George Davatelis, PhD — Contributing Author
Research into Hodgkin lymphoma (HL) has been ongoing ever since Thomas Hodgkin published his seminal paper on lymphatic disease, “On Some Morbid Appearances of the Absorbent Glands and Spleen,” in 1832.1 Although there have been many interesting and exciting finds over the ensuing years, there has been an upsurge in HL research in the past 2 decades, with an accelerated increase in the past few years. Exciting and groundbreaking research is being done in the laboratory, and many of these newly researched compounds are finding their way into clinical trials. All totaled, there are 378 trials either open or ongoing but closed to enrollment, according to the National Institutes of Health Web site, ClinicalTrials.gov.2 This is an astonishing number of active trials for any disease state, so ManagingHodgkinLymphoma.com decided to find out more about the nature of this worldwide attention to HL.
With a look at phase 3 ongoing trials, we found that the German Hodgkin Study Group (GHSG)—established in 1978 to focus on optimizing diagnostics, therapy, and follow-up care in HL3—is doing a follow-up study to its HD14 trial.4 The HD14 trial established the treatment standard for patients with newly diagnosed intermediate-stage HL as a combination of chemotherapy and radiotherapy, consisting of 2 cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone ) and 2 cycles of ABVD (doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine), followed by 30 Gy involved-field (IF) radiotherapy.5
In the latest trial (HD17; overseen by Professor Andreas Engert, MD, at the University of Cologne in Germany), the treatment response after 4 cycles of chemotherapy is investigated by means of fluorodeoxyglucose–positron emission tomography (FDG-PET).6 Patients randomized into the standard arm receive IF radiotherapy according to standard, independent of their FDG-PET result. Patients randomized into the experimental arm do not receive any further therapy if their PET is negative, and patients with a positive PET receive involved-node radiotherapy. GHSG has another ongoing trial, HD16, which is aimed at treatment optimization in the first-line treatment of early stage HL and is stratifying the enrolled patients by means of FDG-PET.7
In an ongoing French trial sponsored by the Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS, which translates to the West-East Study Group of Leukemia and Other Blood Diseases), researchers are undertaking a phase 3 trial studying 3 different therapy regimens to compare how well they work in treating patients with previously untreated HL.8 The GOELAMS study will characterize the impact of different therapeutic strategies on event occurrence at 2, 5, 10, and 15 years. The GOELAMS was established in 1992, and much like its German counterpart at the GHSG, it was established to support diverse hematologic malignancies, including acute leukemias, lymphomas, chronic lymphocytic leukemia, and myeloproliferative syndromes.9
Other international trials include two phase 2 trials being run in China, both focused on CART (chimeric antigen receptor–modified T cells)—immune cells that target CD30-positive lymphomas. One trial is being held at the Chinese PLA General Hospital10 and the other at Peking University.11 A phase 2 trial cosponsored by Yale University and the Peter MacCallum Cancer Centre in Australia12 is an open-label study of lenalidomide and romidepsin for relapsed/refractory HL, mature T-cell lymphoma, and multiple myeloma built on the study hypothesis that “lenalidomide and romidepsin (and dexamethasone for patients with myeloma) will have an acceptable toxicity profile and that in combination will have sufficient activity in the target population (including those previously refractory to histone deacetylase inhibitors [HDACi] monotherapy) to warrant further investigation.”
In the United States, an exciting phase 3 trial being run at the National Cancer Institute will study brentuximab vedotin and combination chemotherapy to see how well they work compared with combination chemotherapy alone in treating younger patients with newly diagnosed HL (NCT02166463).13 According to the listed trial purpose, “Combinations of biological substances in brentuximab vedotin may be able to carry cancer-killing substances directly to Hodgkin lymphoma cells. Drugs used in chemotherapy, such as doxorubicin hydrochloride, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known if combination chemotherapy is more effective with or without brentuximab vedotin in treating Hodgkin lymphoma.”
A few of the most exciting trials currently enrolling are testing novel therapies and approaches such as program cell death 1 (PD-1) and ligand (PD-L1) inhibitors; or Janus-associated kinase (JAK1/2) inhibitors. In PD-1/PD-L1, there is the CheckMate 205 trial,14 which is a phase 2 registrational study of nivolumab in patients diagnosed with HL. In addition, a phase 2 trial will soon open to enrollment that will investigate pembrolizumab after autologous stem-cell transplantation for HL and diffuse large B-cell lymphoma.15 As discussed in our previous newsletter, both of these phase 2 trials are following successful phase 1 proof-of-concept trials that garnered very positive results for both of these PD-1 checkpoint inhibitors in a difficult-to-treat cohort of patients. Regarding the JAK 1/2 inhibitor, a phase 2 study of the oral JAK1/JAK2 inhibitor, INC424, in adult patients with relapsed/refractory classical HL is being sponsored in France and Belgium by the Lymphoma Academic Research Organization.16
At present, there clearly is a worldwide uptick of interest and investigation into exploring new pathways and optimizing therapy; this report barely scratches the surface of all of the exciting research currently being done in HL. With 11 open phase 3 trials, 122 open phase 2 trials, and 99 open phase 1 trials currently ongoing, it is clear that cutting-edge research will continue to hold great promise for the treatment of patients with HL.
1 LymphomaInfo.net. Hodgkin’s disease—historical timeline. http://www.lymphomainfo.net/hodgkins/timeline.html. Accessed March 22, 2015.
2 ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?term=hodgkins+Lymphoma&Search=Search. Accessed March 22, 2015.
3 German Hodgkin Study Group. http://en.ghsg.org/. Accessed March 22, 2015.
4 Von Tresckow B, Plütschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.
5 German Hodgkin Study Group. http://en.ghsg.org/active-trials. Accessed April 9, 2015.
6 ClinicalTrials.gov. HD17 for intermediate stage Hodgkin lymphoma. https://clinicaltrials.gov/ct2/show?term=hodgkins+Lymphoma&recr=Open&no_unk=Y&phase=2&rank=3. Accessed March 22, 2015.
7 ClinicalTrials.gov. HD16 for early stage Hodgkin lymphoma. https://clinicaltrials.gov/ct2/show?term=hodgkins+Lymphoma&recr=Open&no_unk=Y&phase=2&rank=4. Accessed March 22, 2015.
8 ClinicalTrials.gov. Three different therapy regimens in treating patients with previously untreated Hodgkin lymphoma. https://clinicaltrials.gov/ct2/show?term=hodgkins+Lymphoma&recr=Open&no_unk=Y&phase=2&rank=5. Accessed March 22, 2015.
9 Force Hemato. Notre réseau. La grande majorité des publications permettant un progrès médical décisif est issue de groupes multicentriques. http://force-hemato.com/notre-r%C3%A9seau. Accessed March 22, 2015.
10 ClinicalTrials.gov. CD30-directed chimeric antigen receptor T (CART30) therapy in relapsed and refractory CD30 positive lymphomas. https://clinicaltrials.gov/ct2/show?recr=Open&no_unk=Y&cond=hodgkins+Lymphoma&cntry1=ES%3ACN&phase=1&rank=1. Accessed March 22, 2015.
11 ClinicalTrials.gov. CAR T cells targeting CD30 positive lymphomas (4SCAR30273). https://clinicaltrials.gov/ct2/show?recr=Open&no_unk=Y&cond=hodgkins+Lymphoma&cntry1=ES%3ACN&phase=1&rank=2. Accessed March 22, 2015.
12 ClinicalTrials.gov. An open label, international, multi-centre, phase I/IIa study of lenalidomide (Revlimid) and romidepsin (Istodax) for relapsed /refractory Hodgkin lymphoma, mature T-cell lymphoma and multiple myeloma. (RId Study) (RID). https://clinicaltrials.gov/ct2/show/NCT01742793?term=international&recr=Open&no_unk=Y&cond=hodgkins+Lymphoma&phase=1&rank=1. Accessed March 22, 2015.
13 https://clinicaltrials.gov/ct2/show?term=brentuximab+vedotin&phase=2&rank=2. Accessed 4.9.15
14 ClinicalTrials.gov. Study of nivolumab in subjects with Hodgkin’s lymphoma (registrational) (CheckMate 205). https://clinicaltrials.gov/ct2/show/study/NCT02181738?term=international&recr=Open&no_unk=Y&cond=hodgkins+Lymphoma&phase=1&rank=3&show_locs=Y#locn. Accessed March 22, 2015.
15 ClinicalTrials.gov. Pembrolizumab after ASCT for Hodgkin lymphoma and DLBCL. https://clinicaltrials.gov/ct2/show?term=PD-1+hodgkins+lymphoma&rank=1. Accessed March 22, 2015.
16 ClinicalTrials.gov. A phase II study of oral JAK1/JAK2 inhibitor INC424 in adult patients with relapsed/refractory classical Hodgkin’s lymphoma (HIJAK). https://clinicaltrials.gov/ct2/show/NCT01877005?term=hodgkin+lymphoma&recr=Open&no_unk=Y&phase=1&rank=22. Accessed March 22, 2015.