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Oncology Times UK:
International Conference on Malignant Lymphoma

Adult Burkitt's lymphoma treatment enters a new EPOCH

Carlson, Robert H

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Abstract

Researchers reported on a new high‐efficacy, lowtoxicity treatment for adults with Burkitt's lymphoma ‐ the DA‐EPOCH‐R regimen ‐ which has produced a 100% complete response rate, as well as a 100% overall survival rate at 28 months.

At the 10th International Conference on Malignant Lymphoma in Lugano, Switzerland, researchers from the US National Cancer Institute reported on a prospective study of 24 previously untreated patients with Burkitt's lymphoma in whom the DA‐EPOCH‐R regimen ‐ a dose‐adjusted version of the EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) regimen plus rituximab ‐ produced a 100% complete response rate as well as a 100% overall survival rate at 28 months and very low toxicity.

‘Dose‐adjusted EPOCH‐R may be effective in Burkitt's lymphoma, given its established ability to overcome highly proliferative tumours such as diffuse large B‐cell lymphoma and mantle cell lymphoma’

‘DA‐EPOCH‐R represents a radical departure from standard Burkitt lymphoma therapies’, said the lead author, Dr Kieron Dunleavy, an investigator and attending physician with the National Cancer Institute's Metabolism Branch in the Center for Cancer Research.

Dr Dunleavy explained that standard therapies for Burkitt's lymphoma are highly effective but involve intensive, multi‐agent chemotherapy that is associated with high treatment‐related toxicity and mortality, particularly in older patients.

The researchers ‐ senior author Dr Wyndham H Wilson ‐ hypothesised that dose‐adjusted EPOCH‐R may be effective in Burkitt's lymphoma, given its established ability to overcome highly proliferative tumours such as diffuse large B‐cell lymphoma and mantle cell lymphoma.

Adjusting chemotherapy doses based on neutrophil nadir after each cycle allows improved cell kill in rapidly proliferating tumour cells through prolonged drug exposure while reducing haematopoietic toxicity.

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Details of the study

The patients in the study were HIVpositive (8 patients) or negative (16); with a median age of 30 (range of 18 to 66); 79% (11) were male; 79% had extranodal sites; and 54% (13) had ileo‐caecal disease.

HIV‐negative patients received six cycles of DA‐EPOCH‐R. HIV‐positive patients received three to six cycles of DA‐EPOCH‐R for one cycle beyond complete remission for a minimum of three cycles. All patients received intrathecal methotrexate prophylaxis. Outpatient therapy was instituted where possible.

In addition to the 100% complete remission and 28‐month overall survival rates, the event‐free survival rate was 96%, with one patient receiving radiotherapy to a site of residual disease.

Febrile neutropenia occurred in 22% of cycles; 45% of patients had an absolute neutrophil account of less than 500; 38% of cycles required hospitalisation, including one patient who had tumour lysis syndrome.

‘The results of this [regimen] are as good as any other regimen out there, but the toxicity is much less’, Dr Dunleavy said. The next step in research, he said, will be to compare DA‐EPOCH‐R outcomes in newly diagnosed patients with low‐risk versus high‐risk Burkitt's lymphoma.

Session co‐moderator Dr Alfred Reiter pointed out that the basic principle of dose adjustment in diseases with a high proliferation rate and rapid turnover of cells is to cover the cells over three to four days with effective drug concentrations so that each tumour cell can enter the active cell cycle and is exposed to the drug.

Dr Reiter, who is professor of paediatrics and head of the department of paediatric haematology and oncology at the Children's University Hospital at the University of Giessen in Germany, added: ‘In adults there has not been a standard of care for Burkitt's lymphoma. It's difficult to say if this is the standard of care in adults, but it is certainly a new option.’

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50th Anniversary of the discovery of Burkitt's lymphoma

Fifty years after the discovery of Burkitt's lymphoma by Denis Burkitt (1911–1993), the aetiology of the disease is still in question. Much evidence has mounted over the years implicating malaria and the Epstein‐Barr virus, but the data now suggest that these play more of a cooperative role in predisposing an individual to the lymphoma rather than being its cause.

The fascinating story of how this African ‘jaw tumour’ was first fully described and the discoveries that came from that research was presented at the Conference by Dr Ian T Magrath, president and director of the International Network for Cancer Treatment and Research (INCTR) in Brussels, a not‐for‐profit organization providing cancer prevention and treatment strategies to developing countries.

The British‐born Dr Magrath, who also acts as liaison between the INCTR and the US National Cancer Institute (NCI), was at one time head of the NCI's lymphoma biology section in the Paediatric Oncology Branch, and before then was director of the Lymphoma Treatment Centre in Kampala, Uganda.

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Out of Equatorial Africa

Dr Magrath confined his remarks to the history and biology of Burkitt's lymphoma rather than diagnosis and treatment. He began by saying that it is not entirely correct that Dr Burkitt was the first to describe the disease. In 1910, Albert Cooke, a missionary in Uganda, described a jaw tumour, while pathologists later noted the high frequency of lymphomas in African children.

‘The next step in research will be to compare DA‐EPOCH‐R outcomes in newly diagnosed patients with low‐risk versus high‐risk Burkitt's lymphoma’

‘What Burkitt did was describe the clinical syndrome; he didn't realize it was a lymphoma’, Dr Magrath said. In fact, contemporary colleagues were suggesting that some of the tumours resembled lymphosarcoma, and only subsequently recognized the jaw tumour as a lymphoma.

However, Dr Magrath pointed out that Dr Burkitt's achievement took place at a time when there was limited understanding of the immune system, no comprehension of the molecular mechanisms of disease, and few tools available for studying the biology of cancer.

‘Burkitt's lymphoma was literally put on the map by Dr Burkitt’, Dr Magrath said. Furthermore: ‘Burkitt and colleagues in the late 1950s and 1960s provided a valuable paradigm for the understanding of environmental and genetic factors in lymphomagenesis.’

Figure. Dr Denis Bur...
Figure. Dr Denis Bur...
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In terms of treatment since 1958, Dr Magrath said: ‘we've moved from zero to about 90 percent survival rate’.

It is worth pointing out, Dr Magrath said, that Dr Burkitt, an Irish‐born surgeon, had a childhood accident that led to the loss of one eye: ‘Many have commented that even with one eye, Denis Burkitt was able to see much further than most of us with two eyes’, he said.

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EBV connection

A major step in understanding Burkitt's lymphoma came when Dr Burkitt sent tumour samples of the African lymphoma, as it was called then, to Drs Epstein and Barr in London. A connection between viruses and Burkitt lymphoma had been suggested by the geographical distribution of the tumour, which is very similar to other diseases caused by viruses such as yellow fever.

Epstein and Barr eventually found virus particles of what became known as the Epstein‐Barr virus (EBV) in a small number of cells from a Burkitt lymphoma cell line.

In the 1970s, EBV DNA was found in cells that did not express viral antigens at all. This promoted the idea that the virus has two phases of infection, a latent phase in which virus particles are not produced and a lytic virus phase in a fraction of infected cells.

‘The association between Burkitt's lymphoma and Epstein‐Barr virus is less certain today than was thought’

‘The paradigm in the 1970s was that EBV was able to induce proliferation of B cells via latent genes and probably drive proliferation of Burkitt's lymphoma cells', Dr Magrath said. ‘But the pathogenesis of EBV‐negative tumours is unknown.’

A shift in that paradigm occurred when it was found that EBV‐latent proteins that drive proliferation of EBV‐transformed B cells are not expressed in Burkitt's lymphoma and cannot drive proliferation. ‘EBV may be of pathogenetic relevance, but is not a sufficient cause’, Dr Magrath said.

The main driver of proliferation is considered today to be dysregulation of the Myc gene in B cells. The connection with EBV may be that infection prevents apoptosis in cells with dysregulated Myc.

‘This has left the role of EBV uncertain, although previously everybody thought that they understood what it was all about’, Dr Magrath said.

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Holoendemic malaria

Burkitt's lymphoma also mimics the distribution of holoendemic malaria ‐ disease that is perennial and intense ‐ and the rates of the lymphoma are typically higher in areas of intense malarial infection. These observations in the 1960s led to some tantalising findings. One was that the African island of Zanzibar was at one time free of both Burkitt's lymphoma and malaria during a program to eradicate mosquitoes with DDT. But both diseases returned when that program was stopped.

But those investigations did not lead to a cause‐and‐effect finding, Dr Magrath said.

Malaria influences the immune system quite markedly, and the mechanism may be that malaria increases the amount of infectious virus in an individual, and in doing so it may cause earlier EBV infection. Relevant here, for example, is that the more EBV‐infected cells, the greater chance of a Myc gene translocation occurring in an EBV‐positive cell.

‘The high incidence of Burkitt's lymphoma in equatorial Africa is probably a consequence of “cooperation” between malaria and EBV’, Dr Magrath said.

Session co‐chair Dr Alfred Reiter, professor of paediatrics and head of the department of paediatric haematology and oncology at the Children's University Hospital at the University of Giessen in Germany, commented after the session on the puzzling connection between EBV and Burkitt's lymphoma.

‘The association between Burkitt's lymphoma and Epstein‐Barr virus is less certain today than was thought’, Dr Reiter said.

It is curious that the Epstein‐Barr virus was the first virus associated with a human malignancy, ‘but some 40 years later we do not know much more than when Epstein and Barr first detected the virus in the tumour cells’, Dr Reiter added.

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So complex that everybody understood

Besides chronicling the history of Burkitt's lymphoma research and naming many of the important researchers along the way, Dr Magrath also spent some time describing the intricate system of gene translocations, cell transformations, oncogene mutations, and dysregulations suspected in the development of the disease.

Co‐chair Dr Harald Stein, head of the Institute of Pathology at the University Hospital Berlin, may have been alluding to the complexity of these mechanisms after he asked for questions from the audience for Dr Magrath.

There were none, and Dr Stein told Dr Magrath: ‘You can leave the stage with the opinion that everybody has understood you.’

© 2008 Lippincott Williams & Wilkins, Inc.

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