Authored by – Art Levit
One phrase that no CLL / SLL patient wants to hear from his or her doctor in the course of his or her care is Richter transformation (RT). RT represents the conversion of CLL / SLL into an aggressive large-cell lymphoma, which occurs in roughly 2–10% of CLL patients and carries a poor prognosis. When a doctor delivers that diagnosis, the urgency to begin intensive therapy—probably via a clinical trial– is immediate and entirely understandable.
What is less well known is that, under specific circumstances, a lymph node biopsy can look almost exactly like Richter transformation under the microscope yet not be RT at all. These pathological findings may or may not be accompanied by signs and symptoms consistent with RT. This phenomenon has been called pseudo-Richter transformation. It can occur when a patient on a BTK inhibitor has that medication interrupted, even briefly. And it is reversible: when the BTK inhibitor is restarted, the disquieting pathological changes resolve.
How pseudo-RT was discovered
The term was first introduced in 2020 by Barnea Slonim and colleagues at Northwestern University, who described five CLL / SLL patients in whom a brief hold of ibrutinib — for surgery or infection — led to lymph node biopsies initially indistinguishable from true Richter transformation.1 Most also demonstrated B symptoms as well as hematologic changes suggestive of RT. When ibrutinib was restarted, the pathologic findings, along with any accompanying signs and symptoms, disappeared completely within a matter of weeks. Their paper in the British Journal of Haematology explicitly called this “a diagnostic pitfall.” A May 2026 systematic review in Clinical Lymphoma, Myeloma and Leukemia (Marco-Ayala et al.) summarized 15 such cases, all associated with either ibrutinib or acalabrutinib (no cases with zanubrutinib (Brukinsa) had yet been reported).2 In the latter article, authors hypothesized that what may be occurring is that in a context of the sustained BTK blockade, which suppresses B-cell signaling, sudden withdrawal triggers a proliferative surge that imitates RT histologically.
BTK inhibitors are routinely held for approximately three to seven days before and after surgery because of their effects on platelets, increasing bleeding risk. This is standard practice — and precisely the window during which pseudo-RT can emerge.
My case
I am a retired physician, diagnosed with CLL / SLL in 2021 at 74 years old. After two years of watch and wait, I began zanubrutinib, one of the newer second-generation BTK inhibitors, and had been doing well on it for three years with good disease control and minimal side effects.
When I required surgery for a condition unrelated to my CLL, zanubrutinib was held for seven days pre-op and post-op. Lymph nodes were sampled during the procedure, and some of this nodal tissue was read by my community teaching hospital pathologist as showing Richter transformation. A second opinion from an NCI-designated Comprehensive Cancer Center (CCC) pathologist corroborated that interpretation, citing sheets of large cells, frequent cell divisions, and a high proliferation index consistent with transformation to diffuse large B-cell lymphoma. My CLL specialist at this same CCC initially described the Richter’s diagnosis as “unequivocally confirmed” and described the pathologic findings as demonstrating “cells that are basically very much pathognomonic for a diagnosis of diffuse large B-cell lymphoma.”
At no time had I developed any B symptoms — no fever, night sweats, or weight loss. My energy and sense of well-being were unchanged from their status prior to the identification of RT. My diagnosis rested entirely on the lymph node pathology.
I had read of pseudo-RT and proposed it as a possibility to my CLL expert, but she did not consider it likely. After I persisted in this line of questioning, I was offered the possibility of resuming zanubrutinib to see what might happen on follow-up PET scan and re-biopsy three months down the road. Still, I was told that the safest course would be not to delay, that if I did so, my “…outcomes are not going to be as good as they’re going to be right now.” The recommended therapy was a chemotherapy regimen, although I also questioned this, knowing that other newer approaches, offered as clinical trials, might be more effective and possibly associated with fewer adverse reactions.
But as I was preparing to begin the recommended six months of intensive chemotherapy, I sought a third opinion on the lymph node biopsies from a highly trusted team at the National Institutes of Health (NIH), where I was a participant in a natural history study of CLL. They agreed to have a look and did so quickly. That changed everything. The team there, which includes one of the world’s top experts in lymphoma classification, ruled out RT and in its report wrote, “Prominent growth centers can be observed in Pseudo-Richter transformation of CLL / SLL, observed following interruption of therapy with BTK inhibitors.” Both my original pathologist and the second-opinion pathologist soon revised their diagnoses in light of the NIH expert opinion. Along with them, the CLL expert amended her diagnosis and advised me to continue zanubrutinib, which I had already resumed, and follow up with a PET scan in 6 months.
I had come uncomfortably close to undergoing an unnecessary, arduous chemotherapy regimen with uncertain benefit.
Possible Takeaways
What can you take away from my account? If you find yourself in a clinical situation anything like what I described above:
- Make sure your doctors—oncologist, surgeon, pathologist—are proactively aware of the potential pathologic, hematologic, and symptomatic changes that can occur upon BTK interruption, especially if any tissue sampling is to be done
- Make sure to seek the most expert hematopathology review available to you
- If you’re given a diagnosis of RT which doesn’t fit your clinical picture, consider seeking further review and opinion by a major academic center, and don’t hesitate to bring up the possibility of a pseudo-Richter transformation with your clinician if it has not already been discussed and considered
- Barnea Slonim L, Ma S, Behdad A, et al. Pseudo-Richter transformation of chronic lymphocytic leukaemia/small lymphocytic lymphoma following ibrutinib interruption: a diagnostic pitfall. British Journal of Haematology.2020;191(1):e22–e25. doi:10.1111/bjh.16948
- Marco-Ayala J, García Malo M, Ortuño F., Lozano ML Pseudo-Richter Transformation Following BTKi Interruption in CLL: A Systematic Review of Clinical, Biological, and Pathologic Features. Clinical Lymphoma, Myeloma, and Leukemia, 2026; 26, e596-e602
