Volker Diehl, MD
Nearly 200 years ago, Thomas Hodgkin for the first time described a peculiar disease with undulating fever, enlarged lymph nodes, and a big spleen. Its nature was obscure. It was a fatal illness, affecting mainly young adults and children. In 1865, Samuel Wilks named this illness Hodgkin’s disease. Since then, many pioneers in medicine and science have made this illness one of the most astonishing success stories in cancer medicine.
Turning Back the Clock
It is now 54 years since I saw my first patient with Hodgkin’s disease at the Radiumhemmet, the Cancer Clinic of the Karolinska Sjukhuset—a very sick 22-year-old Swedish boy with cervical lymph nodes, hepatosplenomegaly, and Pel Ebstein fever attacks (a high-grade fever that rises and falls on a 7-to 10-day
cycle). At that time, the disease was called “lymphogranulomatosis” and was categorized under “granulomatous diseases” like tuberculosis or sarcoidosis. Histologic prognostic groups were defined after the number of lymphocytes in the tumor lesion, and the clinical disease was defined in stages I to IV.
The main treatment was radiotherapy, resulting in cure for about 60% of patients with localized disease. For the advanced stages, the options were dismal: nitrogen mustard, corticosteroids, and tender loving care. Most patients with advanced disease died of relapses or secondary malignancies within 3 to 5 years.
A Daring Vision in 1968
In 1968, the nature of Hodgkin’s disease was an enigma. The abundance of reactive cells around one large giant cell, named a “Hodgkin cell” or a “Reed-Sternberg cell” (HRSC), pointed to an infectious or inflammatory illness. However, the rapid and often fatal clinical course made a unique type of cancer in this young age group rather possible.
If this disease was cancer, could the HRSC be the bona fide tumor cell, even when accounting for only 1% of the cells within the tumor? Unfortunately, cytogenetic studies were blurred by the fragility and scarcity of these cells, and molecular genetic studies were not yet possible.
In Sweden, we had an abundance of young but dying patients with Hodgkin’s disease. We were confronted with their sorrow, and it stirred up my ambition to come behind the puzzle of this enigmatic illness. I hypothesized that the HRSC is the bona fide tumor cell and that deciphering its clonality and origin would be the key to understanding Hodgkin’s disease. But even more importantly, I had the daring vision and dream of one day curing most patients with Hodgkin’s disease.
This was my vision in 1968.
Based on my Epstein-Barr virus (EBV)-lymphocyte studies with the Henles in Philadelphia, I started a risky project: trying to culture the HRSCs in vitro for cytogenetic and molecular genetic studies, although I was aware that many experienced scientists around the world before had failed because of the fragility of these cells. In 1978, back in Hanover, Germany, after 10 years and 427 culture attempts, I was lucky enough to establish the L428 cell line: the first HRSC line ever cultured in the world.
L428 became the “Hodgkin Drosophila” line, a material giver for hundreds of global laboratories to study its genetic background and transforming intracellular pathways. L428 and some other cell lines established subsequently in our laboratory opened a new world for all clinician-scientists working in Hodgkin’s disease research; it also made one of my American pathology friends call me “Mr. Hodgkin’s Disease.”
Collaborative Research in the 1980s and 1990s
In 1983, I was Chair for Internal Medicine at the University of Köln, Germany, where I continued my work on Hodgkin’s disease in two branches. First, we focused molecular research in cooperation with Harald Stein, Ralf Küppers, and others, and second, clinical research by founding the German Hodgkin Study Group (GHSG) and starting study by study from 1983 to today.
In collaboration with Harald Stein’s group in Kiel, we detected the Hodgkin-associated C-30 antigen and the Ki67 proliferation marker on the L428 cells as well as generated monoclonal antibodies, which later became globally used diagnostic tools in oncology. We learned that L428 cells were aneuploid, EBV-negative, and had multiple markers, but without any hematopoietic-lineage specificity. However, we still could not prove whether the HRSCs in the lymph node biopsies shared their characteristics with the L428 cell line. The question of whether Hodgkin’s disease was cancer or a reactive inflammatory disease remained to be answered.
In 1994, Ralf Küppers and Martin Hansmann in our laboratory showed that HRSCs were aneuploid, monoclonal, postgerminal B lymphocytes, which lack the B-cell phenotype. This astonishing fact is due to crippled mutations in the IgG genes and the resulting loss of the B-cell receptor. These dysfunctional B cells are protected from apoptosis through the constitutive nuclear factor kappa B expression, an antiapoptotic molecule. These results were truly striking, showing for the first time that Hodgkin’s disease is cancer, particularly a monoclonal B-cell lymphoma, with unique genetic and clinical features different from all known non-Hodgkin lymphomas.
From then on “Hodgkin’s disease” was called “Hodgkin lymphoma!”
From Scientific Research to Therapies
This scientific development was paralleled by the rise of the GHSG as a clinical research center, which was carried by the following principles:
Back in 1983, radiotherapy techniques had resulted in reasonable cure rates for patients with early-stage (I–II) disease, but in advanced stages, we were stuck in slow motion with MOPP (mechlorethamine, vincristine, procarbazine, prednisone), COPP (cyclophosphamide, vincristine, procarbazine, prednisone), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), or its combinations. Most international studies resulted in progression free survival rates of 65%, and cure rates moved up to 75% with the use of second-line high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT). Overall, obviously, these results were unacceptable in young adults.
In 1992, the availability of granulocyte-colony stimulating factor (G-CSF) allowed us to intensify chemotherapeutic doses without putting patients at unacceptable risk for neutropenic fever and septicemia. We used G-CSF to develop a new regimen based on two pillars: first, the “Kairos” hypothesis that describes “the chance of the right moment.” According to the Kairos principle, we should hit the tumor as hard and early as possible to avoid development of resistance.
The second pillar is a statistical model incorporating all known active drugs according to their relative efficacy. This model predicted a 15% increase in progression-free survival if the most active drugs (etoposide, doxorubicin, cyclophosphamide) would be escalated in dose by 30% given within a short 21-day interval; thus, the escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine) principle was borne.
In 1993, we evaluated the new escalated BEACOPP regimen in the HD9 trial. We found a 5-year progression-free survival was indeed 15% superior to that with COPP/ABVD, exactly as the model had predicted.
Since then, the GHSG is trying to maintain the excellent efficacy of eight cycles of escalated BEACOPP and, at the same time, to reduce the toxic burden of this very intensive treatment. After the HD12 trial, another new technology allowed us to take the next critical step in HD15 and HD18: patient-tailored treatment intensity guided by metabolic response assessment with the use of FDG-PET (fluorodeoxyglucose–positron-emission tomography). As a result, most patients today can be treated with four instead of initially eight cycles of escalated BEACOPP, reaching progression-free survival rates of around 95% at 5 years without any consolidative radiotherapy.
The development of the anti-CD30 antibody-drug conjugate brentuximab vedotin improved the risk-to-benefit ratio of the cytotoxic treatment approach. We therefore used this new and HRSC-specific targeted drug to modify and further improve escalated BEACOPP. Our global HD21 study with 1,500 patients is evaluating the new BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) regimen and will hopefully show the first results in 2022.
Today’s Unique Progress and Beyond
Today, the GHSG has documented more than 30,000 patients with Hodgkin lymphoma treated in 8 generations of well-designed, prospective, randomized studies. This worldwide unique database allows us to investigate and answer questions even beyond randomized phase II studies. With the enormous knowledge generated over decades in a common effort of clinical and basic research under the roof of the GHSG, we finally have succeeded: we have optimized our treatment options, almost eliminated fatal tumor progression, and lowered treatment-related toxicity. Even though the burden of treatment is relevant still, survival rates in some of our first-line GHSG studies are equivalent to the normal population—huge and unique progress in oncology.
Having deciphered the nature and clonality of the HRSC, we are now beginning to understand the communication and interaction between these cells and the microenvironment, essential for the survival of the tumor cell. This insight scenario represents a new target for molecular and immunologic interventions. As a first example, immune checkpoint inhibitors have been very effective and tolerable in induction and salvage therapies in Hodgkin lymphoma. Hopefully, the new window of immunotherapy may soon be open even wider for our patients, replacing genotoxic chemotherapy and/or radiotherapies in the first-line setting.
With this encouraging development, we are on the way to leaving the time of large, randomized trials. With our deep molecular, immunologic, and clinical understanding, we may develop predictive models and begin to move toward tailored therapies for each individual patient with Hodgkin lymphoma.
In 1968, I had a vision to unlock the mystery of HRSC and the enigmatic Hodgkin’s disease. I had a dream that one day our young patients might have the chance to survive this devastating disease. Today, 54 years later, my visions and dreams have become a reality, and my message to a new generation of clinicians and scientists is never stop dreaming and having visions—and keep working hard!
Acknowledgment: Dr. Diehl would like to acknowledge his friend and coworker Peter Borchmann, MD, who helped him with the GHSG data, and the GHSG team: Andreas Engert,Markus Löffler, Dirk Hasenclever, Michael Fuchs, and Jürgen Wolf.
Dr. Diehl is Director Emeritus, Internal Medicine, University of Köln, Germany, and founder of the German Hodgkin Lymphoma Study Group.
DISCLOSURE: Dr. Diehl reported no conflicts of interest.
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