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Acute Myelofibrosis and stem cell treatment for rare bone marrow cancer

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What is Acute Myelofibrosis?

Acute Myelofibrosis is a rare form of bone marrow cancer. It occurs as a result of bone marrow cells functioning in an abnormal way.

The disease is characterised by a build-up of collagen in the bone marrow, which causes scar tissue to form (fibrosis) and results in bone marrow failure. Scarring inhibits healthy blood production in the bone marrow, which leads to too few red blood cells, white blood cells and platelets being produced (pancytopenia).

This can lead organs other than the bone marrow, forming blood cells to compensate for the shortage, known as extramedullary haematopoiesis. The liver and spleen tend to be most affected, swelling to become dangerously enlarged.

Primary Myelofibrosis is a spontaneous form of the disease. Secondary Myelofibrosis develops as a result of another condition, such as polycythemia vera or thrombocythaemia.

A fifth of cases develop into acute myeloid leukaemia.

Signs and Symptoms

The defining symptom of Myelofibrosis is scarring on the bone marrow, known as fibrosis. This may not be apparent at first, and patients often have no symptoms when they are initially diagnosed. However, the following symptoms may occur:

  • hepatosplenomegaly (enlarged liver and spleen)
  • anaemia, with symptoms including pallor, fatigue and shortness of breath
  • pruritus — severe itching of the skin
  • excess sweating
  • bone pain
  • easy bruising and excessive bleeding due to a shortage of blood platelets
  • loss of appetite combined with weight loss
  • higher susceptibility to infections such as pneumonia

Diagnosis is made via a bone marrow biopsy and a blood count revealing anaemia or abnormally shaped red blood cells.

The majority of cases of Myelofibrosis occur as a result of an acquired genetic mutation. It is thought that long-term exposure to high levels of benzene or ionising radiation can be a contributing factor.

How is it treated?

Some people with Acute Myelofibrosis require no immediate treatment but must be regularly monitored to check on disease progression.

For more severe cases, treatment includes addressing any complications that result from low blood counts and an enlarged spleen.

Blood transfusions may be necessary in cases of severe anaemia or platelet shortage.

A splenectomy may be recommended where an enlarged spleen is causing the need for frequent blood transfusions. This is considered a high-risk procedure for these patients.

The drug ruxolitinib has been shown to reduce spleen size. It seeks to undo the effects of the genetic changes that lead to myeloproliferative disorders such as Myelofibrosis.

Other options to reduce spleen size are the drugs hydroxyurea or thalidomide. However, there are side effects associated with long-term use.

An allogeneic stem cell transplant is currently the only curative treatment for this condition.

How can stem cells help?

An allogeneic haemopoietic stem cell transplant is the only potentially curative treatment for Acute Myelofibrosis.

However, stem cell transplants are major procedures and often require highly toxic chemotherapy preparative regimes. They also require the finding of a compatible donor, which can prove difficult. Transplants also come with the risk of graft failure and Graft-versus-Host Disease (GvHD), which can cause very serious complications.

The risks of a stem cell transplant tend to increase with age. This is particularly relevant for patients with a disease like Myelofibrosis, with a median age of onset of 60 years old. The risk to elderly patients and those with no matched donor means that the number of patients who can undergo the procedure is limited.

However, advances in diagnostic techniques and genetic technology, improved treatments and better medications mean that stem cell transplants are improving and are increasingly becoming viable options for more patients with Myelofibrosis. This includes patients over 60 with HLA-mismatched or unrelated donors.

The best timing for a stem cell transplant for patients with Myelofibrosis is still being debated and varies from patient to patient. Factors that should be taken into account in deciding whether to go ahead with the procedure include the age of the patient, the nature of their disease and donor availability.

If a stem cell transplant is performed too early, it could cause the patient significant and potentially unnecessary side effects; and sometimes a good quality of life can be achieved with other treatment options.

However, delaying the procedure could cause the disease to worsen and result in a worse outcome than if it had been done sooner. Weighing up the risk to benefits for each individual patient is hugely important.

As Myelofibrosis is such a rare disease, there is little data available from which to make comparative studies on the outcomes of such procedures. However, clinical trials are ongoing to improve the outcome of stem cell transplants for patients with this disease.

Reduced-intensity conditioning regimes are being trialled in several centres throughout the world. The reduced toxicity involved makes the procedure viable for elderly patients with Myelofibrosis, who would be unable to withstand standard preparatory conditioning regimes.

Current evidence suggests that a reduced intensity conditioning regime is just as effective as a standard conditioning regime for these patients. The European Group of Blood and Marrow Transplantation investigated 103 patients undergoing a combined RIC regime of fludarabine and busulfan.

Five years on, the overall and event-free survival rates were at 67% and 51% respectively. Matched sibling and matched unrelated donors were similarly successful, whereas those patients who had donors who were mismatched unrelated, had worse results.

The Fred Hutchinson Center has been focusing on ways to improve the preparatory regimes for stem cell transplants and specifically how to prevent GvHD for several years.

One of their latest trials builds on previous work, by testing tacrolimus and mycophenolate mofetil to see how they may prevent GvHD in patients who have undergone total body radiation prior to an allogeneic peripheral blood stem cell transplant.

Giving low doses of chemotherapy before a stem cell transplant inhibits cancer growth and helps to stop the patient’s immune system from rejecting the donor stem cells. The researchers predict that tacrolimus and mycophenolate mofetil might reduce the likelihood of the donor cells from attacking the host’s immune system, the hallmark of GvHD.

Similarly, a research study conducted by the Sidney Kimmel Cancer Center at Thomas Jefferson University is comparing the survival rates of patients with lower risk disease undergoing haemopoietic stem cell transplants compared to the survival rates in the medical literature of equivalent patients, who received reduced-intensity haemopoietic stem cell transplants from matched related donors. This information will add to a more comprehensive understanding of the risk factors and treatment courses for patients with Myelofibrosis.

Umbilical cord blood transplants are being trialled by the Masonic Cancer Center for haematological diseases, such as Myelofibrosis. Patients will be given a myeloablative conditioning regime and total body irradiation prior to transplantation.

Umbilical cord blood is also being used in a trial by the Case Comprehensive Cancer Center as an intra-osseous transplant. In this method, umbilical cord blood and mesenchymal stromal cells are transplanted into the patient’s bone to help stop the growth of cancer cells. The donated stem cells are expected to replace the patient’s immune system, by replacing the white blood cells and thereby help to destroy cancer cells.

In a trial by Northside Hospital Inc, researchers are investigating the combination of a reduced intensity conditioning regime, with HLA mismatched related donors, using peripheral blood as the stem cell source. The researchers will be looking specifically at graft rejection and GvHD.

The Future

There are several ongoing studies seeking to better understand Myelofibrosis so that more targeted treatments can be found that will cure the disease for all patients.

One such study at the University of Utah is trying to find genes whose mutations cause Myelofibrosis amongst another chromosome negative myeloproliferative disorders.

Similarly, the National Institute of Health Clinical Center is conducting a natural history study to ascertain the molecular basis of myeloproliferative disorders, such as Myelofibrosis.

The University Health Network in Toronto is creating an MPN registry by collecting information, including molecular results from patients with myeloproliferative diseases.

A correlative biomarker study, carried out by the Icahn School of Medicine at Mount Sinai, is researching molecules from the blood and bone marrow to better understand the causes of myeloproliferative diseases such as Myelofibrosis. The scientists will use this data to investigate the effectiveness of various treatments.

The aim is to establish a database to understand these conditions better and to improve treatments and patient outcomes. The types of data being collected include details of treatments, results, any complications of treatment as well as molecular and cytogenetic data. Patients at different stages of their disease will be enrolled in the study.

Similarly, the UNC Lineberger Comprehensive Cancer Center is collecting and storing samples of tissue, blood and body fluid from patients with cancers such as Myelofibrosis to help create better, more targeted treatments in the future.

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