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.”

For more information:

• 14th Congress of the Europan Hematology Association (EHA): Presentations.
• Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group Journal of Clinical Oncology. 1998 Vol 16, 3810-3821.
• Patrice Carde P, Cavalli F, Diehl V, Franklin J. Is escalated BEACOPP a standard therapy for advanced Hodgkin's disease? The Hematology Journal (2000) 1, 282 ± 290.
• Jones AV, Chase A, Silver RT, Oscier D, Zoi K, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nature Genetics 41, 446 - 449 (2009) Published online: 15 March 2009

Read these PubMed abstracts:

• Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5
• Bosetti C, Levi F, Ferlay J, Lucchini F, Negri E, La Vecchia C. The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe. Ann Oncol. 2009 Apr;20(4):767-74. Epub 2008 Dec 16.
• Eich HT, Müller RP, Engenhart-Cabillic R, Lukas P, Schmidberger H, et al. Involved-node radiotherapy in early-stage Hodgkin's lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG). Strahlenther Onkol. 2008 Aug;184(8):406-10.
• Ben Arush MW, Shafat I, Ben Barak A, Shalom RB, Vlodavsky E, Ilan N. Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study. Pediatr Hematol Oncol. 2009 Jun;26(4):157-64.
• Gobbi PG, Valentino F, Danova M, Morabito F, Rovati B, et al. Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma. Oncol Rep. 2009 Apr;21(4):1029-35.
• Wood AD, Chen E, Donaldson IJ, Hattangadi S, Burke KA, et al. Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling. Blood. 2009 Jul 1. [Epub ahead of print].
• Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009 May 26. [Epub ahead of print]

What to tell your patients:

• US National Cancer Institute: Definition Hodgkin Lymphoma
• Mayo Clinic: Definition Hodgkin Lymphoma
• WikiPedia: Definition Hodgkin Lymphoma
• LymphomaInfo.Net: Definition Hodgkin Lymphoma
• The Leukemia & Lymphoma Society (USA): Definition Hodgekin Lymphoma
• SteadyHealth.com: Definition of Myeloproliferative Neoplasms.
• UptoDate for Patients: Overview of Myeloproliferative Neoplasms.

Illustrations courtesy of the European Hematology Association.

A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms

Research by Dr. Francois Delhommeau MD, and his team at the Saint-Antoine Hospital, Paris, France (Hôpital Saint Antoine, Service d’hématologie, 184, rue du Faubourg Saint Antoine, 75012 Paris) on treatment advances in leukemia and lymphoma, presented as late-breaking news during the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008), led to the discovery of a new tumor suppressor gene called TET2 (Ten-Eleven Translocation–2).

Because TET2 is altered in 14 percent of patients with myeloproliferative disorders, the discovery provides scientists with a greater understanding of the underlying biology of these conditions, as well as a potential target for the development of future treatments.

All blood cells start out as hematopoietic, or blood-forming, stem cells and have the potential to become mature red blood cells, white blood cells, or platelets. Myeloproliferative disorders develop when the DNA of a stem cell is altered in the bone marrow, causing the overproduction of some blood cells.

Previous research has detected mutations in other genes– JAK2 and MPL – in the blood stem cells of patients with myeloproliferative disorders. These JAK2 and MPL defects cause the overproduction of mature malignant blood cells, but multiple lines of evidence suggest that these are not the only molecular lesions responsible for abnormalities in the stem cell in these disorders. Greater analysis of blood cell development in myeloproliferative disorders with the JAK2 V617F mutation led researchers to identify two subsets of patients. The first subset of patients (85 percent) had an overproduction of malignant cells mainly dependent on the late stages of blood cell differentiation, far downstream from the stem cell. In contrast, a second subset of patients (15 percent) had an early expansion of very immature malignant progenitor cells, close to the stem cell.

Researchers then hypothesized that the second subset of patients had a pre-existent molecular defect able to promote the early expansion of the malignant cells. With high-resolution arrays, researchers were able to identify one single gene, TET2, which belongs to a family of three genes of unknown function.

Researchers then further analyzed cells in five patients with TET2 mutations, which demonstrated that TET2 defects target hematopoietic stem cells. Moreover, they show that in these five patients TET2 inactivation precedes the JAK2 V617F mutation, suggesting that this new molecular lesion could be an early event in cancer stem cell formation.

To further test these findings, researchers sequenced TET2 in 181 unselected JAK2 V617F patients with myeloproliferative disorders. TET2 mutations were found in 25 of the 181 patients, resulting in an overall 14 percent frequency.

For more information, read:

• Delhommeau F, Dupont S, James C, Masse A, et al. TET2 Is a Novel Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms: Identification of a Pre-JAK2 V617F Event. (Late-Breaking Abstracts) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract LBA-3

Also read PubMed abstracts:

• Delhommeau F, Pisani DF, James C., et al. Oncogenic mechanisms in myeloproliferative disorders. Cell Mol Life Sci. 2006 Dec;63(24):2939-53
• Delhommeau F, Dupont S, Tonetti C, Massé A. et al. Evidence that the JAK2 G1849T (V617F) mutation occurs in a lymphomyeloid progenitor in polycythemia vera and idiopathic myelofibrosis. Blood. 2007 Jan 1;109(1):71-7. Epub 2006 Sep 5.

New Data Shows Major Advances in Several Blood Disorders

Late breaking data presented at the 50th Annual Meeting of the American Society of Hematology in San Francisco, CA,(December 6 – 9, 2008) highlighted major research advances in the treatment of cancer and sickle cell disease.

One of the highlighted studies examined the ability of an investigational agent to improve endothelial dysfunction, a malfunction in the inner lining of blood vessels, in patients with sickle cell disease.

‘Abnormal function of the cells lining blood vessels may contribute to the complications of sickle cell disease. Disruption in the synthesis of nitric oxide, an important regulator of blood vessel relaxation, contributes to these abnormalities,' said Nancy Berliner, MD, 2009 ASH President and Chief of Hematology at Brigham and Women’s Hospital in Boston. ‘This study showcases a novel investigational treatment that aims at improving nitric oxide production and reducing endothelial dysfunction.’

Other late-breaking studies are showcasing the results of the first large-scale study examining mortality rates in patients with cancer taking erythropoiesis-stimulating agents (ESAs) for the treatment of anemia, and the discovery of a new tumor suppressor gene in patients with myeloproliferative disorders.

'There is now additional evidence concerning the use of ESAs in patients with cancer. Last year, ASH collaborated with the American Society of Clinical Oncology to release an evidence-based clinical practice guideline on the use of ESAs, and the findings of this study are consistent with the guideline’s recommendations,' said Samuel Silver, MD, Chair of the ASH Subcommittee on Reimbursement and Professor of Internal Medicine at the University of Michigan in Ann Arbor, MI. ‘However, we plan to reconvene the guideline panel to determine whether any updates should be made as a result of these new data.'

Also read blog entry:

• A Tumor Suppressor Gene Inactivated in Myeloproliferative Neoplasms
• A Novel Therapy for Endothelial Dysfunction in Sickle Cell Disease
• Understanding Recombinant Human Erythropoiesis Stimulating Agents in individual Cancer Patients