivors are more likely to experience psychological distress and low quality of life in adulthood compared with the general population.26
Long-term HSCT survivors need continued lifelong surveillance for screening, early detection, and timely treatment of late complications. Although studies vary in methodology and patient characteristics, together they indicate high probability of long-term survival in this patient population, although their life expectancy continues to lag that of age- and gender-matched peers from the general population for at least 15 to 20 years after HSCT.27
From an underwriting point of view, HSCT is a curative therapy for many malignant and nonmalignant hematological diseases. Although the primary disease is a major factor, individuals who have undergone HSCT still have long-term effects and might be offered life cover with a mild-to-moderate risk assessment a few years after a complication-free time interval has passed. HSCT survivors may have morbidity issues such as treatment- related chronic conditions as well as psychological distress and low quality of life. Therefore, offering living benefits may not be feasible.
HSCT is covered as a major payout in many critical illness products. Definitions vary, and a few points raise concern:
HSCT is a curative treatment for many hematological malignancies as well as immunological and hereditary conditions. Over the years, several advances, such as new conditioning regimes (NMA and RIC) and alternative donor and cell source options, have made HSCT safer, leading to increasing numbers, expanding indications, and improved patient survival. In the coming years, HSCT is likely to become more common, efficient, and effective.
