By Luciano Marinelli
Leukaemia is a type of blood cancer that starts in the bone marrow and leads to an excessive production of white blood cells, mostly caused by genetic mutations in developing blood cells (medicalnewstoday.com). It is characterized by immature white blood cells being present in the blood, which results in an increased rate of infections in patients, coupled with symptoms including weakness and shortness of breath (leukaemiacare.org.uk). The National Cancer Institute estimates more than 60,000 cases and 23,100 deaths in 2020, representing 3.4% of all new cancer cases and 3.8% of all cancer deaths (seer.cancer.gov). The growing amount of research on stem cells has given rise to haematopoietic stem cell transplants as treatment for leukaemia, but this treatment option for chronic lymphoid leukaemia (CLL) remains quite controversial. This review will provide an overview on haematopoietic stem cell transplantation and its efficiency in the treatment of CLL.
Leukaemia can be classified as either myeloid or lymphoid, depending on the type of white blood cell that has been affected. If it affects myeloid cells, red blood cells or platelets, it is classified as myeloid leukaemia, whereas if it affects lymphocytes it is classified as lymphoid leukaemia. It can also be further classified as acute or chronic in terms of the rapidity of its development. Acute leukaemia has a quick onset and results in the accumulation of immature blood cells in the bone marrow, which means that the bone marrow will not produce enough healthy, functioning white blood cells. On the other hand, chronic leukaemia has a slower onset and results in the accumulation of relatively mature (but still abnormal) white blood cells (cancercenter.com). The latter takes a longer time to cause problems but is harder to cure compared to the acute version (cancer.org).
Haematopoietic stem cell transplantation (HSCT) can be used to restore healthy immune cells in leukaemia patients. Haematoietic stem cells are constantly dividing cells which can differentiate into different types of blood cells. Therefore, when injected into the blood stream of leukaemia patients, they will travel to the bone marrow and differentiate into healthy white blood cells, restoring the bone marrow’s ability to produce functioning, mature cells, in a process called engraftment (lls.org; Khaddour et al., 2020). HSCT is usually preceded by a preparative regimen consisting of high doses of chemotherapy and radio therapy to kill the cancerous white blood cells, hence preparing the body for transplantation (stjude.org; Khaddour K. et al., 2020).
There are two types of HSCT, autologous and allogenic. Autologous transplantation uses the patient’s own stem cells, which are first extracted from the bone marrow and then frozen and stored, before returning them to the patient’s bloodstream; allogenic transplantation, on the other hand, uses stem cells from a donor (usually a family member). The donor’s stem cells have to be compatible with the patient’s, hence, to tackle this, a process called HLA typing is carried out to determine the best donor. HLA typing uses PCR and next-generation sequencing to detect matched alleles between the donor serum and the recipient (cancer.org; Khaddour K. et al., 2020). Allogenic HSCT has shown much greater efficiency compared to autologous HSCT hence it is more commonly carried out (Reynolds C. et al., 2001; Gladstone D.E. et al., 2015). A study by Yanada M. et al. (Yanada M. et al., 2006) on high-risk acute myeloid leukaemia patients showed that allogenic HSCT resulted in a greater overall survival compared to autologous HSCT as well as a lower probability of relapses, as shown by another study by Li D. et al. (Li D. et al., 2015).
Chronic lymphoid leukaemia is characterized by mature-appearing small B cells which have reduced levels of surface immunoglobulin and CD20, CD23 and CD5 antigens, which are all key in fighting infection (Gladstone D.E. et al., 2012). CLL is dependent on several pathways that promote B cell development and survival, including the B-cell receptor and NF-κB pathways. Tyrosine kinases are key in the transduction of these pathways, so in order to prevent the development and growth of leukaemic B lymphocytes, tyrosine kinase inhibitors (TKIs) have been developed, of which ibrutinib is the most commonly prescribed one (Wiestner A., 2012). Because of the high efficiency of TKIs, HSCT is used only if CLL patients fail initial TKI therapy (emjreviews.com), or, alternatively, if they have a Thr315Ile mutation which prevents the TKI imatinib to bind to its binding site, giving rise to resistance to the drug (Chandrasekhar C. et al., 2019). Because of this, HSCT is normally used as a last resort and was, in fact, the least used treatment for CLL in 2016 (Khaddour K. et al., 2020).
While allogenic HSCT has been proven relatively effective for CLL, autologous HSCT, on the other hand, has shown no benefit at all. A study by Michallet et al. involved a phase III trial on 223 CLL patients comparing autologous HSCT to observation. The results showed no significant difference in 5-year overall survival (85.5% versus 84.3%), even though autologous HSCT did significantly increase the amount of time the patients didn’t experience worsening of their condition (event-free survival) (Michallet M. et al., 2011). Further studies by Sutton et al. (Sutton L. et al., 2011) and Brion et al. (Brion A. et al., 2012) further confirmed the ineffectiveness of autologous HSCT for chronic lymphoid leukaemia. Differently, allogenic HSCT is considered, since 2007, as a reasonable treatment for young CLL patients with nonresponse or early relapse within the first 12 months. However, a study by Bandini et al. reported high toxicity: amongst 25 patients, 12 died because of HSCT-related complications including graft versus host disease (GVHD), which increases with older donor and recipient age (Bandini G. et al., 1991), hence why it is not recommended for older patients.
The high chance of encountering GVHD due to allogenic HSCT, coupled with the inefficacy of autologous HSCT, make HSCT a last resort treatment for chronic lymphoid leukaemia. However, a large amount of research on stem cells is being carried out which can in the future improve the safety and efficacy of HSCT, possibly finding new sources of haematopoietic stem cells. It is also possible that future research may identify previously unknown long-term effects of HSCT which may halt its use as a treatment, so higher emphasis should also be given to developing new drugs for leukaemia.
Medical News Today, (2019). What to know about leukaemia. [online] Available at: https://www.medicalnewstoday.com/articles/142595#risk-factors
Leukaemia Care. Leukaemia. [online] Available at: https://www.leukaemiacare.org.uk/support-and-information/information-about-blood-cancer/blood-cancer-information/leukaemia/
National Cancer Institute. Cancer Stat Facts: Leukaemia. [online] Available at: https://seer.cancer.gov/statfacts/html/leuks.html
Cancer Treatment Centers of America. Types of leukaemia. [online] Available at: https://www.cancercenter.com/cancer-types/leukemia/types
American Cancer Society, (2018). What is Chronic Myeloid Leukaemia? [online] Available at: https://www.cancer.org/cancer/chronic-myeloid-leukemia/about/what-is-cml.html
Leukemia & Lymphoma Society. Stem cell transplantation. [online] Available at: https://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation
Khaddour K, Hana CK, Mewawalla P. (2020). Hematopoietic Stem Cell Transplantation (Bone Marrow Transplant). In: StatPearls. Treasure Island (FL): StatPearls Publishing.
St Jude Children’s Research Hospital. Total body irradiation before stem cell transplant. [online] Available at: https://www.stjude.org/treatment/patient-resources/caregiver-resources/patient-family-education-sheets/radiation-oncology/total-body-irradiation-before-stem-cell-transplant.html
American Cancer Society, (2018). Stem cell transplant for acute myeloid leukemia (AML). [online] Available at: https://www.cancer.org/cancer/acute-myeloid-leukemia/treating/bone-marrow-stem-cell-transplant.html
Reynolds C., Ratanatharathorn V., Adams P. et al. (2001). Allogenic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma. Bone marrow transplant, [online] Volume 27, pp. 801-807. Available at: https://www.nature.com/articles/1703006
Gladstone D.E., Fuchs E. (2015). Hematopoietic stem cell transplantation for chronic lymphocytic leukemia. Curr Opin Oncol, [online] Volume 24(2), pp. 176-181. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696047/
Yanada M., Matsuo K., Suzuki T., Naoe T. (2006). Allogenic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer, [online] Volume 106(12), pp. 2657-63. Available at: https://pubmed.ncbi.nlm.nih.gov/16703597/
Li D., Wang l., Zhu H., Dou L., Liu D., Fu L. et al. (2015). Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation in Intermediate-Risk Acute Myeloid Leukemia Adult Patients in First Complete Remission: A Meta-Analysis of Prospective Studies. PloS One, [online] Volume 10(7). Available at: https://pubmed.ncbi.nlm.nih.gov/16703597/
Wiestner A. (2012). Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood, [online] Volume 120(24), pp. 4684-4691. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520616/
EMJ, (2018). Editor’s pick: allogeneic haematopoietic stem cell transplantation for chronic myeloid leukaemia in the era of tyrosine kinase inhibitors. [online] Available at: https://www.emjreviews.com/hematology/article/editors-pick-allogeneic-haematopoietic-stem-cell-transplantation-for-chronic-myeloid-leukaemia-in-the-era-of-tyrosine-kinase-inhibitors/
Chandrasekhar C., Kumar P.S. Sarma P.V.G.K. (2019). Novel mutations in the kinase domain of BCR-ABL gene causing imatinib resistance in chronic myeloid leukemia patients. Scientific Reports, [online] Volume 2412. Available at: https://www.nature.com/articles/s41598-019-38672-x#citeas
Michallet M., Dreger P., Sutton L., Brand R., Richards S., Marleen van Os et al. (2011). Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood, [online] Volume 117(5), pp. 1516-1521. Available at: https://pubmed.ncbi.nlm.nih.gov/21106985/
Sutton L., Chevret S., Tournilhac O., Diviné M., Leblond V., Corront B. et al. (2011). Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood, [online] Volume 117(23), pp. 6109-6119. Available at: https://pubmed.ncbi.nlm.nih.gov/21406717/
Brion A., Mahé B., Kolb B., Audhuy B., Colombat P., Maisonneuve H. et al. (2012). Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial. Bone Marrow Transplant, [online] Volume 47(4), pp. 542-548. Available at: https://pubmed.ncbi.nlm.nih.gov/21725374/
Bandini G., Michallet M., Rosti G., Tura S. (1991). Bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant, [online] Volume 7(4), pp. 251-253. Available at: https://pubmed.ncbi.nlm.nih.gov/2070129/