For the first time in forty years, there is real hope for better treatment options for patients with Richter transformation (RT), one of the most aggressive and difficult-to-treat forms of lymphoma. Until now, patients with this diagnosis were consistently excluded from clinical trials for both diffuse large B-cell lymphoma (the most common type of lymph node cancer) and chronic lymphocytic leukemia (CLL), the most common leukemia worldwide. Their outlook is extremely poor; most patients do not or only shortly respond to chemotherapy or targeted agents, resulting in a very poor survival: half of all patients survived less than one year after diagnosis.

Breakthrough with a new immunotherapy

Prof. Arnon Kater of Amsterdam UMC – Cancer Center Amsterdam coordinated an international study to investigate whether the body’s own immune cells can improve the prognosis. This was done using the drug epcoritamab. Epcoritamab is a so-called bispecific antibody that binds on one side to tumor cells and on the other side to immune cells (T-cells). Unlike standard chemotherapy and other existing treatments, this therapy shows for the first time that patients in this group can live much longer and that the disease can remain under control for a long time, especially when the treatment is given immediately rather than only after chemotherapy has stopped working. The results are now published in The Lancet Haematology.

Key findings

  • RT develops in patients with CLL due to additional cytogenetic abnormalities that can appear over-time and affects 5–15% of CLL patients worldwide.

  • In the current study, where epcoritamab was given as monotherapy, nearly half of the patients showed clear improvement: the disease shrank or even disappeared completely. The treatment was specifically effective among patients who received the treatment as first-line therapy, with more than half achieving a complete remission. These results surpass what has been achieved for decades with chemotherapy and targeted therapies. Whereas most patients with RT normally die after an average of 9 months, half of the patients who received epcoritamab were still alive after 2.5 years.
  • The treatment was also effective in patients with unfavorable genetic features, who are normally harder to treat.
  • Side effects (including cytokine release syndrome and cytopenias ) did occur, but were generally manageable with supportive care.
Arnon de Kater: “Richter transformation is one of the most challenging and life-threatening forms of lymph node cancer. Because patients with this disease were excluded from almost all trials, no progress could be made for decades. Epcoritamab breaks this impasse; for the first time, we are seeing significantly better survival and a real chance of long-term remission in these patients.”
Looking ahead

Based on these results, new follow-up studies are now underway in which epcoritamab is combined with targeted treatments that may have an additional or reinforcing effect. Early data from these combination approaches are promising. This brings long-awaited structural improvement within reach for a group of patients that, until recently, had no realistic treatment options.

Expanding to CLL

The group is also testing epcoritamab for CLL. Similar to many other cancers, CLL patients suffer from progressively weakened immune cells including T-cells, which is the reason why T-cell–based treatments like CAR T-therapy have shown very limited and short-lived effectiveness in CLL. Both in the lab as well as in a clinical trial, they show that epcoritamab is more potent than previous T-cell therapies in CLL. They currently explore whether targeted therapies already approved for this disease, improve both CLL control and T-cell function. Early clinical data show highly encouraging results, also in patients that became refractory to standard therapies.

Collaboration

These combination studies led by Prof. Dr. Arnon P. Kater in both Richter transformation and CLL are being conducted within HOVON, in close collaboration with the German CLL Study Group and the Scandinavian CLL Study Group.