Bone Marrow Transplantation

Written by Lloyd Damon, M.D., Jeffrey Wolf, M.D. and Charles Linker, M.D.

Introduction

The bone marrow is the organ responsible for the production of blood cells. Bone marrow transplantation (also called stem cell transplantation) is a treatment used primarily for blood and bone marrow cancers (called hematologic malignancies), and also for some other cancers and benign bone marrow conditions, which utilizes the intravenous infusion of hematopoietic (bone marrow derived) stem cells -- cells that have the property of being able to reconstitute the bone marrow. As hematopoietic stem cells (HSC) are now primarily collected from the blood stream rather than the bone marrow, bone marrow transplants are now called hematopoietic stem cell transplants (HSCT).

For most HSCT, the patient is treated with high-dose chemotherapy with or without total body irradiation (TBI) with the goal of killing the patient’s cancer. This high-dose therapy also destroys the patient’s bone marrow, and this is replenished with healthy HSC either from a donor (allogeneic HSCT) or from the patient him/herself (autologous HSCT). These HSC are given to the recipient through an intravenous infusion, so no surgery is involved. The HSC “home” to the bone marrow and spleen, lock into these niches, and regenerate the bone marrow, restarting blood cell production. Unlike most other organs, bone marrow is capable of regeneration, a property of the hematopoietic stem cell.

HSCT has been utilized to treat human disease for over four decades. In 1990, Dr. E. Donnell Thomas won a Nobel Prize in Medicine for his pioneering work in HSCT at the Fred Hutchinson Cancer Center in Seattle. Due to the intensity of destructive therapy delivered to patients just before the HSCT, and for additional post-transplant reasons, HSCT is an inherently difficult and risky treatment. Depending on a number of factors, the treatment-related death rate from HSCT ranges from 1% to 40%, making it the most dangerous of all organ transplants. On the other hand, the potential benefits are enormous, such as cure of a malignancy for which there are no other curative options, or in other instances, achieving the remission of a malignancy with the expectation of longer survival (such as in multiple myeloma). In each individual patient considered for HSCT, the potential benefits of the transplant must outweigh its potential risks.

Stem Cells

Stem cells are primitive cells that demonstrate two defining properties: 1) self-renewal capacity, and 2) potentiality. Stem cells can recreate themselves, assuring an inexhaustible long-term pool of identical cells with potentiality. Potentiality refers to the ability of stem cells, under the appropriate conditions and stimuli, to differentiate and produce less primitive cells, ultimately culminating in functional tissues and organs. As an example, the HSC has the potential to produce all types of blood cells, including white blood cells (leukocytes), red blood cells, and platelets. The HSC also has the ability to produce lymphocytes, cell of the immune system. It is the HSC that regenerates bone marrow and blood production after bone marrow destructive therapy has been administered, and is the critical component of HSCT.

The human hematopoietic stem cell is primarily identified by the specific expression of certain proteins on the surface of the cell. One protein, called CD34, is present on all HSC and is the surrogate ”marker” of the human HSC. CD34 is the measure of the quantity of HSC collected to be used for HSCT in humans. Another HSC surface protein, called CRXC4, links to bone marrow supporting cells (called stromal cells) with the SDF-1 protein on their surface, in a lock-and-key fashion, in order to anchor the HSC to the bone marrow compartment. Human HSC remain anchored in the bone marrow under normal conditions. The CRXC4-SDF-1 linkage can be broken by certain medications, such as chemotherapy or granulocyte-colony stimulating factor (G-CSF), which release HSC into the blood stream, referred to as stem cell mobilization. Stem cell mobilization permits HSC to be collected from the blood stream rather than from the pelvic bone marrow by the older technique of surgical bone marrow harvest.

Allogeneic HSCT

Definition

Allogeneic refers to something other than oneself. In the case of allogeneic HSCT, it refers to the HSCT of HSC from another person. This has the advantage that donor HSC will not contain any malignant cells which can re-grow the cancer after the patient has been treated with high-dose anti-cancer therapy. . However, when HSC cells are collected from the donor, also collected are mature immune cells, called T-lymphocytes (T-cells). In the best case, donor T-cells may recognize the recipient’s cancer cells as ”foreign” and attack and destroy them, the so-called graft-vs-malignancy (GVM) effect. This is the major benefit of allogeneic HSCT, resulting in fewer cancer relapses. On the other hand, these donor T-cells may recognize the recipient (“host”) as foreign, and start an immune attack on the recipient’s normal tissues and organs, called graft-vs-host disease (GVHD). GVHD can be fatal and is the major risk associated with allogeneic HSCT.

GVHD and GVHD Risk

The risk of GVHD is the most important factor in determining the suitability of a potential allogeneic HSC donor. In most instances, the donor needs to be tissue (HLA) matched or near-matched with the recipient, otherwise GVHD is too prevalent. HLA refers to the Human Leukocyte Antigens. HLA antigens are proteins expressed on the surface of white blood cells (leukocytes) that are important in activating or modulating immune responses to external or internal invading entities (i.e., microorganisms, viruses, foreign toxins or proteins, cancer cells, etc.). HLA antigens strongly activate and modulate the T-cell response to foreign tissues and mediate the rejection of transplanted organs. The important transplant-related HLA antigens are called A, B, C, Dr, and Dq (two of each, for a total of 10 “match points”). Close HLA matching of HSC donors to their recipients’ results in fewer deaths due to GVHD and only rare rejections of the HSC graft. Acceptable HLA matches are usually 10/10 or 9/10 identical HLA-matches. Patients have a one-in-four chance of being HLA-matched with each full-blooded sibling. If a suitable sibling donor is not available, then a world search for a HLA-matched unrelated donor takes place. The chance of finding an unrelated donor is best within ethnic groups. While Caucasians have a relatively high probability (70 – 80%) of finding an unrelated HSC donor, it is less so in Latinos, African Americans, and Asians due to fewer potential HSC donors in the pool whose HLA-type has been established (link to NMDP website).

HLA-mismatching between the HSC donor and recipient is the most significant risk for GVHD. Other GVHD risks include: gender mismatch, female donor parity (nulliparous [never pregnant] is the best), advancing recipient age, advancing donor age, and damage of the host’s tissues/organs due to the HSCT conditioning regimen (which stimulates an immune response, i.e., GVHD). (Urbano-Ispizua A. Risk assessment in haematopoietic stem cell transplantation: stem cell source. Best Pract Res Clin Haematology 2007; 20: 265-80), (Chao NJ, Chen BJ. Semin Hematol. 2006; 43 (1): 32-41).

Method of Allogeneic HSCT

Appropriate allogeneic HSCT patients usually undergo HSCT when their bone marrow-related cancer (leukemia or lymphoma) is in remission from prior therapy, although complete remission is not absolutely necessary. If a suitable HSC donor is identified, then the patient receives high doses of chemotherapy, with or without Total Body Irradiation (TBI). Common chemotherapy regimens include fludarabine and busulfan, TBI and cyclophosphamide, busulfan and cyclophosphamide, and TBI and etoposide. These regimens are usually administered while in the hospital. These regimens are intended to ablate both the recipient’s malignancy and the recipient’s immune system (i.e., to prevent rejection of the HSC graft). The recipient is rescued from this ablative therapy by an intravenous infusion of donor HSC. This infusion occurs after all of the prior chemotherapy has been washed from the body so as to not damage the recipient’s new HSC graft. Immunosuppressive medications are started just before the HSCT in order to prevent graft rejection and to minimize the activity of mature donor T-cells that could cause GVHD. The immunosuppressive agents are usually cyclosporine or tacrolimus combined with four post-transplant doses of methotrexate. (Holler, E. Risk Assessment In Haematopoietic Stem Cell Transplantation: GVHD Prevention and Treatment. Best Pract Res Clin Haematology 2007; 20: 281-94)

Since most allogeneic HSCT patients are HLA matched with their donors, it is possible for ”tolerance” to develop between the HSCT recipient and the donor when new T-cells are produced from the transplanted HSC. Many allogeneic HSCT patients are able to discontinue all immunosuppressive medications one–half year post-transplant, unlike the recipients of solid organ transplants (liver, kidney, heart, etc), who are on life-long immunosuppressive medicines, as the critical issue in solid-organ donor selection is blood group compatibility, not HLA matching. It takes months to years for the recipient’s new immune system to approach normality. Therefore, post-HSCT infection is a significant issue and allogeneic HSCT patients are at high risk for Cytomegalovirus (CMV) pneumonia/gastroenteritis, Varicella zoster infections (shingles), fungal infections, and Pneumocystis carinii pneumonia. Strategies to monitor for, and to prevent, these infections are generally employed. (? Link to reference or just reference for post-BMT infections)

Dose-Reduced Allogeneic HSCT

Two observations led to the conclusion that the destruction of one’s bone marrow before allogeneic HSCT was not necessary to permit donor HSCT engraftment. First, some allogeneic HSCT recipients rejected their HSC graft and experienced endogenous recovery of their own blood production, thus proving that ”bone marrow destruction” does not always occur after high-dose therapy. Second, there are numerous examples of allogeneic HSCT recipient’s blood late after transplant showing evidence both of recipient and donor blood cells, a so-called ”mixed chimeric” state. In other words, donor HSC survived in conjunction with recipient HSC long term, so complete recipient destruction of bone marrow was not necessary for long term donor engraftment.

These observations led to the idea of giving reduced doses of pre-transplant therapy, which would be just enough to push back the malignancy somewhat and to prevent rejection of the HSC graft, but without the intention of destroying the recipient’s bone marrow. Since lower doses of chemotherapy and/or TBI are utilized, there would be less damage to the recipient’s tissues and therefore less of a stimulus to start a GVHD response to tissue injury. The hypothesis here is that the bulk of the success of a dose-reduced allogeneic HSCT would be the GVM effect, and not high-dose, bone marrow ablative therapy. This reduced-intensity approach has permitted the allogeneic HSCT of patients up to age 75 years, whereas the age limit for a full intensity allogeneic HSCT is 60-65 years. Early results of this HSCT technique are encouraging. (MaloneyDG. Non-myelo ablative HSCT. Hematology (Am Soc Hematol Educ Program) 2002; 392-421)

Alternative HSC Donor Sources

The alternative HSC donor sources to siblings are: 1) HLA-matched, unrelated living donors; and 2) umbilical cord blood (UCB). UCB provides about 100 mL of fetal blood rich in HSC. UCB that is two-thirds or better HLA-matched with the recipient is acceptable for UCB HSCT. The UCB T-cells are naïve and therefore less likely to cause GVHD; it will be of less intensity if it does occur. The major problem is engraftment failure, largely now overcome by using 2 to 3 UCB units for HSCT in adults. In the setting of multiple-cord unit UCB HSCT, usually only one cord ultimately survives. Whether UCB stem cells provide enough meaningful GVM effect remains an open question.

Autologous HSCT

Definition

Autologous HSCT is the process by which very high doses of chemotherapy can be given in an attempt to cure a patient or extend their survival. High doses of chemotherapy may overcome resistance by the cancer cells to standard doses of chemotherapy, but as an innocent by-stander, the patient’s bone marrow is permanently damaged and cannot recover. In this setting, HSC are collected from the patient before the high-dose chemotherapy and then frozen for long-term preservation. After administration of the high-dose chemotherapy, the HSC are thawed out and given intravenously to “rescue” the patient by reconstituting the bone marrow, and ultimately, blood production.

Method of Autologous HSCT

Stem cell collection. Originally, HSC were collected only by bone marrow aspirations from the patient. In the late 1980s it was recognized that HSC found in the bone marrow could also be found in, and collected from, the peripheral blood using a centrifugation procedure called apheresis. Today, bone marrow harvesting for autologous HSCT is only performed in children too small to be placed on apheresis machines or in other special circumstances (such as in aplastic anemia).

In autologous bone marrow HSCT, approximately 15-20 mL per Kg of liquid bone marrow is removed from the posterior pelvic bones using needles and syringes. This liquid contains both blood and bone marrow, admixed with bone marrow particles (spicules) containing the CD34 positive HSC that are needed for the transplant. Liquid bone marrow is taken to the laboratory to be frozen and preserved in liquid nitrogen. There is pain in the back pelvis that last several days to several weeks but is easily treated with mild anti-pain medications.

Currently, HSC are usually collected from the blood stream. HSC can be collected from the peripheral blood under definable conditions, such as when blood counts are recovering after the administration of chemotherapy and/or after the administration of white blood cell (WBC) growth factors (G-CSF or granulocyte colony-stimulating factor). Often the two methods are combined. The most common chemotherapy used for this purpose is cyclophosphamide

When the CD34 positive cells are circulating in the blood, a catheter is often placed in the jugular vein in the neck so that the patient’s blood can be transferred into an apheresis machine. The machine draws blood from the patient and passes the blood into a centrifuge, where the blood is spun, separating the different blood components based on their densities. The red cells are most dense, followed by the white cells, the platelets and finally, the plasma. The CD34+ cells (HSC) are in the WBC fraction, and the apheresis machine can collect that fraction, thus allowing the rest of the blood components to be returned to the patient through another vein or separate lumen in the catheter.

Storage. In the laboratory, the HSC are concentrated and mixed with an organic compound, DMSO, which protects the cells from damage when deeply frozen. The HSC are placed in special freezer bags and lowered into tanks containing liquid nitrogen. They are generally kept in the gas phase just above the liquid, at temperatures of approximately minus 190 degrees centigrade. These cells are in suspended animation and viable for decades after freezing.

Procedure. The process of the autologous HSCT is straight-forward. A chemotherapy drug, or combination of drugs, is administered in very high doses over 1 to 5 days. The days prior to the transplant (day 0) are referred to as days minus 5, minus 4, etc., while the days following the transplant are referred to as days plus 1, plus 2, etc. After a predetermined number of drug washout days, previously frozen HSC are brought to the patient’s room in freezer bags, thawed in a sterile warm water bath, and re-infused back to the patient through an intravenous catheter. The cryo-protectant (DMSO) causes some smell as it is exhaled, and rarely the patient may experience mild nausea or shortness of breath. This process, called “the transplant,” is in reality nothing more than an elaborate “blood” transfusion. The infused HSC will ”home” to their bone marrow/spleen niche and restart blood production.

Complications of Autologous HSCT

The major risk of autologous HSCT is infection (low WBC counts) or bleeding (low platelet count). The period of low WBC can be shortened by several days with the administration of Neupogen® beginning shortly after the autologous HSCT. During the period of low blood counts, the patient will usually require red blood cell and platelet transfusions. The patient will also require a number of preventive (prophylactic) antibiotics to try and prevent bacterial, fungal, and viral infections. Despite these precautions, the patient may experience fevers and infections requiring additional or different antibiotics, etc. Rarely, these infections can be life-threatening.

The patient may also experience complications from the toxicities of the high dose chemotherapy, including hair loss, nausea, vomiting, diarrhea, mouths sores, loss of appetite, skin rash, and a number of less frequent problems. Most of these improve as the blood cells recover. There are also some long-term complications including continued immuno-suppression and risk of infections. The most common long-term complication is a skin infection due to the chicken pox virus (Varicella zoster) known as “shingles.” This infection can be prevented with specific prophylactic medications.

Finally, there is a risk that the chemotherapy received prior to transplant or at the time of the transplant can cause another cancer. This cancer can occur in as short a time as a year or two, but may occur decades later. The risk of this second malignancy is estimated at 5-10% at ten years post-HSCT. The most common second cancer is leukemia or lymphoma, but solid tumors can also occur, especially in the second decade after treatment.

It should also be remembered that the original cancer may recur. The success rate of high dose chemotherapy and autologous HSCT depends more on the disease being treated and the status of the disease (remission vs. relapse) than it does on complications, since the mortality associated with the procedure is less than 2%.

Allogeneic HSCT versus Autologous HSCT

An important consideration is when to use allogeneic HSC versus when to use autologous HSC for HSCT. The underlying principles are as follows (Table 1): 1) any blood-related malignancy potentially curable with chemotherapy at presentation is potentially curable with an autologous HSCT (i.e., high-dose therapy with a HSC rescue); 2) any blood-related malignancy not curable with chemotherapy would need an allogeneic HSCT for cure because of the needed benefit of the GVM effect (e.g., chronic leukemia or low-grade lymphoma); 3) inherited genetic disorders expressed by blood cells (such as sickle cell anemia or thalassemia) require allogeneic HSCT, that is, the infusion of normal genes expressed by healthy bone marrow cells; and 4) aplastic anemia (failed and empty bone marrow) requires a donor’s healthy HSC, thus must be an allogeneic HSCT. According to Table 1, multiple myeloma is a notable exception as it is a chronic hematologic malignancy, yet the preferred HSCT is autologous, not with curative intent, but rather with the intent to increase the probability of a complete remission and to promote both a longer remission and longer survival compared to conventional-dose chemotherapy. Bone marrow ablative allogeneic HSCT for multiple myeloma is associated with an unacceptable transplant-related death rate and is not generally recommended. Reduced-intensity allogeneic HSCT for myeloma is still experimental. 

Outcomes of HSCT by Type of Hematologic Malignancy (Table 2)

Outcomes of HSCT by disease type and method of HSCT are reported worldwide to the Center for International Blood and Marrow Transplant Research registry (http://www.cibmtr.org/).

Acute Myeloid Leukemia (AML)

HSCT plays an important role in the management of AML. In the modern era, AML should be approached with the intent to cure whenever possible. The chance of cure is best in children and in adults up to age 60. However, patients in their 60s and even healthy patients in their early 70s can sometimes be approached with curative intent. It is difficult to aim for cure in older patients over age 75, and such patients are not candidates for HSCT.

There are many controversies regarding the proper role of HSCT in the treatment of AML. However, there is general agreement that once AML has recurred after initial treatment with chemotherapy, HSCT offers the only realistic chance for cure and long-term survival. In some cases of AML in children, a second round of chemotherapy after an initial disease recurrence does offer a chance for cure, but this is not a realistic option in adults. If AML has recurred, the first step is to re-treat the patient with chemotherapy in order to get the disease back into remission. In general, most experts feel that the best treatment for AML in second remission is with allogeneic HSCT. The first step toward HSCT should be to identify an HLA matched donor, either a patient’s sibling or a well-matched unrelated donor through the National Marrow Donor Program. In general, younger and healthier patients are best approached with full-intensity (ablative) allogeneic HSCT whereas older adults (such as those over age 60) are best approached with reduced-intensity transplants. Depending on a number of circumstances the chance of cure with such an approach is 30% (20-40%).

If no suitable HLA matched donor can be identified, autologous stem cell HSCT also offers a chance for cure for patients in second remission of AML. The cure rate is approximately 25% (20-30%). For patients with the subtype acute promyelocytic leukemia (APL) in second remission the cure rates with autologous transplant in second remission are significantly better, in the range of 60-70%. However, considerable improvements have been made in the initial treatment of APL so recurrences are becoming uncommon.

The role of HSCT in the management of AML in first remission is controversial. The outcomes for treatment for the subgroup of acute promyelocytic leukemia (APL) are sufficiently good that transplant is not usually considered in the initial management of this disease. The approach to treatment of other types of AML in first remission is usually based on a risk-adapted approach with the risk of leukemia relapse best measured by assessing the chromosome abnormalities (cytogenetics) present in leukemia cells. For patients up to age 60 with favorable cytogenetics, standard chemotherapy offers approximately a 50% chance of cure. Because of this, allogeneic HSCT is not usually considered in these cases. However, there is evidence that autologous stem cell HSCT can increase the cure rate to 70-80% in this setting. Patients with AML in first remission with high-risk cytogenetics have only a small chance of cure with non-transplant chemotherapy, and most leukemia specialists feel that allogeneic HSCT is the treatment of choice. However, even with this treatment approach, the chance of cure for these high-risk patients with very-abnormal chromosomes is only 25% (15-30%). Autologous stem cell HSCT does not produce good results in this setting and every attempt should be made to find a good donor for allogeneic HSCT.

The role of HSCT in the management of the majority of AML patients who have standard-risk (also called intermediate risk) AML in first remission remains controversial. Allogeneic HSCT for patients up to age 60 with the most common type of AML offers a 50-60% chance of cure. This appears to be superior to an approximately 30% cure rate of these patients with non-transplant chemotherapy. However, the chance of death due to a treatment complication is sufficiently high (15-30%) that many patients and physicians prefer to reserve allogeneic HSCT until less dangerous treatments have failed to work. The outcomes for allogeneic transplant are better in younger patients, particularly in those under age 30, but the results of chemotherapy are also better in this younger age group. Similarly, patients over age 50 have a more difficult time with both chemotherapy and HSCT.

Autologous HSCT is another treatment that needs to be considered for standard-risk AML patients in first remission, and some leukemia physicians consider this to be the treatment of choice. The risk of fatal complications with this treatment approach is much lower than with allogeneic transplant and is generally in the range of 2-4%. The chance of cure with such an approach is in the range of 40-50%, but there is disagreement as to whether these results are clearly superior to the results with non-transplant chemotherapy.

Some patients develop AML as a complication of chemotherapy and/or radiation therapy given for other diseases or after having initially had a different bone marrow disease, such as myelodysplasia. These types of leukemias are generally called “secondary leukemias” because they developed from prior toxic therapy or a prior abnormal bone marrow condition. For these patients in first remission, allogeneic HSCT is generally felt to be the optimal treatment approach.

Acute Lymphoblastic Leukemia (ALL)

HSCT plays an important role in the treatment of ALL. Many of the considerations regarding the use of HSCT in the treatment of ALL are similar to those in AML, discussed above, and several controversies remain.

In general, as with AML, adult patients in second remission of ALL who have had a disease recurrence following initial treatment with chemotherapy should be treated with HSCT approaches because this offers the only chance of cure and long term survival. Children in second remission of ALL may be treated with a second round of chemotherapy with a chance of cure, but this is not a realistic possibility for adults on whom this discussion will focus. The treatment of choice for patients in second remission of ALL is an allogeneic HSCT, either from a matched sibling or a well-matched unrelated donor. In general, it is felt that full intensity approaches give the best results and that only older or less fit patients should be treated with reduced intensity allogeneic HSCT. The chance of cure with an allogeneic transplant in second remission of ALL varies depending on a number of considerations, but is generally in the range of 30%.

The role of allogeneic HSCT in the first remission of ALL is controversial. Patients with low-risk types of ALL (based on young age, low white blood count and other favorable features of the leukemia cells) are best treated with chemotherapy, and the chance of cure with this approach is in the range of 60-70%. Conversely, patients with high-risk forms of ALL (based on certain abnormal chromosomes in the leukemia cells, the length of time obtaining a remission, or an extremely high white blood count at diagnosis) are optimally treated with allogeneic HSCT while they are in first remission. In general, for high-risk patients, chemotherapy alone offers very little chance of cure, whereas allogeneic HSCT offers a 30-40% chance of cure. The Phildelphia chromosome refers to a short chromosome 22 found in the leukemia cells of some patients with ALL and most patients with chronic myelogenous leukemia. Philadelphia chromosome positive ALL has a particularly poor prognosis. Allogeneic HSCT outcomes appear to be improving for the subgroup of patients with the Philadelphia chromosome based on the addition of new medications, such as imatinib or dasatinib, to the treatment program.

The greatest controversies regarding the role of HSCT are the management of standard risk ALL in first remission. The chance of cure with allogeneic HSCT for such patients is in the range of 50-60%. This appears to be higher than the cure rate seen with standard chemotherapy approaches, which is in the range of 35-40%. However, many patients and physicians are reluctant to accept the risks and difficulties of allogeneic HSCT as an initial treatment approach and prefer to wait to see if chemotherapy alone will be a sufficient treatment.

The role of autologous transplant in the management of ALL has been limited. New approaches to this type of treatment are being explored and may offer a possibility of cure for certain patients with ALL, who need a HSCT, but for whom no suitable HLA-matched donor can be identified.

Chronic Myeloid Leukemia (CML)

Until the year 2001 allogeneic HSCT was considered the treatment of choice for all patients with CML. CML is the disease most susceptible to the immune effect of the donor stem cells (the graft-versus-leukemia effect), and allogeneic HSCT remains (at the current time) the only proven means of cure. However, the remarkable developments of new medications such as imatinib have completely changed the outlook for patients with CML and have dramatically changed the role of allogeneic HSCT. At the present time, the treatment of choice for most patients with CML in its most common form (chronic phase) is with medications such as imatinib (or the alternatives dasatinib or nilotinib). Only patients who do not get an optimal response to these medications are considered for allogeneic HSCT. Patients whose disease is initially controlled with medication but who then become resistant to drug treatment should also be considered for transplant.

Patients with advanced forms of CML, such as those in the accelerated or blast phase, are best treated with allogeneic HSCT. Once CML has transformed to the more aggressive phases of the disease, allogeneic HSCT offers the only chance for cure, but only patients whose disease can come into reasonable control prior to HSCT have a realistic chance for success. Autologous HSCT does not play a role in the management of CML.

Myelodysplasia (MDS)

The term myelodysplastic syndrome (MDS) describes a spectrum of bone marrow diseases characterized by poor blood cell production and a propensity to evolve into AML. Some MDS subtypes are slow paced (indolent) while others are fast paced (aggressive; high-risk). All MDS are forms of chronic leukemia involving the myeloid bone marrow cells (white cells, red blood cells, and platelets). MDS is usually a disease of older adults, although it may be seen in young adults as well. Patients with low-risk forms of MDS are usually not recommended to undergo allogeneic HSCT, the only known cure, as there a number of simpler treatment options for these patients. However, patients with high-risk MDS have considerable more difficulty with MDS complications, such as life-threatening infections and/or bleeding, and/or rapid conversion to AML. For high-risk patients, allogeneic HSCT is the treatment of choice. The development of reduced-intensity allogeneic HSCT has greatly broadened the role of transplant in the management of MDS, since few patients will be young enough to tolerate full-dose HSCT approaches. Autologous HSCT does not play a role in the management of MDS.

Chronic Lymphocytic Leukemia (CLL)

HSCT is not considered as a treatment option for most patients with CLL. Many patients with CLL have such a slow-growing disease that it does not have a significant impact on their overall health or life-expectancy, and many patients do not require treatment for their leukemia for years. In addition, CLL is a disease most commonly seen in older adults who are not candidates for HSCT. When patients with CLL do need treatment, current therapies (chemotherapy, such as fludarabine and/or cyclophosphamide, with or without the antibody protein Rituximab), are very well tolerated and usually produce good results, often controlling the disease for many years. However, there is a subgroup of patients whose type of CLL behaves more aggressively, and particularly in younger patients, allogeneic HSCT can play an important role in their management. CLL cells are very sensitive to the graft-versus-leukemia effect of the donor immune system.

Patients whose disease responds poorly to initial treatment and/or who have disease recurrences after a short period of time can be successfully treated with allogeneic HSCT with curative intent. Recently a small subgroup of patients with CLL with high-risk genetic features (such as a deletion of the short arm of chromosome 17 [called 17p-]) has been identified and research is in progress to determine whether the early use of allogeneic HSCT will improve the outcome for patients with these types of CLL. Autologous transplant does not play a role in the management of CLL. Multiple Myeloma

Multiple myeloma is a cancer of the anti-body producing cells (plasma cells) in the bone marrow. Significant advances are being made in the treatment of this disease, and the use of autologous HSCT has been a major step forward in its management. The first step in treatment is to get the disease under initial control with the use of chemotherapy or non-chemotherapy agents. At the present time the standard of care is to treat patients with myeloma in initial remission with autologous HSCT. Autologous HSCT for myeloma is generally well tolerated and the risk of death from treatment complications is less than 4%. Autologous HSCT produces better quality remissions and longer-lasting remissions than other treatments and gives most patients several years of freedom from either active myeloma or continued treatment for their disease. In most cases the goal of treatment is to prolong remission time and to prolong survival, but not to produce a cure, although a small percentage of patients who have received this treatment have had very long periods of remission and may possibly be cured.

The role of allogeneic HSCT in the management of myeloma remains controversial at this time. Full-intensity allogeneic HSCT for myeloma is not often recommended, because of the high risk of this procedure with fatal complications seen in 40% or more of patients. There is some evidence that these risks are being reduced, but not all experts agree on this. On the other hand, full-dose allogeneic transplant is the only treatment which has shown a potential for cure of the disease. In recent years, reduced intensity allogeneic HSCT has been used in the management of myeloma but the merit of this approach and its possibility of cure are not yet known.

Lymphomas

The lymphomas are malignancies of the lymph nodes that represent a spectrum of diseases, including the Hodgkin’s (HL) and Non-Hodgkin’s (NHL) types, ranging from indolent to aggressive subtypes. The use, timing, and type of HSCT in the management of the lymphomas must be considered within the context of the subtype in question.

The most common type of lymphoma, diffuse large B-cell lymphoma NHL, is initially treated with chemotherapy (plus the antibody Rituximab) with curative intent. Most patients with this type of large cell lymphoma are not considered for HSCT as an initial form of treatment. However, many lymphoma experts feel that there is a subgroup of patients with diffuse large B-cell NHL with high-risk features that warrant treatment with autologous HSCT in first remission. All lymphoma physicians agree that once a large B-cell lymphoma recurs after initial chemotherapy, autologous HSCT is the treatment of choice. The usual approach is to use chemotherapy (with or without Rituximab) to get the patient back into a second remission and to demonstrate that their disease is still responsive to chemotherapy. Once a patient is in second complete or partial remission, autologous HSCT should be performed. The chance of a cure with this treatment approach for patients in second remission is approximately 40-50%. Allogeneic HSCT is used less commonly for this form of lymphoma because of the limited potency of the graft-versus-lymphoma effect.

Another common form of lymphoma is follicular NHL. Most of these patients have a slow-growing type of disease that allows them to live for many years, although with a need for periodic treatment and without a real chance for cure. Patients with follicular NHL have many treatment options, and HSCT is not usually considered in the early phases of the disease. For patients whose disease responds poorly to standard treatments and/or who have an aggressive form of the disease, HSCT may be considered. There is evidence that autologous HSCT can produce good results for patients with advanced follicular NHL, although the chance for cure with this approach remains controversial. On the other hand, allogeneic HSCT has produced very encouraging results for patients with advanced forms of follicular lymphoma and there does appear to be a chance for cure with this treatment. Follicular lymphomas are very sensitive to the graft-versus-lymphoma effect of allogeneic transplant. In general, reduced-intensity forms of allogeneic transplant have been recommended based both on the age of patients and on the sensitivity of this disease to the beneficial immunologic effect of allogeneic HSCT.

Mantle cell lymphoma is an aggressive type of NHL that does not respond well to conventional chemotherapy treatment. At the present time, autologous HSCT is recommended as part of the initial treatment approach for this disease, and appears to produce better results than the standard chemotherapy. It is unclear whether autologous HSCT has curative potential in mantle cell NHL. Allogeneic HSCT can also be an effective form of treatment as is likely curative due to the graft vs. lymphoma immune effect.

Hodgkin’s lymphoma (formerly called Hodgkin’s disease) is highly curable with chemotherapy, so HSCT is not used in the initial management of this disease. However, once HL has recurred after initial chemotherapy, autologous HSCT is recommended and offers the best chance for cure. In general, the approach to treatment after a recurrence is to use chemotherapy to get a patient back into remission. Once this is accomplished the treatment of choice is autologous stem cell HSCT. Depending on a number of factors, the chance of cure for a patient with Hodgkin’s disease in second remission is approximately 40-50%. The most important factor in determining the chance of cure with an autologous HSCT approach is that the disease is still responsive to treatment with chemotherapy. Allogeneic HSCT is also a useful treatment for HL, but usually reserved for those who relapse after a prior autologous HSCT.

Testicular Cancer

Testicular (germ cell) cancer is the only non-hematologic cancer in adults for which HSCT currently plays an important treatment role. Most cases of testicular cancer are cured with chemotherapy alone. However, a small fraction of patients have disease recurrence after a primary treatment and for these patients, autologous HSCT in second remission is the treatment of choice. The chance of cure with this approach is approximately 30-40%.

Pediatric Solid Cancers

Certain solid cancers of childhood, such as neuroblastoma, rhabdomyosarcoma, Wilm’s tumor, and retinoblastoma, are very chemotherapy sensitive. As with testicular cancer, autologous HSCT plays an important curative role with relapsed disease. However, subgroups of children with high-risk features may benefit from autologous HSCT as part of the initial cancer management plan. Depending on a number of features, cure rates from autologous HSCT range 40-60%.

Aplastic Anemia

Aplastic anemia is a disease in which the bone marrow fails to produce adequate numbers of blood cells as a consequence of an immune attack on the bone from the patient’s own immune cells. It is most commonly seen in children and young adults. Some patients, especially those with milder forms of the disease, can be successfully treated with immunosuppressive therapy, that is, treatment designed to control the abnormal part of their own immune system which is shutting down the function of their bone marrow. The success rates with immunosuppressive therapy are in the range of 60-70%.

However, for young patients with the more severe form of the disease, most experts feel that initial treatment with allogeneic HSCT is the treatment of choice if the patient has a HLA-matched family donor. Long-term cure rates for young patients transplanted with this approach are in the range of 80-90%. However, results for older adults (over age 50) or for those for whom family donors are not available and only unrelated donors have been found, results with allogeneic HSCT are less favorable, hence the usual treatment recommendation for these patients is immunosuppressive therapy. Allogeneic HSCT is then attempted for patients for whom this initial treatment is unsuccessful. With new treatment approaches, including the reduction in the intensity of transplant chemotherapy, outcomes are improving for older adults. The cure rates for those undergoing unrelated donor HSCT after failure of immunosuppressive therapy to control the disease is in the range of 40-50%.







Links for further information:

National Bone Marrow Transplant Link

http://www.nbmtlink.org/

National Marrow Donor Program

http://www.marrow.org/

Leukemia and Lymphoma Society

http://www.leukemia-lymphoma.org/hm_lls

Multiple Myeloma Research Foundation

http://www.multiplemyeloma.org/

UCSF Helen Diller Family Comprehensive Cancer Center

http://cancer.ucsf.edu/

Cancer Research Institute

http://www.cancerresearch.org/

National Cancer Institute

http://www.cancer.gov/


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