Richter Transformation to Hodgkin Lymphoma 

A 68-year-old woman was diagnosed with TP53-positive CLL 4 years ago and has been on frontline therapy with continuous acalabrutinib monotherapy for the past 3 years. At her most recent evaluation 2 months ago, her disease appeared to remain under good control with normal laboratory values and no evidence of lymphadenopathy or splenomegaly on physical exam; no B symptoms on patient history.  

The patient called the nurse line with concerns regarding a fever of up to 101.4°F that developed approximately 12 hours prior to the call accompanied by general feelings of malaise. Your registered nurse colleague recommended she be further evaluated in person.  

Upon that evaluation, physical examination demonstrates a fatigued but nontoxic appearing female in no acute distress. You also note splenomegaly, slightly tender to palpation, and a new finding of bilateral diffuse adenopathy, largest in the right axilla, up to 5 cm. Bloodwork is significant for new abnormalities on complete blood cell count including elevated WBC count of 62.1 x 10⁹/L, new anemia (11.6 mg/dL) and thrombocytopenia (120 x 10⁹/L)), in addition to newly elevated lactate dehydrogenase (LDH) of 881 U/L. She denies any recent travel or sick contacts, and aside from fever there is nothing in the history or physical exam suggestive of an infectious process. Of note, neutrophil count is within normal limits.  

You elect to obtain a PET scan, which demonstrates diffuse FDG-avid adenopathy as well as splenomegaly, with a maximum standardized update value (SUVmax) of 11 in the right axillary node. In addition to infectious workup, you decide to obtain an ultrasound-guided core needle biopsy of the right axillary node, which demonstrates diffuse large cells consistent with diffuse large B-cell lymphoma (DLBCL); PD1 expression is noted suggesting a clonal relationship to the underlying CLL. All infectious workup is negative.  

Discussion

This patient’s diagnosis is most consistent with DLBCL-Richter transformation (RT) that is clonally related to her underlying diagnosis of CLL based on the PD1 staining. Her presentation including fevers, malaise, and drenching night sweats can all be seen in patients with progressive CLL, as well as in those with RT.¹ PET scan can help determine the likelihood of progressive CLL vs RT. Prior to the advent of novel targeted therapies with BTK inhibitors or BCL2 inhibitors, an SUVmax of > 10 was a relatively reliable cutoff suggestive of DLBCL-RT.² However, some studies have demonstrated that this cutoff is less reliable in patients on oral targeted therapies such as BTK inhibitors, as in this case. Therefore, an SUVmax of > 5 in a patient with suspected RT should prompt strong consideration for biopsy of the most FDG-avid node.³ Fine needle aspiration biopsies should be avoided in favor of core needle biopsies or excisional biopsies in order to adequately characterize the lymph node architecture and accurately establish the diagnosis.  

Richter transformation (also known as Richter syndrome) is defined as development of an aggressive lymphoma in patients who had been previously or concomitantly diagnosed with CLL. Richter transformation is rare, occurring in 2% to 10% of patients with CLL. Richter transformation can occur in newly diagnosed patients with CLL, but the majority of patients develop RT after CLL diagnosis, typically within a median of 2 to 4 years.^4,5 The vast majority of patients who experience RT (90% to 99%) experience a transformation to DLBCL.^4,6 Although quite rare, patients who experience RT to Hodgkin lymphoma tend to have more favorable outcomes compared to patients with DLBCL-RT. For example, one recent study reported a median overall survival of 12 months in patients with DLBCL-RT,⁷ as opposed to a recent study of HL-RT, which reported a median overall survival of 65 months (95% CI: 34-infinity).⁸  

Several genetic aberrations, including TP53 alterations, increase the risk of developing RT. Other risk factors include a poor Eastern Cooperative Oncology Group (ECOG) performance score, elevated levels of lactate dehydrogenase and beta-2 microglobulin, more advanced disease, and lymph nodes measuring > 3 cm.^4,5 

Infections should be ruled out using laboratory measures, as infectious lymphadenitis can masquerade as RT.⁹ Additionally, presence of a singular enlarged lymph node when the remainder of a patient’s adenopathy has resolved on treatment should prompt the AP to consider whether a lymph node biopsy may be warranted to rule out RT, even in patients without significant B symptoms.¹⁰ 

There is not a true standard of care in choosing treatment for a patient with RT; consult NCCN guidelines and consider clinical trials when deciding on course of treatment for these patients. Ongoing research is needed to improve outcomes for this patient population.  

References

1. Douglas M. Richter transformation: Clinical manifestations, evaluation, and management. J Adv Pract Oncol. 2022;13(5):525-534.
2. Michallet A-S, Sesques P, Rabe KG, et al. An 18F-FDG-PET maximum standardized uptake value > 10 represents a novel valid marker for discerning Richter’s syndrome. Leuk Lymphoma. 2016;57(6):1477. 
3. Wang Y, Rabe KG, Bold MS, et al. The role of ¹⁸F-FDG-PET in detecting Richter transformation of chronic lymphocytic leukemia in patients receiving therapy with a B-cell receptor inhibitor. Haematologica. 2020;105(11):2675-2678. 
4. Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia (CLL)—A pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2022;35(1):169-176.
5. Ben-Dali Y, Hleuhel MH, Andersen MA, et al. Risk factors associated with Richter's transformation in patients with chronic lymphocytic leukemia. Blood. 2018;132(suppl 1):1697.
6. Tadmoor T, Levy I. Richter transformation in chronic lymphocytic leukemia: Update in the era of novel agents. 2021;13:5141.
7. Wang Y, Tschautscher MA, Rabe KG, et al. Clinical characteristics and outcomes of Richter transformation: Experience of 204 patients from a single center. Haematologica. 2020;105(3):765-773.
8. Stephens DM, Boucher K, Kander E, et al. Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: Outcomes from a large multi-center collaboration. Haematologica. 2021;106(11):2845-2852. 
9. Bowen DA, Rabe KG, Schwager SM, et al. Infectious lymphadenitis in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: A rare, but important, complication. Leuk Lymphoma. 2015;56(2):311-314.
10. Condoluci A, Rossi D. Treatment of Richter’s syndrome. Current Treatment Options in Oncology. 2017;18(12):75.