Lymphoma Group

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Future strategies

Early stage Hodgkin’s lymphoma

The BREACH (LYSA/FIL/EORTC-20113) study is expected to open very soon for early stage HL patients, incorporating the anti -CD30 conjugate Brentuximab vedotin in first-line treatment of unfavorable CSI/II disease (AVD-Br vs ABVD, followed by involved node radiotherapy or INRT). The primary goal is to improve the PET negativity after two cycles of chemotherapy. Next to the more common secondary end points (PFS, OS, CR rate after 2 cycles), we are very interested in the toxicity pattern of Brentuximab vedotin in combination therapy. .

Advanced stage Hodgkin’s lymphoma

Even though the majority of patients with advanced HL are cured, a large minority experience failure of first-line therapy. More than half of those patients who fail first line treatment eventually die from the disease. During the last 15 years, we have had two standard treatments in Europe: ABVD and BEACOPPesc. ABVD is the most commonly used regimen in EORTC LG centres, and this treatment results in 65-70% long-term PFS (Canellos 2009). BEACOPPesc is more effective, with long-term PFS of around 85% and significantly higher OS than ABVD (Engert 2012). However, BEACOPPesc carries serious acute and late toxicity, including severe infections, 2-3% risk of secondary AML/MDS, and infertility. So BEACOPPesc yields superior survival at the expense of substantial overtreatment of the majority of patients, who could have been cured with ABVD.

Seeing the high activity of Brentuximab Vedotin (BV) in heavily pretreated patients with relapsed/refractory HL (Younes 2012), there is strong interest in the addition of this drug to the existing regimens for advanced HL. We are exploring the possibility to incorporate Brentuximab vedotin in a BEACOPP-like regimen.

Relapsed or refractory Hodgkin’s lymphoma

Although most patients with HL are cured by current treatment regimens, 10-20% will relapse or not respond to first line treatment. A small number of those patients, with disease restricted to nodal sites not previously irradiated, can still be cured with radiotherapy. However, the majority will need second line systemic treatment. Currently, several potential new drugs have been -or are being- evaluated in early clinical trials. Among these, immunomodulating agents (lenalidomide), kinase inhibitors (e.g. everolimus), histone deacetylase inhibitors, antibodies (e.g. nivolumab) and antibody drug conjugates. The most promising new agent is the anti-CD30, antibody drug conjugate Brentuximab vedotin (BV), which has showed remarkable response rates up to 75% in relapsed /refractory HL (Younes 2012). These results, even in heavily pretreated HL patients have already led to a randomised controlled trial in first line treatment sponsored by the drug company, combining BV with standard first line treatment (ECHELON-1 trial). Several EORTC LG participants are currently participating in an early clinical phase I/II investigator-initiated trial combining BV with DHAP in relapsed refractory HL. At the same time a different approach of sequential BV and DHAP/ICE is being investigated by the MSKCC group. Both trials aim at increasing metabolic response rates as determined by FDG-PET before HDT and ASCT. If successful, this might lead to a randomised intergroup clinical trial comparing one of these BV-salvage combinations with conventional DHAP in relapsed/refractory HL, in which EORTC might take part in future.

For patients with relapsed disease, we still plan to participate in the German-led HDR3 trial. Meanwhile, many active EORTC LG centres participate as individual institutions in the international transplant BRaVE phase I/II trial for relapsed/refractory Hodgkin lymphoma

HL in the Elderly

Whereas Hodgkin lymphoma (HL) is a curable malignancy in the vast majority of patients under the age of 60 years, outcomes for HL patients aged ≥ 60 years are significantly and disproportionally lower. The inferior outcome has been attributed to several factors such as the presence of co-morbidities, poor performance status, inability to tolerate standard chemotherapy at full dose and schedule, and increased treatment related toxicity and mortality. For this reason a standard treatment paradigm for older HL patients is lacking.

A trial design has been proposed implementing a comprehensive geriatric assessment (CGA) as an important tool. Since Brentuximab vedotin seems to be safe and comparably effective also in older patients (Gopal 2014), the group has decided to implement Brentuximab vedotin in such a trial design. Negotiations with the company and also discussions other HL groups in Europe are ongoing.  At a recent meeting in the newly established lymphoma scientific working group under the European Haematology Association, the EORTC LG proposed a trial for elderly HL patient as an ideal subject for pan-European collaboration, mainly due to the lack of ongoing trial and the rare nature of the disease

Translational research

At the moment, diagnostic tissue specimens from the closed H9 trial are being evaluated for prognostic tumour cell markers by immunohistochemistry, including Human Leukocyte Antigen class II, Epstein Barr virus and c-Met. In addition, the number of CD68 positive tumour associated macrophages in the micro-environment are being evaluated. These four diagnostic tissue-based biomarkers have been shown to be associated with disease free survival and the simultaneous evaluation of these markers will identify the most appropriate marker or combination of markers to be used in an upfront risk stratification score. Scoring of the first three markers is completed. CD68 scoring includes morphometry which is more time consuming. Evaluation of prognostic impact will be performed when data for all 4 markers is complete.

The tumor cell derived chemokine CCL17 (TARC) can be measured in plasma. Plasma TARC levels at diagnosis are highly elevated and correlate well with cHL tumour burden. Serial TARC levels correlate with response to treatment in patients and reduce to normal levels as early as after one cycle of chemotherapy in responsive patients, while remaining elevated in non-responsive patients. This biomarker promises to radically change and improve cHL management and deserves to be validated in a large clinical trial.

Survivorship project

The vast majority of patients with Hodgkin lymphoma (HL) will be cured of their disease. Despite the curative treatment there is a lifelong excess morbidity and mortality among long -term survivors. Secondary malignancies, cardiovascular diseases, hormonal dysfunction and chronic fatigue are the most important sequelae of therapy-related late toxicity. How these late events affect physical functioning and perception of quality of life and have influenced life style is  investigated with our Life Situation Questionnaire (LSQ) among all survivors of EORTC/LYSA/FIL Hodgkin trials. This database is used for our new projects in looking at cardiac toxicity (B. Aleman, Amsterdam NL; M. Maraldo, Copenhagen, DK), sexual dysfunction (M. van der Kaaij, Amsterdam, NL) and fatigue (M. Henry-Amar, Caen, F; M. van der Kaaij, Amsterdam, NL). The clinical update comparing LSQ data with clinical data is being perfomed at this time. Our goal is to enable a unique and thorough inventory of physical functioning and subjective perception of quality of life of long-term survivors of HL related to primary treatment and long-term toxicities, by combining the data from the LSQ with this clinical update of the first nine HL trials conducted between 1964 and 2004. Obviously, the clinical update will encompass all patients treated (n=6658), whereas the LSQ addressed only those patients (n=2037) who were alive in 2009-2010 and willing to fill in the questionnaires.

Radiotherapy

Radiotherapy has played an important role in many trials of the EORTC lymphoma group. Trials have been performed studying several aspects of radiotherapy in Hodgkin lymphoma (HL) i.e. radiation volume (H8U), radiation dose (H9) and no radiotherapy in both early and advanced HL (e.g. H34, H9F, H10). In the H10 a new radiotherapy concept was introduced: Involved Node Radiotherapy (INRT). We have recently started a retrospective quality control study to evaluate the implementation of our guidelines on the recently introduced involved node radiotherapy (INRT) and to validate the concept of INRT in a representative sample of all irradiated patients included in H10 (n≈130). This project will be performed in close cooperation with the EORTC Radiation Oncology Group, the FIL and the LYSA.

Furthermore, we have planned prospective quality assurance of radiotherapy in future trials involving the use of radiotherapy.

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