When CLL Shape-Shifts, Lymphoma Is the Dreaded Result

Like a creature from a science fiction movie, chronic lymphocytic leukemia (CLL) can be a shape-shifter. In a small number of cases, patients with CLL will develop lymphoma, a complication known as Richter transformation (RT).

“It’s like having two cancers at once,” said Adam Kittai, MD, a CLL and RT specialist with Icahn School of Medicine at Mount Sinai, New York City.

The prospects are grim for patients with the condition, named after a New York City pathologist who first described it in 1928. Many will only live for a matter of months. That’s in sharp contrast to the steadily increasing lifespans — thanks to the rise of chemoimmunotherapy — for patients who only have CLL.

Still, there’s good news. Patients with CLL seem to be facing less risk for RT than in the past, and some with the condition may live for a median of 4-5 years. And more progress may be close at hand.

“With the recent advances and ongoing efforts in our understanding of the biology of the disease, both novel targets and better application of current agents will be a reality sooner rather than later,” predicted CLL and lymphoma specialist Paul Hampel, MD, of the Mayo Clinic in Rochester, Minnesota.

Here are questions and answers about RT, also known as Richter transformation and Richter syndrome.

What Is Richter Transformation?

“RT is an aggressive lymphoma that develops in a patient with RT, most commonly a diffuse large B-cell lymphoma [DLBCL],” said CLL and lymphoma specialist Erin M. Parry, MD, PhD, of Dana-Farber Cancer Institute, Boston, in an interview. “In the majority of cases, around 80% or greater, the RT arises directly from a CLL cell, which we call clonally related RT. More rarely, it can actually be an unrelated, or separate, lymphoma.”

The transformation of one type of cancer into another isn’t unusual, Parry said. “It can happen due to natural cancer evolution or in the presence of therapeutic selective pressures. In the hematologic malignancies, transformation to aggressive lymphoma is observed across the other indolent B-cell lymphoma entities.”

Do Hematologists See RT Very Often?

It depends on the patient population. “If you are a hematologist with only a handful of patients with CLL, odds are you may go years without seeing a case,” said Hampel in an interview. “On the other hand, if you are a hematologist with a large panel of patients with CLL, you are likely already well aware that Richter transformation remains an area of great unmet need.”

RT incidence appears to be falling. “We used to quote that the risk of RT was 10% per patient with CLL. However, new data shows that the incidence of RT appears to be decreasing. The risk of RT is likely 1%-5% for each CLL patient,” Kittai said in an interview. (Hampel led a study released at the 2023 American Society of Hematology Annual Conference that tracks rates of RT at the Mayo Clinic over time and found that rates were shrinking.)

However, Kittai believes the picture is complicated. “We might be delaying the appearance of Richter transformation with continuous therapies. I also think that chemotherapy might have driven Richter transformation by inducing mutations in CLL.”

Are Certain Patients With CLL More Likely to Develop RT?

“Various high-risk CLL disease features — IGHV stereotypy with subset #8, complex karyotype, TP53 disruption, NOTCH1 mutation — have been associated with increased risk of developing Richter transformation,” Hampel said. “CLL-directed treatment, specifically with chemotherapy, is also associated with increased risk.”

A 2022 report on CLL by the European Research Initiative noted that researchers have variously linked IGHV stereotypy with subset #8 to a 40% risk for RT in CLL and a 10-fold increase in risk. Hampel also noted that RT mostly occurs in patients previously treated for CLL, but it can be detected in newly diagnosed patients too.

What Are Symptoms of RT?

“Patients often present with B symptoms (fevers, drenching night sweats, significant and unintentional weight loss), rapidly enlarging lymphadenopathy or splenomegaly, and fatigue/clinical deterioration,” Hampel said. These symptoms “typically occur at a much quicker tempo than typical for an even aggressive CLL presentation.”

He added that “worsening cytopenias can also be a presentation if the disease is presenting with significant marrow involvement.”

What Are Keys to Diagnosis of RT?

As Parry noted, “Most commonly, RT displays diffuse large B-cell lymphoma histology, but it can also more rarely be a Hodgkin lymphoma or other types of lymphoma. There are also other entities that can mimic RT, including proliferative CLL, CLL disease flare following the temporary cessation of Bruton’s tyrosine kinase, or even infection and other secondary malignancies.”

As a result, “biopsy is absolutely essential to diagnosis,” she said. “Imaging, clinical suspicion, or both are not sufficient. It is very important to obtain an adequate sample of tissue from biopsy sampling to be reviewed by an expert hematopathologist to make the correct diagnosis. A PET scan is useful as a guide the best location to biopsy.”

Hampel cautioned colleagues to be wary of diagnosing RT during an interruption in Bruton tyrosine kinase inhibitor treatment. “This may represent a disease flare phenomenon rather than true Richter transformation. In this event, the histopathology may appear the same, but the clinical course will differ in that simply restarting the Bruton’s tyrosine kinase inhibitor leads to resolution of lymphadenopathy and clinical symptoms.”

What Are the Best Options for Therapy?

In cases of DLBCL that are clonally related to the patient’s CLL, Hampel said first-line treatment options include R-CHOP (with or without a targeted agent), combination therapy with targeted agents (Bruton tyrosine kinase inhibitor and BCL-2 inhibitors) and anti–programmed cell death protein 1 or anti–programmed death-ligand 1 antibodies, and monotherapy with pirtobrutinib (Jaypirca).

Unfortunately, Hampel said, “We lack any Richter transformation–specific approvals or a true standard of care, given the poor efficacy seen with R-CHOP or intensive chemotherapy regimens.”

He added that “in fit patients, allogeneic hematopoietic stem cell transplantation consolidation remains the best chance for long-term durable remission,” he said. “Otherwise, most patients will experience disease relapse even with initial response. Besides alternative first-line choices, CD19-directed CAR T-cell therapy and CD20 × CD3 bispecific antibodies are options for relapsed disease.”

As for patients whose DLBCL is not clonally unrelated, he said, “Then treatment should be as in de novo DLBCL.”

Hampel added that “radiation therapy is a helpful adjunct, particularly when a specific site of bulky disease is present, and bridging is required prior to CAR T-cell therapy.”

What Is the Typical Prognosis for Patients With RT?

“The prognosis remains dismal with most patients,” Hampel said. “A lack of durable remissions with multi-agent, anthracycline-based chemotherapy regimens typically used to treat patients with de novo DLBCL underlies this poor prognosis. Similarly, the targeted agents that have dramatically shifted the treatment paradigm in CLL have had a more incremental impact thus far in the management of Richter transformation.”

But prognoses seem to be improving somewhat. Kittai highlighted his own research into RT in the era of novel therapy therapies, published in a 2025 study, that suggests overall survival (OS) is rising. “Previous studies showed the median OS of RT is less than 12 months, and we have now seen that it is more than 12 months,” he said. “This is exciting news for patients with RT and provides hope that what we are doing might be making a difference.” (The study examined patients who hadn’t previously been treated with chemoimmunotherapy.)

Kittai added that patients with RT that isn’t clonally related to their CLL and those who haven’t had previous treatment for CLL have a median OS of 4-5 years.

Are Promising Treatments on the Horizon?

“We are all very excited about the emergence of immune-based therapies in RT, as these work differently than chemotherapy and look promising in limited early data,” Parry said. “There are now studies investigating bispecific antibody therapies in RT, often in combination with CLL-directed targeted therapies, chemotherapy, or other lymphoma treatments. In addition, trials are investigating how we can make CAR T cells work even better in relapsed or refractory RT.”

For his part, Kittai highlighted two recent studies combining immunotherapy with targeted agents that “look very promising, with long-term responses.” One study examined zanubrutinib plus tislelizumab, which Kittai noted is currently listed as a treatment option in National Comprehensive Cancer Network guidelines. The other study looked at atezolizumab plus venetoclax plus obinutuzumab.

“I am also excited to see bispecific antibodies being studied in RT and CAR T-cell therapies in combination with targeted agents,” Kittai added. “We recently performed a retrospective study showing long-term remissions for patients with RT treated with CAR T that was compelling and supports its use.”

Parry disclosed relationships with the National Institutes of Health, National Cancer Institute, Damon Runyon Cancer Research Foundation, American Society of Hematology, CLL Global Research Foundation, and Lymphoma Research Foundation.

Hampel reported ties between his institution and AbbVie, AstraZeneca, and BeiGene.

Kittai disclosed relationships with AbbVie and BeiGene and an American Society of Clinical Oncology Career Development award.