Refractory anaemia with excess blasts and treatment using stem cell therapies

Peripheral blood stem cells

What is Refractory Anaemia with Excess Blasts?

Refractory anaemia with excess blasts (RAEB), also known as myelodysplastic syndrome with excess blasts (MDS-EB), is a cancer of the blood and bone marrow, characterised by defective formation of all three types of blood cell.

The bone marrow cells are abnormal (dysplastic) and immature, meaning that they have difficulty making new blood cells. Red blood cells, white blood cells and platelets are all affected.

As defective cells tend to die earlier than normal cells, the patient has too few circulating normal blood cells.

Patients with MDS-EB may have refractory anaemia (a shortage of circulating healthy red blood cells), refractory neutropenia (a shortage of white blood cells, called neutrophils) and/ or refractory thrombocytopenia, a shortage of circulating platelets.

In some cases, the disease progresses into acute myeloid leukaemia, a cancer of white blood cells.

MDS-EB1 has a 25% chance of transforming into AML, whereas MDS-EB2 has a 33% chance. MDS-EB2 is the highest grade of MDS, with the poorest prognosis.

Signs that the disease may be progressing include frequent infections, bleeding from the nose or gums and the need for more blood transfusions.

MDS is more common in men than women and usually presents over the age of 50. However, it can occur at any age. Approximately 4 in 100, 000 people develop the condition every year.

MDS-EB is one of the six main types of MDS, as defined by the World Health Organisation (WHO) in 2016. The six types are:

  • MDS with multilineage dysplasia (MDS-MLD)
  • MDS with single lineage dysplasia (MDS-SLD)
  • MDS with ring sideroblasts (MDS-RS)
  • MDS with excess blasts (MDS-EB)
  • MDS with isolated del(5q)
  • MDS, unclassifiable (MDS-U)

The definitions are based on how the bone marrow cells appear under a microscope. The classification system takes into account the proportion of cells that appear abnormal, low blood cell counts, the number of very early cells (blasts), as well as any chromosomal changes.

MDS with excess blasts (MDS-EB) involves higher than normal numbers of blasts in the bone marrow and/ or blood. Patients will have low blood counts in at least one blood cell type. It can also involve abnormal cells in the bone marrow.

Signs and Symptoms

There are often no symptoms in the early stages of RAEB. However, symptoms can include:

  • anaemia – too few red blood cells resulting in weakness, fatigue, breathlessness and pallor
  • neutropenia – too few white blood cells called neutrophils, leading to frequent infections, which can be a serious complications
  • thrombocytopenia – low platelet levels, which results in bruising and excessive bleeding, which can become fatal
  • hepatosplenomegaly — enlarged liver and spleen
  • the appearance of abnormal granules in the cells
  • chromosomal abnormality

Diagnosis is made via a full blood count and bone marrow examination. Genetic sequencing may also be used.

Risk factors associated with developing MDS-EB are:

  • certain drugs
  • chemotherapy or radiation treatment
  • stem cell transplants – due to highly toxic preparative chemotherapy conditioning regimes
  • genetic diseases such as Fanconi anaemia or Diamond-Blackfan anaemia, familial aplastic anaemia, Schwachman-Diamond syndrome
  • smoking – contains chemicals that damage genes
  • environmental factors such as high dose radiation or long-term exposure to benzene
  • exposure to heavy metals like lead or mercury.
  • a diagnosis of a lower grade of MDS

How is it treated?

Treatment primarily targets the complications of having low blood counts.

Anaemia may be treated by erythropoietin, a growth factor, which stimulates erythropoiesis and the development of red blood cells.

Red blood cell transfusions are another option, which may also require chelation therapy to remove the build-up of iron in the blood.

Excessive bleeding and bruising from low levels of blood platelets may be addressed with growth factor drugs or platelet transfusions.

Neutropenia and its associated infections will be treated with antibiotics and growth factors.

Stem cell transplants are the best way to restore blood cell production and allow the bone marrow to function normally. They may be considered for transfusion-dependent patients.

How Can Stem Cells Help?

A successful stem cell transplant can cure MDS-EB as it can restore healthy bone marrow function.

Blood-forming stem cells are taken from a healthy donor – usually a relative or a matched donor – and transplanted into the patient’s bone marrow, where they grow and enable it to produce healthy blood cells.

There are drawbacks to this procedure, however. The donor needs to be a close match and few patients can find a fully matched donor. The donated stem cells need to carry a special genetic marker, a human leukocyte antigen (HLA) that’s identical or very close to the patient’s.

Those who are lucky enough to find a match still run the risk of graft rejection and chronic immune complications such as Graft-versus-Host-Disease (GvHD).

Due to the difficulties and restrictions in finding an HLA-matched donor, research is underway in many centres around the world into alternatives.

A clinical trial by Scripps Health is giving patients with blood malignancies or bone marrow diseases, who lack a related donor, the chance of a transplant from cord blood registries of unrelated donors. .

Meanwhile, a study by the Groupe Francophone des Myelodysplasies is comparing the survival of patients with a matched donor and those without after undergoing an allogeneic haemopoietic stem cell transplant (HSCT) after 36 months.

Medical advances have enabled partially matched or haploidentical donors to be used. This means a 50% match and is usually from a sibling or parent. Partially matched donors have a greater risk of GvHD, as well as a slower immune recovery. However, research is on-going to address these issues and outcomes are continually improving.

GvHD is among the major barriers to a successful outcome following a stem cell transplant. GvHD occurs when the donated cells wage an immune response and attack the host’s cells, causing tissue and organ damage. This is a major cause of post-transplant mortality and is caused by the donor T-cells. Therefore several studies are investigating the effect of removing some of the donor T-cells before transplant.

One trial by the National Heart Lung and Blood Institute is investigating whether altering the stem cell transplant donation procedure will improve its outcome. They will reduce the number of white blood cells in the blood before infusing into the patient. It is the first trial of its kind in paediatric patients.

The various types of stem cells are another area of research to improve the outcome for patients with MDS. One study by Sclnow Biotech Company is investigating the safety and effectiveness of human umbilical cord mesenchymal stem cells in treating MDS.

The Memorial Sloan Kettering Cancer Center is trialling the effect of umbilical cord blood, combined with blood stem cells from a close family member, for patients undergoing peripheral blood stem cell transplants from an unrelated cord blood donor. The aim is to find out if this will make the transplant safer.

A research study by the National Heart Lung and Blood Institute is testing the safety and effectiveness of unlicensed cord blood units for patients undergoing stem cell transplants. Currently not all cord blood available for patient use has been stored according to guidelines.

Another study by the same institute is testing the safety and effectiveness of treating patients with MDS with both peripheral blood from a family member and umbilical cord cells from an unrelated donor.

Stem cell transplants are usually only carried out on children and young adults, as the high levels of chemotherapy involved and the need for a full transplant is generally considered too toxic for adults to withstand. This clearly needs to be addressed, to make the procedure available for a greater number of patients, including older patients with myelodysplastic syndrome.

One major area of research, to understand the factors that improve stem cell transplants for patients with diseases like MDS, is into the various conditioning regimes prior to undergoing a stem cell transplant.

Myeloablative regimes use high doses of chemotherapy and/ or radiation to destroy the bone marrow, allowing the donor cells to take over and proliferate. The rationale behind this is to stop the cancerous cells from coming back after the transplant. Within this type of conditioning regime, various chemotherapy agents can be used.

A randomised clinical trial by the Fred Hutchinson Cancer Research Center will study the effect of different chemotherapies in treating patients with MDS before a donor stem cell transplant, to evaluate the best outcomes, including overall survival and morbidity.

The best conditioning regimes are still being debated, which is why a Chinese prospective randomised controlled study, by the Nanfang Hospital of Southern Medical University, is investigating the best conditioning for patients with refractory anaemia with excessive blasts 1 and 2, before undergoing an allogeneic HSCT.

Non-myeloablative regimes use reduced intensity chemotherapy and radiation, with increased doses of transplant anti-rejection and immunosuppressive drugs. Such regimes reduce the overall toxicity, which opens up the procedure to vulnerable patients who would otherwise be unable to withstand it.

One such trial, led by the University of Pittsburgh, wants to compare the safety and effectiveness of reduced intensity conditioning compared to myeloablative conditioning regimes for high-risk paediatric and young patients with MDS and AML undergoing HSCTs. The researchers hope that the results from this will allow more patients to receive life-saving treatments.

Another trial by the Sidney Kimmel Cancer Center at Thomas Jefferson University is comparing the patient survival following a reduced intensity conditioning regime in treating patients with haematological malignancies, with historical records of patients who underwent stem cell transplants from matched donors. In this way, they will be able to assess the safety and efficacy of the lower toxicity approach to standard treatment.

Gene Therapy

Stem cells are being used in gene therapy, which aims to correct the underlying genetic abnormality by replacing the faulty gene in immune cells with a normal copy. Gene therapy has the potential to offer a gentler option than a stem cell transplant.

Gene therapy involves taking stem cells from a patient’s blood or bone marrow and inserting a normal copy of the defective gene into the DNA. This is usually done with a viral vector; viruses by their very nature survive and spread by inserting their genes into the host’s genome.

As in a stem cell transplant, these new stem cells find their way to the bone marrow, where they start to produce healthy immune cells. This is known as ‘somatic gene therapy’ – altered genetic material is only present in cells derived from the infused stem cells and cannot be passed on to future generations.

Although there are no current trials investigating gene therapy as a cure for MDS, several medical research centres are using gene-editing techniques to improve stem cell transplants or immunotherapy for patients with MDS.

For example, the Fred Hutchinson Cancer Research Center is using gene-treated T-cells in a phase I/II trial to investigate the effect of adoptive immunotherapy to treat the high risk of relapsed MDS, for patients previously treated with an allogeneic stem cell transplant. The hope is that these T-cells will help the body build an immune response to target cancer cells.

Similarly, a current study by the Baylor College of Medicine is looking into the effect of donor T–cells programmed with a “suicide gene” on patient engraftment and immune system recovery rates after undergoing a haemopoietic stem cell transplant. Because T-cells are responsible for the immune response that leads to GvHD, the cells would self-destruct following onset of GvHD.

A phase I/II trial by Cell Medica in association with University College London is researching gene-modified WT1 T-cell receptor (TCR) therapy in patients with myelodysplastic syndrome. The patient’s T-cells will be modified by transfer of a gene that allows them to make new TCRs that can identify a particular antigen found on the surface of MDS and AML cells.

An improved understanding of the genetic cause of the different types of myelodysplastic syndrome will help determine the best course of treatment for patients, as well as open up the possibility of further gene therapy trials in the future.

A non-therapeutic study by the Boston Children’s Hospital is underway to collect and store samples of patients with blood diseases for future genetic and genomic research. It is hoped that this will lead to a better understanding of the causes of diseases such as myelodysplastic syndrome and help provide more effective treatments for them.

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