Acute Lymphoblastic Leukemia and Bone Marrow Transplantation
Author, Editor: Tilda Barliya PhD
Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells was previously discussed for the genetic origin and the prognostic factors used in clinical trials (1). We will now focus on the treatment options with emphasis on the bone marrow transplantation (2).
According to the National Cancer Institute (NCI), the treatment of childhood ALL usually has 3 phases (3a):
- Induction Therapy: The goal is to kill leukemia cells in both the blood and the bone marrow and induce a remission.
- Consolidation/Intensification Therapy: It begins once the leukemia is in remission. The goal is to kill any remaining leukemia cells that may not be active but may regrow and cause relapse.
- Maintenance Therapy: The goal is to kill any remaining leukemia cells that may regrow and cause relapse. In this phase the different cancer treatments are usually been given at lower doses than those in the previous phases.
Four types of cancer treatment are used:
- Chemotherapy – The way the chemotherapy is given depends on the child’s risk group. Children with high-risk ALL receive more anticancer drugs, higher doses of anticancer drugs, and receive treatment for a longer time than children with standard-risk ALL.. The full list of approved drug (3b)
- Radiation Therapy– is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. External radiation therapy may be used to treat childhood ALL that has spread, or may spread, to the brain and spinal cord.
- Chemotherapy with stem cell transplantation – A method inwhich stem cells (immature blood cells) are removed from the blood or bone marrow of a donor. After the patient receives treatment, the donor’s stem cells are given to the patient through an infusion. These reinfused stem cells grow into (and restore) the patient’s blood cells. Stem cell transplant is rarely used as initial treatment for children and teenagers with ALL. It is used more often as part of treatment for ALL that relapses
- Targeted Therapy – Tyrosine Kinase Inhibitors (TKIs) are targeted therapy drugs that block the enzyme, tyrosine kinase, which causes stem cells to become more white blood cells or blasts than the body needs. For example, imatinib mesylate (Gleevec) is a TKI used in the treatment of children with Philadelphia chromosome-positive ALL. However, because patients can develop resistance to these drugs, new tyrosine kinase inhibitors are being investigated. For example, nilotinib (AMN-107) is being studied for patients with Philadelphia chromosome positive ALL who are resistant to imatinib
Bone Marrow or Peripheral Blood Stem cell Transplant for ALL
Stem cell transplants (SCT) offer a way for doctors to use high doses of chemo. Although the drugs destroy the patient’s bone marrow, transplanted stem cells can restore the bone marrow’s ability to make blood. Stem cells for a transplant come from either the blood or from the bone marrow. Bone marrow transplants were more common in the past, but they have largely been replaced by peripheral blood stem cell transplant (PBSCT).
Types of Transplants (4).
The stem cells can come from either the patient (an autologous transplant) or from a matched donor (an allogeneic transplant).
- Allogeneic stem cell transplant: In an allogeneic transplant, the stem cells come from someone else – usually a donor whose tissue type is a very close match to the patient’s. The donor may be a brother or sister if they are a good match. Less often, an unrelated donor may be found. An allogeneic transplant is the preferred type of transplant for ALL when it is available.
- “Mini-transplant”: “mini-transplant” (also called a non-myeloablative transplant or reduced-intensity transplant), where they get lower doses of chemo and radiation that do not destroy all the cells in their bone marrow. They then are given the donor stem cells. These cells enter the body and form a new immune system, which sees the leukemia cells as foreign and attacks them (a graft-versus-leukemia effect). This is not a standard treatment for ALL, and is being studied to find out how useful it may be.
- Autologous stem cell transplant: In an autologous transplant, a patient’s own stem cells are removed from his or her bone marrow or blood. They are frozen and stored while the person gets treatment (high-dose chemo and/or radiation). The stem cells are then given back to the patient after treatment.
One problem with autologous transplants is that it is hard to separate normal stem cells from leukemia cells in the bone marrow or blood samples. Even after treating the stem cells in the lab to try to kill or remove any leukemia cells, there is the risk of returning some leukemia cells with the stem cell transplant
Stem cell transplants and side effects (4):
Early side effects: Early side effects are much the same as those caused by any other type of high-dose chemo, such as nausea, vomiting, loss of appetite, mouth sores, and hair loss. Because of the high doses of chemo used, these can sometimes be severe.
Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 – 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally. Low red cell count and platelet counts are also early-side effects that when happens are treated with blood transfusion.
A rare but serious side effect of stem cell transplant is called veno-occlusive disease of the liver (VOD). In this disease, the high doses of chemo given for the transplant damage the liver. Symptoms include weight gain (from fluid collecting), liver swelling, and yellowing of the skin and eyes (jaundice). When severe, it can lead to liver failure, kidney failure, and even death.
Long-term side effects: Some side effects can last for a long time, or may not happen until years after the transplant. These long-term side effects can include the following:
- Acute/Chronic Graft-versus-host disease (GVHD), which occurs only in a donor transplant
- Organ damage: lungs ( shortness of breath), ovaries (infertility and loss of menstrual period), thyroid, eyes (cataract), bone etc.
- Developing another type of leukemia or other cancer several years later.
ALL (and AML), Bone Marrow transplant and Clinical Trials
Back in the early 80’s, chemotherapy was shown to cure a substantial portions of patients with ALL. Yet some patients had high risk of relapse when treated using conventional regimens, due to patient- and disease-related variables. Bone marrow transplantation (BMT) was found to have encouraging results depending on the circumstances, yet the relative role between chemo and BMT to high-risk patients was controversial.
It was believed that the factors which predict poor outcome with chemo do not adversely affect the transplant outcome, yet this assumption was not based on comparing similar predicting factors . More so, the prognostic factors for outcome after BMT were not well-defined and the optimal regimen for transplant was not agreed upon. Thus, researches aimed to identify the characteristics and factors affecting good outcome after transplantation for ALL in first and second remission.
For this, 690 patients with HLA-identical sibling receiving allogeneic BMT either after first or second complete remission (CR). Numerous factors were accounted for including; age, sex, donor-recipient sex match, chemo regimen and presence of GVHD.
Of the many factors evaluated, several were highly significant in BMT outcome:
- GVHD – It may have both favorable and unfavorable effect on the outcome. On one hand it may reduce leukemia relapse but on the other hand it may increase transplant-related mortality.
- Conditioning chemo regimens – most chemo regimens had negative effects of the BTM outcome. By, since the study group included only a small number of patients and these studies were conducted before the new chemo types/regimes using high-does etoposide, this factor may need to be reevaluated.
- Donor-recipient sex match – This factor was found to be highly significant in female receiving donors from male-matched donors. These patients had higher risk of relapse and treatment failure. This was probably due to host sensitization to the H-Y antigens. This data is also needed to be handled with cautious due to the small number of patients.
- Immune phenotype – Blood cell type and leukocyte levels at the beginning of the treatment is a another crucial factor. Higher leukocyte levels and non-T cell phenotype resulted in adverse outcome which led to remission.
- Patient age – Age did not play a role when comparing the outcome after first relapse, but was found to be more favorable for younger ages (<16) when comparing the outcome after second relapse.
- First relapse – a failure of first therapy override any other variable. The medical situation ( on/off chemo) at the time of a first relapse is highly important. If relapse occurred while OFF chemo, patients had better prognosis.
A recent study conducted by Wing Leung, M.D., Ph.D from St. Jude Children Hospital shows that that transplantation offers real hope of survival to patients with high-risk leukemia that is not curable with intensive chemotherapy. Bone marrow transplant survival more than doubled in recent years for young, high-risk leukemia patients who lacked genetically matched donors (5).
Five years after transplantation, survival was 65 percent for the 37 St. Jude patients with high-risk ALL treated at the hospital between 2000 and 2007, compared to 28 percent for the 57 St. Jude ALL patients who underwent treatment between 1991 and 1999. For AML patients, success rates grew from 34 % to 74%.
Dr. Leung explains that historically, transplant patients fared best and suffered fewer complications when the donors were relatives who carried the same six proteins on their white blood cells. Known as HLA proteins, they serve as markers to help the immune system distinguish between an individual’s healthy tissue and diseased cells that should be eliminated.
However, St. Jude investigators pioneered the use of haploidentical transplants (=partially genetically matched donors such as parents), demonstrating that careful matching of patients and donors and proper processing of the hematopoietic donor cells enhances the anti-cancer effect of transplantation without significantly increasing side effects.
The process involves careful testing and HLA screening of potential donors to identify the one whose immune system is likely to mount the most aggressive attack against remaining leukemia cells using specialized immune cells known as natural killer cells (5).
Dr. Leung further explains that the odds of finding a good haploidentical donor are 70 to 80 percent, compared to about a 25 percent chance of having a matched sibling donor, Leung said. The likelihood of finding a genetically identical, unrelated donor ranges from about 60 to 90 percent depending on the patient’s race or ethnicity.
Previous study have identified several factors that may affect the outcome of BMT in high-risk patients and included GVHD, blood count, chemo regimen prior to the transplantation, donor-sex matched and others. In a more recent study, however, the results indicated that all patients with very high-risk leukemia should be considered as candidates for HCT (Allogeneic hematopoietic cell transplantation) early in the course of diagnosis or relapse treatment, regardless of the availability of a matched donor or the intensity of prior chemotherapy. HLA typing, donor search, and transplant center referral should be performed as soon as possible. Patients with persistent minimal residual disease (MRD) or hematologic relapse while on therapy are also considered candidates for HCT in current protocols. There are several major differences between previous years study-analyses and this current one that needs to be taken into consideration before including or excluding each of them. [A]; 24% of the allogeneic HCTs in patients younger than 20 years worldwide were performed using cord blood grafts vs the previous bone marrow transplant procedure, [B] differences chemo-regimens between the previous and current years, [C] different transplant approaches evolved simultaneously, and therefore it is difficult to conduct retrospective analyses and [D] matching in HLA-C was not required for unrelated donor HCTs before 2008 in several institutes and therefore outcomes after contemporary 8 of 8 loci-matched transplantations may even be better than those favorable rates reported.
The data reported within is highly important and may increase patients survival rates and increased quality of lives. It is therefore necessary that different clinical-trial centers will re-evaluate current protocols and consider this new approach.
1. Acute Lymphoblastic Leukemia (ALL) and Nanotechnology. Author Tilda Barliya PhD
2. In Focus: Identity of Cancer Stem Cells. Author Ritu Saxena
3a. NCI: Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®).
3b. Drugs Approved for Acute Lymphoblastic Leukemia (ALL)
4. American Cancer Society: Leukemia–Acute Lymphocytic Overview
5. W. Leung, D. Campana, J. Yang, D. Pei, E. Coustan-Smith, K. Gan, J. E. Rubnitz, J. T. Sandlund, R. C. Ribeiro, A. Srinivasan, C. Hartford, B. M. Triplett, M. Dallas, A. Pillai, R. Handgretinger, J. H. Laver, C.-H. Pui. High success of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood, 2011; DOI: 10.1182/blood-2011-01-333070
6. AJ Barrett, MM Horowitz, RP Gale, JC Biggs, BM Camitta, KA Dicke, E Gluckman, RA Good, RH Herzig, and MB Lee. Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood August 1, 1989vol. 74 no. 2 862-871
7. Fujii H, Tradeau JD., Teachey DT., Fish JD., Grupp SA., Schlts KR and Reid GS. In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides. Blood 2007, 109: 2008-2013.
8. Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Wolfram Ebell P, Zimmermann M, Niggli F, Wolf-Dieter Ludwig, Riehm H, Welte K, and Schrappe M. Superiority of Allogeneic Hematopoietic Stem-Cell Transplantation Compared With Chemotherapy Alone in High-Risk Childhood T-Cell Acute Lymphoblastic Leukemia: Results From ALL-BFM 90 and 95. J Clin Oncol 2006 24:5742-5749.
9. O. Ringde´n, M. Labopin, A. Bacigalupo, W. Arcese, U.W. Schaefer, R. Willem. Transplantation of Peripheral Blood Stem Cells as Compared With Bone Marrow From HLA-Identical Siblings in Adult Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia. Journal of Clinical Oncology 2002, Vol 20, No 24 (December 15),: pp 4655-4664.
10. Bunin N, Carston M, Wall D, Adams R, Casper J, Kamani N, King R, and the National Marrow Donor Program Working Group. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 2002, May 1, vol 99: 3151-3157. http://bloodjournal.hematologylibrary.org/content/99/9/3151.full.pdf+html
11. Mehmet Uzunel, Jonas Mattsson, Marie Jaksch, Mats Remberger, and Olle Ringde´n. The signiﬁcance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 2001 98: 1982-1985. http://bloodjournal.hematologylibrary.org/content/98/6/1982.full.pdf+html
12. Marina Cetkovic-Cvrlje, Bertram A. Roers, Barbara Waurzyniak, Xing-Ping Liu, and Fatih M. Uckun. Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice. Blood 2001 98: 1607-1613. http://bloodjournal.hematologylibrary.org/content/98/5/1607.full.pdf+html
13. Kate A. Wheeler, Susan M. Richards, Clifford C. Bailey, Brenda Gibson, Ian M. Hann, Frank G. H. Hill, and Judith M. Chessells for the Medical Research Council Working Party on Childhood Leukaemia. Bone marrow transplantation versus chemotherapy in the treatment of very high–risk childhood acute lymphoblastic leukemia in ﬁrst remission: results from Medical Research Council UKALL X and XI. Blood 2000 96: 2412-2418. http://bloodjournal.hematologylibrary.org/content/96/7/2412.full.pdf+html
14. O. Ringde´n, M. Remberger, T. Ruutu, J. Nikoskelainen, L. Volin, L. Vindeløv, T. Parkkali, S. Lenhoff, B. Sallerfors, L. Mellander, P. Ljungman, and N. Jacobsen, for the Nordic Bone Marrow Transplantation Group. Increased Risk of Chronic Graft-Versus-Host Disease, Obstructive Bronchiolitis, and Alopecia With Busulfan Versus Total Body Irradiation: Long-Term Results of a Randomized Trial in Allogeneic Marrow Recipients With Leukemia. 1999 93: 2196-2201. http://bloodjournal.hematologylibrary.org/content/93/7/2196.full.pdf+html
15. Christopher J.C. Knechtli, Nicholas J. Goulden, Jeremy P. Hancock, Victoria L.G. Grandage, Emma L. Harris, Russell J. Garland, Claire G. Jones, Anthony W. Rowbottom, Linda P. Hunt, Ann F. Green, Emer Clarke, Alan W. Lankester, Jacqueline M. Cornish, Derwood H. Pamphilon, Colin G. Steward, and Anthony Oakhill. Minimal Residual Disease Status Before Allogeneic Bone Marrow Transplantation Is an Important Determinant of Successful Outcome for Children and Adolescents With Acute Lymphoblastic Leukemia. Blood 1998 92: 4072-4079. http://bloodjournal.hematologylibrary.org/content/92/11/4072.full.pdf+html
16. Daniel J. Weisdorf, Amy L. Billett, Peter Hannan, Jerome Ritz, Stephen E. Sallan, Michael Steinbuch, and Norma K.C. Ramsay. Autologous Versus Unrelated Donor Allogeneic Marrow Transplantation for Acute Lymphoblastic Leukemia. Blood 1997 90: 2962-2968. http://bloodjournal.hematologylibrary.org/content/90/8/2962.full.pdf+html