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The Lancet Oncology

Wednesday, July 1, 2009

Escalated Dose-Intensified Combined Modality Treatment Shows Survival Benefit In Patients With Early Unfavourable Hodgekin Lymphoma

With more than 7,500 participants from more than 100 European and non-European countries in attendance, the 14th congress of the European Hematology Association (EHA), which was held in Berlin, Germany, from June 4 – 7, 2009, proved record-breaking. The delegates gathered in Berlin to share the most recent developments in hematological research and improvements in care.

The program included sessions on clinical and laboratory hematology and covered all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.

The program featured a session, presented by Prof. Peter Borchmann on behalf of the German Hodgkin Study Group / GHSG (abstract number 0553) discussing an analysis of Dose-Intensified Combined Modality Treatment In Patients With Early Unfavourable Hodgekin Lymphoma (HL).

As a result of intensified medical research, Hodgkin's lymphoma has become one of the most curable tumors in adults. Today, about 80% - 90% of patients experience long-term disease free survival (DFS). This is mainly the result of numerous large clinical trials initiated by the German Hodgkin Study Group and other organizations, taking place since the late 1970's, using risk-adapted, highly effective therapy modalities. From the late '70s nearly 15,000 patients have been randomized and treated in these prospectively randomized trials.

Risk Groups
Patients with Hodgkin lymphoma are divided in three risk groups according to the initial staging and additional clinical risk factors: early favorable, early unfavorable and advanced-stage risk groups.

Abstract 0553 (Interim Analysis of the GHSG HD14 Trial for Patients With Early Unfavourable HL) compared the results of the arms of the GHSG HD14 trial. The rational of this trial was to improve the prognosis of patients with early unfavorable disease by comparing the old standard treatment, 4 courses of ABVD (adriamycin, bleomycin, vinblastine, and dacarbacine) followed by localized radiotherapy (30 Gy IF-RT), with a more intensive chemotherapy regimen consisting of 2 cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by 2 cycles of ABVD and the same radiotherapy as in the standard arm.

Treatment-associated toxicities
A previous GHSG trial (GHSG HD11) compared 4 cycles of ABVD with BEACOPP, followed by either 30 or 20 Gy IF-RT. This trial showed no difference with respect to outcomes, and despite excellent initial remission rates, approximately 15% of patients with early unfavorable-stage HL relapsed within 5 years and another 5% suffered from progressive disease. Nevertheless, these good results of the GHSG trials are threatened by treatment-associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies.

Improving trial results
The GHSG HD14 trial showed a significantly better outcome in terms of progression-free survival in the more intensive escalated BEACOPP regimen than the standard regimen of 4 cycles of ABVD in patients with early unfavorable Hodgkin's lymphoma (HL).
The study, conducted by the German Hodgkin Study Group (GHSG), included 1645 patients in 346 centres. These patients had early unfavorable Hodgkin's lymphoma, clinical stage 1 or 2 and risk factors, including large mediastinal mass, extranodal disease, high erythrocyte sedimentation rate, and 3 or more areas affected.

Interim analysis
After the third interim analysis with 1127 patients, researchers decided to terminate the GHSD HD14 trial early because of the significantly better outcome for patients treated with BEACOPP compared to ABVD. The interim results showed that progression free survival (PFS) was significantly better for patients treated with the hybrid regimen than for patients treated with 4 courses of ABVD. After 3 years, progression-free survival was observed in 97% of patients in the escalated BEACOPP group and 91% in the ABVD group.

Furthermore, the interim analysis showed freedom from treatment failure to be 95% in the escalated BEACOPP group versus 91% in the ABVD group. Overall, there were more patients with progressive disease, relapse and a higher mortality in those receiving 4 cycles of ABVD. These results prompted the GHSG to adopt a regimen of two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy radiotherapy as the new standard treatment for patients with early unfavorable Hodgkin's lymphoma.

Escalated BEACOPP, compared to standard BEACOPP, uses a higher doses of etoposide (200 vs 100 mg/m2), doxorubicin (35 vs 25 mg/m2), cyclophosphamide (1200 vs 650 mg/m2), with added granulocyte colony-stimulating factor support. Combined with local irradiation, the escalated regimen showed superior disease control compared with ABVD. Patients experienced more hematological adverse events in the escalated BEACOPP group compared to the ABVD group. This included leukopenia (22% vs , including 81%), thrombocytopenia (<1%>

Predisposition to Myeloproliferative Neoplasms
An unrelated presentation by Prof. Nick Cross, Salisbury, United Kingdom, discussed research aimed to understand what causes a group of related conditions known collectively as myeloproliferative neoplasms (abstract number 0555).

Researchers have found a common genetic 'signature' that predisposes to these disorders. The predisposition is relatively subtle and so it cannot by itself be used to predict whether anyone will develop disease or not, but it is an important step towards understanding why some people get cancer and why others do not. In the future it is possible that the abnormality we have found might be combined with other genetic and environmental risk factors to enable much better predictions of disease susceptibility to be made.

Myeloproliferative neoplasms or MPNs are conditions of the blood that are related to leukemia but in effect they are a very mild form that resembles the first steps towards cancer. They are characterised by the overproduction of red and white blood cells, which increases the risk of strokes and heart attacks. Many cases of MPDs are caused by a mutation in a gene called JAK2. When the JAK2 gene has mutated, it sends abnormal messages to the blood stem cells to produce more and more blood cells.

Scientists have found that a particular region of chromosome 9 that carries the JAK2 gene is predisposed to acquiring mutations, but only in individuals with a particular genetic makeup. It is likely that this finding will lead to a much better understanding of how the JAK2 gene mutations happen and why they lead to an increased risk of someone developing an MPD.

The study, carried out at the Wessex Regional Genetics Laboratory in Salisbury and the University of Southampton, has proved that people carrying this mutation-prone region of DNA on chromosome 9 that includes the JAK2 gene have triple the risk of developing an MPD. The chromosome 9 variant is present in 40% of the population in the United Kingdom but only 1 in 20,000 people develop an MPD each year. Nonetheless, the new research has confirmed that the inheritance of this genetic variant can contribute to inherited susceptibility to develop an MPD.The study found that the link was especially strong in polycythaemia vera (PV), one of the main three MPDs.

Professor Nick Cross, from the University of Southampton (University RoadSouthampton SO17 1BJ, United Kingdom, Tel. +44 (0)23 8059 5000, Fax +44 (0)23 8059 3131) who led the research team, said: “This research provides strong evidence that at least half of the cases of PV diagnosed each year are linked to an inherited genetic variant on chromosome 9. Whilst this risk is still very small it nonetheless confirms that individual susceptibility to acquiring cancer-causing mutations is linked to genetic inheritance. Now that we have this evidence we can carry out studies to determine exactly how the variant contributes to this risk.”

Dr Shabih Syed, Scientific Director at UK-based Leukaemia Research who sponsored the reserach, adds: “This is a very important step forward in our knowledge of the causes of myeloproliferative disorders. It helps us to understand why some people might be predisposed to acquiring genetic mutations that lead to cancers.”

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Illustrations courtesy of the European Hematology Association.

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