New Advances in Cancer Treatments
Historically, blood cancer treatment has depended almost entirely on cytotoxic (cell-killing) drugs, often combined with radiotherapy (X-ray radiation treatment). These drugs can be almost as harmful to normal cells as they are to cancer cells. New treatments entering clinical use specifically target the vulnerabilities of cancer cells. Although they are not free of side effects, their side effects are much less severe than those of traditional therapies.
Maintenance therapy for acute promyelocytic leukaemia (APL) – 17 April 2013
Acute promyelocytic leukaemia (APL) is a subtype of acute myelogenous leukaemia (AML), covering about 10% of AML cases.
A systematic review run by The Cochrane Library has found information brought together to question low-toxicity treatment (maintenance treatment) in patients diagnosed with APL.
This study took a review of 10 randomized controlled trials including 2072 patients. Results imply that in patients with newly diagnosed APL, combined maintenance therapy may pose potential to improve freedom from disease.
The range of trials in terms of maintenance therapies and treatment options has limited the overall results. Many outstanding factors have not yet been reported and as such further trials are to be expected.
NICE Prelim Appraisal on Pixantrone – 11 April 2013
The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using pixantrone in the NHS in England and Wales.
This document summarises the evidence and views that have been considered, and sets out preliminary suggestions made by the Committee. NICE invites comments from the consultees and commentators for this appraisal and the public.
The review is open to comments with the closing date being 1st May 2013.
The appraisal consultation document (ACD) has reviewed the use of pixantrone for treating multiply relapsed or refractory aggressive Non-Hodgkin's lymphoma. NICE have stated that the he benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy.
People currently receiving pixantrone for relapsed or refractory aggressive Non-Hodgkin’s lymphoma should be able to continue treatment until they and their clinician consider it appropriate to stop.
Dasatinib for High-Risk Myelodysplastic Syndromes (MDS) - 25 Mar 2013
Scientists at Moffitt Cancer Center, Tampa, have completed a phase II clinical trial to better understand the safety and effectiveness of the drug dasatinib for patients with higher-risk myelodysplastic syndromes (MDS).
The therapy may not be effective for all patients, but those with trisomy 8 have found higher responsive rates to treatment with dasatinib.
Myelodysplastic syndromes are disorders of the stem cell in bone marrow. The marrow does not produce enough normal blood cells for the body. The number and quality of blood-forming cells reduce, resulting in blood production problems.
At present, stem cell transplantation is the only potential cure option for MDS. New therapies for MDS need to be explored for the future.
Dasatinib has been approved for patients diagnosed with chronic myeloid leukaemia.
New approach to Chemotherapy potentially less harsh on Fertility - 25 Mar 2013
Advances in cancer therapy means more patients are surviving, but many female patients often face a temporary or permanent loss of fertility after undergoing traditional chemotherapy.
Scientists at Feinberg School of Medicine, Northwestern University in Chicago, using nanoparticles as a delivery system have designed and tested a way to deliver a chemo drug that kills cancer cells, but that has a lower impact on the ovaries. If successful this new method of drug delivery may help to protect the fertility of women undergoing cancer treatment. The overall goal is to create smart drugs that kill the cancer but don't cause fertility problems in young women.
When tested against lymphoma, this new form of the cancer drug was more potent than the drug in its traditional free form.
Researchers chose to test the new drug on lymphoma because Hodgkin's lymphoma and Burkitt's lymphoma are highly prevalent in patients of reproductive age.
Monoclonal Antibodies
Monoclonal antibodies can be thought of as ‘magic bullets’, because they are drugs designed to treat particular individual diseases. Antibodies have exquisite specificity; they will only lock onto a target (a protein) with a particular shape, just like a lock and key. These drugs can be identified by the ‘mab’ in their name.
Monoclonal antibody therapy uses a very pure preparation of antibody against a single marker on the cancer cells to target treatment. In some cases the antibody alone can trigger the killing of the cell. In others it is bound to a radioactive molecule or to another drug, which is released on or near the target cells.
Rituximab (Rituxan™ {US}, MabThera™ {UK})
Rituximab is targeted against a cell surface molecule called CD20, which is found on B lymphocytes. It has been found to be effective against many diseases where the target cells carry the CD20 protein including B-cell lymphoma’s such as diffuse large B-cell lymphoma and follicular lymphoma, as well as leukaemia’s including chronic lymphocytic leukaemia (CLL.)
Gemtuzumab ozogamicin (Mylotarg™)
Gemtuzumab ozogamicin is a combination of a monoclonal antibody targeted for specific AML cells in combination with a chemotherapy drug called ozogamicin. Ozogamicin is a cytotoxic agent from the class of drugs called calicheamicins. This group of cytotoxic drugs are very effective at killing AML cells but, if given in the conventional way, are far too toxic. Gemtuzumab ozogamicin overcomes this problem; at present Mylotarg™ is in clinical trials as a treatment for AML in older patients. Gemtuzumab is targeted at CD33.
Mylotarg has been withdrawn from the American and European markets but it may still be used in clinical trials in the UK.
Alemtuzumab (MabCampath™ {UK} Campath™ {US})
MabCampath™ is the UK name for a drug marketed in the US as Campath™. It is a monoclonal antibody targeted at CD52 found on the surface white blood cell called lymphocytes. Alemtuzumab is mainly used to treat chronic lymphocytic leukaemia (CLL).
Targeted Therapies
Whereas monoclonal antibodies rely on the ability to bind only to the cancer cells, other targeted therapies rely on specific vulnerabilities of the cancer cells for their effectiveness. An example of this targeting is the abnormal protein called BCR-ABL found in the CML cell.
Imatinib (Glivec™)
Chronic myeloid leukaemia (CML) cells contain a protein called BCR-ABL that is not found in normal cells and which is responsible for most of the features of the disease, at least in the earlier stages. Imatinib binds to, and blocks the activity of, BCR-ABL; this can offer very effective control of the disease. Although imatinib is not completely free of side effects, it is much more readily tolerated than the previously available treatments. Initial results indicate that it is also far more effective. With over 10 years of experience with imatinib, it is clear that in many cases it can totally control the disease and may eventually allow patients to live a normal life span, although it is perhaps too early to be sure of this. The benefits of imatinib are so clear-cut that it is currently recommended that all newly diagnosed CML patients should receive this treatment.
Some patients’ disease may become resistant to imatinib or the patient may develop an intolerance of it. Luckily a new generation of similar drugs has been developed which are as specific as imatinib, are more potent and may work when imatinib no longer does. Two such drugs, Sprycel™ (dasatinib) and Tasigna™ (nilotinib) have recently (2008) been licensed for use in Europe and the UK. A third new drug called bosutinib is currently being processed by the European licensing authority but as yet has no trade name.
Nilotinib now has a NICE approval for use for CML which is resistant to imatinib or for patients who cannot tolerate imatinib.
Bortezomib (Velcade™)
All cells contain structures called proteasomes – their task is to break down proteins no longer needed by the cell, particularly messenger and regulatory molecules which might confuse or disrupt cell control if they were not removed. All cells produce a protein called NF-B, which protects the cell against apoptosis (programmed cell death) and promotes cell growth and division. NF-B is deactivated by binding to a protein called I B; the proteasome then breaks down I B and releases NF-B to carry out its normal role. Myeloma cells have excessive amounts of NF-B and there is insufficient I B to keep this under control. Bortezomib blocks breakdown of I B by the proteasome and thus allows enough I B to accumulate to block the extra NF-B and bring the myeloma cell back under control. There is some evidence that Bortezomib may also be effective in other diseases.
Thalidomide and derivatives
In the 1960s use of thalidomide as a treatment for morning sickness in pregnancy led to the birth of many children with severe limb abnormalities and for many years the drug fell into disuse; more recently it has been found to be effective against some forms of blood cancer.
Thalidomide belongs to a class of drugs called “IMiDs” (immunomodulatory drugs), and it was clear that this class of drugs would be important in treating certain types of cancer, so scientists began to develop derivatives of thalidomide. One of these derivatives is a drug called lenalidomide (Revlimid™). Lenalidomide has shown promise in the treatment of both myelodysplastic syndrome (MDS) and myeloma. In MDS the main group to benefit seem to be those who have low-grade disease with a specific abnormality of chromosome 5. Because lenalidomide is related to thalidomide it is crucially important that any woman taking the drug does not become pregnant. {Revlimid™ is not currently licensed for use for MDS – any such use will be after full discussion between a patient and the specialist.}
Azacitidine (Vidaza™)
Azacitidine is now licensed in the UK and Europe for the treatment of adult patients who are not eligible for stem cell transplantation with: intermediate-2 and high-risk myelodysplastic syndromes (MDS); chronic myelomonocytic leukaemia (CMML); myeloproliferative disorder and acute myeloid leukaemia (AML). Since February 2011, azacitidine has had NICE approval for these same indications.
It is thought that azacitidine’s main mode of action is to break the methylation process, interfering with cell regulation processes in which genes are switched on and off. In several forms of blood cancer, tumour suppressor genes are switched off by methylation. Azacitidine can reverse this and allow the tumour suppressors to regulate growth and division.
Another abnormality in some cancer cells is that they block the signals which cause a cell to mature and eventually to age and die – the cancer cell becomes immortal. Once again, by removing this restriction, azacitidine can overcome some of the changes which make the cancer cell dangerous.
Radioimmunotherapy
Radioimmunotherapy (RIT), uses an antibody labelled with a radionuclide to deliver cytotoxic radiation to a target cell. For blood cancer, an antibody with specificity for a tumour-associated antigen is used to deliver a lethal dose of radiation to the tumour. Current treatment uses an antibody that targets CD20. The first radioimmunotherapy agents were approved for the treatment of refractory non-Hodgkin lymphoma.
Radiolabelled antibodies consist of tiny amounts of radioactive material attached to a monoclonal antibody, which circulates in the body until it locates and binds to the surface of B cells. Once the monoclonal antibody has attached itself to the B cell, the radioactive substance kills the diseased cell, and any nearby lymphoma cells that the monoclonal antibody cannot target.
The ability for the antibody to specifically bind to a tumour-associated antigen increases the dose delivered to the tumour cells while decreasing the dose to normal tissues. By its nature, RIT requires a tumour cell to express an antigen (e.g. CD20) that is unique to the cancer or is not accessible in normal cells.
These treatments, which include ibritumomab tiuxetan (Zevalin™) and tositumomab iodine-133 (Bexxar™), are among the options that can be given to patients with relapsed indolent non-Hodgkin lymphoma (follicular lymphoma) that no longer responds well to conventional chemotherapy with or without rituximab.
Zevalin™ is available in the UK but has yet to receive NICE approval.
Radioisotopes
Radioisotopes are chemicals that give off energy in the form of radiation. Zevalin™ is a monoclonal antibody that is combined with the radioisotope Yttrium-90 (90Y) and Bexxar™ with the Radioisotope iodine 133. (See above)
Arsenic trioxide
Arsenic trioxide (Trisenox™) is licensed to treat people who have acute promyelocytic leukaemia (APL) that has come back after treatment, or has not gone into remission with treatment. This drug is made from the poison arsenic, but is given at low, safe doses.
Clofarabine (Evoltra™)
Clofarabine is very similar to another drug commonly used to treat people with AML called fludarabine. It is thought that as clofarabine has fewer side effects than fludarabine it may be more suitable for older people who are less able to have intensive chemotherapy. It is also used to treat children with acute lymphoblastic leukaemia (ALL) that has come back (relapsed) after initial treatment.
CEP701 (Lestaurtinib™)
CEP701 is an experimental new treatment designed to act against cells that have a change (or genetic mutation) called a FLT3 mutation. (About 1 in 3 people diagnosed with Acute Myeloid Leukaemia (AML) have a FLT3 mutation in the leukaemia cells). This mutation can increase their risk of the leukaemia coming back in the future. It is hoped that by giving CEP701 between courses of chemotherapy this risk can be reduced. Some people taking part in the AML-15 trial who have the FLT3 mutation will be offered CEP701.
Tipifarnib (Zarnestra™)
Tipifarnib is designed to block the messages that tell cells to grow from reaching leukaemia cells. It is a tablet you swallow. Tipifarnib belongs to a group of drugs called farnesyltransferase inhibitors (FTIs). Farnesyltransferase is a special protein that stimulates acute myeloid leukaemia (AML) cells to grow. FTIs block this problem. It has fewer side effects than standard high-dose chemotherapy usually used to treat AML, because it is a more targeted therapy. Doctors therefore hope that when it is given with lower doses of chemotherapy it will improve the effectiveness of treatment for older people who are less able to have intensive chemotherapy.
Some people taking part in the AML-16 trial will be given tipifarnib along with their chemotherapy treatment.