Allogeneic bone marrow transplantation for hematologic malignancies
What every physician needs to know about allogeneic bone marrow transplantation for hematologic malignancies:
Allogeneic blood and marrow transplantation
Allogeneic blood and marrow transplantation (BMT) (also often called stem cell or hematopoietic cell transplantation) is the treatment of choice for many blood diseases, both malignant and non-malignant.
It involves the administration of lymphohematopoietic cells after immunosuppressive chemotherapy or radiochemotherapy, to establish new donor-derived bone marrow and immune functions. Lymphocytes are critically important components of the graft from both efficacy and toxicity standpoints, and so “stem cell” and “hematopoietic cell” transplantation are really misnomers. While more commonly employed to treat hematologic cancers, the first successful allogeneic transplants were for non-malignant conditions (inherited immunodeficiencies and aplastic anemia).
BMT is part of the treatment paradigm of most hematologic malignancies. For those diseases curable with conventional dose therapy, such as aggressive lymphomas and many acute leukemias, allogeneic BMT is reserved for, and is often the treatment of choice, at initial relapse.
Autologous BMT (using the patient’s own cryopreserved stem cells) also has curative potential for this group of hematologic malignancies, but recent data suggest the effectiveness is declining, as more patients are cured with conventional dose therapy; it is likely that those patients who now relapse have biologically worse disease.
For hematologic malignancies incurable with conventional dose chemotherapy, such as low-grade lymphomas, multiple myeloma, myelodysplastic syndromes, and poor risk acute leukemias, allogeneic BMT usually becomes the treatment of choice at the time survival duration is felt to be relatively short. Allogeneic BMT is also curable therapy for non-malignant diseases that affect blood cells, including aplastic anemia and other autoimmune disorders, as well as inherited diseases such as hemoglobinopathies and immunodeficiencies. Both the pretransplant conditioning regiment which provides the entire benefit of autologous BMT, and the allogeneic graft versus leukemia (or tumor) effect (GVL) are responsible for allogeneic BMT’s antitumor activity .
The new immune system from the donor not only plays an important role in achieving engraftment and eliminating the malignancy, but it is also the major cause of toxicity (graft-versus-host disease [GVHD], see below).
Types of allogeneic BMT
Allogeneic BMT can be categorized by whether the donor cells were harvested from the bone marrow or obtained by apheresis of peripheral blood. While peripheral blood grafts may seem to be logistically easier to collect, as a bone marrow harvest requires multiple needle puncture in the pelvic bone in an operating room under anesthesia, it requires five days of growth factor injections and 6-12 hours on an apheresis machine. As more donor T cells are collected with peripheral blood than bone marrow, most studies have shown GVHD to be increased. Overall, survival is probably similar with both bone marrow and peripheral blood grafts, with the higher toxicity and improved tumor control associated with GVHD offsetting each other.
Allogeneic BMT can also be classified according to the intensity of the regimen used to condition the patient for the procedure. Historically, most patients received high-dose cytotoxic therapy, the intensity of which was reached by determining non-hematopoietic end organ toxicity, that is, the highest non-lethal dose that could be rescued with transplanted hematopoietic stem cells.
These so-called myeloablative conditioning regimens most commonly use the marrow-toxic agents busulfan or total body irradiation (TBI), usually in combination with high-dose cyclophosphamide. Over time, it becomes clear that several immunosuppressive drugs such as cyclophosphamide and fludarabine, would allow engraftment of allogeneic grafts in the absence of myeloablation.
Such non-myeloblative (also called reduced intensity or “mini”) transplants can be used in older and less fit patients who are not candidates for high-dose myeloablative conditioning. Although the toxicity of myeloablative transplants is higher than non-myeloablative, they are also associated with less relapses. Currently, there is no clear evidence that either myeloablative or non myeloablative transplants are superior in terms of overall disease-free survival, with ongoing clinical trials exploring this question.
Donor selection and bone marrow transplant preparation
Once the decision to proceed with allogeneic BMT has been made, a donor needs to be found. The first step is to type the patient’s blood cells for histocompatibility antigen (HLA) expression. HLA antigens are encoded by a linked gene complex on chromosome 6p, so a patient will inherit one set of class I antigens (A, B, and C loci) and class II antigen (DR, DP, and DQ) from each parent.
HLA matched sibling donor BMT historically has been associated with the lowest rates of GHVD, because the donor and recipient inherit the same major HLA haplotype from each parent. GVHD still occurs with matched sibling transplants, because of minor HLA antigen (any genetic polymorphism that can lead to an antigenic protein) differences. The possibility of finding a HLA matched sibling can be calculated by the function 1 – (0.75)n, where “n” equals the number of siblings. Thus, if the patient has one full sibling, the possibility of finding a match is 25%, while it is 68% if the patient has four.
Matched unrelated donors also share all major HLA antigens with the recipient (by chance), but historically are associated with higher rates of GVHD than matched sibling donors, because unrelated individuals will have more minor HLA antigen differences than family members. It is important to remember that the searches for an unrelated donor through national and international registries can take several months. Partially matched or haploidentical related donors are any first degree relative (parent, sibling or child) that shares one major HLA haplotype with the patient.
Historically, such transplants were associated with unacceptably high rates of GVHD. Partially matched umbilical cord blood cells cause less GVHD than equally mismatched adult marrow, because the immune system is less experienced. However, recent major advances in GVHD prevention and treatment have made partially matched allogeneic transplant safe and feasible. BMT from an identical twin (or syngeneic BMT) behaves like most autologous BMT in that there is no GVL or GVHD.
Once the donor has been identified, both the donor and patient undergo evaluations to determine their suitability for donating and undergoing BMT, respectively. They both will be assessed for suitable organ function. In addition, they will be evaluated for communicable infectious agents (for example, HIV) that routine blood donors undergo. The patient’s evaluation will also include disease assessment, as it is advantageous for the patient’s disease to be quiescent at the time of BMT.
Toxicities from bone marrow transplantation and graft-versus-host disease
The potential toxicities from BMT are somewhat dependent on the specific type of conditioning. Nausea, vomiting, alopecia, and bone marrow aplasia (with infection risks) are universal with myeloablative conditioning regimen. More serious complications, including mucositis, sinusoidal obstruction syndrome (also called veno-occlusive disease of the liver) and pulmonary fibrosis, are seen in 10 to 30% of patients receiving myeloablative conditioning and can be fatal. Late effects of the BMT conditioning regimen include cataracts, sterility, hypothyroidism, and growth retardation in children.
The incidence of these conditioning regimen toxicities is much less with non-myeloablative conditioning regimens. Regardless of the intensity of the conditioning regimen, all recipients of allogeneic BMT experience prolonged periods of immunosuppression from the conditioning regimen and post-BMT GVHD prophylaxis. Thus, patients are at risk for opportunistic infections including cytomegalovirus pneumonitis, herpes zoster, viral hemorrhagic cystitis, and fungal infections. The use of prophylactic antibiotics aimed at limiting each one of these opportunistic infections is routine.
Mortality from conditioning regimen complications ranges from 5 to 10% with myeloablative conditioning and 0 to 5% with non-myeloablative conditioning. Patients with advanced disease and in poorer medical shape at the time of transplant are at highest risks for conditioning regimen toxicity.
GVHD is the most common cause of serious complications, including mortality, related to allogeneic BMT. It is the result of HLA-antigen differences between the patient and donor, that lead to the transplanted immune system recognizing and attacking cells expressing unshared HLA antigens. Historically, GVHD rates of 30 to 60% have been observed after HLA-matched allogeneic BMT. The recipient’s immune system can also attack donor cell HLA antigens leading to graft failure (similar to the rejection of solid organ transplants), but this occurs much less commonly than GVHD, because of the immunosuppression given to the patient. Graft failure is rare with myeloablative conditioning and in HLA-matched donors, but can be seen in 5 to 10% of recipients of partially matched grafts.
Classically, GVHD is divided into acute and chronic forms of the disease. Acute GVHD most commonly affects the skin, gut, and liver, presenting with a skin rash, nausea, vomiting, diarrhea, and liver test abnormalities. It can present anytime after initial engraftment, but rarely beyond day 100. This constellation of affected tissues corresponds to those harboring high number of antigen-presenting cells, most likely as a result of their contact with foreign antigens in the environment. Chronic GVHD usually first presents 4 to 24 months after BMT and often resembles an “autoimmune” disease, affecting eyes, oral mucosa, lungs, and liver.
The primary treatment of GVHD (either acute or chronic) involves corticosteroids and other immunosuppressive agents. While the initial response rate to steroids is high (in acute GVHD, as high as 90%), it is not uncommon for the GVHD to flare during taper of steroids; long-term steroid-free control of GVHD is achieved in around 50% of patients. Moreover, the immunosuppression is associated with opportunistic infections, hyperglycemia, psychiatric abnormalities, renal failure, and osteoporosis. Acute GVHD is graded (I-IV) depending on the extent of skin involvement, hyperbilirubinemia, and stool volume, and there is an inverse correlation between grade and survival. However, patients with grade I to II acute GVHD have a better survival than those without GVHD; this is due to lower relapse rates related to the allogeneic GVL effects. Severe chronic GVHD also impacts survival, but there is no grading system which has been agreed upon.
Because of the high incidence of GVHD, its attendant toxicities, and the relatively ineffective treatment, prophylaxis strategies are universally employed. Since a strategy that completely prevents GVHD will likely also abrogate GVL activity (as was seen with strict T-cell depletion of allografts), modulating the severity is important. Historically, the most commonly used intervention to limit GVHD prophylactically is the combination of methotrexate and a calcineurin inhibitor such as tacrolimus or cyclosporine. However, this combination has not allowed safe and effective partially matched allogeneic BMT, and other promising regimens that include high-dose cyclophosphamide, sirolimus, anti-thymocyte globulin (ATG), or mycophenolate mofeil are being tested.
Donor lymphocyte infusion
Although allogeneic BMT arguably generates the greatest antitumor activity against hematologic malignancies of any treatment, many patients still relapse and die of their underlying disease. However, the transplanted new immune system affords the possibility of additional immune manipulations that can produce remissions after relapse. Rare patients will go back into a remission with just stopping GVHD prophylaxis, thus augmenting the GVL. Another alternative is the use of donor lymphocyte infusions, or transfusion of T cells from the original donor. Patients with myeloid leukemias and low grade lymphomas tend to respond best to these manipulations, while patients with aggressive lymphomas and acute lymphoblastic leukemia very rarely have meaningful, long-lasting responses.
What features of the presentation will guide me toward possible causes and next treatment steps:
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
What conditions can underlie allogeneic bone marrow transplantation for hematologic malignancies:
When do you need to get more aggressive tests:
What imaging studies (if any) will be helpful?
What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
What other therapies are helpful for reducing complications?
What should you tell the patient and the family about prognosis?
“What if” scenarios.
What other clinical manifestations may help me to diagnose allogeneic bone marrow transplantation for hematologic malignancies?
What other additional laboratory studies may be ordered?
What’s the evidence?
Cutler, C, Giri, S, Jeyapalan, S. “Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis”. . vol. 19. 2001. pp. 3685-3691. (This paper describes the different rates and characteristics of graft-versus-host disease after allogeneic transplants, using the most common types of grafts: bone marrow and peripheral blood stem cells.)
Luznik, L, O’Donnell, PV, Symons, HJ. “HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide”. . vol. 14. 2008. pp. 641-650. (Very interesting study on the feasibility of haploidentical bone marrow transplants for patients with hematologic malignancies, using high dose post-transplant cyclophosphamide for graft-versus-host disease prophylaxis.)
Luznik, L, Bolaños-Meade, J, Zahurak, M. “High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease”. . vol. 115. 2010. pp. 3224-3230. (This study established the use of high-dose cyclophosphamide post-transplant as a single agent to prevent graft-versus-host disease. This strategy eliminates the prolonged exposure to immunosuppressants with its associated risks and side effects.)
Ratanatharathorn, V, Nash, RA, Przepiorka, D. “Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation”. . vol. 92. 1998. pp. 2303-2314. (Ratanatharathorn et al. established that both, methotrexate and tacrolimus, and methotrexate and cyclosporine are valid alternatives for patients to prevent graft-versus-host disease.)
Nash, RA, Antin, JH, Karanes, C. “Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors”. . vol. 96. 2000. pp. 2062-2068. (Nash et al. established that both, methotrexate and tacrolimus, and methotrexate and cyclosporine are valid alternatives for patients to prevent graft-versus-host disease)
Koreth, J, Schlenk, R, Kopecky, KJ. “Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials”. JAMA. vol. 301. 2009. pp. 2349-2361. (An interesting study on the role of allogeneic bone marrow transplantation on patients with acute myeloid leukemia in first remission.)
Bolaños-Meade, J, Vogelsang, GB. “Acute graft-versus-host disease”. . vol. 2. 2004. pp. 672-682. (Detailed review about acute graft-versus-host disease: pathophysiology, therapy, and prevention.)
Bolaños-Meade, J, Vogelsang, GB. “Chronic graft-versus-host disease”. . vol. 14. 2008. pp. 1974-1986. (Detailed review about chronic graft-versus-host disease: pathophysiology, therapy and prevention.)
Anasetti, C, Logan, BR, Lee, SJ, Waller, EK. “Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors”. N Engl J Med. vol. 367. 2012 Oct 18. pp. 1487-96. (This study established bone marrow grafts as the preferred source of cells for patients undergoing unrelated stem cell transplants over peripheral blood stem cells given the decreased incidence of chronic graft versus host disease.)
Copelan, EA, Hamilton, BK, Avalos, B, Ahn, KW. “Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI”. Blood. vol. 122. 2013 Dec 5. pp. 3863-70. (This large registry database study established that the combination of busulfan and cyclophosphamide is superior to cyclophosphamide and total body irradiation for patients undergoing myeloablative bone marrow transplants in first complete remission given the superior non-relapse mortality.)
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- Allogeneic bone marrow transplantation for hematologic malignancies
- What every physician needs to know about allogeneic bone marrow transplantation for hematologic malignancies:
- What features of the presentation will guide me toward possible causes and next treatment steps:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What conditions can underlie allogeneic bone marrow transplantation for hematologic malignancies:
- When do you need to get more aggressive tests:
- What imaging studies (if any) will be helpful?
- What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- “What if” scenarios.
- What other clinical manifestations may help me to diagnose allogeneic bone marrow transplantation for hematologic malignancies?
- What other additional laboratory studies may be ordered?
- What’s the evidence?